Contents

1 Pathophysiology of the respiratory system ( I. Hulı́n ) 3

1.1 The transport of oxygen to the organism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.1.1 Oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.1.2 Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.1.3 Dyspnoea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.2 Pathophysiology of respiration and respiratory organs . . . . . . . . . . . . . . . . . . . . . . . 7
1.2.1 Pulmonary ventilation and its disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.2.2 Distribution of ventilation and its disorders . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.2.3 Changes in diffusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.2.4 Changes in perfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.2.5 Exchange of respiratory gases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.2.6 Ventilation-perfusion abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
1.3 Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.3.1 Alveolar macrophages and lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.3.2 Inflammatory reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.4 Hypersensitive pneumonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.4.1 Eosinophilic pneumonias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.5 Pulmonary disorders caused by harmful substances in the inhaled air . . . . . . . . . . . . . . . 19
1.6 Chronic diseases of the airways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
1.6.1 The simple and obstructive chronic bronchitis . . . . . . . . . . . . . . . . . . . . . . . . 21
1.6.2 Pulmonary emphysema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
1.6.3 Bronchial asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1.7 Bronchiectasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
1.8 Cystic fibrosis (of the lungs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
1.9 Interstitial lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
1.9.1 Interstitial diseases of lungs of unknown etiology . . . . . . . . . . . . . . . . . . . . . . 31
1.9.2 Interstitial diseases of lungs of known etiology . . . . . . . . . . . . . . . . . . . . . . . . 31
1.9.3 Interstitial lung diseases induced by drugs . . . . . . . . . . . . . . . . . . . . . . . . . . 32
1.10 Respiratory failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
1.10.1 Acute and chronic respiratory failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
1.10.2 The causes of origin and deterioration of the respiratory failure . . . . . . . . . . . . . . 33
1.10.3 Adult respiratory distress syndrome – ARDS . . . . . . . . . . . . . . . . . . . . . . . . 35
1.11 Tumours of the lung and bronchi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
1.11.1 Benign tumours of lungs and bronchi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
1.11.2 Primary malignant tumours of lungs bronchi . . . . . . . . . . . . . . . . . . . . . . . . 36
1.11.3 Metastatic malignant tumours of the lungs . . . . . . . . . . . . . . . . . . . . . . . . . 37
1.12 Disorders of the diaphragm, thorax, pleura and mediastinum . . . . . . . . . . . . . . . . . . . 37
1.12.1 Disorders of the diaphragm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

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1.12.2 Disorders of the thorax configuration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

1.12.3 Disorders of the pleura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
1.12.4 Disorders of the mediastinum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

2 Pathophysiology of blood and haematologic system ( I. Hulı́n ) 44

2.1 Haematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.1.1 Development of blood cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.1.2 Haemoglobin biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
2.1.3 Metabolism of erythrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
2.1.4 Absorption of iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
2.2 Anaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.2.1 Anaemia due to iron deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.2.2 Sideroblastic anaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
2.2.3 Megaloblastic anaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.2.4 Haemolytic anaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
2.2.5 Acquired haemolytic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.2.6 Haemoglobinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2.2.7 Normochromic normocytic anaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
2.2.8 Anaemia in uraemic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
2.2.9 Anaemia in hepatic cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
2.2.10 Anaemias in endocrine disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
2.2.11 Anaemias in chronic inflammatory processes . . . . . . . . . . . . . . . . . . . . . . . . . 64
2.2.12 Anaemias due to impaired haematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . 65
2.3 Haemostasis and haemocoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
2.4 Disorders of primary haemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.4.1 Disorders of thrombocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.4.2 Vascular purpurae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
2.5 Disorders of haemocoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
2.5.1 Haemorrhagic diatheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
2.5.2 Disseminated intravascular coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
2.5.3 Thromboembolic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
2.6 Disorders of leucocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
2.6.1 Leucocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
2.6.2 Leucopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
2.7 Malignant haematologic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
2.7.1 Myeloproliferative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
2.7.2 Leukaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
2.7.3 Myelodysplastic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
2.7.4 Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
2.7.5 Disorders of plasmacytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

3 Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.) 88

3.1 Functional characteristics of the cardiac muscle structure (F. Šimko) . . . . . . . . . . . . . . . 88
3.2 Metabolism of cardiac muscle cell (F. Šimko) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
3.2.1 Energy production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
3.2.2 Energy storing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3.2.3 Energy utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3.3 Contraction-relaxation cycle (F. Šimko) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3.4 Contractile function of myocardium and pumping function of the heart (F. Šimko) . . . . . . . 97
3.4.1 Preload . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
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3.4.2 Contractility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
3.4.3 Afterload . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
3.4.4 Frequency of contractions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
3.4.5 Synergic activity of ventricles and the contractile ability of atrii . . . . . . . . . . . . . . 100
3.4.6 Pumping activity of the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
3.5 Pathomechanism of heart failure (F. Šimko) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
3.5.1 Symptoms of left ventricular heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . 107
3.5.2 Right heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
3.6 Pathomechanism of cardiomyocyte damage in heart failure (F. Šimko) . . . . . . . . . . . . . . 115
3.6.1 Pathophysiological principles of therapy in heart failure . . . . . . . . . . . . . . . . . . 116
3.7 Hypertrophy of the heart – mechanism of adaptation to chronic hemodynamic overload
(F. Šimko) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
3.7.1 Pressure and volume overload of the heart . . . . . . . . . . . . . . . . . . . . . . . . . . 120
3.7.2 Direct stimulus of hypertrophic growth . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
3.7.3 Hypertrophy stages and their characteristics . . . . . . . . . . . . . . . . . . . . . . . . . 122
3.7.4 The problem of hypertrophy regression . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3.7.5 Physiological hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3.7.6 Hypertrophy and dilatation of the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
3.8 Valvular defects of the heart (F. Šimko) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
3.8.1 Mitral stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
3.8.2 Pathogenesis of clinical symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
3.8.3 Mitral insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
3.8.4 Aortic stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
3.8.5 Aortic insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
3.8.6 Valvular defects of the right heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
3.9 Cardiomyopathies (F. Šimko) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
3.9.1 Dilating cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
3.9.2 Hypertrophic cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
3.9.3 Restrictive cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
3.9.4 Specific diseases of myocardium (secondary cardiomyopathies) . . . . . . . . . . . . . . 138
3.10 General adaptation syndrome – stress (F. Šimko) . . . . . . . . . . . . . . . . . . . . . . . . . . 139
3.10.1 Adaptation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
3.10.2 Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
3.10.3 Civilization diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
3.11 Congenital heart diseases (I. Hulı́n, L. Zlatoš) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3.11.1 Atrial septal defect (ASD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
3.11.2 Ventricular septal defect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
3.11.3 Patent ductus arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
3.11.4 Anomalies of coronary artery emergence . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
3.11.5 Congenital aortic stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
3.11.6 Coarctation of aorta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
3.11.7 Pulmonary artery stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
3.11.8 Transposition of the great vessels (arteries) TGA . . . . . . . . . . . . . . . . . . . . . . 149
3.11.9 Ebstein anomaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
3.11.10 Tetralogy of Fallot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
3.12 Infective endocarditis (I. Hulı́n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
3.13 Pathological changes of the blood pressure (H. Sapáková) . . . . . . . . . . . . . . . . . . . . . 152
3.13.1 Functional anatomy of the circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
3.13.2 Regulation of the blood pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
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3.14 Systemic arterial hypertension (H. Sapáková) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

3.14.1 Essential hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
3.15 Secondary arterial hypertension (H. Sapáková) . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
3.15.1 Renal hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
3.15.2 Endocrinal hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
3.15.3 Hypertension in cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
3.15.4 Hypertension in diseases of the nervous system . . . . . . . . . . . . . . . . . . . . . . . 166
3.15.5 Hypertension in gravidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
3.15.6 Hypertension caused by drugs and toxic substances . . . . . . . . . . . . . . . . . . . . . 168
3.16 Systemic arterial hypotension (D. Maasová) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
3.16.1 Orthostatic (postural) hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
3.17 Syncope (D. Maasová) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3.17.1 Cardiac syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3.17.2 Vasomotor syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3.18 Shock states (I. Hulı́n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
3.18.1 The adapting and compensatory mechanisms activated by the low tissue perfusion dur-
ing shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
3.18.2 Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
3.18.3 Some common signs of the individual types of shock . . . . . . . . . . . . . . . . . . . . 180
3.18.4 Clinical manifestation of shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
3.19 Septic shock and septicemia (I. Hulı́n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
3.20 Etiopathogenesis of atherosclerosis (L. Zlatoš) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
3.20.1 Atherosclerosis of important vascular regions (B. Mladosievičová) . . . . . . . . . . . . . 192
3.20.2 Aorta diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
3.21 Coronary circulation disturbances (I. Hulı́n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
3.22 Ischaemic heart disease (I. Hulı́n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
3.22.1 Angina pectoris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
3.23 Acute myocardial infarction (J. Murı́n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3.24 Pathophysiology of the brain circulation (B. Mladosievičová) . . . . . . . . . . . . . . . . . . . . 205
3.24.1 Stroke – acute cerebrovascular accident . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
3.24.2 Subarachniod haemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
3.24.3 Aneurysms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
3.24.4 Generalized arteriosclerosis of the small cerebral arteries . . . . . . . . . . . . . . . . . . 210
3.24.5 Thrombosis and thrombophlebitis of the cerebral veins and sinuses . . . . . . . . . . . . 210
3.25 The basis of the electrical action of the heart (I. Hulı́n) . . . . . . . . . . . . . . . . . . . . . . . 211
3.25.1 The resting (membrane) potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
3.25.2 The action potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
3.25.3 Automatic cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
3.25.4 The progress of activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
3.25.5 Anatomy and physiology of the conductive system of the heart . . . . . . . . . . . . . . 217
3.25.6 The electrocardiographic changes in cardiac disorders . . . . . . . . . . . . . . . . . . . 224
3.26 The electrophysiological basis in the generation of cardiac arrhythmias (I. Hulı́n) . . . . . . . . 228
3.26.1 Automacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
3.26.2 Automacity disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
3.26.3 Excitability disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
3.26.4 Conduction disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
3.26.5 Sinoatrial node dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
3.26.6 Disturbances of AV conduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
3.27 Tachyarhythmia (I. Hulı́n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
CONTENTS v

3.27.1 Extrasystole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

3.27.2 Tachycardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
3.27.3 Paroxysmal supraventricular tachycardia . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
3.27.4 Ventricular fibrillation and ventricular flutter . . . . . . . . . . . . . . . . . . . . . . . . 247
3.27.5 Pathophysiological outcomes of antiarrhythmic treatment . . . . . . . . . . . . . . . . . 248
3.28 Diseases of the venous system (J. Holzerová) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
3.28.1 Varices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
3.28.2 Thrombophlebitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
3.28.3 Phlebothrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
3.28.4 Pulmonary embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
3.28.5 Chronic venous insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
3.29 The role of endothelium in the reactivity of the vascular smooth muscle (R. Sochorová) . . . . . 253
3.29.1 Effects of endothelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
3.29.2 The mechanism of endothelin effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

4 Pathophysiology of kidneys and urinary system ( I. Hulı́n ) 257

4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
4.1.1 Important tasks of uropoietic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
4.2 Basic anatomic notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
4.2.1 Nephron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
4.2.2 The urinary outflow tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
4.3 Peculiarities of renal blood flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
4.4 The urine formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
4.4.1 Glomerular filtration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
4.4.2 Tubular functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
4.5 Disturbances of glomerular functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
4.5.1 Decrease of glomerular filtration rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
4.5.2 Alterations of glomerular membrane permeability . . . . . . . . . . . . . . . . . . . . . . 275
4.5.3 The involution of nephrons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
4.6 Acute renal failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
4.7 Chronic renal failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
4.7.1 Cell – organ – and metabolic alterations due to uraemia . . . . . . . . . . . . . . . . . . 282
4.7.2 Pathophysiology of symptoms in uraemia . . . . . . . . . . . . . . . . . . . . . . . . . . 283
4.7.3 Consequences of alterations occuring in chronic renal failure . . . . . . . . . . . . . . . . 283
4.8 Inflammatory processes of kidneys due to immunopathogenic mechanisms . . . . . . . . . . . . 285
4.8.1 Renal damage due to antibodies against basement membrane . . . . . . . . . . . . . . . 285
4.8.2 Renal damage induced by immune complexes . . . . . . . . . . . . . . . . . . . . . . . . 287
4.9 Glomerulopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
4.9.1 Acute glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
4.9.2 Rapidly progressive glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
4.9.3 Nephrotic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
4.9.4 Isolated asymptomatic renal disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
4.9.5 Glomerulopathies in other diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
4.9.6 Hereditary glomerulopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
4.10 Infections of the urinary tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
4.10.1 Cystitis, acute pyelonephritis, urethritis . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
4.10.2 Prostatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
4.10.3 Chronic pyelonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
4.10.4 Papillary necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
4.11 Tubulointerstitial renal diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
vi CONTENTS

4.11.1 Nephropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

4.12 Renovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
4.12.1 Diseases related to the blood supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
4.13 Prae-eclampsia and eclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
4.14 Hereditary renal diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
4.14.1 Polycystic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
4.14.2 Disturbances of tubular functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
4.15 Urolithiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.16 Urinary outflow tract disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
4.17 Tumors of urinary tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

5 Pathophysiology of endocrine system ( L. Zlatoš ) 308

5.1 Types of endocrine disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
5.2 Etiology of endocrine disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
5.3 Pathophysiology of hypothalamic-hypophyseal system . . . . . . . . . . . . . . . . . . . . . . . 310
5.3.1 Pathophysiology of hypothalamic-neurohypophyseal system . . . . . . . . . . . . . . . . 310
5.3.2 Pathophysiology of hypothalamic-adenohypophyseal system . . . . . . . . . . . . . . . . 312
5.4 Pathophysiology of thyroid gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
5.4.1 Goiter (struma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
5.4.2 Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
5.4.3 Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
5.4.4 Inflammations of the thyroid gland (thyroiditis) . . . . . . . . . . . . . . . . . . . . . . . 348
5.4.5 Thyroid neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
5.5 Pathophysiology of parathyroid glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
5.5.1 Hypoparathyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
5.5.2 Pseudohypoparathyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
5.5.3 Hyperparathyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
5.6 Pathophysiology of the adrenal glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
5.6.1 Pathophysiology of the adrenal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
5.6.2 Pathophysiology of adrenal medulla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
5.7 Endocrine disorders of the ovaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
5.7.1 Ovarian endocrine hypofunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
5.7.2 Ovarian endocrine hyperfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
5.7.3 Secretion of hormones atypical for the ovaries . . . . . . . . . . . . . . . . . . . . . . . . 397
5.8 Endocrine disorders of the testes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
5.8.1 Hyposecretion of testicular hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
5.8.2 Hypersecretion of testicular hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
5.9 Pathophysiology of the endocrine pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
5.9.1 Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
5.9.2 Tumors of the endocrine pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426

6 Pathophysiology of the nervous system ( M. Bernadič et al.) 430

6.1 The basic anatomical and physiological aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
6.2 Neuronal injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
6.3 Neuroglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
6.4 The basic etiopathogenetic factors in the nervous system disturbances . . . . . . . . . . . . . . 437
6.4.1 Diseases with mainly intrinsic causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
6.4.2 Diseases mainly die to extrinsic causative agents . . . . . . . . . . . . . . . . . . . . . . 439
6.4.3 Diseases with mixed or unknown etiology . . . . . . . . . . . . . . . . . . . . . . . . . . 440
6.5 Some syndroms occuring upon the injury of the nervous system . . . . . . . . . . . . . . . . . . 440
CONTENTS vii

6.6 Head injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442

6.6.1 Brain tissue injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
6.7 Brain edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
6.8 Intracranial hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
6.9 Hydrocephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
6.10 Demyelination disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
6.10.1 Multiple sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
6.10.2 Acute disseminated encephalomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
6.10.3 The acute haemorhagic leukoencephalopathy . . . . . . . . . . . . . . . . . . . . . . . . 453
6.10.4 Experimental alergic encephalomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
6.10.5 Dysmyelination diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
6.11 Degenerative diseases of the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
6.11.1 Parkinson disease (paralysis agitans) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
6.11.2 Alzheimer disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
6.12 Epilepsy (J. Holzerová) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
6.12.1 The etiopathogenesis of the epileptic attack . . . . . . . . . . . . . . . . . . . . . . . . . 457
6.12.2 The epileptic focus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
6.12.3 Classification of the epileptic seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
6.12.4 Experimental epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
6.13 Disturbances of the oxygen supply to the brain (M. Bernadič) . . . . . . . . . . . . . . . . . . . 464
6.13.1 Hypoxic syndrom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
6.13.2 Localized ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
6.13.3 Hyperoxic syndrom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
6.14 Cerebral infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
6.15 Intracranial haemorhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6.15.1 Intracerebral haemorhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6.15.2 Subarachnoid haemorhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6.16 Aging changes and brain tissue atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
6.17 Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
6.17.1 Bacterial infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
6.17.2 Viral infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
6.17.3 Infections with yeast and fungi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
6.17.4 Protozoal infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
6.17.5 Metazoal infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
6.18 Nutritional, toxic, and metabolic dysfunctions of the brain (encephalopathies) . . . . . . . . . . 472
6.18.1 Diseases caused by nutritional disturbances . . . . . . . . . . . . . . . . . . . . . . . . . 472
6.18.2 Diseases caused by exogenous toxic substances . . . . . . . . . . . . . . . . . . . . . . . 473
6.18.3 Secondary conditioned metabolic injury to the nervous system . . . . . . . . . . . . . . 473
6.18.4 Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
6.19 Tumors of the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
6.20 Injury of the spine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
6.20.1 Ascending and descending degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
6.20.2 Injury of the motorpathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
6.21 Diseases of the motor neuron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
6.21.1 Progressive bulbar paralysis and pseudobulbar paralysis . . . . . . . . . . . . . . . . . . 478
6.22 Peripheral nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
6.23 Neuromuscular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
6.23.1 Myasthenia gravis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
6.24 Autonomous (vegetative) nervous system (A. Král’) . . . . . . . . . . . . . . . . . . . . . . . . . 480
viii CONTENTS

6.24.1 The architecture of the ANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481

6.24.2 The sympathetic nervous system and the adrenal medulla. The dopaminergic system. . 483
6.24.3 Parasympathetic NS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
6.24.4 Non-adrenergic and non-cholinergic autonomic nerves . . . . . . . . . . . . . . . . . . . 489
6.24.5 Involvement of the ANS in the pathophysiology of disease states . . . . . . . . . . . . . 490

7 Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.) 496

7.1 Introduction (I. Ďuriš, I. Hulı́n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
7.2 Oesophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
7.2.1 Deglutition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
7.3 Diseases of the oesophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
7.3.1 Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
7.3.2 Gastro–oesophageal reflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
7.3.3 Motor impairments of the oesophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
7.4 Stomach and duodenum (I. Hulı́n, I. Ďuriš) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
7.5 Diseases of the stomach and duodenum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
7.5.1 Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
7.5.2 Peptic ulcer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
7.5.3 Stress ulcers and erosions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
7.5.4 Helicobacter pylori and diseases of GIT . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
7.6 Exocrine pancreas (M. Bernadič) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
7.6.1 Classification of pathological states of the pancreas . . . . . . . . . . . . . . . . . . . . . 507
7.7 Impairment of the exocrine function of pancreas (M. Bernadič) . . . . . . . . . . . . . . . . . . 508
7.7.1 Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
7.7.2 Cystic fibrosis of the pancreas (mucoviscidosis) . . . . . . . . . . . . . . . . . . . . . . . 510
7.8 Small intestine (I. Hulı́n, I. Ďuriš) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510
7.8.1 Digestion and absorption in the small intestine . . . . . . . . . . . . . . . . . . . . . . . 511
7.8.2 Motility of the small intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
7.9 The large intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514
7.10 Malabsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
7.10.1 Inadequate digestion (maldigestion) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
7.10.2 Inadequate absorption (malabsorption) . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
7.11 Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
7.11.1 Secretory diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
7.11.2 Osmotic diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
7.11.3 Diarrhea due to abnormal intestinal motility . . . . . . . . . . . . . . . . . . . . . . . . 518
7.12 Constipation (H. Sapáková) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519
7.12.1 Etiology and pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
7.12.2 Irritable bowel syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
7.12.3 Congenital and acquired megacolon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
7.13 Intestinal obstruction (M. Turčáni) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
7.13.1 Terminology, classification, clinical impact . . . . . . . . . . . . . . . . . . . . . . . . . . 522
7.13.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
7.13.3 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
7.13.4 Pathophysiological principles of ileus prevention . . . . . . . . . . . . . . . . . . . . . . 526
7.14 Inflammation and other intestinal diseases (I. Hulı́n, I. Ďuriš) . . . . . . . . . . . . . . . . . . . 526
7.14.1 Ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
7.14.2 Crohn’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
7.14.3 Ischaemic colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
7.14.4 Diverticulitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
CONTENTS ix

7.14.5 Extraintestinal manifestation of inflammatory intestinal diseases . . . . . . . . . . . . . 529

7.15 Tumours of the GIT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
7.15.1 Carcinoma of the oesophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
7.15.2 Carcinoma of the stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
7.15.3 Carcinoma of the large intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
7.15.4 Polyps in GIT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
7.16 Bleeding from GIT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
7.17 Abdominal pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
7.18 The Liver (D. Maasová) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
7.18.1 Metabolism in liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
7.19 Pathophysiology of the liver (D. Maasová) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
7.19.1 Acute hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
7.19.2 Chronic hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
7.19.3 Acute hepatic failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
7.19.4 Chronic hepatic failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
7.19.5 Hepatic cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
7.19.6 Portal hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
7.19.7 Ascites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
7.19.8 Hepatic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
7.19.9 Hepatorenal syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
7.20 Jaundice (D. Maasová) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
7.21 Diseases of the gallbladder (D. Maasová) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
7.21.1 Cholelithiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
7.21.2 Cholecystitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
7.22 Gastrointestinal hormones (I. Ďuriš) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553

8 Pathophysiology of bones and joints ( D. Maasová et al.) 557

8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
8.1.1 Remarks to the anatomy and physiology of bones . . . . . . . . . . . . . . . . . . . . . . 557
8.1.2 Hormones influencing the bone tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
8.2 Generalized skeleton disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
8.2.1 Skeleton balance disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
8.2.2 Disorders of ground substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565
8.2.3 Disorders of mineralization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
8.2.4 Renal osteodystrophy – a combined disturbance of mineral metabolism . . . . . . . . . 567
8.3 Localized bone disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
8.3.1 Locally enhanced bone resorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
8.3.2 Local disorders of blood supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
8.4 Disorders of joints (I. Šulková, M. Bakošová) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
8.4.1 Some remarks on anatomy and physiology . . . . . . . . . . . . . . . . . . . . . . . . . . 569
8.4.2 Degenerative disorders of the joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
8.4.3 Inflammatory disorders of the joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
8.4.4 Arthritis urica (gout) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575

9 Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský ) 577

9.1 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
9.1.1 Principles of inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
9.1.2 Exudation and swelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
9.1.3 Cells participating in inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
9.1.4 Mediators of inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
x CONTENTS

9.1.5 Molecular mechanisms of the acute cell-mediated inflammatory reaction . . . . . . . . . 624

9.1.6 Categories of inflammation mediated by the immune system . . . . . . . . . . . . . . . . 628
9.2 Fever (I. Hulı́n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
9.2.1 Regulation and control of body temperature . . . . . . . . . . . . . . . . . . . . . . . . . 634
9.2.2 Pathogenesis of fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635
9.2.3 Causes of fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
9.2.4 Progress of the fever and accompanying symptoms . . . . . . . . . . . . . . . . . . . . . 637
9.2.5 Fever from the clinical point of view . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639

10 Pathophysiology of malignant disease ( B. Mladosievičová ) 641

10.1 Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
10.1.1 Chemical carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
10.1.2 Radiation carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
10.1.3 Viral carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
10.1.4 Hormones and carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
10.1.5 Irritation and carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
10.2 Cellular oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
10.3 Characteristics of cancer cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
10.3.1 Tumor cell markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
10.3.2 Similarity of embryonic and malignant cells . . . . . . . . . . . . . . . . . . . . . . . . . 649
10.4 Tumor growth and development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
10.4.1 Tumor classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
10.4.2 Malignant tumor growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
10.4.3 Tumor angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
10.4.4 Pathogenesis of metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
10.5 Predisposing factors of cancer cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
10.6 Characteristics of benign tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
10.7 Pathophysiology of malignant disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
10.7.1 Cachexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
10.7.2 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
10.7.3 Anaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
10.7.4 Leukopenia and thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
10.7.5 Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658
10.8 Immune surveillance and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658

11 Fluids and electrolytes ( H. Sapáková, D. Maasová ) 659

11.1 Fluid disorders (H. Sapáková) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
11.1.1 Extracellular fluid (ECF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
11.1.2 Fluid in other extracellular spaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
11.1.3 Intracellular fluid (ICF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
11.1.4 The characteristic of the main body fluid compartments . . . . . . . . . . . . . . . . . . 661
11.1.5 Changes in the volume of body fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
11.1.6 Dehydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
11.1.7 Hyperhydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
11.2 Electrolyte balance and its disturbances (H. Sapáková) . . . . . . . . . . . . . . . . . . . . . . . 666
11.2.1 Sodium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
11.2.2 Chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
11.2.3 Potassium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
11.2.4 Calcium and Magnesium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
11.2.5 Phosphorus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
CONTENTS xi

11.3 Disorders of acid-base homeostasis (D. Maasová, Š. Navarčı́ková) . . . . . . . . . . . . . . . . . 674

11.3.1 Regulation mechanisms of acid-base homeostasis . . . . . . . . . . . . . . . . . . . . . . 674
11.3.2 Classification of acid-base disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
11.3.3 Compensation of acid-base disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
11.3.4 Metabolic acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
11.3.5 Metabolic alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
11.3.6 Respiratory acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
11.3.7 Respiratory alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
11.3.8 Therapeutical principles of acid-base disturbances . . . . . . . . . . . . . . . . . . . . . 680

Key words index 683

Chapter 1

Pathophysiology of the respiratory

system

and acetoacetic acid are converted to acetyl-CoA

which is transported into the mitochodria. Acetyl-
1.1 The transport of oxygen to CoA is a common intermediate metabolite of carbo-
hydrates, proteins and fats, which initiates the oxida-
the organism tive phosphorylation after its entry into the Krebs cy-
cle. Mitochondria contain enzymes forming a chain
for transport of electrones. The external membrane
separates the mitochondria from the cellular cyto-
The transport of substances across the mem- plasm. It is smooth and contains channels enabling
branes, the synthesis of necessary substances, the the passage of small molecules. The inner mitochon-
maintenance of bioelectric potentials and many other drial membrane is infolded thus forming the cristae
processes in the organism can be kept in action at and its permeability is very low. The space between
the required level only by continual supply of en- the membranes, i.e. the intermembraneous space, is
ergy. One part of the energy is consumed by the called matrix. The matrix contains enzymes respon-
mechanical activity of organs and of the organism sible for several metabolic processes. The inner mi-
as a whole. The generation of ATP, as a form of tochondrial membrane contains enzymes of the res-
energy utilization in the cells, depends on oxygen piratory chain. A part of ATP, as a product of Krebs
supply. The atoms of hydrogen are released in mito- cycle, is synthetized in mitochondria. Approximately
chondria from molecules of glucose and subsequently 90 per cent of ATP is generated by the subsequent
bind with oxygen in a series of oxidative reactions, oxidation of the released hydrogen. Atoms of hy-
while energy from adenosine diphosphate is utilized drogen and electrons (H+ and e− ) are transferred
for generation of ATP. The lack or insufficient sup- through a chain of oxidation-reduction reactions to
ply of oxygen, and also the inability to utilize oxygen oxygen which represents the final recipient for the
result in a condition called hypoxia. If hypoxia lasts formation of water. During these reactions ATP is
for a certain time, it causes a functional impairment generated. This process of electron transfer from the
of the cells and finally their death. Hypoxia leads donor to the recipient, resulting in phosphorylation
to an important deterioration of energy production of ADP to ATP is called oxidative phosphorylation.
in the cells and hence it disturbs their equilibrium. The molecules of ATP are sythetized in the mito-
Several disorders of organism may result in hypoxia. chondrial matrix. Their utilization takes place in
If the cell needs energy, the ATP phosphate rad- the cellular cytoplasm. They are tranferred through
ical is hydrolized, energy is released from its bond the mitochondrial membrane by the enzymatic sys-
and ADP remains. The repeated synthesis of ATP tem called translocase. By this system one molecule
depends on series of chemical reactions. Cytoplas- of ATP is exchanged for one molecule of ADP.
matic enzymes convert glucose to pyruvate, fatty
acids and amino acids to acetoacetic acid. Pyruvate The oxidative phosphorylation depends on ade-

3
4 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

quate oxygen supply, on demands of the cells, and enabling the oxygen transport between alveoli and
on their ability to utilize oxygen. The demands of blood. It depends on the pumping capacity of the
the cells for oxygen depend on their metabolic ac- heart, the condition of the pulmonary vessels, and
tivity. The higher the metabolic activity, the higher on pressure relations.
the concentration of hydrogen ions which are the fi- The utilization of oxygen represents processes by
nal products. The consequent change in pH of blood which oxygen is used in ATP formation. It depends
acts as a stimulus for the respiratory centre to in- on the condition of cells and the mitochondrial mech-
crease the oxygen supply for the oxidative phospho- anisms. The rate of oxygen utilization depends on
rylation. The rate and the depth of respiration, the the metabolic activity.
blood saturation with oxygen and carbon dioxide,
the total capacity of the oxygen transfer and the de- 1.1.2 Hypoxia
gree of perfusion determine the quantity of oxygen,
entering the cells per minute. The intact mitochon- Between the requirements of cells and the actual oxy-
dria, the respiratory chain enzymes and the trans- gen supply can arise differences due to disturbance
port of electrons determine the ability of the cell to of some processes. The result is the lack of oxygen
utilize the oxygen effectively. in tissues. It means that oxygenation is not effective.
In this situation a condition develops which is called
hypoxia. Hypoxia, as a term is used frequently. But
1.1.1 Oxygenation
it should be used exclusively in relation to the con-
This term includes the processes of oxygen transport dition in which the oxygenation at the cellular level
to the tissues and of carbon dioxide and other waste is impaired or inadequate. The partial pressure of
products elimination. The oxygenation is effective oxygen (pO2 ) in tissue is usually lower. It can be the
when there is equilibrium between the supply and consequence of the disturbed oxygenation.
the need of oxygen. The oxygen supply of the cells Under the condition of hypoxia in organism the
depends on pulmonary ventilation, perfusion, on ex- oxidative phosphorylation is disturbed and therefore
change and binding of respiratory gases and on the also the generation of energy in the cell is impaired.
ability and capacity of blood to transport the oxy- During the lack of oxygen lasting one minute, the
gen. ATP to ADP ratio falls ten times. Glycolysis, which
Ventilation, perfusion and exchange of the respi- is a series of chemical reactions, by which glucose is
ratory gases in the lungs are the primary functions converted to pyruvate and hydrogen, does not need
of the cardiopulmonary system. Ventilation includes oxygen. Glycolysis can function also during hypoxia,
the mechanics of inspiration and the providing of at- the gain of ATP however, is low. If the supply of oxy-
mospheric air to the alveoli, and the mechanics of ex- gen is normal, glycolysis cannot continue, because it
piration during which the air with decreased oxygen is inhibited by the feedback mechanism of pyruvate
and increased carbon dioxide levels is expired. Ven- and hydrogen. Under anaerobic conditions pyruvate
tilation depends on many factors – neurogenic and and hydrogen are converted to lactate, which inhibits
chemical factors, respiratory muscles, compliance of the glycolysis by the feedback mechanism. Anaero-
the lung tissue, and the airway resistance to the air- bic glycolysis provides energy during the insuficient
flow. The exchange of respiratory gases in the or- oxygen supply. This way of energy gaining cannot
ganism depends on oxygen diffusion from alveoli to be useful for a long period of time. After a certain
the blood and then from the blood to the tissues. In time it leads to the impairment of cells. A higher
this way, but vice versa carbon dioxide is eliminated level of lactic acid during hypoxia shifts the pH in
from the body. The exchange of respiratory gases the cell to the acid values. When the lactic acid dif-
depends also on the integrity, thickness and area of fuses from the cells into the environment, metabolic
the membrane which represents the site of the gas acidosis develops very quickly. In this situation the
exchange. It further depends on the relative gradi- efficiency of the Na+ K+ pump decreases, as there is
ent of gases and their solubility on both sides of the not enough energy for its activity. Finally, the low
membrane, on the affinity of haemoglobin to oxygen, efficiency of the Na+ K+ pump results in an accumu-
and on the distribution of ventilation and perfusion. lation of Na+ in the cells and the escape of K+ into
The perfusion of the lung represents the bloodflow the intercellular space. The changes in ion concentra-
1.1. The transport of oxygen to the organism 5

tions are the underlying cause of osmotic oedema of the organism is permanently on the border of tis-
mitochodria and cells. These changes affect just the sue hypoxia. Increased oxygen supply demands can
metabolically active cells. The function of mitochon- be caused by hyperthyroidism. Thyroxine enhances
dria could recover by an adequate oxygen supply. metabolic processes and the oxygen consumption. If
But if the pH drops without control, the intracellular the demands further increase, hypoxia can develop
enzymes can be released damaging thus the intracel- rapidly.
lular structures including the nucleus. They inhibit
the chemical reactions and the homeostatic control 1.1.2.2 The influence of hypoxia on organs
of cells. These changes result in cellular death. The and systems
effect of hypoxia is identical in all types of cells. First
of all, anaerobic metabolic processes take place, sub- The blood flow through the tissues is principally de-
sequently lactic acid is produced, the mitochondrial termined by local oxygen requirement. The myo-
ATP production decreaeses, the pH shifts to the acid genic theory supposes that the concentration of oxy-
values, an finally acidosis in cells and irreversible gen regulates the contractility of precapillary sphinc-
changes in cellular structure and their nuclei due to ters. When the concetration of oxygen in the tissues
the released intracellular enzymes develop. increases, the precapillary sphincter contracts. It re-
mains contracted until the concentration of oxygen
returns to normal. When the concetration of oxygen
1.1.2.1 Causes of hypoxia regains its physiological value, the sphincter opens.
The metabolic or vasodilatory theory assumes that
Hypoxia can be induced by combined action of vari- substances causing vasodilatation affect the precap-
ous factors concerning the supply of oxygen or actual illary sphincter directly. Decreased oxygen concen-
oxygen demands of cells and tissues. tration induces the production of vasodilatatory sub-
Stagnant or ischaemic hypoxia results from re- stances. Under the condition of the oxygen deficiency
duced perfusion of tissues. they cause vasodilatation of the precapillary sphinc-
Anaemic hypoxia is caused by a decrease in oxygen ters. The essential vasodilating substance is lactic
transport capacity of blood. acid, the product of the anaerobic processes.
Hypoxic hypoxia occurs when the oxygen concen- The blood flow through the tissues depends on
tration decreases in arterial blood. the degree of their activity. It means, according to
Histotoxic hypoxia arises when the cells are not the myogenic and also to the metabolic theory, that
able to utilize the transferred oxygen. the metabolically active tissues have a better oxygen
Hypoxia of tissues can arise also when the oxygen supply, resp. they involve mechanisms preventing
demand of cells is very high owing to the raise of the development of tissue hypoxia. The problems
their metabolic activity. begin if the organism is not able to keep the oxygen
The disorders of ventilation and of exchange of supply at the required level. The reasons reside in
gases cause a decreased saturation of arterial blood global or often in local disorders concerning the tissue
with oxygen. That is why hypoxic hypoxia arises. blood supply.
The disorders of perfusion cause that the capacity The degree of hypoxia can vary. It is also impor-
of blood for the oxygen transfer is poorly utilized. tant whether the hypoxia lasts for a short time, or
Some toxic substances inhibit the transport of elec- whether it is of chronic character. During chronic hy-
trons in the respiratory chain. That is why the ox- poxia compensatory mechanisms develop, which can
idative phosporylation is decreased or even stopped. be useful until a certain stage. Hypoxia stimulates
This kind of hypoxia (histotoxic hypoxia) is caused the kidneys to produce erythropoietin which causes
by cyanide and arsenic compounds the release of erythrocytes from the bone marrow,
In some diseases the oxygen supply is normal, thus stimulating erythropoiesis. If global hypoxia is
yet it fails to satisfy the enormously increased de- involved, the highest increase of erythropoietin is ob-
mands. It occurs usually when the metabolic pro- served after 5 days. These events can result in useful
cesses increase markedly. Increased demands for oxy- polycythaemia. It occurs regularly in patients with
gen supply occur during physical effort, fever, anx- chronic obstructive bronchitis and in patients with
iety and stress. In severe injury, burns and sepsis, congenital heart defects.
6 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

During local hypoxia, a collateral circulation de- oxygen concentration available for the liver cells, but
velops as a compensatory mechanism. Besides, the in spite of that, they get only the essential quantity
sensitivity of the cells to hypoxia varies. Some cells of oxygen. Arterial hypoxia has an immediate influ-
(the nervous tissue) survive merely a few minutes, ence on hepatocytes, which are very sensitive to the
others a relatively long time (fibroblasts) without oxygen insufficiency.
oxygen supply. The cells of the central nervous sys- Hypoxia is often manifested as pain. Reduced per-
tem are extraordinarily sensitive to hypoxia. During fusion of tissue decreases not only the oxygen supply
hypoxia the permeability of capillaries in the brain but also the removal of waste products of metabolism
increases very quickly. Hypoxia can result in cere- from tissues. During hypoxia lactic acid cumulates
bral oedema. Hypoxia of the brain causes a variety in tissues. This directly stimulates the nerve endings
of clinical symptoms: disorders in behaviour, syn- thus causig the pain during hypoxia.
copes, disorders in concetration, lethargy, confusion Fatigue, weakness and intolerance to effort are
and perceptive disorders. None of these symptoms is very often due to insufficient production of energy in
specific for hypoxia, however in their evaluation, the mitochondria during hypoxia. In fact, fatigue repre-
hypoxia must be considered as the underlying cause. sents physical and psychical exhaustion. The term
In the pulmonary circulation hypoxia causes vaso- weakness refers to the lack of strength for common
constriction of precapillary vessels increasing thus daily human activities. The intolerance to effort is,
the resistance in the pulmonary circulation. If hy- in fact, an inadequate reaction of the organism even
poxia lasts for a long time, its consequences include to small physical effort.
a change in the right ventricular function and as a Extreme hypoxaemia can be manifested by
matter of course a permanent pressure increase in cyanosis. Cyanosis is a clinical sign of a violet-blue
the pulmonary circulation. colouring of the skin and visible mucous membranes.
It appears when the amount of reduced haemoglobin
Myocardium in comparison with other tissues has
exceeds a certain limit. Cyanosis does not reflect
a very small capacity to gain energy under anaero-
the oxygenation degree, because it is caused by the
bic conditions. It is sufficient merely for a few min-
amount of the reduced haemoglobin. Cyanosis ap-
utes. Anaerobic glycolysis cannot cover the required
pears when there are more than 5 grammes of re-
production of ATP. The stores of glycogen decrease
duced haemoglobin per 100 ml of capillary blood. In
very rapidly and markedly during oxygen deficiency.
this case the saturation with oxygen (in the capil-
In the myocardium are only few anaerobic glycolytic
lary blood) is lower than 75 per cent. It is evident,
enzymes present. That is why irreversible damage
that if the haemoglobin level is low, 5 grammes of
of myocardium and death of cardiomyocytes arise
reduced haemoglobin per 100 ml of capillary blood
very soon during insufficient oxygen supply. The
is impossible to be found. People with a low
conducting system of heart is also very sensitive to
level of haemoglobin are hypoxic without signs of
the insufficient oxygen supply. Usually at the onset
cyanosis. On the contrary, in polycythaemia (in-
of hypoxia tachycardia occurs. If hypoxia lasts for
creased number of erythrocytes) and if the amount of
a longer period of time, bradycardia supersedes the
haemoglobin is increased, cyanosis can be observed
tachycardia. In hypoxia also the resting membrane
even when oxygen supply is sufficient. The presence
potential changes in consequence of a disturbance in
or absence of cyanosis does not represent an indica-
sodium, potassium and water equilibrium in the cell
tor of oxygenation. Cyanosis has to be considered in
membrane, leading to subsequent action potential al-
relation with other findings.
teration and changes in the electrocardiogram.
The renal functions depend on the oxygen supply.
During hypoxia they can be seriously impaired. A 1.1.3 Dyspnoea
marked renal hypoxia may cause a clinically mani- Dyspnoea is another symptom of disturbed oxygena-
fested acute renal failure. tion. It is, in fact, a subjective feeling perceived as
The blood is flowing to the liver from the arterial difficulty or distress in breathing, so called shortness
system and from the portal vein. The portal vein of breath. This feeling can appear in healthy per-
blood contains low concentration of oxygen. The ad- sons too, if the demands on the breathing exceed
mixture of arterial and portal blood increases the their possibilities, e.g. during extreme physical effort
1.2. Pathophysiology of respiration and respiratory organs 7

or excitement. In ill persons it can occur already

during moderate physical effort or even at rest. Dys-
pnoea is always a subjective feeling of breathlessness 1.2 Pathophysiology of respi-
or of dificulty in breathing. A variable clinical pat-
tern of this condition is described. Some patients ration and respiratory or-
describe dyspnoea as lack of air or impossibility to gans
get a breath. . Higher effort and breathing with a
greater participation of respiratory muscles can be
observed. Dyspnoea does not reflect directly the
condition of oxygenation. It is rather a symptom Respiratory organs from pathophysiological point
expressing the disproportion between the require- of view can be considered as two parts of one system.
ment of respiration and the ability of respiratory The first part is represented by organs in which gas
organs and the organism as a whole to maintain the exchange takes place, i.e. airways and lungs. The
required respiration. Dyspnoea can be a permanent other part is represented by all structures and their
condition, or it can occur in episodes. The afferent functions responsible for the air transport from the
information plays a certain role in the dyspnoea de- external environment into the gas exchange units.
velopment. An episode of dyspnoea can arise during This ”pumping” is performed by the chest, respira-
the night. The nocturnal, paroxysmal dyspnoea can tory muscles, nerves, nervous centers, and neurohu-
be very dramatic as it can be accompanied by cough moral control.
and a subjective feeling of breathlessness. In other
cases dyspnoea can be associated with a certain en-
forced position – orthopnoea. Orthopnoea is a severe 1.2.1 Pulmonary ventilation and its
degree of breathlessness, during which the patient is disorders
not able to stay in a recumbent position, just in sit-
ting position, or is for a short time not able to stay in Ventilation of the lungs is a complex of processes
standing position. In patients with cardiopulmonary ensuring the transport of air into the lungs and the
diseases can often be the so called panic dyspnoea ob- expiration of air enriched in carbon dioxide with
served. There are probably more mechanisms which low oxygen content. The complex of these processes
are responsible for the arise of dyspnoea. But almost which are the basis of ventilation depends on the in-
regularly during dyspnoea a congestive pulmonary tact chest, perfectly working airways, neurochemical
circulation can be observed. The changes of the pul- regulative control of breathing, and lung tissue itself.
monary circulation have greater participation in arise During inspiration the thoracic cavity enlarges due
of dyspnoea than the single. to the contraction of the respiratory muscles. When
It is not possible to measure directly the condi- the diaphragm contracts, it moves downward into
tion of oxygenation in the tissues. There are how- the abdominal cavity. The elevation of sternum and
ever several possibilities of indirect estimation of the of ribs causes enlargement of the thoracal cavity in
cellular oxygenation degree. Firstly, the determina- the back to front diameter. The inspiration is an ac-
tion of blood saturation with gases of respiration is tive process which depends on several factors. The
performed, furthermore the condition of ventilation, expiration is a passive process, depending on relax-
perfusion and the lung volumes are determined, and ation of inspiratory muscles. The elastic properties
in addition, the cardiovascular system functions are of chest and lungs are important factors. The chest
measured. The transport of oxygen to the tissues and the lungs have generally a permanent tendency
depends on the efficiency of circulation and thus on to restriction. The intrapleural pressure is negative
the heart performance. The capacity of blood to and keeps the lungs distended. During inspiration
transport oxygen has an important role. Together the intrapleural pressure becomes more negative thus
with the patientďs subjective sensations these meth- distending the lungs. The distension of the lungs
ods represent a better possibility to approach to the during more negative intrapleural pressure depends
conception of the supply of tissues with oxygen. on elastic fibres and the total elastic properties of
the lungs. Alveoli have a tendency to collapse. It
is caused by the moist surface of alveoli tending to
8 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

connect the opposite sides together. This connec- elicit a reflex inhibition of inspiration (it hinders the
tion is hindered by a secrete produced by specialized further air flow into the lungs). The reflex inhibition
cells known as pulmonary surfactant. It is a lipopro- of inspiration is termed Hering-Breuer reflex. Essen-
tein lowering the surface tension of the alveolar fluid tially, it protects the lungs against excessive disten-
and hindering the potential collapse of alveoli. In- sion. The saturation of blood with oxygen and car-
spiration and expiration take place according to the bon dioxide influences the frequency and the depth
principle of pulmonary distension and compression. of breathing so that they can comply with the actual
During inspiration is the pressure in the lungs lower requirements. The chemosensitive receptors are sit-
than the atmospheric pressure and during the expi- uated in the medulla oblongata. They are sensitive
ration the situation is reverse. During regular (quiet) to changes of carbon dioxide and H+ concentrations
breathing some alveoli are collapsed. Distensibility in the surrounding fluid. Under physiological condi-
of the lungs is in relation to the intraalveolar pressure tions, the concentration of carbon dioxide is a pri-
which is necessary for attaining a certain distension mary stimulus for ventilation. The increase in CO2
of lungs. Distensibility during the elevation of the in- causes a raise in H+ . It results from the formation
traalveolar pressure is a property of the lungs. This of carbonic acid from CO2 and water and its subse-
property is called compliance. The lung compliance quent dissociation to H+ and HCO− 3 . The increase in
expresses the change in lung volume due to increase carbon dioxide or hydrogen ion levels stimulates di-
in intraalveolar pressure. During distension of the rectly the neurons of respiratory centre. This process
lungs energy is spent to overcome the viscosity of results in increased frequency and depth of breathing
the pulmonary tissue and the airways resistance to and with a subsequent decrease in CO2 . When the
the air flow during inspiration. The respiratory work concentration of hydrogen ions decreases, the respi-
is the sum of the effort spent during inspiration and ratory centre slows down the respiration and CO2
expiration to overcome the airways resistance to the can be retained, so that equilibrium between bicar-
air flow. Decrease in the lung compliance, increase bonates and carbonic acid in the body fluids can be
in airway resistance and the requirement of active attained. Hypoxia, under usual circumstances, acts
expiration increase the respiratory work. as a secondary stimulus for the ventilation.
The rhythm and frequency of breathing is regu- Peripheral chemoreceptors, situated in the carotid
lated by nervous and chemical mechanisms. The res- arteries and aorta are connected with the respira-
piratory centre is localized in the medulla oblongata tory centre by afferent nerve fibres. These receptors
and in pons Varolii in the medulla oblongata. The are sensitive to a low oxygen and high CO2 levels
respiratory centre controls the frequency of breath- in blood. Impulses from these receptors stimulate
ing, the rhythm, the depth of breath and the level the respiratory centre. The respiratory centre is also
of alveolar ventilation. During inspiration and expi- stimulated from the cerebral cortex and thalamus.
ration afferent impulses come to the centre having The stimulation from the cerebral cortex induce the
alternating stimulatory or inhibitory effects. The ef- state of vigilance. The stimulation from thalamus
ferent fibres transfer impulses from the respiratory acts especially during emotions. The stimulation of
centre to the respiratory muscles via the phrenic and baroreceptors due to increased blood pressure results
intercostal nerves. in a moderate suppression of the respiratory centre.
The respiratory centre is influenced by afferent When there is a marked decrease in alveolar ven-
impulses from the pulmonary receptors being sensi- tilation (e.g. by an half), the blood saturation with
tive to tension (distension), from central and periph- oxygen decreases just about 10 per cent in compar-
eral chemoreceptors, from cerebral cortex and tha- ison with the normal values. Alveolar ventilation
lamus, and from arterial and venous baroreceptors. participates in regulation of respiration by means of
Receptors sensitive to tension are situated at several carbon dioxid level in blood. The decrease in alveo-
sites in the lungs. Many of them are situated in the lar ventilation manifests itself more markedly in the
bronchi and bronchioles. They are stimulated dur- increase of CO2 level in blood rather than in decrease
ing distension of the lungs. During stimulation the of oxygen. Therefore it is physiologically useful that
impulses are transferred via afferent fibres of nervus the alveolar ventilation takes part in regulation of
vagus to the respiratory centre. Afferent impulses respiration by means of CO2 level in blood.
1.2. Pathophysiology of respiration and respiratory organs 9

The acinus is the essential functional unit of the enlarges the airways, then the epiglottis closes the su-
lungs. It consists of terminal and respiratory bron- perior aperture of the pharynx, and a very vehement
chioles, alveolar ducts and alveoli. The inspiration is contraction of the expiratory muscles follows, the in-
performed by the enlargement of the thoracic cavity trathoracic pressure increases, the epiglottis opens
by aid of respiratory muscles. In this situation the and the air is expelled explosively. During the con-
air flows from the outside into the lungs and to alve- traction of muscles the intrapleural pressure remains
oli. The airways are arranged in such a way that they high. Just then (after the opening of glottis) the
form in fact a biological filter for the air flow. The air pressure in airways decreases. That is the reason for
in the upper airways is warmed up to the body tem- the expulsion of air with secretion which resides on
perature. It becomes saturated with water vapours the airway walls. Problems arise when the neuromus-
to 100 per cent and is cleansed by adhesion of various cular function of respiratory muscles is disturbed, or
particles to the airways walls. The air entering the if the thorax is injured, if the airway resistance is
alveoli is free of almost all undesirable components, increased, or if the cough reflex is suppressed.
including the pathogenic microbes. The lung tis-
The pulmonary ventilation is provided by inspira-
sue is thanks to these useful mechanisms, kept clean
tion and expiration. The tidal volume (VT ) is the
and sterile. The function of the mucociliary system,
volume of air which enters and leaves the respira-
the reflex mechanisms (cough, bronchospasm), secre-
tory organs during normal inspiration and expira-
tion of lactoferrin, lysosyme, IgA and the presence of
tion. The minute ventilation is the volume of air
macrophages aid to this cleanliness.
moved in and out of the lungs per minute. It is the
The primary role in the continuous cleansing of VT multiplied by the number of breaths per minute
airways plays the mucociliary system. Besides the (VE = VT · f). The amount of air which enters the
motion of cilia, the secretion of the mucous mem- respiratory organs consists of two parts. The first
branes and the production of periciliary fluid partic- one represents the volume which reaches the alve-
ipate in the cleansing. The motion of cilia is directed oli, the other one is the volume of air in airways
towards the nose and the mouth cavities. The mu- where the gas exchange does not take place (dead
cous membrane of trachea, bronchi and bronchioles space). Therefore VE = VA + VD , where VA is the
contain cylindrical ciliated cells. Among these cells volume representing the alveolar ventilation and VD
there are situated cells producing mucus. The secre- is volume of air in dead space. Physiologically use-
tion in airways is produced also in the submucous ful is only the alveolar or effective ventilation. It is
glands of the cartilaginous airways. During one day that portion of the minute ventilation volume which
about 100 ml of mucus is produced. The majority of enters the alveoli where gas exchange realizes. To
mucus is reabsorbed. About 10 ml of mucus in the determine precisely the air volume which represents
airways is removed by expectoration and swallowing. the alveolar ventilation is not easy. The physiological
parameter providing information on alveolar ventila-
The mucous or gelous layer is swimming like ice-
tion is the CO2 pressure in arterial blood.
floe upon the surface of the periciliary fluid in the
form of sol which surrounds the cilia. The mucous About 150 ml of air remain in the airways. This
layer moves towards nasopharynx in coordination volume cannot be utilized in gas exchange. It rep-
with the respiratory movements. This can take place resents the ventilation of the dead space (regarding
providing the mucociliary system is intact. Firstly, the gas exchange it is of no value). The relation be-
the epithelial cells with the cilia have to be morpho- tween the dead space and the tidal volume (VD /VT )
logically and functionally intact. The ciliar motion is a convenient expression for the efficiency of ven-
depends on the thickness and the rheologic qualities tilation. Respiration realizes to ensure the alveolar
of the mucus and the periciliary fluid. The speed ventilation. The transport of oxygen and also the
of the transport decreases: if the viscosity of mucus speed of CO2 elimination depend on the efficiency
increases, if its elasticity decreases, if the amount of of alveolar ventilation. The speed of CO2 exhala-
mucus is augmented, or if the mucociliary system tion determines the magnitude of alveolar ventila-
is damaged. To ensure the cleaning of airways also tion. Normal alveolar ventilation is measured by the
under these conditions, cough is involved. An ef- level of arterial CO2 . The optimum alveolar ventila-
fective cough begins with a deep inspiration, which tion has to be performed at a level which can manage
10 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

the exhalation of the necessary amount of CO2 . Un- 1.2.1.1 Hyperventilation

der physiological circumstances the pressure of CO2
in arterial blood cannot exceed 45 mm Hg during During hyperventilation the volume of CO2 in the
normal alveolar ventilation. In analysis of the blood arterial blood decreases and that is why there is
gases it is of course the partial pressure of CO2 (the a minor possibility for the carbonic acid formation
total pressure of a certain volume of a mixture of from water and CO2 . In fact it means a decrease in
gases is the sum of partial pressures of every compo- the carbonic acid level and a subsequent decrease in
nent of the mixture forming the gas volume). The concentration of hydrogen ions. That is why the pH
partial pressure of CO2 can be determined from the of plasma becomes alkaline. This condition is called
total pressure by assessing the percentage of its par- respiratory alkalosis, hypocapnia or non-metabolic
ticipation in the mixture. Under physiological con- alkalosis. The kidneys compensate this condition by
ditions, the pH of plasma ranges from 7,36 to 7,44. eliminating the bicarbonate ions, retaining the hy-
The saturation of blood with oxygen attains 93–98 drogen ions and non-bicarbonate anions. It results
per cent. In this case the partial pressure of CO2 in excretion of alkalic urine and improvement of the
in arterial blood (pCO2 ) is 35–45 mm Hg and that of plasmatic pH.
O2 (pO2) is 75–100 mm Hg during intact ventilation. During alkalosis the level of ionized calcium de-
By analysing the exhaled air the volume of CO2 can creases. The reduced ionized calcium induces en-
be estimated. This value does not provide any infor- hanced neuromuscular excitability because of the dis-
mation on alveolar ventilation. turbed membrane potential. The decrease in ionized
Ca2+ results from the fact that the protein bound
calcium (CaPr) is in equilibrium with the hydro-
Information about the mechanics of ventilation
gen ions. When the H+ concentration decreases,
can be obtained by measuring the pulmonary vol-
the amount of protein bound calcium increases to
umes and speed of the airflow. Useful values can be
maintain the equilibrium. The amount of the ion-
obtained by spirometric examination. Simple and es-
ized Ca2+ is reduced. The increased neuromuscular
sential is the information on the value of vital capac-
excitability can be manifested by several symptoms.
ity of the lungs (FVC). It is the volume of air expi-
It can lead to spasms and tetany. Tetany appears
rated after maximal inspiration. Graphic illustration
especially when alkalosis develops very quickly. The
of expiration provides information on the volume of
bloodflow through the vital organs is decreased. It
air which has been exhaled within 1, 2 and 3 seconds
is due to the vasoconstrictive effect of low carbon
(FEV 1, FEV 2, FEV 3). These are the components
dioxid concentration. The release of oxygen from
of FVC, nevertheless they have a great importance in
oxyhaemoglobin is impaired during alkalosis. As a
evaluation of pathological conditions. A very useful
result, tissue hypoxia develops. The brain is ex-
information provides the relation of FEV 1 and FVC
tremely sensitive to hypoxia, hence various symp-
(FEV 1/FVC), especially in cases of obstructive lung
toms of central nervous system disorders arise.
diseases.
As mentioned above, alveolar hyperventilation
leads to respiratory alkalosis because CO2 is exhaled
The maximal minute ventilation is the volume of and the level of its concetration in arterial blood de-
air which a person can exhale and inspire in one creases. One of the most common causes of alveolar
minute during maximally intented ventilation. hyperventilation and of subsequent alkalosis is an ab-
normally rapid respiration, that accompanies psychi-
The level of ventilation must ensure the metabolic cal tension and extreme emotional conditions. Hy-
requirements of organism, especially regarding the perventilation is also caused by severe pathological
carbon dioxide exhalation. The partial pressure conditions such as high fever, encephalitis, meningi-
of CO2 in the arterial blood ought not exceed tis, and several states leading to increased excitabil-
the limit of 45 mm Hg. Ventilation, which exceeds ity of the respiratory centre. The result is an in-
the metabolic requirements is called hyperventila- creased respiratory effort, which originates in physi-
tion. Ventilation which is insufficient regarding the ological impulses. Drugs, e.g. salicylates, pathologic
metabolic requirements of organism is called hy- conditions as brain tumors and traumas of central
poventilation. nervous system can increase the sensitivity of the res-
1.2. Pathophysiology of respiration and respiratory organs 11

piratory centre. Bleeding can cause hyperventilation the optic nerve can be found. The headache is usu-
in a similar way. Hyperventilation occurs also during ally localized in the occipital area.
pulmonary diseases (pneumonias, fibroses, oedema of The increase in hydrogen ions concentration in the
the lungs) as a result of the stimulation of pulmonary extracellular fluid causes their penetration into cells.
J receptors. To maintain the electric equilibrium on membranes,
Alveolar hyperventilation can occur as compen- potassium ions escape from the cells. The level of
satory mechanism during metabolic acidosis, or it potassium in serum increases at the beginning, but
can be caused by hypoxaemia. Low arterial con- later deficit in potassium stores of organism develops.
centration of oxygen can stimulate the peripheral The intracellular deficiency of potassium causes mus-
chemoreceptors, which in turn stimulate the respi- cular weakness. A long lasting hypokalaemia leads
ratory centre. In this manner the increased input to degenerative alterations in myocardial cells. The
of oxygen is ensured, but CO2 is exhaled simultane- most important changes are those occuring in the nu-
ously because of hyperventilation. clei of myocardial cells, and the development of my-
ocardial fibrosis. As a consequence of hypoxia and
1.2.1.2 Hypoventilation hypercapnia effects on myocardial cells, arrhythmias
may occur.
Alveolar hypoventilation is an insufficient ventila- A very rapid increase in carbon dioxide concetra-
tion, with regard to the metabolic processes. Hy- tion easily causes convulsions and unconsciousness.
poventilation can result from disturbed regulation Prolonged hypercapnia combined with hypoxaemia
of respiration or disorders of the respiratory system.
causes behavioural changes, lethargy, desorientation
Alveolar hypoventilation leads to hypercapnia which
and confusion of a varying degree.
is associated with hypoxaemia. The increase in car-
Hypoxaemia and acidosis are the causes of vaso-
bon dioxide concentration together with the decrease
constriction in the pulmonary circulation with a
in O2 is acompanied with a rise in carbonic acid.
subsequent increase in the pressure. The purpose
The condition is called respiratory acidosis or non-
of these changes is to minimize the ventilation-
metabolic acidosis, hypercarbia and hypercapnia.
perfusion inequalities. Chronic vasoconstriction with
The functioning kidneys react to this condition by
increased pressure is a load for the right ventricle,
compensation. Because of the increased level of car-
because it has to eject the blood against increased
bonic acid in the extracellulary space they retain bi-
resistance. This leads to hypertrophy of the right
carbonate ions and excrete hydrogen ions and nonbi-
ventricle, possible consequent failure. The right ven-
carbonate anions.As a result, excretion of acide urine
tricle hypertrophy under changed circulatory condi-
and a useful retention of plasma bicarbonates take
tions in the lungs produces a condition called cor pul-
place. It is clear, that before this compensation, pH
monale chronicum. This complex processes include
in the plasma has been shifted to the acid values. If
also other changes being the consequences of primary
the increase in carbon dioxide tension in the plasma
chronic hypoxia due to hypoventilation. In patients
persits for a long time period, the participation of
with these changes a compensatory polycythaemia
kidneys in regulation of pH of the plasma becomes
and increased vascularisation in peripheral parts of
reduced. The increase in the carbon dioxide ten-
organism develops.
sion stimulates the receptors in the aorta and in the
carotid arteries, resulting in an enhancement of heart When there is pulmonary emphysema with an in-
rate and contraction force, and subsequent changes creased amount of CO2 in arterial blood, it is the
in circulation. manifestation of the terminal phase which lasts for a
The increase in arterial carbon dioxide concen- relatively short time.
tration causes vasodilatation in the cerebral circu- The increase in CO2 during moderate hypoxia can
lation. The blood flow through the brain increases cause a state with complete desorientation, lethargy
too. These changes cause a rise in cerebrospinal fluid or even unconsciousness and death. It is a narcosis
pressure and create conditions for development of induced by hypercapnia.
cerebral oedema. Patients complain of unconfort- Hypoventilation can be caused by several drugs,
able feelings like nausea, headache, tension in the which decrease the sensitivity of the respiratory cen-
head and confusion. Papilloedema or its impact on tre. In this way act anaesthetics, sedatives, hyp-
12 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

notics and strong analgesics. The respiratory centre Restrictive ventilatory disorders arise when a cer-
is depressed also by inhalation of pure oxygen. The tain lung volume is reduced. The hallmark of a re-
changes in bloodflow in the brain stem can also cause strictive disorder is a decrease in the vital capacity.
depression of the respiratory centre. It is necessary to exclude the diagnosis of obstruc-
Alveolar hypoventilation occurs in several patho- tive ventilatory disease, because in this condition the
logical conditions. The underlying cause is the dis- lung volumes are also reduced. There are many pul-
turbance of respiration mechanisms. The causes can monary disorders, disturbances of the control system
be classified as obstructive ventilatory disorders, re- of respiration and alterations of the thorax, causing
strictive ventilatory disorders and the defficiency of restrictive pattern of abnormal ventilatory function.
the pulmonary surfactant. In principle it involves the following conditions:
1. alterations of the chest and muscles of respira-
1.2.2 Distribution of ventilation and tion (kyphoscoliosis, myasthenia gravis)
its disorders 2. lung diseases and related condions (diffuse in-
terstitial fibrosis, pulmonary oedema)
During inspiration the inhaled air passes through the
branching bronchi and bronchioles into the terminal 3. disorders of the pleura
respiratory units – the alveoli. These are situated at
the end of the 26th generation of the bronchial and 4. restriction of the thoracic cavity (tumours, car-
bronchiolar tree. Even in healthy poeple the airflow diomegaly, pneumothorax, haemothorax, pleu-
is not distributed and directed equally into all alveoli. ral effusion)
In pulmonary diseases, the differences in the supply
of air between the alveoli can enormously increase. 5. pneumonectomy
The inequality of ventilation is present also in Obstructive ventilatory disorders are caused by
healthy persons. There are marked differences be- disturbances in airflow. The most frequent cause is
tween the highest and the lowest parts of the lungs. the increase in the resistance in the airways. The
The causes of this vertical gradient are, first of all, test of the forced expiration and especially the ratio
the anatomical arrangement and the impact of grav- of the forced expiratory volume in 1 second to forced
itation on the blood in the pulmonary circulation. In vital capacity (FEV 1/ FVC) provides very useful in-
addition, the mechanisms of ventilation are involved. formation.
During expiration, the lower parts of the lungs are Obstructive ventilatory disorders can be found
drained more intensively. Therefore during inspira- in patients with asthma, bronchitis, emphysema,
tion the lower parts receive more air than the upper bronchiectasis or other diseases narrowing the tra-
parts of the lungs. This mechanism acts during quiet cheobronchial system.
respiration. During exercise (physical work) the ven-
tilation of the lungs increases and is more uniform
than during breathing at rest. The differences be-
1.2.3 Changes in diffusion
tween the distribution of regional ventilation can be Diffusion can be defined as the movement of
estimated by analysis of the expired air after preced- molecules from region of higher concentration to re-
ing inhalation of pure oxygen. Another possibility is gion of lower concentration. Diffusion is a passive
to measure the emission of the radionuclide of xenon process, which does not require any energy. Oxy-
after its inhalation in a low concentration. gen in the lungs diffuses, from the alveolar space
Disturbances of regional ventilation arise easily. into capillaries. The same principle is involved in
When the pulmonary parenchyma is damaged, the tissues during the oxygen diffusion from capillaries
air flows predominantly into the intact parts of lungs, into the adjoining cells. In the same way, however, in
and the damaged areas receive air only to a limited the reverse direction, CO2 diffuses. For the transfer
extent. According to the character of lesion two cate- of oxygen and CO2 chemical reactions are utilized.
gories of abnormal ventilatory function can be distin- O2 is binding with haemoglobin and carbon diox-
guished: restrictive and obstructive ventilatory dis- ide is binding with bicarbonates and partially with
orders. haemoglobin.
1.2. Pathophysiology of respiration and respiratory organs 13

1.2.3.1 Diffusing capacity 1.2.4 Changes in perfusion

The diffusing capacity of the lungs for any gas refers In principle the pulmonary blood circulation has a
to the volume of gas diffusing across the alveolar cap- single purpose. It is the adequate provision of blood
illary membrane per time unit in response to the dif- for the pulmonary capillaries for the exchange of
ference in the gas pressures within the alveoli and gases. The involved processes have to function in
pulmonary capillaries. accordance so that the gas exchange can take place
The diffusing capacity of the lungs can be mea- undisturbed. The blood flow has to be in accord
sured just for oxygen and CO2 , because of their ap- with ventilation. Ventilation has to be in accord with
proximately equal ability to bind with haemoglobin. the metabolic processes in organism. The ventilation
The diffusing capacity cannot be assessed sepa- and blood flow have to be proportionally distributed
rately without the presence of erythrocytes and in the lungs. The processes of ventilation are under
haemoglobin. The volume of the diffusing gas central control. The pulmonary blood flow is not dis-
(e.g. CO2 ) and its bond to haemoglobin per unit of tributed uniformly. There are obvious differences in
time depends on the difference between its pressure the blood flow between single parts of the lungs. The
in alveoli and that in capillaries. The diffusion de- differences in the blood flow under physiological con-
pends on: ditions concern the upper and the lower parts of the
1. solubility and diffusibility in each layer of alve- lungs. In the regions with increased arterial pressure
olar capillary membrane the flow is higher and vice versa. In standing posture
the apical parts of the lungs are perfused minimally.
2. surface dimensions and thickness of the barrier The local perfusion is determined by regional fac-
3. rate of chemical reaction of CO2 with haemoglo- tors. In areas with vasoconstriction induced by hy-
bin poxia, the blood flow is low. As a result, the blood
is passed into the less ventilated areas. Changes in
When the pulmonary blood flow increases, the distribution of the pulmonary blood flow can be
e.g. during muscular exercise, it increases also in the also induced by disorders affecting the vessels, in-
previously nonperfused capillaries. As a result, they cluding the vasculitis, embolism or the compression
dilate and therefore the resultant diffusing capacity of a larger vessel by e.g. tumour, cyst or emphysema.
increases. Increased diffusing capacity and capillary More often they result from vasoconstriction due to
perfusion in the lungs is physiological in people who alveolar hypoxia. The alveolar hypoxia can occur in
live at high altitude. consequece of local changes in ventilation.
The perfusion of the lungs serves for the purpose
1.2.3.2 Changes in diffusing capacity of gas exchange. In addition, the pulmonary circu-
The diffusing capacity can be changed in several lung lation has other very important roles regarding the
diseases. In principle, the thickening of the alve- functions of the whole organism. It represents a filter
olar capillary membrane or a decreased blood flow for the venous blood. It acts as a reservoir of blood
through the capillaries, or both of them, are consid- for the left ventricle. It is involved in the endocrine
ered to play an important role. The most common regulation by changing some substances. Its surface
cause of reduced diffusing capacity is the decrease in is large enough for effective filtration and absorption
blood flow through the capillaries. Embolism of the of many substances.
pulmonary artery or microemboli can exclude from
function a part of the capillary vascular bed. There- 1.2.5 Exchange of respiratory gases
fore diffusing capacity of the lungs is decreased in
these conditions. Also infiltrative processes localized The result of the complex activity of respiratory sys-
in the interalveolar septa are similarly manifested. tem, is a state, when pO2 and pCO2 in arterial blood
They are responsible for destruction of the capil- are within the physiological limits. Respiration is en-
laries (interstitial fibrosis, collagenosis, sarcoidosis). sured by ventilation of the lungs, the distribution of
Reduction of the diffusion surface together with the the inhaled air via the tracheobronchial system to
destruction of capillaries arise in emphysema or after the alveoli, by diffusion and perfusion, and by the
simple pneumonectomy. control of respiration. These processes are mutually
14 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

linked in order to compensate actual deterioration of is a continuous process which takes place within the
some of their parts by other activities. alveolar-capillary membrane. The exchange of respi-
During inspiration the air is warmed, and satu- ratory gases across the alveolar-capillary membrane
rated with water vapours. In consequence, the par- depends on several factors:
tial pressures of N2 and O2 decrease proportionally.
Under physiological conditions, a larger volume of O2 1. adequate ventilation has to procure the neces-
is transferred to the alveoli than that of CO2 removed sary volume and concentration of oxygen in alve-
from them. During all physiological changes the oli (ventilation)
alveolar-arteriolar difference in pO2 is maintained as
2. normal blood flow through the pulmonary cap-
an important factor for the respiratory gas exchange.
illaries (perfusion)
The distribution of inhaled air and the pulmonary
blood flow are not equal or mutually proportional. 3. thickness and quality of the alveolar-capillary
That is the reason why during physiological actions membrane
in healthy people there is a moderate ventilation-
perfusion disproportion. The most frequent cause 4. total surface of the alveolar-capillary membrane
of this imbalance is the arterial hypoxia. Almost
every pulmonary disease is associated with certain 5. relative gradient and solubility of the gases on
ventilation – perfusion abnormalities. both sides of the alveolar-capillary membrane
If some parts of lungs are less ventilated in rela- (diffusion)
tion to their perfusion, the diffusion of O2 decreases.
6. normal affinity of oxygen to haemoglobin.
At the end of capillaries the pO2 is below the nor-
mal. The partial pressure of CO2 tends to increase. The effective exchange of the respiratory gases
The result is that pO2 is lower than pCO2 . In the needs optimum conditions for ventilation and perfu-
hyperventilated parts of lungs are opposite relations. sion. If there is balance in these processes, their ratio
The gas exchange requires certain conditions to is 1.0 or 0.8. Perfusion of poorly ventilated alveoli
be effective and adequate to the actual metabolic decreases the concentration of O2 in arterial blood
situation in organism. The first requirement is the with a simultaneous increase in CO2 concentration.
diffusion of O2 from alveoli to the blood and from When poorly perfused alveoli are well ventilated, the
the blood to tissues. CO2 passes in the same way, dead space becomes larger.
however in a reverse direction. The exchange of res- Several disorders in the lungs which affecting ven-
piratory gases is dependent upon the adequate level tilation or perfusion, are manifested as ventilation-
of alveolar ventilation and perfusion, sufficient gradi- perfusion disproportion. Alveolar hyperventilation
ent of gases, intact alveolar-capillary membrane, and cannot increase the diffusion of oxygen. Oxygen
upon the surface on which the gas exchange takes is bound to haemoglobin and any intensification
place. In addition, the affinity of haemoglobin, espe- of ventilation cannot cause its further binding to
cially to oxygen is a necessary factor. haemoglobin. This is valid exclusively for oxy-
The lung tissue contains an immense amount of gen. During alveolar hyperventilation, CO2 can be
capillaries localized in close vicinity to the alveoli. exspired in a higher amount. In such parts of the
The alveolar-epithelial layer consists of flat type I lungs it leads to normal oxygenation with hypocap-
cells. The function of these cells is to transfer the nia. The blood from such regions is mixed with the
respiratory gases. These cells can be very easily dam- blood from other regions where this disproportion
aged by other gases being toxic. It is of great impor- does not occur. And there is still another fact to be
tance that these cells are not able to regenerate after considered: the binding of oxygen to haemoglobin.
being damaged. In such case, they are replaced by The ability of haemoglobin to bind oxygen at dif-
cells of type II, which are able, in case of need, to ferent tensions of oxygen can be expressed by the
transform themselves to cells of type I. The walls known non-linear dissociation S curve. The affinity
of capillaries and alveoli are separated by a narrow of haemoglobin to oxygen depends on pO2 , temper-
interstitial space. Together they form the alveolar- ature, pH in erythrocytes and the concentration of
capillary membrane.The diffusion of oxygen and CO2 2,3-DPG.
1.2. Pathophysiology of respiration and respiratory organs 15

The respiratory gas exchange disturbance is de- arises when ventilation does not take appropri-
fined as a state, where a disproportion between sat- ate part in the gas exchange (due to excessive
uration of blood with oxygen and elimination of CO2 ventilation or perfusion below average)
at the level of the alveolar-capillary membrane is
present. The disorder of gas exchange results usu- A shunt can be expressed as a part of the heart
ally from changed ventilation-perfusion ratio. The output blood volume, which does not participate in
disturbance of gas exchange may be caused by alter- gas exchange. Following states may be involved:
ations of alveolar-capillary membrane, reduction of
the capillary bed, or change in normal affinity be- • anatomical shunt: about 2–3 per cent of the
tween haemoglobin and oxygen. right ventricular cardiac output passes the pul-
monary circulation circuit and returns to the
left ventricle without being oxygenated, it is the
1.2.6 Ventilation-perfusion blood flowing particularly through the bronchi
abnormalities and pleura
The alveolus in connection with the capillary bed
forms the essential functional unit for exchange of • the capillary shunt: represents the blood which
respiratory gases. On this level several states can flows via entirely unventilated alveoli. It is the
arise: so called true or absolute shunt. The extent of
this shunt cannot be affected by any measure,
• normal respiratory unit: ventilation and perfu- not even by therapy with oxygen.
sion are in equilibrium
• the shunt effect appears when the perfusion is
• respiratory unit as dead space: alveolus is ven- greater than the ventilation; usually due to de-
tilated but the blood flow is reduced or absent creased ventilation or high blood flow velocity
within the pulmonary circulation.
The essential issue in these conditions is that in
• shunt respiratory unit: alveolus is not ventilated bronchial and pulmonary diseases such changes arise
or the ventilation is reduced, the perfusion is which cause the enlargement of dead space and si-
normal multaneously the shunt of pulmonary blood flow.
That is why in the initial phases hypoxaemia is
• excluded respiratory unit: the alveolus and cap- present. pCO2 is usually not increased at the be-
illaries are not functional ginning. If there is a low ventilation-perfusion ratio,
an increased amount of CO2 is expired. The progres-
Extreme situations are presented by respiratory sion of the disease leads later to CO2 retention.
units as dead space and shunt respiratory units. The perfusion of the lungs can be disturbed in con-
Dead space is that part of ventilation which is a com- sequence of haemodynamic changes. Pulmonary em-
ponent of total capacity, yet does not participate in bolism, the decrease in heart output, reduction of the
gas exchange. Total dead space participate in several capillary circulation or the decrease in pulmonary
states: circulation resistance can cause an enlargement of
the dead space.
• anatomical dead space is represented by the con-
ducting airways

• alveolar dead space is represented by alveoli

which are ventilated, but not perfused with
blood

• the dead space effect: arises when the venti-

lation is greater than perfusion; this condition
16 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

The antibacterial capacity of normal secretion in

airways was intensively examined in the past. The
1.3 Pneumonia greatest attention was concentrated on lysosyme,
complement and immunoglobulins. The biological
importance of these factors can be demonstrated
experimentally, however they are of uncertain and
Pneumonia is an inflammatory process affecting probably very little importance for the organism as a
the pulmonary parenchyma. It afflicts the termi- whole. The factor of adhesion of microbes to the sur-
nal parts of airways, the respiratory bronchioles and face of mucous membrane is of greater importance.
the alveolar units. Histological examination reveals The cells of the mucous membrane of airways con-
alveolitis associated with accumulation of exudate. tain several surface receptors for different species of
In majority of cases it is caused by infection. It microbes. Some of the microbes are binding to fi-
spreads to the interstitium surrounding the alveoli. bronectin, which is not an integral part of the cell
Therefore impaired gas exchange occurs in the in- membrane. Its presence can be detected after expos-
volved region of the lungs. Microorganisms can en- ing the mucous membrane to the effect of respiratory
ter the lungs: secretion. Other microbes, on the contrary, adhere
to the cell surface only when fibronectin is removed.
• by direct inhalation of microbes from the air
The anatomical barrier can be surmounted very
• from the mouth and nasopharynx probably during sleep. During sleep aspiration of
oropharyngeal secretion probably occurs. Pneumo-
• by the haematogenous spread from another part nia may develop due to aspiration of as little as
of organism 0.0001 ml of secretion. The aspired secretion can be
removed by the mucociliary system of airways with
• by penetration from the surroundings participation of mucus secreting cells in submucousal
glands and the goblet cells of the mucous mem-
Most often the microbes reach the lungs by inhala-
brane. The secretion, together with the pathogens,
tion from the mouth or nasopharynx. The upper air-
are moved towards the mouth by the cilia. The speed
ways are colonized by a microbial flora consisting of
of ciliar movement is very high (1200 per minute). It
aerobic bacteria like Streptococci, Neisseria, Staphy-
is not quite cleare what a role can be ascribed to the
lococci, Haemophilus. Aerobic gram-negative bacilli
possible resorption of a part of secretion by the mu-
like Pseudomonas aeruginosa, Klebsiella pneumoniae
cous membrane of the airways. The change in the
or Escherichia coli only rarely occur in healthy peo-
secretion viscosity or in the mucociliary system ac-
ple. Numerous anaerobic bacteria occur in gingival
tivity evidently participate in successful elimination
fissures and on the teeth with carious lesions. Un-
of pathogens.
der physiological conditions, balance between the mi-
crobes and the nasopharyngeal mucous membrane is Nevertheless, when undesired particles and infec-
maintained. tious agents reach the terminal respiratory units,
Pneumonia does not usually occur in otherwise another group of defense mechanisms begin to oper-
healthy persons. It can arise due to the disturbances ate. The terminal respiratory units contain neither
of several mechanisms of the defence system consist- the mucociliary system, nor the goblet cells. The
ing of a complex of anatomical barriers, cleansing ac- undesired particles cannot be eliminated from these
tivitity of airways, cellular and humoral mechanisms regions, not even by cough. The clearence of these
in the alveoli. The normal lungs are sterile already regions is dependent on phagocytic cells and humoral
below their first bronchial branching. factors.
The upper airways represent anatomical barriers When the bacteria or dust particles reach the alve-
of mechanical type. The airflow is directed in such olar surface, they are very rapidly phagocytized.
a way, that it is actually filtered. The mucous mem- Phagocytosis differs according to the phagocytized
brane uptakes the particles entering the airways and substrate. The inert particles are phagocytized very
the mucociliary system removes them. The cough rapidly by alveolar macrophages. The undamaged
also participates in the clearing process. bacteria are phagocytized slowly. The opsonization
1.3. Pneumonia 17

of bacteria enhances phagocytosis by ten times. 1.3.2 Inflammatory reaction

The nonimmune opsonines are present in a thin
layer lining the alveoli. It consists of a lipopro- At the beginning the alveolar macrophages are ac-
tein surfactant from pneumocytes of type II, and tivated. After their contact with the pathogen they
fragments of glycoprotein fibronectin, produced by initiate the inflammatory reaction of the organism
alveolar macrophages or delivered from intravascu- in several ways. First of all, it is the production
lar space. of chemotactic factors, particularly leukotriene B4.
This factor acts chemotactically on polymorphonu-
The immune opsonines in the alveoli are IgG
clear leucocytes and affects the permeability of the
antibodies and the complement factor C3b, which
pulmonary capillaries and venules. The polymor-
potentiates the bond to the membrane recep-
phonuclear leucocytes pass through the capillary en-
tors. IgG and its subgroups are present in the
dothelium into the alveoli. Also C3a and C5a com-
bronchioalveolar lavage fluid of healthy people in
ponents of the complement and the components of
an approximately identical amount as in serum.
the kinin system can induce change in the capillary
IgG2 contains antibodies to capsular saccharides of
permeability. By combination of these factors an
the pathogens, namely Streptococcus pneumoniae,
abundant supply of polymorphonuclear leukocytes
Haemophilus influenzae, Staphylococcus aureus and
to the alveoli is ensured. These changes lead usually
to the lipopolysacharides of the gram-negative bac-
to infiltration detectable by radiography. The pro-
teria. IgG1 and IgG4 adhere to the membranes of
duction of interleukin 1 and tumour necrosis factor-
alveolar macrophages. The Fc-gamma receptors of
α by alveolar macrophages cause systemic effects as
macrophages are responsible especially for IgG3 and
chills, fever, myalgia and malaise. The polymor-
to lesser extent for IgG1 binding. The complement
phonuclear leucocytes are useful in the destruction
system can be activated in the airways. It functions
of pathogens. Yet during this process proteolytic
as a barrier against the pathogenic factors.
enzymes are released, being capable to damage the
lung tissue. Through the damaged endothelial cells
1.3.1 Alveolar macrophages and lym- the fluid permeates into the interstitial space. Prote-
olytic enzymes are neutralized by protein inhibitors,
phocytes
alpha 1 antitrypsin and alpha 2 macroglobulin. They
Alveolar macrophages can survive in alveoli months are present in serum and in the secretion of the air-
to years. They are capable to phagocytize and kill ways. In this way the inflammatory reaction is accel-
the microorganisms repeatedly. Besides, they are erated on one hand, and depressed on the other. It is
able to migrate. They pass through the pores to not clear, in what way the reparative arrangements
the adjoining alveoli and migrate to the more proxi- leading to recovery are initiated.
mal parts of the respiratory tract. Macrophages are The state is complicated when interstitial or alveo-
capable to destroy the antigenic material and engage lar oedema develop. Phagocytosis,which has an im-
also the alveolar lymphocytes to participate in this portant role in the development of pneumonia and
process. In addition, macrophages can enter the lym- especially in the elimination of pathogens, can be af-
phatic system and are transported to the regional fected. In the past when antibiotics were not used, a
lymph-nodes, which also participate in humoral and dramatic improvement on the 7th day of pneumonia
cellular immunity responses in the lungs. was often observed. The improvement has been as-
The alveoli contain about 10 % of all lymphocytes sociated with a rapid fall of body temperature. This
which occur in the airways. Two thirds of these lym- state was called crisis or ”the breaking of fever”. It
phocytes are T lymphocytes. One part of the helper was due to antibody production and to change in
T lymphocytes are HLA-DR positive lymphocytes the phagocytosis. Nowadays, due to antibiotic treat-
which produce interleukin 2. This is involved espe- ment, the crisis is usually not observed. Several an-
cially in viral diseases. Several important cytokines tibiotics participate in the killing of pathogenic mi-
produced by T lymphocytes activate the alveolar crobes.
macrophages. The killer T cells can be activated by The major symptoms of pneumonia are the cough,
gamma-interferon and can affect pathogenic germs fever, production of sputum, chest pain and dysp-
directly. noea (tachypnoea). A typical pneumonia usually de-
18 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

velops subsequently to a systemic viral disease. The The contact with pathogenic substance very soon
pathogenic microorganism is Streptococcus pneumo- evokes immediate reaction of organism, character-
niae. In this case high number of neutrophil leuko- ized by an increase in polymorphonuclear leukocytes
cytes and a excessive number of Pneumococci can be in alveoli and terminal bronchioles which is imme-
found in the sputum. diatly followed by an increase in the mononuclear
Pneumonia can be complicated by development of leucocyte number. Later, changes characteristic for
pulmonary abscess. The pulmonary abscess is a con- the repeated contact whit the antigen (reactions of
dition, when the destroyed area of lungs containing type II, or of type IV) occur. In the bronchioalveo-
pus and the necrotic tissue is covered by so called lar lavage fluid T lymphocytes can be observed, or
pyogenic membrane. The necrotic and purulent ma- polymorphonuclear leucocytes, especially in patients
terial cannot be eliminated due to bronchial obtura- exposed for a long time to the effect of antigen. The
tion. Pulmonary abscess can arise also during a neo- findings include also the rise in the numbre of mast
plastic process in the lungs. Yet, it can be induced cells. During asymptomatic period T lymphocytes
by septic thrombi, e.g. in staphylococcal endocardi- (CD4) can be found in the bronchioalveolar lavage
tis localized on the tricuspid valve. More often it fluid.
occurs during aspiration pneumonia. Anaerobic pul-
monary abscess occurs due to purulent processes in The major clinical symptoms are cough, fever
the oral cavity. More often it occurs in alcoholics and dyspnoea. In severe cases cyanosis develops.
and in patients suffering from certain neurologic dis- Chronic forms are progressing and lead to involve-
eases. An abscess can become clinically apparent ment of interstitium. All forms are usually acom-
as a chest pain with fever, intermittent haemoptysis panied with increase in erythrocyte sedimentation
and dyspnoea. The manifestations of chronic ab- rate, C-reactive protein and serum immunoglobu-
scess are less dramatic. Usually the clinical pattern lins. In acute states neutrophilia and lymphopenia
includes productive cough, foul-smelling breath and are usually present.
sputum, dyspnoea, intermittent fever, weight loss, In long lasting process discrete nodular infiltration
anorexia, chest pain. This clinical manifestation re- of the lungs appear which can develop into diffuse
sembles that of the lung gangrene. reticulonodular infiltration.
During the hypersensitive pneumonitis the lung
volumes decrease, the diffusing capacity is impaired,
compliance decreases and during physical effort hy-
poxaemia arises. In advanced states hypoxaemia is
1.4 Hypersensitive pneumoni- present already at rest. Biopsy examination of the
tis lung tissue does not provide any unambiguous pic-
ture which could enable to establish the diagnosis
precisely. In the active phase of the disease an in-
terstitial infiltration can be observed. The infiltra-
Hypersensitive pneumonitis or exogenous allergic tion contains plasma cells, lymphocytes, sometimes
alveolitis is an inflammatory process with the par- eosinophils and neutrophils. In advanced stages
ticipation of the immunity system. It affects the interstitial fibrosis occurs. Chronic forms can be
pulmonary parenchyma, especially the alveolar wall hardly distinguished from other interstitial disorders
and the terminal bronchioles. The confirmation of and from idiopathic lung fibrosis. The spirometric
the diagnosis requires the concordance of the clinical and radiographic examinations, identification of the
state and radiographic findings, together with patho- potential antigen and detection of antibodies are very
physiological changes and the immunologic criteria. important for determination of the clinical stage of
The etiologic agents include several substances oc- the disease. The therapy is based on glucocorticoids,
curing in the external environment. Often it is or- however the elimination of the causative antigen from
ganic dust of various origin or the components of environment or entire alteration of the living and
agricultural production. In one third of cases the working environment of the patient are the most ef-
underlying cause are fungi. fective therapeutical measures.
1.5. Pulmonary disorders caused by harmful substances in the inhaled air 19

1.4.1 Eosinophilic pneumonias

It is a group of diseases, which have a common 1.5 Pulmonary disorders cau-

characteristic sign-eosinophilic lung infiltration and sed by harmful substances
eosinophilia in the peripheral blood.
in the inhaled air
• Allergic bronchopulmonary aspergillosis. The
most common causative agent is Aspergillus fu-
migatus. The radiographic examination can re- It is a very important problem for the poeple ex-
veal infiltrations and bronchiectasis. posed to a long lasting effect of unfavourable factors
which get into the atmosphere by various human ac-
tivities.
• Tropical eosinophilia. It is usually caused by fi-
larial infection. A similar type of damage can be 1. Inorganic dust
seen also in other parasitic diseases as ascariasis,
toxocariasis and others. Asbestosis Asbestos is a material, consisting of
several mineral substances. In people working with
asbestos, pneumoconiosis occurs (lung fibrosis), and
• Drug induced pneumonias – arise often after also higher occurence of malignant diseases of respi-
nitrofurantoin treatment. Diffuse lung infiltra- ratory system and pleura is observed (less frequently
tions can be observed. A similar picture can also malignant tumours of peritoneum).
arise after sulphonamides, penicillins, chlorpro- Asbestosis is a diffuse interstitial fibrosis of the
mazine, hydralazine and other drug therapy. lungs, which develops due to the exposure to as-
bestous dust. Usually it appears after a ten-year
lasting exposure.
• The Loeffler‘s syndrome is an acute benign The inhaled particles of asbestous dust reach
pneumonia characterized by migrating lung in- the alveoli due to their small size, where they
filtrates with minimal clinical manifestations. are phagocytized by macrophages. The phagocyto-
sis of asbestic particles damages the membrane of
macrophages. This damage results in the release
• Chronic eosinophilic pneumonia with lung infil- of lysosomal enzymes injuring the lung parenchyma.
tration is presented by symptoms as fever, chills, The clinical manifestations correspond with the gen-
nocturnal sweating, cough, anorexia, weight eral charateristics of other types of lung fibrosis. Fi-
loss. Sometimes it occurs in patients with brotic changes cause obliteration of acinary units. A
bronchial asthma. typical honeycomb-picture of the lungs is formed.
The exposure lasting for 15–20 years leads very
often to pulmonary cancer. Simultaneous smoking
• Alergic angiitis and granulomatosis. It is a mul- increasis the risk of cancer.
tisystemic vasculitis, present in the skin, kid- Long-term exposure to asbestous dust is usually
neys and nervous system. The lungs are also associated with the occurance of pleural or peri-
involved. toneal mesotheliomas. About 80 per cent of pleural
mesotheliomas are usually associated with asbesto-
sis.
• The hypereosinophilic syndrome. Marked e-
osinophilia in the peripheral blood without
Silicosis This condition develops by effect of parti-
any parasitic or allergic disorder is present.
cles of SiO2 which are produced in the processing of
Eosinophilic infiltrates occur in the heart, lungs,
flint and during several abrasive industrial technolo-
liver, spleen, skin and nervous system.
gies. In badly ventilated factories (working in tun-
nels) silicosis can develop already after 10 months of
20 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

exposure. It can be lethal in less than 2 years. Sil- Byssinosis The condition develops due to the ef-
icosis usually develops in the course of 15–20 years. fect of organic dust present in air during production
By histological examination an interstitial fibrosis of of yarn of cotton, flax, hemp and jute. The clini-
lungs is observed, caused by the particles of SiO2 . In cal manifestations are dominated by a change in the
some cases it can develop as a nodular fibrosis with lung function indicating an obstruction of airways.
a perinodular emphysema. The character of the af- It is probably caused by the release of histamine.
fliction is determined by different perceptiveness of
the individual parts of the lungs to causative agents. The farmer’s lung In most cases it is an acute
The progression of silicosis can result in respiratory state, which develops after 4–8 hours of exposure.
failure. The clinical manifestations are dominated by fever,
cough and dyspnoea without wheezing. The farmer’s
lung is a form of exogenous allergic alveolitis (hy-
Anthracosis This condition arises in one half of
persensitive pneumonitis), occuring in agricultural
all coal miners after 20 years of exposure. The com-
workers. During their work they are in contact with
bination of the coal dust and smoking is very un-
thermophil actinomycetes (in mouldy hay or straw).
favourable. The development of fibrosis is the conse-
Organic dusts occur also in consequence of indus-
quence of the crystalline SiO2 presence in inhaled
trial production, particularly the production of plas-
aerosol. It is called anthracosilicosis. It reduces
tic materials. During the plastic material produc-
significantly the diffusing capacity of the lungs and
tion, especially polyurethans, chronic cough can de-
leads to premature mortality. It is not quite clear
velop in workers after prolonged exposure. The se-
why in some cases the fibrosis is accelerated enor-
cretion of mucus increases and asthma bronchiale re-
mously (the progressive fibrosis of the lungs). A
sembling conditions occur.
great amount of dust can also act as an unfavourable
factor. In this case the clearing mechanism of the 3. Carcinogenic substances in the air
mucociliary system fails.
It is interesting that the production of collagen Information on carcinogenic substances in the
is minimal in a pure coal pneumoconiosis. In min- air are gained on the basis of epidemiological ob-
ers in coal-mines the Caplan’s syndrome has been servations of people working in specific environ-
described. It is a seropositive rheumatoid arthritis ments. Several observations were confirmed in ex-
accompanied with progressive lung fibrosis. Usually periments with animals. During processing of or-
antinuclear antibodies and an increased level of gam- ganic materials one of the intermediary products
maglobulins are present. bis(chlormethyl)ether occurs. The experiments on
animals have proven its carcinogenic qualities. How-
ever, more often the compounds of chrome, nickel,
Berylliosis Beryllium can induce an acute pneu- uranium, oxides of iron, and several organic sub-
monitis or chronic interstitial pneumonitis. In biop- stances are involved.
tic material granulomatous formations resembling
those in sarcoidosis can be observed. 4. Air pollution
Generally, the interstitial fibrotic alterations in Air pollution represents a very important problem,
lungs can be caused by different kinds of inorganic namely the active and passive smoking and the nox-
dust. Some dusts act by their irritant effect on the ious gases and substances dispersed in the air. For
mucous membrane. As a result a chronic hypersecre- some of them the lungs serve just as the site of en-
tion of the mucous membrane and chronic brochitis trance into the organism. The lungs need not be
develop. evidently damaged. E.g. benzene enters the organ-
ism through the lungs. Its target organ is, however,
2. Organic dust the bone marrow. There are many similar examples.
That is why the fact, that some inhaled substances
The organic dust usualy causes hypersensitive do not damage the lungs is of no significant value in
pneumonitis and is involved also in the pathogenesis reference to their malignant influence on the organ-
of asthma bronchiale. ism.
1.6. Chronic diseases of the airways 21

• impairs the clearing function of the mucociliary

system
1.6 Chronic diseases of the • reduces the resistance toward infections of respi-
airways ratory system by damaging the alveolar macro-
phages
Microscopical analysis of the airways reveals en-
largement of mucousal folds in large airways. Rather
Chronic airways disease represent a group of dis- hyperplasia than hypertrophy of the cells of the sub-
eases attacking the airways, yet their clinical man- mucous glands is involved. Inflammatory alterations
ifestations and states are not strictly defined and of various degree can be observed. In the obstruc-
specified. This group includes diffuse disorders of tion of small bronchioles participates also the ac-
the airways: cumulated secrete. Microscopic examination shows
1. simple and obstructive chronic bronchitis centrilobular emphysema although clinical manifes-
tation of emphysema is not present. Symptomless
2. pulmonary emphysema smokers have usually this histological findings al-
though their state can be clinically considered as
3. bronchial asthma physiological. The cause of these changes in smokers
is not clear.
1.6.1 The simple and obstructive Three main factors participate in the obstruction
of airways. The first is the chronic inflammation.
chronic bronchitis It leads to structural changes in the mucous mem-
The simple chronic bronchitis is characterized by brane of airways, inducing increased resistance of air-
a chronic productive cough. It is caused by a ways toward the air flow. The second factor is the
pathogenic factor irritating the airways, neverthe- bronchoconstriction due to the inflammatory pro-
less, hyperreactivity of airways is not involved. The cess. The third factor is the gradually developing
clinical symptomatology is represented by: decrease in lung tissue elasticity.
Clinical manifestation of chronic bronchitis is the
• excessive production of mucus (expectoration of cough. Typical is that it occurs in the morning af-
the mucus) ter getting out of bed. Very often the cough appears
following the smoking of the first morning cigarette.
• cough lasting for three months in course of two The cough is productive, the patient expectorates a
or more following years mucous sputum. At the end of this expectoration
wheezing can occur. It is caused probably by bron-
• the abscence of bronchiectasis, tuberculosis or
chospasm induced by the cough. If the sputum is
any other cause of mentioned symptoms
purulent, in cultivation are Haemophilus influenzae
The individual symptoms can be of varying inten- and Streptococcus pneumoniae found. In this case is
sity. Some patients are almost symptomless. With the term muco-purulent bronchitis more convenient.
the exception of smoker’s morning cough they have It is necessary to exclude a neoplastic process. Cough
no troubles. can be provoked by every respiratory manoeuvres.
The simple chronic bronchitis can be found in Patients with chronic bronchitis often have over-
about 10–25 per cent of the adult population. The weight and are usually cyanotic. The right ventricu-
productive cough can be more often observed in men lar hypertrophy is often present. Alveolar hypoven-
than in women and more often in persons older than tilation and hypoxia cause pulmonary vasoconstric-
45 years. The criteria of chronic bronchitis are ful- tion and increased blood pressure in pulmonary cir-
filed by almost every smoker over 45 years of age. culation. After a certain time the muscularization of
The pathogenic factor present in the inhaled air: arterioles and fixed high pressure in pulmonary circu-
lation occur. The condition can progress until a right
• stimulates the secretion of mucus in the mucous heart failure develops. Hypoxia stimulates erythro-
membrane of airways poiesis. Polycythaemia intensifies the cyanosis and
22 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

increases the pulmonary hypertension by increasing ing, that patients with inherited deficit of alpha-
the blood viscosity, which overlaods the right ventri- 1-antitrypsin have a very marked and progressive
cle, and thus the circulus vitious closes. panacinar emphysema. In the airways and in serum
of these patients is either a very low level of alpha-
1.6.2 Pulmonary emphysema 1-antitrypsin or it is absent completely. The defi-
ciency of this antiprotease factor enables the elestase
It is characterized by an abnormal and permanent from neutrophil leukocytes to act. In smokers are
distention of alveoli. This enlargement is usually also the levels of other inhibitors of elastase de-
associated with destruction of alveolar walls with- creased. The cigarette smoke inactivates the in-
out the development of fibrosis. The destruction of hibitor of alpha-1-proteinase. In addition, smoking
capillaries can be the underlying cause of pulmonary influences unfavourably the reparative processes in
hypertension development. In consequence of these the lungs (Fig. 1.1).
changes the elastic qualities of the lung tissue de-
crease leading to the collapse of airways during ex-
piration. As a result the obstruction of airways and
increase in their resistance develop which is mani-
fested during the expiration by air retention in alve-
oli. This condition could be termed as chronic ob-
structive pulmonary disease. From this point of view
the described emphysema would be the type A of
chronic obstructive pulmonary disease. Obstructive
bronchitis without emphysema would be the type B.
The prevalence of pulmonary emphysema in the
industrially developed countries is very high. In
necroptic findings evident signs of emphysema can
be found in 65 per cent of deceased men and in
15 per cent of deceased women. The relation be-
tween smoking and destruction of alveolar septa is
proved. Several factors however participate in the
process of destruction. Smoking increases the num-
bre of polymorphonuclear leucocytes and pulmonary
alveolar macrophages in the lungs. The underlying
cause can be the fact that the cigarette smoke stim- Figure 1.1: Pressure changes in lungs in obstructive
ulates the pulmonary alveolar macrophages. These bronchitis and in emphysema
cells produce chemotactic factors which attract poly-
morphonuclear neutrophils. Several components The genetically conditioned deficiency of alpha-
of the cigarette smoke induce the release of elas- 1-antitrypsin occurs in 2 per cent of patients with
tase from polymorphonuclear neutrophils. Also the chronic obstructive pulmonary disease. Family ag-
macrophages, stimulated by the cigarette smoke, en- gregation of this disorder has been demonstrated.
hance their own secretion of enzymes similar to elas- This deficiency is transmitted as an autosomal re-
tases. The elastases of polymorphonuclear leuko- cessive trait. In heterozygotes a moderately reduced
cytes and pulmonary alveolar macrophages can cause autoproteolytic activity in serum is found.
destruction of cells and the alveolar elastic net. This The destructive processes result in the alveolar
situation is in fact a load for the lungs with ex- septa destruction, hence leading to reduction of the
cess of elastases (proteases) which have to be contre- respiratory surface. The involvement is usually not
balanced by the antiprotease system of the lungs. homogenous. In centrilobular emphysema the de-
So on the one hand the proteases are released, and struction is localized mainly in the central parts of
on the other hand the antiprotease system is present. the lobules. In panacinar form the lesion is almost
The conception of the protease and antiprotease the- diffuse. In the large airways inflammatory changes
ory gained a support especially based on the find- are present. The airways are narrowed, there are
1.6. Chronic diseases of the airways 23

signs of obliteration and the bronchioles are filled bronchi to various stimuli and by a reversible bron-
whith mucus closely adherent to the lumen. choconstriction occuring in attacks, with expira-
The clinical symptomatology is dominated by dys- tory dyspnoea, cough and a noisy breathing asso-
pnoea. At the onset of disease the dyspnoea occurs ciated with wheezing during the attack. Wheezing
during physical exertion, later it appears already at is caused by turbulent airflow through the narrowed
rest. The patients are asthenic. Cyanosiss is present airways which contain abundance of viscous secre-
only in the terminal stages. The examination of the tion. During the attack the resistance of airways
lungs reveals hyperinflation. increases 5–6 times in comparison with physiological
Chronic bronchitis and emphysema develop as two conditions. The vital capacity is usually reduced bel-
distinct processes usually simultaneously. The whole low 50 per cent. During the attack simulataneously
development of disease can be temporarily or per- both, hyperinflation and atelectasis can be observed
manently dominated by one of these processes. The on chest radiogram. The patient is usually restless
inflammatory processes of the airways, increased se- and anxious, he may be confused in consequence of
cretion of mucus and bronchospasm can reach dif- hypoxia. Especially in the beginning of disease, be-
ferent intensities. Similar to chronic bronchitis, also sides the attack, the patient is usually symptomless.
the emphysema causes obstruction of airways and Gradually a state of a moderate, yet permanent ob-
decrease in the lung tissue elasticity. The narowing struction of airways may develop. Also in this state
of the airways is associated with an increase in the attacks occur, during which bronchoconstriction is
resistance and decrease in velocity of the air flow dur- intensified.
ing expiration, which can be detected by functional The reversible disorder of small airways is a com-
examination of the lungs (Fig. 1.1 and Fig. 1.2). bination of bronchiolar smooth muscle contraction,
and of bronchial mucous membrane oedema due to
increased permeability of capillaries and cellular in-
filtiration. The hypersecretion of viscous mucus con-
tributes to this state.
Bronchoconstriction dominates the clinical man-
ifestation of asthma. Bronchoconstriction can be
caused by several different factors. That is why
asthma is a heterogenous disease with various etiolo-
gies. In spite of considerable differences more types
of asthma can be distinguished according to the dom-
inating factor:
• Bronchial asthma is often in a close relation to
allergic disease as allergic rhinitis, urticaria and
eczema. There is a positive reaction to aller-
gens and increased level of IgE in the serum of
patients.
• In other cases neither relation to allergy nor in-
creased level of IgE in serum can be found. Ex-
actly defined immunologic mechanisms are not
considered to play a role in pathogenesis of this
Figure 1.2: Forced expirium curve in functional ex- type of asthma bronchiale.
amination of lungs • In many patients the allergic components are
present just at the onset of the disease. These
patients belong later to the non-allergic group,
1.6.3 Bronchial asthma or to the group with mixed etiology.
Bronchial asthma is a disease of airways charac- The common sign of various types of bronchial
terized by increased responsiveness of trachea and asthma is the non-specific hyperirritability of trachea
24 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

and bronchi. Generally the reactivity of the respira- In asthma the constriction of bronchial smooth
tory system in persons with, or without asthma is muscles, thickening of the mucous membrane and
increased after viral infections, after exposure to dif- presence of mucus in the airways are always taken
ferent oxidative substances e.g. ozone, and after the into consideration. Until now, most attention was
application of the exogenous platelet activating fac- devoted to the constriction of the smooth muscles
tor. Allergens are capable to increase the reactivity elicited very probably by the release of bioactive me-
of the airways within minutes. It can persist for sev- diators or neurotransmitters. Explanation of the re-
eral weeks. lease mechanism of these molecules remains merely
speculative.
After being inhaled, the allergens get in contact
with the molecules of IgE, which are bound to the 1.6.3.1 The participation of mediators
surface of mast cells, dispersed in epithelial luminal in asthma development
surface of airways. Degranulation of mast cells arises,
thus the mediators for the antigen-antibody reaction Histamine (beta-imidazolyl-ethylamine). It is the
are released. Mast cells contain preformed mediators oldest substance known to have the bronchoconstric-
or precursor molecules of these mediators: histamine, tive effect. The greatest amount of histamine is pro-
kinins, kininogens, thromboxanes, leukotrienes C4, duced by mast cells which are abundant in mucous
D4 and E4, eosinophil chemotactic factors of ana- membrane of airways. Histamine evokes bronchocon-
phylaxis (ECF-A), heparin, superoxide dismutase, striction also indirectly by affecting the endings of
prostaglandins PgG2, PgF2 alpha, PgD2, platelet nervus vagus.
activating factor, neutrophil chemotactic factor of Acetylcholine. Acetylcholine is released from
anaphylaxis (NCF-A), inflammatory factors of ana- the itrapulmonary endings of vagus nerve branches.
phylaxis, chymotrypsin, trypsin and many other en- Acetycholine causes directly constriction of smooth
zymes. These enzymes can cause or contribute to muscles by stimulation of the muscarinic receptors.
the destruction of tissue closely surrounding the mast The effect of atropine derivates in the therapy of
cells. An intense inflammatory reaction with bron- asthma confirms the importance of acetylcholine in
choconstriction and increased permeability of the the pathogenesis of asthma.
capillaries, with congestion of the vessels and devel- Kinins. Bradykinin and other molecules with sim-
opment of oedema can occur after the release of sev- ilar effect are released from plasmatic precursors by
eral mediators. Simultaneously the enzymes evoke proteolytic effect of kallikrein. One type of kallikrein
a long lasting contraction of airways smooth mus- is released from mast cells during their activation.
cles and oedema of the mucous membrane. The re- Besides inducing the bronchospasm, it increases also
leased leukotrienes increase the production of mucus the permeability of capillaries and accelerates the de-
and impair the mucocciliary transport. Chemotac- velopment of oedema. In the clinical practice no sub-
tic (eosinophil and neutrophil) factors of anaphylaxis stances are used which would influence the produc-
and leukotriene B4 attract eosinophils, thrombocytes tion and the efect of kinins.
and polymorphonuclear leucocytes to the site of mast Adenosine. Adenosine is formed from ATP during
cells stimulation. Eosinophils are very important. the metabolism acceleration. Above all, the bron-
After being activated they can produce leukotriene chodilatatory effect of theophylline- an adenosine
C4 and the platelet activating factor, thereby they antagonist- indicates that adenosine participates in
contribute directly to the narrowing of airways and the pathogenesis of asthma bronchiale. Theophylline
development of mucous membrane oedema. Vice is an inhibitor of phosphodiesterase. That is why the
versa, the eosinophils activate the mast cells to re- concetration of cAMP is increased. The increased
lease histamine and chemotactic factors. As a result, ratio cAMP/cGMP has a bronchodilatatory effect.
additional accumulation of eosinophils takes place (The majority of bronchoconstrictive substances act
and a circulus vitiosus arises. Eosinophils are the by increase of cGMP).
source of electrically charged proteins, which inhibit Leukotrienes. The leukotriene LTC4 , LTD4 , LTE4
the motility of cilia and impair the integrity of the (formerly called the slow reacting substance of ana-
mucous membrane, and cause exfoliation of epithe- phylaxis – SRS – A), and LTB4 are formed from
lial cells into the bronchial lumen. the arachidonic acid after its release from cellular
1.6. Chronic diseases of the airways 25

membranes. Mast cells, eosinophils and alveolar It can act as a triggering factor, or a factor support-
macrophages can produce them. The molecules of ing the persistence of bronchial asthma. Emotional
LTC4 and LTD4 are three thousand times more ef- hyperventilation plays a certain role as well.
fective in bronchoconstriction than histamine.
PAF-platelet activating factor. It is a phospho- 1.6.3.2 The histological findings in asthma
lipid produced by several cells, which take part in
the development of inflammation. It is produced by Necroptic examination shows hypertrophy of smooth
mast cells and eosinophils. It acts as a bronchocon- muscles in bronchioles, hyperplasia of the mucosal
strictive agonist by activation off specific receptors. and submucosal vessels, oedema of mucous mem-
Tachykinins are small peptides (substance P, neu- brane of bronchi and bronchioles, denuded epithe-
rokinin A, neurokinin B), released from specific nerve lial surface, pronounced thickening of the base-
endings. Activation of specific receptors can cause ment membrane and eosinophilic infiltration in the
constriction of smooth muscles and secretion of mu- bronchial wall. Sometimes also mucous cylinders can
cus. These peptides are very rapidly degraded by be found in bronchioles. Typical emphysematous tis-
action of specific peptidases. sue destruction is not observed.
From the pathophysiological standpoint, the main
There are several ways to induce the constriction of
cause, responsible for typical alterations in asthma
bronchial smooth muscles. Bronchocostriction dom-
is the reduced lumen of airways caused by contrac-
inates the clinical picture, however its underlying
tion of bronchial and bronchiolar smooth muscles.
causes can be considerably diverse.
In addition, the wall of bronchioles is oedematous,
Many drugs can induce asthmatic episodes. The
the mucous membrane is covered with a closely ad-
most known is the effect of acetylosalicylic acid,
herent secretion. The deterioration of pulmonary
very probably by interference in the metabolism of
functions is considerably diverse. Certain changes
arachidonic acid with leukotriene formation. Yet
usually dominate in patients leading to almost the
also other non- steroid anti-inflammatory drugs, beta
same consequences: increased resistance of airways,
adrenergic antagonists (blocking the ”dilating” beta-
decreased volume of air in forced expiration, hyperin-
receptors), dyes and other substances can induce
flation of the lungs, an increased work of breathing,
asthmatic attacks. The mechanism how they evoke
changes in elasticity of the lungs, abnormal distri-
the episodes is not precisely known.
bution of the pulmonary ventilation and perfusion,
In large urban agglomerations with a high con- and a change in saturation of blood with oxygen and
cetration of noxious substances in the atmosphere CO2 . Asthma is characterized by a primary disorder
the manifestation of respiratory disorders arise also of the airways. The changes result in a series of alter-
in healthy population, and patients suffering from ations ending with hypertrophy of the right ventricle
bronchial asthma can develop attacks. and pulmonary hypertesion. During the attack the
There are numerous substances with bronchocon- vital capacity decreases to, or below 50 per cent of
strictive effect in our surroundings: the salts of heavy normal. The forced expiratory volume per second is
metals, wooden dust, pollen, components of plastic about 30 per cent and the airflow rate reaches just 20
materials, animal hairs and secretions. In some cases per cent of the normal values. The residual volume
specific IgE is produced. The noxious substances of the lungs is enormously increased. It can reach
from the surroundings can also directly release bron- 400 per cent in comparison with the norm.
choconstrictive substances. During the attack hypoxia, hypocapnia and respi-
Infections of the respiratory system may evoke ratory alkalosis are observed. Absence of hypocap-
asthma. The triggering mechanism can include phys- nia signalizes a very severe obstruction of airways.
ical exercise. During physical exercise the pul- Similarly,the metabolic acidosis appearing during an
monary ventilation increases. The inspired air is asthmatic attack is a sign of marked obstruction of
colder and less saturated with water vapours. That the airways. The volume of respiratory gases in
is why the winter sports are more provocative than blood per se does not correlate with the clinical pic-
e.g. swimming. ture.
An emotional stress can, in some patients, repre- Cyanosis occurs in patients very late. Other im-
sent an important factor of bronchial constriction. portant symptoms, like retention of CO2 , tachycar-
26 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

dia, tachypnoea have a high predictive value. It is tive bronchodilator. It prevents the adenosine for-
very hazardous to judge the state of the patient just mation and inhibits its receptors.
according to the clinical symptomatology alone. It is Antihistamines act as antagonists of H1 receptors.
inevitable to measure the tension of respiratory gases They block the effect of histamine on smooth muscles
in blood. of airways.
Clinical symptomatology is always represented by Anticholinergic drugs inhibit the release of acetyl-
a triad of symptoms, which are constantly observed choline from nervus vagus endings in the airways.
: dyspnoea, cough and wheezing. They are always The effect of atropine is known for more than a hun-
present during the attack in advanced phases of the dred years.
disease. Atacks often occur at night. The cause is Substances acting as antagonists of LTD4 and PAF
not quite clear. It may reflect the circadian vari- receptors are tested nowadays. The glucocorticoids
ations in catecholamine and histamine levels or the are widely used in the therapy of asthma. These
increased tone of parasympathetic nervous system at drugs reduce the allergic and inflammatory reactions,
night. During the attack the expiration is prolonged, decrease the numbre of cells participating in the de-
tachypnoea, tachycardia and increased systolic pres- velopment of inflammation. They can be applied
sure are present. Sometimes also an unproductive also by inhalation. The bronchoconstriction is influ-
cough occurs. The lungs are overfilled with air, enced indirectly, mediated by mitigation of the mu-
the back to front diameter of the thorax increases. cous membrane inflammation.
The retained air in lungs increases the pressure in
the thoracic cavity. That is why the breathing be-
comes more difficult, the patient is restless, cyanosis,
tachycardia and increased filling of jugular veins
may occur The episode of attack usually ends with
1.7 Bronchiectasis
coughing out some viscous sputum, containing cylin-
ders of mucus formed in distal parts of bronchioles
(Curschmann’s spirals – i.e. cylinders from the bron-
Bronchiectasis is an irreversible dilatation of one,
chioles, consisting of mucus and cells), eosinophils
or several bronchi. Dilatation is caused by destruc-
and Charcot-Leyden crystals (crystallized proteins of
tion of the bronchial elastic-muscular wall. It occurs
eosinophils).
usually as result of a chronic inflammatory process.
Sometimes the cough during the attack may be in- The surroundings of the bronchus are affected by in-
effective. The mucus can obturate some bronchioles flammatory alterations leading either to destruction
and as result atelectasis in some areas of the lungs of the bronchial wall, or they develop secondarily due
occurs. Pneumothorax is a very rare complication. to the stagnation of the secretion. Before the era of
An attack of bronchial asthma has to be distin- antibiotics bronchiectasis was an incurable disease,
guished from other diseases associated with dysp- which participated not only in morbidity, but also in
noea. Wheezing occurs also in other endobronchial mortality of patients suffering from infections of the
diseases (neoplasms, aspiration of foreign bodies), or respiratory system.
in bronchial stenosis. An attack of bronchial asthma In addition to the infections associated with the
can resemble the acute failure of the left ventricle. destruction of bronchial wall there are other al-
During the left ventricle failure gallop rhythm occurs terations and disturbances (long lasting obstinate
and the sputum is sanguinolent cough) which participate in the development of
bronchiectasis. Several disorders of mucociliary func-
The therapy of asthma is aimed, above all, at the tion form favourable conditions for bronchiectasis
elimination of bronchoconstriction. The relaxation development. Dyskinesis of cilia or the complete
of bronchial smooth muscles can be induced by stim- absence of their motility may be transmitted as an
ulation of beta 2-adrenergic receptors. Several sub- autosomal recessive trait (primary ciliary dyskinesis,
stances having these effects are used in therapy of immotile cilia syndrome). In men with this disor-
asthma (fenoterol, salbutamol, terbutaline). der sterility occurs because of absence of the sperm
Theophylline is also used as an moderately effec- cell motility. Also in women decreased fertility ap-
1.7. Bronchiectasis 27

pears because the cilia of the oviducts are affected, can be complicated by a decrease in function of mu-
and the tubal pregnancy occurs more often in such cociliary system, or by immunodeficiency. Dilatation
cases. These poeple are predisposed to the respira- of bronchi occurs in central parts of the respiratory
tory system infections. The absence of the clearing system. The bronchodilatation can reach fourfold di-
mechanism of mucociliary system participates in the mensions in comparison with those under physiolog-
development of infections. Also providing the phago- ical conditions. Peripheral parts of lungs are poorly
cytosis is intact, problems occur due to the fact that ventilated. The stagnation of the secretion, the dis-
the waste of phagocytosis is not removed. In patients turbance of the mucociliary system function and the
with the Kartagener’s syndrome a triad of symptoms proteolytic activity of polymorphonuclear leucocytes
due to immotility of cilia is observed i.e. sinusitis, participate in the progressive destruction of the tis-
bronchiectasis and complete situs viscerum inversus. sue. Purulent secretion contributes to the destruc-
(Situs viscerum inversus occurs most often in pres- tion of tissue by its high content of proteases (elas-
ence of ciliar dyskinesia). In the embryonal tissues tase, collagenase, katepsine G). The mucous mem-
the motility of cilia is a condition allowing normal ro- brane in the dilated part of bronchi is oedematous,
tation of organs. If the ciliar motility is absent, the inflammed, with possible necrotic defects. Granulo-
rotation of organs is accidental, and the dextroro- matous tissue can be produced.
tation and the sinistrorotation are equally frequent.
According to radiographic findings three types of
bronchiectasis can be distinguished :
Bronchiectasis occurs also in patients with cystic
fibrosis when the lungs are involved. In cystic fi- • cylindric bronchiectasis
brosis the secretion of exocrine glands is disturbed.
Production of viscous secretion aids the development • varicose (fusiform) bronchiectasis
of infection.
• saccular or cystic bronchiectasis
Bronchiectasis occurs in immunodeficient condi-
tions due usually to defective humoral immunity. In saccular bronchiectasis the preformed cavities
Bronchiectasis occurs especially in patients with are filled with pus. It can reache the peripheral re-
agammaglobulinaemia. The cause resides in greater gions of lungs.
disposition to repeated infections and their progres-
sion. Bronchiectasis is associated often with cough of
paroxysmal type. In the morning after awakening
Bronchiectasis occurs also after necrotising pneu- expectoration increases. It occurs in 90 per cent of
monia and in allergic pulmonary aspergillosis. patients. About 50 per cent of them have haemop-
Bronchiectasis occurs in an infrequent yellow nail tysis. The disturbance of respiratory function de-
syndrome. It is a combination of lymphoedema pends on the anatomical type and the extent of
of lower extremities, reccurent pneumonia and yel- bronchiectasis. In advanced cases also dyspnoea can
low nails. There is also a so called poststenotic be present. In extensive bronchiectasis, hypoxia can
bronchiectasis. In such case stagnation of secretion develop usually without hypercapnia. The diagnosis
occurs and bronchiectasis develops due to the steno- is confirmed by X-ray examination of the bronchial
sis of the bronchial lumen (caused by e.g. tumor, tree, by bronchography and computed tomography.
foreign body or pressure of enlarged lymph-node in The cultivation of sputum enables an aimed causal
hilus). The so called cirrhotic form arises by me- antibiotic treatment. Such a therapy minimizes the
chanical traction developed in the surroundings of respiratory dysfunction and the progression of the
bronchus due the fibrotic alterations of lungs (fibrotic disease.Bronchiectasis can be complicated by gradu-
tuberculosis, diffuse pulmonary fibrosis and sarcoido- ally developing pulmonary hypertension and cor pul-
sis). monale chronicum.

At the onset of the development of bronchiectasis

an infectious or chemical pathogen is always present.
Damage of the epithelium develops. The situation
28 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

1.8 Cystic fibrosis (of the

lungs)

It is an inherited disorder, which has the charac-

ter of a multisystemic disease. Its essence resides in
abnormal function of exocrine glands. Almost every
patient with this disorder develops a chronic progres-
sive disease of the respiratory system which is the
most frequent cause of the morbidity and mortal-
ity in patients with cystic fibrosis. Besides the pul-
monary manifestation pancreatic dysfunction, hep-
atobiliary and urogenital disturbances can occur in
cystic fibrosis.
The ”cystic fibrosis gene” is localized on the long Figure 1.3: Disturbed transport of Cl− ions in cystic
arm of chromosome 7 . The genetic defect causes fibrosis
a disturbance in secretion of chloride ions. Under
physiological conditions the channels for the chloride
ions on the luminal side of epithelial cells are closed. flation of the lungs. Often bronchitis is present and
When the channels are open, chloride ions enter the bronchiectasis develops. The altered secretion causes
lumina of the glands. In this manner a concentration an obstruction of small airways, resulting in atelec-
gradient is produced attracting water into the lumen. tasis of the lung tissue. The oxygenation in the or-
The disorder of secretory cells concerns the release ganism is impaired and pulmonary hypertension de-
of chloride into the secretion. In the ductal (drain- velops. Besides, in some patients hyperreactivity of
ing) part of the glands the reabsorption of chloride the airways can be observed.
from the secretion is simultaneously decreased. The Patients with cystic fibrosis have an evident distur-
anomalous secretion of glands in the airways, but bance of pancreatic exocrine function. It is usually
also in other organs, contains an inadequate amount present in 95 per cent of patients. It leads to malab-
of water. The physical qualities of the mucous secre- sorption, steatorrhoea, deficiency of fat-soluble vita-
tion and the secretion of other glands are changed. mins and B12 vitamin (protein intrinsic factor does
That leads to an uncontrollable secretion of macro- not release the vitamin B12 because it cannot be hy-
molecular substances (glycoproteins and other sub- drolyzed by proteases and this situation results in
stances). The ”cleansing” function of the secretion megaloblastic anaemia). Sometimes biliary cirrhosis
is disturbed. These changes determine the develop- of the liver occurs, probably because of bile stagna-
ment of clinical manifestation (Fig. 1.3). tion due to its increased viscosity.
In the early post-natal period gastrointestinal dis- The sweat glands in the skin are anatomically un-
orders dominate. In the newborn children the inspis- changed. Just the analysis of sweat can show dif-
sated meconium can evoke the symptoms of intralu- ferent concetrations of sodium and chloride, which
minal obstruction. Respiratory symptoms – cough are usually increased. The main problems of the
and repeated respiratory infections dominate later. patients originate in the respiratory system. Unex-
A chronic pansinusitis can be present secondary to pected complications occur during respiratory infec-
stagnation of secretion in the paranasal sinuses. Res- tions. Bronchiectasis can develop quickly. Atelecta-
piratory infections in these patients last longer than sis can occur in any area of the lungs. In young pa-
expected. The cough is more intense at night and tients the atelectatic part of lungs can reexpand and
in the morning. The sputum is usually viscous and refill with air. In other cases spontaneous pneumoth-
purulent. The X-ray examination reveals hyperin- orax can appear, especially during the development
1.9. Interstitial lung diseases 29

of bullous emphysema. As the disease progresses hy- basement membrane of capillaries is very often in im-
poxaemia and pulmonary hypertension develop. Cor mediate vicinity to the basement membrane of the
pulmonale appears in all patients. The therapy is alveolar walls which is lined on its other side with
symptomatic and the prognosis obscure. epithelial cells of type I. Here are the sites where
the gas exchange takes place. In intact lungs the
thickness of alveolar walls is 5–10 µm. In interstitial
diseases the wall of alveoli is several times thicker at
the expense of the alveolar space. In the first type,
the alveolar walls can deform in consequence of in-
1.9 Interstitial lung diseases flammatory cell accumulation in interstitium. This
condition results in the derangement of alveolar wall
architecture. These changes are reversible. They can
be repaired after elimination of material participat-
Interstitial lung diseases are defined as a group ing in the inflammatory process In the second type
of conditions with a common sign of diffuse inflam- there are fibrotic changes. This type ocurs in id-
matory alterations in the terminal parts of lungs iopathic pulmonary fibrosis or frequently when the
and airways. The term of interstitial lung diseases pathogenic factor is present in the inhaled air. The
refers especially to the fact, that the interstitium of epithelial cells of type I are destroyed and they are
alveolar walls is thickened in consequence of fibrotic replaced by cuboid cells being, in fact, the prolifer-
changes. Changes of the epithelial cells in alveoli ated cells of type II. The cells from terminal bron-
and terminal bronchioles are present, as well as al- chioli also migrate into the alveoli. Simulteneously,
terations of the capillary endothelial cells in the alve- the capillary endothelial cells are destroyed. In the
olar walls, and in the lung parenchyma. Interstitial interstitium oedema and proliferation of mesenchy-
diseases can progress slowly, as long as the alveolar- mal cells producing collagen occur. The interstitium
capillary units become gradually destroyed and irre- undergoes fibrotic changes. A very aggressive form
versibly lost. The condition can lead to respiratory develops when the accumulated material from in-
failure which ends lethally. Interstitial lung diseases terstitium enters the alveoli through their destroyed
have an inexpressive clinical symptomatology. Dys- alveolar basement membranes. This material is con-
pnoea during physical effort and an unproductive nected with the alveolar walls and forms a picture
cough can occur. An expressive clinical manifesta- of intraalveolar fibrosis. Such type of alterations has
tion does not occur usually before the respiratory an especially bad prognosis.
surface of lungs becomes really reduced.
Disorders appearing during interstitial lung dis- According to the etiologic factor, two groups of
interstitial lung diseases can be distinguished. The
eases are caused by the inflammatory reaction which
is induced by activation of inflammatory cells, accu- first one includes diseases where the etiologic factor
mulated in alveolar walls. is not exactly defined, or it is complex. The second
group includes interstitial lung diseases where the
Terminal bronchioles and alveoli with the capillar-
etiologic factor is represented by pathogenic particles
ies and venules form together mutually cooperating
or noxious gases present in the inhaled air.
functional pulmonary untis. The walls of alveoli con-
sist of a single layer of epithelial cells situated on a Inflammatory changes that are the cause of de-
thin basement membrane. 95 per cent of these cells stroyed alveolar walls are mediated by inflamma-
are epithelial cells of type I. The remaining 5 per tory – immunity cells accumulated in the lung
cent are the cells of type II, producing surfactant – parenchyma. The inflammatory process is localized
a complex substance which prevents the collapse of especially in the alveoli (therefore it is called alve-
alveoli by reducing the surface tension. Under the olitis), but also in the alveolar walls, in small bron-
thin basement membrane there is the interstitium chioles and sometimes also in the pulmonary vessels.
which contains mesenchymal cells and the support- The troubles of patients result from the disturbed gas
ing tissue consisting of collagen, elastic fibres, proteo- exchange and from the destroyed alveolar-capillary
glycans and several glycoproteins. The pulmonary units of the lungs. It is not always clear, how the in-
capillaries are in very close contact to alveoli. The flammatory reaction in the alveoli is initiated. In the
30 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

idiopathic fibrosis of lungs, alveolar macrophages are gen, which destroy the parenchymal cells. In ad-
activated by means of immune complexes. Activated dition, they produce specific proteases, degrading
macrophages release chemotactic factors, which at- the interstitial collagen and basement membranes.
tract in particular the neutrophils. In sarcoidosis ac- Eosinophils are also able to damage the parenchy-
tivated T cells release the chemotactic factor which mal cells of lungs, yet they are not as aggressive as
attracts monocytes. In these cases the activation neutrophils. Activated alveolar macrophages release
of the inflammatory process is evident. Sometimes, toxic oxidants which have a cytotoxic effect on the
several substances damage directly the alveolar wall parenchymal cells of the lungs. They influence also
and initiate the onset of the inflammatory reaction, the accumulation of mesenchymal cells by releasing
e.g. several types of drugs, especially cytostatics and the platelet-growth factor, fibronectin, and the in-
antibiotics. sulin like growth factor. The platelet factor attracts
Under physiological conditions, in healthy people the mesenchymal cells, fibronectin conects the mes-
each alveolus contains about 80 potential inflam- enchymal cells with the extracellular matrix. The
matory cells. Of this number 65–70 are alveolar insulin-like growth factor influences the proliferation
macrophages, the rest are T cells. There are few of mesenchymal cells. As a result, the alveolar walls
B cells in the alveoli. Polymorphonuclear leucocytes thicken and their architecture is deranged.
occur rarely. An exception is in smokers, in whom The damage and the thickening of the alveolar
polymorphonuclear leucocytes occur in alveoli. As a walls lead to a disturbance of oxygen transport. The
rule, the alveolar macrophages, T cells and B cells clinical manifestation of the disease results from hy-
are not activated in normal lungs. poxia of the tissues and organs. The patients com-
The distal parts of lungs contains immunoglobu- plain of fatigue and dyspnoea during effort. Along
lins. The majority of them are IgG, to a lesser extent with the progression of the disease dyspnoea deteri-
IgA and the least are IgM. Also some components of orates. The delivery of oxygen to the tissues is si-
the complement are present. Moreover, there are multaneously limited by the number of the existing
macromolecules protecting the tissue from damage alveolar-capillary units. Their number determines
caused by the inflammatory reaction. They include, also the pressure relations in the pulmonary blood
above all, the antiproteases and antioxidases. flow. After their destruction the hypertension de-
The activated interstitial inflammation is charac- velops, which has no tendency to lead to the right
terized by a marked increase in numbre of inflam- heart failure with its typical clinical manifestation.
matory cells in the alveolar walls, but also on the The fatal end is usually caused by the deficiency of
alveolar epithelial surface. Sometimes neutrophils oxygen and not by the right heart failure. Cyanosis
and macrophages preponderate. This condition is occurs very late. Analysis of blood gases reveals a
called neutrophil-macrophage alveolitis. In alveolitis moderate hypoxaemia without hypercapnia. It is
eosinophils play an important role. However, their caused by the fact, that the patients with intersti-
number usually does not prevail. tial fibrosis tend to hyperventilate mainly because
of their subjective feeling of dyspnoea and not be-
The inflammatory process with the participation
cause of hypoxia, which is moderate. During phys-
of different cells can be improved by treatment to
ical exercise the pO2 decreases, but pCO2 does not
such extent that the original structure of alveoli is al-
change. The measurements of ventilatory function
most restored. However, if during the inflammatory
reveal a decreased vital capacity and normal value
process the proliferation of mesenchymal cells and
of forced expiratory volume per second (because the
accumulation of collagen appear, the original struc-
airways are free, without obstruction). The chest
ture of alveoli can never be restored. Providing a
roentgenogram is usually not typical. Only when
sufficient number of lymphocytes and macrophages
the reticulonodular form develops the roentenogra-
participate in the infammatory process and activated
phy shows a honeycomb resembling alterations. The
CD4 + T helper cells accumulate, granulomas de-
clubbing belongs to the regular clinical findings.
velop. In fibrosis the damage of parenchyma and
accumulation of mesenchymal cells are present. Neu- The interstitial fibrosis is hardly responsive to the
trophils are the most damage-causing cells, namely therapy. A certain stabilization can be reached by
by production of high reactive metabolites of oxy- glucocorticoid therapy.
1.9. Interstitial lung diseases 31

1.9.1 Interstitial diseases of lungs of In idiopathic pulmonary haemosiderosis alveolar

unknown etiology haemorrhage anaemia due to iron deficiency, and a
transitory parenchymal infiltration of lungs is found.
In general the interstitial lung diseases are preva- The histological examination reveals focal haemor-
lently of unknown etiology. The most typical are the rhage, alveolitis with dominating macrophages, or
idiopathic fibrosis of lungs and sarcoidosis. haemosiderin-positive macrophages.
Idiopathic fibrosis of lungs. It is a classic pro-
totype of an interstitial lung disease. It represents The chronic eosinophilic pneumonia is character-
a neutrophil-macrophage alveolitis leading progres- ized by cough, dyspnoea, fatigue, fever, nocturnal
sively to destruction of the alveolar-capillary units. perspiration, weight loss and eosinophilia in periph-
In patients with idiopathic fibrosis of lungs viral in- eral blood. The histological analysis shows alve-
fections occur more frequently and in their blood olitis with the preponderance of eosinophils and
circulating immune complexes are present. In bron- macrophages. The stimulus for the accumulation of
choalveolar lavage fluid neutrophils and macrophages eosinophils is not well known. Eosinophils can de-
preponderate. It is assumed that the circulating stroy the alveolar walls by production of toxic oxygen
immune complexes activate alveolar macrophages radicals and peptides with a high electric charge.
which release neutrophilic chemotactic factors. Neu- Interstitial pneumonitis arises as a result of infil-
trophils release toxic oxygen radicals and proteases. tration of the alveolar structures with lymphocytes.
Macrophages increase their own production of the The same picture occurs also in HIV infection. In
platelet-activating factor, the insulin-like growth fac- alveolar proteinosis the alveoli are periodically filled
tor (IGF) and fibronectin leading to fibrosis of alve- with proteinic-lipidic material. This is usually asso-
olar walls and to increase in number of mesenchymal ciated with mononuclear alveolitis and fibrosis.
cells.
Sarcoidosis. It is a chronic multisystem disorder
of unknown etiology, where the organs are damaged
by inflammatory process. The inflammatory pro-
cess takes place in the alveolar and bronchiolar walls. 1.9.2 Interstitial diseases of lungs of
Alveolar macrophages are activated by an unknown known etiology
antigen. Interleukin 1 released by macrophages in-
duces an accumulation of the T helper lymphocytes. There are many known factors which cause intersti-
The process continues as further components of in- tial lung diseases. Different particles and infections
flammatory process are activated. may act as pathogenic factors. In addition, useful
Fibrosis of the lungs in systemic diseases. Alter- substances having undesirable effect on pulmonary
ations in lungs are found in about 25 per cent of tissue can be also involved.
patients with rheumatoid arthritis. Interstitial fibro-
sis can be caused also by the therapy of rheuma- Inhalation of anorganic dusts. It is a group of
toid arthritis. It occurs most frequently during diseases termed pneumoconioses. At the beginning
methotrexate treatment. the particles of anorganic dusts always damage the
The systemic lupus erythematosus is usually asso- pulmonary parenchyma evoking an inflammatory re-
ciated with lymphocyte alveolitis caused probably by action which can result in destruction of the alveolar-
deposition of circulating immune complexes within capillary units. (Pneumoconioses are described in a
the alveolar wall. particular chapter).
Antibodies to alveolar basement membrane can Inhalation of organic dusts. If effect of organic
be detected in Goodpasture’s syndrome. This dis- dusts is involved the hypersensitivity pneumonia or
ease is characterized by pulmonary haemorrhage, allergic alveolitis occur. If the episodes are repeated,
interstitial disease of the lungs, glomerulonephritis in a part of the involved people the interstitial pul-
with circulating antibodies to basememt membrane monary disease may develop. At the beginning a
of glomeruli and the antibodies to alveolar basement macrophage-lymphocytic alveolitis occurs with the
membrane. It is assumed that the antibodies to both participation of neutrophils which can later lead to
types of basement membranes are identical. pulmonary fibrosis.
32 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

1.9.3 Interstitial lung diseases in arterial blood; when pO2 falls below normal val-
induced by drugs ues (excluding the right to left shunt in the heart)
and pCO2 rises above the physiological value (ex-
The effects of drugs can be very different. They can cluding the respiratory compensation of metabolic
lead in some cases to fatal end. The biopsy shows alkalosis). The definition of the respiratory failure
damage of parenchymal cells and oedema of alveo- has results from laboratory findings, completed by
lar walls. Macrophage-lymphocytic alveolitis with clinical symptoms. Respiratory failure is not a dis-
neutrophils, but also with eosinophils can be found ease, it is a state, developing during various disor-
in alveoli. The chronic form of impairment induced ders. Sometimes the lungs can be intact. E.g. after
by drugs is very difficult to prove. In the major- an overdose of sedatives, hypnotics the respiratory
ity of cases there is macrophage-lymphocytic alveoli- failure may develop because of the respiratory cen-
tis with polymorphonuclear leucocytes of the mixed tre depression.
type.
Antineoplastic drugs cause in 2–3 per cent of pa-
tients interstitial fibrosis. Similarly antibiotics, salts pO2 10,0 – 13,3 kPa (75–100 mm Hg)
of gold and other drugs can initiate the arise of inter-
stitial fibrosis. A close correlation between effects of pCO2 4,8 – 6,1 kPa (36–46 mm Hg)
some herbicides and arise of interstitial fibrosis has
been found. Radiotherapy can also act as the initi-
ating mechanism. Table 1.1: Normal values of blood gases
Infection caused by Mycoplasma, Legionella pneu-
moniae, and HIV infections associated with parasitic
infection caused by Pneumocystis carinii, progress
into the form of interstitial lung disease. pO2 < 8 kPa (60 mm Hg)
It is very important to bear in mind that also the
inhalation of oxygen in high concentration for several pCO2 > 7 kPa (55 mm Hg)
days causes a damage of the pulmonary parenchyma.
The toxicity of oxygen can be very dangerous to pa-
tients with respiratory failure. The respiratory fail- Table 1.2: Values of blood gases in respiratory failure
ure breaks down as chronic pulmonary fibrosis begins
to develop. Respiratory failure is traditionally distinguished as
being acute or chronic. It is an artificial classification
which is more traditional than logical. A rapid dete-
rioration in chronic respiratory failure should be con-
sidered as an acute respiratory failure which does not
1.10 Respiratory failure agree with our conception of the acute state being
changed to a chronic one. Nevertheless, this classifi-
cation is important from the etiologic point of view
and from that of the possibilities of treatment.
Respiration includes four processes: ventilation,
1.10.1 Acute and chronic respiratory diffusion, perfusion, the governing and control of res-
failure piration. Disturbance of any of these four activities
can cause the respiratory failure.
The respiratory organs procure the necessary supply During hypoventilation the changes in pO2 and
of O2 and elimination of CO2 in all physiological sit- pCO2 in the arterial blood are parallel. The sim-
uations, in order to maintain the optimal pO2 and ple, uncomplicated hypoventilation leads to decrease
pCO2 in the arterial blood. Respiratory failure rep- in pO2 and to increase in pCO2 by identical value.
resents a condition with impaired exchange of gases However, this is not an universal principle.
between the alveolar space and pulmonary capillar- Disorder of diffusion during normal activity is usu-
ies. It is manifested by changes of the pO2 and pCO2 ally not manifested by marked changes in pO2 and
1.10. Respiratory failure 33

pCO2 . Very severe disorders of diffusion can be man- 3. hyperinflation of the lungs, that increases resis-
ifested by changes in levels of arterial blood gases at tance in the pulmonary circulation
rest.
The disturbance of ventilation-perfusion balance 4. reduced contractility of the myocardium, in-
can participate in origin of hypoxia and hypercapnia. duced by arterial hypoxia
The uncomplicated disorder of ventilation-perfusion
It is very important to distinguish these factors not
ratio becomes apparent especially by an elevation of
just because of their reversibility, but also because of
the pCO2 without a marked decrease in pO2 , be-
a complex approach to the respiratory failure treat-
cause the increased pCO2 stimulates the chemorecep-
ment.
tors and causes hyperventilation. This will procure
The respiratory failure is defined, as mentioned
a better supply of oxygen, however when there is a
above, by arterial hypoxia with or without hypercap-
ventilation-perfusion imbalance, hyperventilation is
nia. According to this if hypoxia with hypercapnia
not sufficiently effective in elimination of the ”over-
are found,the condition can be considered as global
volume” of CO2 . Under physiological conditions,
respiratory failure, and if only hypoxia without hy-
during hyperventilation, carbon dioxide is eliminated
percapnia is observed, the state has to be regarded
more intensively (it is more diffusible than oxygen),
as a partial respiratory failure.
and thus, there is a tendency to alkalosis.
If right-to-left pulmonary shunts are present, one
part of the deoxygenated blood flows into the sys- 1.10.2 The causes of origin and de-
temic circulation. It occurs in pulmonary arteriove- terioration of the respiratory
nous fistulas, pulmonary oedema, pneumonias and failure
intraalveolar haemorrhage. This changes are mani-
fested by increase in pCO2 . Diseases causing acute or chronic obstructions of air-
A decrease in O2 in the inhaled air leads to a de- ways very often result in respiratory failure (about
crease in pO2 in arterial blood. It can occur when 80 per cent). Whether the respiratory failure will
barometric pressure falls, however more often during develop or not, depends on the extent of obstruction
a fire or industrial breakdowns, when in consequence and the velocity of its development. The obstruc-
of the presence of unwanted gases in the atmosphere tion of the upper airways is accelerated by inflamma-
the partial pressure of oxygen is lower in the air. The tory process, oedema of the mucous membrane,or by
condition resulting from these changes is not consid- chemical or mechanical damage. Acute obstruction
ered to be a respiratory failure. of the lower airways deteriorates not only by oedema
The right ventricle of the heart, having a relatively of the mucous membrane, but also by increased se-
thin wall, is not a good generator of pressure. It is cretion of mucus, and bronchospasm.
not able to keep an increased pressure in the pul- Besides the airways also the alterations of
monary circulation for a longer period. A rapid in- parenchyma participate in the origin of respiratory
crease in the pulmonary circulation resistance can failure. An acute infiltration of the pulmonary
lead to the cor pulmonale acutum. Besides in mas- parenchyma in pneumonia can lead to respiratory
sive pulmonary embolism, it can occur also during failure. Besides pneumonia, the acute infiltration
acute asthmatic attack or acute obstruction of air- can occur also after inhalation of various toxins. In
ways. Cor pulmonale acutum can develop also in pa- the development of the chronic diffuse infiltration of
tients with chronic lung diseases if an acute respira- lungs many causes may be involved. After reaching a
tory failure arises. It occurs usually in patients whith certain degree, it is manifested as a respiratory fail-
already developed hypertrophy of the right ventricle. ure. The condition is accelerated and deteriorated
In the deterioration of right ventricle function par- by infections of the airways.
ticipate: The pulmonary oedema, chronic or acute, is an
important factor in the origin of respiratory failure.
1. alveolar hypoxia and acidaemia, causing arterial The increase in hydrostatic pressure in pulmonary
vasoconstriction in the pulmonary circulation capillaries is unfavourable not only from the haemo-
dynamic point of view, but also concerning the ex-
2. reduced perfusion in a certain region of lungs change of respiratory gases.
34 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

Respiratory failure appears or deteriorates if pul- tions. One of the first signs may be ataxia remind-
monary oedema is combined with heart disorders. ing the effect of alcohol. A more expressive hy-
Increased permeability of the endothelial layer of poxia with its depressive effect on the respiratory
the capillaries and alveolar-epithelial layer is ob- centre can start the circulus vitiosus. The respira-
served. In this situation a generalized pulmonary tory centre depression leads to the deterioration of
oedema with hypoxaemia may develop. Hypoxaemia ventilation which intesifies the hypoxia. In the ini-
is caused by the right-to-left functional shunt due to tial phase of hypoxia the cardiovascular symptoms
the present oedema. A state arises (not a disease) i.e. tachycardia and increased blood pressure appear.
termed adult respiratory distress syndrome (ARDS), If hypoxia becomes profound bradycardia and de-
which is associated with diffuse damage of the lung pression of the myocardium occur. The blood pres-
parenchyma. It can occur in several conditions be- sure falls in consequence of decreased cardiac output.
ing not explicitly of pulmonary origin. It occurs An increased level of reduced haemoglobin is man-
in generalized infections, acute hypotension and in ifested by cyanosis. The hypoxia compensation in-
metabolic disturbances. Histological examination re- cludes enhanced amplitude and frequency of breath-
veals in particular the damage of alveolar epithelial ing. The sympathetic nervous system becomes ac-
cells of type I. Usually the capillary endothelium is tivated, hence the heart rate and the cardiac out-
partially damaged; oedema and itraalveolar haemor- put per minute increase. If the compensation is in-
rhage are present. Later also changes in epithelial sufficient, the amount of 2,3 DPG in the erythro-
cells of the type II can be observed, as well as in- cytes increases due to anaerobic metabolism. The
filtration of tissue and depositions of collagen. The erythrocytes count, the amount of haemoglobin, and
mortality reaches up to 70 per cent. the haematocrit are elevated owing to the hypoxia of
Embolism in the pulmonary circulation can kidneys. The change in the blood viscosity impairs
severely deteroriate the respiratory failure. It oc- further the oxygen supply of tissues. The blood flow
curs commonly during disseminated intravascular co- in the capillaries slows down and cyanosis occurs.
agulation when thrombocyte-fibrin aggregates are Hypercapnia during the respiratory failure affects
formed. The state deteriorates severely if pulmonary very markedly the functions of CNS. The commu-
vasculitis is present. Respiratory failure can develop nication with the patient worsens; the raising level
also due to injury of thorax caused by trauma (frac- of CO2 induces somnolence, confusion, finally coma
tures of sternum or ribs deteriorate the ventilation and death. The effects of hypercapnia on the cir-
very markedly), or during the spontaneous pneu- culation are complicated. In general, the activation
mothorax. of the sympathetic nervous system prevails, it is lo-
Disorders of neuromuscular system are manifested cally influenced by accumulation of CO2 and that
by decrease in pulmonary ventilation. Polyneuritis is why in some areas vasoconstriction and in others
as well as the myopathies and muscular dystrophies, vasodilatation preponderate. Tachycardia is usually
accelerate the progression of the respiratory failure. present. The blood pressure can be increased, de-
Reduced ventilation appears in disorders of the CNS creased, or normal.
(trauma, vascular disorders, infections) and follow- The gradually raising hypercapnia is not very dra-
ing administration of substances depressing the res- matic. In chronic respiratory failure with hypercap-
piration centre: e.g. anaesthetics, sedatives, opiates, nia the patients complain of headaches and somno-
barbiturates alcohol etc. lence. These symptoms are probably caused by va-
A special situation arises in obese patients. Pauses sodilatation of cerebral vessels due to increased CO2 .
of apnoea are observed during the sleep acompanied The acute respiratory failure can lead to dead very
with decreased respiratory amplitudes due to pa- quickly. Dead results from hypoxia in the CNS. The
tients obesity. Apnoeic pauses may occur also dur- administration of oxygen in high concetration to the
ing the day (daytime somnolence), the condition pro- patient is a possible solution of hypoxia. In chronic
gresses and chronic respiratory failure develops (the respiratory failure, the administration of O2 does not
Pickwickian syndrome). improve the condition; retention of CO2 increases
Hypoxia due to respiratory failure results in and the relations between ventilation and perfusion
changes in CNS and cardiovascular system func- change. A certain solution is a prolonged administra-
1.10. Respiratory failure 35

tion of O2 in low concetrations (to 15 hours daily). addition, the polymorphonuclear leucocytes release
In typical cases the arterial pO2 can be 30 mm Hg, their lysosomal enzymes. The lesions of alveolar
pCO2 70 mm Hg and pH 7.30. These three values membranes lead to the leak of fluid, macromolecules
signalize a fatal hypoxia. Inhalation of oxygen in and cellular particles from capillaries into the inter-
high concetration improves the hypoxia, but simul- stitium and due to further deterioration also into
taneously it causes a depression of respiration lead- the alveoli. Increased permeability of capillaries to
ing to increased hypercapnia. The stimulants of the proteins facilitates the development of pulmonary
respiratory centre are considered to be obsolete, be- oedema. The damage of pneumocytes in the alveoli
cause although improving the hypoxia at the begin- impairs the production of surfactant. These changes
ning, later they intensify the hypercapnia. Hyper- accompanied with the presence of fluid and fibrino-
capnia causes dilatation of the cerebral vessels and gen in the alveoli lead to their collapse. The ven-
hence increases the intracranial pressure, resulting tilation – perfusion relation in the lungs is changed
in papilloedema. Hypercapnia associated with hy- owing to the collapsed alveoli. In addition, the accu-
poxia have catastrophic consequences on the CNS mulated fluid in the lungs decreases the compliance
functions. The gradually increasing hypercapnia has of lung tissue. And that is why the respiratory work
a narcotic effect. Disturbances of the heart rhythm increases. Yet it cannot eliminate the progressing
occur. In this situation the mechanical lung ventila- hypoxia.
tion represents the only possible treatment. Clinical manifestation of ARDS includes increased
frequency of breathing, arterial hypoxaemia and dys-
pnoea.
1.10.3 Adult respiratory distress syn- A similar condition arises rather frequently dur-
drome – ARDS ing a haemorrhagic shock (or after an overdose of
certain drugs). It is called the shock lung. In
This term is applied to acute states of diverse etiolo- the haemorrhagic shock the capillary endothelium is
gies, characterized by diffuse infiltrative lung lesions damaged (hypoperfusion, hypotension, the complex
with very severe arterial hypoxia in adults. The of adaptation and compensatory mechanisms and
neonatal form is distinguished mainly by the fact, factors, and humoral substances). Capillaries are
that primarily the immaturity in alveolar surfactant obliterated by microaggregation of leucocytes and
production is involved. In ARDS the changes con- thrombocytes. The released hydrolytic enzymes de-
cerning surfactant are secondary. stroy the endothelial cells. As a resut the increase in
In the ARDS of any etiology is always an in- capillary permeability and interstitial oedema super-
creased volume of fluids in lungs present. How- vene. Because of the decreased pulmonary blood flow
ever, no cardiopulmonary oedema is present. The (probably) the production of surfactant decreases.
pressure in the pulmonary capillaries in ARDS is Decreased production of surfactant facilitates the de-
not elevated, but the permeability of the alveolar- velopment of oedema. Pulmonary vasoconstriction
capillary membranes is increased. The increase in induced by hypoxia of tissues deteriorates further
permeability results from the direct chemical dam- the state of the capillaries. Finally alveolar haem-
age caused by inhalation of toxic gases. More of- orrhages occur.
ten an indirect damage occurs, caused by activa- The mortality in patients with ARDS or with con-
tion and aggregation of blood elements inside the ditions called shock lungs is very high. In the past
pulmonary capillaries. It occurs e.g. in septicaemia it reached almost 100 per cent. Now it is about
or endotoxinaemia. Aggregation of thrombocytes 50–60 per cent. In favourable cases, after overcom-
appears. Monocytes and polymorphonuclear leuco- ing ARDS, the recovery lasts 4–6 months. Fibrotic
cytes adhere to endothelial surface. They induce changes can persist, these are irreversible.
an inflammatory reaction and release the inflamma-
tory mediators e.g. leukotrienes, tromboxanes, and
prostaglandins. Alveolar macrophages as well as
monocytes release oxidants, mediators, and a series
of degrading enzymes and peptides, which damage
directly the endothelial and alveolar surfaces. In
36 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

There are endogenous factors (genetic, immunologic,

hormonal) and exogenous factors (mutagens, ioniz-
1.11 Tumours of the lung and ing radiation, asbestos, asphalt, chrome, arsenic, iron
oxides and nickel). It often occurs in scars after tu-
bronchi berculosis. 95 per cent of the invovled patients are
smokers.
The bronchogenic cancer arises in the basal layer
Tumours of lungs and bronchi can have origin in of the bronchial mucous membrane. In this stage it
any structure. Their structural classification as tu- could be detected merely by cytologic examination
mours of lungs and bronchi is not decisive. The tu- of the sputum. Hitologically it can be classified as
mours of bronchi gradually obturate the bronchi and epidermoid carcinoma, small cell carcinoma, adeno-
cause alterations in the pulmonary parenchyma. It carcinoma, and large cell carcinoma. The histologic
is not possible to find later the site of the tumour ori- classification of malignant tumours is the domain of
gin. The classification as benign, primary malignant pathologists. Carcinomas occur more often in right
and metastatic tumours is principal. lung and in the superior than in the inferior lobes. It
arises usually from the mucous membrane of segmen-
tal and subsegmental bronchi. It grows into the sur-
1.11.1 Benign tumours of lungs and
rounding tissues infiltrating and destructing them.
bronchi If it is localized centrally near to the hilus it pene-
They are usually charatrerized by a limited alter- trates the mediastinum, attacks the pericardium, the
ation of the pulmonary parenchyma, slow growth phrenic an recurrent nerves, vena cava superior and
and by consequences of compression developed upon the oesophagus. If it is localized in peripheral areas
the neighbouring bronchi. The most frequent is the it penetrates the pleural cavity. If it is localized in
bronchial adenoma. It grows from the bronchial mu- the apical region it spreads into the upper thoracic
cous membrane into the lumen of bronchi, but also aperture, destroys the ribs, cervico-brachial plexus
extrabronchially. The manifestations reside in the and the sympathetic trunk. It has the tendency
consequences of mechanical impact of the tumour. to metastize via lymphatic or haematogenous ways.
Cough and haemopthysis occur. If an obturation of Most often it metastizes into the lymphatic nodes,
bronchus is present, atelectasis develops in the per- pericardium, brain, suprarenal glands and kidneys.
tinent area of lungs; or a poststenotic bronchopneu- Yet it can metastize into any organ of the human
monia and bronchiectasis may occur. Sometimes an body.
abscess develops. Bronchial adenoma can be com- The manifestation of cancer is very multiform. It
bined with an overproduction of serotonin. In this depends on its localization, histological type, relation
case abdominal spasms and asthmatic attacks occur. to the lumen of bronchus, and on the consequences of
Histologically the benign adenoma of lungs resem- infiltration. In other cases the metastatic symtoms
bles the adenoma of the salivary glands. Benign tu- occur. At the beginning is the bronchogenic can-
mours of bronchi include fibroma, lipoma, myxoma, cer completely symptomless. An accidental exami-
angioma and other rare types. nation reveals roentgenographic abnormalities. The
Chondrohamartoma also belongs to the benign cough, pain in the chest, dyspnoe, haemoptysis, and
pulmonary tumours. It is usually localized in the repeated bronchopulmonary infections occur later.
distal lobes. It grows slowly. The cough is irritant, dry and unproductive. The
pain in the chest can ressemble that of angina pec-
1.11.2 Primary malignant tumours of toris. Dyspnoea is a late symptom. Haemoptysis is
not a standard symptom. The mentioned symptoms
lungs bronchi
are often accompanied by weakness, weight loss, fa-
Bronchogenic carcinoma. It is the most frequent tigue, anorexia and fever. The growth of tumour
malignant tumour in men. In Europe it is in the is manifested later by variable clinical picture. All
first place as cause of mortality of malignant tu- depends on the structures which are affected. The
mours. Several factors participate in its etiology. hoarseness is the manifestation of n. recurrens pare-
1.12. Disorders of the diaphragm, thorax, pleura and mediastinum 37

sis. Dysphagia is due to the compression and infil- with bronchogenic carcinom is in spite of application
tration of oesophagus. Paresis of the phrenic nerve of the most proven therapeutic methods not satis-
with elevation of the diaphragm can lead to dysp- factory. Since the diagnosis has been established
noea. Involvement of pericardium can be manifested merely 10 per cent of patients survive the period of
by arrhythmias or heart failure. five years.
Carcinomas, invading the pleura from the apical Sarcoma of the lungs. It is a rarely occuring malig-
parts into the upper thoracic aperture are the cause nant tumour. It occurs in older persons. The prog-
of the Pancoast’s syndrome. They infiltrate the nosis is bad.
brachial plexus, the thoracic and cervical parts of
sympathetic nervous system, the ribs and vertebrae. 1.11.3 Metastatic malignant tumours
A cruel pain in the shoulder is present, later paresis of the lungs
of the hand, with muscle atrophy, loss of sensibil-
ity and the Horner’s syndrome (constriction of the Metastatic malignant tumours of the lungs consti-
pupil, ptosis, anhidrosis on the affected side of the tute 20–30 per cent of all malignant tumours. Direct
head and neck) occur. penetration of tumours arising from the adjacent or-
gans (breast carcinoma, tumours of the thymus, of
The compression of superior vena cava leads to the
the thyroid gland, oesophagus and tumours of the
vena cava superior syndrome development. Cyanosis
mediastinum) can be involved. Osteosarcoma, ma-
and oedema of the head and neck are present, ac-
lignant tumours of testes, kidneys, suprarenal glands,
companied with oedema of upper extremities and
stomach, large intestine, prostata and breast metas-
the trunk. The veins are congested and winding.
tasize into the lungs by blood vessels.
The patient suffers from headache and disturbances
Solitary metastases are not accompanied with clin-
of vision.
ical symptomatology. Clinical manifestations of dis-
The extrapulmonary symptoms form the parane- seminated metastases include an irritant cough and
oplastic syndromes. They are usually present in progressive dyspnoea. Solitary metastases are re-
bronchogenic carcinoma, yet they occur also in other sected. The patients with disseminated metastases
malignant tumours. Their cause is not well known. are treated by chemotherapy or radiotherapy. The
Sometimes they precede the primary tumour, or they prognosis is bad.
disappear following its removal, and during the re-
lapse they reappear. The manifestation of the bone
and joint involvement includes the clubbing and hy-
pertrohic osteopathy with pain in joints imitating the
rheumatoid arthritis. Pains in long bones, profuse
sweating and myastenic syndrome are also present.
1.12 Disorders of the diaph-
Peripheral neuropathies (manifested by paresis of ragm, thorax, pleura
the fibular nerve) are observed. Sometimes also en-
docrine disturbances are present. Cushing’s syn-
and mediastinum
drome develops due to extreme hyperproduction of
a peptide similar to ACTH. Because of overproduc-
tion of a peptide imitating the effects of pituitary
hormones which stimulate the ovaries, gynecomastia
develops. Hyponatriaemia is due to the production 1.12.1 Disorders of the diaphragm
of a peptide with effects of ADH. The cancer cells of- The diaphragm is the most important respiratory
ten produce calcitonin. The endocrine changes can muscle. It separates hermetically the thoracic cav-
be associated with the resemblance of the cancer cells ity from the abdominal cavity. The central part is
with those of the APUD system. tendinous and not contractile. The peripheral part
Phlebitis migrans, anaemias, leucocytosis and consits of muscle fibres attached to the distal osseous
thrombopenia are commonly occuring extrapul- part of thorax. Some formations and structures pass
monary manifestations. A nonbacterial thrombotic the diaphragmatic openings from the thoracic into
endocarditis can develop. The prognosis in patients the abdominal cavities. The muscles are governed
38 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

by the phrenic nerve, the motor neurons originate in The hiccup can be elicited also by psychogenic
the cervical part of the spinal cord from segments stimuli. A transitory hiccup can be caused by a cold
C3–C5. During the contraction of diaphragma the drink, intake of greater volume of food, concentrated
organs in the abdominal cavity are displaced down- alcohol, but also by a cold shower and other non –
ward. This creates a negative pressure in the tho- specific stimuli.
racic cavity during the inspiration. The function Traumatic rupture of diaphragm results in dis-
of diaphragm has to be perfectly coordinated with placement of abdominal organs into the thoracic cav-
the function of other respiratory muscles. In ad- ity. Also the inborn diaphragmatic defects may be
dition, the diaphragm has an extraordinary impor- involved.
tance in non-respiratory functions (delivery, defeca-
tion, speech). The diaphragmatic muscles are very
well supplied with blood.
1.12.2 Disorders of the thorax config-
uration
The dysfunction of diaphragm occurs during hy-
perinflation of the lungs. The hyperinflation can be Disorders of the thorax configuration lead to very
of acute character e.g. in the asthmatic attack, or similar consequences, concerning the respiratory
permanent in chronic obstructive ventilatory disor- functions. They are especially:
ders. Hyperinflation inhibits the necessary move-
ments of the diaphragma. In this situation the di- 1. alveolar hypoventilation
aphragm is not able to fulfill the reqiurements of
2. changes in the compliance of thorax
increased ventilation of the lungs. During forced
breathing, paradoxical movements of anterior ab- 3. various degrees of lung compression
dominal wall can be observed (the abdominal para-
dox). 4. irregular ventilation-perfusion ratio
Sometimes unilateral diaphragmatic paralysis can
5. pulmonary hypertension and cor pulmonale
develop. It usually occurs in phrenic nerve afflic-
tion, e.g. in bronchogenic cancer, poliomyelitis, en- Clinical symptoms include dyspnoea without
cephalitis and herpes zoster. Paralysis of the phrenic cough, sputum and chest pain.
nerve can develop also after a cardio-surgical inter- Kyphoscoliosis. It is a deformity of the spine in
vention. Paralysis of the diaphragm can be caused two directions. Kyphosis is a pathologic backward
by aortal aneurism, substernal goitre, trauma of the deformity of the spine in the sagittal plane. Scolio-
thorax and spine (bilateral paralysis). Muscle dys- sis is a lateral curvature of the spine in the frontal
trophies and myelopathies affect also the muscles of plane. It is always associated with rotation of verte-
diaphragm. During diaphragmatic paralysis dysp- brae around the long axis. Kyphosis is important re-
noea or its deterioration are observed. garding the respiration, if the deformity of the spine
A rapid, sudden contraction of the diaphragm as- exceeds the 70o C angle. Scolioses are classified as be-
sociated with a reflexive closure of glottis and accom- ing either functional or structural. Functional scol-
panied with a sound phenomenon is called singultus ioses are due to the shortening of the lower extremity,
(hiccup). It is a reflex; the afferent impulse of which can be postural and hysterical. The structural scol-
originates in the sensitive fibres of the phrenic or ioses include the idiopathic, neuromuscular, congen-
vagus nerves. It leads to the respiratory centre in ital forms and scolioses due to other diseases (neu-
the brain stem. The efferent pathway consists of the rofibromatosis, rheumatic diseases, disorders of the
phrenic nerve motor fibres leading to the diaphragm. mesenchyma, posttraumatic scolioses). Idiopathic
The peripheral hiccup arises due to irritation of the scolioses constitute more than 80 per cent of all sco-
phrenic nerve, in disorders of mediastinum, lungs, lioses. The children’s scoliosis is found in children
heart, oesophagus, diaphragm, or diseases localized below the age of 3 years, the juvenile scoliosis be-
in the abdominal cavity, and after surgical interven- low the age of 9 years and the adolescent scoliosis
tions. Central hicccup occurs in encephalitis, menin- before the end of growth. The main problem regard-
gitis, stroke, brain tumours, uraemia and alcoholic ing the respiratory functions arise from the rigidity
intoxication. of the thorax. During infection hypoventilation and
1.12. Disorders of the diaphragm, thorax, pleura and mediastinum 39

hypoxaemia can impair intensively. The progression The pain arising from pleura is always unilateral.
of the disease leads to the cardiopulmonary failure. It spreads into the arm and neck, or into the ab-
Pectus excavatum. It is a congenital deformity domen. Dyspnoea can be present because of the lung
of the distal part of the sternum. Sternum is im- compression, due to accumulation of fluid in the pleu-
pressed into the thorax, especially in its distal part. ral space. The fluid in pleural space does not have
This disorder (a tunnel-shaped thorax) is often asso- to be detected by the roentgenographic imaging in
ciated with a number of other abnormalities and with the back to front projection in a recumbent patient
high mortality. It is often combined with the mitral (e.g. at an intensive care station).
valve prolapse. Deformations of a lesser degree do The pleural fluid examination has a great diag-
not cause troubles and have rather the character of nostic importance The thoracocentesis has only few
cosmetic defects. contraindications (haemorhagic diatheses, anticoag-
There are still other deformations of the thorax, ulant therapy and mechanical ventilation). The ex-
disturbing to different degree the function of respira- amination of the pleural effusion detects the total
tory organs. In ankylosing spondylitis the mobility content of proteins, lactate dehydrogenase, the leu-
in the costovertebral joints is reduced. Deformities cocytes count and their differential count, the level of
may occur after traumatic injuries and after disor- glucose and pH. The analysis of the pleural effusion
ders of the pleural cavity. attests these facts :

1. ratio of the proteins in the pleural fluid and in

1.12.3 Disorders of the pleura
serum is above 0.5
Pleura is a semitransparent membrane which con-
sist of a network of fibroelastic tissue, lymphatic and 2. ratio of LDH in pleural liquid and in serum is
blood vessels. It contains a layer of mesothelial cells above 0.6
of different size. The mesothelial cells have their sur-
face fine cilia-microvilli. The surface of mesothelial The pleural fluid is examined for the presence of
cells is lined with fine cilia-microvilli. The mesothe- malignant cells, pus, microorganisms, erythrocytes
lial cells produce glycoprotein rich in hyaluronic acid. and also other substances according to the assumed
This facilitates the sliding of pleural surfaces over cause of the effusion. So e.g. the ratio of the crea-
each other. Parietal pleura covers the surface of the tinine level in the pleural fluid and in serum is in
chest wall, diaphragm and mediastinum. It is sup- urinothorax above 2. The level of glucose is be-
plied with blood from the systemic circulation. It low 3.33 mmol/l in infections, rheumatoid pleuritis
contains sensitive nerves and cells with a dense cil- and tuberculosis. A decrease in pH below 7.2 is
iary layer. The visceral pleura covers the surface of observed usually in emphysema, in malignant pro-
lungs, including the interlobar fissures. The visceral cesses, tuberculosis and pleuritis. Polymorphonu-
pleura is supplied with blood from the pulmonary clear leucocytes signify very probably a bacterial in-
circulation. It does not contain sensitive nerves and fection. Lymphocytes are present in tuberculosis, yet
the cells have few cilia. Boths pleural surfaces closely also in lymphomas and in leukaemic effusion.
adhere to each other. The pleural space contains Transudation into the pleural space. Transuda-
only 5–10 ml of fluid enabling the lungs to follow the tion, in general, is a state, when the leakage of fluid
movements of the thorax during inspiration and expi- into the serous cavities is evident. The cause of tran-
ration. The pleural fluid contains, under physiolog- sudation is the change in osmotic and hydrostatic
ical conditions, few proteins (less than 2 g/100 ml). pressures. In heart failure the volume of fluid in
The level of glucose and pH are identical with those the pleural space increases owing to the venous pres-
in the plasma. The hydrostatic pressure in the pari- sure elevation, especially in the failure of both heart
etal pleura is identical with the pressure in the sys- ventricles. Changes concerning filtration and reab-
temic circulation and that in the visceral pleura is sorption of fluid in the capillaries are involved. The
identical with the pressure in the pulmonary circu- process of filtration continues normally, but the re-
lation. The parietal lymphatic system serves as a absorption is retarded due to the increased pressure
draining system for the fluid of pleural space (see in the venous end of capillaries. The increase is not
the figure 1.4). caused by heart failure, i.e. by the inability of heart
40 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

Figure 1.4: Pressure relations in pleural cavity

1.12. Disorders of the diaphragm, thorax, pleura and mediastinum 41

to pump the necessary ”offered” volume of the ve- rheumatoid arthritis. In such cases the exsudate con-
nous blood from the venous part of circulation into tains a low level of glucose (less than 1.66 mmol/l),
the arterial part. Heart failure leads within several high level of LDH and low pH. The clinical manifes-
months to an increase in the content of proteins in tation is not very remarkable. Increased body tem-
the pleural fluid above 3 g/100 ml. Transudation into perature does not have to be present. The condition
the pleural space is observed also in hepatic cirrhosis. may be complicated by formation of fibrotic tissue
The ascitic fluid can get through the diaphragmatic connecting both pleural surfaces.
defects into the pleural space or it can be removed Pleura is affected also in other diseases. Fluid can
by the lymphatic system and ”trasferred” from the appear in the pleural space especially in consequence
abdominal to the thoracic cavity. Transudation in of lung diseases. In asbestosis an unilateral serous-
nephrotic syndrome is due to very low oncotic pres- sanguinolent exudate can be present. The number
sure. Peritoneal dialysis can also be the cause of fluid of polymorphonuclear or mononuclear leucocytes is
transudation into the pleural space. increased. Uraemia leads to development of poly-
Exudation into the pleural space. Exudation is a serositis. The pleural lesion in uraemia displays a
state, with an evident production and accumulation picture called urinothorax. This condition must be
of fluid in the serous cavities. The cause of exu- distinguished from the hydrothorax, which develops
dation resides in the serous membrane. The exu- during the nephrotic syndrome without the renal fail-
dation is induced by neoplasma, infection, inflam- ure.
mation or trauma. In the process of exudation the Frequent causes of the pleural exudation forming
mesothelial cells play an important role. Exudation are the malignant processes. The breast carcinoma
is often observed in pneumonias and pulmonary ab- and carcinoma of the lungs, more rarely those of the
scesses. Uncomplicated exudation can be effectively ovary and stomach penetrate the pleural space or
treated by antibiotics. The count of leucocytes in metastasize in it. Patients can be asymptomatic, or
the pleural fluid is not too high, pH usually does not they suffer from cough, pain in the chest and dysp-
exceed 7.3 and LDH is below 0.8 µkat/l. In compli- noea. The exudate usually contains erythrocytes and
cated cases, the number of polymorphonuclear leuco- mononuclear leucocytes (lymphocytes more than 50
cytes is higher than 100 000/µl and pH is below 7.2, per cent). Glucose is lower than 3.33 mmol/l. The
the level of glucose does not reach 2.2 mmol/l, LDH pH is lower than 7.3. The exudate contains malig-
is above 16 µkat/l. The exudation contains bacte- nant cells. Pleural exudate if present in malignities
ria. The pleural sepsis is a very severe complication. has a very unfavourable prognosis. It occurs also
Exudation into the pleural space occurs very often in non-Hodgkin’s lymphomas. Moreover, if a medi-
in pulmonary tuberculosis, yet it occurs also during astinal invasion is present, lymphatic blockade can
other infections. develop. In 80–90 per cent of patients with mani-
Haemothorax is usually the complication of a trau- fested asbestosis malignant mesothelioma of pleura
matic injury of the thorax. The pleural space con- develops. Mesothelioma is accompanied with dysp-
tains bloody effusion with haematocrit exceeding 20 noea, cough, weight loss and chest pain. The tumour
per cent. It can occur in disorders of blood coag- spreads diffuselly from the pleura into the lungs. The
ulation, in pleural malignant processes and due to pleural exudate is abundant. The cytological iden-
rupture of aortal aneurysm. The blood in the pleu- tification of mesothelioma is not unambigous and so
ral space does not coagulate. It is relatively quickly is the differential diagnosis between the benign and
eliminated by the lymphatic system. malignant forms of mesothelioma. Benign mesothe-
lioma has the character of fibrosis, reaches great
Chylothorax is a state, when chyle accumulates dimensions and is usually combined with a hyper-
in the pleural space. It is usually associated with trophic pulmonary osteoarthropathy.
malignant processes in the thoracic cavity, e.g. lym-
Pneumothorax.Pneumothorax is characterized as
phomas, and with disorders of lymphatic vessels.
air accumulation in the pleural space. It can occur
Pleural exudation can develop also in other dis- due to:
eases. In about a half of patients with rheuma-
toid arthritis in various stages pleural exudate is ob- 1. perforation of visceral pleura and the leakage of
served. Sometimes it preceds the manifestation of air from the lungs
42 Chapter 1. Pathophysiology of the respiratory system ( I. Hulı́n )

2. penetration of thoracic wall, diaphragm, medi- the vertebrae, descending aorta, oesophagus, tho-
astinum and oesophagus racic duct, the azygos and hemiazygos veins, the
lower portion of the vagus nerve, the sympathetic
3. production of gas by microorganisms in empye- ganglia, and mediastinal lymph-nodes (see fig. 1.5).
ma
The perforation of visceral pleura can occur also
in healthy young people without any disorder of the
respiratory organs. Most commonly the rupture oc-
curs in the apical parts of the lungs. Acute chest
pain, dyspnoea and cough are the main symptoms of
pneumothorax. In 7–14 days the air can be sponta-
neously reabsorbed.
Pneumothorax can arise due to traumatic injury
of the thorax or pulmonary diseases. The injury of
the thorax enables in some cases the air to enter
the pleural space during the inspiration. This con-
dition is termed the valvular pneumothorax. Pneu-
mothorax can be partial or complete. In emphysema
the rupture of a subpleural bulla can easily occur.
Also the rupture of pulmonary abscess can occur. In
such cases pyopneumothorax develops. Pneumoth-
orax can arise also during an asthmatic attack, in
interstitial diseases of the lungs and in neoplasmas.
At intensive care stations iatrogenic pneumothorax
may occur caused by barotrauma during mechani-
cal ventilation or during introduction of the caval
Figure 1.5: Mediastinal compartments
catheter. A severe complication is the pneumotho-
rax associated with bronchopleural fistula.
The symptoms of expansive processes in the medi-
astinum include pain in the chest, cough, hoarseness
and dyspnoea. Stridor, dysphagia and the Horner’s
1.12.4 Disorders of the mediastinum syndrome occur rarely. About a half of the patients
Mediastinum is an anatomical space in the centre of with myastenia gravis suffer from thymomas. Hypo-
the thorax, which separates both pleural spaces. It glycaemia may occur in patients with mesothelioma,
is limited by the diaphragm and the upper thoracic fibrosarcoma or teratoma.
aperture. In the small mediastinal space some im- Neurogenic tumours in the mediastinum lead to
portant vital organs are localized. That is why the neurological symptoms. The tumours are repre-
changes in mediastinum are manifested by marked sented mainly by benign tumours (neurofibroma,
symptoms. The anterior compartment of medi- ganglioneuroma). They can produce hormones. Hy-
astinum is limited by the pericardium, ascendent pertension is usually present. Neuroblastoma (a
aorta, brachiocephalic trunk and sternum. Herein malignant tumour consisting of sympathetic ganglia
are situated: the thymus, substernal part of the cells) has a little better prognosis than the neuroblas-
thyroid gland, and the parathyroid glands, vessels, toma originating in suprarenal gland medulla. Neu-
pericardium and lymph-nodes. The midle compart- rogenic tumours manifest themselves by pain in the
ment is limited by the anterior compartment, and chest, unproductive cough and the compression of
at the back by the pericardial line. It contains the trachea.
heart, large vessels, trachea, the main bronchi, lymph Thymomas represent about 20 per cent of all me-
nodes, and the phrenic and vagus nerves. The pos- diastinal tumours. Thymomas are considered to be
terior compartment reaches from the posterior line malignant tumours. Among the lymphatic tumours
to the back wall of the thorax. Here are situated most frequently occur the Hodgkin’s lymphomas.
1.12. Disorders of the diaphragm, thorax, pleura and mediastinum 43

The non-Hodgkin’s lymphomas, plasmacytomas and quent are the malignant liposarcomas, mesothe-
hamartomas have the same clinical manifestation as liomas, rhabdomyosarcomas and mesenchymomas.
other mediastinal tumours. Their prognosis is un- Diaphragmatic hernias can be presented as expan-
favourable. The intrathoracic goitre is accompanied sion of the mediastinum. The clinical manifestation
with stridor, cough and dyspnoea. Pericardial cysts of the pneumomediastinum may be similar. It occurs
are usually situated in the anterior compartment of usually in consequence of a rupture of the bronchi or
the mediastinum. The vascular tumours are usu- oesophagus. An alveolar rupture and the subsequent
ally represented by vascular hamartomas, lymphan- pneumomediastinum can arise due to the mechanical
giomas, haemangiomas. They are benign. Less fre- ventilation.
Chapter 2

Pathophysiology of blood and

haematologic system

2.1 Haematopoiesis

The blood cells circulating in peripheral blood are

the end-product of differentiation and maturation of
recognizable precursor cells in the bone marrow. In
the fetal period of development the formation and
maturation of blood cells occurs first in the reticu-
loendothelial system. The formation of erythrocytes,
granulocytes and thrombocytes in adults takes place
exclusively in the bone marrow. The lymphocytes
in the peripheral blood are already mature, but they
can undergo the rapid proliferation as response to
various specific stimuli.
The singular types of cells circulating in the blood
differ morphologically, as well as functionally. Their
origin is extraordinarly closely connected. From the
point of view of its architecture the zone marrow is
in fact an immense network of fibroblasts and en-
dothelial cells forming a framework of progenitors
and stem cells, interconnected by fibronectin into
a net of tissue macrophages and T-cells. Mature
cells have then to pass the slits between the endothe-
lial cells and fibroblasts to reach the sinusoides from
where they enter directly the circulation. The outer
surface of sinuses is formed by reticular cells. They Figure 2.1: Entry of blood cells from bone marrow
send projections forming a network with endothelial into the sinuses
cells and fibroblasts. The fans of haematopoietic tis-
sue are localized in the network of reticular cells (see
Fig. 2.1). must be balanced in speed and rate of their loss.
Under physiological conditions the cell production The mean erythrocyte life span in man is about 120

44
2.1. Haematopoiesis 45

days. The daily amount arising de novo in each mi- There are few pluripotent cells in the bone mar-
croliter of blood is 5 · 104 (which represents 2 per row, hence it is difficult to isolate them. The
cent of new blood cells). The thrombocyte survival blood cell maturation is maintained by a group
is 7 to 10 days. Their daily production have to reach of glycoproteins called the haematopoietic growth
2 · 104 of thrombocytes in each microliter of blood. factors – HGF. Except the blood cell maturation
White blood cells (leucocytes) have different kinetics. they also influence their function. Under their
Granulocytes survive in intravascular milieu about 6 influence the growth of CFU cells becomes en-
to 12 hours. To ensure their constant number, it hanced. Thus, these growth factors are called also
must be produced daily about 2 · 104 granulocytes the colony stimulating factors (CSF) for granu-
per each microliter of blood. The survival period of locytes G-CSF (granulocyte-colony-stimulating fac-
lymphocytes is considerably different. Their life du- tor) and for macrophages M-CSF (macrofage-colony-
ration varies from several months to several years, stimulating factor) or GM-CSF for both of them.
it means that a complete bone marrow failure in its Except for lymphocytes, all other development lines
initial phase is manifested by a fall in granulocyte need the presence of IL-3 or GM-CSF for maturation.
number. On the contrary, the increased bone mar- Generally IL-3 and GM-CSF stimulate proliferation
row activity is manifested by elevated granulocyte and differentiation of progenitor cells. The stem cells
number. The bleeding leads rapidly to the fall of can be stimulated by at least three interleukins (IL-1,
thrombocyte number. The information about ery- IL-4, IL-6). Interleukin 6 in combination with IL-3
throcyte and thrombocyte production and life- span accelerate the dividing of the stem cells.
can be obtained using the Na51 2 CrO4 method. The localization and the maturation of lympho-
cyte precursors is in comparison with other blood
2.1.1 Development of blood cells cells more complex. The primary precursors of B-
The blood cell development and formation occurs in cells originate from bone marrow, spleen and lymph
several consecutive periods. Moving back from the nodes. The differentiation and maturation of B-cells
mature cell we get to the basis of the haematopoiesis. occur in lymph nodes. The primary precursors of
Its earliest stage is represented by the pluripotent T-cells are in the bone marrow, from where they are
stem cells – PSC. They are the basis for the differ- travelling into the thymus, where their further differ-
entiation of myeloid, as well as of lymphoid cells. The entiation follows. Then they get into the spleen, the
lymphoid stem cells give rise to precursor and mature bone marrow and lymph nodes. Here is their ”resi-
progenitor cells of T- and B-cells. The basal three- dence” and the site, where they obtain the necessary
lined myeloid stem cells are termed unit forming functions. T- and B-cells pass then into the blood
cells – spleen colony forming units CFU-S. During and the tissues, where they are needed. The circu-
in vitro cultivation of the bone marrow cells three- lating lymphocytes are only one very small part of
lined myeloid stem cells are capable to form colonies the global lymhocyte number division (see Fig. 2.2).
of identical cells. These colonies were originally dis- The differentiation of progenitor cells is signifi-
covered in the spleen of lethal doses irradiated mice cantly influenced by monocytes and T-cells. The
to whom the bone marrow of histoidentical donors monocytes produce IL-1 and TNF as a response to
was applied. The spleen colonies contain megakary- the bacterial products action (IL-1 is a cytokine in-
ocytes, granulocytes and erythroid precursors. fluencing many functions in organism:, TNF – tu-
The CFU-S further differentiate in three lines. mor necrosis factor, named also cachectin). IL-1 and
TNF stimulate fibroblasts and endothelial cells to
1. CFU-E (colony forming unit – erythroid) produce haematopoietic growth factors (HGF with
CFU-Meg (colony forming unit – megakary- the exception of IL-3 and IL-5). The antigens of
ocyte) various types stimulate the T-cells to IL-3, IL-5 and
CFU-B (colony forming unit – basophil) GM–CSF production. These haematopoietic growth
2. CFU-G (colony forming unit – granulocyte) factors act on progenitor cells, thus ensuring the
CFU-M (colony forming unit – macrophage) blood cells development. Fibroblasts and endothe-
lial cells have an important function in forming a
3. CFU-Eo (colony forming unit – eosinophil) layer where the progenitor cells adhere and where
46 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

Figure 2.2: Development of blood cells

their differentiation occurs. The progenitor cells are tially substitute the numerous transfusions in pa-
bound to this layer with fibronectin receptors. tients chronically dialysed for renal failure. Under-
standing of the mechanisms having a central position
The haematopoietic growth factors are perspec-
in cell production is necessary for exact diagnosis and
tive for clinical use. GM–CSF is promising for use
therapy.
in aplastic anaemias in children, in granulocytope-
nia due to chemotherapy. Erythropoietin can par- The erythrocytes are the ”descendents” of the
2.1. Haematopoiesis 47

pluripotent stem cell. The progenitor cell of remaining 3 per cent of haemoglobin is of type A2
the erythrocytes is the erythroid burst-forming (α2,δ2). Fetal haemoglobin (HbF or α2, γ2) does not
unit (BFU), sensitive to erythropoietin and further exceed more than 1 per cent of the total haemoglobin
haematopoietic factors. More mature cell is the amount in healthy adult persons. HbF persists in
erythroid colony-forming unit (CFU-E) producing congenital haemolytic anaemias in adult age.
smaller colonies of erythroid cells. In cell cultures The first step of haem production in precur-
it lasts about four to seven days. The erythroid cell sor cells is the condensation of succinyl-coenzyme
production is higly sensitive to erythropoietin. A (CoA) with glycine to form delta-aminolevulinic
Erythropoietin is a glycoprotein with a molecular acid. This reaction occurs in mitochondria and re-
weight of 34 000 daltons. Cloning of erythropoietin quires the glycine activation by pyridoxine phos-
gene enables to produce great amount of active ery- phate. Therefore in sideropenic anaemias with im-
thropoietin. Erythropoietin is primarily produced paired haem production the treatment with pyri-
in kidneys as a response to hypoxia. Its plasmatic doxine is sometimes successful. The second step of
level is directly proportional to the degree of hypoxia. haem synthesis occurs in cytosol. Two molecules of
Erythropoietin is bound to the specific receptor on delta-aminolevulinic acid form the porphobilinogen
the surface of erythroid stem cells. After the binding ring. Further reactions proceed again in mitochon-
it induces the differentiation of these cells to proery- dria. Iron is incorporated into the protoporphyrin
throblasts. The proerythroblasts are the first differ- IX forming the haem. The haem is bound to globin
entiated precursor cells of erythrocytes. Under the in cytosol forming the haemoglobin.
physiological conditions the evolution from proery-
throblast to the completely mature normoblast last 2.1.2.1 Role of haemoglobin
about 4 days. During this period the nucleus be-
comes progressively smaller and the haemoglobin The primary role of red blood cells is the oxygen
produced in cytoplasm raises. The last step is the ex- transport from lungs to the tissues and the carbon
trusion of the pycnotic nucleus out of the normoblast. dioxide transport in the opposite direction. The
In this way the normocyte changes into the reticulo- tridimensional structure of human haemoglobin opti-
cyte remaining still 2 to 3 days in bone marrow. The mizes its perfect function. During the blood flowing
reticulocytes are released into the circulating blood through the lung capillaries the oxygen binds with
about 24 hours before their mitochondria and ribo- haemoglobin. On each gram of haemoglobin 1,34 ml
somes disappearing. Thus, they become mature red of O2 is bound. The haemoglobin affinity to oxygen
blood cells. is modified by three intracellular factors:
The erythrocyte precursors from pronormoblast
1. the hydrogen ion
to reticulocyte contain a specific surface receptor for
iron-transferrin complex, enabling to incorporate a 2. the carbon dioxide
sufficient amount of iron for haemoglobin formation.
The bone marrow is able to enhance the erythro- 3. 2,3-diphosphoglycerate (2,3-DPG)
cyte production three to five times during one to two
weeks if it is stimulated by high erythropoietin level. Increase in concentration of any of these factors
In chronic haemolytic anaemias is the erythropoiesis shifts the oxygen dissociation curve to the right. The
five to seven times enhanced. 2,3-DPG molecule binds to the beta-chain of deoxy-
haemoglobin. In this way it reduces the oxygen affin-
ity to haemoglobin. The consequence of this fact is
2.1.2 Haemoglobin biosynthesis an increased oxygen release.
Haemoglobin is a tetrameral compound composed of The oxygenation of tissues depends on three main
two pairs of peptide chains (α, β, γ, δ), connected by factors:
covalent bonds to the haem group. The globin syn-
1. the blood flow
thesis is controlled by relevant gene. Haemoglobin
makes up about 98 per cent of cytoplasmatic pro- 2. the oxygen capacity of blood
teins in circulating erythrocytes. There is 97 per cent
of haemoglobin of type A (α2, β2) in adults. The 3. the haemoglobin affinity to oxygen.
48 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

The oxygen release of haemoglobin is expressed by ented to the outer surface of the membrane and the
the dissociation curve of haemoglobin. pH elevation, other to its inner surface. So is the glycoforin sit-
temperature fall and decrease in 2,3-DPG lead to uated, containing polysaccharidic antigens of blood
oxygen affinity enhancement (the shift to the left). groups, similarly situated is the protein 3 forming
Fall in pH, elevation of temperature and of 2,3-DPG channels through which anions can pass into and out
reduce the oxygen affinity (shift to the right). The of erythrocytes. Other proteins are only at the in-
shift of dissociation curve to the left represents si- ner surface of membrane: several enzymes a struc-
multaneously the decrease of oxygen release. Shift of tural proteins, like spectrin and actin, being inter-
dissociation curve to the right occurs under unfavor- connected. They form a network giving the inner
able conditions in organisms. It means also increased structure of the membrane. Tropomyosin and pro-
oxygen release into the tissues. tein 4.1 also participate in the structure formation.
The protein ankyrin binds spectrin and a fraction
2.1.3 Metabolism of erythrocytes of proteins involved on ionic transport. Protein 4.1
binds glycoforin, actin, tropomyosin and spectrin
During their release from bone marrow the erythro- (Fig. 2.3).
cytes lose the nuclei, ribosomes and mitochondria. The erythrocyte are destroyed when their mem-
Thus they lose the ability of proteosynthesis and of brane have lost its flexibility. This quality is needed
oxidative phosphorylation. The glucose, entering the to enable the erythrocytes to pass across the capil-
erythrocytes by diffusion, is converted into glucose laries and especially across the splenic sinuses. The
6-phosphate. About 80 to 90 per cent of it is con- erythrocyte membrane alteration arises by successive
verted into lactate. During the metabolization of two ATP depletion in erythrocytes leading to erythrocyte
molecules of glucose two molecules of ATP are gen- shape change and to forming of sharp projections at
erated. About 10 per cent of intracellular glucose 6- the membrane surface. The ATP depletion causes
phosphate is oxidized in the hexose-monophosphate breaking of the connections in the spectrin and actin
shunt in which glutathione is produced, protecting network. Thus, the localization of proteins at the
the haemoglobin sulphhydryl groups and membranes inner surface of membrane is changed, and irregular
against oxidation by peroxides and superoxides and protein aggregation arises.
against effects of certain drugs and toxins. If the continuity of erythrocyte membrane is im-
The considerable part of ATP, generated by gly- paired the released components are metabolised.
colysis, is spent for the functioning of Na-K-pump. The haem is catabolised by the microsomal oxidative
This pump is required to maintain the ionic balance system. The porphyrin cycle is converted into the
in cytoplasm. The erythrocyte survival in the circu- bile pigments. The released iron is incorporated into
lation is determined by its membrane integrity and the ferritin or it is transported by transferrin into
its flexibility. The membrane of erythrocytes con- the erythrocyte precursors. Iron reversibily binds
tains 50 per cent of proteins, 40 per cent of lipids and the oxygen. Except for this it participates in sev-
10 per cent of carbohydrates. The bilayer membrane eral oxidation-reduction reactions. Substantially the
contains phospholipid and cholesterol molecules in anorganic ion of iron is extremely toxic. Under physi-
the ratio of 1,2 to 1. The molecules are arranged ological circumstances is the iron homeostasis strictly
in the membrane with the hydrophobic chains ori- controlled and balanced.
ented inside the membrane and the polar groups
to the outer plasmatic surface of membrane and to
2.1.4 Absorption of iron
the cytoplasmatic surface of membrane. The outer
(plasmatic) part is richer in lecithin and sphingomye- The absorption of iron occurs mainly in duodenum
lines. The inner part consists of relatively more phos- and in the upper part of jejunum. Anorganic iron
phatidylserine and phosphatidylethanolamine. The salts contain bivalent (Fe2+ ) or trivalent (Fe3+ ). The
lipids of the outer part are freely exchangable with iron enters the organism with food, mainly in form
plasmatic lipids. of trivalent ion. The salts containing Fe3+ are insol-
The cell membrane of erythrocytes contains 8 uble. The acid gastric juice enables the absorption.
types of fundamental proteins. Some polypeptides The low pH value makes the iron salts solubles. The
are located in the membrane so that one end is ori- intake of iron by food is 10–20 mg daily. About 10 per
2.1. Haematopoiesis 49

Figure 2.3: Structure of the red blood cell membrane

cent of this amount is absorbed. The haem present relation exists between the plasmatic ferritin concen-
in the food is more easily absorbed than the anor- tration and iron stores in organism. Ferritin may
ganic iron. The iron is absorbed by epithelial cells be absorbed (swallowed up) by lysosomes, catabo-
in the upper part of gastrointestinal tract. The com- lized to haemosiderin and decomposed to protein,
ponents of the tea, particularly tannin, but also the lipid and iron. Daily loss of iron from organism is 1
phosphates and several other substances, inhibit the to 2 mg. Most frequently the loss originates, under
iron resorption. The iron absorption is connected physiological conditions, in desquamation of cells of
with absorption of heavy metals like lead, mercury, gastrointestinal tract. This loss is compensated by
cadmium and strontium. Increased iron absorption adsorption of iron from food. If the iron loss raises,
is associated with increased absorption of these met- its absorption from gastrointestinal tract becomes
als. enhanced proportionally. The iron absorption can
The precise mechanism by which the iron passes be increased by 30 to 40 per cent. So it is ensured
through the epithelial barrier is not understood. It that the enhanced iron loss is compensated by its
is known that the serum glycoprotein-transferrin proportionate absorption. There is not any mecha-
(m.w. 80 kDa) transports iron into the tissues. One nism to remove the excessive iron and to attain the
molecule of transferrin can bind two atoms of iron. necessary balance available.
All binding-sites together represent the total binding About 80 to 90 per cent of resorbed iron gets into
capacity for iron – TIBC (total iron-binding capac- bone marrow and is available for erythropoiesis. The
ity). Under normal circumstances 20 to 45 per cent half-time between the plasmatic level of iron and its
of this capacity is occupied by iron. Specific recep- concentration in bone marrow is about 75 minutes.
tors at the cells catch up the transferrin from which The iron is incorporated into the haemoglobin. The
the iron is released into the cytoplasm of these cells. iron stores are created in the bone marrow. The
Precursors of erythrocytes in the bone marrow have richest iron stores are deposited in the cells of MPS
a high density of transferrin receptors. (mononuclear phagocytic system) in the bone mar-
Excess of iron in organism is deposited in form of row, in extrahepatocytic structures of the liver, in
ferritin or haemosiderin. The iron in ferritin is pro- the spleen and hepatocytes.
vided with protein coverig and forms iron-apoferritin The reserves of iron in liver can be quantitatively
complex, in which iron is present as trivalent ion determined by virtue of modern methods (atomic ab-
(Fe3+ ). The apoferritin synthesis is stimulated by sorption spectroscopy). Information about the iron
iron. Under physiological circumstances a close cor- stores provides the serum ferritin level. The fer-
50 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

ritin concentration in serum raises according to iron to supply tissues with oxygen. The formation of
amount present in organism and in turn, it falls when 2,3-diphosphoglycerate (2,3-DPG) in erythrocytes is
the iron amount decreases. However, the serum fer- elevated during anaemia. 2,3-DPG binding with
ritin level is elevated in inflammation in oncologic haemoglobin results in the oxyhaemoglobin curve
conditions and in hepatic diseases. During the iron shift to the right. It means, that in tissues is more
deficiency protoporphyrin IX is accumulated in ery- oxygen released from haemoglobin.
throcytes, because it cannot be converted into the The periphery responds to anaemia with compen-
haem. Computerized tomography (CT) of the liver satory dilatation and fall in peripheral resistance of
enables to reveal the iron stores, this method is es- vessels. Owing to this change, cardiac output rises
pecially succesful in excessive increase in iron re- with an increase in stroke volume and mild increase
serves. An other sensitive method is the nuclear mag- in heart rate. Therefore the pulse pressure is elevated
netic resonance. It is particularly useful in long-term and later the systolic pressure falls. Even in a patient
follow-up. with hypertension normal values of systemic arterial
pressure can appear during development of anaemia.
The anaemia treatment may result in reappearing
of hypertension, similarly during the treatment with
erythropoietin. Decreased oxygenation in coronary
vessels impairs the myocardial contractility.
2.2 Anaemias The hypoxia in organism is the cause of develop-
ment of several symptoms. Dyspnea following exer-
cise, headache, tinnitus, palpitations, syncopes, de-
creased libido, sleepdisorders, lability of mood, in-
Anaemia is one of the most frequent manifesta- capability to concentrate may be evident. Anemia
tions of diseases. About one third of patients ad- impairs considerably existing angina pectoris in el-
mitted to the hospital exhibits anaemia. Frequently derly patients with vessel diseases. The long-lasting
the urgent symptoms dominate at the admission and untreated anaemia may unmarked premature de-
anaemia remains unobserved, shifted out of sight on mentia and claudicatio intermittens. Anorexia ap-
later periode. Nevertheless, it could play a key role pears. Further impairment of anaemia may be asso-
in solving of the given status. It is sometimes incor- ciated with tachycardia. A systolic murmur is often
rectly considered to be the consequence of pathologic heard over the precordium owing to the changes in
alteration although the contrary can be right. blood viscosity and blood flow rate changes. Oede-
Anaemia is a condition with haemoglobin reduc- mas of extremities appear. Further progression of
tion in blood below the physiological value relevant anaemia is sometimes associated with thrombocy-
to the given person according to the sex, age, exter- topenia which may land to haemorrhage from various
nal conditions of life and important circumstances in organs, retinal haemorrhage occurs frequently.
organism in the given situation. Reduced concentra-
tion of erythrocytes is frequently accompanied with
decreased haemoglobin. If the changes of water con-
2.2.1 Anaemia due to iron deficiency
tent or its shift in organism are not involved, the The iron deficiency is the most frequent under-
haemoglobin level correlates with the haematocrit lying cause of the classic hypochromic microtic
value (during dehydration even in an anaemic pa- anaemia. The haemoglobin content in erythro-
tient are normal haemoglobin and erythrocyte values cytes is decreased. The hypochromic anaemia with-
due to the plasma volume decrease). out microcytosis occurs in bone marrow dysplasia.
The important role of erythrocytes is to trans- Microcytosis without hypochromia appears some-
fer the oxygen in organism. When the amount of times in anaemias developing during chronic dis-
haemoglobin falls the oxygen supply of tissues be- eases. Hypochromia associated with microcytosis
comes disturbed, therefore the most severe conse- most frequently occurs in anaemias due to iron defi-
quence of anaemia is the hypoxia of tissues. ciency.
If the anaemia is developing slowly the com- The iron deficiency is due to the iron loss from the
pensatory mechanisms begin to function helping organism or its utilization. Enhanced loss of iron is
2.2. Anaemias 51

easier detectable than the intricate problems of iron ysis with haemoglobinuria, pulmonary haemorhage,
utilization. Increased requirement of iron supply oc- bronchiectasias and the blood loss from urogenital
curs during the period of rapid growth commonly in system may also be the cause of iron deficiency.
early postnatal period and during the puberty. The
mother’s milk contains equal amount of iron like the 2.2.1.3 Iron deficiency consequences
cow’s milk however, newborn is easily able to utilize
iron from mother‘s milk. Iron deficiency in newborn The cell growth and proliferation disturbances are
can be manifested by anaemia. Not only anaemia generally observed in iron deficiency. Erythrocyte
itself, but also the iron deficiency itself influences in- formation is impaired owing to their requirements for
favorable the development of the child. During the the iron supply. The iron deficiency has infavourable
puberty is the cereal nutrition insufficient to ensure influence on various systems and functions of organ-
the necessary iron intake. Parasitic diseases are a ism. Infirmity, torpidity, palpitations, dyspnea and
further factor inducing the iron loss from organism. very commonly all symptoms of chronic anaemias
appear.
Many symptoms of iron deficiency originate in
2.2.1.1 Decreased (defective) iron absorp-
the gastrointestinal tract region. Gingivitis, glos-
tion
sitis with red, smooth and shing tongue surface is
Decrease in iron absorption is observed in several frequently present. Atrophic gastritis with achlorhy-
pathological conditions. Following partial or total dria also occurs. In long-lasting iron deficiency the
gastrectomy is the iron absorption impaired, in par- Plummer-Winson’s syndrome may occur, with angu-
ticular owing to the acceleration of motility and of lar stomatitis, hyperkeratosis of oral mucosa, break-
the food passage in the proximal part of jejunum. ing nails, atrophic glossitis, atrophic oesophageal
In this part of the gut is the site of iron absorption. alterations and microcytic, hypochromic anaemia.
Achlorhydria is a further factor impairing the iron The nails in addition to the fragility are concave and
resorption. Patients with chronic diarrheas and with thin. In women menorhagia and atrophic gastritis
malabsorption may have disturbances of iron absorp- occurs. The iron deficiency may lead to very specific
tion. symptoms like excessive eating of starch (amylopha-
gia), of ice (pagophagia), earth (geophagia) also of
2.2.1.2 Increased iron loss plaster, or even of lead dyes. All these substances
bind with iron in the gastrointestinal tract and fur-
Physiological iron loss occurs during menstruation ther impair the iron deficiency. The iron deficiency
and pregnancy. To maintain the iron balance during enhances the lead absorption from gastrointestinal
the menstruation, double intake of iron is needed. tract in so far that lead intoxication may develop.
During the pregnancy 500 mg of iron passes daily The iron deficiency is developing insidiously. In
from the motherďs organism into the fetal body. The detailed observation firstly a decrease of iron stores
increased requirement is ensured by augmented iron without affecting the erythropoiesis is found. In the
absorption in GIT. An increased supply of iron in further stage deficient erythropoiesis is found due to
food is, as matter of course, needed. iron deficiency. The end-stage is the iron deficiency
Gastrointestinal disturbances can usually cause in- anaemia. The erythrocytes are hypochromic and
creased loss of iron. Blood loss and thus the iron loss small. Bizzarre shapes of erythrocytes – the poikilo-
is observed in gastric or duodenal ulcers, in gastri- cytes are present. The life span of erythrocytes in
tis, haemorhoids and adenocarcinoma of the colon. the circulating blood is considerably shortened. The
During chronic intake of salicylates blood loss arises reticulocyte number use to be normal, or moderately
due to the haemorhagic gastritis induced also by elevated. It culminates about on tenth day after iron
other nonsteroidal antiphlogistic drugs. In all pa- administration.
tients with gastrointestinal carcinoma anaemia due
to iron deficiency develops.
2.2.2 Sideroblastic anaemias
Gastrointestinal blood loss may be present also in
haemorhagic diatheses and blood coagulation distur- The sideroblastic anaemia is a hypochromic anaemia
bances of various origin. The intravascular haemol- with elevated iron level in serum and enhanced trans-
52 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

ferrin saturation. This condition is due to haemosyn- 2.2.3 Megaloblastic anaemias

thesis disturbance. In the peripheral blood siderob-
lasts are present. Sideroblast is a normocyte con- Megaloblastic anaemias are due to the impaired
taining the non-haemoglobin iron. Mitochondria DNA synthesis. The cells with a high metabolic
are localized around the nucleus forming the typical turnover are affected primarily, especially the
ringlet of sideroblasts. Sideroblasts are regarding the haematopoietic precursor cells and gastrointestinal
haemoglobin content hypochromic. They are smaller epithelial cells. The division of these cells becomes
than the mature erythrocytes. slower, but the cytoplasm development is normal,
thus the cell dimensions grow large, they become
Hereditary sideroblastic anaemia is due to the im- megaloblastic. The RNA to DNA ratio increases.
paired activity of delta aminolevulic acid synthetase. Megaloblastic erythroid cells tend to desintegration
This enzyme acts at the beginning of haem biosyn- in the bone marrow leading to so-called noneffective
thesis. This type of anaemia can often be succesfully erythropoiesis. The megaloblastic anaemias are most
treated with high doses of pyridoxine. frequently due to the vitamin B12 and / or folic acid
Acquired sideroblastic anaemia can be induced by deficiency.
isoniazide application or by excessive alcohol intake.
In both cases induced disturbance of pyridoxine me-
2.2.3.1 Folic acid
tabolism is involved. In lead intoxication the haem
synthesis is impaired. In about 30 per cent of pa- Folic acid is a trivial term of pteroylmonoglutamate
tients admitted to hospitals for chronic alcohol abuse (pteridine, P-aminobenzoic acid and L-glutamic
treatment are sideroblasts present in blood smears. acid). It is synthesized by many plants and bacte-
Sideroblastic anaemia can appear in neoplastic dis- ria. Fruits and vegetables contain sufficient amount
eases usually due to cytostatic treatment. It may of folic acid to saturate the normal human demands.
occur also in inflammatory conditions (rheumatoid However it can be decomposed by cooking. An aver-
arthritis). age consumption is about 50 µg daily. The demands
The sideroblastic anaemia appears most frequently are many times higher in conditions with enhanced
without apparent cause, usually in elderly people. metabolism (e.g. during the pregnancy). The fo-
The time of cell maturation is always impaired. Dur- lates (salts and esters of the folic acid) are in the
ing the progression of sideroblastic anaemia neu- intestine converted into the mono- and diglutamates,
tropenia and thrombocytopenia appear associated which are absorbed in proximal jejunum. There are
with bleeding enhancement. Specific treatment of id- proteins binding with folates present in the blood
iopathic forms of sideroblastic anaemias is unknown. plasma. The plasmatic folates are present mainly in
Application of erythropoietin, GM-CSF and inter- the form of N–methyltetrahydrofolate. In this form
leukin 3 might be promising. they are transported into polyglutamate form. There
is about 5 to 20 mg of folic acid present in the hu-
man body. One half of this amount is stored in the
liver. The folic acid deficiency is manifested months
2.2.2.1 Haemosiderosis due to blood trans- after its intake with food, or its deficient absorption
fusion decreased.
Folates provide the transfer of methyl, methy-
Iron level in organism may inadequately rise follow- lene and formyl groups in the process of DNA and
ing repeated blood transfusions in severe anaemias. RNA synthesis. During folate deficiency the growth
The symptoms reflect the alterations of organs being and the maturation of rapidly developing cells in
the iron depots (heart and liver). The cardial sidero- bone marrow are impaired. The thymidylate syn-
sis is the cause of arrhythmias, conduction defects thase catalyzes the thymidine synthesis of deoxyuri-
and the cause of congestive heart failure. Elevated dine and of 5,10-methylenetetrafolate. If this syn-
iron deposits in the liver impair the hepatocytes, lead thesis is impaired, the intracelullar concentration of
to necrosis, fibrosis and cirrhosis. Gonadal dysfunc- deoxyuridinephosphate rises and is incorporated into
tion and ACTH deficiency appear in this condition the DNA at the site where, under normal circum-
as a results of iron depositions in pituitary gland. stances, the deoxythymidinetriphosphate is present.
2.2. Anaemias 53

This DNA has an increased fragmentation, respon- Methylcobalamin is an essential cofactor in homo-
sible for the cell growth and maturations deviations cysteine conversion into the methionine. Folates are
during the folate deficiency. involved in this process. The methionine produc-
tion from homocysteine is catalysed by methionine
2.2.3.2 Cobalamin – vitamin B12 synthetase requiring the presence of methylcobal-
amin and the transfer of methyl-group from CH3
It is an organometalic compound with structure sim- tetrahydrofolate to the homocysteine. Methionine
ilar to porfyrin containing an atom of cobalt. The and tetrahydrofolate arise. In methylcobalamin and
human organism is unable to synthesize cobalamin in 5-methyltetrahydrofolate (CH3 -tetrahydrofolate)
(Cbl). Intake of the daily minimum (2,5 µg of cobal- defficiency homocysteine is accumulated. Impair-
amin) is accomplished by food. ment of homocysteine conversion to the methionine
The source of vitamin B12 is the meat and the can be responsible for neurologic complications dur-
milky products. Cobalamin is released from the food ing cobalamin deficiency. Methionine is needed for
in the stomach. The released cobalamin is bound choline and choline containing phospholipids produc-
with gastric R-protein (R-binding protein), which is tion and for methylation of myelinic protein.
present in various synthethase of some glands (saliva, Adenosylcobalamin is important for conversion of
gastric juice, bile, milk), in plasma and in phago- methylmalonylcoenzyme A (CoA) in to the succinyl-
cytes. Its precise physiological function is unknown. coenzyme A. Adenosylcobalamin deficiency leads to
The R-Cbl complex passes from the stomach into the increase of methylmalonyl-CoA and its precursor
duodenum, where the R-protein is released and Cbl CoA in tissues resulting in fatty acids alterations and
is bound to the intrinsic factor IF. Intrinsic factor is a disturbance of neuronal lipids.
glycoprotein with molecular weight of 50 000 daltons.
It is produced in the gastric parietal cells and its pro- 2.2.3.3 Types of megaloblastic anaemias and
duction is directly proportional to the hydrochloric their incidence and prevalence
acid production. The Cbl-IF complex is resistent to
the proteolytic digestion. It enters unchanged the Four types of megaloblastic anaemias exists:
distal ileum. Here are at the mucosal surface re-
1. due to cobalamin deficiency,
ceptors present binding with Cbl-IF complex. The
complex enters the cells of ileal mucosa where the IF 2. due to deficiency of folic acid,
is during several hours destroyed and the free cobal-
amin is bound to an other transporting protein – the 3. induced by some drugs,
transcobalamin II (TC II). The complex cobalamin 4. seldom occuring forms of enzymic disturbances.
– TC II enters then the blood circulation and its up-
take occurs preferentially in the liver and in the bone The first two types may be due to low cobalamin
marrow. About one half of the cobalamin intake is or folic acid intake, to impaired absorption of these
stored in the liver. The other half is deposited in substances or their utilisation.
other tissues and organs including the bone marrow. Drugs which can induce megaloblastic anaemia be-
If the demands for cobalamin are minimal, its stores long to the groups of purine or pyrimidine antago-
in organism will be sufficient for some years. nists, or to the substances inhibiting the DNA syn-
The cobalamin bound to transcobalamin I (TC I) thesis.
prevails in the blood. The transcobalamin I is a gly- Megaloblastic anaemia in cobalamin deficiency is
coprotein. TC II complex and TC I complex dif- often termed pernicious anaemia. This term should
fer from each other by the rate of cobalamin re- be used for designation of the megaloblastic anaemia
lease availability. The organism can obtain cobal- due to a lesion of gastric mucosa leading to the intrin-
amin from TC II complex in a few hours, but from sic factor deficiency. The term pernicious anaemia
TC I complex even in a few days. has been accepted because until 1926 this type of
There are two active forms of cobalamin present anaemia was frequently fatal.
in human organism: methyl-cobalamin and adeno- In folic acid deficiency the megaloblastic anaemia
sylcobalamin. Cyanocobalamin is converted into ac- occurs less frequently. Its occurence is observed in
tive forms before entering the tissues. chronic alcoholism.
54 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

The chemotherapy of malignancies and disorders tor, most frequently due to the gastric mucosa at-
of immune system may also lead to megaloblastic rophy. It is not a simple atrophy of mucosa. Very
anaemia. frequently a further pathological condition is found,
At present the cobalamin deficiency occurs more e.g. thyroidal disease, suprarenal cortical atrophy,
frequently in vegetarians and especially in vegans. or insulin-dependent diabetes mellitus. A polyen-
Megaloblastic anaemias in cobalamin deficiency docrinopathy is offer involved. Antibodies against
are manifested by haematologic, gastrointestinal and the adrenal, thyroid, parathyroid glands, and against
neurologic alterations. the stomach are detected.
The anaemia prevails in blood smears. Throm- During the lymphocyte analysis a significant de-
bocytopenia is sometimes observed. Symptoms of crease in the circulating supressor cell number is
anaemia include weakness, bradypsychia, dizziness, found. In the bioptic examination of gastric mucosa
tinnitus, palpitations, angina pectoris, and signs of a high number of lymphocytes is observed. Some
congestive heart failure. The patient is pale, his skin lymphocytes bind directly with the intrinsic factor
and sclerae are slightly subicteric. Heart rate is ac- in gastric mucosa. Parietal cells of gastric glands
celerated. The heart is usually enlarged and systolic produce intrinsic factor and the hydrochloric acid.
murmurs are present. Liver and spleen may be also The circulating antibodies to the gastric parietal cells
enlarged. Subfebrility can be present. are found in 90 per cent of patients with pernicious
The gastrointestinal alterations are observed in anaemia. The antibodies react with the membranes
the mouth. The tongue is usually smooth, red and of parietal cells. The parietal cells are progressively
often painful. Anorexia is present, leading to body destructed, the production of hydrochloric acid and
weight loss. Decreased intake of nutrients is often of intrinsic factor decreases and the atrophic gastritis
complicated by frequent diarrhea. is developing. Antibodies to the intrinsic factor are
Neurological disorders are very variable. They be- found in serum and in gastric juice in aproximately
gin with demyelinisation and continue with axonal 70 per cent of patients. The underlying cause of pari-
degeneration and finaly end with complete loss of etal cells destruction is the activation of inflamma-
neurons. These alterations attack first the peripheral tory reaction components, triggered of antibodies or
nerves, the medulla dorsalis and cerebellum. The immune complexes. The histological examinations
disturbances of sensitivity appear first, then anaes- show the cellular atypia.
thesia and weekness. Later ataxia and disorders of Following total gastrectomy without vitamin B12
movement coordination are found. Disturbances of intake megaloblastic anaemia appears in every case.
sphincter functioning are also observed. Patient is Megaloblastic anaemia may occur also in jejunal
irritable, or dementia can develop. The anaemia is strictures and diverticles. In these conditions can
usually tremendous during the examination. The pa- a large number of microorganisms colonize the small
tient tolerates this condition quite well, because of intestine and destruct the present cobalamin. Com-
very slow progress of the anaemia. plicated enteritis may also be the underlying cause
of cobalamin deficiency. The jejunum resection and
Pernicious anaemia malabsorption are commonly the cause of vitamin
B12 deficiency. An inborn disturbance of vitamin
This disease is characterized by the presence of
B12 resorption associated with proteinuria may in-
macrocytes in peripheral blood and of megaloblasts
frequently be involved.
in the bone marrow. The asynchronous matura-
tion of erythroblasts is due to the impaired DNA Megaloblastic anaemia may develop in associa-
synthesis. The cytoplasm of macrocytes contains tion with cytostatic treatment, especially if agent
more haemoglobin than under physiological circum- influencing the DNA synthesis are used. Substances
stances. Owing to this, and to the impairment of nu- with antiviral effects can also induce megaloblastic
cleus development, the erythrocytes exhibit deforma- anaemia.
tions (anisocytosis, poikilocytosis). The neutrophiles Macrocytes are found in peripheral blood in mega-
use to be hypersegmented. loblastic anaemia. There is decrease in the throm-
Pernicious anaemia is due to cobalamin deficiency, bocyte and leucocyte count and the erythrocytes ex-
which itself is caused by the absence of intrinsic fac- hibit various shapes and size. The anisocytosis and
2.2. Anaemias 55

poikilocytosis is usually associated with ovalocyto- and LDH are increased in plasma so is the urobilino-
sis and with the presence of nucleus in macrocytes. gen in urine. The life-span of erythrocytes in periph-
The presence of six or more lobed neutrophils found eral blood is significantly shortened. Splenomegaly
in blood examination is commonly sufficient to iden- and hepatomegaly and cholelithiasis are frequently
tify the megaloblastic anaemia. The bone marrow present in chronic haemolytic anaemia. The skin is
is hypercellular. Erythrocyte precursors are very icteric and pale. Erythroid hyperplasia is present in
large. The ineffectiveness of the erythropoiesis is the bone marrow.
manifested by possible destruction even of 90 per The haemolysis can be extra- or intra-vascular.
cent of erythrocyte precursors in bone marrow. Ab- Haemolysis occuring in the reticuloendothelial sys-
normal mitoses and gigant metamyelocytes occur. tem is termed extravascular haemolysis.
Megakaryocyte number is reduced and they have ab-
normal shape. 2.2.4.1 Intravascular haemolysis
The identification of the actual pathogenesis of
megaloblastic anaemia requires the serum cobalamin The intravascular haemolysis appears following
level determination, the GIT investigation and mi- transfusion, in patients with arteficial valve, or as a
croscopic examination of bone marrow. result of paroxysmal cold or noctural haemoglobin-
uria, or as cold-agglutinins or by clostridial in-
2.2.4 Haemolytic anaemias fection induced haemolysis. Haemoglobin is actu-
ally released from intact erythrocytes in these cases.
The haemolytic anaemia is due to the increased ery- The released haemoglobin is bound to haptoglobin,
throcyte destruction. The bone marrow is capable haemopexin, or to albumin in blood plasma. The up-
to increase the erythrocyte production even up to take of haptoglobin-haemoglobin and haemopexin-
the eight fold values. If anaemia appears during in- haemoglobin complexes runs rapidly in the liver.
creased erythrocyte destruction it is the sign that The haem-albumin complexes (methaemalbumin)
the compensatory capacity of bone marrow has been circulate in the blood during some days. If the
exceeded. Under physiological circumstances the en- binding capacity of plasmatic proteins is exceeded,
zymic activity in erythrocytes falls progressively and haemoglobinuria appears. The haemoglobinuria it-
they become not easily deformable. The erythro- self does not damage kidneys, nevertheless, other
cytes fulfil their functions in organism 120 days in components (stroma) of disturbed erythrocytes exert
average. a very infavorable effect on kidneys. The accumula-
Their life-span is substantially shortened in tion of ”these rests” of erythrocytes in kidneys can
haemolytic anaemia. It can last only several days induce acute renal failure. Chronic haemoglobinuria
or even several hours. results in iron deficiency. Renal tubules participate
From pathophysiological point of view haemolytic in this process. During haemoglobinuria the tubular
anaemias may be caused by cells become destructed because they are ”overfilled”
• abnormalities of erythrocyte membrane with haemosiderin originating from iron absorbed
from haem. There is a significant fall of plasmatic
• enzymic deviations haptoglobin level and elevation of lactate dehydro-
genase (LDH) values, originating from haemolysed
• haemoglobin alterations erythrocytes in acute intravascular haemolysis.
• interaction of erythrocyte membranes with an-
tibodies 2.2.4.2 Extravascular haemolysis
• effects of toxins or microbial products The extravascular haemolysis represents a premature
elimination of erythrocytes from circulation. Ery-
• high temperature or mechanical injury
throcytes are sequestrated by fixed phagocytes in
In haemolytic anaemia erythrocytes with normal spleen and in liver. Only a very little amount of
or abnormal shape may occur. The reticulocyte haemoglobin gets into the plasma. The iron recir-
number in peripheral blood is elevated. Erythro- culates and is used for further erythropoiesis. Dur-
cytes with the rests of nuclei may occur. Bilirubin ing the haemolysis its plasmatic level rises, the hap-
56 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

toglobin level falls, but nevertheless haemoglobinuria toskeleton and the alterations of spectrin. The spec-
is not present. The values of LDH, originating from trin deficiency correlates usually with the severity of
destructed erythrocytes, are elevated. The level of anaemia. A structural anomaly of ankyrin may be
conjugated bilirubin depends on haemolysis and the sometimes present. In addition to this, the sodium
functional capacity of liver. During noneffective ery- permeability of spherocytes is enhanced and the re-
thropoiesis the intramedullar haemolysis appears be- quirement of ATP supply is increased to ensure the
ing also an extravascular haemolysis. cation pumps functioning. If not, water accumula-
tion in the cell appears.
2.2.4.3 Underlying causes of haemolytic Hereditary spherocytosis is an autosomal domi-
anaemias nant inborn disorder characterized by production of
abnormal erythrocytes which are precociously de-
The causes leading to haemolytic anaemias can be stroyed in the unaltered spleen. Clinical manifesta-
various. To understand the etiopathogenesis of tions of the hereditary spherocytosis are the anaemia,
haemolytic anaemias a classification according to the splenomegaly and jaundice. This condition was for-
underlying cause is needed. The two basic groups of merly termed the inborn haemolytic icterus. It is im-
haemolytic anaemias in this classification form the possible to prevent the enhanced haemolysis of sphe-
inborn and the acquired haemolytic anaemias. The rocytes. The splenectomy – removement of the or-
underlying cause may be the abnormalities of ery- gan, where the erythrocytes sequestration occurs the
throcytes or the alterations in plasma, or in circula- most intensively, may be the only way of the effective
tion. The factors participating in the etiopathogen- treatment.
esis may be various: antibodies, mechanical injury
or infections or toxic substances. According to the There exist similar membrane abnormalities, with
disease course and duration the haemolytic anaemia occurence of eliptocytes or stomatocytes in the pe-
may be acute or chronic. The antibodies can be ripheral blood. The stomatocytes have atypical
localized at the erythrocyte surface or they can be darker central area. They occur also in hereditary
present in the plasma. spherocytosis and can be observed in blood smears
Haemolysis of erythrocytes can appear owing in alcoholism, in hepatic cirrhosis and sodium pump
to the intracorpuscular abnormalities. There are defects. Some drugs and considerable pH change can
frequently defects of erythrocyte membrane, of induce a similar deformation of normal erythrocytes.
haemoglobin, or of enzymes. Sclerocytosis is the The hereditary spherocytosis should be distinguished
manifestation of the most common membrane de- from the spherocytosis in haemolytic anaemia, which
fect. Erythrocytes with spheric shape are present in is due to antibodies.
the peripheral blood. The mean haemoglobin con- The most common enzymic disturbance is the glu-
tent in this type of erythrocytes is elevated. The os- cose 6-phosphate dehydrogenase (G6PD) deficiency.
motic resistance is decreased and the life-span of ery- There are also other enzymic defects but their oc-
throcytes in the circulating blood is shortened. The curence is very uncommon (pyruvate kinase and hex-
splenomegaly, bilirubin concrements in the gallblad- okinase deficiency). Normal erythrocytes use the
der are present and intermittent jaundice often oc- glucose to form ATP and 2,3-diphosphoglycerate
curs. Icterus appears especially following stress, in- (2,3-DPG). ATP is necessary for maintenance of the
fections and pregnancy. During infections the aplas- membrane flexibility and the cation pumps function-
tic crisis may appear. It is usually due to the bone ing. 2,3-DPG influences the oxygen binding with
marrow depression, and to the enhanced haemolysis haemoglobin and especially the oxygen uptake in tis-
of spherocytes. The basis of the haemolysis is the se- sues. About 10 per cent of glucose is metabolized
questration of erythrocytes with reduced deformabil- in the hexose monophosphat shunt where NADPH
ity. These erythrocytes require extremely high ATP is formed. NADPH is necessary for regeneration
supply to maintain the membrane flexibility. The of glutathione protecting the haemoglobin against
molecular basis of the spheric shape of erythrocytes denaturation, and the sulphydril groups in cellular
is not understood precisely. A complex of several membranes. So the integrity of cellular membrane is
causes is probably involved. The most important maintained. NADPH detoxicates also the hydrogen
are those concerning the proteins forming the cy- peroxide and oxygen radicals. G6PD deficiency leads
2.2. Anaemias 57

to oxidative impairment of erythrocytes. There is an like collagen–vascular diseases, chronic inflammatory

inherited disturbance involved having several forms. processes of intestine, chronic lymphatic leukaemia
The variant occuring in blacks is milder. Another or lymphomas are frequently accompanied with au-
variant the so-called mediterranean (occuring in the toimmune haemolytic anaemias. Autoantibodies in-
region of Mediterian Sea) is a condition with very crease with age. Haemolytic anaemia need not to be
low values of G6PD, reaching only 5 per cents of always present. The haemolysis itself does not de-
normal values. G6PD deficiency is the cause of the pend on the presence of antibodies. A complex of
haemolysis during hepatitis, during high intake of vi- factors as density of antibodies at the erythrocyte
cia faba or of drugs with oxidative effects. A further surface, implication of complement and tendency to
form of G6PD deficiency is observed in some intesti- phagocytize the erythrocytes by macrophages in the
nal disorders associated with an increase in number spleen are involved in these processes. Autoimmune
of bacteria and in uraemia. haemolytic anaemias (AIHA) can be divided into two
groups:
2.2.5 Acquired haemolytic disorders 1. the warm-antibody induced haemolytic anae-
mias,
The life-span of erythrocytes may be shortened in
infectious diseases, in malignant processes, in car- 2. the cold-antibody induced haemolytic anaemias.
diovascular and immune disorders. The cause of
haemolysis is the most frequently apart from erythro- 2.2.5.2 Warm-antibody induced haemolytic
cytes themselves. The acquired haemolytic anaemias anaemias
can be classified into two categories according to the
positivity or negativity of the Coomb’s test. These conditions are mediated by IgG antibodies
bound with erythrocytes at normal body temper-
2.2.5.1 Anaemia mediated by antibodies ature. They can fixe also the complement. This
group of anaemias is usually associated with col-
This group comprises conditions where the antibod- lagenoses, lymphomas, it occurs in chronic lympho-
ies are directed straight against the antigens of ery- cytic leukaemia, in ovarial teratomas or in colitis
throcytes and are directly or indirectly responsible ulcerosa. More than one half of cases are of un-
for the haemolysis. The antibodies formed follow- known origin, nevertheless the idiopathic haemolytic
ing the blood transfusion or by sensitization to ”for- anaemia can be a sign of later appearing systemic
eign” cells during pregnancy are termed alloantibod- diseases. The clinical manifestation of anaemia may
ies. The antibodies formed without the sensitization be various. It can be a form manifested by moder-
are the autoantibodies representing the deviations of ate asymptomatic jaundice and splenomegaly. The
the immunity regulation itself. Presence of the anti- haemolysis is very prominent and the signs of ery-
bodies at the erythrocyte surface decreases their flex- throcyte loss compensation by bone marrow can be
ibility and make them more sensitive to the phagocy- observed in severe cases. If the level of antibodies is
tosis performed by macrophages in the spleen and the high they are detectable by positive indirect Coomb’s
liver. Macrophages destroy and ”engulf” the portion test in plasma. Coomb’s indirect and direct antiglob-
of membrane covered with antibodies or the comple- ulin test is used to detect the antierythrocytic anti-
ment. Erythrocytes which have lost a part of their bodies or other plasmatic proteins participating in
membrane become spherical, their flexibility is de- the erythrocyte agglutination. The agglutination is
creased and their life-span in the circulating blood is used as evidence of the antibody presence at the sur-
shortened. face of erythrocytes. There are components of com-
Autoimmune haemolytic anaemias (AIHA) are plement C3b and C3d.
characterized by antibodies against the own anti- Thrombocytopenia is often observed in AIHA aris-
gens of erythrocytes. Autoantibodies arise sponta- ing also on immune basis. The number of reticulo-
neously or as response to a situation where an hap- cytes in peripheral blood is usually increased. The
ten (often a drug) is present. A manifestation of haptoglobin level in serum is commonly low. Sphe-
a systemic disease is involved about in 40 per cent rocytes are present sometimes in peripheral blood.
of cases. Diseases and disorders of immune system Their number is variable. Bilirubin level raises.
58 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

The possible therapeutic intervention is to influence is called acrocyanosis. This condition can be posi-
the binding and the production of antibodies. The tively influenced by minimalization of the exposure
splenectomy is an extreme solution. Immunosupres- to the cold.
sive drugs may be useful in refractory forms of dis-
ease. The blood transfusion is inefficient because the
transfused blood corpuscules are more rapidly de- 2.2.5.4 Paroxysmal cold haemoglobinuria
stroyed than the own erythrocytes of the patient.
The treatment with steroids reduces the antibody It is an infrequent condition. Under the influence of
binding with the fixed macrophages and thereby the cold the polyclonal IgM antibodies are bound with
rate of erythrocyte destruction becomes decreased. erythrocytes fixing the complement. During the re-
warming the complement cascade becomes activated
and a very intense intravascular haemolysis arises.
2.2.5.3 Cold-antibody induced haemolytic This condition is associated with syphilis or with vi-
anaemias ral infections.
Cold agglutinins inducing the haemolytic anaemias
have a large temperature range. They are bound
with erythrocytes at the temperature up 4o C to 2.2.5.5 Drug-induced haemolytic anaemias
about 30 to 32o C. This temperature (30 to 32o C)
Are relatively common conditions. According to the
occurs in acral parts of organism during exposure
type of haemolysis three forms can be distinguished:
to moderate cold. In low temperature reacting IgM
antibodies may be produced in organism during the
1. The hapten type
infectious mononucleosis, cytomegaloviral infections
The drug binds with the erythrocyte membrane
and mycoplasmal pneumonia or during protozoal in-
forming a neoantigen against which antibod-
fections. The produced antibodies may survive in
ies are produced. The presence of the drug
organism days and weeks.
is needed for arising haemolysis. Examples of
An independent idiopathic by cold agglutinin in-
hapten drugs are most commonly penicillins and
duced syndrome is characterized by the presence
cephalosporines.
of monoclonal IgM antibodies. It can precede the
Waldenstrom’s macroglobulinaemia, but it can per-
sist years without malignant transformation. The 2. The ”innocent” harmless type
polyclonal cold antibodies IgM are formed imme- The drugs binding to the plasmatic proteins
diately after the infection. They may not persist stimulate the antibodies forming the immune
long time in organism, in the contrary to the mon- complexes and activate the complement. To the
oclonal cold-antibodies IgM persisting years in or- erythrocytes as with – the innocent passangers
ganism. Cold-IgM antibodies are bound with the – the complement is bound. These erythro-
erythrocytes during the organism exposure to cold. cytes can haemolyze intra- or extravasculary.
They fixe the complement at the surface of erythro- The rate of haemolysis depends on the speed
cytes. When the erythrocytes become rewarmed, the of complement activation and inactivation. At
antibodies dissociate and only the activated comple- the erythrocyte surface is only the complement
ment remains at the erythrocyte surface. The fixed present. This type of haemolysis occurs follow-
C3b component of the complement is sufficient to ing sulfonamide-, phenothiazid-, quinine- and
make erythrocyte being removed by macrophages in isoniazid- treatment.
the spleen. The C3 component fixed to the erythro-
cyte membrane is converted into the inactive C3d 3. The alpha-methyldopa type
form. This influence the further binding or activa- Haemolytic anaemia develops in chronic treat-
tion of C3. These processes are responsible for the ment with alpha-methyldopa. Alpha-methyl-
rate of haemolysis. dopa probably modifies the antigen system of
The patients with haemolytic anaemia induced by erythrocytes. Levodopa and antiinflammatory
cold-antibodies have various kinds of pains. Their drugs may also induce a similar type of haemol-
acral parts become blueish if exposed to cold – what ysis.
2.2. Anaemias 59

2.2.5.6 Hypersplenism heavy metals. Arsenic and copper bind to sul-

phydryl groups of various endogenous compounds
This term designates a condition with massive se- (e.g. glutathion, coenzyme A etc.). The venoms
questration of erythrocytes, leucocytes and throm- (snake venom) contain lysolecithinase inducing the
bocytes in abnormally functioning spleen. Under lysis of erythrocytes destroying directly their mem-
pathological circumstances the aging erythrocytes branes. In patients with advanced hepatic cirrhosis
are taken up by spleen in its convoluted poorly oxy- the haemolytic anaemias may develop because the
genated sinusoids. In hypersplenism young active erythrocyte membranes absorbe an immense amount
erythrocytes are taken up by the spleen and so are of cholesterol. The most common causative factor of
unaltered leucocytes and thrombocytes. Therefore parasitic diseases it is malaria.
pancytopenia appears, however also bicytopenia –
the decrease of two types of blood cells, or only of
a single type of blood cells may be present. Hyper- 2.2.5.9 Haemolytic anaemias induced by
splenism is characterized by the presence of reduced trauma of erythrocytes
number of blood elements in the circulating blood During extracorpolar circulation the erythrocytes
and of a large number of them in the bone marrow. may be mechanically impaired. This is the so-called
Decreased number of a certain type of blood el- fragmentation haemolysis. The plastic heart valves
ements in peripheral blood is associated with com- or vascular shunts can be in the development of
pensatory hyperplastic haemopoiesis in the given line haemolytic anaemia implicated. Fragments of ery-
of differentiation and with consequent disorder of throcytes are found in peripheral blood. The re-
maturation. Hypersplenism may develop in chronic maining erythrocytes are small spherical microsphe-
haemolytic anaemias due to whatever causative rocytes with increased polychromia. The level of
factor, during chronic infections, leukaemias and plasmatic haptoglobin is decreased and the values of
myeloproliferative diseases, lymphomas, rheumatoid bilirubin and of LDH are elevated. If the conditions
arthritis and in lipid metabolism disturbances. duration is very long, iron deficiency can develop ow-
ing to the haemosiderinuria. The erythrocyte frag-
2.2.5.7 Paroxysmal nocturnal haemoglobin- mentation arises also in extensive burns. Intravascu-
uria lar haemolysis without fragmetnation of erythrocytes
arises following extreme physical exertion. It is com-
This condition is an acquired disorder associated monly described in Marathon runners and during or
with enhanced sensitivity of erythrocytes to comple- after long-lasting marches.
ment – mediated impairment. Also the precursors of
erythrocytes may be involved. This condition occurs
2.2.5.10 Microangiopathic haemolytic
in bone marrow aplasia and leukaemia. Apart from
anaemia
erythrocytes also the granulocytes and thrombocytes
exhibit enhanced sensitivity to the lytic effect of the This condition occurs when fibrin is formed inside
complement. The binding of the complement com- the vessels and the small vessels are partially oc-
ponent C3 to erythrocytes and granulocytes is in- cluded by microthrombi. Normal erythrocytes are
creased. The paroxysmal nocturnal haemoglobinuria fragmented in this condition. The microangiopathic
may occur also independently, not only in bone mar- haemolytic anaemia develops during the dissemi-
row aplasia or leukaemia. It can result in leukaemia. nated intravascular coagulation (DIC), in thrombotic
In the bone marrow is usually a compensatory hy- thrombocytopenic purpura, haemolytic uraemic syn-
percellularity found. Iron deficiency is uncommon. drome, in malignant hypertension and in transplant
rejection. The thrombocytopenia is present owing
2.2.5.8 Haemolytic anaemias due to chemi- to the simultaneously occurring intravascular coag-
cal substances, toxins and parasites ulation in these conditions. The thrombofilic condi-
tion occurring in malignant tumors (particularly in
The underlying cause of haemolytic anaemia can be the mucous-producing adenocarcinomas of GIT) as-
caused by various anorganic substances and com- sociated with the occurrence of thrombosis is termed
plexes of organic compounds, toxins, venoms and Trousseau’s syndrome. DIC may be only one of the
60 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

haemostasis alterations which are theirs paraneoplas- gen transport or anaemia. The mutations concerning
tic manifestation. haemoglobin function may be manifested by impair-
ment of its solubility, by instability or by changes
2.2.6 Haemoglobinopathies in affinity to oxygen. The impaired globin synthe-
sis is secondarily connected with disorders in haem
Haemoglobin is an allosteric protein responsible for synthesis leading usually to haemolytic anaemia.
the O2 , CO2 a H+ transport. It is the substan- The altered structure is accompanied with abnor-
tial protein of erythrocytes. Haemoglobin is com- mal haemoglobin function.
prised of four polypeptide chains containing more
than hundred aminoacids. The iron present in the
2.2.6.1 Sickle cell anaemia (drepanocytosis)
haem group is responsible for the reaction with the
oxygen. The chains are denoted as alpha, beta and This condition is a single base mutation of DNA
delta chains. The haemoglobin of healthy adults molecule leading to the substitution of valine for
(adult haemoglobin) contains two alpha and two non- glutamic acid. This type of haemoglobin exhibits
alpha chains (beta or delta). The basic configuration decreased solubility. If the HbS is less satu-
of chains is linear, the alpha chain contains 141 and rated with oxygen it polymerates in erythrocytes
the remaing chains 146 aminoacids. One portion of (drepanocytes). The alterations arise in the mem-
haemoglobin forms in the chain alpha helix, another brane of erythrocytes, cellular dehydratation devel-
portion is three dimensional and the further part is ops and their deformability becomes decreased. The
of tetrahedral shape. altered erythrocytes may cause occlusion in the mi-
The haemoglobin molecule operates as an impor- crocirculation resulting in microinfarctions of vital
tant component of buffer system. The imidazole organs. Crises arise characterized by bone pains,
group at the histidin operates as acceptor of pro- spleen autoinfarctions and renal damage. HbS gene
teins with disociation constant within the physiolog- is detected in about 10 per cent of American blacks
ical range of the blood pH. Haemoglobin exhibits a and in 25 per cent blacks in Africa. The only advan-
large buffering capacity (about 53 mmol/l) what en- tage of this hemoglobinopathy is, that the patients
ables to minimize the pH value changes in blood dur- with this condition are resistent against malaria
ing the O2 binding and CO2 release in lungs, and vice caused by Plasmodium falciparum. 90 per cent of
versa in tissues. haemoglobin in homozygotes is HbS, the remainder
The oxygen saturation of haemoglobin falls from is HbF or HbA2. This condition is clinically mani-
100 to 75 per cent during the oxygen transport fested already early, after the birth, when the HbF
from the lungs (pO2 100mm Hg) into the tissues begins to decrease physiologically. Main symptoms
(pO2 40 mm Hg). The oxygen release is enhanced by are oedemas of extremities, splenomegaly, infarc-
2,3-diphosphoglycerol acid (2,3-DPG) binding with tions of lungs and bone marrow and cerebrovascular
haemoglobin. 2,3-DPG is a product of glycoly- complications. Further organs may be also impaired.
sis. The pH changes and CO binding also partic- Intrahepatic disturbance of microcirculation uses to
ipate in oxygen release from haemoglobin. Struc- be the underlying cause of hepatic dysfunction and of
tural changes of globin may be the cause of altered hyperbilirubinaemia. The intrarenal disturbance of
haemoglobin affinity for oxygen molecule. microcirculation may lead to papillary necrosis and
Mutations in DNA sequences, controlling the haematuria accompanied with decrease in renal con-
globin synthesis, may produce abnormal haemo- centration capacity. Impairment of skin microcircu-
globins (the haemoglobinopathies), or cause a de- lation is the underlying cause of necrotic ulcerations,
crease of the haemoglobin synthesis rate (thalas- localized most commonly around the ankles. Severe
semia). The term haemoglobinopathy is used for retinal alterations may occur. Microinfarctions in
structural anomalies of haemoglobin associated with the bone marrow and in bones are commonly lead-
its altered function. Thalassemia represents a muta- ing to an aseptic necrosis forming favorable condi-
tion resulting in decreased synthesis of haemoglobin tions for osteomyelitis development. Growth distur-
of a certain type. Many similar mutations may occur, bances are observed. The extremities are long and
however, only some of them are the underlying cause the habitus is asthenic. The chronic haemolysis uses
of altered haemoglobin function concerning the oxy- to be the underlying cause of frequently occurring
2.2. Anaemias 61

cholelithiasis with bilirubin concrements. There is a crises manifested by acute haemolysis and jaundice.
tendency to folic acid deficiency, to impairment of
immunity partially due to the splenic tissue loss and 2.2.6.3 Haemoglobins with impared oxygen
to decreased IgM production. Infections and car- affinity
diomyopathy occur frequently in these disorders.
In sickle cell anaemia are the haemoglobin val- The capacity of haemoglobin to saturation by oxygen
ues about 6 to 8 g/dl, the haematocrit is usually is an appropriate indicator of oxygen affinity. Under
only 18–24 per cent. The number of reticulocytes physiological circumstances is the HbA saturated by
uses to be elevated above 20 per cent. Erythro- oxygen to 50 per cent, if the partial pressure is about
cytes containing nuclei are present in the peripheral 25 mm Hg. The enhancement as well as the fall of the
blood. On the blood smear sickle shaped erythro- affinity is unfavorable. The haemoglobins having a
cytes are found. Their number can be more pre- higher affinity to oxygen are usually associated with
cisly determined on wet smear under anaerobic con- erythrocytosis and with tendency to thrombotic dis-
ditions. Precise identification may be performed by orders. The haemoglobins with low affinity to oxygen
using the haemoglobin electrophoresis. The contri- use to be connected with anaemias.
bution of HbS in sickle cell anaemia reaches 90 to
95 per cent. The plasmatic level of direct react- 2.2.6.4 Methaemoglobinaemia
ing bilirubin raises, the haptoglobin in serum is de- Methaemoglobin is haemoglobin with oxidated iron
creased, the values of LDH are elevated. Evidence of in the haem part of haemoglobin molecule. Instead
sickle cells in the peripheral blood can be performed of Fe2+ it contains Fe3+ . Methaemoglobin is un-
very easily. To the patient’s blood sample sodium able to transfer the oxygen and thus completely use-
metabisulphid is added desoxygenating the erythro- less for respiration, (resp. for oxygen transport).
cytes. These erythrocytes become typically shaped The underlying cause can be the enzyme defficiency
– the haemoglobin is localized excentrically in form (e.g. NADH-methaemoglobin reductase) or the ef-
of a stripe. fect of some chemical substances and drugs. The
There are also mild forms termed sickle cell syn- nitro- and amino- derivates of benzene or nitrates
dromes where the participation of HbS in the entire are frequently involved. These substances cause the
haemoglobin content is less than 80 per cent. The haemoglobin oxidation by molecular oxygen during
symptoms worsen especially during the pregnancy. which the iron remains in form of Fe3+ . Hence, it can
The pathogenesis of sickle cell anaemia is unknown not bind reversibly the oxygen and transport it. Es-
and the treatment can be only symptomatic. During pecially the nitrates are very dangerous in children.
the crisis the acidosis may be corrigated, oxygen and The methaemoglobin presence changes the colour
analgetics applied. The microinfarctions cause the of blood into dark brown. If the methaemoglobin
fever. The blood transfusion is dangerous because amount in peripheral blood reaches 1,5 g/100 ml the
of the iron content elevation above the limit with all cyanosis appears. Under physiological circumstances
consequences. Oxygenation and avoiding the cold is about 1 per cent of methaemoglobin present in
are recommended. During the pregnancy the pla- healthy subject.
cental infarctions with following placental dysfunc-
tion are the most severe complications. 2.2.6.5 Thalassaemia
It comprises a group of inherited haemoglobinopa-
2.2.6.2 Unstable haemoglobins
thies characterized by quantitative fall of production
They represent autosomal dominant mutants with or by complete absence of normal globin chain. Un-
impaired binding of the haem to the globin. This der normal circumstances haemoglobin contains α or
mutation results in intracellular haemoglobin pre- non α (α2, β2, or α2, χ2) chains. Clinically impor-
cipitation in form of Heinz bodies binding with the tant are cases with impaired α or β chain production.
membrane. These cells are rapidly taken up by the According to this is distinguished α thalassaemia or
mononuclearphagocytic system. Erythrocytes with β thalassaemia. The defect in haemoglobin synthesis
this type of haemoglobin have a shorter life-span. can be of various degree. Therefore the hidden car-
Impairments of these conditions appear in form of riers exist (heterozygotes for α thalassaemia) up to
62 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

very severe anaemia – thalassaemia major (homozy- duction and four alleles responsible for its regulation
gotes for β thalassaemia). may be absent. The clinical picture reflects these
In β thalassaemia there is a deficiency or complete disturbances.
absence of β chain. It is classified according to the Silent α thalassaemia is usually an asymp-
β chain suppression (thalassaemia major, minor, in- tomatic form. The heterozygous α thalassaemia is
termedia, δ – β, χ and Lepore thalassaemia). manifested by microcytic hypochromic anaemia of
Thalassaemia major (homozygous) is termed Coo- medium degree. HbH disease is a severe haemolytic
ley’s anaemia. The absence or an considerably re- anaemia compatible with life. It is characterized
duced number of β chains is associated with over- by hypochromic microcytic anaemia with fragmen-
production of α or χ chains. In peripheral blood tation of erythrocytes. Haemoglobin H contains four
abnormal findings are present: microcytosis, ex- β chains and is detectable by electrophoresis. It rep-
treme poikilocytosis, target cells and ovalocytosis, resents 5 to 30 per cent of the global haemoglobin.
Cubot’s ring bodies, Howell-Jolly bodies, nuclear The α chain synthesis is depressed, the haemoglobin
fragments, siderocytes, anisochromia and anisocyto- not effective in oxygen transport. In the homozy-
sis. These anomalies reflect a very severe anaemia gous α thalassaemia only χ chains are formed. No
associated with ineffective erythropoiesis. There is HbA is produced. The χ chains are the cause of
usually outstanding bone marrow-, spleen- and liver- haemoglobin incapability to transport oxygen. The
hypertrophy. With the alterations of organs are ab- fetus dies before the birth.
normalities of bones, fractures and mongoloid face
associated. There has been a hope to save the pa-
tient by repeated blood transfusions, however this 2.2.7 Normochromic normocytic
treatment is accompanied with troubles induced by anaemia
action of accumulated iron.
The mean volume of erythrocytes and the mean
Thalassaemia intermedia is a quantitative less
haemoglobin content in erythrocytes (HbEry) is nor-
severe disturbance than the previous type. The
mal in normocytic normochromic anaemias. This
haemoglobin concentration reaches 6 to 10 g/100 ml.
type of anaemia occurs during many diseases, espe-
Without being stressed the organism can prosper
cially in systemic diseases. Anaemia is frequently the
during long time without the crisis and inevitable
first finding in correct enddiagnosis together with re-
transfusion.
vealing the underlying causes of anaemia itself. The
Thalassaemia minor with mutation responsible for causes are usually considerably various. In spite of
the globulin β chain synthesis occurs in heterozy- this the fundamental question is the fact if the bone
gotes. Microcytic, moderately hypochromic anaemia marrow is or is not responsible for anaemia. Normal
with eliptocytosis provails. The bone marrow is bone marrow is capable to enhance the erythropoiesis
lightly hyperplastic. The HbF content reaches 5 to eightfold. This erythropoiesis enhancement is always
20 per cent of the total haemoglobin content. associated with the finding of reticulocytosis in the
δ – β thalassaemia is a variant of β thalassaemia. peripheral blood. Providing that the reticulocytosis
There is a combination of β and κ chain synthesis. is outstanding the mean volume of erythrocytes may
κ thalassaemia is manifested by hyperchromic mi- be larger owing to the accelerated erythropoiesis. It
crocytic anaemia. Decrease or complete absence of is due to the presence of young erythrocytes having
chain is associated with β chain hyperproduction. larger proportions. The reticulocytosis is manifesta-
This condition in homozygotes is incompatible with tion of bone marrow response to acut haemorhagia
life. or haemolysis.
Lepore thalassaemia is a variant of β thalassaemia. In case that in existing anaemia no signs of accel-
Three haemoglobin variants, being a combination of erated erythropoiesis are found the disorder may be
δ and β chain disorders, has been described in this directly or indirectly in bone marrow. The suspicion
syndrome. of bone marrow disturbance may be declared when
α thalassaemia. In this type of thalassaemia there the leukopenia, thrombocytopenia or morphologic al-
is a molecular defect concerning α globin gene dele- terations of erythrocytes are observed simultaneous.
tion. Several alleles from two ones for β chain pro- The morphologic abnormalities of erythrocytes are
2.2. Anaemias 63

the erythrocytes with nuclei, poikilocytes, immature 2.2.8 Anaemia in uraemic syndrome
granulocytes, fragments of megakaryocytes or large
thrombocytes. Renal, hepatic and endocrine diseases Anaemia occurs frequently during the uraemic syn-
may influence the erythropoiesis and reduce the ery- drome. The haemoglobin level uses to be variable
thropoietin production. and the degree of anaemia is usually proportional
to the degree of azotaemia. The haemoglobin level
reaches in severe cases only 40 g/l. In spite of this,
2.2.7.1 Acute posthaemorrhagic anaemia the patients tolerate this anaemia rather passably
It occurs following loss of large blood volume. Clini- owing the blood redistribution and affinity for the
cal signs of anaemia depends on the volume of blood oxygen.
lost, on the bleeding rate and on the bleeding dura- Anaemia in uraemia is usually normochromic and
tion. normocytic. The process of erythrocyte forming is
The first phase lasts by three days. In this phase usually not impaired and also the morphology of
period the blood loss regarding the volume dom- erythrocytes uses to be normal. On blood smear
inates. The clinical picture depends on the fact echinocytes – erythrocytes with prominent edged
whether the hypovolaemia induced by the blood surface are present. The reticulocyte number is de-
loss persists. In this case the anaemia is not de- creased. The basis of anaemia is most probably the
tectable by the haematocrit and haemoglobin deter- reduced erythropoiesis. Renal damage is the cause
mination. If the hypovolemia becomes to be compen- of reduced production of erythrocytes and in erythro-
sated anaemia and often also reticulocytosis appear. poietin production. In patients is the erythropoietin
If the blood volume is reduced by 20 per cent, level always decreased. Except for this the retained
no symptoms may appear. In case that the blood substance in uraemia cause the depression of erythro-
loss reaches 30 to 40 per cent of the total blood poiesis. The iron incorporation into the erythrocytes
volume, the haemorrhagic shock develops. During is usually also impaired.
acute blood loss is not posible to estimate its extent In uremic patients in advanced of disease
by haematocrit – and haemoglobin values. The vol- haemolytic attack may occur. Several factors can
ume of plasma may be compensated by endogenous support the haemolysis. Renal failure can be the
mechanisms in 24 hrs. The compensation is attained consequence of thrombotic thrombocytopenic pur-
above all by the shift of electrolytes and water from pura or of the haemolytic uraemic syndrome. An
tissues into the intravascular space. Anaemia ap- intense microangiopathic haemolytic anaemia may
pears only as late as the dilution of plasma by com- develop in these cases. In some patients the anaemia
pensation is attained. The erythropoietin secretion may becomes worsen also by water contamination
rises immediately with plasma dilution and anaemia with aluminium. The impairment is manifested in
appearing. The hyperplasia of bone marrow can be these cases by microcytosis and hypochromia. Re-
observed later. nal transplantation causes dramatical reverse and so
The reticulocytosis occurs on 3rd or 5th day fol- does the erythropoietin application.
lowing the haemorrhagia. Reticulocytosis reaches
the highest values on the sixth to eleventh day. The 2.2.9 Anaemia in hepatic cirrhosis
degree of reticulocytosis is in certain relation with
the volume of blood loss. Infrequently however, it ex- Liver cirrhosis and other hepatic diseases are fre-
ceeds 14 per cent. Transient increase in mean volume quently accompanied with anaemia, usually of nor-
of erythrocytes can be observed. During some hours mocytic normochromic type. Macrocytic anaemia
following the haemorrhage a dramatical increase in occurs infrequently. In liver cirrhosis the underly-
thrombocyte- and leucocyte- number occurs. In ex- ing cause of anaemia is often the chronic alcoholism
treme situation the thrombocytes may rise in 1 to influencing the haemopoiesis directly or undirectly.
2 h up to 1000x109/l and the leucocytes up to 25 to Important factors contributing to anaemia develop-
35x109/l. The number of leucocytes increases during ment are: the iron deficiency due to the blood loss
2 to 5 h after the haemorrhage. In about 3 to 5 days in gastritis, peptic ulcer, oesophageal varices, in de-
the values of thrombocytes and leucocytes return to ficiency of coagulating factors, sequestration of ery-
the norm. throcytes and other blood elements in the enlarged
64 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

spleen due to portal hypertension. In cirrhosis often severity of anaemia is proportional to the severity
occurs and due to it the lipid content in membrane of inflammatory process. Anaemia occurs usually
of erythrocytes increases leading to their premature in chronic infections like endocarditis, osteomyelitis,
sequestration in the spleen. pulmonary abscess, tuberculosis and pyelonephritis.
The occurrence of anaemia associated with non infec-
2.2.10 Anaemias in endocrine disor- tions diseases appears in chronic inflammatory pro-
cess due to rheumatic arthritis, lupus erythematosus,
ders
vasculitis, sarcoidosis, regional enteritis and in tissue
It is generally known that the thyroxin, glucocorti- damage by injury like the fractures of long bones.
coids, testosterone and growth hormon influence the This type of anaemia occurs frequently in neoplas-
proliferation of erythroid cells in vitro. It is not sur- tic processes e.g. Hodgkin’s disease, lung carcinoma
prising therefore that in endocrine diseases moderate and breast carcinoma. More severe anaemia develops
to severe normocytic normochromic anaemia occur. in patients with cancer of gastrointestinal or urogen-
Anaemia occurs most frequently in hypothyroidism, ital system, where the blood loss contributes to the
Addison’s disease, hypogonadism and in panhypopi- anaemia appearence. Iron deficiency is developping
tuitarism. It is understandable, that the anaemias thus anaemia may progress rapidly. When metas-
associated with hypothyroidism and panhypopitu- tases in bones arise invading the bone marrow a type
itarism are in relation with reduced oxygen consump- of anaemia with very rapid progression develops.
tion due to the T3 and T4 deficiency, or to the ab-
sence of growth hormone. The anaemias mentioned above are characterized
The anaemia in myxedema is usually normocytic. by decrease in haemoglobin values, moderate micro-
In some patients anaemia is due to the folic acid – cytosis and normochromia. In bone marrow exam-
or B12 vitamin deficiency. In patients with hypothy- ination normal maturation of erythroids is found.
roidism and especially in women with metrorrhagia During chronic infections the myeloid hypoplasia de-
the microcytic anaemia and iron deficiency may de- velops. The number of reticulocytes in peripheral
velop. In hypothyroidism hidden amaemia can occur blood is usually decreased. Extracorpuscular mech-
owing to the decreased volume of plasma of these pa- anism are probably involved in the etiopathogene-
tients causing an increase in erythrocytic mass and in sis of anaemia. It is known that enhanced haemol-
the erythrocyte number in volume unit. The symp- ysis is present in mononuclear phagocytic system.
toms of myxedem may be inaparent and to make the In some diseases is the life-span of erythrocytes evi-
correct diagnosis is not easy. dently shortened e.g. in chronic infections, especially
In Addison’s disease is anaemia also masked by in infective endocarditis, miliary tuberculosis, and in
reduced volume of plasma. Even untreated pa- splenomegaly. Spherocytosis is observed frequently
tients have the haemoglobin level 130 g/l. The in these cases. The iron and ferritin levels in serum
anaemias become revealed at the beginning of hor- are usually lowered. Values of other plasmatic pro-
monal treatment because the volume of plasma in- teins are elevated in inflammatory processes prob-
creases. Anaemia, however recovers later sponta- ably owing to stimulations with interleukins being
neously. released from activated macrophages. The picture
In adolescence the testosterone effect is manifested of this inflammatory process is completed by increase
by increase in haemoglobin values. In eunuchs the in gamaglobulin level, C3 component of complement,
haemoglobin level is lower. The hypophysis dys- haptoglobulin, α 1 antitrypsin, orosomucoid and fib-
function is usually associated with normochromic, rinogen. This increase of proteins is the underlying
normocytic anaemia, occasionally accompanied with cause of elevated sedimentation of erythrocytes used
leukopenia. in practice as indicator of inflammatory process.
The primary cause of anaemias in chronic inflam-
2.2.11 Anaemias in chronic inflamma- matory processes is the defective production of ery-
throcytes and their reduced life-span. There is
tory processes
a discrete disturbance of iron transfer in erythro-
In patients with chronical systemic inflammatory dis- cyte production, manifested finaly by smaller ery-
eases anaemia can develop in several months. The throcytes and impaired haem synthesis. Hyperpla-
2.2. Anaemias 65

sia of mononuclear phagocytes is responsible for the In many cases of aplastic anaemia immune mech-
shorter life-span of erythrocytes. The macrocytes anisms are involved. A possible damage caused by
catch the iron from haemoglobin, hence it cannot be antibodies or by autoimmune process are supposed
transported into the bone marrow. The aggressivity in some patients with aplastic anaemia.
of macrophages towards the iron is caused by inter- The bone marrow aplasia can develop as an ad-
leukin 1. The interleukin releases lactoferrin from verse consequence of cytostatic or immunosuppres-
neutrophiles. Lactoferrin is an iron binding protein sive treatment or of ionising radiation. A severe
taking up the free iron and transports quickly it into aplastic anaemia can be induced by folic acid antag-
the macrophages. onists, anthracyclines, nitrosourea and further sub-
Anaemias in chronic inflammatory processes are stances. This type of aplastic anaemia can be at the
usually not cureble by iron, folic acid or vitamin B12 . beginning reversible. After the treatment omission
the bone marrow function recovers spontaneously.
Long lasting combined treatment may lead to irre-
2.2.12 Anaemias due to impaired versible bone marrow aplasia.
haematopoiesis The broad spectrum antibiotic agent – chloram-
The primary bone marrow disturbance represents the phenicol can induce aplastic anaemia, if taken in
underlying cause of an important group of anaemias. lower doses it may lead to reversible suppression
There is an impairment of erythropoietic precursor of erythroids and sometimes also the precursors of
forming. The term aplastic anaemia should be used granulocytes and megakaryocytes. Vacuoles appear
for conditions with bone marrow hypocellularity and in these cells, like in chronic alcoholism. After the
pancytopenia. Thus, in peripheral blood anaemia, chloramphenicol application develops in some cases a
neutropenia and thrombocytopenia are present. Se- severe pancytopenia with irreversible fatal bone mar-
lective aplasia of erythroid cells prevails sometimes. row aplasia. The appearance of this condition does
The myelophtisic anaemia with erythropoiesis sup- not depend of the chloramphenicol dosis and can not
pression owing to the bone marrow infiltration by tu- be predicted.
mor or fibrosis represents an other type of anaemia. Aplastic anaemia occurs rather often in infectious
The anaemias due to bone marrow impairment are hepatitis, more frequently in non-A, non-B hepatitis
frequently associated with various degree of neu- (NANB) but also in other types of hepatitis. Apla-
tropenia and thrombocytopenia due to pluripotent sia may reach a threatening degree and may result in
stem cell disturbances. lethal end. The aplastic anaemia may develop also
during viral diseases, especially during viral infec-
tions of respiratory system. It is named idiopathic
2.2.12.1 Aplastic anaemia aplastic anaemia.
The aplastic anaemia is actually the consequence Aplastic anaemia is manifested at the beginning by
of pluripotent stem cell impairment and of succe- progressive weakness, petechiae, ecchymoses in skin
sive population of cells impairment and destruction. and gingivae, nosebleeding, gingival, vaginal or gas-
Frequently various toxins, especially benzene, an en- trointestinal bleeding. Retinal and cerebral haem-
dogenous or inborn disturbance may be involved. orrhage occur. Thrombocytopenia and neutrope-
The congenital underlying causes are more outstand- nia are usually present. Fever can occur present.
ing in Fanconi’s syndrome, a constitutional aplastic The degree of aplastic anaemia is substantial. Ad-
anaemia being an autosomal, recessive inherited con- vanced aplastic anaemia is characterized by the fall
dition. It appears soon in childhood and is usually of granulocytes below 500/µl, of thrombocytes be-
associated with somatic abnormalities, e.g. with re- low 20 000/µl, and of reticulocytes below 1 per cent.
nal or cardiac deformations, skin hyperpigmentation, The bone marrow is hypoplastic. The patient with
malformations of bones, hypoplastic thumb or ab- aplastic anaemia is always at risk of death from fa-
sence of radius. The chromosomal abnormalities in- tal bleeding or from infection. The patients with
volve DNA defects. A progressively impairing bone the moderate degree of aplastic anaemia may sur-
marrow function dominates in these patients, being vive even several years.
concomitantly risk of leukaemia development. The diagnosis is based on the pancytopenia pres-
66 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

ence in peripheral blood. The erythrocytes are nor- Myelophtisis results in normochromic normocytic
mochromic and moderately macrocytic. Marked anaemia. In the peripheral blood normoblasts may
reticulocytopenia is present. The thrombocytope- occur. At the beginning the number of reticulocytes
nia and neutropenia must be confirmed through re- moderately elevated.
peated examinations. The bone marrow examination
reveals the hypocellularity and replacement of bone
marrow tissue by adipose tissue.
Patients with severe aplastic anaemia may be
treated by bone marrow transplantation requiring
multidisciplinary approach. The blood transfusion
represents rather a risk than a method of treatment.
2.3 Haemostasis and haemo-
Except for hepatitis and haemosiderosis, the blood coagulation
transfusion can cause an undesirable sensibilisation
before the bone marrow transplantation. The bone
marrow responses sometimes favorably to the andro-
gen application. GM-CSF (granulocyte-macrophage Normal haemostasis is the result of complicated
colony stimulating factor) is effective in pancytope- relations between the vessel wall, thrombocytes and
nia developing during AIDS, during myelodysplasia, coagulation and fibrinolytic system. If the mutual
or under the influence of myelotoxic substances. proportions are not impaired the whole system is
balanced. The balance is continuously maintained
between the systems supporting the local haemosta-
2.2.12.2 Primary bone marrow disturbances
sis and those inhibiting the disseminated thrombosis.
The aplasia of erythrocyte line represents a selec- The inner surface of vessels – endothelium – is a
tive disorder in production of erythroid cells. Gran- nonthrombogenic barrier inhibiting the interaction
ulopoiesis and megakaryopoieses remain intact. Pa- of blood components with subendothelial structures.
tients have normochromic normocytic anaemia, but If these substances have been in contact the throm-
with associated reticulocytopenia. The underlying bus formation would be initiated. This inhibitory
causes of this condition are not known. A very sim- function of endothelium is its primary function and
ilar clinical picture of aplasia is observed with fre- is called the non-thrombogenity.
quent findings of thymoma and of myasthenia gravis. The thrombocytes circulate in an inactive form.
In these case the erythropoiesis may by inhibited by They do not contain nucleus and have irregular dis-
IgG affecting selectively the erythroblasts in bone coid shape. Their surface is covered with phospho-
marrow. Erythropoietin inhibitors have been ob- lipid membrane and the contractile filaments are sit-
served in some patients. uated below it. They contain three types of gran-
The myelodysplastic syndrome is considered to be ules (dense, alpha and lysosomal) and the system of
an independent clinical unit. It is the refractory minute channels through which the content of gran-
anaemia associated with neutropenia and thrombo- ules is released into the plasma.
cytopenia. If the endothelium is damaged, the thrombus is
formed immediately. First the thrombocytes adhere
2.2.12.3 Myelophtisic anaemia to the subendothelial components. The thrombo-
cyte adhesion is an interaction between the membra-
Infiltration of bone marrow by tumors, fibrosis neous thrombocytic receptor (glycoprotein Ib) and
and granulomas may lead to anaemia development. the subendothelial collagen with participation of the
Among the solid tumors prevail the metastatic de- plasmatic cofactor (von Willebrand’s factor – vWF).
posits from breast carcinoma, stomach, prostata, To this reaction contributes a further plasma pro-
lung and thyroid gland. tein – fibronectin (glycoprotein present in cell mem-
The bone marrow fibrosis is usually associated branes and is a component of plasmatic proteins, it
with myeloid metaplasia. In tuberculosis, but also is produced in fibroblasts, in endothelial cells and
in metabolic disturbances e.g. osteoporosis, anaemia in macrophages). To the impaired site adhere sev-
may develop. eral thrombocytes simultaneously. Such a thrombo-
2.3. Haemostasis and haemocoagulation 67

cyte aggregation becomes activated. This activation cium and factor V converts prothrombin into throm-
begins with membrane receptor activation by sev- bin.
eral agonists especially by collagenous fibrils, ADP, The intrinsic pathway is triggered via contact sys-
adrenaline, serotonin, thrombin and some arachi- tem. The proenzyme-factor XII is activated by dam-
donic acid metabolites. The thromboxan A2 is a aged cells or by subendothelial structures. In com-
potent vasoconstrictive agent. Some agonists are re- bination with kallikrein and kininogen it activates
leased from the thrombocytes themselves, the others the factor XI. Factor XIa activates the factor IX
from the vessel wall. ADP is released also from ery- which, in combination with negative charge of phos-
throcytes occuring in near surroundings. The activa- pholipids, calcium and factor VIII forms the complex
tion of thrombocytes triggers the action of thrombo- activating the factor X. Further course of coagulation
cyte contractile system. Thrombocytes change their cascade is identical (as above described in extrinsic
shape from irregular discs to small globules with nu- pathway) regard less of the beginning.
merous pseudopodia and begin to connect with one
The thrombocytes accelerate the haemocoagula-
another-forming the thrombocyte aggregation. The
tion:
thrombocyte aggregation runns simultaneously with
the arachidonic acid metabolism activation, with in- 1. by increasing the contact activity through the
crease in free cytoplasmatic calcium level and with receptors for factor XI,
the release of a lysolecithinic substance. The aggre-
gation of thrombocytes ceases to be reversible. Af- 2. by tissue thromboplastin production,
ter the above mentioned reaction is triggered, begins 3. by supply of membrane phospholipids which fa-
the release of platelet granule content. ATP, ADP, cilitate the factor X and prothrombin activation.
serotonin, calcium are released from dense granules.
Platelet factor 4, the platelet growth factor, be- Thrombin modifies the factor V and VIII to in-
tathromboglobulin, vWF and a lot of other factors duce rapidly the coagulation cascade into its most
are released from alpha granules. During release of important phase, – the thrombin formation and the
these factors the thrombocyte membrane is rebuilt. fibrinogen conversion into the fibrin.
The negative charge of phospholipids is ”unveiled” Fibrinogen is a large six-chained molecule.
and the platelet factor 3 is generated. Thrombin cleaves first the two A peptides and later
two B peptides from this molecule. The fibrin
During the thrombus formation the surrounding monomer formed in this way is able to non enzy-
intact endothelium inhibits its excessive growth. The matic polymerization and it changes into a gel. Fib-
control is performed by inactivation of ADP (a po- rin formed in this way remains relatively easily sol-
tent agonist) by ADP-ase. Adrenaline and serotonin ubel and can be destructed by fibrinolytic system.
inactivate the endothelial cells. Endothelium en- The non soluble fibrin polymer is produced after its
ables the thrombin binding with antithrombin III; interaction with factor XIII. Factor XIII can stabilize
endothelium synthesizes and releases the antiaggre- fibrin only when it is converted by thrombin.
gation PGI2 . PGI2 binds with specific receptors lo- The action of thrombin and of other coagulation
calized on the membranes of thrombocytes activating enzymes is limited by three mechanism:
so cyclic AMP bound with the membrane. In such
a way the arachidonic acid metabolism, the calcium 1. The activated coagulation enzyme are drifted by
flux and the aggregation of thrombocytes are inhib- blood flow from the site of impairment. The
ited. drifted enzymes are rapidly inactivated during
the passage through the liver. This clearance
At site of impairment the coagulation cascade is mechanism includes the action of inhibitors and
activated via extrinsic or intrinsic pathways. All the interaction of macrophages.
damaged cells in organism produce thromboplastin
or the tissue activating factor, which further acti- 2. The proteolytic enzymes produced during coag-
vates the factor VII (extrinsic pathway). In the pres- ulation not only activate the coagulation fac-
ence of calcium and tissue activating factor activated tors but they destroy them simultaneously. The
factor VIIa may convert factor X into factor Xa. Fac- degradation is directly performed by degrada-
tor Xa with negative charge of phospholipids, cal- tion of factor Xa by thrombin, or it can be the
68 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

result of activation of inhibitory system through nase (fibrinolytic substances) are applied into
protein C (a vitamin K – dependent plas- the blood flow.
matic protein activated by serine proteinases).
Plasmin hydrolysis many fibrin bindings causing
Thrombin forms a complex with thrombomod-
thus fibrinolysis. The fibrin rests are named fibrin
ulin (a protein localized on the surface of en-
degradation products (FDP). Besides fibrin, plasmin
dothelial cells having a strong affinity for throm-
bin). The thrombin-thrombomodulin complex involved in the factor V and VIII degradation. Mas-
sive fibrinolysis is simultaneously inhibited by a po-
activates the C protein. In the presence of phos-
tent inhibitor – the alpha-2-antiplasmin and by a less
pholipids and of S protein (a further cofactor)
strong alpha-2-macroglobulin.
the activated C protein inactivates the factor
Va and VIIIa. C protein is involved also in fib-
rinolysis initiation.
3. The third control mechanism are the original in-
hibitors: especially the alpha 2 macroglobulin (a 2.4 Disorders of primary hae-
component of serum proteins), α-1-antitrypsin
(a glycoprotein with inhibitory action in serum), mostasis
antithrombin III (the main regulator of blood
coagulation; it neutralizes the thrombin serine
proteinase), α-2-antiplasmin (one single-chained
glycoprotein forming a complex with plasmin) The spontaneous stopping of bleeding from a
and other factors. In coagulation cascade regu- smaller damaged vessel is performed with essentially
lation antithrombin III plays the key role. It in- important life saving mechanisms. In the process
activates the serine proteases. Heparin and the of bleeding stopping from a vessel a complex of reac-
contact with damaged endothelium accelerates tions between three participating systems is involved:
this effect. 1. the vessel wall,
The fibrin deposition and its removal from circula-
2. the thrombocytes,
tion is regulated by fibrinolytic system – a multicom-
ponent system composed of circulating plasminogen 3. the plasmatic coagulation factors.
proenzyme, of activators, cofactors and inhibitors.
The human plasminogen is a single-chained globulin If all occurs in framework of physiological useful-
easily adaptable by proteolysis. Plasminogen (lys- ness the result is the normal haemostasis. In case
plasminogen) has higher affinity for fibrin and alpha that certain limits are exceeded, the reactions may
2-antiplasmin. It is easily activated also by uroki- lead to pathologic bleeding or to undesired throm-
nase. The plasminogen molecule contains two parts bosis. The haemostasis initiation occurs during few
– one of them has an active site and the other has a seconds following vessel injury. Its termination may
binding site for the binding with fibrin and alpha-2- last even an hour. In the temporary consequence
antiplasmin. The plasminogen activation occurs in three successive plases can be distinguished:
the case when the activator cleaves the peptide bind-
The first phase – the primary haemostasis in-
ing and two chains of plasmin enzyme arise. The
cludes:
plasmin activation may occur in three ways:
• the constriction of the injured vessel
1. Intrinsic mode represents the proactivator acti-
vation through the contact system • the subendothelial collagen exposure
2. In the extrinsic system are the activators re- • the adhesion and agregation of thrombocytes on
leased into the blood flow from damaged tissue the demaged surface
of blood vessel wall or of thrombocytes
During these processes the primary haemostatic
3. During the treatment the streptokinase or uroki- (thrombocytic) plug is formed in about 3 to 7 min-
utes. In this process the von Willebrand’s factor
2.4. Disorders of primary haemostasis 69

(vWF) is involved mediating the adhesion of throm- acid, non-steroidal antiphlogistic drugs, antibiotics,
bocytes, the release of vasoactive substances and anticoagulant drugs and the alcohol also impair the
the intensification of thrombocyte aggregation. The haemostasis. These substances may induce bleed-
primary haemostasis may be investigated in clinical ing. The basic information on haemostatic integrity
practice e.g. by the bleeding time determination. can be obtained by prothrombin time, bleeding time,
The second phase – the secondary haemostasis partial thromboplastin time, and thrombocyte count
represents the fibrin clot formation at the site where determination.
before the primary haemostatic (thrombocytic) plug
has been formed. The surface of activated thrombo-
cytes catalyzes the thrombin formation by its ability
2.4.1 Disorders of thrombocytes
to involve coagulation factors in presence of mem- The normal function of thrombocytes is necessary
brane phospholipids into the action. The thrombin for the maintenance of the primary haemostasis.
activation results in several important effects: In addition to their normal function, certain num-
1. Thrombin catalyses the conversion of fibrinogen ber of thrombocytes is inavitable for optimal func-
into fibrin. Fibrin forms a network in which the tion of haemostasis. Under physiological circum-
erythrocytes are caught, thus the definitive clot staces the thrombocyte number should be higher
and vessels plug arise. than 150 000/µl of peripheral blood. The thrombo-
cyte number reflects their production in bone mar-
2. Thrombin stimulates the further activation of row and their destruction in peripheral blood. The
thrombocytes, the prothrombin conversion and bone marrow can increase the thrombocyte produc-
the TXA2 production. tion 8 to 10 times. The life-span of thrombocytes
3. Thrombin activates the coagulation factor XIII in peripheral blood is 10 days. Younger thrombo-
– the fibrin stabilizing factor promoting the sta- cytes are more active in their metabolic and haemo-
bility of fibrin. static functions than the older ones. The adhesion
of thrombocytes, the procoagulation activity, the ag-
The state of haemostasis can be considered in clin- gregation, and release of vasoactive substances have
ical practice according the time needed to clot for- to be normal in order that the haemostatic effec-
mation of whole blood. It lasts in average 8 to 10 tivity may be functionning. Impairment of any of
minutes. these thrombocyte functions may be the underlying
The third stage of haemostasis (coagulation) is cause of bleeding. Petechial bleeding into the mu-
the coagulum retraction during which the free net cous membranes and skin are typical in these cases.
of aggregated thrombocytes, the fibrin net and the This condition if generalized is named purpura.
cought erythrocytes are formed into a solid for-
mation. During this process the thrombostenin
is retracted (thrombostenin is a contractile protein 2.4.1.1 Thrombocytopenia
present in thrombocytes – similar to muscle acto- Decrease in number of thrombocytes under 100 000
myosin) compressing the coagulum. This process /µl increases the risk of bleeding. If the number is
lasts about one hour, if observed in vitro. less than 50 000/µl even spontaneous bleeding may
Clinically important disorders associated with the occasionally occur. Bleeding arises more frequently
possibility of undesired bleeding may occur like con- in anaemic patients and in patients with fever. In
sequence of vessel, thrombocyte or coagulation pro- these case the bleeding is an evidence of long-lasting
tein defects being of various degree, quality or quan- thrombocytopenia. A rapid acute fall in thrombo-
tity. It is necessary to know the haemostasis sta- cyte number is usually not the cause of bleeding.
tus before a surgical intervention, in case of inap- The underlying cause of severe thrombocytopenia
propriate bleeding after trauma, or if spontaneous can be:
bleeding arises, which can not be stopped by usual
methods. It is also necessary to realize the fact, 1. the decrease in thrombocyte production in bone
that liver diseases, malignant haematological pro- marrow or an ineffective production
cesses, and uraemia impair the status of haemosta-
sis. Among the drugs and toxins the acetylsalicylic 2. increase in peripheral thrombocyte destruction
70 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

3. hypersequestration of thrombocytes The posttransfusion purpura is uncommon syn-

drome. It occurs following transfusion of blood with
4. intravascular thrombocyte dilution thrombocytic antigen PLA1 to a patient in whom
this antigen is not present. The recipient response
Reduced thrombocyte production observed in according this principle to the recieved antigen is the
systemic infections, nutritive defects (folic acid production of Anti PLA1 antibodies leading usually
or vitamin B12 deficiency), following irradiation, to thrombocytopenia in 5 to 8 days following the
chemotherapy or bone marrow replacement by fi- transfusion. The thrombocytopenia may persist for
brosis or by tumor. A transient decrease in throm- several weeks. The above mentioned principle may
bocyte production occurs frequently in viral infec- function also between the mother and fetus.
tions. Many drugs may inhibit the megakaryocy- Thrombotic thrombocytopenic purpura – Mo-
topoiesis. The most important ones are the anti- schkowitz’s syndrome is an acute repeated condition
convulsive drugs and thiazides. The bone marrow where the microcirculation is affected. It is char-
hypoplasia in aplastic anaemia or in Fanconi’s syn- acterized by thrombocytopenia, microangiopathic
drome is usually associated with thrombocytopenia. haemolytic anaemia, neurologic disorders, renal dys-
The thrombocyte destruction is caused by various function and fever. It occurs most frequently in
drugs: digitalis, qinidine, thiazides, imipramin, phe- young women. A viral disease preceeds almost al-
notiazines, sulfonamides, antibiotics (especially peni- ways its occurrence. The most typical finding is the
cillins, cephalosporins) and the chrysotherapy. These presence of hyaline thrombi containing fibrin and ag-
drugs cause thrombocytopenia by immune mecha- gregation of thrombocytes. These thrombi occlude
nism. The antibodies against the drugs or the com- small arterioles and capillaries. Except for this,
plexes of plasmatic proteins with drug are passively endothelial proliferation is observed, but a typical
adsorbed to the Fc receptor on the surface of throm- vasculitis is not present. The blood smears show
bocytes (the thrombocytes are, in fact, innocent vic- schistocytes, increased reticulocyte number and the
time of these processes). In this way marked throm- presence of normoblasts – a picture of microangio-
bocytes are quickly sequestrated into the spleen from pathic haemolytic anaemia. Thrombocytopenia is
circulation. Several substances may be adsorbed outstanding the values of LDH and bilirubin are el-
on the thrombocyte surface. A neoantigen arises evated. This condition is usually lethal.
stimulating the production of antibodies against the
Haemolytic uraemic syndrome occurs commonly
thrombocytes.
in children. Characteristic signs are the microangio-
Idiopathic thrombocytopenic purpura (autoim-
pathic haemolytic anaemia, thrombocytopenia, diar-
mune). This type of thrombocytopenia (thrombo-
rhea and acute renal failure. Neurologic symptoms
cytopenic purpura) appears without toxic or drug
are not present in this condition. The most impor-
influence. Increase in thrombocyte bound IgG and
tant finding are the hyaline thrombi in renal micro-
complement is found. Large thrombocytes in periph-
circulation.
eral blood and increased number of megakaryocytes
in bone marrow are present. The life-span of throm- Thrombocytopenia in splenomegaly. Under phys-
bocytes is shortened. The acute form of idiopathic iological circumstances the spleen contains about
thrombocytopenic purpura (ITP) occurs preferen- 1/3 of all thrombocytes. Enhanced sequestration of
tially in children during viral diseases. The recovery thrombocytes in the spleen occurs in splenomegaly.
is usually spontaneous. In adults the acute form does In this condition the spleen is capable to sequestrate
not occur. In some cases the autoimmune haemolytic 90 per cent of all thrombocytes present in the body.
anaemia accompanies the lupus erythematosus, lym- The life-span of thrombocytes is usually not short-
phoproliferative disorders and AIDS. Homosexual ened.
patients with ITP are nearly all HIV positive. In Dilution thrombocytopenia occurs following a
pregnant women with ITP the antithrombocytic an- massive blood transfusion and can last for some days.
tibodies, usually the IgG1 and IgG2 passes through Thrombocytopenia due to extracorporeal circula-
the placenta. Splenectomy has usually a favorable tion. The extracorporeal circulation is used in sur-
effect in severe cases, even if the spleen is not en- gical interventions on open heart. The thrombo-
larged. cytes may adhere to membrane surface of oxygena-
2.4. Disorders of primary haemostasis 71

tor, to the dialysis membrane or other parts of equip- cyte’s surface and for thrombocyte aggregation. The
ment for extracorporeal circulation. The thrombo- bleeding can be life-threatening in this condition.
cytic dysfunction and thrombocytopenia in associa- Release defects of thrombocytes resulting in im-
tion with the extracorporeal circulation may lead to paired platelet aggregation comprise several syn-
postoperative bleeding. dromes. It can be a defect similar to the acetylsal-
icylic acid effect, where the thrombocyte structure
2.4.1.2 Thrombocytosis is normal but the thrombocyte activity is impaired.
Defect of phospholipase activity or enzyme deficiency
Increase in thrombocyte number above 500 000/µl in prostaglandin formation, like cyclooxygenase or
can appear on physiological basis. It can occur as re- thromboxane synthetase, may be involved. In other
sponse to the bleeding. Thrombocytosis may appear cases a defect of the content of thrombocytic gran-
commonly in infections, trauma or can be due to the ules may be present, especially of ADP or serotonin
primary bone marrow disease. Transient and mild content. In Hermansky–Pudlak syndrome is the dis-
thrombocytosis can appear after physical overexer- order of thrombocytes associated with albinism. The
tion or other stress. The underlying mechanism is ADP release is needed for normal function thrombo-
the thrombocyte release from spleen and lungs me- cytes, thus this defect becomes manifest in trauma,
diated by adrenaline effect. birth or another stress.
Secondary or reactive thrombocytoses are due to Disorders of thrombocyte adhesion. This condi-
increased thrombocyte production after the bleed- tion occurs in two inherited haemorrhagic diatheses:
ing, during haemolysis, infections (TBC), inflamma-
tory processes or malignancies. Thrombocytosis also 1. in von Willebrand’s disease and
appears following splenectomy, its duration is short,
some weeks only. The secondary thrombocytosis 2. in Bernard-Soulier syndrome.
does not lead to thrombotic complications.
The primary thrombocytosis is named essen- In von Willebrand’s disease occuring in both men
tial thrombocytosis. Increased thrombocyte num- and women is the thrombocyte count normal. Ow-
ber is due to their enhanced production. The ing to the plasmatic factor deficiency needed for in-
thrombocytes are of bizzare shape and the signs of teraction of thrombocytes with collagen is the adhe-
their dysfunction are often present (reduced num- sivity of thrombocytes to subendothelium impaired.
ber of adrenaline receptors and abnormal reaction to Von Willebrand’s factor (vWF) is under physiologi-
adrenaline). The thrombocytes may occur in clus- cal circumstances syntetised in endothelial cells and
ters. in megakaryocytes. The vWF formed circulates in
blood in a makromolecular complex with coagula-
2.4.1.3 Qualitative disorders of platelets tion factor VIII. Patients with von Willebrand’s dis-
ease exhibit except for vWF missing also decrease in
Inborn defects of thrombocytic functions are uncom- the factor VIII. In von Willebrand’s disease the lab-
mon. If occuring they are associated with mucosal oratory tests show prolonged bleeding time, reduced
bleeding. Acquired defects of thrombocyte functions adhesion of thrombocytes, normal aggregation, but
are more frequent, especially during acetylsalicylic the agglutination of thrombocytes is not present. It
acid taking and in haematologic diseases. They be- is manifested by mucosal bleeding and menorrhagia.
come clinically important if a haemostatic effect oc- The condition can improve after application of vWF.
curs simultaneously (e.g. thrombocytopenia, antico- In Bernard-Soulier’s syndrome giant thrombocytes
agulant therapy). are found in peripheral blood, the bleeding time is
Thrombasthenia (Glanzmann’s syndrome). This prolonged and mucosal bleeding is present. Gly-
condition is an inborn disorder characterized by pro- coprotein Ib mediating the binding of vWF is not
longed bleeding time, absence of thrombocyte aggre- present in platelet membrane. The level of vWF is
gation and their adhesion to collagen, therefore mu- nevertheless normal, but the defective adhesion of
cosal bleeding occurs. In thrombasthemia there is thrombocytes is not corrigable by vWF owing to the
absence of two surface glycoproteins (IIb and IIIa), absence of thrombocytic receptors. This hereditary
necessary for binding of fibrinogen with thrombo- condition occurs infrequently.
72 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

Inherited deficiency may affect alpha granules con- manifested by abdominal pain, haematuria, glomeru-
taining the vWF, fibronectin and thrombospondin. lonephritis, haemorrhagic urticaria, arthralgia. An-
These proteins are needed for normal adhesion and other type is the hereditary haemorrhagic teleang-
aggregation of thrombocytes. iectasia (morbus Osler-Weber-Randu). The bleed-
ing arises from mucosal teleangiectasia as a autoso-
2.4.1.4 Acquired disorders of thrombocyte mal dominant trait. Manifestations of vascular ab-
function normalities are more outstanding in puberty. The
bleeding can affect all mucosae. The nasal bleed-
Acetylsalicylic acid (Aspirin) and other non-steroid ing (epistaxis) is frequently observed and bleeding in
antiphlogistic drugs inhibit the cyclooxygenase the mucosae of respiratory system, GIT, urogenital tract
key enzyme in arachidonic acid transformation into are present. Fistulae use to be present in pulmonary
cyclic endoperoxides and thromboxan A2. These vessel bed. Teleangiectasia may be present also in
compounds induce the thrombocyte aggregation and the skin.
mediate the reaction of thrombocytes to agonists
like ADP, adrenaline and collagen. The contact of
thrombocytes with acetylosalicylic acid impairs the
platelet aggregation. The cyclooxygenase inhibition
following one dosis of acetylosalicylic acid lasts at
least a week. The effect of other non-steroid an- 2.5 Disorders of haemocoagu-
tiphlogistic drug lasts about 24 hrs. Acetylosalicylic lation
acid (Aspirin) given during haemophilia, thrombo-
cytopenia or anticoagulant treatment may induce se-
vere bleeding.
In uraemia is a tendency to bleeding. Ecchymoses The haemocoagulation is initiated by generation of
and gastrointestinal bleeding appear. The throm- a strong serine protease – the thrombin. Thrombin
bocyte aggregation and the bleeding time are pro- splits the soluble plasmatic protein – fibrinogen. A
longed. The thrombocyte dysfunction and throm- non-soluble fibrin network is formed ”traping” the
boxane synthesis can be due to the accumulation of erythrocytes and thrombocytes. This complicated
toxic metabolites in plasma. Haemodialysis improves process is triggered by blood vessel or tissue injury.
the function of thrombocytes. In neoplastic diseases Strictly controled interaction between more than 20
can the paraproteins (formed in this condition) in- various proteins is rapidly developing, potentiating
duce the haemorrhage. The underlying cause can be the initial activity of some molecules to create an
the binding of monoclonal immunoglobulin with the adequately large clot. The damaged vessel and the
surface of thrombocytes. This binding inhibits the thrombocyte aggregation form the specialized base
binding of thrombocytes to each other. Disorders where these molecules are localized catalyzing the
of thrombocytes occur frequently in leukaemia and coagulation reactions.
DIC. The coagulation proteins circulate in form of inac-
tive zymogens in amount farly exceeding the needs
of blood coagulation. The process can begin with two
2.4.2 Vascular purpurae
mechanisms – the intrinsic and the extrinsic. The ex-
In these conditions insufficiency of haemostatic trinsic mechanism requires the lipoprotein activity of
mechanisms is involved due to vascular disturbance. damaged tissue in form of tissue factor. Factor X be-
Typical finding in vascular purpurae is the positive comes active at the thrombocyte surface. The plas-
tourniquet test (Rumpel-Leede test). It is a proof of matic coagulation proteins are mostly proteinases of
increased capillary fragility at normal count of nor- serine type some of them operate like cofactors be-
mal thrombocytes and physiologic spectrum range ing without the enzymic activity (factor V and fac-
of coagulation factors. Congenital vascular purpura tor VIII).
occurs in inborn disturbances of connective tissues. The intrinsic mechanism begins with the factor
In children occurs the acquired Hennoch-Schönlein XII activation on the damaged vascular surface (en-
purpura – a type of vasculitis of allergic genesis dothelium, subendothelium) or on another surface
2.5. Disorders of haemocoagulation 73

Figure 2.4: Simplified scheme of blood clotting

with negative charge (e.g. glass). Intact cell sur- The accumulated prothrombinase complex on the
face is positively charged. The cofactors and pro- surface of thrombocytes accelerates in presence of
moters of factor XII are the prekallikrein, kininogen factor V the conversion of prothrombin into the
with high molecular weight – HMWK (high molec- thrombin. Thrombin splits the soluble fibrinogen
ular weight kininogen) and factor XI. On a suitable (m.w. 340 000 daltons). Fibrinogen is composed of
surface this complex activates the factor XII. Factor three pairs of polypeptide chains. Thrombin splits
XIIa converts then factor XI into its active form – first the small peptides from fibrinogen chain A al-
XIa and prekallikrein into the kallikrein. Kallikrein pha. By this is its polymerization started end to
splits HMWK into bradykinin. Factor XIa activates end. Fibrin I is formed. Thrombin splits than
factor IX and can activate factor VII too; as well the small peptides from B beta chain. By side to
as the plasminogen into the plasmin. By this way is side polymerization fibrin II is created. By the ac-
the fibrinolysis as well as the haemocoagulation initi- tion of plasmatic glutaminase (factor XIII) the be-
ated. In presence of Ca2+ and of phospholipids factor come crossed fibrin fibres – a nonsoluble fibrin clot is
IXa activates factor X into Xa. This activation usu- definitively formed. Thrombin plays the main role
ally occurs at the plasmatic membrane of stimulated by converting the fibrinogen into fibrin. Besides
thrombocytes or on vascular endothelium, but it can this it has further important effects. It activates
occur also without them (in vitro) (see picture 2.4, the thrombocytes by opening the binding sites for
page 73). prothrombokinase complex. Thrombin induces the
Extrinsic mechanism. During the extrinsic mech- release of thrombocytic coagulation substances like
anism released tissue factor from damaged tissue di- thromboxan, Ca2+ , ADP, von Willebrand’s factor, fi-
rectly activates factor X into Xa in presence of Ca2+ . bronectin and thrombospondin. Thrombin activates
74 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

the factor VIII and factor V, potentiates the coagula- Willebrand’s factor and the factor VIII circulate in
tion by its action on factor XIII. Thrombin influences the peripheral blood together in form of a macro-
the endothelium by activating the C protein which molecular complex, although they are produced on
binds to the surface protein – the thrombomodulin. different sites. Their production is regulated by dif-
C protein inactivates the factor Va and factor VIIIa, ferent genes. Their structures and functions are also
and stimulates the fibrinolysis. Thrombin elicits the different.
endothelial cell contraction. Tending to a balance the
endothelium can bind and inactivate the thrombin,
2.5.1 Haemorrhagic diatheses
and sometimes it may produce vasodilating prosta-
cyclines in response to the thrombin effect. Severe bleeding after injury, during epistaxis, or sur-
gical intervention, bleeding into the muscles or joints
The terminal phase of coagulation is the fibrinol-
are suspect to be the manifestation of coagulation
ysis. The fibrinolysis process is initiated in fact al-
disorder. If in family history is the statement of
ready during the coagulation. Besides the fibrin for-
bleeding in males, it should be considered a possibil-
mation thrombin namely activates the C protein and
ity of occurence of haemophilia.
releases the plasminogen activators from the vessel
wall. C protein in combination with protein S (the
C protein cofactor) inhibits the coagulations activ- 2.5.1.1 Haemophilia A
ities of factor Va and VIIIa. The circulating plas-
The classical haemophilia is the most common se-
minogen is converted into an active protease – the
vere inherited disorder of blood coagulation. In
plasmin. The splitting is provided by plasminogen
haemophilia A is a quantitative decrease of factor
activators. Then plasmin solubilizes the fibrin. The
VIII accompanied with its qualitative alteration –
activity of plasminogen tissue activators is potenti-
molecular dysfunction of this factor. The gen of fac-
ated by their binding with fibrin, therefore is the
tor VIII has been recently identified. In 70 per cent
plasmin generation localized just at the clot (coag-
of cases is a positive family history of haemophilia
ulum). Moreover, the plasmatic inhibitors of pro-
occurence in male population stated. Spontanneous
teases – alpha1-antitrypsin, alpha2-antiplasmin in-
mutations occur in 30 per cent of haemophilia. Ran-
hibitor, and alpha2-macroglobulin rapidly inactivate
dom inactivation on X chromosome in women usually
the serine proteases including thrombin and plas-
causes, that the mother is the carrier of haemophilia,
min. Antithrombin III binds with procoagulation
her level of factor VIII is only 50 per cent of the
proteins (proteases) (factor Xa and thrombin). The
normal value. In patients with severe haemophilia
antithrombin activity is enhanced by heparin and the
A is the factor VIII activity below 1 per cent of
heparin-like substances. The antithrombin III – pro-
the norme leading to spontaneous or posttraumatic
teases formed complexes are rapidly eliminated from
bleeding epizodes from the birth. The level of factor
the blood flow by liver and the mononuclear phago-
VIII above 5 per cent represents the medium severe
cyte system.
form of haemophilia. The motor activity of children
Liver is the site of synthesis of a great number usually leads to the bleeding into the muscles and
of coagulation proteins. Factors II, VII, IX and X joints. The bleeding into the the joints may result in
and the C and S proteins requires vitamin K pres- severe deformations of extremities. Bleeding can oc-
ence in order to be synthesized. In K vitamin ab- cur also in usual stress situations. Haemorrhage can
sence molecules are produced lacking the carboxyl- occur in every organ. Vitally important structures
glutamate binding sites for Ca2+ . This abnormal can be involved where by the life can be threatened.
molecules are ineffective in coagulation. Fibrinogen, In supplementary treatment the concentrated fac-
factor V and inhibitors of proteases are also produced tor VIII is applied. The factor VIII application im-
in the liver and their production may be reduced in proves the condition acutely, but the problem is not
hepatic diseases. Factor VIII is probably also syn- solved by this approach. The (biological) half-life of
thesized in liver and spleen, nevertheless the right factor VIII is namely very short, 8 to 12 h.
site of its production is not strictly known. Von Factor VIII has to be given before dental and sur-
Willebrand’s factor and the tissue plasminogen ac- gical interventions and in stress situations. Repeated
tivator are produced by endothelium of vessels. Von factor VIII administration is the cause of high inci-
2.5. Disorders of haemocoagulation 75

dence of hepatitis B and of AIDS in these patients. level. During the gravidity the condition may im-
New methods of factor VIII preparation considerably prove owing to the raised vWF and antihaemophilic
reduced the risk of hepatitis and AIDS viruses trans- factor levels. Acetylsalicylic acid and the nonsteroid
fer. Repeated administration leads to forming of antiphlogistic drugs are dangerous for these patients.
factor VIII inhibitors and its rapid destruction after
application. The patients should not receive acetyl- 2.5.1.3 Defects of contact factors
salicylic acid, or nonsteroid antiphlogistics. These
substances impair the functions of thrombocytes and These defects occur infrequently. They are recog-
in this way they impair the bleeding. Longstanding nized in laboratory examinations. They are not
treatment with factor VIII leads to several compli- clinically manifest because they do not enhance the
cations: bleeding tendency. In factor XII (Hageman’s fac-
tor) are the patients asymptomatic. Absence of
1. generation of factor VIII inhibitors prekallikrein and of high molecular kininogen is un-
common. The factor XI deficiency occurs in Japones
2. hepatitis and Jews.
Defects of vitamin K-dependent coagulation fac-
3. hypertension
tors are accompanied with a strong tendency to
4. AIDS bleeding.
Factor IX deficiency is in clinical manifestations
similar to haemophilia. It is an inherited disorder
2.5.1.2 Von Willebrand’s disease
manifested by haemarthrosis, bleeding into the GIT
Under physiological circumstance the thrombocyte and CNS. It is termed haemophilia B. Application of
adhesion to the vascular endothelium may be per- factor IX, with biological half-life of 20 h has a favor-
formed only in presence of a plasmatic glycoprotein able effect except the fact, that it could be connected
termed von Willebrand’s factor (vWF). VWF circu- with thromboembolic complications.
lates in peripheral blood with antihaemophilic factor The factor VII deficiency is a rare autosomal re-
(factor VIII) in form of multimer. The vWF level is cessive defect. The bleeding is usually considerably
in von Willebrand’s disease reduced or is lacking at variable. Treatment is performed with application of
all. VWF can be present in sufficient amount, is plasma or with concentrates of prothrombin complex
however functionally impaired. The antihaemophilic factors. Factor VII has a short half-time, 2 to 6 h
factor (VIII) level may be moderately or consider- only. It is necessary to repeat its application.
ably decreased. The factor X deficiency is an infrequent autoso-
This inherited condition occurs frequently. Both mal recessive defect with bleeding. There exist two
sexes are affected. A double disturbance also ex- types of this condition. In the first quantitative al-
ists with abnormal thrombocyte adhesion in com- teration of factor X (decrease) and in the second the
bination with decreased factor VIII activity. The dysfunction of factor X are involved. The bleeding
clinical state of patients with von Willebrand’s dis- is similar to the bleeding in haemophilia. Bleeding
ease is usually variable. Frequent symptoms are mu- and menorrhagia post partum may be very severe.
cosal bleeding, ecchymoses, epistaxis, gastrointesti- Afibrinogenaemia or congenital dysfibrinogenae-
nal bleeding and menorrhagia. In some patients may mia is a disorder with decreased fibrinogen plasmatic
haemarthrosis occur like in haemophilics. In about level, or abnormal fibrinogens are formed. Abnormal
75 per cent of patients are the vWF and factor VIII fibrinogens may cause the bleeding, but also throm-
levels decreased. This condition is designated as type boses. About 80 types of dysfibrinogenaemia have
I. In some cases is the vWF level reduced only mod- been described till now. The treatment implies the
erately, but the bleeding time is considerably pro- application of plasma rich in fibrinogen or of fib-
longed (type IIa). In type IIb the vWF is lacking rinogen concentrates. The half-time of fibrinogen is
at all. In long lasting bleeding the transfusion of 4 days.
normal plasma or cryoprecipitate is given, being rich The factor XIII deficiency is a seldom autosomal
in vWF. In moderate bleeding desmopressin (amino- recessive defect. The deficiency of fibrin stabilizing
arginine vasopressin) is applied elevating the vWF factor may be manifested by difficult wound healing.
76 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

The factor XIII level can be lower than 1 per cent of may these drugs induce severe gastrointestinal bleed-
normal values. ing or bleeding into CNS.
In hepatic diseases disorders of K vitamin-depen-
dent factors synthesis appear. Impaired fibrinogen
2.5.1.4 Acquired disorders of haemocoagula- and factor V production is usually involved in termi-
tion nal stage. In severe bleeding is the K vitamin appli-
cation insuficient. Application of plasma should be
Acquired haemocoagulation disorders are the conse- considered.
quences of several causes. Insufficient production or In uraemia bleeding into mucosae, skin and GIT
enhanced consumption of coagulation factors may be frequently occurs due to complex causes. In ne-
involved. Functionally defective molecules, selective phrotic syndrome with proteinuria the factor IX de-
inhibitors may be produced sometime, or the coag- ficiency can appear. Finaly, in dialyzed patients
ulation factors can be absorbed. The absorption of (with long termed dialyzing program) repeated hep-
factors e.g. on vascular amyloid is possible, however arinization (heparin application) may contribute to
seldom. the bleeding. In addition to mentioned alterations
Vitamin K – dependent haemocoagulation factors thrombocytopenia due to bone marrow inhibition is
are dependent on the protein synthesis in the liver. in uraemia usually present. There is an important
Prothrombin (II), factor VII, IX, X, C and S pro- thrombocyte dysfunction. The thrombocyte aggre-
teins are involved. Vitamin K is a compound sol- gation and adhesion are impaired.
uble in lipids. It is absorbed in small intestine and Antibodies with anticoagulant effect. In haemo-
store in the liver. It is partially synthesized by sapro- philics with substitution therapy and in immune dis-
phytic microbial flora in small intestine and in colon. eases like lupus erythematosus, lymphoproliferative
Following absorption is vitamin K converted into its diseases, in post partum period and in aged per-
active form. Its main site of action are the hepato- sons antibodies – inhibitors of factor VIII and of fur-
cytes where it contributes to the definitive forming ther factors may be created leading to haemorrhagia
of coagulation factors II, VII, IX, X, of C and S pro- and also the thrombosis. Antibodies may be formed
teins. It operates like cofactor in glutamic acid rests against the von Willebrand’s factor. It is observed
carboxylation of above mentioned coagulation fac- mainly in lymphomas.
tors. During this process binding sites for calcium
are formed on these factors. The serine proteases
can not be activated and the haemocoagulation can 2.5.2 Disseminated intravascular co-
not run without calcium binding. Vitamin K defi- agulation
ciency will be first manifested on factor VII, than
on C protein because these compounds have a short Acute disseminated intravascular coagulation with
biological half time. life threatening bleeding and intravascular coagula-
K vitamin deficiency can appear during malabsor- tion is occuring more frequently in its chronic form.
ption if there is deficiency of biliar salts, in reduced This condition can appear in many diseases. It oc-
intake and after ”sterilization” of GIT by antibiotic curs very often in obstetric catastrophes, in metasta-
treatment and finaly in peroral anticoagulant treat- tique malignant processes, in extended trauma and
ment. Vitamin K deficiency appears most frequently bacterial sepsis. In each of these condition the under-
in inmature newborns, in whom the liver functional lying triggerin mechanism of disorder can be defined.
capacity is not developed yet and the K vitamin syn- On tumors, trauma, tissue necrosis and tissue factor
thesis is lacking in the intestine without bacterial initiating the haemocoagulation is release into cir-
colonization. culation. In sepsis the endotoxin of gram–negative
The coumarin anticoagulans inhibit competitively bacteria activates some steps of coagulation cascade.
the K vitamin effect on carboxylation. The K vi- Endotoxin activates directly the Hageman’s factor
tamin dependent coagulation factors become there- (XII) and the binding of tissue factor with the mono-
fore ineffective. It is manifested by the prothrombin cyte and endothelial surface wich accelerates the co-
time prolongation, above all. Several drugs posses agulation reactions. All triggering alterations result
the coumarin like anticoagulant action. In overdoses in small thrombi and emboli formation in microcir-
2.5. Disorders of haemocoagulation 77

culation. This is characteristic for the early phase bilization, gravidity, malignant processes, hormonal
of disseminated intravascular coagulation. System of anticonception (with high estrogen doses), thrombo-
coagulation inhibitors and the fibrinolytic system are cytopenia, increase in blood viscosity and in plas-
activated. During the thrombi formation the coagu- matic coagulation factors level. The hypercoagula-
lation factors and the thrombocytes are consumed. tion condition may lead to formation of fibrin degra-
The plasmatic coagulation factor and throm- dation products.
bocyte consumption, the fibrinolysis activation
and haemocoagulation inhibition lead to a severe
2.5.3.1 Antithrombin III deficiency
hypocoagulation condition with haemorrhagia. It
is always a very severe state. Haemorrhagia can Antithrombin III is a serine proteases inhibitor
appear on many sites. Bleeding into the skin and blocking the action of coagulation enzyme throm-
mucosae are observed in patients. Bleeding from bin. It inhibits also factor X and potentiates the
wounds, at site of injections or cathethers can oc- anticoagulation effect of heparin. Heterozygous an-
cur. Sometimes acrocyanosis, thrombosis and gan- tithrombin III deficiency is associated with venous
grene of fingers, genitalia and nose are present. The thrombosis in young persons. In a severe deficiency
microthrombi presence elicit vasospasm. In patients of antithrombin III resistance to heparin is observed.
with malignant processes may the disseminated in- In laboratory determined prothrombin III level need
travascular coagulation persist as chronic state. not to be a sign of its intact function. A functionally
In laboratory examination in consuption coagu- abnormal protein may be involved nevertheless the
lopathy the thrombocytopenia, presence of schizo- deficiency of prothrombin III can be also acquired. It
cytes or of fragmented erythrocytes are found in is usual in hepatic diseases, in nephrotic syndrome,
blood smears. The fibrinogen level is decreased. in disseminated intravascular coagulation and in cy-
These are the signs of coagulation factors depletion. tostatic treatment of malignant processes.
The content of fibrin degradation products is in-
creased. The fibrinogen level corresponds with the
2.5.3.2 C and S protein deficiency
bleeding stage.
Treatment of this condition is very complicated. Both these proteins belong to the group of hepatic vi-
If there are signs of bleeding it is necessary to apply tamin K – dependent proteins. C protein is activated
fresh plasma to compensate the deficient coagulation by thrombin. This activation is potentiated when
factors and the thrombocytes. But if there is acro- thrombin binds with thrombomodulin (endothelial
cyanosis and incipient gangrene or thrombose present cell receptor). The activated C protein (in presence
anticoagulants are to be administered, heparin above of S protein) destructs the factor Va and factor VIIIa.
all intravenously. The prophylactic heparin applica- The fibrin formation is inhibited by this, and so is the
tion is most frequently used in patients with tumors, further thrombin generation. The activated C pro-
mainly in the period of cytostatic therapy. tein stimulates also the fibrinolysis. In patients with
this inborn disorder thromboembolic epizodes occur
2.5.3 Thromboembolic diseases and in neonatal period the purpura fulminans ap-
pears. The lack of suppressive system of coagulation
Disorders of haemostatic mechanisms may appear can be therapeutically compensated by application
easily in various diseases. It is important to know the of anticoagulants.
mechanisms which may lead to the haemostasis im-
pairment. The tendency to thrombosis is observed in
surgical interventions, inflamatory processes, during 2.5.3.3 Principles of antithrombotic treat-
gravidity, in vessel diseases and further conditions. ment
Inherited disorders characterized with tendency to Arising of haemostasis mechanisms there exist four
thrombosis concern the C and S proteins, antithrom- basic types of therapy inhibiting the thrombosis:
bin III deficiency, disfibrinogenaemia and disorders
of fibrinolytic system. 1. Substances influencing the thrombocytes
The hypercoagulation condition development is fa-
cilitated by predisposing diseases, long lasting immo- 2. Heparin
78 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

3. K vitamin antagonists
4. Thrombolytic drugs 2.6 Disorders of leucocytes
The first group – substances influencing the
thrombocytes are used in profylaxis of arterial
thrombosis. In the initiation of arterial thrombo-
The main function of leucocytes is to defend the
sis the most important role play the thrombocytes.
organism against diseases, especially against the in-
The acetylsalycilic acid is used the most frequently
fection. Mononuclear phagocytes (monocytes and
for this purpose. It inhibits the enzyme cyclooxyge-
the tissue macrophages) and granulocytes perform
nase thus reducing the thromboxan A2 production
this function by swallowing up the microorganism
in thrombocytes. Activated thrombocytes are the
and digesting the tissue detritus. The lymphocytes
TXA2 producers. TXA2 is a potent vasoconstrictive
participate in activating of immune system functions.
agent. It influences the thrombocyte aggregation and
The polymorphonuclear leucocytes form the high-
the release of further substances from thrombocytes.
est percentage of leucocytes. They do not di-
vide themselves or differentiate further in circulat-
Heparin is used to prevent both the venous and ing blood. They have the ability to move actively
arterial thrombosis. The parenteral administration and to phagocytise various microorganisms and niert
of heparin inhibits the thrombin formation (heparin particles. They release enzymes from cytoplasmatic
is not a homogenous substance, it is a mixture of granules into the phagocytic vacuoles and in certain
polysacharides with molecular weight 3000 to 4000 circumstances into the extracellular space. The neu-
daltons. For the first time it was isolated form the trophils use their ability of chemotaxis (motion in di-
liver therefore it was termed heparin. It activates rection of ascending concentration of the substance
the antithrombin III). of target organism), of phagocytosis (ingestion of the
Coumarin anticoagulants inhibit the synthesis of microbe into the phagocytic vacuole) and the capa-
coagulation factors. This is why their effect appears bility to scarve the microbe chemically by releasing
only in some days. They are administered as preven- the content of granules into the phagocytic vacuoles
tion of both, arterial and venous thromboses. Fol- (bactericidal proteins, myeloperoxidase, cathepsins)
lowing oral application they are absorbed in the in- and by forming of free oxygen radicals as superox-
testines. In plasma they are bound with albumin and ide and hydroxylated anion. In presence of halogens
are transported into the liver, where they are inhibit- e.g. Cl-toxic substances are formed killing the swal-
ing the vitamin K – dependent coagulation factors lowed up microbes.
(II,VII,IX,X). Chemotaxis of neutrophiles is extraordinarly im-
Fibrinolytic substances (the tissue plasminogen portant. They are able to force the neutrophils to be-
activator) and fibrinolytic enzymes (streptokinase come attached to the vascular endothelium and ther-
and urokinase) activating plasminogen into the plas- after to penetrate across the vascular wall (throngh
min are used in last occurs. Fibrinolytic substances the intercellular junctions and to migrate into the ex-
can dilute thrombi in few hours. travascular space. The migration in sense of concen-
The greatest danger of thrombolytic treatment is tration gradient may be influenced significantly by
the bleeding. Patients with thrombocytopenia and bacterial peptides, components of complement sys-
chronic alcoholism, uraemia, and those taking the tem and leucotrien B4 .
acetylsalicylic acid tend to this complication. Except The ability of leucocytes to distinguish microor-
of the drugs mentioned, there exist many substances ganisms or other particles facilitates the phagocyto-
having the anticoagulation as side effect. sis. So do the opsonization or the proteins bound to
the surface of microorganisms. Fragments of com-
plement C3b, the plasmatic protein fibronectin and
immunoglobulins are involved. These substances ad-
here to surface of microorganism enhance the bind-
ing with the receptors of neutrophil plasmatic mem-
brane.
2.6. Disorders of leucocytes 79

During the phagocytosis the phagocytic vacuole system. Monocytes and macrophages activate the T
fuses with intracellular vacuoles containing enzymes. cells. This function performs a special monocyte sub-
The neutrophils contain two types of cytoplas- population – the dendritic cells and the Langerhans’s
matic granules. The azurophil granules contain cells in the skin. The dendritic cells form a very
lysozyme, acid hydrolases, neutral proteases includ- small subpopulation of monocytes with long projec-
ing the cathepsin G and the elastases, myeloperoxi- tions. They act like antigen presenting cells in blood.
dase and basic proteins. The specific granules con- Langerhans’s cells have similar function in the skin.
tain lysozyme, transcobalamin 3, apolactoferin, col- Lymphokinins secreted by activated T-cells induce
lagenase, C5 protease. The azurophil granules con- the accumulation and activation of monocytes. One
nect with the phagocytic vesicules and the plasmatic of these leukokinins – interleukin-2 acts as growth
membrane. During this connection the content of factor of T-cells enabling them the expansion of T-
azurophil granules is discharged into the acid mi- cell population and the immune response. Moreover
lieu of vesicules. The specific granules are connected the macrophages stimulate the proliferation and dif-
with phagocytic vesicules and plasmatic membrane ferentiation of B lymphocytes by interleukin-1 secre-
so that their content is released into the vacuoles also tion. Prostaglandin E2 secreted by monocytes and
arround the neutrophils. These enzymes facilitate macrophages inhibits, in contrast, the lymphocytic
the bacterial covers, dissolve the connective tissue, reactions.
decompose the tissue detritus, or bind with specific The participation of leucocytes in many haema-
substances, useful for bacterial metabolism, e.g. the tologic, infections, inflammatory and neoplastic pro-
iron. cesses is evident. This is why the leucocyte count
Granulocytes have a short biological half-life, determination and their histological examination is
about 6 h. They circulate early after their release considered to be the fundamental laboratory estima-
in to the blood, enter the tissue and there they can tion of pathologic alterations in organism.
survive even several days. All five types of leucocytes (neutrophils, eosino-
phils, basophils, lymphocytes, monocytes) originate
Circulating monocytes and fixed macrophages in a common stem cell. In spite of the common ori-
(phagocytes) have a broader functional adaptabil- gin their development, function and distribution are
ity then the neutrophiles. They survive much longer quite different. Basal laboratory examination deter-
than neutrophiles. They contain granules not di- mines the leucocyte count and their percentual dis-
vided in subtypes. The circulating monocytes have tribution according to the types.
less chemotactic activity than the neutrophils and
appear later in the focus of inflammation. Their
phagocytic effects are directed against the intracellu- 2.6.1 Leucocytosis
lar microorganisms. Lipopolysaccharides and gama The leucocyte count elevation – the leucocytosis is
interferon activate the monocytes. It is manifested in organism atteined by several mechanisms. Un-
by their higher motility, metabolic activity, propor- der physiological circumstances about a half of all
tions and microbocide potency. leucocytes adheres freely to the vascular endothe-
The monocytes have three basic functions: 1 se- lium or remains in the microcirculation. If the state
cretion, 2 phagocytizing capability, 3 interaction of organism is altered, e.g. during exertion or after
with lymphocytes. Monocytes synthesize 50 vari- adrenaline application, leucocytes are released and
ous protein mediators and enzymes and release inter- circulate in the whole organism. This process of
leukins which influence the lymphocytes and cause leucocyte release from the marginal pool is named
the fever. They have a very active metabolism of demargination. Neutrophils are not involved. Neu-
arachidonic acid leading to the prostaglandin pro- trophil stores are in bone marrow – it is the so-
duction (PGE2 ). PGE2 regulates the bone marrow called medullar reserve of neutrophils, from where
and the cells involved in immune response prolifera- they are released in stress, infection and corticos-
tion. A further product are leukotrienes and throm- teroid administration. If the stimulus is very intense
boxane. Activated monocytes have tumoricide effect. – e.g. the bacterial infection apart from mature neu-
Interaction between monocytes and leucocytes are trophils the immature forms – the metamyelocytes
necessary for maintaining normal function of immune may be released. This type of leucocytic respons to
80 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

the infection is named the shift to the left. Leuco- moderately severe neutropenia 1 µl of blood contains
cytosis can be due to increase in leucocyte produc- 500 to 1 000 neutrophils and in a mild form 1 000 to
tion. It may reach very intense stimulation 25 000 to 2 000 neutrophils. The risk of infection and its sever-
50 000 Le in microliter. Such an alteration is named ity is augmented if the neutrophil count is less than
leukemoid reaction. 1 000 in 1 microliter of blood.
The leucocyte release from the marginal pool in Neutropenia may be due to ineffective neutrophil
to the circulation occurs during some minutes. The production or to increased margination, eventually
release of neutrophils from bone marrow lasts several to enhanced neutrophil utilization.
hours. Increase in leucocyte production in bone mar- Probably commonly the neutropenia appears ow-
row becomes manifest in the peripheral blood only ing to the bone marrow suppresion following cyto-
in several days. static treatment. Neutropenia appears in conditions
The leucocyte production is controled. Under affecting haemopoietic stem cells, i.e. in leukaemia,
physiological circumstances there is the local con- myelodysplastic syndrome or in pernicious anaemia.
trol in bone marrow, thymus, lymphatic glands and In B12 and folic acid deficiency is the neutrophil
spleen. Interleukins and CFS (colony stimulating production ineffective. Defective neutrophils are de-
factor) are involved in the control. Interleukin-2 stroyed in bone marrow earlier than they get into the
(IL-2) and IL-4 can cause increase in T and B lym- blood flow.
phocytes. G-CSF (granulocyte colony stimulating In cyclic neutropenia fever, weakness, ulcerations
factor), GM-CSF (granulocyte-macrophage colony of oral mucosa and absence of neutrophils in periph-
stimulating factor), M-CSF (macrophage colony eral blood are observed. This condition returns in 21
stimulating factor) and four interleukins: IL-1, IL-2, day intervals. Between these episodes is the patient
IL-3, IL-5 and IL-6 enhance the production of neu- very well. In the phase of impairment the throm-
trophils, monocytes and eosinophils. In leucocy- bocyte and reticulocyte fall also occurs. A defective
tosis mostly prevail the neutrophils. Leucocytosis regulation of stem cells is supposed to be the under-
with prevailing lymphocytosis is observed in chronic lying cause. The G-CSF application increases the
leukaemia, infectious mononucleosis, infectious hep- neutrophil production and moderates the infection
atitis, infectious lymphocytosis, pertussis (whooping course.
cough), tuberculosis and lues. A moderate increase
In chronic idiopatic neutropenia is the neutrophil
in lymphocyte count is usually associated with thy-
count substantially reduced, nevertheless the mono-
rotoxicosis and Addison’s disease.
cyte count is elevated. Bone marrow is not consid-
Increase in circulating monocytes is observed in
erably altered. Decrease in count of mature neu-
chronic inflammatory processes like tuberculosis,
trophils is observed only. In some cases antibodies
bacterial endocarditis, brucellosis, malaria, sarcoido-
against the neutrophils are found. The role of these
sis, Crohn’s disease and collagenoses. It can be im-
antibodies is not known.
portant in myeloproliferative syndromes.
Neutropenia may be induced by many drugs. In
these cases fever, sore throat and perianal ulcera-
2.6.2 Leucopenia tions are present. The mechanism of drug action
If the leucocyte count falls there is mostly dicrease may be toxic or immune. After interruption of treat-
in neutrophil leucocytes involved. There is an asy- ment the neutrophil count returns to normal values.
metric decrease in all types of leucocytes. Neutropenia is sometimes observed in relation with
Neutropenia. The severity of neutropenia is ex- increasing of drug doses (chloramphenicol, propylth-
pressed by the absolute neutrophil count (from per- iouracyl).
centual participation of neutrophils in differential Isoimmune neonatal neutropenia is transient con-
blood picture the absolute number of neutrophils is dition due to the transplacental transfer of antibod-
counted of the number of all leucocytes in 1 µl of ies from the mother’s body into the fetal organism.
blood. Under physiological conditions are 2 500 to Antibodies directed against neutrophils are involved.
3 500 leucocytes present in 1 microliter of blood). In this condition spontaneous recovery occurs during
Natable neutropenia represent a condition with less some month after the birth.
than 500 neutrophils in 1 microliter of blood. In In systemic lupus erythematosus occurs usually
2.7. Malignant haematologic diseases 81

neutropenia of medium severity. In some patients

with rheumatoid arthritis severe form of neutrope-
nia with splenomegaly and high levels of rheumatic 2.7 Malignant haematologic
factors (Felty’s syndrome) occur.
diseases
Neutropenia may develop in bacterial, viral, par-
asital, rickettsial diseases. Abnormal production,
margination or utilization of neutrophils may be in-
volved. In infectious mononucleosis, infectious hep- The haematologic malignancies comprise a group
atitis and HIV infection the neutrophil production of conditions originating in bone marrow and lym-
is impaired. In influenza and in rickettsial infections phatic glands. Primary bone marrow diseases are the
increased neutrophil margination occurs. In gram- leukaemias, the immunoproliferative and the myelo-
positive infections the utilization of neutrophils is el- proliferative syndromes. It is evident in all these dis-
evated. Neutropenia may develop in splenomegaly eases, that the origin lies in cell mutation being the
due to hypersplenism owing to the increased uptake basis for development of malignant clone. The malig-
of neutrophils in the spleen. nant clone exhibits an abnormal growth potency. In
Lymphocytopenia (lymphopenia) is a condition chronic lymphocytic leukaemia the malignant lym-
the count of lymphocytes in 1 µl of blood falls to less phocytes produce an identical immunoglobulin. In
than 1 500 in adults and to 3 000 in young people and chronic myelogenous leukaemia all cells of myeloid
children. series, the erythroid precursors, the megakaryocytes
and B lymphocytes have an identical Ph1 Philadel-
It occurs most commonly in congenital immun-
phia chromosome. Many further facts indicate that
odeficiency syndrome. It is observed also following
the malignant cells arise from one cell and by their
irradiation, cytotoxic and corticosteroid treatment.
expansion the clone of malignant cells is formed.
Lymphopenia accompanies the lymphomas, aplas-
tic anaemia, renal failure, right cardial failure, and
cachexia. 2.7.1 Myeloproliferative disorders
Monocytopenia appears in acute infections, in Four diseases may be included in this group, each of
stress and following glucocorticoid application. It them being an independent clinical unit:
is developing in aplastic anaemia, acute myeloid
leukaemia, after myelotoxic, immunosuppressive 1. Polycythaemia vera
treatment.
2. Myelofibrosis with myeloid metaplasia
Eosinopenia occurs in stress, infections anf follow-
ing glucocorticoid application. 3. Essential thrombocytopenia
Eosinophilia can appear during chronic myeloic
leukaemia. It may be severe in parasitic and aller- 4. Chronic myelogenous leukaemia
gic diseases. The underlying causes of eosinophilia
In all these conditions are an uncontrolled expan-
are usually chronic inflammatory and malignant dis-
sion of bone marrow elements included. Increase in
eases.
erythroid, myeloid and megakaryocyte cells produc-
In idiopathic hypereosinophilic syndrome there tion is due to malignant transformation of pluripo-
is hepatosplenomegaly, peripheral neuropathy, and tent stem cell. Fibrosis of bone marrow is frequently
congestive heart failure. present owing to growth stimuli affecting normal fi-
broblasts. The origin of these growth stimuli is in
neoplastic cells. They are produced most probably
by megakaryocytes in bone marrow. In myeloprolif-
erative disorders the megakaryocytes count is usually
extremely elevated.
Polycytaemia vera is a myeloproliferative neoplas-
tic disease. The stem erythroid cell is primarily af-
fected. Hyperplasia of all bone marrow components
82 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

is usually observed however the raise in erythroid ical character. This type of absolute polycythaemia
precursors is dominant. The enhanced erythrocyte (secondary) occurs in conditions associated with hy-
production is completely autonomous. Any stimulus poxia of tissues. This condition occurs frequently
is not present like hypoxia or enhanced erythropoetin during insufficient saturation of blood with oxygen.
production, which could be responsible for increase Hypoxia induces increase in erythropoietin produc-
in erythrocyte production. In polycythaemia vera tion in kidneys. Erythropoietin stimulates the ery-
rise the values of haematocrit. If haematocrit above throid precursors and the erythrocyte production
54 per cent in men or above 50 per cent in women which should provide tissues with oxygen. Increased
is stated it is necessary to look for the cause of this erythrocyte production and larger erythrocyte mass
increase. Important is to know if there is increase will be however manifested by increased blood vis-
in absolute acount of erythrocytes or if the volume cosity what actually causes that the oxygen supply in
of plasma is not falling. Information above the ery- tissues does not increase. This state develops e.g. in
throcyte mass provides the method performed with patients with congenital cyanotic heart diseases and
erythrocytes labeled by 51 Cr. in patients with pulmonary diseases. If the haemat-
In polycythaemia vera are leucocyte and thrombo- ocrit values are more than 75 per cent, the venepunc-
cyte values usually increased. In other myeloprolifer- tion remains the only intervention to decrease the
ative disorders polycythaemia may be present. The volume of circulating blood. The erythrocytic mass
underlying cause of polycythemia vera is not known. loss, however, will be soon restituted. Every haemat-
The patients are sometimes without difficulties. Dif- ocrit elevation is very infavorable condition. Causing
ficulties originating in hypervolaemia, hyperviscosity the viscosity elevation it diminishes the blood flow
and thrombocyte dysfunction appear. These alter- through the brain, reduces the heart volume and
ations represent a severe risk of myocardial infarc- forms favorable conditions to thrombosis develop-
tion development and of venous thromboembolism. ment.
Enhanced cell formation and destruction leads to hy- Myelofibrosis and myeloid metaplasia is a myelo-
peruricaemia. Increase in basofil production enables proliferative disorder with expansion of all cell types
the enhancement of histamin release, manifested by in bone marrow, due to pluripotent stem cell ma-
severe itching. lignant deformation. The bone marrow fibrosis is
The confirmation of polycythaemia vera is not a response to the expansion and malignant trans-
easy. But, erythropoietin is usually not increased. formation. In advanced stage may fibrosis occupy
In few per cent of affected patients develops acute the whole space in bone marrow. The extramedullar
leukaemia. The leukaemia appears more frequently haemopoiesis in the liver and the spleen with hepato-
in patients treated by cytostatics for polycythaemia and splenomegaly becomes the cardinal symptom of
than in untreated patients. The bone marrow fibrosis disease. The extramedullar haemopoiesis is the pic-
may develop in polycythaemia to such a degree that ture of reactivation of fetal sites of haemopoiesis, or
the erythrocyte production is reduced. As conse- it is due to bone marrow stem cell migration.
quens the anaemia and extramedullar haemopoiesis
Clinical manifestation of myelofibrosis with
with splenomegaly is present.
myeloid metaplasia need not to be marked. In the pe-
Relative polycythaemia (false polycythaemia, ripheral blood are erythrocytes with nuclei observed.
stress polycythaemia). This condition occurs in They are the sign of extramedullar haemopoiesis.
obese persons, in hypertension or in chronic stress. Leukocytosis with the shift to the left is found.
The haematocrit values are usually 55 to 60 per cent. Myelofibrosis with myeloid metaplasia (MMM) can
The mass of erythrocytes is normal and the volume progress very slowly. Splenomegaly, hepatomegaly
of plasma is decreased. The causes of this condition and anaemia with thrombocytopenia are develop-
are not completely understood. ing. The splenomegaly may attein an extreme de-
Absolute polycythaemia. This condition can be gree and may lead to portal hypertension. These
due to enhanced erythrocyte production like in poly- alterations prevail frequently in the clinical pattern.
cythaemia vera. In this case we could speek about In treatment of progressive anaemia is to consider
primary absolute polycythaemia. The production the iron and folic acid supplementation or transfu-
may raise however owing to the stimuli of physiolog- sion. The splenectomy solves only the problemes
2.7. Malignant haematologic diseases 83

connected with enhanced pressure symptoms in the found. In the initial stage is splenomegaly usually
abdominal cavity. present, often with thrombocytosis. During periodic
Essential thrombocytaemia is a myeloprolifetative oral chemotherapy anaemia occasionally with throm-
disorder, dominant sign of which is the elevated bocytosis appear following 3 to 5 years of treatment
thrombocyte count (above 1 000 000 in 1 µl). Main duration. Patients use to have fever and weakness.
symptoms of this condition are due to thrombosis In peripheral blood promyelocytes and myeloblasts
or to haemorrhage. Nevertheless, the patients may occur. This stage is named the blastic phase.
be without troubles. Acral pain can appear some- A promissing therapeutic strategy is the applica-
times due to thrombosis in microcirculation and is tion of human alpha interferon which may induce
manifested by gangrene of toes. The thrombocyte disease remission and suppress the Philadelphia chro-
agregability inhibition by acetylsalicylic acid is used mosome.
to suppress the thrombus appearence in microcircu-
Chronic lymphocytic leukaemia (CLL). This con-
lation.
dition is named also the accumulative disease of im-
munologically incompetent small lymphocytes. It
2.7.2 Leukaemias occurs more frequently in men than in women. In
peripheral blood is absolute lymphocytosis. Lym-
Leukaemia is a condition where the bone marrow is
phocytosis is permanent and reaches values above
replaced by malignant clone of lymphocytes, mono-
15x109 /l of lymphocytes. The bone marrow is hy-
cytes or granulocytes, resp. of plasmocytes and ery-
percellular. More than 40 per cent of all cells in bone
throcytes. The immature cells are released into the
marrow are the lymphocytes. In the peripheral blood
peripheral blood. The progress may be chronic or
in the bone marrow too prevail the small mature
explosive. When the leukaemias are not treated they
lymphocytes. In blood smears typical Gumprecht’s
end always lethally.
shadows are present. Owing to the neoplastic lym-
Lymphomas are tumors arising from cells of lym-
phocyte accumulation the spleen and the liver be-
phatic system. The bone marrow in lymphomas can
come slowly enlarged. The lymphocytes are immuno-
be infiltrated by lymphoid cells, nevertheless is very
logically incompetent. Therefore hyporgammaglobu-
seldom the site of origin of primary lymphomas. linaemia and predisposition to infections are present.
The lymphocytes in chronic lymphocytic
2.7.2.1 Chronic leukaemias leukaemia are clonic proliferation of B lymphocytes.
The chronic myeloid leukaemia (CML) is frequently The surface immunoglobulins are the IgM and IgD.
classified as myeloproliferative disorder because of The proliferation of T lymphocytes is found in only
evident expansion of all bone marrow cell types, 1 per cent of patients with CLL. The etiology of CLL
which all have the Philadelphia chromosome indicat- is not known. The course of disease is typical. In
ing the pluripotent stem cell mutation as the initial the 0 stage only lymphocytosis is present. In the
alteration. The Philadelphia chromosome represents first and second stages tumors (of lymphatic glands,
the long branch part of chromosome 22 transloca- liver and spleen) appear. In further stages: third and
tion to chromosome 9. This translocation can be the fourth anaemia and thrombopcytopenia appear due
underlying cause of cellular oncogenes activation. to bone marrow suppression. The splenomegaly is
CML appears in adults of age between 40 to 50 the underlying cause of hypersplenism (erythrocyte
years. Sometimes it appears also in chidren. Pa- and thrombocyte sequestration).
tients need not have findings about the exposure to Leukaemic reticuloendotheliosis (hairy cell leukae-
effects of carcinogenes or radioactivity in their per- mia – HCL) is a neoplastic disorder with typical hairy
sonal medical history. Following explosion of atomic cells in peripheral blood and bone marrow. The hairy
bombs in Hiroshima and Nagasaki the number of pa- cells are similar to the lymphocytes with thin pro-
tients with CML raised significantly in 7 years in jections. The course of disease may be leukaemic
persons who survived the catastrophe outside of epi- or aleukaemic with very slow development. Pancy-
centre. topenia and splenomegaly dominate in the clinical
In patients with CML the leukocytosis and pres- pattern. The deoxyformycin treatment can result in
ence of myeloid precursors in peripheral blood are complete haematologic remission in some patients.
84 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

The most preferal treatment of first choice remains having myeloid and monocytic signs)
the splenectomy. M5 – acute monocytic leukaemia (monoblasts with
abundant cytoplasma)
2.7.2.2 Acute leukaemias M6 – erythroleukaemia
In acute leukaemias the immature haematopoietic M7 – acute megakaryocytic leukaemia
cells proliferate without differentiation to normal
mature blood cells. The normal erythrocyte, gran- Acute lymfoblastic leukaemias:
ulocyte and thrombocyte production is limited by L1 – with predominant population of small cells with
myeloblast or lymphoblast proliferation. This leads small nuclei
to the clinical manifestation of disease. Anaemia, L2 – acute leukaemia with heterogenous group of
reduced resistance to infections and bleeding are ob- cells with various size and nucleus form
served. Irradiation damage, viral infections, genetic
predisposition or exposition to effects of some chem- L3 – acute leukaemia with homogenous cell popula-
ical agents (substances) is frequently stated in the tion similar to the Burkitt’s lymphoma
medical history of patient. The precise mechanism Single subgroups are characterized not only by
of action of these factor, or their interaction with (the) morphologic finding in blood samples but by
normal stem cells is not known. It is not understood more or less typical clinical pattern. In promyelo-
how the production of malignant clone arise under cytic leukaemia M3 , e.g., the disseminated intravas-
their influence. Acute leukaemias are classified into cular coagulation frequently occurs. The promyelo-
two large groups: cytes release enzymes from their granules stimulating
the coagulation cascade and facilitate the intravas-
1. Acute lymphoblastic leukaemia (ALL)
cular coagulation. The acute monocytic leukaemia –
2. Acute myeloblastic leukaemia (AML) M5 is usually associated with skin and oral mucosa
infiltration with leukaemic cells. The lymphoblas-
The ALL occurs primarly in children, the AML, tic leukaemia of L1 subtype occurs above all in chil-
on the other hand, occurs primarly in adults. About dren and the subtype L2 in adults. L3 – has an un-
20 per cent of acute leukaemias appear in adults, favourable prognosis.
however those are of lymphoblastic type. Precise de- Acute leukaemia is clinically manifested by out-
termination of leukaemia type is important regarding standing symptoms. Infections are observed ow-
the treatment. It is performed on the basis of his- ing to the impaired function of bone marrow lead-
tological examination of bone marrow, histochemi- ing to granulocytopenia. Bleeding due to thrombo-
cal examination of leucocytes and of surface cyto- cytopenia and anaemia caused by disorders of ery-
plasmic markers. The chromosomal alterations in throid maturation. Bone pain may occur due to the
acute leukaemia correlate with certain type of cells. leukaemic marrow expansion. In ALL splenomegaly
There is e.g. a subgroup of patient with atypical and lymphadenopathy are frequently present. The
ALL with cells containing the Philadelphia chromo- global lymphocyte count is usually elevated. It may
some. In despite of a considerable heterogeneity be sometimes more than 100 000 lymphocyte in 1 µl
acute leukaemias are classified into following sub- of blood. In aleukaemic form nevertheless it can be
groups. less than 3 000 in 1 µl. Analysis of the blood smears
reveals pathologic finding almost regularly. Some
Acute myeloblastic leukaemias: leucocytes are mature a great part however is on the
M1 – acute myeloblastic leukaemia without differen- level of blasts. In the peripheral blood single forms of
tiation of blasts development are present. The uneven blood cell (of
various differentiation degree) distribution is termed
M2 – acute myeloblastic leukaemia with differentia-
hiatus leukaemicus. Values of haemoglobin, counts
tion (especially of myeloblasts and promyelocytes)
of erythrocytes and thrombocytes use to be reduced.
M3 – acute promyelocytic leukaemia (with preva- Uric acid level is usually elevated due to the excessive
lence of abnormal promyelocytes) production and desintegration of leucocytes. The hy-
M4 – acute myelomonocytic leukaemia (with cells peruricaemia leads to the renal damage. The bone
2.7. Malignant haematologic diseases 85

marrow examination reveals almost in every case the hypercellular with rise in iron stores and with abnor-
hypercellularity and cells without differentiation re- mal erythroid precursors and higher portion (partic-
placing of the normal bone marrow. ipation) of immature myeloid cells. This condition
Acute leukaemia is always an urgent condition. is named the refractory anaemia or preleukaemia.
Decision on further treatment should be made con- The beginning and course is usually rather variable.
sidering the global findings and the severity of the These conditions therefore are classified in five types
state. If the leucocyte count is higher than 100 000 of myelodysplastic syndromes:
in 1 µl the patient is treatened with cerebral haem-
orrhage usually due to leukostasis. High count of 1. Refractory anaemia
leucocytes, especially the presence of rigid blasts pro- 2. Refractory anaemia with sideroblasts
duce an obturation plug (stopper). The therapeutic
reduction of leucocyte count elevates the uric acid 3. Refractory anaemia with rise in blast count
level. The patient is threatened with infections par-
ticularly when the granulocytes in circulation are 4. Chronic myelomonocytic leukaemia
lacking or there are only very few of them. The whole
5. Refractory anaemia with transformation
blood transfusion leads to haemoglobin, erythrocyte
and thrombocyte count rise. It is prevention of The risk of acute leukaemia development increases
haemorrhagia. The cytostaic treatment is used with with rise of blast number in bone marrow. The
intention to stop the proliferation of cells. The drugs primary treatment is directed to improvement of
act in various phases of cell cycle. The bone marrow anaemia. Application of high vitamin B6 doses has
transplantation is to be considered preferentially in been successful in some patients.
young patients respecting a suitable donor regard-
ing the HLA. For bone marrow transplantation are
suitable candidates those patients in whom follow- 2.7.4 Lymphomas
ing the initial treatment complete remission occured. The lymphomas form a group of malignant diseases
The bone marrow transplantation presents a risk of arising from lymphatic glands or from extralym-
infection, haemorrhagic complications and intersti- phatic tissue. Regarding the pathologic and clini-
tial pneumonia. Bone marrow aplasia may appear cal pattern this group of malignant diseases is het-
later. The leukaemic clone is eradicated by cyto- erogenous. Two large subgroups are represented
toxic drugs before transplantation. Reappearing of by Hodgkin’s disease and the non-Hodgkin’s lym-
leukaemia can be due to insufficient eradication of phomas. In both these subgroups is the enlarge-
leukaemic clone or to the transferrable agent tran- ment of lymphatic glands the most frequent clinical
sition into the new cell line. A perspective hopeful sign. It should be excluded at the very beginning,
therapeutic possibility are the monoclonal antibodies if an ordinary enlargement of lymphatic glands is
against the surface antigens of leukaemic cells. involved, observed in various local or generalized in-
fections. Bioptic examination of lymphatic glands is
2.7.3 Myelodysplastic syndrome performed subsequently.

On the contrary to acute leukaemia the myelodys-

2.7.4.1 Hodgkin’s disease
plastic syndromes are characterized by slow develop-
ment ending in anaemia refractory to the standard This condition occurs most frequently in young per-
treatment. The affected patients are usually elderly sons, but it can appear also in children or in older
people. In younger people may the myelodysplas- people. Asymptomatic lymphadenopathy is usually
tic syndromes develop following radiotherapy combi- observed in patients. A lymphadenopathy accessible
nated with antineoplastic chemotherapy of diseases by aspection and palpation may be involved, however
like m. Hodgkin or carcinoma ovarii. At the be- a mediastinal lymphadenopathy may be observed in
ginning weakness and a marked decline in physical X-ray examination. Fever and night sweats, weight
performance appear. Macrocytic anaemia is usu- loss, cough and itching are present in some patients.
ally present in addition to leukopenia combined with From clinical point of view is Hodgkin’s disease
thrombocytopenia or without it. The bone marrow is classified in subtypes A and B according to present
86 Chapter 2. Pathophysiology of blood and haematologic system ( I. Hulı́n )

symptoms. Four histopathologic subtypes are the performed determining more accurately the involved
following: nodular sclerosis; type with lymphocyte origin of malignant cells (lymphoma from sup-
predominance; mixed type and lymphocyte depleted pressor T-lymphocytes, lymphoma from helper T-
type. In all four types is the only patognomic sign lymphocytes). The T-lymphocytes may become
the presence of Reed-Sternberg cells confirming the transformed into T-immunoblasts (in vitro they can
diagnosis. The Reed-Sternberg cells are large cells bind directly to their surface the sheep erythrocytes
with two or more nuclei. Each nucleus contains a – forming E-rosettes). B-lymphocytes, especially
nucleolus with an outstanding halo resembling the those located inside the follicles of lymphatic tissue,
owl eyes. The progenitors of Reed-Sternberg cells can be transformed gradually into B-immunoblasts.
are the macrophages. Hence, the tumor lineage may originate in B-line
Nodular sclerosis is the most frequently occuring or in T-lymphocytes. The cytologic picture of non-
subtype of Hodgkin’s disease. In lymph nodes broad Hodgkin’s lymphomas is very motley. Lymphomas
fibrotic strips are present changing the typical ar- originating in T-lymphocytes have more malignant
chitecture of lymphatic nodes. In the nodes lacunar development (course) than the lymphomas arising
cells and dispersed Reed-Sternberg cells are found. from B-lymphocyte lineage. Nevertheless, it is im-
This type of Hodgkin’s disease is usually asymp- portant that the lymphocytes are mobile cells pass-
tomatic. The mediastinal lymph nodes are especially ing through lymphatic vessels across the tissues. So
affected. This condition occurs more frequently in can the lymphocytes colonize distant tissues and or-
young women. gans. The colonization of some tissues depends on
The mixed subtype of Hodgkin’s disease is charac- determinants of surface membrans.
terized by mixed cellularity with lymphocytes, plas- The morphological picture of non-Hodgkin’s lym-
matic cells and Reed-Sternberg cells. It occurs pref- phomas is important regarding the malignity degree,
erentially in middle-aged men. The lymphocyte pre- the prognosis and the treatment strategy determi-
dominant subtype is usually seldom. In this condi- nation. The non-Hodgkin’s lymphomas are divided
tion are found enlarged lymphonodes on the neck. into the lymphomas with low grade malignity (lym-
The prognosis of this type is very favourable. The phocytic lymphoma, centrocyto-centroblastic lym-
lymphocyte – depleted subtype is also infrequent oc- phoma, immunocytic lymphoma, centrocytic lym-
curing in older people. It uses to be accompanied phoma); the lymphomas with higher grade of malig-
with fever, night sweats and body weight loss. nity (centroblastic, lymphoblastic, and immunoblas-
In Hodgkin’s disease the stages are determined tic lymphomas).
(I. to VI.) because it is important regarding the treat- In non-Hodgkin’s lymphomas chromosomal abnor-
ment. When the treatment begins in more advanced malities are more frequently observed. However any
stages the prognosis is worse. Immunologic disorders specific abnormality does not exist in comparison
due to T-cell dysfunction occur in Hodgkin’s disease. with e.g. the Ph1 chromosome presence in chronic
In patients appear frequently herpes zoster, bacterial myeloic leukaemia. Non-Hodgkin’s lymphomas oc-
infections and opportune infections. cur more frequently in persons of higher age groups.
The primary focus is localized often apart of lymph
2.7.4.2 Non – Hodgkin’s lymphomas node. The prognosis depends on clinical stage.

The non-Hodgkin’s lymphomas form a heteroge-

2.7.5 Disorders of plasmacytes
nous group of tumorous diseases arising as mono-
clonal proliferation from malignant cell of lymphatic Plasma cells disorders form a group of malignan-
origin. The underlying cause is not known as it cies basis from which is a clone of cells producing
is in Hodgkin’s disease. Viruses, radiation, im- the monoclonal immunoglobulin. If the production
munosuppression and genetic conditions should be of IgM is involved the Waldenstrom’s macroglob-
considered. About 70 per cent of non-Hodgkin’s ulinaemia develops. When the monoclonal im-
lymphomas arise from B-lymphocytes, 20 per cent munoglobulins IgG, IgA, IgD resp. IgE are pro-
from T-lymphocytes and in 10 per cent of cases duced myeloma multiplex is developing. The ba-
the surface signs of lymphocytes can not be de- sis are the malignant plasmacytes. Under normal
tected (non-B/non-T). The subtypization can be conditions are the plasmacyte, in fact, specialized
2.7. Malignant haematologic diseases 87

B-cells (Fig. 52-3, p.). The plasma cells release, im- ring spontaneous fractures. A severe complication
munoglobulins and are responsible for humoral im- is the hypercalcaemia and the syndrome of hyper-
munity under physiological conditions. Increase in viscosity. Fatigue, weakness, body weight loss and
monoclonal immunoglobulin is (usually) detected in haemorrhagic diathesis, fever occur. In patients
about 10 per cent of cases of chronic lymphocytic with severe damage of kidneys massive proteinuria
leukaemia. or nephrotic syndrome may develop. The severity of
the condition is evaluated by quantitative determi-
2.7.5.1 Myeloma multiplex nation of monoclonal protein in serum and in urine.
Chemotherapy is usually successful at the beginning
This malignant disease of plasma cells (plasmacytes –
of disease. It causes however a dangerous cytopenia
B-lymphocytes) is characterized by presence of mon-
with all consequences.
oclonal immunoglobine or its light chains in serum
and urine associated with bone destruction. Neopla-
sia formed of plasmacytes or B-lymphocytes produc- 2.7.5.2 Waldenstrom’s macroglobulinaemia
ing immunoglobulins are caused by clonal prolifera-
This malignant disease is characterized by neo-
tion of an altered cell. Neoplasia is diffuse or con-
plasia arising from B-lymphocytes responsible for
centrated in small loci localized especially in bone
immunoglobulin M synthesis. This condition
marrow. The patients affected are usually over 50
has a course of long duration and occurs in
years old. Back pain is the most common com-
older people. In patients arise usually anaemia
plaint of patients. Middle severe anaemia and ele-
with further symptoms – lymphadenopathy hepato-
vated values of erythrocyte sedimentation rate occur.
splenomegaly, haemorrhagic diathesis and the blood
In roentgenologic examination osteoporosis or oste-
hyperviscosity of blood due to monoclonal IgM –
olytic alteration can be observed. Renal damage may
a large molecule remaining in intravascular space.
be present due to light chains Ig filtered in glomeruli
As consequence of high viscosity appears epistaxis
and to other factors (myeloma kidney). The im-
retinal haemorrhages, mental confusion and conges-
munoelectrophoretic examination reveals increase in
tive heart failure. Some IgM molecules praecipi-
monoclonal immunoglobulin values (e.g. of IgGk ).
tate under lower temperature. This is why the syn-
Levels of other immunoglobulin types are lowered.
drome of cryoglobulinaemia may become clinically
Free, light chains kappa or lambda (Bence Jones pro-
manifest. Striking by cyanotic are acral parts ex-
tein) are increased and occur in urine, detectable by
posed to cold, as fingers, nose, ears. On legs ap-
immunoelectrophoresis of urine. The finding of light
pear ulcerations and gangrenes due to vessel occlu-
chains is sometimes more outstanding than the pres-
sion. Some IgM molecules act directly as antibodies
ence of monoclonal immunoglobulin. In few cases
against the erythrocytes. In these cases occur Ray-
prevail the malignant clonal plasma cell proliferation
naud’s fenomenon with haemolytic anaemia.
without an important paraprotein production.
Under physiological circumstances fewer than In some patients the antimyelin activity of mono-
5 per cent of plasma cells are present in bone mar- clonal IgM has been observed. This activity is con-
row. In myeloma multiplex their count increases to sidered to be the underlying cause development of
more than 10 to 20 per cent in bone marrow. Some peripheral neuropathy. Macroglobulin inhibits the
plasma cells are bizzarly shaped. Cells containing thrombocyte aggregability contributing to the ap-
two or more nuclei use to be present. pearence of haemorrhagic diathesis.
The clinical manifestation are due to the conse- In patients with Waldenstom’s macroglobuli-
quences of monoclonal protein (paraprotein) pres- naemia is sometimes the heavy chain disease iden-
ence and to immunodefficiency. In the bone marrow tified (diagnosed). Malignant alteration of plasmo-
an invasion of malignant cells is found. Migratory cytes secreting a defective heavy chain with normal
bone pain is frequently present with possibly occu- part Fc but with deletion of Fd parts, is involved.
Chapter 3

Pathophysiology of the cardiovascular

system

bands forms the characteristic striation. Magnified

500x. According to Šimko et al., 1986)
3.1 Functional characteristics Sarcolemma separates cells from the extracellular
of the cardiac muscle fluid and serves to transfer electric activity via cel-
lular surface. Its semipermeable character enables a
structure precisely regulated exchange of ions and metaboli-
cally active substances with the surroundings. The
cellular surface is covered with glycocalyx. It is a
chemically complex layer which to a great measure
affects the cellular permeability for calcium. The sar-
The basic unit of cardiac muscle is represented
colemma is modified into the so-called intercallary
by cardiac muscle cell – cardiomyocyte. It is sub-
discs in sites of mutual contact of myocytes. These
stantially larger than other nonmuscular cells of the
areas have low electric resistance and enable a free
heart. Cardiomyocytes are cylindrically shaped with
flow of ions between cells. Hence the heart behaves as
several processes. By means of the cylindric end-
an electrically homogenous substance – electric syn-
ing and lateral processes they communicate with the
cytium. In some sites the sarcolemma invaginates
neighbouring cells.
deeply into the interior of cells thus forming the so-
Regarding the contractile function of the heart, the
called T-tubules. The latter participate in transport
most important cardiomyocyte organelles include:
of calcium ions.
cellular membrane – sarcolemma, sarcoplasmic retic-
ulum (SR), mitochondria and contractile proteins. Sarcoplasmic reticulum (SR) – comprises a system
See fig. 3.1 on page 89 (the cell is characterized by of cisternae and minute channels mutually intercon-
its clubbed cylindrical shape and pronounced articu- nected. The cisternae represent ”reservoirs” filled
lation in the intercallary disc area. Intercallary discs with calcium and the channels serve as ”tunnels” via
are situated also on the lateral side of the cardiomy- which intracellular transport of calcium takes place.
ocyte. According to Šimko et al., 1987), fig. 3.2 on Mitochondria represent ATP producing ”facto-
page 89 (apparent are the T tubules which course ries”. The majority of metabolic processes take place
mutually parallel, and perpendicular to the longitu- therein. The cellular cytoplasm represents environ-
dinal axis of the myocyte - one arrow. Mitochondria ment where sugar is metabolized – aerobic and anaer-
(two arrows) are localized subsarcolemmally. Mag- obic glycolysis. Practically all other energy produc-
nified 1000x. According to Šimko et al., 1987 fig. 3.3 ing events take place in mitochondria (breakdown of
on page 90 (ID – intercallary discs, M – mitochon- fatty acids, Kreb‘s cycle, oxidative phosphorylation).
dria, Z – Z line of the sarcomere. Magnified 12 500x. Contractile proteins include actin, myosin, tro-
According to Šimko et al., 1990) and fig. 3.4 on page ponin and tropomyosin. Myosin filaments are com-
90 (Regular serial repetition of lighter and darker prised of a great number of club shaped molecules

88
3.1. Functional characteristics of the cardiac muscle structure (F. Šimko) 89

Figure 3.1: Isolated cardiomyocyte in scanning electrone microscope

Figure 3.2: Surface of isolated cardiomyocyte in scanning electrone microscope

90 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.3: Isolated cardiomyocyte in transmissive electrone microscope

Figure 3.4: Intercalar disc of isolated cardiomyocyte in light microscope

3.1. Functional characteristics of the cardiac muscle structure (F. Šimko) 91

Figure 3.5: Contractile proteins

Figure 3.6: Interaction of thin (actin, troponin and tropomyosin complex) filament and myosin one during
contraction of the heart

with a widened ending which contains myosin ATP- movement of the thin filament. According to Katz,
ase. Actin filaments are formed by two chains of 1992). The tropomyosin molecule is of fibrous shape
small molecules which are mutually wound about and spreads along seven actin molecules. A troponin
each other thus forming a helix. See fig. 3.5 on molecule is bound to one of the tropomyosin molec-
page 91 (Scheme of protein arrangement in the thin ular endings. The latter is tightly bound with the
actin filament. Two chains of actin molecules are tropomyosin molecule and at the same time contains
mutually wound about each other thus forming a a binding site for calcium.
helix. The tropomyosin molecule is formed by a The ultrastructure of contractile proteins displays
thin filament which is in contact with seven actin thick filaments of myosin, and thin filaments of
molecules of each chain. Troponin complex is con- tropomyosin. The arrangement of these thick and
sists of three protein molecules which adhere to each thin filaments results in formation of myofibrils. My-
of the tropomyosin molecular endings. According to ofibrils represent the basic functional elements of car-
Katz, 1992) and fig. 3.6 on page 91 (the scheme of diac muscle cell and they run along it lengthwise.
spatial alterations between the thin and thick fila- They are formed by regularly repeating structures
ments during contraction. In consequence of mutual – sarcomeres, which represent the basic contractile
interaction of actin and myosin the myosin molecu- units.
lar orientation alters, which results in a longitudinal
The structure of sarcomeres is determined by the
92 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

specific arrangement of actin and myosin filaments 1. energy production

which telescopically slide in between each other thus
2. energy storing
forming a number of characteristical lines and bands.
Regarding the proper comprehension of function, the 3. energy utilization
most important are the Z-lines. They issue thin actin
filaments and at the same time demarcate the bor- 3.2.1 Energy production
ders of sarcomeres. The distance between two Z-lines
represents the length of the sarcomere. The diastolic Myocardium is able to produce energy from sev-
length of the latter varies between 1,5–2,2µm. Short- eral substrates: fatty acids, glucose, lactate, pyru-
ening of muscles is realized by the procedure of tele- vate, ketone bodies and even aminoacids. Preference
scopic insertion of thin myosin filaments in between of individual substrates representing the particular
thick myosin filaments thus shortening the distance sources of energy depends on their current concen-
between Z-lines and the sarcomere itself. tration in both blood and cardiac muscle cells. This
Several myofibrils form one functional unit, in determines the concentration gradient of the given
which the Z-lines of individual sarcomeres precisely substrate on the level of cardiomyocyte membrane.
align each other. Aside from the concentration gradient, the selection
of substrates is also determined by natural capacity
of particular enzymatic systems of the cardiac muscle
cell, which limitates predominantly the utilization of
atypical sources of energy also in case of their high
concentration in blood.
3.2 Metabolism of cardiac If the oxygen supply is sufficient, the dominant
muscle cell fuel is represented by fatty acids which are predom-
inantly utilised and they cover 50-70 % of the to-
tal energy demands myocardium, and glucose which
covers the remnant 30 %. Lactate is utilized as an
The contractile function of the heart is a process energy substrate under the condition of increased
with extraordinarily high energy demand. Oxygen muscular activity, during which the lactate concen-
consumption in the beating heart depends on three tration in blood augments rapidly. Ketone bodies
main factors wall stress, contractile state of my- and aminoacids are utilized exclusively under spe-
ocardium and freqency of contractions. Although cial pathological conditions (e.g. in diabetic ketoaci-
the weight of the heart mass represents merely 1 % dosis). They participate in ATP production by more
of the body weight (in adults), the myocardium con- than 10 %.
sumes app. 10 % of the total body oxygen consump- The process of the splitting of each of the men-
tion. The heart is a typical aerobic organ with a tioned substrates provides a common intermediate
minimal ability to work under oxygen debt. The product – acetyl KoA. In the case of fatty acids it is
amount of energy consumed during systole must be formed by their splitting in the process of beta oxi-
inevitably re-supplied during the diastolic recovery dation. Glucose is by means of glycolysis or pentose
period. An adequate and fluent supply of cardiac cycle converted to pyruvate and the subsequent ox-
muscle cells with oxygen and substrates is inevitable idative decarboxylation converts pyruvate to acetyl-
in order to replenish the consumed energy.It is to KoA. The latter is formed also during the processing
say, that already under rest conditions the extrac- of lactate, ketone bodies and aminoacids.
tion of oxygen from arterial blood is almost maximal. The common intermediate product of all these re-
Therefore when heart activity increases, the augmen- actions, the acetyl - KoA, enters the Krebs cycle in
tation of oxygen supply takes place almost exclu- mitochondria where it is split to CO2 and hydrogen.
sively by means of the increase of coronary blood The latter is subsequently processed in the process of
flow. oxidative phosphorylation. It is a sequence of reac-
During each cardiac revolution the energy expen- tions in which the cellular respiration (oxidation) is
diture takes place in three phases which are tightly couppled with energy in form of ATP (phosphoryla-
bound (see fig. 3.7 on page 93): tion). Cellular respiration represents the transfer of
3.2. Metabolism of cardiac muscle cell (F. Šimko) 93

Figure 3.7: Metabolism of cardiomyocyte

94 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

hydrogen onto oxygen within the respiratory chain,

thus forming H2 O. Simultaneously, phosphorylation
is carried out, which means that energy produced by 3.3 Contraction-relaxation cy-
means of respiration and liberated in a cascade-like
manner is being bound gradually by the conversion cle
of ADP+Pi to ATP.
36 to 38 molecules of ATP are produced by pro-
cessing of 1 molecule of glucose in the mentioned
aerobic manner. Processing of 1 molecule of fatty The most specific property of the cardiac muscle
acid results in a several-fold higher ATP production, is the ability to contract.
the particular value of which depends on the chain Contraction is a complex process which is rep-
length of the particular fatty acid. resented by a precisely balanced interaction be-
tween contractile proteins (actin, myosin and
tropomyosin), calcium ions, cellular transportation
3.2.2 Energy storing
systems of calcium (sarcolemma, sarcoplasmic retic-
The energy within heart muscle is stored in form ulum, mitochondria) and high energy phosphates
of two basic macroergic compounds – adenosine (ATP, KP). The initial step in this complex reac-
triphosphate (ATP) and kreatin phosphate (KP). tion is the origin of action potential (excitation) and
ATP serves as a prime energy donor for the process the resultant action is the shortening of muscular
of contraction as well as for energetically dependent fibers (contraction).
transportation membrane systems (ATP-ases). KP The thick filaments of myosin and thin filaments
is a substance which stores energy. Under the condi- of actin are the proper elements of contraction. Tro-
tion of a fluent and sufficient supply with oxygen and ponin is firmly bound with tropomyosin thus forming
substrates, the ADP and Pi formed by splitting are one functional unit, troponin-tropomyosin complex.
resynthetized to ATP and the energy necessary for The latter participates in contraction as a regulatory
this resynthesis is provided from kreatinphosphate. protein. During diastole, the troponin-tropomyosin
The ATP level is preserved while the cytoplasmic complex is firmly bound on actin and thus inhibits
level of KP, representing a form of stored energy, de- chemical interaction between actin and myosin. The
creases. When energetic situation improves, KP is surface of troponin contains a receptor which is able
replenished by energy from the respiratory chain. to bind calcium. Providing this site is not occupied
The store of kreatinphosphate in the cardiac mus- by calcium ion, the troponin-tropomyosin complex is
cle is relatively small and can preserve the ATP level in a position which inhibits the chemical interaction
merely for a relatively short period of time. A severe between actin and myosin. Such a situation super-
ischemia finally implies a decrease of ATP and thus venes during diastole. During excitation (during the
a decrease of cardiac muscle function. plateau period of action potential) which closely pre-
Besides its store function, kreatinphosphate plays cedes the systole, the cytoplasmic concentration of
the role of a transporter of energy from mitochondria calcium elevates. Calcium is bound with troponin.
toward myofibrils. ATP, that is to say, originates in Thus the troponin-myosin complex is released from
mitochondria, but is being utilized in other intracel- the binding with actin. In this way the inhibitory ef-
lular sites – predominantly in myofibrils. fect of troponin-myosin complex on actin is removed,
and chemical interaction between actin and myosin
3.2.3 Energy utilization takes place. The clubbed molecules of myosin after
being bound with actin are leant thus shifting actin
Energy is utilized in the process of contraction which and myosin filaments propel in mutually opposit di-
is going to be explained in the following chapter. rections. According to the sliding theory the actin
filaments slide telescopically between the myosin fil-
aments while the length of either of filaments is not
changed. This process is manifested as contraction.
Hence, in this difficult process, calcium plays an im-
portant role of being the contraction inducer.
3.3. Contraction-relaxation cycle (F. Šimko) 95

Calcium which induces contraction may originate vesicles located closely beneath the sarcolemma sur-
from several sources: face due to action potential of cellular membranes.
In consequence, these vesicles depolarize thus becom-
• from extracellular space, in which calcium is ing more permeable to calcium. Depolarization itself
present in two sites. On the superficial film induces a release of calcium from the sarcoplasmic
of sarcolemma – glycocalyx, and in sarcolemma reticulum in an amount which is sufficient for the
per se. event of contraction.
The presented events result in an increase of cal-
• from sarcoplasmic reticulum which is formed by cium concentration level from 10−7 to 10−5 which is
a system of vesicles and minute channels mutu- the value necessary for contraction.
ally transconnected and forming a sort of cal-
Periodic repetition of systole and diastole does
cium depot.
not require purely the increase of Ca2+ from level
10−7 to that of 10−5 mmol/l during contraction, but
The calcium ions are transferred from the extra-
subsequently a reverse decrease to the former level
cellular space inside the heart muscle cell during de-
10−7 mmol/l must take place. The latter enables the
polarization of myocardial tissue (see fig. 3.8 on page
96). This transfer takes place via slow calcium chan- relaxation of myocardium and the event of diastole.
nels which are open during the plateau period of Several mechanisms participate in this process. The
main role is assigned to sarcoplasmic reticulum which
action potential. Since, via these channels, a rel-
uptakes calcium into its depot vesicles. The decrease
atively small amount of calcium ions is transferred
of Ca2+ concentration takes place also due to sar-
into the cell, this process is supported also by the
colemma which rejects calcium ions by active mech-
so-called Na+ –Ca2+ exchange mechanism. This sys-
tem is capable of calcium and sodium transportation anisms into extracellular space. Under normal cir-
cumstances the diastolic amount of rejected calcium
in both directions. When intracellular concentration
ions into the extracellular space equals the amount of
of sodium ions is high and that of calcium outside
calcium ions which had entered the cell during sys-
the cell low, the mentioned mechanism secures the
tole. This process assures the cellular homeostasis.
transfer of calcium inward and sodium outward the
cell. At opposite concentrations the transportation The process of contraction does not represent
takes place in opposite directions. solely a result of interaction of contractile proteins
Extracellular calcium ions which enter the cell by with calcium. A very important role is played by
means of the two mentioned mechanisms can be ef- ATP and the products of its splitting. High energy
fective in myocytes in two different manners (see adenosine triphosphate is inevitable not only as a
fig. 3.8 on page 96). They may function directly as donor of chemical energy in the event of contraction
activating calcium. It means that after entering the (systole), but it is equally necessary for relaxation
cell they bind directly to troponin triggering thus of contractile proteins – diastole.
the contraction. However they may also be effec- During diastole the ATP is bound in the myosin
tive in the process of the so-called calcium induced molecule. In a certain way ATP yields a similar func-
release of calcium from sarcoplasmic reticulum. In tion as the troponin-myosin complex. Hence, ATP,
the beginning of this process a small amount of cal- by its linkage to myosin, inhibits the actin-myosin
cium transported into the cell during action poten- interaction. This property of ATP is called the ATP
tial binds on the sarcoplasmic reticulum. In conse- plasticizing effect. Hence, the process of relaxation
quence, the SR becomes irritated and liberates its is secured by two distinct mechanisms.
own calcium, the amount of which is sufficient to The increase of the cytoplasmic level of Ca2+
be able to activate the cellular contractile apparatus ions at the beginning of systole affects the con-
(see fig. 3.8 on page 96). tractile proteins in two ways. Calcium combines
Besides these actions it is assumed that there is with troponin, due to which the inhibitory effect
still another mechanism of calcium liberation into of troponin-tropomyosin complex on actin increases.
the cytoplasm. It is the so-called release of calcium Aside from this, Ca2+ ions activate myosin ATP-
from SR induced by depolarization (see fig. 3.8 on ase which is present in the myosin molecule. The
page 96). This mechanism is based on irritation of activated myosin ATP-ase splits ATP bound to the
96 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.8: Calcium as an inductor of contraction

3.4. Contractile function of myocardium and pumping function of the heart (F. Šimko) 97

myosin molecule into ADP+Pi. By this, on the one abilities of the myocardium and from the standpoint
hand, the inhibitory effect of ATP on the formation of the pumping function of the heart.
of the actin-myosin connection is supressed and on The contractile ability of myocardium is deter-
the other hand the chemical energy from the ATP mined by two factors: by preload and contractility.
molecule is acquired, which is converted to mechan- On the other hand the pumping function of the
ical work of contraction. This process results, as it heart is a much more wider term. It depends on
is previously stated, in telescopical sliding of thin three basic factors:
filaments of actin in between the thick filaments of
myosin. In this mutually inserted position (the so- • preload
called rigorous state) the actin and myosin fibres re- • contractility
main until a new molecule of ATP is bound on that of
myosin. It is then, when the filaments return into the • afterload
previous relaxed position and diastole takes place.
Let us briefly summarize the process of contrac- Besides these three basic factors the pumping func-
tion as follows: Solely the filaments of actin and tion is influenced by:
myosin are exclusively responsible for the process • frequency of contractions
of contraction. During diastole two inhibitory sys-
tems come into play, which inhibit the interaction • synergic activity of ventricles and contractile
between actin and myosin. On the one hand it is ability of atrii
the troponin-tropomyosin complex which binds with
actin and on the other hand it is the ATP molecule 3.4.1 Preload
which binds with myosin. Calcium concentration
in the cell increases during depolarization. Calcium A general principle regarding the contraction of my-
binds with troponin, and simultaneously it activates ocardium is that the velocity of contraction is in-
the myosin ATP-ase which splits ATP. This results versely related to contractile force of contraction.
in elimination of the inhibitory effect of the troponin- This dependence has a hyperbolic, not a linear char-
tropomyosin complex on actin and of ATP molecules acter.
on myosin and thus interaction between actin and It is very difficult to define preload, or afterload.
myosin takes place. Simply, preload can be imagined as a ”load” which
is put into the ventricle prior to the onset of sys-
tolic contraction. It means that this is a term tightly
bound with the late diastole. Since increase of the
end-diastolic volume brings along end-diastolic pro-
longation of muscular fibers, often the term preload
is equalled with late diastolic length of muscular
3.4 Contractile function of fibers. The end-diastolic length of muscular fibers in-
myocardium and pumping fluences the force of systolic contraction, and thus the
heart stroke in a manner which is known as Frank–
function of the heart Starling mechanism. Essentially the greater is the
end–diastolic length of muscular fibers, the greater
is the force of contraction during systole. The curve
of the relation between force and velocity of contrac-
In order to produce enough energy for their entity tion is shifted rightward due to the increase of the
and function, it is necessary for organs and tissues initial length of muscular fibers. See fig. 3.9 on page
to be sufficiently perfused with blood. 98 (Up: alterations of relation between force and ve-
A sufficient blood flow depends on the heart func- locity of contraction caused by alteration of the ini-
tion, blood distribution and on the entire volume of tial length of muscular fiber. Prolongation of the
the circulating fluid. muscular fiber shifts the relation between force and
The heart function should be considered from two velocity of contraction rightward whereas the maxi-
distinct points of views: from the point of contractile mal velocity of contraction – V max is not changed.
98 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.9: Relationship between the power and speed of contraction

1,2,3 – different length of muscular fibers: in the case tility, shift the relation between force and velocity
of the longest muscular fiber length represented by rightward while the maximal contraction velocity –
curve 3, the curve of relation between force and veloc- V max increases. 1 – contraction without the effect
ity is shifted rightward to the greatest extent. Down: of positively inotropic substance, curves 2 and 3 –
Alterations of relation between force and velocity of influence of the increasing concentration of inotropic
contraction caused by changes in contractility. Pos- substance).
itively inotropic substances which increase contrac-
From the subcellular point of view, the Frank-
3.4. Contractile function of myocardium and pumping function of the heart (F. Šimko) 99

Sterling mechanism is determined purely by mechan- tin-myosin connections formed per time unit is in-
ical principles. When the length of sarcomere is be- creased.
tween 1,5–2,0µm, the actin filaments are partially Hence, on the level of actin-myosin connections,
overlapped. Regarding the contraction mechanism the contractility affects the activity of the heart
the overlapping is not advantageous as the over- on the basis of both quantitative and qualitative
lapped parts of actin cannot get into contact with changes.
myoxin. The sarcomere is prolonged when the end- Similarly as in the augmentation of preload also
diastolic length of muscular fiber increases and mu- the increase in contractility shifts the curve of the
tual overlapping of actin filaments decreases. When relation force-velocity rightward. The difference is,
the length of sarcomere is 2,0–2,2 µm, the actin fila- however, that while the change in the initial length of
ments cease to overlap mutually. The reactive sites muscular fibre does not affect the maximal velocity
on actin filaments and clubbed molecules of myosin of contraction (V max), the change in contractility
filaments get thereby into position which is optimal brings about also the change in V ma. It is, however,
for interaction. Thus the greatest possible number merely a theoretic value which under in vivo condi-
of actin-myosin bridges is formed and the force of tions can be achieved by extrapolation of measured
contraction is maximal. Prolongation of sarcomere values (see fig. 3.9 on page 98).
above 2,2 µm is inhibited by the natural rigidity of This dissimilar behaviour of maximal velocity of
myocardium. contraction in regard to the changes of preload and
The increase in contraction force is in this case de- on the other hand in regard to contractility changes,
termined by purely quantitative principle – increased bears a certain analogy with people who pull a bur-
number of actin-myosin interactions. den on a rope. The more people pull, the faster they
move and the heavier burden they manage to draw.
The number of load pullers is analoguous to the num-
3.4.2 Contractility ber of sites on the myofilaments which have the occa-
sion of interaction. If the pulled rope is burdenless,
Contractility represents a factor which affects the the maximal velocity of movement does not depend
contractile ability of the heart independently on the on the number of pullers. The positive inotropic sub-
end-diastolic length of muscular fibers. The con- stances increase both the velocity and force of con-
tractility increases under the influence of the so- traction by accelerating the reaction in active sites.
called positively inotropic substances (adrenaline, Using our comparison, the velocity of pullers is be-
noradrenaline, glucagon, digoxin). These substances ing changed without the necessity of increasing the
increase the amount of calcium which comes into number of pullers, but by greater activity of each of
contact with contractile elements per time unit. the participants.
Thereby they simultaneously increase the force and
velocity of contraction. The action does not involve
3.4.3 Afterload
augmentation of the total number of actinomyosin
bridges which does not increase, but remains un- In general, we can state that afterload regulates the
changed. Principally, the contractility increases by pumping activity of the heart in an opposite way
means of increasing the number of actinomyosin con- than preload and contractility. Both increase in
nections formed per time unit, in other words, by preload and increase in contractility positively affect
acceleration of their formation. the pumping activity of the heart, on the other hand
E.g. catecholamines by means of stimulating the increase in preload decreases the stroke volume. In
β1 receptor system, adenylcyclase, cAMP and pro- practice, afterload is represented by the aortic im-
teinkinase phosphorylate and thereby activate the pendance which is determined by three factors:
sarcolemma, sarcoplasmic reticulum and troponin.
By activation of the sarcolemma and sarcoplasmic • arterial compliance, i.e. elasticity of large arter-
reticulum the offer of calcium ions toward troponin ies
increases. Troponin is also phosphorylated and thus • total peripheral resistance of arterioles
activated by catecholamines and promptly binds the
offered of calcium. Thereby the number of ac- • blood volume in arterial bed
100 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

From the hemodynamic point of view, the after- increased frequency actually results in the shortening
load is comprehended as stress in the ventricular of diastole. At a particular frequency the diastole du-
wall during systole. According to the Laplace law ration equals that of systole. When the so-called crit-
this stress is directly proportional to intraventricular ical value of the contraction frequency (cca. 170/min)
pressure, the radius of the ventricular cavity, and in- is achieved, the duration of diastole is so short that
versely related to the doublefold of the thickness of the ventricle cannot be filled sufficiently. Hence, the
the ventricular wall. stroke volume is reduced to such an extent that in
spite of the high frequency vigour, the total minute
P ·r volume declines.
T =
2·w
where: T . . . tension; P . . . intraventricular pressure; 3.4.5 Synergic activity of ventricles
r . . . ventricular radius; w . . . thickness of the ventric-
and the contractile ability of
ular wall
atrii
It is obvious that augmentation of the total periph- Maintenance of optimal complex activity of the heart
eral resistance results in elevation of intraventricular requires coordination of its individual parts namely
pressure and thus the afterload increases. Afterload of those of the left ventricle (septum and free wall,
is, however, simultaneously increased also due to the basis, the central part and apex), synchronized ac-
enlargement of the ventricular cavity radius and by tivity of the left and right ventricles, and harmo-
thinning of its wall. These two alterations may, how- nization of the atrial activity with that of ventri-
ever, occur also by means of increase of the end- cles. The most important factor in this matter is
diastolic volume, i.e. by increase in preload. Thus, the correct coordination of the left and right ven-
the term afterload includes not only the stress which tricles. The arterial volumes of the right and left
is formed as late as during systole when arterial im- ventricles are not exactly identical and their mutual
pendance comes into force (afterload in narrow sense size fluctuates reciprocally in relation to the course
of the term), but also the wall stress formed already of the respiratory cycle. During inspiration the right
in the phase of late diastole. In other words augmen- ventricular volume increases in consequence of the
tation in preload leads automatically to an increase increased filling and restricted evacuation. The left
in afterload. ventricular volume on the contrary decreases in con-
sequence of the diminished inflow and easier evac-
3.4.4 Frequency of contractions uation. Expiration has the opposite consequences.
This phenomenon can become more expressed under
Frequency represents a hemodynamic parameter certain physiological conditions, namely respiratory
which enables to increase the minute ejection volume dysrrhythmia, profound respiration, Valsalve‘s ma-
by means of increased number of ventricular evacua- neuvre. These differences between the stroke volume
tions per minute. In addition, frequency augmenta- of the left and right hearts mutually counterbalance,
tion stimulates the contractility of the myocardium. hence the minute volumes of the right and left ven-
The explanation of this so-called frequency effect is tricles are identical. Under pathological conditions
complex. Basically it resides in a more optimal uti- the impairment of the coordination of the ventri-
lization of electro-mechanical association, i.e. associ- cles becomes evident as e.g. by impairment of the
ation of depolarization and subsequent contractility. sequence of depolarization processes (bundle-branch-
The positive inotropic effect of increased frequency block), movement disturbances of a certain part of
enables a better evacuation of ventricles in states of the left ventricle (myocardial infarction).
tachycardia. An important factor in this matter is the main-
In the case of venous blood return being sufficient, tenance of the atrial contractile ability which takes
the minute volume increases in direct proportional place at the end of diastole. During this period of
relation to the increase of frequency. In regard to atrial contraction the ultimate 20 % of the total ve-
the fact that when the heart rate is normal the dias- nous blood return is pressed into the ventricle. Re-
tole duration is substantially longer than systole, the duction of atrial contractile ability occurs primar-
3.4. Contractile function of myocardium and pumping function of the heart (F. Šimko) 101

ily due to intensive atrial dilatation, and the total of catheterization. Since in many pathological states
loss of contractile ability occurs within atrial fibril- the values of pressure in individual cardiac cavities
lation. The loss of the final 20 % of venous blood undergo typical alterations, it is inevitable to ap-
return which is transported to the ventricle by atrii prehend the physiological course of pressure changes
under physiological conditions can be hemodynami- which impendingly coincide with the pumping activ-
cally significant especially in states with reduced ven- ity of the heart.
tricular compliance. In such cases the deficiency in The record representing atrial pressure parame-
contractile ability of atrii can cause deterioration of ters displays three positive and two negative waves
the clinical state. (see fig. 3.10 on page 102. The first positive wave is
formed at the end of ventricular diastole. It is caused
3.4.6 Pumping activity of the heart by active atrial contraction. The second wave is
formed at the beginning of ventricular systole. This
The heart functions as a valve pump. It ejects blood is the period of ventricular pressure elevation and
toward the periphery, however not continuously, but this increase in pressure is conveyed via AV valves
in particular amounts – ejection volumes. The car- into the atrii. During the systolic blood ejection the
diac cycle takes place in two basic periods. The pe- basal part of the ventricle together with the AV an-
riod of filling, when the heart fibers are in relaxed nulus get nearer to the cardiac apex, in response to
position – diastole, and the period of contraction, which the atrial cavity is temporarily enlarged and
when the blood is ejected toward the periphery – the pressure decreased. These events become evi-
systole. dent as the first moderately negative wave. There-
During systole the blood is ejected into the aorta after the atrial pressure increases in direct proportion
and pulmonary artery. At the end of the ventricular to the amount of blood flowed into the atrii which
systole the atrii are already filled with the inflowed is recorded as the third positive wave. At the on-
blood. The enlargement of atrial content results in set of diastole the AV valves open and the blood is
increase in atrial pressure. Following the ventricu- propelled from atrii into ventricles. The decrease of
lar systole termination the intraventricular pressure atrial pressure is recorded as the second – more ex-
decreases below the value of atrial pressure in conse- pressed negative wave.
quence of the relaxations the muscular fibers. These Pressure curves of both atrii are almost identical,
events result in the opening of atrioventricular valves although the intracavity pressure in the left ventricle
and the ventricles begin to be filled with atrial blood. differs from that of the right. This difference con-
In the beginning the blood flow into the ventricles is cerns mostly the altitude of pressure as the value of
rapid – referred to as the phase of rapid ventricu-
the right ventricular pressure represents merely one
lar filling. It lasts cca. one third of diastole and the fifth of the left ventricular pressure value. The char-
ventricles receive 70 % of the total amount of blood acter of the pressure curve is, however, in spite of
which had flown in during diastole. During the sec- the presented quantitative differences, almost identi-
ond third of diastole the blood flow from the atrii cal in both ventricles.
almost ceases. This period is referred to as diasta-
sis. The last third of diastole represents a period of The ventricular pressure curves yield several
active contraction of atrii. This is the period during phases which are precisely demarcated. See fig. 3.10
which the remnant cca. 20 % of the total amount on page 102 (The cardiac cycle can be divided into
of blood which flows into ventricles during diastole, 8 phases. Three upper curves represent the pressure
is forced into ventricles, already against considerable alterations in aorta, left atrium and left ventricle.
intraventricular pressure. The curve representing the left ventricular volume
alterations represents to a certain degree a mirror
reflection of pressure alterations. I, II, III represent
3.4.6.1 Atrial and ventricular pressure the cardiac sounds. P sound – contraction of atrii.
curves According to Katz 1992).
Individual phases of the cardiac activity entail alter- The first phase of the ventricular systole repre-
ation of pressure parameters in both atrii and ventri- sents a period of the so called izometric, i.e. izo-
cles. These pressure values can be detected by means volumetric contraction. In this phase the tension
102 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.10: Pressure curves of left atrium and left ventricle

3.5. Pathomechanism of heart failure (F. Šimko) 103

of fibers gradually increases, but they do not be-

come shorter. The ventricular pressure rapidly el-
evates which consequently evokes enclosure of AV 3.5 Pathomechanism of heart
valves. In this phase the semilunar valves are still
enclosed, since the ventricular pressure has not yet failure
transgressed those in aorta and a.pulmonalis.
As soon as the ventricular pressure transgresses
the diastolic pressure in aorta and a.pulmonalis, the
semilunar valves open and the blood begins to be Heart failure is a state when in spite of normal or
ejected into large vessels. This phase is referred to increased filling pressure, the heart fails to secure an
as ejection phase, in the course of which the volume adequate perfusion of peripheral tissues. The term
of ventricles decreases by the ejected volume. The heart failure does not include the states when hy-
ventricular pressure augments as high as to the max- poperfusion of tissues supervenes in consequence of
imal systolic value (130 torr in the left ventricle and reduced filling pressure (e.g. shock), or when hypop-
cca. 25 torr in that of the right) At the end of sys- erfusion is accompanied by increased filling pressure
tole the intraventricular pressure decreases. Hence, due to extracardiac reasons (e.g. inadequate exten-
the end-systolic pressure is lower than the maximal sive and rapid infusion therapy).
systolic pressure. There is a certain difference between the clinical
Half of the ejected blood volume is being ejected and pathophysiological comprehensions of the term
during the first fourth of the ejection phase. The sec- heart failure. The clinical comprehension of the term
ond half is being ejected during the subsequent two includes foremostly the secondary consequences of
fourths. During the last fourth no blood is ejected heart failure per se (dyspnea, edemas), eventually
into large vessels in spite of the fact that the ven- the symptoms of compensatory mechanisms (hyper-
tricles are subdued to contraction. This period is trophy). The term congestive heart failure used in
referred to as protodiastole. During the ejection literature explicitly comports the clinical conception
phase under resting conditions cca 60-70 % of the of this syndrome in which heart failure is equalled
end-diastolic volume of blood is ejected. with the conception of congestion. The left-sided
During the period of protodiastole the blood pres- heart failure results in congestion in the pulmonary
sure decreases as no blood is ejected from the heart, circulation circuit which is accompanied by dyspnea.
on the contrary it flows toward the periphery. Rapid The right-sided heart failure results in congestion in
stoppage of blood ejection from ventricles causes that the systemic circulation circuit which is often accom-
the arterial pressure transgresses the value of the panied by peripheral edemas. In addition, as the
ventricular pressure. In consequence of such pres- definition implies, the primary consequence of heart
sure alterations the aortic and a.pulmonalis semilu- failure is represented by insufficient perfusion of pe-
nar valves close. The ventricular musculature be- ripheral tissues. The fact that the clinicians notice
gins to slacken. This period is referred to as izomet- especially the congestion as a secondary consequence
ric or izovolumetric relaxation. During this phase of heart failure, results from the fact that these symp-
the ventricular pressure achieves the lowest values. toms are much more conspicuous in comparison with
When the ventricular pressure drops below the level the consequences of hypoperfusion of peripheral or-
of atrial pressure, the AV valves open and the ventri- gans as e.g. oliguria, muscular weakness, fatigability,
cles begin to be filled with blood from atrii. By the dyspepsia. The symptoms of peripheral hypoperfu-
opening of AV valves the ventricular diastole is ini- sion are not only less conspicuous, but also better
tiated. At the end of diastole the atrii and ventricles tolerated by a patient. Usually it is the dyspnea, or
are activated from the sinus bundle. By means of edemas which force the patient to consult the physi-
atrioventricular valves enclosure the ventricular sys- cian.
tole is reinitiated. Heart failure does not represent a clinical unit. It
is a state which can supervene in consequence of var-
ious cardiac diseases.

1. Causes of heart failure:

104 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

(a) Myocardial impairment due to ischemic system, kidneys, liver, brain etc. (see fig. 3.11 on
heart disease page pagerefo2-11).
(b) cardiomyopathies Backward failure – is caused by the fact that by
(c) toxic impairment of myocardium (diph- means of the decrease of ejection fraction greater
teric, etanaltoxic, meadicamental – Adri- amount of blood remains in the inflicted ventricle at
amycine) the end of systole. Due to the reduction of ejection
fraction, e.g. to 50 %, the 50 % of the end-diastolic
(d) myocardial impairment due to endo-
volume persists in the inflicted ventricle in contrast
crinopathies (diabetes mellitus, hyper-
to normal 30 %. In regard to the fact that during
thyreoidism and hypothyreoidism)
diastole normal amount of blood flows into the ven-
2. Chronic hemodynamic overload of the heart tricles, the end-diastolic volume and pressure in the
inflicted ventricle gradually increases. Inleft ventric-
(a) pressure overload (hypertension disease, ular failure this pressure elevation is conveyed into
stenosis and coarctation of the aorta – left the right atrium, pulmonary veins, and finally into
heart, pulmonary hypertension, a. pul- pulmonary capillaries. This process manifests itself
monalis stenosis – right heart) clinically by various levels of dyspnea. Failure of
(b) volume overload (mitral, aortic insuffi- the right heart brings along augmentations in volume
ciency, arterio-venous shunts, all types of and pressure in the right ventricle. The increase in
hyperkinetic circulation) pressure is conveyed into the right atrium, capacity
bed and finally into capillaries in peripheral organs.
3. Disturbances of the heart rhythm Augmentation of the hydrostatic pressure in capil-
(a) extreme tachyarrhythmia (supraventricu- laries finally leads to peripheral edemas (see fig. 3.11
lar tachycardia, fibrillation and flutter) on page o2-11).
(b) extreme bradycardia (sinus or AV block of A various period of time can elapse from the par-
higher grades) ticular moment of heart impairment until the clini-
cal symptoms of heart failure become evident. Dur-
4. Restricted filling of ventricles (constrictive peri- ing this period the heart impairment manifestation
carditis, cardiac tamponade, endomyocardial fi- is being eliminated by the so-called compensatory
brosis) mechanisms, which may be acute (applied practi-
cally immediately after heart failure onset), or chron-
The most frequent causes of heart failure are
ical which become evident as a result of a long-
the ischemic heart disease and hypertension disease.
term hemodynamic overload. In the acute phase
These together represent cca 70 % of reasons of heart
of heart insufficiency two compensatory mechanisms
failure.
come into play: Frank-Starling mechanism and cat-
The moment which triggers off a series of subse-
echolamines which stimulate contractility and heart
quent events leading to the development of heart fail-
rate. In cases of chronic failure in consequence of
ure is the decrease of ejection volume of the heart.
long-term hemodynamic overload, still another com-
In consequence heart failure manifests itself in two
pensatory mechanism develops, namely myocardial
different ways: forward failure - in the direction of
hypertrophy.
blood flow, and backward failure - against the direc-
tion of blood flow. If compensatory mechanisms entirely prevent the
Forward failure - represents the consequence of a onset of clinical manifestation of heart failure it is
decreased stroke and minute cardiac volumes deter- referred to as compensated heart failure. Decom-
mined by the decrease of ejection fraction. Under pensated heart failure supervenes when in spite of
normal circumstances the amount of ejected blood the fact that compensatory mechanisms are in ac-
forms cca 70 % of the end-diastolic volume. Heart tion the clinical symptoms of heart failure become
impairment leads to the reduction of this amount, evident.
which results in the deterioration of the blood supply Catecholamines-derived stimulation and Frank-
in peripheral tissues and organs. It results in insuf- Starling mechanism begin to act immediately after
ficient performance of various organs, e.g. digestive
3.5. Pathomechanism of heart failure (F. Šimko) 105

Figure 3.11: Hypertrophy and dilatation of the heart

106 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

the origin of heart impairment associated with a de- tional character and enable the heart to deal with
creased minute ejection. the hemodynamic overload for a long period.
The reduction of aortic pressure, elevation of pres- Hence, while in acute myocardial impairment the
sure in the left ventricle, and later in the left atrium heart failure is prevented by catecholamines and
and pulmonary bed stimulate the special receptors, Frank-Starling mechanism, in chronic hemodynamic
namely pressoreceptors and chemoreceptors in aorta, overload it is foremostly hypertrophy of the heart
cardiac ventricles and atrii as well as in pulmonary which to a significant extent normalizes the hemo-
bed. These receptors provide information to vegeta- dynamic situation.
tive centres in the fundus of the fourth brain cham-
The presented compensatory mechanisms able to
ber, by means of which the activity of nervus vagus
maintain the adequate minute volume of the failing
is supressed. Consequently, the sympathetic ner-
heart are, however, limited by the extent of heart im-
vous system becomes dominant. Noradrenaline re-
pairment and its duration. The pathological process
leased from the sympathetic nerve endings, and no-
in the heart can be so intensivesince the very be-
radrenaline and adrenaline released from the medulla
ginning that the compensatory mechanisms in spite
of suprarenal glands stimulate by means of the β1
of their maximal activation are not able to compen-
receptor the system of proteinkinase in cardiomy-
sate adequately (e.g. in the case of extensive my-
ocytes. These via phosphorylation of subcellular
ocardial infarction). In other cases the formerly ad-
structures accelerate the Ca2+ supply toward con-
equate compensation may become insufficient dur-
tractile elements and the muscular contractility in-
ing the course of pathological process. This second
creases. Catecholamines simulataneously stimulate
alternative develops either in consequence of heart
the electric events in the heart and the frequency in-
impairment progression, or due to the exhaustion of
creases. Increased contractility and frequency result
the compensatory mechanisms. The Frank-Starling
in augmentation of the minute heart volume, improv-
mechanism has a very restricted capacity which is
ing thus the perfusion of peripheral tissues.
limited by expansion of sarcomere to 2,2 µm. Also
In additon to catecholamines also the Frank- the sympathetic system fails after its prolonged acti-
Starling mechanism comes into force since the very vation A long-term hyperfunction of the sympathetic
onset of heart impairment. The reason to it is that nervous system results in impaired catecholamines
the reduced ejection fraction results in augmenta- synthesis, reduction of catecholamines uptake and
tion of the end-diastolic ventricular volume. Con- reduction of the number of β-receptors on the sur-
sequently, also the initial length of muscular fibers face of myocytes. Hypertrophy of myocardium in
increases and saromeres are prolonged to the opti- the majority of cases fully compensates the increased
mal value near 2,2 µm, which enables the heart to hemodynamic overload for a long period. Neverthe-
exert the maximal force of contraction. Both acute less, it becomes insufficient after a particular time
mechanisms participate in prevention of heart fail- (often decades). A whole series of mechanisms par-
ure manifestation in spite of the fact that the heart ticipate in this process, part of which are elucidated
which is responsible for the maintenance of blood and some still remain unexplained.
flow toward the periphery is already impaired.
If even maximal exploitation of compensatory
At long-term hemodynamic overload of the heart, mechanisms is not able to maintain the adequate per-
the chronic heart hypertrophy representing a chronic fusion of peripheral tissues, the heart failure starts
compensatory mechanism comes into play. to be also clinically manifested. Heart failure repre-
It is a so important and complex process that it sents a stress situation for the organism which has
must be subdued to thorough analysis in the entire many characteristics in common with the general
following chapter. stress syndrome. Hence, all the following adapta-
Herein it is necessary to emphasise at least the fact tional mechanisms bear the character of stress re-
that hypertrophy does not mean merely the growth action with the typical neurohumoral reaction and
of cardiac tissue mass. It represents a complex re- subsequent rebuilding of circulation and metabolism.
construction of architecture, ultrastructure and bio- In this stage the maintenance of adequate pumping
chemism of the myocardium. These alterations, performance of the heart ceases to be the actual
both quantitative and qualitative, are of adapta- aim. There is nothing more to be mobilized within
3.5. Pathomechanism of heart failure (F. Šimko) 107

the heart as the compensatory mechanisms are al- quence of vasoconstriction of the capacity bed does
ready maximally activated. The organism struggles not improve the pumping ability of the heart. Frank-
to maintain an adequate perfusion of vital organs – Starling mechanism is as a matter of fact already ex-
heart, brain (and eventually kidneys) in spite of the ploited to the maximal extent and an increase in the
reduced minute volume of the heart. This state of venous return does not increase the cardiac ejection,
course can be achieved exclusively by redistribution but deteriorates the pulmonary congestion. In ad-
of the blood flow, i.e. the increased perfusion of vital dition elevation of both afterload and preload have
organs is achieved owing to vasoconstriction (and rel- a negative impact on ATP reserves in myocardium,
ative ischemia) of all other systems (skin, splanchnic which supports the deterioration of the cardiac func-
region, striated muscles, etc.). tion.
The main neurohumoral component of the ulti- Conclusion: Heart failure represents a state when
mate adaptational reaction when an organism no the heart is not able to secure an adequate perfusion
longer struggles to maintain a harmonic performance of peripheral organs in spite of normal blood return.
of individual systems, but merely to survive, are At its onset the impairment of cardiac function does
catecholamines and renin – angiotensin II – aldos- not manifest itself clinically since the compensatory
terone system. However, the position of catech- mechanisms stimulate the reserve forces of the heart
lamines in this typical stress reaction substantially and circulation in order to prevent the deterioration
alters in comparison with the initial stage of heart of the hemodynamic situation. When the patholog-
failure. Their secretion remains to be administered ical process becomes more prominent, the effectiv-
by stimulation of baroreceptors and chemoreceptors ity of compensatory mechanisms decreases. In spite
by relative hypotension of central parts of arterial of their maximal exploitation they are not able to
bed and by raised pressure in the pulmonary venous maintain an adequate perfusion of the periphery any
system, however neither their maximal stimulation is longer. At this stage, the stress reaction in response
capable to increase the pumping activity of the heart. to the impaired performance of the heart comes into
Intesified stimulation of the sympathetic nerve sys- play. Preservation of the adequate peripheral per-
tem manifests itself however by an excessive vaso- fusion ceases to be the aim of subsequent neurohu-
constriction of the peripheral organs which secures moral alterations. The only aim is to delay the death
the elevation of the mean arterial pressure. Vaso- of the organism per se. The stress mechanisms main-
constriction in kidneys and subsequent hypoperfu- tain perfusion via vital organs, namely the brain and
sion of vas afferens evokes activation of the system heart on the account of other tissues. The life qual-
renin – angiotensin I – angiotensin II – aldosterone. ity of such an individual is considerably deteriorated.
Angiotensin II supports the pressoric effect of no- The stress reaction is an energetically demanding
radrenaline, and aldosterone helps to preserve the event even in a healthy cardiovascular system. In
blood volume and thus to maintain the mean arte- failing heart despite the positive adaptive character
rial pressure. Antidiuresis is intensified also by the of stress reaction, the heart function worsens gradu-
antidiuretic hormone which is released either by di- ally and the heart definitively fails.
rect stimulation of the posterior lobe of the pituitary
gland by the activated sympathetic nerve, or on the
basis of hyperosmolarity. The latter is caused by re-
3.5.1 Symptoms of left ventricular
sorption of sodium with a relatively less intensive re- heart failure
sorption of water under the influence of aldosterone.
The symptoms of cardiac failure resulting from hy-
Peripheral compensatory mechanisms which rep- poperfusion of tissues (forward failure) most fre-
resent a component of the typical alarm reaction are quently occur at the beginning, but are less salient
effective merely for a short period. The general vaso- than the consequences of blood stagnation before the
constriction in the peripheral tissues forces the left heart (backward failure). Hence, the clinical severe-
ventricle to work against great resistance. The after- ness of heart failure is judged mainly in dependence
load increase decreases the pumping ability of the on the stage of dyspnea due to left ventricular failure
heart, and the minute volume decreases. At this and on the severity of peripheral edemas due to right
stage even the increase in venous return in conse- ventricular failure.
108 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

3.5.1.1 Dyspnea that the stimulation threshold of the respiratory

centre during sleep is decreased and the informa-
Dyspnea is a subjectively percieved sensation of
tion about hypoxemia development is delayed.
breathlessness in a patient. This being so, the in-
A sleeping patient can thus tolerate relatively
formation of it can be gained only from the patient‘s
severe pulmonary swelling and may awaken after
reference. Hence it is incorrect to use this term in
three or six hours, i.e. when hypoxemia reaches
coincidence with an unconscious patient with breath-
a severe stage. By this time the stagnating fluid
ing difficulties, or experimental heart failure induced
transudates into the interstice. In such cases
in laboratory animals.
the recovery of dyspnea by means of changing
According to the severity of heart insufficiency sev-
position from recumbent to sitting posture is
eral forms of dyspnea are distinguished:
slow and some cases require pharmacological in-
• exertional dyspnea occurs in a person with tervention. Bronchospasm participates in this
impaired heart functions, though symptomless form of dyspnea. It originates on a reflex basis
during rest, owing to exploitation of compen- when the congestion in the pulmonary bed and
satory mechanisms. Increased physical strain swelling of bronchial mucosa play the stimula-
accompanied by increased tonus of the sympa- tory role. This form of dyspnea is called cardiac
thetic nervous system and vasoconstriction of asthma.
the capacity bed results in elevated venous re-
turn. Nevertheless the impaired heart works on 3.5.1.2 Pulmonary edema
the borders of its possibilities already under rest
Pulmonary edema means accumulation of excessive
conditions. Increased preload therefore does not
amount of fluid in pulmonary interstice or even in
evoke an increase in heart ejection, but elevates
alveoli. There are at least three mechanisms which
pressure in pulmonary capillaries. The stagnat-
participate in formation of pulmonary edema.
ing fluid, though, does not transudate into in-
terstice at the beginning, but reduces the pul- • increased hydrostatic pressure in pulmonary
monary compliance. Hence, the ventilation abil- capillaries
ity deteriorates and the development of hypox-
emia stimulates the activity of the respiratory • increased permeability of the capillary wall
muscles by means of stimulation of the respira-
tory centre. • decreased coloidosmotic pressure in blood

• dyspnea during rest - its more moderate form is There are several protective factors which act
orthopnea, i.e. dyspnea which occurs in recum- against edema formation: Lymphatic drainage, the
bent position. In horizontal position the blood is capacity of which increases five to sixfold already
redistributed from the distal parts of the body several hours following the onset of pulmonary con-
toward the heart. This effect of increased ve- gestion. In addition great difference between hydro-
nous return is the same as when evoked in con- static pressure in the capillaries (7 torr) and coloid
sequence of physical exercise. When the patient osmotic pressure of blood proteins (28 torr) which
acquires a sitting posture, the venous return de- has an opposite impact, also play a protective role.
creases and the state recovers quickly. A more Pulmonary edema develops as late as when both the
severe form of dyspnea is the nocturnal paro- capacity of lymphatic drainage and pressure reserve
xysmal dyspnea. Besides the effect of horizon- are exceeded.
tal position also the increase of the parasympa- Pulmonary edema develops in coincidence with
thetic tonus during sleep participates in its on- various diseases:
set. The latter decreases the contractile ability
1. Diseases of the cardiovascular system:
of the heart and reduces also the activity of the
respiratory centre. Nocturnal paroxysmal dysp- (a) Acute heart failure
nea is accompanied not only by congestion but
also by transudation into interstice which results (b) Chronic heart failure
in interstitial pulmonary edema. The reason is (c) Excessive infusion therapy
3.5. Pathomechanism of heart failure (F. Šimko) 109

(d) Hyperdynamic circulation the fluid to enter the alveoli. Intraalveolar edema
develops.
2. Diseases of the respiratory system:
The clinical picture of pulmonary edema is ex-
(a) Pneumonia traordinarily dramatic. A patient is significantly
breathless, cyanotic, and expectorates pink foamy
(b) Tumors causing lymphatic vessels obstruc- sputum. Similarly as in myocardial infarction, this
tion state is associated with the sensation of anxiety of
(c) Inhalation of toxic and irritating gases death – horror mortis.
The pathogenesis of pulmonary edema developed
3. Diseases of the kidneys
due to heart failure is of a complex character. Its
(a) Glomerulonephritis origin is to the major extent the result of increased
postcapillary pressure in the lungs and thereby the
4. Diseases of the central nervous system increase of capillary hydrostatic pressure. Besides
the latter also some additional factors participate in
(a) Vascular incidents this process. Hypoxemia of the liver with subse-
(b) Inflammatory diseases quently reduced albumin synthesis cause reduction
of coloid osmotic pressure of proteins. If the right
(c) Neoplastic diseases
heart simultaneously fails, the long-term hepatic con-
5. Intoxications gestion participates in impairment of the proteosyn-
thetic function of the liver. Hepatic congestion can
(a) Oxygen lead to the origin of Pick‘s cirrhosis. Long-term re-
(b) CO duction of renal perfusion sometimes results in renal
impairment with subsequent proteinuria. Protein-
(c) ether, hashish, etc. uria continues in deteriorating the hypoproteinemia.
Prolonged hypoperfusion of the kidneys at the same
Cardiac diseases bring about the development of
time stimulates the renin-angiotensin II-aldosterone.
pulmonary edema especially in cases of abrupt ele-
As a result the so-called secondary hyperaldostero-
vation of the capillary pressure. This process takes
nism develops which maintains the amount of circu-
place in acute heart failure. The most frequent car-
lating fluid and thereby also the blood flow toward
diac causes of pulmonary edemas are the following:
the lungs via the right heart. This process supports
extensive myocardial infarction, hypertension crisis,
transudation of fluid.
bacterial endocarditis with perforation of the mi-
tral or aortic valves, pneumonia accompanying se- The oxygen level gradually decreases as a result
vere aortic or mitral stenoses which were until then of deteriorated exchange of gases in consequence of
compensated. Chronic heart failure and repeated fluid being present in interstice or pulmonary alve-
formation of interstitial edema cause a thickening of oli. At the same time the ventilation deteriorates due
alveocapillary membranes, thus forming a barrier for to pulmonary congestion which is associated with
transudation of fluid into alveoli. Therefore, alveolar decreased pulmonary elasticity. Finally hypoxemia
edema relatively seldom accompanies chronic heart completes the damage and thus increases permeabil-
failure. ity of the alveolocapillary membrane which facili-
The onset of pulmonary edema is associated with tates the pulmonary edema development. Alveolo-
accumulation of fluid in interstice which is able to capillary membrane is often impaired iatrogenically
absorb a double amount of fluid in comparison with due to prolonged therapeutic application of oxygen
physiological circumstances. This state is referred to in high concentrations.
as intraalveolar edema (see fig. 3.11 on page 105). Especially in elder people the congestion con-
It manifests itself clinically as nocturnal paroxysmal tributes to the origin of inflammatory process in
dyspnea. In regard to the fact that then the only the lungs and hypostatic pneumonia may develop.
barrier for liquid transudation is the thin alveolar Swollen hila of lymphatic nodes can deteriorate the
membrane, even moderate excercise with subseqent lymphatic drainage and support the onset of pul-
increase of capillary pressure are sufficient to enable monary edema.
110 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Summary: The pathogenesis of pulmonary edema character. It is probably evoked by stimulation of

due to the left heart failure includes several factors. receptors in the distended pulmonary vessels and in
The main role is ascribed to the elevation of the hy- edematous mucosa of spastic bronchi.
drostatic pressure in pulmonary capillaries in con- Nycturia – nocturnal micturition is a sign of se-
sequence of postcapillary hypertension. Hypoxemia, vere heart failure. During the day the peripheral
when at its onset, increases the capillary permeabil- mechanisms of vasoconstriction are maximally ex-
ity. Hypoproteinemia with reduced coloid osmotic ploited. This results in decreased production of urine
blood pressure develops due to hepatic impairment, and oliguria. During sleep the tonus of the sympa-
namely by hypoperfusion and retrograde congestion. thetic nerve decreases, kidneys are better perfused
Under specific circumstances the deteriorated lym- and production of urine increases.
phatic drainage may also participate in pulmonary Dyspeptic syndrome originates in consequence of
edema development. insufficient perfusion of digestive organs. Impair-
Similarly also the subjective sensation of dyspnea ment of digestion and absorption of nutriments de-
is caused by several reasons. The main role is as- velop. Detoxication functions of the liver are dis-
cribed to stimulation of receptors in pulmonary ves- turbed. Both exogeneous and endogenous functions
sels by means of their increased tension due to con- of pancreas are decreased. Sugar, lipid and protein
gestion. The sensation of dyspnea occurs obviously metabolisms are impaired. The sugar metablism is
due to increased respiratory work and consequent impaired in consequence of decreased insulin pro-
muscular fatique along with decreased elasticity of duction due to vasoconstriction of pancreas. ľ- ox-
the lungs. An important role is played also by direct idation of lipids is disturbed in the impaired liver
stimulation of the respiratory centre due to hypox- and in muscles. Proteosynthesis in the ischemic
emia and lactic acid which accumulates in respira- liver is decreased and catabolism of proteins is in-
tory muscles. The subjective picture of dyspnea is creased due to a high level of stressogenic glucocor-
supported by bronchoconstriction evoked by edema ticoids. This complex of alterations together with
of bronchial mucosa. pronounced anorexia lead to generalized reduction
of muscular mass and cardiac cachexia develops.
Increased muscular fatigue and decreased physi-
cal performance belong to less salient but often ini-
tial signs. In consequence of the decreased minute 3.5.1.3 Cyanosis
volume, and in advanced stages of heart failure also
Cyanosis refers to a bluish colour of the skin and
in consequence of concommitant sympathetic vaso-
mucous membranes. It develops in consequence of
constriction, the oxygen supply of muscles decreases.
increased amount of reduced hemoglobin in the cap-
Anaerobic glycolysis is not able to meet fully the en-
illary blood. It is the absolute amount of reduced
ergetic needs and thus the level of high energy phos-
hemoglobin, rather than the ratio of the reduced
phates in muscles decreases. In consequence of ATP
and oxidized forms which is important in produc-
deficiency the muscles slacken. In such muscles the
ing the cyanosis. The limitating amount of reduced
proprioreceptors are being less stimulated. A smaller
hemoglobin which triggers the development cyanosis
number of impulses passing via afferent pathways
is considered to be 50 mg/l. It is app. one third of the
into CNS is conceived as a sensation of fatigue. Fa-
total amount of hemoglobin at its normal level being
tiguability of muscles is supported by accumulation
150 g/l. Since it is the absolute amount of reduced
of lactate and formation of muscular acidity which
hemoglobin which is important in cyanosis develop-
blocks the glycolytic enzymes prior to the exhaustion
ment, there is no, not even theoretical possibility of
of glycogen reserves. ATP is inevitable not only for
cyanosis development in patients with severe anemia
contraction but also for relaxation of muscles. ATP
in which hemoglobin decreases below 50 g/l, and even
deficit may lead to muscular spasms.
patients with light anemias rarely display cyanosis.
Cerebral symptoms include somnolence, sleep dis- On the contrary, in polyglobulia in which the level
orders, headache, decreased psychical activity. They of absolute hemoglobin is high, the critical value of
originate in consequence of cerebral hypoperfusion its reduced form is achieved relatively easy. There-
and decreased load of oxygen carried by blood. fore cyanosis is a frequent symptom of polyglobulia.
Cough is of intermittent, weak, nonproductive Regarding the cyanosis development, the deter-
3.5. Pathomechanism of heart failure (F. Šimko) 111

mining amount of reduced hemoglobin is that in the vate above the critical value. This state accurs espe-
capillary blood, not in arterial or venous blood. Cap- cially due to increased physical exersise, when the tis-
illaries run closely below the surface and that is why sues extremely extract oxygen. The central cyanosis
they determine the colour of the skin and mucous appears in inborn heart defects with right-left shunts
membranes. The value of reduced hemoglobin in the and in some pulmonary diseases. It is, however of-
capillary blood represents approximately the aver- ten seen in the syndrome of heart failure. Naturally,
age value of its arterial and venous levels. Under the in such a case the central cyanosis is not a sign of
condition of normal oxygen saturation in blood, the retarded blood flow in capillaries but represents a
capillary value of reduced hemoglobin is app. 25 g/l. concomittant sign of the disease which has caused
This value assures the phenomenon that cyanosis heart failure (right-left shunt, respiratory disease).
does not develop under physiological conditions. Since the cause of central cyanosis resides on the
Cyanosis can be of central or peripheral character. level of central organs (heart, lungs) the conse-
In pathological processes in the heart both forms may quences inflict all tissues, which is especially visi-
occur. ble on the skin and mucous membranes, and is not
limited merely to acral localization. The signs in-
Peripheral cyanosis (stagnating, cold cyanosis) de-
clude also the cyanotic tongue, palate, internal mu-
velops at normal saturation of blood with oxygen.
cous membrane of the lips). While the peripheral
In consequence of blood stagnation the tissues ex-
cyanosis is associated with vasoconstriction, the cen-
tract a relatively larger amount of oxygen from the
tral cyanosis manifests itself by symptoms of periph-
blood. This condition is typical in heart failure. In
eral vasodilatation. It can be explained as a struggle
heart failure the blood flow via capillaries is slowed
of tissues to compensate their oxygen hyposaturation
down and the contact of tissues with blood pro-
by enhancement of the blood flow. Vasodilatation
longed. The factors which trigger off the onset of
manifests itself by warm skin, capillary pulsation,
peripheral cyanosis development due to heart fail-
dilated veins of the forearms and hands. The next
ure include also reduction of the minute volume of
compensatory mechanism of central cyanosis is rep-
the left heart. In consequence of peripheral vasocon-
resented by polyglobulia. Clubbed fingers are a sign
striction of arterioles the capillary region receives a
of chronic hypoxemia and they are the evidence of
reduced amount of blood. This fact alone, regardless
prolonged duration of the disease (years, or decades).
of the congestion in the systemic circuit prolongs the
contact of erythrocytes with tissue. Moreover, due
to tissue acidosis and Bohr‘s effect increased dissocia- 3.5.1.4 Disturbances of rhythm in heart fail-
tion of oxygen from oxyhemoglobin takes place. Nat- ure
urally, peripheral cyanosis occurs in all states char-
The term rhythm includes periodic electrical and
acterized by prolonged contact of blood with tissues
subsequent hemodynamic changes, the aim of which
(e.g. vasoconstriction due to exposure to cold, shock,
is to pump blood from the venous into the arterial
or locally obstructed blood return) (see fig. 3.11 on
system. Smooth coordination of the presented elec-
page 105).
trical and mechanical events manifests itself acousti-
Because of the fact that this form of cyanosis is ac- cally by rhythmic changing of sounds of typical in-
companied by vasoconstriction with a reduced blood tensity and quality. When the events of depolariza-
flow, the tissues are cold. This form manifests itself tion and repolarization are disturbed, or when the
especially in those regions where the capillary bed characteristics of the myocardial tissues alter per se
is situated closely below the surface (auricles, nose, (contractility alteration, resp. myocardial stiffness),
cheeks, external lips, tips of fingers and toes). various changes in regularity and quality of the exter-
Central cyanosis (arterial, warm cyanosis) orig- nal signs of cardiac activity develop. Their hemody-
inates in consequence of the fact that the arte- namic and prognostic consequence may be insignifi-
rial blood itself contains a smaller amount of ox- cant, but on the other hand they may represent sig-
idized hemoglobin than under physiological con- nals of severe impairment of cardiac functions.
ditions. When the tissues extract the adequate One of the most typical manifestations of the al-
amount of oxygen from blood, the level of reduced teration of normal rhythmicity in failing heart is the
hemoglobin at the venous capillary ending can ele- gallop rhythm. In gallop rhythm during one cardiac
112 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

revolution, three instead of two sounds can be heard. in hyperkinetic states it is caused by a large volume
The mechanism of their origin is quite complex and of blood flowing into a ventricle. Presence of gallop
its comprehension requires a concise conception of in patients with constrictive pericarditis is dependent
atrial hemodynamics. upon the restrictive effect of calcified pericardium
Hemodynamic manifestation of atrial activity can which due to its minimal elasticity halts the diastolic
be simply divided into three periods: Period of rapid filling abruptly, the expanded ventricles rapidly take
ventricular filling which represents an early phase of up their initial shape. Consequently the atrioven-
diastole. The blood flows freely into ventricles on tricular valves are enclosed rapidly in the middle of
basis of pressure gradient. Hence the ventricle re- diastole.
ceives 80 % of the total amount of the end-diastolic The situation in heart failure is different. The elas-
blood volume. The subsequent diastasis, i.e. a pause ticity of a failing heart is significantly decreased and
in ventricular filling, is followed by a period of ac- does not participate in the gallop origin. In con-
tive contraction of atrii. By means of the latter the sequence of congestion in the pulmonary circuit the
remnant 20 % of blood is distributed into ventricles. pressure gradient between the left atrium and ventri-
Regarding the chronological localization of the cle, achieves high values at the beginning of diastole.
third heart sound protodiastolic and presystolic gal- This situation causes rapid elevation of ventricular
lops are distinguished. Protodiastolic gallop (dias- pressure during the passive blood filling of ventricles
tolic gallop being a more correct term) produces the in the first phase of diastole and rapid temporary en-
third heart sound at the end of rapid filling of ventri- closure of atrioventricular valves in the early phase
cles. It occurs aside from the states of heart failure of diastole.
e.g due to mitral or aortic regurgitations, constric- Presystolic gallop is dependent upon the origin of
tive pericarditis and in infants and adolescents. The the third heart sound in late diastole, i.e. presystole.
mechanism of the third heart sound origin is some- The mechanism of the third heart sound coincides
times explained by an abrupt expansion of ventricles with a strong contraction of atrii in the last phase of
in the phase of their rapid filling. In fact the situa- diastole. Assumedly also the premature enclosure of
tion is much more complex. The third heart sound either the mitral or tricuspidal valves at the end of
is dependent not only upon the abrupt expansion of diastole participate in its origin. Premature enclo-
the ventricular wall, but also upon its rapid return sures of one or two atrioventricular valves take place
to its original shape. During this event the ventricu- owing to the rapid increase of ventricular pressure
lar pressure elevates, the pressure gradient between during strong contraction of atrii.
the atrium and ventricle transiently swaps and at the Under normal circumstances the enclosure of atri-
end of the rapid ventricular filling the atrioventric- oventricular valves is a component of the first heart
ular valves enclose abruptly for a short while. The sound. It originates during ventricular systole. The
latter is assumedly the most important component third heart sound is physiological in young people
of the third heart sound in the diastolic gallop. The and is caused by increased sympathetic tonus (rapid
atrial pressure, however, continues to elevate due to contraction of atrii) and increased elasticity of ven-
the venous return, the atrioventricular valves subse- tricles (premature enclosure of AV valves). However
quently reopen and owing to atrial contraction the at an older age it indicates a pathological situation,
remnant 20 % of the diastolic volume of blood flows namely hemodynamic overload, rather than heart
in. This is the particular moment, which is followed failure per se. When the ventricle is hemodynami-
by an enclosure of the atrioventricular valves for a cally overloaded, it holds up a larger amount of blood
longer period of systole. at the end of diastole. Therefore, in the final phase of
The third heart sound can be physiological in chil- diastole it is more difficult for atrii to press the last
dren, since large elasticity enables the ventricle to 20 % of blood into ventricles. A strengthened and
expand and subsequently to take up the previous accelerated contraction of atrii rapidly elevates the
shape. This process results in an abrupt pressure ventricular pressure and determines thus the enclo-
elevation and the atrioventricular valves enclose tem- sure of AV valves prior to the isometric contraction of
porarily. The pathological gallop occurs due to vari- the ventricle. If the hemodynamic overload is associ-
ous reasons. In mitral and aortic insufficiencies, and ated with chronic heart failure, the presystolic gallop
3.5. Pathomechanism of heart failure (F. Šimko) 113

reflects besides the momentary hemodynamic over- trary, some fibres from the first beat are in a refrac-
load, also the increased stiffness of ventricles. Both tory state in the subsequent contraction. The pre-
factors are responsible for the fact that the acoustic sented facts, however, do not explain at all the al-
phenomenon accompanied by premature enclosure of teration of pulse, since through the suggested mech-
AV valves ceases to represent a component of the anism all pulses would be attenuated.
first heart sound and manifests itself chronologically An explanation that pulse alteration depends upon
closely prior to the latter as being the third heart the reflex stimulation of atrii by means of sinus
sound. It can occur in cases of failure either of the caroticus pressoreceptors is much more acceptable.
left or right side of the heart, respectively in cases of This theory is supported by the fact that pulsus al-
simultaneous failure of both sides of the heart. Sum- ternans is triggered by ectopic beat. When the pres-
mation gallop. If under pathological circumstances sure in arterial bed elevates due to the prolongation
both protodiastolic and presystolic sounds occur si- of diastolic pause after ectopic beat, and consequent
multaneously, they may merge into a single sound larger end-diastolic volume, the activity of nervus
which is referred to as the summation gallop. vagus is stimulated on a reflex basis via sinus caroti-
Tachycardia and extrasystoles are frequent find- cus. Nervus vagus reduces the force of atrial systole
ings in cases of heart failure. If tachycardia is of diminishing thus the diastolic content of ventricles.
sinus character, it has a compensatory aim and orig- At the following beat less blood is ejected. A rel-
inates in consequence of the sympathetic nerve acti- atively decreased pressure in sinus caroticus stimu-
vation and sinoatrial bundle stimulation. Extrasys- lates reflexively the sympathetic nerve system which
toles can be atrial or ventricular. Their origin re- supports the contraction of atrii. This mechanism el-
sides in both distension of the atrial or ventricular evates the end-diastolic ventricular volume and the
walls and enormous sympathetic stimulation. Con- following beat is more vigorous than normal. The
sequently, depletion of ATP supervenes. According more is the ventricular filling dependent upon the
to Laplace‘s law the ventricular distension with in- atrial contraction, the longer lasts the alternating
creased tension in ventricular wall has a devastating pulse after the ectopic beat.
effect on ATP reserves. It is supported also by the Alternating pulse is a frequent phenomenon in
increased frequency of contractions and the so-called heart failure. It coincides with both frequent oc-
oxygen vasting effect of catecholamines. The oxygen curence of extrasystoles and simultaneous decrease
vasting effect originates in consequence of the ability in compliance of the failing heart‘s ventricle. In con-
of catecholamines to uncouple oxidation from ATP sequence of the decreased compliance of ventricles its
production. Consequently energy formed in the res- diastolic content is significantly dependent upon the
piratory chain leaks as heat, being inexploited. En- contractile function of atrii.
ergy depletion in a failing heart disturbs the Na+ - Cheyne–Stokes’s respiration manifests itself by
K+ -ATP-ase activity (and other ATP-ases), which cyclically repeated, and gradually profound respi-
impairs the normal ions-transport, and cardiomy- ration until the maximal profound respiration is
ocytes may become the source of pathological au- achieved. Consequently the respiration is debilitated
tomation. This mechanism gives origin to extrasys- to the extent of apnoe. After remaining in apnoe for
toles, respectively tachycardia and atrial fibrillation, several seconds the whole sequence is repeated. Such
and in the terminal phase of heart failure also to respiration occurs in all states where the respiratory
ventricular fibrillation. centre is suppressed in consequence of deteriorated
Pulsus alternans is characterized by regular alter- metabolism. They develop in cases of heart failure,
ation of pulses with both larger and smaller volumes. but also in atherosclerosis of cerebral arteries due to
The mechanism of its origin has not been explicitly skull injuries and in some intoxications.
explained yet. A theory exists that on the basis of re- In consequence of deteriorated perfusion and thus
polarization impairment, and thus partial refractori- decreased formation of ATP, the respiratory cen-
ness, less contractile fibers participate in the event of tre becomes hyposensitive to normal levels of CO2
contraction during the weaker pulse. The impaired and O2 . Therefore, the respiration gradually ceases.
fibres recover during the weaker pulse and become During the apnoic pause carbon dioxide accumulates
active in the subsequent contraction. On the con- in the blood and oxygen level decreases. When these
114 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

changes in blood gases are significantly marked, the Forward failure develops in consequence of a de-
respiratory centre starts to react again in spite of creased pumping capacity of the right ventricle. Due
its hyposensitivity, and respiration is revived. Dur- to this the lungs and the left side of the heart receive
ing respiration normal levels of blood gases are soon a smaller amount of blood. On the one hand this phe-
set up and respiration ceases again. The respiratory nomenon has a negative impact in the deterioration
centre is suppressed until a sufficiently high level of of the peripheral blood supply. On the other hand
carbon dioxide and a sufficiently low oxygen tension the decreased pumping activity of the right ventricle
are developed which are able to stimulate even the developed due to primary left-sided heart failure, re-
hyposensitive respiratory centre to its activity. stricts the blood supply into the lungs. As a result
the pulmonary congestion and thus also breathless-
3.5.2 Right heart failure ness may decrease. This paradoxical mysterious im-
provement occurs in severe forms of left-sided heart
The term heart failure designates prevalently fail- failure when as a consequence of increased pressure
ure of the left ventricle. It is natural however, that in a. pulmonalis the right ventricle dilates. The offer
failure can inflict also the right compartment of the of blood to the lungs decreases and as a result the
heart. Hypertrophy and dilatation of the right ven- breathlessness withdraws. However, this takes place
tricle is often identified with the terms of chronic at the cost of a decreased blood flow into the left
or acute cor pulmonale. In these cases the causes ventricle and thus decreased peripheral perfusion.
of right ventricular failure reside in hypertension in Backward failure – manifests itself as a stagna-
a.pulmonalis. This hypertension develops in con- tion of the blood in the venous system before the
sequence of pulmonary disease which evokes the so right atrium and has several symptoms: edemas of
called pre-capillary pulmonary hypertension. How- the lower limbs, ascites, hydrothorax, hepatomegaly,
ever, right ventricular failure can develop in conse- hepatojugular reflux, increased content of jugular
quence of many more pathological states. veins, dyspepsia. All of these symptoms manifest
The right ventricle most frequently fails secondary congestion of the systemic circuit. Formation of ede-
to the left ventricular failure. The first step resides mas, similar to the pulmonary edema has a complex
in elevation of pressure in pulmonary veins, and later pathogenesis:
in capillaries. The raised pressure can be gradually
conveyed into a.pulmonalis and even into the right • increased hydrostatic pressure in capillaries
ventricle. Hence, the right ventricle is inflicted sec- • hypoproteinemia in consequence of venostatic
ondary to the left ventricular impairment. However, impairment of the proteosynthetic function of
the right ventricle may fail without dependence on the liver
left ventricular impairment or on pulmonary disease.
This type of heart failure can be caused by ischemic • increased permeability of capillaries in conse-
heart disease, valvular diseases of the right side of quence of hypoxemia in regions of blood stag-
the heart, myocarditis, or hyperdynamic circulation. nation
It is necessary to realize that the compensatory
capacity of the right side of the heart is much smaller • deteriorated outflow of lymph from edematous
than the compensatory capacity of the left heart side. regions.
Therefore a pathological process inflicting the right
ventricle causes dilatation much sooner than it would
have developed due to an analoguous infliction of the
left ventricle.
Right-sided heart failure is subjectively less un-
pleasant for a patient and therefore better tolerated
than breathlessness which represents the main symp-
tom of left-sided ventricular heart failure.
Similarly as in left-sided heart failure also the
symptoms of right-sided heart failure may be dis-
tinguished as forward and backward failure.
3.6. Pathomechanism of cardiomyocyte damage in heart failure (F. Šimko) 115

plasm and KrebÝs cycle and respiration chain in mi-

tochondria may be also decreased through enhanced
3.6 Pathomechanism of car- Ca2+ cytoplasmic level.
diomyocyte damage Also the metabolism of catecholamines is im-
paired. The number and function of beta-receptors
in heart failure is decreased and the content of catecholamines in the
cardiac tissue is reduced. Since the catecholamines
stimulate the contractility of the heart under phys-
iological circumstances, their insuffient amount can
Failure of the pumping function of the heart de- lead to contractility impairment of the heart.
velops in consequence of pathological changes in the
Intracellular ion metabolism is significantly altered
smallest contractile elements. The impaired function
in a failing heart. These alterations can be caused by
of the heart has its correlation on the cardiomyocyte
some of the above mentioned changes. On the other
level.
hand however, they themselves can evoke the impair-
Impairments on subcellular level can be of vari-
ments of organelles. Sodium, potassium, magnesium
ous character in dependence on etiology of the un-
and calcium ions and their mutual proportion can
derlying cardiac disease. Most thoroughly analyzed
be inflicted. The calcium ions represent the direct
are the subcellular changes in coincidence with long-
factor determining the connection between excita-
term hemodynamic overload. Heart failure per se
tion and contraction processes, whereas the rest of
is almost in all cases of chronic overload associated
ions influence this process indirectly, namely by cat-
with impairment of contractile properties of the car-
alytic intervention into a whole series of metabolic re-
diac muscle. There is experimental evidence that
actions (glycolysis, oxidative phosphorylation, beta-
primary impairment can develop practically in any
oxidation of fatty acids). These ions participate
of the cellular organelles participating in the contrac-
also on electrical changes on the level of cellular
tile process.
membrane. Insufficiency in potassium manifests it-
Impairment of contractility of the myocardium can
self by undesired hyperpermeability of sarcolemma,
develop in consequence of alteration in proteosyn-
sarcoplasmic reticulum and mitochondria. Excess
thesis of contractile proteins per se, namely in sense
in intracellular sodium osmotically attracts water
of decreased proteosynthesis, or owing to alteration
and leads to intracellular hyperhydration. Simulta-
in quality of synthetized proteins. Also their inad-
neously, however, sodium-calcium exchange mecha-
equate degradation can represent one of the causes.
nisms entail the increasing of intracellular calcium
Impairment of contractile proteins results in the de-
concentration. Inadequately high concentration of
crease in the number and velocity of actin-myosin
calcium can have a toxic impact on cells and even
bridges formation and so the contractility of the
cause chemical death of cells. Magnesium is designed
heart decreases.
to catalyze a whole series of biochemical reactions,
Also the function of sarcoplasmic reticulum may
to participate in the normal response of cardiomy-
be decreased in the myocardium of a failing heart.
ocytes to stimulation, and is important for normal
There is evidence that the velocity of both the re-
activation of myosin ATP-ase.
lease and uptake of calcium, and binding capac-
ity for calcium ions are decreased. Association be- Let the primary impairment be located in
tween excitation and contraction may be thus im- whichever organelle or enzyme, in ultimate conse-
paired. Depolarization of sarcolemma and tubuli do quence two basic types of changes take place in a
not evoke an adequate increase of calcium level in cy- cardiomyocyte: overloading of a cell with calcium,
toplasm. Hence, the offer of this ion for contractile and ATP depletion. In dependence on subsequent
functions is decreased and consequently the contrac- order in which the two changes develop the cellular
tion properties of the heart deteriorate. The activ- impairments are referred to as being calcium induced
ity of central enzymes responsible for ATP splitting or ATP depletion-induced.
(myosin ATP-ase) and transport of ions (sarcolem- In a case of calcium induced impairment of my-
mal and sarcoreticular ATP-ases) as well as the ac- ocytes the order of processes is as follows: The level
tivity of enzymes designed for glycolysis in the cyto- of cytoplasmic calcium which under physiological cir-
116 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

cumstances fluctuates between 10−7 and 10−5 dur- The primary ATP-dependent impairment of car-
ing systole and diastole gradually begins to increase. diomyocytes is not evoked by calcium ions at the be-
The reason of this inadequate increase is the impair- ginning, but the ATP depletion is entailed by other
ment of transport capacity of sarcoplasmic reticulum factors (hypoxia, deficit of substrates, glycolysis inhi-
for calcium as well as increased calcium influx via bition). Such a state is present in ischemic heart dis-
hyperpermeabile sarcolemma. Homeostatic mecha- ease and in some cardiomyopathies, resp. myocardi-
nisms of cardiomyocytes are under physiological cir- tis. In consequence of energy insufficiency the mem-
cumstances set up to maintain precisely the cytoplas- brane ATP-ases responsible for transmembrane ac-
mic calcium level. Its decrease leads to a reduction tive transport cease to work. Failure of sarcolemmal
of actinomyosin bridges, owing to which the contrac- Na+ – K+ ATP-ase leads to accumulation of sodium
tile ability of the heart decreases. On the other hand in a cell. Intracellular sodium ions osmotically at-
the inadequate increase of the calcium level in a car- tract water and cellular edema originates. Owing to
diomyocyte can have a catastrophic impact. In order Na+ – Ca2+ ions exchange mechanisms, the increased
to prevent it a cell begins to use the calcium trans- intracellular load of sodium may finally lead to the
port capacity of mitochondria. In a case when the increase of cellular calcium. The level of calcium
stress factor is of temporary character (e.g. tem- increases also due to the decreased activity of sar-
porary hemodynamic overload) and thereby also al- colemmal ATP-ase and calcium sarcoretiular ATP-
terations in sarcoplasmic reticulum and sarcolemma ase. ATP depletion and subsequent excess in cal-
are transient, the calcium transport ability of mi- cium ions lead to necrosis of myocytes by means of
tochondria is able to maintain the adequate cytoso- the mechanism described above.
lic concentration of calcium. A prolonged hemody- Summary. Failure of the heart per se has always
namic overload and irreversible impairment of trans- its correlate on the cardiomyocyte level. Various eti-
port structures cause permanent accumulation of cal- ologic factors leading to heart failure can cause car-
cium in mitochondria. This leads to the impairment diomyocyte impairment on various levels. In spite
of the process of oxidative phosphorylation and ATP of a great variability of primary impulses leading to
synthesis. ATP depletion is supported also by its cardiomyocyte impairment, the order of subsequent
leak via hyperpermeabile sarcolemma. actions is very similar. Either the cell is overloaded
by calcium ions, or ATP depletion develops. In con-
In spite of mitochondrial calcium buffer activity, sequence of one of these two alterations a vitious cir-
the level of plasma calcium may become inappropri- cle of negative and mutually supporting processes
ately high. Calcium ions during systole saturates develops leading ultimately to both ATP depletion
practically all binding sites on contractile proteins, and toxic impairment of cells owing to an excessive
but during the diastole calcium is not completely re- calcium load. These impairments finally lead to func-
moved due to its high level in plasma. Actin-myosin tional and morphologic extinguishment of cardiomy-
interactions persist in many sites also during dias- ocytes.
tole and the so-called irreversible contractures repre-
senting permanent shortening of contractile elements
develop. It leads to structural and functional extin- 3.6.1 Pathophysiological principles of
guishment of contractile proteins. The impairment therapy in heart failure
of relaxation of these structures is supported also
by ATP deficit, the molecules of which function not The basic requirement in therapy in each of patholog-
only as donors of energy in favour of contraction, but ical states is represented by elimination of its cause.
their plasticizing effect is inevitable also for the pro- This is valid also in therapy of acute and chronic
cess of relaxation. The development of contractures heart failure. Mainly in acute heart failure the re-
is supported also by impairment of ATP utilization placement of the trigerring cause has a prompt ther-
in consequence of decreased myosin ATP-ase activity. apeutic effect. E.g. elimination of extreme tachycar-
ATP depletion, as well as the origin of contractures dia immediately improves, respectively completely
significantly decrease the function of cardiomyocytes normalizes the heart function, and dilatation of the
and gradually lead to morphologic and functional ex- heart and the concomittant breathlessness is re-
tinguishment of cardiomyocytes. moved. A similar effect is achieved by elimination of
3.6. Pathomechanism of cardiomyocyte damage in heart failure (F. Šimko) 117

other acute causes of heart failure (e.g. abolishment influencing the three basic regulatory mechanisms of
of hypertension crisis, reduction of excessive volume the heart - contractility, preload and afterload.
of circulating fluid, restoration of adequate oxygen
and substrate supply in the case of acute ischemia
etc.). 3.6.1.1 Stimulation of contractility
In cases of chronic heart failure it would be optimal Frequently (in the past almost in general) the main
to remove the pathological agens and at the same part of therapy is considered to be represented by the
time to begin the therapy in the initial phase of heart application of positive inotropic substances which
failure. At this time the function of cardiomyocytes stimulate contractility. Stimulation of contractility
is impaired only in a specific manner which can be of cardiomyocytes is accomplished by means of the
influenced therapeutically. In addition, in the initial increasing of the level of activating calcium in car-
phases of the impairment of function of myocytes diomyocytes which can be achieved by means of var-
the cardiac muscle cells have reserves which can be ious mechanisms:
therapeutically stimulated.
The situation in clinical practice is entirely differ- 1. Inhibition of Na+ –K+ ATP-ase entails accumu-
ent. The diagnosis of heart failure is stated when lation of Na+ ion which entered the cell during
a patient is afflicted by considerable subjective diffi- depolarization. Its high intracellular concentra-
culties. In this phase the reserve capacity of cardiac tion stimulates the Na+ –Ca2+ exchange mecha-
muscle cells is usually exhausted in consequence of nism while the cells dispose sodium and increase
long-term ecploitation of compensatory mechanisms. the level of calcium (cardiac glycosids – digox-
In addition the neurohumoral compensation reaction ine).
is escaladed to such an extent that it is able to as-
sure only the perfusion of vitally important organs, 2. Stimulation of the beta 1 receptor of cardiomy-
on the behalf of perfusion of peripheral tissues. In ocytes - adenylcyclase - proteinkinase - the
the developed phase of cardiac insufficiency the etio- phosphorylation of subcellular structures which
logical agens can be influenced only with difficulties, transport and bind calcium increases the supply
or it cannot be influenced at all. This is so either be- with calcium and enhances its effectivity (cate-
cause in many diseases the etiologic factor is not suf- cholamines).
ficiently ascertained (various forms of cardiopathies,
myocarditis) or in the late phase of failure the origi- 3. Inhibition of cardiac phosphodiesterase which
nal cause cannot be explicitly ascertained. However, acts as a degradating enzyme of cAMP results
even if the primary factor of the heart impairment in increased level of cAMP. This stimulates the
would be successfully detected in the phase of de- proteinkinases and phosphorylation processes
veloped heart failure, neither the entire elimination and in the ultimate consequence evokes the same
of the etiologic factor would not have to necessar- effect as in case 2 (methylxantines, amrinon,
ily lead to improved cardiac function as alterations milrinon).
on the subcellular level are irreversible. In such a
situation the therapy of cardiac insufficiency is only Positive inotropic substances are effective exclu-
of symptomatic character. It does not eliminate the sively under under the pressumption that a cell still
cause of failure, but improves the hemodynamic situ- has functional reserves which can be stimulated. The
ation in the heart and peripheral tissues, it eliminates offer of intracellular calcium in favour of contractile
the negative consequences of excessive compensatory proteins in severe forms of heart failure is however
mechanisms and mitigates the subjective unpleasant sufficient in consequence of the stimulation of the
sensations of a patient. sympathetic nerve with a subsequent abundant re-
The pathomechanism of therapy resides in the re- lease of endogenous catecholamines. Further intra-
duction of requirements on the work of the heart, in cellular increase in calcium concentration owing to
improvement of the output of the heart per se and positively inotropic substances does not evoke any
in improvement of the function of peripheral organs further increase in contractility, but has an explicit
(especially kidneys). This can be accomplished by toxic impact on cells.
118 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

3.6.1.2 Stimulation of preload lation of the sympathetic nerve, vasoconstriction of

all peripheral organs including the kidneys develops
Failing heart is overfilled with blood and the ventric- by means of stimulation of alpha receptors in ves-
ular cavities are of large diameters at the end of di- sels. Therefore the positive efect may be achieved by
astole. The capacity of Frank-Starling’s mechanism such medicaments which dilate the arterial bed (hy-
is maximally exploitated as the length of sarcomeres dralasine preparates, alphasympatholytics) decreas-
is closely near to 2,2 µm. Further elevation of the ing thus the peripheral resistance.
filling pressure does not increase the length of mus- The heart works agains decreasing resistance and
cular fibres, but deteriorates the stagnation of fluid consequently the stroke volume increase improving
above the left side of the heart – in pulmonary veins thus the peripheral perfusion. As during each sys-
and capillaries provoking thus dyspnea. Moreover, as tole the heart ejects a larger amount of blood a rel-
a consequence of further increase in the filling pres- atively smaller amount of blood remains in ventri-
sure the heart can even more expand in spite of the cles and the end-diastolic pressure and volume are
fact that sarcomeres are not being prolonged. This is decrease. Decreased ventricular radius and intraven-
performed by means of the shift of muscular layers in tricular pressure in accordance with Laplace’s law
the ventricular wall. The increase of the ventricular result in a decrease in ventricular wall stress and the
diameter and the thinning of ventricular wall evokes energetic needs of the myocardium decrease. The
enhancement of ventricular wall stress which is en- heart thus performs a greater work under lower en-
ergetically infavourable from the point of Laplace’s ergy consumption, in other words the effectivity of
law. Therefore the therapy struggles to achieve such the heart increases. Dilatation of peripheral arte-
a ventricular filling where the length of sarcomeres at rial system improves also the perfusion of the kid-
the end of diastole would be optimal for utilization neys, owing to which urine production increases and
of Frank-Starling’s law, but under such a filling pres- the volume of circulating fluid decreases. This re-
sure which does not evoke stagnation of blood in the sults in a reduced venous return and optimalization
lungs. In other words it is desirable to decrease the of preload.
venous return to the optimal level. This effect can
be achieved by the restriction of physical exercise,
bz a decreased intake of salt in food (sodium osmot- 3.6.1.4 Inodilators
ically retains water, increases the circulating volume Substances which yield simultaneously both in-
and venous return) and by substances having a dilat- otropic and arteriodilatory effects become very pop-
ing impact on the venous system (the blood persists ular. For their simulataeous inotropic and vasodila-
in the capacity bed and returns to the heart in a tory effects they are sometimes referred to as inodila-
reduced amount). Such a therapeutical procedure tors. The mechanism of their effect resides in having
naturally does not improve the perfusion of periph- a flexible molecule which is able to influence several
eral tissues, but eliminates the subjective sensation types of receptors. Inodilators stimulate contractil-
of breathlessness. At the same time by means of de- ity in the heart by means of β1 receptors, they cause
creased stress in the ventricular wall the economy of vasidilatation by stimulating β2 receptors in the ar-
contraction improves. terial system, and on the level of the kidneys they
dilate arterioles via histamine DA1 receptors. More-
3.6.1.3 Stimulation of afterload over, by stimulating also the DA2 receptors at the
sympathetic nerve hindering thus the nerve’s end-
Afterload means the stress in the ventricular wall ings they inhibit the release of noradrenaline and
during systole. This stress depends on several fac- noradrenaline-induced alpha-receptor effect of vaso-
tors according to the Laplace’s law (intraventricu- constriction.
lar pressure, ventricular radius and thickness of the As a result the contractility increases, the arte-
ventricular wall). In the narrower sense of the term, rial bed dilates and the volume of circulating fluid
however, afterload is understood as the resistance decreases. In this way not only the ejection frac-
against the heart work and this resistance is deter- tion, but also the economy of the heart work increase.
mined by arterial resistance. In the developed phase This is why dopamine and some of its derivates have
of heart failure, in consequence of maximal stimu- a triple effect. They influence not only the contractil-
3.7. Hypertrophy of the heart – mechanism of adaptation to chronic hemodynamic overload (F. Šimko) 119

ity and afterload, but by means of increased diuresis contractile state and frequency increase the minute
and decreased volume of circulating fluid they re- volume and improve peripheral perfusion. The in-
duce also the preload. Obviously in the near future crease in wall stress wastes a considerable amount
they are going to become the alternative approach to of energy without any positive perfusion effect (the
the generally used therapy by digitalis and diuretics so-called internal work).
and they might mean a significant prolongation and
Hypertrophy is stimulated particularly by a non-
improvement of life quality in patients with heart
adequate increase in ventricular wall stress. Hyper-
failure.
trophy may be then interpreted as an protectory
mechanism helping the heart to recover wall stress
to the original level.
Ventricular wall stress is from the physical point
of view defined by means of Laplace’s law:
3.7 Hypertrophy of the heart
– nechanism of adaptation P ·r
T =
2·h
to chronic hemodynamic
where T . . . stress, P . . . intraventricular pressure,
overload r . . . ventricular radius, h . . . ventricular wall width

The fact that the denominator represents a dou-

The Frank-Starling’s mechanism and increased blefold value of the wall width, implies that even
sympathetic stimulation represent acute compen- a relatively small thickening of the ventricular wall
satory mechanisms. They manifest themselves im- significantly decreases the value of wall stress. The
mediately after the heart work demands have been formula implies that the larger the ventricular radius
increased thus preventing acute heart failure. How- the larger ventricular stress (force) is needed in order
ever, when the heart has to perform increased vol- to achieve the given pressure.
ume or pressure work for a longer period (neither
In order to make the relation between particular
minutes, nor hours, but weeks or years) chronic com-
quantities more comprehensible it is recommended to
pensatory mechanism come into force – hypertrophy
imagin an insuflated balloon. Providing the balloon
of the heart muscle.
is inflated but moderately, it has a small radius, low
Hypertrophy represents a structural adaptation
intraventricular pressure and the wall is moderately
of the heart to a long-term hemodynamic overload.
tense. As soon as it is blown up with a large amount
Regarding energy metabolism, it is the effectivity
of air, its radius increases, its intraventricular pres-
of the work which is of importance beside the gen-
sure elevates, and simultaneously the wall becomes
eral amount of work being performed. The effectivity
thinner and almost transparent. The wall of such a
means the amount of performed work in dependence
balloon is significantly tense and there is the threat
on the amount of supplied energy, in other words
of bursting.
the performace. It is easy to achieve for the heart
to perform a great amount of work providing it con- From the biochemical point of view it is essential
sumes a large amount of ATP. Such a state can last that the increased stress wastes ATP completely in
but several minutes, or at the longest several hours. vain. Macroergic phosphates are not utilized on the
However if it is necessary to perform intensive work behalf of increased work, but their prevailing amount
for a long period the consumption of energy must is spent on the behalf of the mere survival of car-
be inevitably adequate to the amount of performed diomyocytes in state of their prolongation. From
work. the energetic point of view the high ventricular wall
The consumption of energy in the heart is deter- tension represents a disadvatageous state which the
mined by three basic factors: wall stress, contractile heart struggles to eliminate by means of hypertro-
state of myocardium and frequency. The increases in phy.
120 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

3.7.1 Pressure and volume overload sion in the ventricular wall also at the beginning of
of the heart systole – afterload. The latter determines the growth
of myocytes width which is however smaller at the
Two types of hemodynamic overloads of the heart volume overload than at pressure overload. The vol-
are distinguished – pressure and volume overload. ume overload thus results in a significant volume in-
Pressure overload is referred to in cases where the crease of the ventricle and simultaneously less promi-
primary cause is the increase in afterload. Afterload nent thickening of its wall. It is specific of the ex-
is the stress in ventricular wall during systole. It is centric hypertrophy that the proportion between the
determined in a decisive measure by resistance jux- wall width and its volume is shifted in favour of the
taposed to blood flow by aorta and peripheral ves- ventricular volume.
sels. In a case of left ventricle this type of over- In a case of volume hypertrophy the increased ten-
load is represented by stenosis and aortic coarctation, sion in the ventricular wall evoked by increased end-
arterial hypertension and obstructive hypertrophic diastolic volume is according to Laplace’s law com-
cyrdiomyopathy. Increased pressure overload of the pensated by a subsequent prolongation of muscular
right ventricle is entailed by stenosis of a.pulmonalis cells, thus accompanied by the growth of ventricu-
and pulmonary hypertension of variable etiology. lar cavity resulting in a decrease in intraventricular
Since during systole the blood flow is hindered by pressure. The thickening of the ventricular wall also
an obstacle, the intravenricular systolic pressure el- participates in the decrease of tension. These two
evates. Increased systolic intraventricular pressure factors overbalance the third factor of the Laplace’s
causes systolic tension in the ventricular wall which law, namely the radius which is increased in the case
stimulates the growth of the width of myocytes. This of excentric hypertrophy.
process results in the thickening of the ventricular
wall. At the same time the end-diastolic volume
does not change substantially. Hypertrophy at pres- 3.7.2 Direct stimulus of hypertro-
sure overload, i.e. concentric hypertrophy, is there- phic growth
fore characterized by the fact that the proportion In spite of the fact that non-muscular elements form
between the wall width and end-diastolic volume as much as 75 % of the total number of cells in the
changes remarkably in favour of the wall width. heart, the main mass is formed by cardiomyocytes
In a case of concentric hypertrophy the transiently since they are much larger than the remnant cellular
increased ventricular wall stress evoked by increased elements. In comparison with other cells in the my-
intraventricular pressure is according to Laplace’s ocardium the cardiomyocytes are capable of repro-
law eliminated by the thickening of the ventricular duction merely during prenatal life. After birth the
wall at a constant ventricular radius. muscle cells do not divide, their number remains un-
Volume overload is referred to when the primary changed throughout the postnatal life. The growth
cause is represented by increased preload. The par- of contractile mass within hypertrophy is determined
ticular value of preload depends predominanntly on exclusively by the growth of muscular cells.
the blood volume which is present in the ventricle at Increased proteosynthesis of cardiomyocyte struc-
the end of diastole. Increased preload of the left ven- tures is a response to increased ventricular wall
tricle is usually present under the circumstances of stress. This response can take place providing that
insufficiency of aortic or mitral valves, open ductus the information about the increased ventricular wall
Botalli and aortopulmonary bypass Increased volume stress is transfered into the cellular nucleus. The
overload of the right ventricle is observed under the nucleus is a place where the genetic information for
circumstances of insufficiency of pulmonal or tricus- cellular proteosynthesis is stored. The question as
pidal valves and defect of the atrial septum. Vol- to which factor represents the direct stimule trigger-
ume overload in some cases inflicts both the left and ing the proteosynthesis is not explicitly settled. The
the right sides of the heart – increased physical ex- situation is complicated by the fact that in various
cercise, bradycardia, so-called hyperdynamic circu- types, due to intensity and duration of overload dif-
lation, ventricular septum defect. ferent stimulators may come into play:
Increased ventricular volume and thus the tension
at the end of diastole automatically increase the ten- 1. In consequence of increased tension in the ven-
3.7. Hypertrophy of the heart – mechanism of adaptation to chronic hemodynamic overload (F. Šimko) 121

tricular wall, respectively in consequence of the sulin, and other hormones are able to stimulate
fact that each unit mass of the contractile tissue the growth of cardiac tissue. However it is not
must perform more work, a marked increase in known which of the hormones particularly plays
energy consumption takes place. This results in the role of the stimulator under in vivo condi-
a decrease in concentration of macroergic phos- tions. Investigators discuss catecholamines as
phates in myocardium – ATP which is the direct being likely involved as stimulators. The lev-
donor of chemical energy and KP which rep- els of catecholamines in the blood and in the
resents a chemical compound in which a form heart per se significantly change during individ-
of energy is stored. Simultaneously, the intra- ual stages of hypertrophy. The catecholamines
cellular concentration of the products of their intermediate the activation of sarcolemma and
breakdown – ADP, creatindiphosphate and cre- sarcoplasmic reticulum by activating the me-
atinin increases. The manner of stimulation brane receptor-adenylcyclase-proteinkinase sys-
of proteosynthesis inside the nucleus is proba- tem. Due to this the intracellular concentration
bly identical with the Jacobs-Monod’s opinion of calcium which is supposed to be the possible
concerned with derepression of genetic informa- direct inducer of genetic derepression increases.
tion. The products of the splitting of high en- The activated proteinkinase could though stim-
ergy phosphates bind to the repressor, in con- ulate the genetic expression also by means of
sequence of which the latter loses its inhibitory direct phosphorylation of the repressor. Marked
effect to the operator gene. Deblockated oper- stimulatory effects supporting the growth of car-
ator gene stimulates the activity of structural diac cells were discovered in thyroxine and glu-
genes and transcription of information carried cocorticoids. The mechanism of the thyrox-
by DNA to a molecule of RNA messenger can ine effect resembles that of catecholamines (by
take place. Subsequently, mRNA binds on ribo- means of the second messenger – cAMP). Gluco-
somes. Molecules of transfer RNA carrying indi- corticoids do not bind with the membrane recep-
vidual aminoacids are arranged in order accord- tor of sarcolemma but pass through the mem-
ing to the compatibility of their triplets with brane. They bind with the intracellular cyto-
mRNA (translation). The order of aminoacids plasmatic porter which transports them into the
determines the particular type of protein which area of the nucleus. Here, owing to the interac-
is to be synthetized. tion with the repressor gene they have an impact
as being inducers of expression of a particular
2. The state of increased ventricular wall stress en- part of genome.
tails an increase in the turnover of subcellular
structures. This results in accumulation ... of 5. In the recent period a considerable attention has
the products of the splitting of structural pro- been paid, namely in coincidence with hyper-
teins (especially the constituents of myofibrils) trophy, to the struggle of isolating the cardiac
which can play the role of further stimulators of growth factor. The consideration of the exis-
nuclear DNA. tence of a particular substance responsible for
3. It is agreed upon the assumption that the ten- hypertrophic growth of the heart was enhanced
sion of sarcolemma per se can influence the ge- by clinical and experimental observations that
netic expression. It takes place either by changes the overload of one of the ventricles enlarges
in transport properties of sarcolemma to various the mass of the other ventricle. It is considered
ions, but obviously also by the increase in trans- that the hemodynamic overload is the triggering
port af aminoacids. The change in ion concen- factor of a specific substance production which
tration, respectively the increase in intracellular stimulates hypertrophy of the heart. In spite
concentration of aminoacids can stimulate the of several positive experimental results the exis-
nucleus to the increase in protheosynthesis. tence of such a hypertrophy stimulator is until
now hypothetic. Since until now it has not been
4. Substances of hormonal character. It is experi- isolated, nor has its structure been assessed. It
mentally proved that catecholamines, glucocor- is assumed that it is produced in the pituitary
ticoids, thyroxine, somatotropic hormone, in- gland or in the cortex of suprarenal glands. It is
122 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

supposed to be of steroid structure and its effect compensate this energetic deficit leads the myocytes
takes place by means of the Na+ –K+ ATP-ase to synthetize an increased amount of mitochondrial
inhibition. Assumedly a whole group of sub- proteins and in the first days of hypertrophy develop-
stances is involved. Since both the mechanism ment the ratio mitochondria: myofibrils significantly
of their effect, and structure resemble those of increases in myocytes. After several days also the
digoxin, these presumedly hypertrophy stimu- synthesis of contractile proteins increases. As a re-
lating factors are called digoxin like substances. sult the ratio mitochondria: myofibrils is brought to
In regard to their resemblance to digoxin also normal and later it may even turn out in favour of
the resultant effect of these two factors could myofibrils.
theoretically reside in the increase of contrac-
At the beginning the hemodynamic overload en-
tility. Simultaneously, by means of the Na+ –
tails ventricular dilatation, but the effects of Frank-
K+ ATP-ase blockade in the tubules of the kid-
Starling mechanism and catecholamine stimulation
neys they could inhibit resorption of sodium
help to maintain the ejection fraction at normal val-
and subequently resorption of water and thus
ues. Later, increased overload of the heart as a whole
increase diuresis. This mechanism would serve
is gradually compensated by enlargement of the mass
as means of the delaying of the acute heart fail-
of contractile elements. This helps to decrease the
ure. Their prolonged discharge within the frame
overload accounted to a unit mass of contractile tis-
of chronic hemodynamic overload could possibly
sue. The contractility is at the beginning markedly
stimulate the growth of myocardium. The idea
decreased, later in the period of developed hypertro-
that this substance could be produced by car-
phy it achieves an approximately normal value. The
diomyocytes themselves is not entirely excluded.
ejection fraction does not change connsiderably, nei-
Either all cardiomyocytes with increased ten-
ther in the later period of overload.
sion, or only a specific group of cardiomyocytes
might be involved. Confirmation of these theo- 2. The situation in a growing heart becomes
retical considerations requires inevitably chemi- gradually stabilized, and ultrastructure, biochemism
cal isolation of the subjective substance. and function yield the character similar to that prior
to overload exposition. It is the period of stabilized
- developed hypertrophy.
3.7.3 Hypertrophy stages and their
characteristics 3. In spite of the fact that the hemodynamic
overload which had represented the stimule to triger-
In spite of considerable differences in the nature of ring the growth and leading to the formation of sta-
hypertrophic growth in individual types of overload, bilized, fully compensated state, persists in an un-
the adaptation of the heart at increased hemody- changed form, after a various period disadvantageous
namic overload can be (on the basis of experimental changes develop in the heart. This period is referred
results) divided into several characteristic periods: to as hypertrophy regression. It is accompanied by
a decrease in mass weight of the left ventricle, de-
1. period of hypertrophy development
creased synthesis of proteins of mitochondria and
2. period of developed hypertrophy myofibrils, and their increased proteolysis. The con-
tractile function of the heart is simultaneously de-
3. period of hypertrophy regression creased and in consequence of increased content of
fibrous tissue in the myocardium the left ventricle be-
4. period of heart failure comes stiffer. It results in deterioration of relaxation
and restricts the filling of ventricle during diastole.
1. Period of hypertrophy development – begins
It is to say that this period of spontaneous regression
subsequently after the exposition to increased over-
was proved in rabbits with aortal insufficiency.
load – e.g. valve rupture, experimental stenosis of
aorta, etc. . The stress in the wall of ventricle rapidly 4. The stage of regression transits ultimately
increases, which in turn increases the consumption of into the stage of heart failure. This is characterized
energy by unit mass, and the content of macroergic by continued increase in proteocatabolism in a cell,
phosphates in the heart decreases. The struggle to insufficient utilization of energy and progressive de-
3.7. Hypertrophy of the heart – mechanism of adaptation to chronic hemodynamic overload (F. Šimko) 123

terioration of systolic and diastolic functions of my- pends upon the type of overload, its duration and in-
ocardium. tensity, as well as upon the state of myocardium and
age of organism. For example many hypertonic pa-
tients yield a morphological and functional recovery
3.7.4 The problem of hypertrophy of the concentrically hypertrophic heart after elim-
regression ination of hypertension. In a number of patients,
however, in spite of successful therapy of hyperten-
The experimental investigations leave the problem sion, hypertrophy of the heart persists and gradually
of hypertrophy regression unsettled. The point at leads to deterioration of the cardiac function. The
issue is why in severe experimentally evoked valvu- situation is similar in patients operated due to valvu-
lar defect (aortic insufficiency) the achieved stage of lar defects with a pronounced hypertrophy of the
hypertrophy is not maintained, namely in spite of left ventricle (e.g. aortic insufficiency). Elimination
the permanent presence of the etiologic factor. A of the cause of hypertrophy entails its withdrawal
plausible explanation is offered that in spite of that obviously in cases where severe ultrastructural and
the hypertrophic left ventricle as a whole performs molecular defects had not developed. When serious
a greater amount of work than normal, the contrac- alterations of myocardium develop, hypertrophy will
tile overload accounted to a mass unit of myocardial not withdraw in most cases. Regarding the prog-
substance is however significantly reduced. Hence, nose of hemodynamic overload it might be conve-
one mass unit of myocardial substance performs a nient to distinguish not only the physiological, but
smaller amount of work than prior to the origin of also pathological regression of hypertrophy. The
overload. It is probable that the adaptation pro- pathological regression is characterized not only by
cess to chronic hemodynamic overload is overpiled. reduction of the mass weight of the heart but simul-
Hypertrophy achieves a measure greater than is in- taneously by deterioration of biochemical and func-
evitable for compensation of the hemodynamic over- tional parameters. Physiological regression develops
load per se. The contractile mass is therefore never due to the elimination of the cause of hemodynamic
fully exploited under the conditions of rest. It is overload in cases where the hemodynamic overload
not out of the question that this reserve ability is to had not evoked irreversible changes in the cardiac
serve as a contractile potential enabling a hemody- muscle. In such a case the reduction of mass weight
namically adequate performance of myocardium not is accompanied by improvement of biochemical and
only under rest conditions, but also due to hemody- functional parameters.
namic stress – e.g. at physical exercise. If this reserve
ability is not being functionally exploited, its gradual
breakdown takes its course. 3.7.5 Physiological hypertrophy
Another explanation of hypertrophy regression Hypertrophy does not occur only as a chronic com-
and heart failure is feasible, namely exhaustion of pensatory mechanism of the heart hemodynamically
genetic information. It is assumed that the genetic overloaded in consequence of a pathological process
apparatus is set up to a particular number of syn- which ultimately leads to heart failure. Controver-
theses of each protein molecule. In a case of hemo- sely to this pathological hypertrophy there exists
dynamic overload the individual structural and en- physiological hypertrophy which develops as a re-
zymatic proteins wear out faster. Their halftime is sponse to physiological overload. It does not lead,
therefore shortened. Resyntheses of individual types neither in cases of its prolongated duration to heart
of protein molecules take place in shorter intervals. failure, and elimination of the etiologic factor makes
The total posssible number of syntheses of individual it completely reversible.
protein molecules of a cardiomyocyte is exhausted Physiological hypertrophy is conceived, regarding
sooner than under physiological circumstances. As the etiologic factor, to include 2 forms of overload.
a result the functional life span of the heart as an Firstly, it is the growth of the heart during the pe-
organ is shortened. riod from birth to adult age (ontogenetic develop-
The above mentioned experimental results differ ment) and secondly an adaptation of the heart to in-
considerably from the clinical situation. The nature creased physical activity. Postnatal development of
of hypertrophic growth to a considerable extent de- the heart represents in principle groundwork a hyper-
124 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

trophic growth which takes place due to an increased point of view such a type of stimulation which evokes
volume load. Volume overload is determined by in- on the nuclear level the expression of those genes
creasing blood volume in the growing organism and which are responsible for the growth of nuclear struc-
thus increased minute volume which represents a re- tures with a short half-life (sarcolemma, mitochon-
sponse to the increase in metabolism of the enlarged dria, sarcoplasmic reticulum). Since these structures
mass of tissues and organs. are responsible for energy production and transport
Increased physical activity can be either of volume of ions as well as electrical activities of a muscular
character when dynamic overload prevails (e.g. speed cell, enhancement of their working capacity acceler-
excercise – running) or of pressure character when ates the formation of actin-myosin connections. This
the pressure overload is dominant (strength excercise increases the contractility of cardiac tissue.
– body-building). The factors determining whether
the physiological or pathological hypertrophy is go-
3.7.6 Hypertrophy and dilatation of
ing to develop are the following:
the heart
• the degree of hemodynamic overload (quantity
of overload) In clinical practice it is quite obvious that the terms
hypertrophy and dilatation are confused and incon-
• duration of hemodynamic overload (quantity of sistently used. It implies from the incompletely set-
overload) tled interpretation of concentric and excentric hyper-
• the character of hemodynamic overload (quality trophies.
of overload) The terms concentric and excentric hypertrophy
have their origin in the endeavour to interprete x-ray
Physiological hypertrophy is apt to develop when findings of an enlarged shadow of the heart. When
the intensity and duration of overload do not exceed the x-ray shadow of the heart is symetrically enlarged
particular measure, when the overload develops grad- while its position in the thorax does not change sub-
ually, and when it is interrupted. stantially, it is referred to as concentric hypertro-
Similarly as in pathological hypertrophy also the phy. The concentric hypertrophy is a synonym to
physiologically hypertrophic heart is able to perform hypertrophy due to pressure overload (viz. fig. 3.12
increased work as a whole. However, controversely to on page 125).
the pathologically hypertrophic heart, the function of When the x-ray shadow of the heart enlarges asy-
each mass unit is normal, or even increased. Hence, metrically (predominantly leftward), it is referred to
improved contractile ability of a physiologically hy- as excentric hypertrophy. Excentric hypertrophy is
pertrophic heart is not determined merely by en- a synonym to hypertrophy due to volume overload.
largement of the muscle mass, but also by simul- Uncertainty resides in the fact that an x-ray pic-
taneous improvement of contractility of each mass ture of an excentrically enlarged heart occurs not
unit. The biochemical fundament resides assumedly only in hypertrophy due to volume overload but also
in the increase in myosin ATP-ase activity (in the in the case of heart dilatation. This is the reason
way of which energy utilization improves) and ob- why the terms excentric hypertrophy and heart di-
viously also in improvement of the transport ability latation are often inconsistently used and mutually
of sarcoplasmic reticulum. The presented biochemi- interchanged. difference is in the fact that in hyper-
cal changes determine especially the improvement of trophy of the volume type beside the enlargement of
systolic heart functions. In a physiologically hyper- the left ventricular volume the ventricular wall be-
trophic heart, moreover conntroversely to the patho- comes thicker. Dilatation includes enlargement of
logical hypertrophy the content of connective tissue the heart in which the ventricular wall becomes ab-
does not increase. This contributes to the mainte- solutely or relatively thinner.
nance of elasticity and thus to sufficient relaxation With respect to the fact as to whether the atten-
during diastole which determines preservation of di- uation of ventricular wall is absolute or relative the
astolic function. dilatation is distinguished as being primary or sec-
Hence, physiological hypertrophy represents a ondary.
fully adequate growth of myocardial tissue. In-
creased physical exercise represents from the genetic • Primary dilatation develops when the ventricle
3.7. Hypertrophy of the heart – mechanism of adaptation to chronic hemodynamic overload (F. Šimko) 125

Figure 3.12: Hypertrophy and dilatation of the heart

distends in consequence of acute overload. As a large), it stimulates by means of increased ventricu-

result the ventricular wall becomes thinner than lar wall stress its hypertrophic growth). Secondary
in physiological state (viz. fig. 3.12 on page 125). dilatation develops after the compensatory mecha-
nisms become exhausted and represents the cardiac
• secondary dilatation (viz. fig. 3.12 on page 125) failure.
develops when the heart which is already hyper-
trophic due to chronical hemodynamic overload Fundamentally both forms of dilatation, however,
begins to fail. The ventricular volume enlarges can be considered (to a particular extent) as compen-
and the already hypertrophic wall becomes thin- satory mechanisms. It resides in the fact that the ab-
ner ( in comparison to its hypertrophic width). solute size of the ejection volume at the enlarged ra-
dius of the ventricle (because Frank-Starling’s mech-
Primary dilatation can end up in compensatory anism comes into play) increases in spite of a signifi-
hypertrophy (when the developed overload is of cant decrease in contractility. Dilatation is though at
long-term character providing it is not inadequately the same time disadvantageous as there is an enor-
126 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

mous tension in the ventricular wall, namely not only The majority of cases yields a simultaneous devel-
during diastole, but also in consequence of decreased opment of both types of valvular lesions.
contractility during systole. As a result this type Valvular lesions can be inborn or acquired. Ac-
of maintenace of the minute volume is very uneco- quired valvular lesions develop most frequently due
nomical. The excessive tension in the ventricular to rheumatic fever. Less frequently they can develop
wall replenishes energy of the heart, and its pump- in consequence of bacterial endocarditis, syphilis and
ing function in spite of maximal utilization of Frank- at an older age degenerative changes as valvular fi-
Starling’s mechanism definitely fails. brotization and calcification.

3.8.1 Mitral stenosis

Stenosis of the mitral valve develops predominantly
in consequence of rheumatic endocarditis. It devel-
3.8 Valvular defects ops in the course of several years following the attack
of the rheumatic fever. In consequence of immunoal-
of the heart terative inflammatory process the free margins of the
mitral valve stick together. The mitral orifice which
is in an adult person 4–6 cm2 in surface diminishes.
The clinical picture depends upon the degree of nar-
The role of both atrioventricular and semilunar rowing of this orifice.
valves is to assure an interrupted movement of the The hemodynamic disturbance manifests itself
blood in the direction from atrii toward the aorta during ventricular diastole when the blood flows from
or a. pulmonalis. In dependence on the degree and the left atrium into the left ventricle. Moderate
speed of the development the valvular disorder has a stenosis of the left AV orifice does not manifest itself
distinct impact on organism. A moderate degree of hemodynamically. It is the stenosis below 2,0 2 when
a valvular lesion does not entail any hymodynamic the blood flow from the left atrium into the left ven-
changes. The only symptom may be an ausculta- tricle deteriorates. The subsequent consequence is
tion finding, sometimes it is even entirely symtom- represented by accumulation of the blood in the left
less. On the other hand a severe anatomical valvu- atrium with a subsequent elevation of atrial pressure.
lar change can lead to a significant deterioration of The character of the diastolic filling of the left ventri-
hemodynamics and to alteration of the health state cle substantially alters. A normal diastole has three
of a patient. An especially dramatic clinical picture phases:
develops when the severe valvular lesion supervenes
rapidly. The resultant clinical picture is moreover 1. The phase of rapid filling of ventricles when af-
determined also by the functional reserve of the car- ter the opening of AV valves the ventricles are
diac muscle. dumped with 80 % of the total amount of in-
Two types of valvular lesions are distinguished: flowed blood.

• valvular stenosis – manifests itself in that phase 2. The first phase is followed by the phase of dias-
of the cardiac cycle, when the valve is closed tasis. The elevated pressure in the left ventricle
and the blood is thus propelled via a narrowed encloses the AV valve nearly completely, and the
orifice. blood flow into the ventricle soon ceases.

• valvular insufficiency – manifests itself in the 3. The third phase is the period of atrial systole;
phase of the cardiac cycle when the valve is to during this time the remnant 20 % of the filling
be closed; in consequence of imperfect packing volume of blood is forced into the ventricle
of the valvular orifice a part of the blood regur-
gitates into the precedent compartment of the The stenosis of the mitral valve disturbs the three
heart. - phase character of the diastolic filling. The blood
during diastole flows but gradually via the narowed
Pure valvular stenosis or insufficiency are rare. orifice into the left ventricle. In consequence of high
3.8. Valvular defects of the heart (F. Šimko) 127

pressure in the left atrium during diastole there is a sidered to protect the lungs against the pulmonary
large pressure gradient between the left atrium and edema:
ventricle. The ventricle is being filled in a slow even
manner during the entire diastole. The ventricle is 1. Significant thickening of alveolocapillary mem-
being filled for a longer period and under a higher brane, which acts as a barrier against the en-
pressure gradient. Providing the stenosis is not too trance of fluid into alveoli.
tight such a filling assures a normal diastolic volume
2. The enhanced resistance in pulmonary arteri-
of the left ventricle.
oles which is both functionally and later also
Tachycardia accompanying the physical exercise anatomically determined. Functional vasocon-
substantially deteriorates the hemodynamic situa- striction originates due to hypoxaemia in con-
tion in the heart afflicted with mitral stenosis. In- sequence of the deteriorated ventilation of the
crease in frequency hence takes place chiefly on lungs which are overfilled with blood. Aside
the account of diastole which becomes significantly from this, pressure elevation in pulmonary veins
shorter. Thus the period of the left ventricular fill- and capillaries alone which is brought about
ing becomes shorter. Tachycardia deteriorates the by stimulation of vascular receptors, reflexively
left ventricular filling in a heart afflicted with mitral evoke spasms of arterioles. Prolonged dura-
stenosis in a greater extent than in a heart with a tion of pressure elevation in a.pulmonalis brings
normal mitral orifice. The substantial part of the about morphologic changes as well. They man-
blood in a normal heart (app. 80 % of the total vol- ifest themselves by the thickening of intima and
ume of inflowed blood) reaches the ventricle during media.
the first phase of diastole. Therefore the shortening
of the diastolic period in tachycardia decreases the Increase in resistance in pulmonary arterioles has
diastolic filling of the ventricle in a healthy heart to a both positive and negative impacts on the heart. The
proportionally only a little. In contrary to the latter positive implication resides in a decreased supply of
the stenosis of the mitral orifice entails a continu- blood into the lungs which inhibits the origin of pul-
ous filling of the ventricle during the entire diastole monary edema. On the other hand the increased
and therefore shortening of diastole significantly de- resistance in the pulmonary arterioles elevates the
creases the end-diastolic volume of the left ventricle. pressure in a. pulmonalis and in the right ventricle.
As a result the right ventricle fails, the blood supply
The situation deteriorates also due to the advance-
into the lungs is decreased and the dyspnea with-
ment of the mitral stenosis. As a result, the fill-
draws. The life of a patient is prolonged on the ac-
ing of the left ventricle is reduced diminishing thus
count of the reduced minute volume of the left side
the stroke volume. (forward failure). Simultaneously
of the heart and right ventricular failure. The qual-
the pressure in the left atrium, pulmonary veins and
ity of a patients life with a severe mitral stenosis is
pulmonary capillaries elevates. It manifests itself as
therefore significantly decreased.
dyspnea of various degree up to pulmonary edema
The chief clinical symptom of mitral stenosis is
(backward failure). The symptoms resemble those
dyspnea. The degree and character of dyspnea have
of the left side heart failure. Conversely to the left
similar character as in left ventricular failure. The
ventricular heart failure in which the left ventricle is
degree of dyspnea correlates with the size of the mi-
dilated the left ventricle in mitral stenosis is of nor-
tral orifice surface and pressure in the left atrium.
mal size or even atrophic as it works with smaller
Reduction of the orifice to 0, 5 cm2 results in very
amount of blood. The minute volume is decreased in
high pressure in the left atrium and pulmonary
severe mitral stenosis. Arterial hypotension reflex-
edema threats to develop.
ively stimulates the sympathetic system. The latter
increases the contractility of the left ventricle and The picture of a severe mitral stenosis includes the
evokes peripheral vasoconstriction in order to assure classical triade of symptoms: embolization into ar-
perfusion of vital organs – the cardiac muscle and terial system, hemoptysis and cyanosis.
brain. • Embolization is caused by turbulent blood flow
Prolonged duration of a severe form of mitral and blood stagnation in the left atrium. The
stenosis evokes pulmonary changes which are con- predilection site of thrombi formation is the
128 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

atrial auricle. This is located aside from the Fatigue and decreased physical performance.
main stream of blood flowing into the left atrium They originate in consequence of the decreased car-
and thus the blood in the auricle almost does not diac output and of decreased minute volume. They
flow. Therefore thrombi originate and may tear are not caused by left ventricular failure. The func-
off causing embolization. Embolization occurs tion of the left ventricle is on the contrary excel-
most frequently in the brain. It can however oc- lent and the ejection fraction is even increased. The
cur in any part of the arterial system (Limbs, low minute volume is determined by insufficient left
kidneys, mesenterial arteries). Embolization of- ventricular filling during diastole. If mitral stenosis
ten occurs repeatedly. develops in children it may result in retardation of
physical and psychical development due to chronic
• Hemoptysis occurs either in the form of minute hypoperfusion of the peripheral tissues.
hemorrhage or as a massive apoplexy. It is Less characteristic symptoms of mitral stenosis
brought about predominantly by rupture of are: dysfagia and hoarse voice (in consequence of
the anastomosis between the pulmonary and compression of oesophagus and nervus reccurens ow-
bronchial veins. Under normal conditions the ing to left atrial dilatation).
blood does not flow through these two veins. In Heart failure and pulmonary oedema occurs most
consequence of retrograde pressure elevation in often in coincidence with tachycardia and tachyfib-
the pulmonary veins the anastomoses open wide rillation of atrii which deteriorate the ventricular fill-
and as their walls are thin they are likely to rup- ing. The cause may reside also in intercurrent infec-
ture. tion which increases the demands of the periphery
to oxygen, or a progression of the mitral valve steno-
• Cyanosis is of cold, acral type. As a result sis in consequence of a prolonged course or repeated
of compensatory peripheral vasoconstriction the attacks of rheumatic fever.
blood flow via capillaries is decreased. On the
basis of tissue acidosis the extraction of oxy-
gen intensifies and thus the amount of reduced 3.8.2 Pathogenesis of clinical symp-
hemoglobin at the venous end of capillaries in- toms
creases. The typical facies mitralis is determined
by means of combination of cyanosis of the lips Auscultation reveals an accentuated first heart
and erhytema of the cheeks. sound, a clap sound due to the mitral valve opening
and holodiastolic murmour with a presystolic accen-
Cases of severe mitral stenosis are frequently tuation.
linked to atrial fibrillation. The reason of atrial fib-
rillation origin is the dilatation of the left atrium • Accentuation of the first heart sound is deter-
and the high intraatrial pressure. According to the mined by several factors. Under normal cir-
Laplace’s law the stress in the atrial wall is thus sig- culmstances at the end of diastole the venntri-
nificantly increased and the energy consumption as cle is filled with blood amd the mitral valve en-
well. The Na+ –K+ ATP-ase fails and numerous ec- closes. If the mitral orifice is narrowed, the end-
topic foci originate in atrii. These represent the basis diastolic content is not large enough to enclose
for the origin of extrasystoles, atrial tachycardia, or the mitral valve. Mitral valve is enclosed as late
if the ectopic foci are numerous, atrial fibrillation as during the rapid ventricular pressure eleva-
may occur. Atrial fibrillation has three basic conse- tion in the phase of isometric contraction. This
quences: sudden enclosure of mitral valve brings about
the accentuation of the first heart sound which
• deterioration of the left ventricular filling is also delayed. Loud enclosure of the mitral
valve is supported also by strong contraction of
• disadvantageous tachyarrhythmia the left ventricle. The latter takes place in con-
sequence of activation of the sympathetic nerve
• stagnation of the blood in the dilated left atrium due to insufficient left ventricular stroke volume
and thus formation of thrombi and peripheral hypotension.
3.8. Valvular defects of the heart (F. Šimko) 129

• The opening mitral tone is determined by an cusps. At an older age calcification is often
abrupt opening of the mitral valve and also by present with consequently restricted movement
fast blood flow into the ventricles in consequence of the cusps.
of the increased atrioventricular gradient. The
opening mitral tone is not audible when the • Fibrous tendons which attach the valves to the
valves are rigid due to their calcification. pappilary muscle – are often calcified or coales-
cent after rheumatic carditis
• The diastolic murmour at the apex is of low-
frequence and lasts throughthout the entire di- • Papillary muscle – is often hypofunctional in is-
astole. The presystolic accentuation is caused chemic heart disease, and infarction may bring
by accelerated blood flow via the narowed ori- about its rupture accompanied with huge regur-
fice in consequence of atrial contraction in the gitation.
final phase of diastole. The presystolic accen-
• Mitral anulus – is dilated in left ventricular fail-
tuation dissappears when atrial fibrillation oc-
ure. Intact valves with preserved movability do
curs. The mourmour is best audible on the left
not manage to to enclose the enlarged mitral ori-
side position. The pulse in mitral stenosis is
fice and the so-called relative mitral insufficiency
small (pulsus parvus) (In consequence of pul-
develops.
monary hypertension the pulmonal proportion
of the second heart sound is usually accentu- The basic functional defect in mitral insufficiency
ated). is the backward flowing of the blood from the left
The methods of imaging detect dilatation of the ventricle into the left atrium during ventricular sys-
left atrium and the small left ventricle. In late phases tole. The left atrium is filled with the blood from the
both the right atrium and right ventricle dilate as pulmonary veins and, surplus, it is filled also with the
well. In consequence of the right ventricular dilata- blood from the left ventricle. An increased volume
tion the anulus of the tricuspidal valve extends and overload of the left atrium is in effect.
a functional tricuspidal insufficiency develops. This During the ventricular diastole the left ventricle
state is referred to as tricuspidal mitral defect. Pul- ventricle receives blood, the amount of which is in-
monary hypertension can determine the functional creased by the volume which had escaped into the
insufficiency of the pulmonal valve. The course of left atrium during the systole. The left ventricle is
the disease depends upon the fact as to whether the thus volume overloaded.
stenosis is deteriorating, as well as upon possible con- During the ventricular systole the blood flows in
commitant complications. The states which deteri- two directions. The insufficient mitral valve lets the
orate the course of mitral stenosis include gravidity excessive amount of blood to regurgitate into the left
(augments the circulating volume), virus infections atrium and the periphery receives a normal amount
(increase the demands of tissues in oxygen), great of blood. The volume which in consequence of mitral
physical exertion. These factors should be avoided insufficiency returns into the left atrium moves in a
by patients. pendulous manner between the left atrium and ven-
tricle. Volume overload inflicts both the left atrium
and left ventricle.
3.8.3 Mitral insufficiency The above mentioned changes result in an in-
Represents the most frequently occuring acquired creased amount of blood in the left ventricle at the
valvular defect. It can occur alone or in combina- end of diastole. It determines left veentricular hy-
tion with mitral stenosis. In dependence on etiology pertrophy development of volume type which com-
various parts of the valve may be afflicted: pensates the presented volume overload:

• The front or back cusps of the mitral valves - 1. The extent of regurgitation is determined fore-
may be deformed in consequence of rheumatic mostly by anatomical changes in the mitral
carditis. The cusps themselves are usually af- valve. Aside form this the backward blood flow
flicted also in the so-called prolapse of mitral depends upon the pressure in the left ventri-
valve, and in an inborn splitting of one of the cle. High ventricular pressure is accompanied
130 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

by a large ventriculo-atrial gradient. Therefore, of large volume which the left ventricle has to pro-
all the states which elevate the intraventricular cess and also of dysrhythmias present. Hemoptoe,
pressure (hypertension, stenosis or aortic coarc- embolization, cyanosis and fibrilation occur less fre-
tation) augment the reflux of blood into the quently than in mitral stenosis. Severe regurgitation
atrium even in moderate degree of mitral insuf- entails congestion in the pulmonary circuit and pul-
ficiency. monary edema and later even dilatation of the right
compartments of the heart with triculspidal and pul-
2. The state of atrial musculature. Providing the monary insufficiencies.
atrial musculature is of optimal elasticity and The auscultatory finding is characterized by the
contractile state, the left atrium ”resists” to first heart sound being weak and a blowy holosys-
the excessive delivery of blood by increasing its tolic murmour.
tonus. The pressure in atrii and pulmonary
veins thus elevates. On the contrary the atrii • The attenuation of the first heart sound develops
afflicted with degenerative processes and thus as a result of imperfect enclosure of a deformed
having their musculature partially substituted mitral valve during ventricular systole.
with afunctional connective tissue dilate in con-
• The murmour is soft, blowy and of low fre-
sequence of overload in the blood volume, but
quence. It develops as soon as during isometric
the atrial pressure does not elevate significantly.
contraction of ventricles when the pressure in
Under these conditions regurgitation of blood
the left ventricle exceeds the pressure in the left
manifests itself by an enlarged left atrium and
atrium. It lasts throughout the entire systole
but a small increase in pressure in pulmonary
and overlaps the beginning of diastole. Its inten-
veins and capillaries.
sity is maintained on the same level throughout
the whole systole. It is best audible at the apex
3. The velocity of mitral insufficiency development.
and propagates into the direction of axilla. The
Gradual enlargement of mitral regurgitation ex-
intensity of the murmour is well correlated with
poses the left atrium to an increased delivery of
the degree of regurgitation. The second heart
blood. The left atrium accomodates to this sit-
sound is in case of pulmonary hypertension split
uation by hypertrophy and dilatation, by virtue
with an accentuation of its second component.
of which the pressure in pulmonary beds elevates
but moderately. Sudden infliction with mitral The prognosis depends upon the degree of hemo-
regurgitation (rupture of the papillary muscle dynamic change, the progression of the disease and
due to infarction, perforation of a valve due to upon the complications. The disease is deteriorated
bacterial endocarditis) abruptly elevates pres- by intercurrent infections (the demands of the pe-
sure in an unprepared left atrium. The pressure riphery put on the heart work increases), tachyfib-
elevation is conveyed into the pulmonary capil- rillation of atrii (diastole shortens and the overfilled
lary bed and pulmonary edema develops. left ventricle insufficiently evacuates) and repeated
attacks of rheumatic carditis (incompetence of valvu-
3.8.3.1 Pathogenesis of clinical symptoms lar enclosure deteriorates).

It is generally known that the individual heart parts

can cope easier with volume than with pressure over-
3.8.4 Aortic stenosis
load. This can be applied also as far as mitral insuffi- Aortic stenosis develops most frequently as a result
ciency is concerned. The symptoms due to mitral in- of rheumatic fever. Less frequently represents a con-
sufficiency are therefore similar but less serious than sequence of sclerotic changes in valves, or bacterial
symptoms due to mitral stenosis. endocarditis. Stenosis of the aortic valve often oc-
Small mitral insufficiency manifests itself solely by curs together wit aortic insufficiency or mitral steno-
an auscultatory finding. However, danger impends sis. The surface of the aortic mouth which is in an
in the origin of bacterial endocarditis on an anatomi- adult app. 3,5 cm2 diminishes. The clinical picture
cally altered valve. Palpitations frequently represent depends upon the degree of the aortic valve narrow-
an initial symptom. They develop in consequence ing.
3.8. Valvular defects of the heart (F. Šimko) 131

Hemodynamic impairment manifests itself during gradual onset of the triade symptoms: angina pec-
systole of ventricles when the blood is ejected from toris, syncope, left heart failure. In addition there is
the left ventricle into the aorta. Moderate narowing a significant risk of sudden death in these patients.
of the aortic orifice has not any hemodynamic mani-
festation. Yet, aortic narowing down to 50 % or even 1. Angina pectoris originates in consequence of
25 % invalidates the blood flow from the left ventricle oxygen insufficiency. A combination of sev-
into the aorta. The resistance against blood ejection eral factors participates in the latter: decreased
increases. According to LaplaceÝs law the systolic aortic diastolic pressure and thus decreased
tension in the wall of the left ventricle, i.e. after- coronary perfusion pressure, increased pressure
load, increases. Such gradually developing increased work of the heart, and quite often concomittant
pressure overload is compensated by left ventricular aterosclerosis of coronary arteries in older pa-
hypertrophy. The left ventricular wall thickens, but tients.
its internal volume does not change. Hence hyper- 2. Syncopes originate mostly due to physical work.
trophy originates being of pressure type and referred They are the consequence of the left ventric-
to as concentric hypertrophy where the ratio of the ular inability to increase the heart ejection in
wall width to ventricular volume changes in favour order to fulfil the increased oxygen demands
of wall width. Hypertrophy has two basic impacts: of periphery. Muscular strain causes that the
ejected blood is preferentially moved into the
1. The wall stress returns to original values.
dilated muscular vascular bed with consequent
hypotension and cerebral hypoxia. Cerebral hy-
2. At the same time the total left ventricular con-
poperfusion results in vertigo and collapse.
tractile ability improves. Left ventricle is thus
able to force the blood via constricted orifice and 3. Aortic stenosis can reach a stage in which de-
secure adequate pumping function of the heart spite compentatory hypertrophy of the left ven-
against increased resistance. tricle the stroke volume decreases and the blood
begins to stagnate in the left ventricle. Gradu-
Despite the secured adequate perfusion of periph- ally a complex picture of left ventricular fail-
ery, the situation in the heart is substantially altered. ure develops. Left ventricular failure is in-
Both systolic and diastolic pressures increase in the cluded among late symptoms and signalizes in-
left ventricle. The systolic pressure reaches enor- favourable prognosis.
mous values – 200 to 300 torr. Intraventricular pres-
sure during systole mounts more steeply and reaches 4. The late stage of aortic stenosis with developed
the peak sooner than under physiological conditions. stenocardia yields a high risk of sudden death.
There is a great pressure gradient between the left It originates mostly due to physical strain. As
and right ventricles. The systolic pressure in aorta the blood flows preferentially into the working
achieves lower values and increases less rapidly than muscles, it may even deepen the myocardial hy-
under physiological conditions. poxia. Numerous ventricular ectopic foci orig-
Also the diastolic pressure in the left ventricle is inate with high risk of ventricular fibrillation.
increased. This is a consequece of the loss of elastic- Ventricular fibrillation or a pronounced cerebral
ity of the left ventricle due to its increased thickness. hypoxemia represent the direct cause of sudden
Due to this situation the normal end-diastolic pres- death.
sure does not evoke adequate expansion of walls, it
The ausculatation finding in aortic stenosis is char-
causes though excessive growth of end-diastolic pres-
acterized by a systolic ”clapp”, rasp loud ejection
sure.
murmour with its maximum above aorta (second in-
Owing to compensatory hypertrophy the pumping tercostal space parasternally on the right) and weak-
activity of the heart as a whole is maintained and
ened second heart sound.
patients need not suffer from any difficulties for a
rather long period of the disease. • The systolic ”clapp” has an analogic reason as
Pathogenesis of clinical picture. Clinical picture the mitral opening tone. It originates by abrupt
in cases of severe aortic stenosis is characterized by opening of the aortic valve in consequence of
132 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

a great gradient between the left ventricle and symptoms (stenocardia, collapse, or left ventricular
aorta. failure) occur, it means that the compensatory abil-
ities of the heart are exhausted. The prognose is
• The typical rasp murmour is propagated into hence restricted to a period of three or four years.
carotids, to the apex and into interscapular In such a stage the only solution which prolongs a
space. It is of crescendo decrescendo (spindle) patient’s life significantly and improves its quality is
character. Chronologically it is localized into an operation.
the meso or even telesystole. It is more pro-
nounced in a sitting leaning forward posture,
3.8.5 Aortic insufficiency
and and with the breath held at the end of ex-
piration. Aortic insufficiency occurs either alone, or more fre-
quently in combination with aortic stenosis or mitral
The typical spindle shape of this murmour is defect. The most frequent cause is rheumatic fever,
caused by the fact that at the beginning and at the less frequently aterosclerosis of the valvular cusps,
end of ejection period of systole the pressures in the bacterial endocarditis and syphilitic aortitis. The
left ventricle and in aorta are nearly the same with aneurysm of ascendent aorta brings about dilatation
a relatively small gradient through the aortic orifice. of the aortic annulus and results in insufficient en-
The blood flow is minimally turbulent and both at closure of the aortic orifice by intact valvular cusps.
the beginning and end of ejection the murmour is The basic functional impairment in insufficiency of
weak. During the ejection the pressure in the left aortic valve is represented by reverse blood flow from
ventricle elevates to the maximum. The pressure gra- aorta back into rhe left ventricle during the ventricu-
dient grows, turbulent flow originates and the mur- lar diastole. The left ventricle is filled simultaneously
mour reaches its maximum. During the second part by both the blood from the left atrium and regurgi-
of ejection the gradient is of declining character, the tated blood from aorta. The latter fact thus increases
turbulence decreases and thus also the intensity of the volume load of the left ventricle.
the murmour. During the ventricular systole the aorta receives
The chronologic localization of this murmour into an amount of blood increased by the volume which
the mid and late phase of systole originates in conse- regurgitated into the left ventricle during systole. In
quence of stenosis of the aortic orifice. The smaller this way also the aorta is overloaded and its dilata-
the orifice, the later the sufficient pressure elevation tion may arise.
in the left ventricle is achieved in order to force the The blood in aorta thus flows in two directions dur-
blood through the stenotic orifice. ing diastole. Via the incompletely closed aortic valve
The weakening of the second heart sound is deter- the ”excessive” volume of blood returns into the left
mined by slow pressure elevation in aorta. In conse- ventricle and the periphery receives a normal amount
quence of this the closure of aortic valve is not rapid, of blood. The volume which in consequence of aor-
but gradual, which fact deprives the intensity of the tic insufficienxy returns into the left ventricle moves
second heart sound. therefore pendulously between the left ventricle and
Palpation above aorta reveals a rasp scratching aorta.
whirl. It has the same localization and propagates The presented alterations result in increased
itself into the same areas as the murmour. It is de- amount of blood in the left ventricle at the end of
termined by the turbulent blood flow. diastole. In consequence of volume overload the in-
The peripheral pulse is small, with a slow growth ternal volume of the ventricle increases and the ven-
and decline (similarly as the intensity of murmour) – tricular wall less markedly thickens. The ratio of
the so-called pulsus parvus and tardus. It is delayed ventricular volume to the wall width shifts in favour
after the apex beat, which coincides with the delayed of the volume. Hypertrophy of the volume type –
increase in aortic pressure. excentric hypertrophy develops which compensates
During the period of many years the patients with the volume overload for a long period (10–30 years).
aortic stenosis do not suffer from any difficulties. The The regurgitated amount of blood can represent
left ventricle, being the strongest compartment of the 30–70 % of the stroke volume. The hypertrophic
heart has a great ability of compensation. When the left ventricle reaches enourmous size and weight of
3.8. Valvular defects of the heart (F. Šimko) 133

700–1000 grammes. The working capacity of the on the right). It propagates into Erb’s point – third
heart markedly increases. The stroke volume of the to fourth intercostal space parasternally on the left
left ventricle inclusive of the regurgitated component approximately 3 cm from the sternum. It has a high
can reach 300 ml, which corresponds with a minute frequence decrescendo character. Chronologically it
volume of 30 l. This cardiac output resembles the is localized into the proto- and mesodiastole. It is
maximal output of a trained sportsman. It suggests more pronounced at a leaning forward sitting pos-
that the maximal cardiac working capacity is approx- ture with a breath held at the end of exspirium. The
imately equal under physiological and pathological first heart sound is attenuated. It is caused by a pre-
circumstances. mature enclosure of the mitral valve as a consequent
The pressure conditions in the left ventricle de- of high intraventricular pressure, owing to which the
pend on the size of regurgitation, state of ventricular mitral component does not participate in the ori-
musculature and frequence of contractions. gin of the first heart sound. Also the second heart
sound can be weakened. In this case the weakening
1. The size of regurgitated volume depends on the is caused by incomplete enclosure of the deformed
severity of the valvular defect. In addition to aortic valve.
that the regurgitation increases paralelly with Severe aortic insufficiency produces a diastolic
the increase of arterial pressure. Flint-Austin’s murmour audible over the apex. It
2. The left ventricular wall hypertrophy itself de- resembles the murmour audible in mitral stenosis.
teriorates the elastic properties and at the given On the contrary to mitral stenosis the accentuated
end-diastolic volume the ventricular pressure first sound is not present, neither the mitral opening
thud increases. tone. The origin of this murmour can be caused by
several factors:
3. The increased frequency shortens the whole car-
diac cycle, and especially the diastole. Tachy- • Relative mitral stenosis is caused by enclosure
cardia thus restricts regurgitation and decreases of one of the mitral valve cusps by the regurgi-
the diastolic pressure. In this disease tachycar- tating flow.
dia may act as a certain compensatory mecha- • Premature enclosure of mitral valve by high in-
nism. traventricular pressure.

3.8.5.1 Pathogenesis of clinical symptoms • Collision of the mitral and regurgitation

streams.
Clinical symptoms are similar but less pronounced
than in aortic stenosis and have also a similar patho- The systolic pressure is in consequent of large
genesis. Angina pectoris, syncopes, left ventricular stroke volume high. The diastolic pressure is on the
failure, sudden death occur relatively late and man- contrary very low and in severe insufficiency drops to
ifest a severe stage of the disease. Earlier symptoms zero. The decrease in diastolic pressure is caused by
include: regurgitation of blood into the left ventricle on one
hand and peripheral vasodilatation on the other.
1. Palpitations, which coincide with a large sys- Pressure changes correspond with the character of
tolic stroke volume, strong pulsation of the left pulse. The pulse quickly reaches high values and
ventricle and ventricular extrasystoles. rapidly declines – pulsus celer et altus.
2. The consequences of peripheral vasodilatation. Enormous progressive movement of the blood dur-
In consequence of high systolic pressure the pe- ing systole and retrograde movement of the blood
ripheral vessels reflexively dilate. The patients during diastole manifest themselves as a Musset’s
suffer from vertigo, increased perspiration and symptom (rhythmic movement of the head simulta-
do not tolerate heat. neously with each ventricular systole) and Quincky’s
capillary pulsation (cyclic reddening and paling of
Auscultation finding is characterized by the di- the nail’s bed and skin of fingers). The develop-
astolic decrescendo blowing murmour, best audible ment of the disease and prognose are similar to those
above aorta (second intercostal space parasternally in aortic stenosis. The hypertrophic left ventricle
134 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

compensates the volume overload for decades. The mour with a weakened first heart sound. It is typical
patients even manage physical strain. This situa- of this murmour that it intensifies in inspirium, when
tion implies that tachycardia which is concomitant to the blood supply from the capacity bed into the right
physical exertion, shortens the diastole and thus also heart increases.
regurgitation and to a certain extent has a compen-
satory impact. Occurrence of symptoms shortens the 3.8.6.2 Tricuspidal stenosis
survival to 3-4 years. Deterioration of clinical state
is entailed especially by progression of the primary Tricuspidal stenosis occurs as a consequence of
disease and thus increased regurgitation and by po- rheumatic fever together with mitral or aortic valvu-
tential setting of bacterial endocarditis. Experimen- lar defects. Stenotic valve inhibits the inflow of the
tal and clinical studies suggest that also unchanging blood into the right ventricle during diastole. The
extent of regurgitation may result in left ventricular blood accumulates in the right atrium which fails.
failure after prolonged duration of the disease. The clinical picture resembles that of tricuspidal in-
sufficiency.
Obstruction of the tricuspidal orifice evokes regur-
3.8.6 Valvular defects of the right gitation of the blood from the right atrium into the
heart jugular veins causing thus their pulsation. This state
3.8.6.1 Tricuspidal insufficiency is referred to as atrial venous pulse.
Auscultation reveals diastolic murmour which is of
Tricuspidal insufficiency is in most cases a relative a similar character as that audible in mitral stenosis.
valvular disorder. It may be seen in the connection It is though localized at the inferior border of the
with right cardiac failure with consequent dilatation sternum.
of the right ventricle. This situation causes dilata-
tion of the annulus of tricuspidal valve and thus a
3.8.6.3 Insufficiency of the pulmonary valve
complete enclosure of the valve becomes impossible.
The right atrium is thin and has a small compen- Pulmonary insufficiency rarely originates on the ba-
satory ability. It relatively quickly fails and signes of sis of rheumatic or bacterial endocarditis. Predom-
blood congestion before the right heart develop. inantly it occurs as a relative-functional incomplete
The clinical manifestation of the disease results enclosure in states with pulmonary hypertension and
from stagnation of the blood in the systemic circuit: dilatation of pulmonary arteria which bring about
increased content of jugular veins, hapatomegaly, distension of the pulmonary annulus.
hepatojugular reflux, oedema, ascites. Palpably re- The ausculatation finding is similar to that in aor-
vealed manifestations include systolic pulsation of tic insufficiency. It is characterized by a blowing,
the liver which originates by transfer of the re- proto- and mesodiastolic murmour being of high fre-
gurgitation wave into hepatic veins. Stagnation of quency, (Graham-Steel’s murmour). It is best audi-
the blood in the liver deteriorates the hepatic func- ble above the pulmonary artery, i.e. above the sec-
tion. Hepatocellular icterus arises and symptoms of ond intercostal space parasternally on the left. The
haemorrhage originates in consequence of decreased second sound is weakened in consequence of the de-
production of blood clotting factors. Dyspepsia orig- formed pulmonary valve.
inates as a result of stagnation of the blood in the
digesting tract. A symptom of severe right heart fail-
3.8.6.4 Stenosis of pulmonic valve
ure is considered a rapid withdrawal of dyspnea in
patients with left ventricular failure. This situation It is rare and originates in consequent of rheumatic
occurs in consequence of deteriorated pumping func- endocarditis. The right ventricle becomes hyper-
tion of the right ventricle. This results in decreased trophic. Its compensatory abilities are though sig-
blood supply into the lungs and decreased capillary nificantly smaller than in case of the left ventricle.
pulmonary pressure. Right heart failure takes place relatively fast. The
Ausculation finding resembles that of mitral insuf- auscultation finding resembles that of aortic stenosis
ficiency but is localized at the inferior left border of – it is a systolic, loud, scratchy murmour which is of
the sternum. It is a holosystolic, soft, blowing mur- crescendo-decrescendo character. It is best audible
3.9. Cardiomyopathies (F. Šimko) 135

above the pulmonary artery. The second sound is Let simultaneous occurrence of more of them, un-
weakened in consequence of deformation of the pul- known etiology of the particular state of the heart
monic valve. and an echographic finding of dilated heart enable to
state the diagnosis of dilating cardiomyopathy. The
most important features of this disease include:

• dilatation of the left ventricle, alone, or in con-

nection with dilatation of the left atrium and
right compartments of the heart.
3.9 Cardiomyopathies
• diffuse impairment of the kinetics of the left ven-
tricular walls (sometimes the same can be ap-
plied by the right ventricle)
Cardiomyopathies represent a group of heteroge-
nous diseases of the heart which involve a chronic, • significant reduction of systolic cardiac function
idiopatic pathologic process inflicting especially the • formation of thrombi in hypokinetic compart-
cardiac muscle. The group of cardiomyopathies in- ments of the heart with subsequent embolization
cludes neither ischemic nor inflammatory impair-
ment of myocardium. • impairments of cardiac rhythm which may be of
The term cardiomyopathies (respectively myocar- malign character (ventricular tachycardia, ven-
diopathies) has currently a significantly different tricular fibrillation)
meaning in comparison with its original content. It
was a tradition to distinguish coronary and noncoro- • heart failure
nary cardiomyopathies. Coronary cardiomyopathies
The given set of signs originates in consequence
included diffuse ischemic impairment of the cardiac
of primary impairment of cardiac contractility. In
muscle. Noncoronary cardiomyopathies included
consequence of impaired contractility the pumping
nonischemic impairments of myocardium, namely
function of the heart decreases. The ejection fraction
those with unknown etiology (primary cardiomy-
decreases from normal 60–70 % to extremely low val-
opathies), or secondary affliction of the cardiac mus-
ues – often just 15–20 % and first symptoms of left
cle in the frame of a particular extracardiac disease
ventricular failure appear. The right ventricle can
(secondary cardiomyopathies).
fail in consequence of primary failure of the left ven-
Nowadays cardiomyopathies are comprehended as
tricle by propagation of pressure into the pulmonary
noncoronary diseases of the cardiac muscle with un-
artery, or it can fail at the beginning of the disease
clear etiology. If the myocardium is afflicted in
simultaneously with the left ventricle. In sporadic
the frame of extracardiac primary disease we speak
cases the left ventricle begins to fail as first.
about specific diseases of the cardiac muscle (these
Marked dilatation of ventricles yields mitral or tri-
are not included into cardiomyopathies).
cuspidal insufficiency in consequence of dilatation of
Currently the classification of cardiomyopathies is the left atrioventricular valve annulus. These valvu-
accepted including three basic types: lar defects lead to further volume overload of the
• dilating cardiomyopathy heart and enhance heart failure.
Thrombi originate in any of dilated heart com-
• hypertonic cardiomyopathy partments in consequence of stagnation of the blood.
They may tear off and cause embolism in the arte-
• restricting cardiomyopathy rial bed (in case of their left heart origin) or pul-
monary bed (if they come from the right heart com-
3.9.1 Dilating cardiomyopathy partments). Consumption of ATP increases in the
dilated ventricles with increased wall stress, and ec-
Dilating cardiomyopathy is characterized by several topic foci of electric activity originate. In this way
typical properties which are however not specific and extrasystoles, tachycardia, resp. atrial or ventricular
can occur in different types of heart impairments. fibrillations occur. In consequence of fibrotic changes
136 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

which may inflict also the septum, various degrees of 3.9.2 Hypertrophic cardiomyopathy
blocks are brought about. Gallop rhythm often de-
velops in hemodynamically overloaded heart. This type of cardiomyopathy is characterized as fol-
lows:
Despite the intensive experimental and clinical re-
search the cause of dilating cardiomyopathy remains • Asymetric hypertrophy of the left ventricle. The
unclear. The histologic picture is characterized by left ventricle is usually not diffusely thickened
minute focal fibrosis. The latter occurs in many (as in aortic stenosis and hypertension disease),
types of chronic impairments of the heart and does but hypertrophy of a particular part of the sep-
not contribute to elucidation of the etiology of con- tum or left ventricle are developed.
tractility impairment. The possible etiologic factors
include: • Expressive impairment of the left ventricular re-
laxation ability. Deterioration of diastolic func-
• genetic predisposition tion is caused by both the thickening of the mus-
culature and increased mass of connective tissue
• immunoalterating process in the myocardium

• damage caused by chemical substances (conser- • Reduction of the left ventricular cavity in con-
vation substances, alcohol) sequence of wall hapertrophy

• Excellent contraction of the left ventricle, the

• heavy metals
ejection fraction of which is higher than 80 %
• hormonal impairments • The character of histologic picture of hyper-
trophic parts. The thickened parts are charac-
Dilating cardiomyopathy may develop in the case teristic by irregular crossing of muscular fibers
when reverse potential etiologic factors act together. (so called zig-zag picture) in contrast to parallel
Chronic alcoholism can serve as an example. Ethy- course of muscular fibers seen under physiologi-
lalcohol and its metabolic products have a toxic im- cal conditions.
pact especially on mitochondria reducing thus energy
production. Some specific components of alcoholic Hypertrophic cardiomyopathy is an autosomally
drinks may also have toxic influence on myocardium. dominant disease. The genetic predisposition how-
Cobalt which has been used in some countries in or- ever manifests itself solely in some cases. The fam-
der to improve the quality of beer froth is included ily histories of patients often yield cases of positive
among such substances. Moreover, chronic alcoholics genetic basis where hypertrophic cardiomyopathy is
substitute a major part of their caloric intake by lacking. The genetic basis may manifest itself as a
alcohol which brings about the deficit of essencial clinical disease providing there is an accord of both
aminoacids, important vitamins especially those of the genetic basis and particular external etiologic fac-
the B group, and impairment of ion balance. In spite tors.
of this cardiomyopathy does nor develop in a major- The main sign of hypertrophic cardiomyopathy is
ity of alcoholics. Cardiomyopathy develops probably the hypertrophy of some part of the left ventricular
only in persons with a particular genetic perdisposi- musculature. The diagnosis can be predominantly
tion or those with altered myocardium due to prece- stated on the basis of echocardiographic examina-
dent inflammation or immunoalterative process. It is tion. Some cases however yield an echocardiographic
assumed that although the inflammation had healed, finding which is not explicit and solely on the basis
the heart became permanently more sensitive to neg- of family history, imaging examinations and respec-
ative external factors (e.g. alcohol, medicaments). tively bioptic examination of the myocardium it is
Dilating cardiomyopathy has a progressive char- possible to build the diagnosis of hypertrophic car-
acter and infavourable prognosis. As the etiology of diomyopathy.
the disease is not known yet, the therapy is predom- Two basic types of hypertrophic cardiomyopathy
inantly symptomatic. are distinguished:
3.9. Cardiomyopathies (F. Šimko) 137

1. type with obstruction (formerly called idiopatic obstruction does not develop in those types of hy-
hypertrophic subvalvular stenosis) pertrophic cardiomyopathiy in which hypertrophy of
the septum is lacking.
2. type without obstruction
Hypertrophy of the septum, respectively of further
1. Obstructive type – is characterized by the parts of the left ventricle does not develop on the
narrowing of the outflow tract of the left ventricle. basis of obstruction with subsequent hamodynamic
As this obstruction is not of permanent character but overload. It is a genetically determined thickening
manifests itself only during systole we refer to func- of the left ventricular walls. The developed hyper-
tional type of obstruction. Two factors participate trophy thus results in specific anatomical and func-
in its development: tional changes in the outflow tract of the left ventri-
cle, which is ultimately manifested as obstruction.
• Hypertrophy of the proximal part of the inter-
ventricular septum. This part of the septum 2. Hypertrophic cardiomyopathy without ob-
thickens during systole to such an extent that struction is characterized by hypertrophy of various
it causes stenosis of the outflow tract of the left parts of the left ventricle. This type of disease is not
ventricle. accompanied by obstruction of the left ventricular
outflow tract.
• The second factor which participates in obstruc-
tion is the systolic anterior movement of the mi-
tral apparatus (systolic anterior motion-SAM).
During systole the anterior cusp of the mitral 3.9.2.1 Pathomechanism of clinical symp-
valve and often also the whole mitral apparatus toms
move towards the thickened septum which sup-
ports even more the stenosis of the outflow tract
The clinical picture of the obstructive hypertrophic
of the left ventricle caused by the thickening of
cardiomyopathy resembles aortic stenosis: stenocar-
the septum.
dia, collapse, heart failure, sudden death. Pathome-
Pathomechanism of the systolic anterior motion of chanism of these signs is similar to that of the men-
the mitral valve as well as the impact of this phe- tioned valvular disorder.
nomenon on the development of obstruction is a fre- Auscultation reveals a rough ejection murmour
quently discussed problem. It is assumed that SAM sound in the second half of systole which is in com-
is rather a hemodynamic consequence of the stenotic parison with aortic stenosis localized parasternally
outflow tract than its cause. Hypertrophy of the sep- on the left and in the area of the apex.
tum results in gradient between the left ventricle and
aorta during systole. The blood flows faster through In the recent years studies have appeared which
the stenotic orifice which results in relative under- revealed the so-called hypertrophic cardiomyopathy
pressure in comparison with the pressure within the without hypertrophy. The heart of those patients is
inflow part of the left ventricle. Consequently the not hypertrophic. They have however a positive fam-
whole mitral apparatus (especially the anterior cusp ily history and the histologic picture of a part of left
which is located mostly proximally) is being drawn ventricle is characterized by typical crossing of the
towards the site of underpressure. The nearer is the muscular fibres. It is not clear yet as to whether a la-
mitral valve to the septum, the more expressive is the tent - histologic form of disease is involved or whether
obstruction, the faster is the blood flow and the un- each clinical disease is initiated regulary with histo-
derpressure pulling the mitral valve toward the sep- logic changes.
tum grows. Consequently the anterior motion of the The prognosis is uncertain. Hypercontractility of
mitral valve becomes more expressive. The presented hypertrophic areas in some patients decreases to,
facts imply that the mitral anterior motion is rather or below normal and also the ejection fraction de-
a concomitant sign and a factor supporting the devel- creases. The heart does not dilate, but the deteriora-
opment of obstruction. The primary factor causing tion of systolic abilities manifests itself by increased
obstruction is the thickening of the proximal septum. intraventricular pressure and pulmonary blood stag-
The fact which supports the hypothesis is that the nation.
138 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

3.9.3 Restrictive cardiomyopathy tricular cavity and contributing to the restriction of

ventricular filling.
This group includes two diseases. Endomyocardial
It is assumed that endocardial fibrosis is an ac-
fibrosis and fibroelastosis of the myocardium.
quired disease which develops on the basis of infec-
tious or immunoalterative inflammation.
3.9.3.1 Endomyocardial fibrosis
The disease occurs in tropical regions at the equator. 3.9.3.2 Fibroelastosis of myocardium
It is characterized by the thickening of endocardium
It is an inborn disease in children. It is characterized
in consequence of proliferation of callagenous fibres.
by a diffuse proliferation of collagenous and elastic
The changes are localized at the beginning in the
connective tissue of endocardium of the entire left
inflow parts of either the left or right ventricle, later
or right ventricle. Similarly as in the previous dis-
the thickening of endocardium can inflict a larger
ease fibroelastosis of myocardium manifests itself by
part of one or both ventricles.
symptoms of restricted ventricular filling.
The furher development yields scar formation and
retraction of connective tissue of endocardium and
adjacent parts of myocardium. Three essential 3.9.4 Specific diseases of myocardi-
changes take place: um (secondary cardiomyopa-
• reduction of the left or right ventricular cavity
thies)
Impairment of myocardium can develop as a sec-
• reduction of elasticity and thus also the impair-
ondary manifestation of extracardial diseases.
ment of diastolic abilities of ventricles
• Endocrine: hyperthyreosis, hypothyreosis,
• retraction of the pathological collagenous tissue
Cushing’s syndrome, Addison’s disease, hyper-
of chordae and papillary muscles cause incom-
parathyreosis and hypoparathyreosis, acromega-
plete closure of the mitral and/or tricuspidal
ly, foechromocytoma and diabetes mellitus.
valves and the development of mitral or tricus-
pidal regurgitation • Neurologic, neuromuscular diseases and col-
lagenoses: progressive muscular dystrophy,
Although the fibrotic rebuilding of both endo-
Fridreich’s ataxia. disseminated lupus erythe-
cardium and adjacent myocardium does not alter
matosus, dermatomyositis, and diffuse sclero-
the ability of contraction, it reduces the end-diastolic
derma.
volume. Currently the end-diastolic pressure in ven-
tricles elevates. The blood which in consequence of • Metabolic diseases: amyloidosis, haemochro-
restriction does not reach the ventricles, stagnates in matosis, glycogenosis
the atrii. The atrii become hypertrophic and finally
they dilate. The dilatation of atrii is brought about • Nutritional diseases: beri-beri, kwashiorkor.
not only by restriction of diastolic filling of ventri-
cles, but also by mitral and tricuspidal insufficiency. • Haematologic diseases: anemia, polycytemia
Ultimately the elevated pressure is propagated into • Pharmacies: adriamycin, cyclophosphamid, and
the pulmonary bed causing thus dyspnea. The mor- heavy metals
phologic picture of the heart in a later stage of this
fidease is characterized by small ventricles and di- Various etiologic factors evoke secondary cardio-
lated atrii. Hemodynamic indices include a conspic- myopathies by various pathomechanisms. Haemody-
uously elevated end-diastolic pressure. The systolic namic consequences can include deterioration either
function is proportionally well maintained, the dias- of the contractile ability (e.g. hypothyreosis) or relax-
tolic function is essentially deteriorated. In conse- ation ability (e.g. haemochromatosis, glycogenosis,
quence of high ventricular pressure there is mitral sarkoidosis, diabetes mellitus), respectively deterio-
and tricuspidal regurgitation even when the valvular ration of both functions. Some diseases even increase
insufficiency is not pronounced. Large thrombi de- the contractile function of the heart and the relax-
velop often in the ventricles, reducing thus the ven- ation ability of myocardium may remain maintained
3.10. General adaptation syndrome – stress (F. Šimko) 139

(hyperthyreosis, feochromocytoma). The heart im- cular system to physical or psychical overload, heat,
pairment in these diseases is caused in consequence pressure, or gravitation differ according to the evok-
of long-term increased ineffective performance which ing factor. The development of all subsequent reac-
results in depletion of macroergic phosphates and tions is however very similar. Therefore these sit-
sometimes even in the development of numerous uations are not individually presented. We pay in-
necroses. creased attention to the general term of adaptation
as well as to possible negative consequences of an ex-
tensively or frequently repeated reaction to overload.

3.10.1 Adaptation
Man, being a psychosomatic entity is in comprehen-
3.10 General adaptation syn- sion of modern biology an open system. In con-
drome – stress trary to the entirety per se which represents merely
a conglomerate of entities there exist dynamic and at
the same time constant hierarchically arranged rela-
tions of super and subordination between the com-
The theory of stress belongs unambiquously to the ponents of the system. Organism is comprehended
greatest achievements in medecine of the 20 th cen- as an open system as its borders are sufficiently firm
tury. However, this problem is not analyzed with ad- not to be diffused into the surrounding space, but at
equate attention in textbook literature. The general the same time partially permeabile, thus allowing the
adaptation syndrome – stress is a specific disease en- substances, energy and information pass in both di-
tity and terefore it seeks its place in internal medicine rections. An organic system accepts substances rich
with difficulties. The textbooks of pathologic physi- in energy and excludes products with lower amount
ology traditionally included stress into their general of energy. This energy gradient is utilized for inter-
parts. It coincided with the fact that not a single, nal performance of an organism. Entropy, i.e. mea-
but several systems participate in the stress reaction sure of derangement decreases during the process
and consequently the entire organism is altered. of growth and maturation, afterwards its constant
Without the need of appologizing it is necessary to level is maintained and at the old age the entropy
admit that the adaptation syndrome has appeared at increases. An organism achieves the maximal degree
the brink of attention of both pedagogues and stu- of disorganization after death. At that time, how-
dents. One of the most complex theories of modern ever, the hierarchical manner of arrangement of its
medecine represented for a long time an untraced site subsystems, as well as active exchange of substance
in the system of medical education and postgradual and energy with the surrounding space cease to be
study and therefore it has not become such a diag- functional.
nostical and therapeutical instrument in the daily One of the basic characteristics of organisms which
medical practise as it could have become due to its secure a relative constancy and independence from
significance and impact. changes of environment is the capability of autoregu-
Especially the facts mentioned above lead us to lation. The term regulation refers to minimalization
including the theory of stress into the tuition of car- of the difference between the actual values and the
diovascular system. The cardiovascular system has required value of the regulated variable, namely on
a crucial role in adaptation response of organism to the basis of investigation of the above mentioned gra-
stressor. Despite the central, i.e. regulatory and co- dient. Phylogenetically lower animals yield chemical
ordinatory function of nerves and hormones, the ma- regulation. Higher organisms yield humoral regula-
jor effective organ is the cardiovascular system. The tion which is allied to chemical regulation, and the
heart and vessels deliver the blood which is rich in phylogenetically youngest nervous regulation which
oxygen and substrates in adequate amount to organs supervises all levels of regulation. Both humoral and
which perform the greatest activity during stress. nervous regulation are basically of chemical charac-
When presenting the stress reaction it is not our ter (hormones, mediators).
aim to specificate it. The reactions of the cardiovas- While the number of impulses from the exter-
140 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

nal and internal environment which may irritate be explained by the possibility of adaptation on the
the organism is infinite, the variation of instan- basis of enormous redundant genetic information.
taneous responses of organism is relatively very One property can be coded by a whole series of genes,
small. Pathogenic stimuli evoke two possible re- but only a minimmal amount of them is manifested.
actions of organism: direct protection (localization Other genes are blocked by repressor genes. The
of the pathogenic agent, respectively its extinguish- external impulses may activate some of the blocked
ment) or adaptation to changed conditions. genes and the manifested genes can be on the con-
From the phylogenetic point of view adaptation is trary partially or completely inhibited. This results
comprehended as acquirement of new properties un- in modification of the involved phenotypic manifes-
der new conditions, namely those which are as far as tation - formation of new characteristics.
life and survival of each biologic species concerned It is probable that in the historical development
more advantageous in comparison to the previous the organisms reacted to any stimuli by a larger num-
properties. The basic question which still cannot ber of reactions, or by a transitory acceptance of a
be unambiquously answered is as to whether what much larger number of variations of a certain charac-
mechanism is responsible for acquirement of these teristic than it is normal currently. The acceptance
altered properties. of a particular property or manner of reaction was
All genes have a biochemical basis. Genes rep- determined by maximmal appropriateness regarding
resent codes under influence of which a particular the momentary conditions. However, those possibil-
enzyme (or protein) is formed and the existence of ities which had taken place and did not guarantee
which together with other enzymes (or proteins) are the possibility of existence under conditions differ-
responsible for morphologic and functional signs and ing from those under which the characteristics had
manifestetions of organism. been formed, i.e. those which represented too spe-
cific adaptations and coincided regarding the appro-
It is assumed that the offer of new possibilities
priateness with a quite narrow constellation of con-
for the development of new properties is realized ac-
ditions, remained a reality from the developmental
cidentally, by means of genetic mutations. It is a
point of view merely for a very short period. It was
spontaneous accidental change in the genome which
caused by the fact that already a small change in
is promoted under the influence of various factors.
conditions implied that the characteristic which had
However, mutations are rare and only 1 % of mu-
been under the previous conditions favourable for the
tations are favourable and preserved. In this way
organism (or even optimal) became useless or even
during history only a minute proportion of muta-
harmful and caused death or extinguishment of the
tions could have been profitable and the development
individual. On the other hand such manner of re-
would have taken place in a much slower pace than
action which under particular conditions had been
it actually did in reality.
favourable and at the same time of a sufficiently gen-
Aside from mutation also combinatory variance eral character in order to be positively exerted also
has its impact. It is realized on one hand by inde- under different conditions it became a permanent
pendent distribution of chromosomes in meiosis and characteristic and at the same time a characteristic
their accidental connection at fertilization and on feature of the species. Hence, from an enormous vari-
the other hand by crossing over and recombinations. ability of possible genetic combinations only those
This type of variance represents but a new combi- groups of genes are permanently fixed, the realiza-
nation of unchanged genes, while mutation means tion of which in form of phenotype secures survival
formation of new genes. Symbolically this type of and the possibility of the individual’s existence in a
accepting new properties is compared to a pack of relatively wide range of conditions.
playcards, the structure of which changes according
to changed order caused by their shuffling, while in-
dividual cards stay unchanged. 3.10.2 Stress
Often the formation of new properties takes place Regarding the degree of diversity of situations under
surprisingly fast, already during a single generation, which a reaction is manifested as being favourable
where the above mentioned mechanisms cannot have for an organism, the following reactions can be dis-
the possibility of their exertion. This situation can tinguished:
3.10. General adaptation syndrome – stress (F. Šimko) 141

• highly specific (e.g. production of specific anti- symbols may play the role of an intensive stressor
bodies) despite its nonbiological character (spoken or written
word).
• general (fever, cough, inflammation . . .)
In spite of the fact that the terms stress and home-
• general adaptation syndrome – stress is the most ostasis on first sight differ in sense, in fact they are
general reaction allied to a great extent. Homeostasis is a set of
regulatory stabilizing principles of live matter ow-
The term stress was introduced in 1927 by a Cana- ing to which organisms have the ability to self-attain
dian pathophysiologist Hans Selye whose predeces- a certain level of internal organization. The system
sors came from Komárno. Stress in the original con- of regulatory devices maintains variables (pressure,
ception does not mean overload exerted upon organ- temperature, volume of fluids, ion composition of in-
ism (as it is often interpreted), but a response of or- ternal environment, level of metabolites, etc . . .) in
ganism to this overload. Salye introduced the term the frame of a certain narrow interval, thus enabling
stressor which referred to overload which is respon- its bearer a relative independence from the external
sible for stress development. Both terms are often environment.
confused and stress is often used in sense of over-
load. Both homeostasis and stress involve hence a reac-
Despite the intensive research in the field of stress tion of organism to its relatively changed relation to
there does not exist any unified definition as none environment. Consequently those mechanisms are
of the suggested characteristics depicts all aspects of activated, the task of which is to secure adequate
the stress reaction. Even the Sealye’s original defini- function of individual systems. The two reactions
tion - stress is a nonspecific, stereotypic response to differ by the fact that while the homeostatic mech-
any demands exerted upon organism - does not suit anisms secure integrity of the organism and a rel-
the current conceptions. Selye himself admits, ”We ative balance of functions under usual rest condi-
all know that there is stress, but nobody knows what tions, the stress mechanisms are activated when the
stress is.” We can agree without any doubts with integrity and life of organism are endangered. How-
the fact that stress is a state of organism affected by ever, both homeostatic and stress mechanisms are
stressor. A system of protective and reparatory pro- basically equal (regulation of blood pressure, cardiac
cesses is mobilized with the aim of survival. As an frequency, volume of somatic fluids). Stress, though,
organism is an open system stress can be in general sets the function of important organs on a higher
explained as a state of organism which is acquired level. Stress, that is to say, was formed during the
if the organism accepts or gives out a too large or phylogenetic development as a reaction of fight or
too small amount of matter, energy or information, flight, which naturally required an increased perfor-
or when the interior environment of organism is af- mance of striated muscles. All changes coinciding
fected by such factors which compell variables to with stress are aimed at the development of a bal-
overstep the borders of the allowed variability. anced state in which the organism is able to perform
Any factor can represent a stressor: enormous physical and psychical performance. Un-
economical amounts of energy, matter and informa-
• physical factors (cold, heat, radiation, vibra- tion are exerted merely in order to secure survival
tions. . .) under the condition of stressogenic situation. The
presented facts imply that the difference between
• chemical factors (toxic substances, mediators of homeostasis and stress results from quantitative dif-
inflammation, products of metabolism. . .) ferences between both reactions.
• pain The mechanism of alarm reaction is quite com-
plex (viz. fig. 3.13 on page 142). Information from
• intensive psychical activity the external world is conveyed into CNS by means of
• informative deprivation or over-supply sensory organs, while the stress information from the
internal environment is intermediated via interore-
Owing to the second signal system which is based ceptors. Aside from specific sensory effectors, non-
on the principle of existence of symbols, any of the specific mechanisms are activated from the reticu-
142 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.13: The most important endocrinological, metabolic and organic changes in stress
3.10. General adaptation syndrome – stress (F. Šimko) 143

lar formation. On the one hand cerebral cortex is latation takes place), namely in working muscles,
activated, on the other hand and striated muscles heart and brain.
(somatomotor component), tonus and movement of Adrenaline mobilizes glucose from the liver being
smooth muscles (visceromotor component) and en- the initial energetic contribution by means of the
docrine organs (humoral component) by means of b phosphorylase activation with subsequent break-
the stressor. The original purpose of activation of down of glycogen. At the same time adrenaline acti-
all three presented systems was to prepare organism vates lipase which splits neutral lipids to glycerol and
to intensive muscular performance. To meet this de- fatty acids in adipose tissue. Glucose is inevitable for
mand it is necessary for working muscles to receive the activity of CNS, while the myocardium and stri-
an adequate amount of energy. The most effective ated muscles are able to utilize also fatty acids, lac-
energy producing reaction in phylogenetically higher tate, pyruvate, aminoacids and ketone bodies. Pref-
animals is the process of oxidative phosphorylation erence of fatty acids to glucose which takes place in
where the substrate is oxidized in presence of oxy- the heart and muscles is secured by the inhibitory
gen producing thus CO2 and H2 O. The produced effect of adrenaline on insulin on one hand, and by
energy accumulates in biologically utilizable form as direct inhibition of glycolytic enzymes by fatty acids
adenosine triphosphate (ATP). With a little bit of on the other, saving thus glucose for the brain.
simplification we can state that the reason why the
The second phylogenetically oldest neuroen-
stress reaction is to be performed is an increased ATP
docrine system which is activated in the initial phase
requirement of striated muscles. A sufficient amount
of stress is the antidiuretic hormone (ADH). It is syn-
of oxygen delivered to muscles during overload is se-
thetized in nucleus supraopticus and n. paraventric-
cured by increased perfusion of muscular capillaries
ularis in hypothalamus, and stored in neurohypoph-
and a sufficient level of substrate is secured by in-
ysis from where it is released into the blood. Subse-
creased level of fatty acids and glucose. Aside from
quently after entering the circulation it supports the
that also the heart’s output must be increased se-
reverse reabsorption of water in distal and collecting
curing thus a sufficient blood perfusion of working
channels of the kidneys and aside from that it bears
organs and the cerebral activity, the regulatory and
huge pressoric effects (vasopressin). ADH thus in-
coordinatory functions of which are significantly in-
creases blood pressure on the basis of both volume
creased in a stressed organism. Practically all en-
and resistance principles.
docrine and neurogenic reactions and subsequent cir-
culatory and metabolic changes take place with the At the beginnig of the stress situation periph-
aim to enable the performance of increased physical eral vasoconstriction causes hypoperfusion of the
and psychical outputs necessary in order to survive kidneys. Decreased number of impulses for the
the stress situation. wall of vas afferens activates the system renin-
angiotensinogen-angiotensin I, II-aldosterone. Al-
Activation of endocrine organs preserves a partic- dosterone increases the volume of somatic fluids by
ular historical sequence. Sympathetic centre in hy- a reabsorption of sodium and subsequently of water
pothalamus, being phylogenetically the oldest, is ac- in the distal portions of nephrone. Angiotensin II
tivated as the first, stimulating thus the sympathetic is one of the central hormonal substances of stress
nerveous system, and by means of the latter also reaction. It directly stimulates constriction of ar-
suprarenal glands are activated. The nervous end- terioles, enhances the synthesis and elimination of
ings of the sympathetic nerve release noradrenaline, noradrenaline on the nerve endings and blocks its re-
the pulp of suprarenal glands release adrenaline and uptake, it stimulates the release of aldosterone from
noradrenaline. By means of their impact on beta- the cortex and adrenaline from the pulp of suprarenal
receptors the contractility of the heart increases re- glands as well as of vasopressin from neurohypoph-
sulting in the increase in frequency and minute vol- ysis, it increases the sensitivity of vessels to vasoc-
ume. Vasoconstriction is achieved by means of alpha- strictory effects. To a certain extent it hence plays
receptors in vessels of peripheral tissues (periphery the role of a coordinator of stress reaction.
refers to the digestive organs and skin) resulting thus Simultaneously to stimulation of the sympathetic
in redistribution of the blood to those organs where nerve and suprarenal pulp the second defence line is
vasoconstriction is not present (resp. where vasodi- activated. It is the system of hormones of the an-
144 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

terior lobe of the pituitary gland which are released The final nature of alarm reaction depends also on
and the most important of them in coincidence with the somatotropic hormone, tri- and tetraiodothyro-
stress is the adrenocorticotropic hormone (ACTH). nine, insulin, glucagon and lactotropic hormone (pro-
Its effect supervenes as late as after tens of min- lactine).
utes from the beginning of irritation, but the effect is
in comparison with catecholamines of a longer-term 3.10.3 Civilization diseases
character. It causes a release of glucocorticoids from
the pulp of suprarenal glands (the most important is Experience has repeatedly convinced us that stress
cortisol). In spite of the fact that its effect manifests can evoke or deteriorate a number of diseases. As
itself by a whole series of external reactions, basi- many as in 50 % of subjective difficulties of patients
cally all of them reside in the ability to synthetize their case histories yield certain forms of chronic
glucose de novo from nonsugar sources – glucoplas- stress. The most frequent so-called civilization dis-
tic aminoacids (which are mostly gained by split- eases which are to a smaller or greater extent deter-
ting of lymphatic and muscular tissue), from lactate mined by insufficient adaptation to various forms of
(which is produced at a relative depletion of oxygen stressors include atherosclerosis, ischemic heart dis-
in working muscles) and from glycerol (which gets ease (and infarction of myocardium being its most
into the blood due to the splitting of neutral fats). serious form), duodenal ulcer, hypertension, distur-
The meaning of cortisole resides hence in the fact bances of cardiac rhythm, colitis ulcerosa . . . Aside
that after a fast depletion of hepatic glycogen under from these organic diseases civilization diseases in-
the influence of the sympathetic nervous system the clude a much larger number of disturbances being
permanent supply with glucose to the brain is se- of functional character, where patients despite of a
cured from nonsugar sources. Catecholamines force series of subjective symptoms have only minimal or
organs to high performance under very uneconom- no morphological or biochemical disturbances. All
ical conditions and can have a utterly toxic effect these diseases are treated by an advise to be aware
on tissues. Under a common intensity of stress re- of stress, change of job, appropriate life style. In fact
action the toxic effect is manifested only in individ- the problem is more complex.
uals with decreased release of cortisol. This implies First of all it is inevitable to adopt an attitude to
that glucocorticoids secure a somewhat protective ef- the question as to why is the stress reaction which
fect on tissues against toxic effects of noradrenaline had been during the phylogenetic development mil-
and adrenaline. An especially intensive stress can be lion times proved as being positive for organism, is
sometimes managed by massive doses of glucocor- in a nowaday man a frequent cause of health distur-
ticoids. Catecholamines and glucocorticoids increase bances.
blood clotting which can have in case of injury of tis- Life had been formed billions of years ago. Prac-
sues due to fight or flight reaction often a protective tically sice their origin the organisms had to acco-
effect against exsanguination. modate to changing external environment. Stress in
modified forms occurs in all species of organisms and
even in plants. The stress reaction has been form-
Parallel to ACTH also the so-called beta lipotropic ing since the beginning of life. Human civilization,
hormone is relaeased. Lipotropic hormones give ori- however, began to form only several ten thousands
gin to endorphines and enkephalines. The reason years ago. It brought about enormous changes – ad-
of parallel production of ACTH and beta lipotropic vanced technique, abundance of information, system
hormone is the same precursor molecule – propiome- of standard behavour, (moral, ethics, law). First of
lanocortin. Endorphines and enkephalines belong all it brings about a distinctly different world in com-
among the so-called endogenic opiates which bind parison to that in which man had developed. It is
on receptors of the morphine type. The main role a world of symbols. Symbols, although not having
of these neurohormones is the modulation of affec- any biological value, are worth while for a man to be
tive and reactive components of stress. Endorphines capable of deeds of various values. The biologic basis
have an analgetic, euphorizing and hypotensive ef- started to being dominated by the II. signal system
fects. They play probably also the role of modulator represented by word.
of elimination of the rest of stressogenic hormones. The problem resides in that while the biologic al-
3.11. Congenital heart diseases (I. Hulı́n, L. Zlatoš) 145

terations were formed millions of years ago, the civ- decade of life. An example of this are shunts, in these
ilized world brings about changes in material and cases problems appear only when the pulmonary hy-
spiritual world often during one or several gener- pertension is stabilized due to the structural changes
ations. Human biosystem cannot always manage in the lung field. Pulmonary hypertension accom-
to adapt to these facts. The alarm reaction rep- panies more than one cardiovascular malformation.
resents in fact an unconditioned automatic reflex. The state of pulmonary area or (the lungs) will de-
It functions immediately unerroneously, stereotypi- cide the intensity of clinical manifestation of the dis-
cally. However, it has a disadvantage in lacking plas- ease, as well as the possibility of a surgical treatment.
ticity and ability of modification, resulting thus in In the beginning the pressure in the pulmonary field
loosing its justification. The stressor evokes a reac- depends on the pulmonary blood flow. Later it de-
tion according to experience gained during millions pends as well on the vascular resistance, finally there
of years. Today majority of stressors do not entail will be some structural changes in the lung field.
fight, but flight. The majority of stress reactions are That is why it is very important to measure the blood
not linked to muscular work. In spite of that human flow into the lungs as well as the pulmonary vascular
organism mobilizes catecholamines, glucocorticoids, resistance.
and other stress hormones. The blood pressure el-
As an attempt to compensate for oxygen insuf-
evates, glucose and fatty acids are mobilized, blood
ficiency and in chronic hypoxia here will be incre-
circulation is rebuilt, sodium is resorbed, potassium
ment in the number of erythrocytes in the periph-
and magnesium decrease, blood clotting increases.
eral blood. That is why here will be an extreme
What is mobilized is not subsequently utilized by
increase in the haematocrit. As a result of this there
muscular work.
will be a change in blood viscosity. Increase in the
These facts result in inadequately prolonged in- erythrocyte count (polyglobulia) is a cause of hy-
creased blood pressure, which gradually becomes pervolaemia. Polyglobulia, a high haematocrit, and
permanent and primary hypertension develops. Hy- hypervolaemia accompany congenital cyanotic heart
pertension and hyperlipemia may cause accumula-
diseases. On one hand by the effect of these changes
tion of lipids in vascular walls and development of
it is easier for the blood to carry oxygen due to high
atherosclerosis. blood capacity for oxygen transport, but on the other
hand these changes give many side effect. There is
the occurrence of thrombotic complications and hem-
orrhages. That is why drugs that potentiate vascular
thrombosis are strictly contraindicated in patients
with congenital cyanotic heart diseases. In cases of
3.11 Congenital heart diseases a very prominent polycythemia we have to reduce
the erythrocyte number by replacement with plasma
or albumin to decrease the blood viscosity, increas-
ing blood flow through the tissues, and hence provide
Congenital cardiovascular malformations result more oxygen supply. Yet repeated venepunctions are
not indicated because by this the organism is loos-
from an abnormal embryonal development of the
ing too much iron and to compensate the erythro-
normal structures or its absence. They develop due
to genetic causes and the effect of the external envi- cyte loss they are replaced by fast formation of small
ronment, which is affecting the growing embryo be- erythrocytes - microcytes. They have a lower defer-
tween 3–7 week of justation. Those factors are (ion- ability, and hence are not good for oxygen transport.
izing radiation, some chemical substances, pharma- The inborn incorrected cardiac diseases are a risk
ceutics, viruses). factor in females in time of gravidity and during
Cardiac and large vessels malformation have dif- birth. During gravidity the condition deteriorates
ferent clinical manifestations. Some disorders are in case there is already presence of pulmonary hy-
well tolerated by the body. Yet during adulthood pertension. Mortality rate is increasing in the group
the haemodynamic situation may deteriorate. Some of females, in whom gravidity is terminated by ce-
malformations are manifested late in the 4th or 5th sarean section. In mothers with corrected cardiac
146 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

malformation or with artificial valves there is a ten-

dency for the development of thrombotic complica-
tions. But the possible anticoagulative treatment is
dangerous for the fetus. Most commonly it is the
threatening of possible intra cranial hemorrhage dur-
ing birth. In the first two trimesters of gravidity the
anticoagulative treatment can lead to abortion.
Surgically corrigated congenital malformations of
the heart are accompanied by the risk of developing
infective endocarditis. In later stages post surgically,
many examination methods and some surgical at-
tempts may also lead to infective endocarditis. This
is why in these patients antibiotics are given preven-
tively during procedures like cystoscopy, proctosig-
moidoscopy, in gastrointestinal, surgical and stoma-
tological procedures.
The congenital cardiovascular diseases are classi-
fied by many ways. Commonly according to haemo-
dynamic changes, anatomical changes, or according Figure 3.14: Defect of atrial septum
to clinical manifestations. The used classification is
that one which devides the malformation into cyan-
otic and non cyanotic. The non cyanotic group is
further classified into two types depending on the apertum or persistens can combine with a defect of
presence or absence of left to right shift. the neighboring part of the septum. The size of the
The presence of cyanosis and the direction of the defect and the pressure changes in the atria will de-
shunt are in dynamic development. Cyanosis should termine the amount of blood flowing from the left
be absent from the beginning and shunt can occur to the right atrium. In physiological state the pres-
later on due to morphological changes in the heart sure in the left atrium is higher than the pressure in
and vessels which are caused by the primary defect. the right atrium. So the determining factors of the
That is why we will not consider the last type of clas- size of (left to right shunts) are the amount of the
sification so that we can concentrate on the effects blood flow, the pulmonary resistance, and the state
of the malformation on the heart, vessels, and the of both atria. The flow of blood through the defect in
circulation. the atrial septum during diastole, leads to an incre-
ment of the filling of the right ventricle and hence an
increment of the blood flow through the pulmonary
3.11.1 Atrial septal defect (ASD)
area. More blood flows to the left atrium yet once
Corresponds for a certain type of communication be- again part of it is transferred to the right atrium via
tween the atria (see fig. 3.14 on page 146). the defect and is recirculated through the lung field.
It is often discovered during examination of adults. In long lasting and markedly increased pulmonary
It is more common in females. The atrial septal de- blood flow there will be an increased arterial vascular
fect can be in the upper or lower part of the septum. tonus of the lung field. So the arterial blood pressure
Here it can be associated with other defects. The is gradually increasing in the pulmonary artery and
atrial septal defect represents a state where foramen as a consequence of this there will be right ventricular
ovale is closed only functionally from the embryonal hypertrophy, then to an increment in the connective
period. It is known as foramen ovale persistents. tissue and finally even the formation of atheroscle-
In some cases it is closed anatomically but in such rosis in the small circulation. These organic changes
a way that there will be an opening which remains result in further increase of the arterial wall resis-
and this opening is of different sizes. This case is tance in the lung field and hence progression of pul-
known as foramen ovale apertum. The atrial sep- monary hypertension and right ventricular hypertro-
tal defect are markedly variable. The foramen ovale phy. Those patients are not symptomatic from the
3.11. Congenital heart diseases (I. Hulı́n, L. Zlatoš) 147

beginning. Usually there are some respiratory infec- young age. In early neonatal period there is usu-
tions. In older ages there are cardiorespiratory prob- ally heart failure because neonatal myocardium can
lems. Later there might be atrial arrhythmias and not tolerate a haemodynamic load. It is the re-
pulmonary hypertension. When there is hypoxia due sult of immature intracellular structures of cardiomy-
to other causes than cardiac ones, pulmonary hyper- ocytes (myofibrils, mitochondria, sarcoplasmic retic-
tension develops much earlier. ulum) and hence a low functional capacity of their
An increased diastolic filling of the right ventricle myocardium. Another factor of the low capacity of
can be the cause of the accentuation of tricuspid clo- their myocardium. Another factor of the low capac-
sure sound. Second heart sound is usually doubled. ity of a newborn myocardium to tolerate high work-
Commonly there might be some rhythm disturbances ing demands is that the heart rate and the end dias-
which arise in the atria for example atrial fibrilla- tolic volume are both markedly high even at rest. In
tion. Right ventricular hypertrophy can present in a long lasting defect there might be a development
children. of pulmonary hypertension. In cases of large defect
The abnormality can be corrected in optimal situ- with pulmonary hypertension there is a large risk of
ations between 3rd and 6th year of life. Good results possible development of an anatomical obstruction
are achieved before the age of 40, but there should of pulmonary vessels. This condition is irreversible.
not be pulmonary hypertension. That is why the correction of this problem is lim-
ited by the reconstruction of the pulmonary vascu-
lar field. Pulmonary vascular obstruction is man-
3.11.2 Ventricular septal defect ifested by dyspnoe, retrosternal pain, syncope and
hemoptysis. In normotensive pulmonary blood pres-
It usually occurs in combination with other abnor- sure the VSD (ventricular septal defect) carries very
malities (see fig. 3.15 on page 147). good prognosis even without correction.

3.11.3 Patent ductus arteriosus

During the fetal period ductus Arteriosus forms a
normal junction between aorta and the pulmonary
artery. (Ductus arteriosus in the fetal period is a
junction which arises from the pulmonary artery bi-
furcation). During this period blood flows form the
pulmonary artery to the aorta. This duct is closed
immediately after birth. The closure occurs as a re-
sult of a change in the pressure relations and partly
due to the active contraction of this duct which fol-
lows changes in oxygen saturation in the blood. In
cases of a patent ductus arteriosus which persists
even after birth the blood flows form aorta to the
pulmonary artery. This flow is continuous during
the whole cardiac cycle (see fig. 3.16 on page 148).
The blood flow is faster during systole. This is why
we can usually hear a very typical systole-diastolic
murmur which is marked as a machinery or con-
Figure 3.15: Defect of ventricular septum tinuous murmur. When the amount of blood flow-
ing through the duct is large, pulmonary hyperten-
It is usually localized in the membranous or mus- sion and shunt would be later irreversible (hyper-
cular part. The resulting situation depends on the tension is fixed by fixed vascular obstruction) and
size of the defect and on the state of lung field. more over becomes reversed. Blood then flows from
Very small defects can close spontaneously. Larger the pulmonary artery back to the descending aorta.
ones can be fatal due to cardiac decompensation in Cyanosis is noticed in the lower limb but not in the
148 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

cases pulmonary hypertension or cardiac decompen-

sation might develop.

3.11.5 Congenital aortic stenosis

We can devide aortic stenosis into valvular aortic
stenosis supravalvular aortic stenosis and discrete
sub aortic stenosis.
Valvular stenosis. In this congenital deformity
the aortic valve is actually formed of two crescen-
tic valves of irregular shape. Only later the valve is
narrowed, stenozed. Sometimes it is very hard to dis-
tinguish this case from the rheumatic or degenerative
stenosis. Stenosis leads to concentric hypertrophy of
the left ventricle and a post stenotic dilatation of
the ascending aorta. Stenosis result in a high pres-
sure gradient between the left ventricle and the aorta.
patients may remain asymptomatic for a long time.
If stenosis develop suddenly the patient complains of
Figure 3.16: Ductus arteriorus apertus weakness, syncope, and myocardial ischemia. There
might be sudden death, ventricular arrhythmia, and
acute myocardial ischemia. On auscultation we find
upper limbs (hands). This case eventually leads to a systolic murmur which propagates to the carotids.
cardiac decompensation. A fatal end could be caused The bicuspid aortic valve is a very favored place for
by rupture of the duct and its aneurysm, dilatation, the colonization of bacterial endocarditis. That is
or calcification. why stenosis can be later on combined with aortic
regurgitation of blood.
Supravalvular stenosis. Is narrowing of aorta at
3.11.4 Anomalies of coronary artery the upper edge of the semilunar valves. In usual
cases the site of coronary arteries emergence is not
emergence
affected.
The left coronary artery emerges form the pulmonary Subaortic stenosis. Is already present at birth.
artery. Here the myocardial perfusion is supplied by There is a fibrous ring situated immediately below
the right coronary artery. Collaterals develop be- the semilunar valves. The ring can have a membra-
tween the two arteries. Never the less there will be nous character.
myocardial fibrosis. Myocardial infarction is not un-
usual. Only 20 % of the affected children reach the
3.11.6 Coarctation of aorta
age of adolescence. In cases of ischemia or repeated
myocardial infarction there will be papillary muscle Presents a narrowing or asphyxiation of the aortic
dysfunction. Papillary muscle dysfunction eventu- lumen. That might occur anywhere along the aorta.
ally leads to mitral regurgitation. Surgical correction The narrowing is usually distal to the branching of
is possible. The prognosis are dependent upon the the left subclavian artery near the insertion of liga-
extent of the myocardium which is already injured mentum arteriosus. It is more common in boys, in
by hypoxia. whom we quite often find gonadal disgenesis. The
Sometimes there might be an abnormal communi- haemodynamic state depends on the extent of the
cation between the coronary artery and one of the narrowing and on the presence of other anomalies. In
ventricles or the right atrium. This is called arterio small coarectation the defect might be symptomless.
- venous coronary fistula. The shunt is usually tiny. More prominent coarectation can result in frequent
There might be a potential thrombus formation or headaches, epistaxis, cold extremities, and claudica-
there might be a development of aneurysm. In some tion on exertion, hypertension in the upper limbs
3.11. Congenital heart diseases (I. Hulı́n, L. Zlatoš) 149

and a weak pulsation of the femoral artery. Up- sis with hypertrophy and affected fibrous ring of the
per limbs and chest is more developed in comparison heart. The right ventricular failure and the right
with the lower limbs. It is the result of the haemo- atrial dilatation are booth outcomes of a haemody-
dynamic state. We can hear a systolic murmur on namic overload on the right ventricle.
the lateral thoracic wall. There are many collaterals
which are compensatory dilated. The left ventricle 3.11.8 Transposition of the great
hypertrophies. Aorta dilated above and below the
site of coarectation. A non corrected aortic coarec-
vessels (arteries) TGA
tation is the cause of a marked hypertension, which Occurs in combination with other abnormalities.
might lead to cerebral aneurysms, hemorrhages, aor- The aorta arises from the right ventricle and the pul-
tic ruptures, left ventricular failure and infectious monary artery from the left ventricle. In such cases
endocarditis. Surgical correction in form of resec- there is usually a patent ductus arteriosus (PDA) or a
tion of the affected site (site of coarectation) and ventricular septal defect (VSD). Otherwise this case
end to end anastomosis, will relief the haemodynam- (Transposition of the great arteries) is incompatible
ics exertion on the heart but not necessary remove with life. The whole condition depends upon the ven-
the hypertension. The reason of hypertension can be tricular function and the state of pulmonary (lung)
due to a haemodynamic obsticles that were present field. It also depends on whether there is enough
before the correction, as well as the participation of oxygen in the blood of the coronary arteries.
renin angiotensin system which resulted from the low
blood flow through the kidneys. Prior to surgical cor-
3.11.9 Ebstein anomaly
rection the hypertension presents only in the upper
part of the body. Collaterals are palpable between The tricuspid valve is absent, dysplastic, and pushed
the scapulae, and on the sides of chest. They are into the right ventricle, it is partially adherent to the
more prominent on bending. Coarectation without right ventricular wall. This is why actually the right
a prominent hypertension turns to be normotensive ventricle is small compared to the large right atrium.
after correction. In 80 % of the corrected cases there In this case there is a considerable tricuspid regur-
will be development of hypertension. gitation. There might be a presence of tachyarhyth-
mia.
3.11.7 Pulmonary artery stenosis
3.11.10 Tetralogy of Fallot
When it occurs individually without other malforma-
tions it is usually localized in supravalvular, valvular, The classical picture of tetralogy of Fallot repre-
and subvalvular position. The most common posi- sents the simultaneous presence of major and basic
tion is the valvular localization. In case of normal changes which are: pulmonary stenosis, ventricular
right ventricular function there will be a high pres- septal defect, transposition of the aorta, and a right
sure gradient between the ventricle and pulmonary ventricular hypertrophy (see fig. 3.17 on page 150).
artery. It reaches 50–80 mm Hg. The progress of this The pulmonary stenosis can be valvular or in-
disorder and patient’s symptoms are dependent upon fundibular type. The dextroposition of the aorta can
the extent of the stenosis. Usually there is syncope, be partial or complete. The increasing right ventricu-
weakness, dyspnoe and right ventricular failure. In lar pressure during systole leads to right ventricular
cases of severe stenosis the pressure in the right ven- hypertrophy. The increasing pressure is the conse-
tricle might become equal to the level of pressure quence of the communication between both ventri-
in the left ventricle. The ejection time of the right cles and pulmonary artery stenosis. The pulmonary
ventricle is prolonged. The right ventricle is then stenosis can occur together with stenosis of the pul-
markedly hypertrophied. Yet, this hypertrophy de- monary artery branches. The blood flows to the pul-
creases the compliance of the right ventricle, and con- monary vasculature instead of flowing to the aorta.
sequently worsens the right ventricular filling. The The right to left shunt is the cause of hypoxemia
stenosis is the cause of a systolic murmur. Tricuspid and cyanosis, finger clubbing, and polyglobulinemia.
regurgitation might result from a progressed stage Cyanosis doesn’t manifest itself from the very be-
of stenosis the main cause is the pulmonary steno- ginning of this anomaly. If cyanosis doesn’t occur
150 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

3.12 Infective endocarditis

When the endocardium is colonized by microbes

the resulting disease is known as infective endocardi-
tis. The most significant pathological changes are
taking place on the edges of valves. There is some
distraction which is mainly shown as changes in the
shape of the valves and formation of vegetation. In-
fective endocarditis is the new term of what is pre-
viously known as bacterial endocarditis. the main
reason of the new nomenclature is that this disease
Figure 3.17: Fallot’s tetralogy can be caused by fungi or chlamidia. From the clin-
ical point of view we are usually talking about acute
and sub acute bacterial endocarditis, valvular en-
shortly after birth, it usually appears before the first docarditis, and valvular endocarditis occurring after
year of life. The explanation of this phenomena is valve transplantation. Non bacterial thrombotic en-
that ductus arteriosus remains patent for few months docarditis is an individual clinical unit.
after birth (its closure is opposed by the pressure gra- Infective endocarditis is most commonly (80 %)
dient). The limiting factors of the proper haemody- caused by streptococci, staphylococci. Streptococ-
namics are the pulmonary stenosis in the first place cus a-haemoliticus viridians is the dominant bacteria
and the size of ventricular septal defect in the second causing infective endocarditis. It forms 65 % of cases.
place. The blood flow across the pulmonary artery Infective endocarditis can occur following many var-
can represent only Y3 the blood flow in the aorta. ious infective diseases. The can even form complexes
of diseases such as pneumococus pneumonia, menin-
When Fallot tetralogy is associated with an atrial
gitis, and endocarditis, this triad is called Austrian
septal defect we are dealing with a case of pentalogy.
syndrom.
The child becomes cyanosed during feeding and Valvular defects were the previously dominating
when crying. The child will be become bluish, dys- problem in the developed countries, those defects
pnoic, spasms may occur, and there might be loss were the results of a chronic rheumatic process.
of consciousness. Later in the child development we Meanwhile these causes are in regression. The prob-
notice a marked loss of performance and frequent lem now is infective endocarditis which result from
resting. There is a retardation of growth. There will some predisposing factors like some congenital dis-
be what is know as cardiac nazism with infantilism. eases and mainly some discrete changes being for
An increased blood viscosity and hypoxia are help- example mitral valve prolapse. Another predispos-
ing factors in the occurrence of thrombi, especially ing factors are some cardiosurgical procedures. Of
in the infective endocarditis. course every overcomed or treated case of infectove
In those children the precordium is usually promi- endocarditis carries a potentional danger of reoccur-
nent and we can palpate a right ventricular heave. rence. Many factors predispose to the occurrence
We can hear a harsh systolic murmur in the left of infective endocarditis. Bacteriemia as such being
parasternal area in the second and forth intercostal (the presence of pathological microbial agents in the
spaces. The second heart sound above the pul- blood) is not enough to cause infective endocardi-
monary artery can not be heard. tis. The first condition for the occurrence of this
3.12. Infective endocarditis (I. Hulı́n) 151

disease is that the endocardium has to be prepared procedures. It might be skin infection or just simply
for microbial colonization. We mean by this endo- post prandial infection.
cardial injury. The second condition is the ability Adhesive microorganisms are actually provided
of the microorganisms to adhere to the endocardial by the current non bacterial thrombotic endocardi-
surface. The third condition is the replication of the tis. Although there are some known cases of infec-
microorganisms and the infecting vegetation on the tive endocarditis where no evidence of non bacte-
endocardium. rial thrombotic endocarditis could be proven to ex-
Endocardial injury can be caused by many fac- ist. Colonization of the endocardium is not an easy
tors. A direct injury of the endocardium can be for event. Most probably could be performed only by
example caused even in cases when the patient is pathogenic strains of the microorganisms, that have
exposed to a severe cold or a general hypoxia. A the ability to survive in the presence of circulating
turbulent blood flow that accompanies valvular de- complement system, antibodies, and thrombocytic
fects is in some conditions also a factor causing en- aggregation on the endocardial surface. It is very
docardial injury. The endocardium is many times likely that bacteria form polysaccharides like dextran
a proper culture media for many microorganisms, and fibronectin, that disturb the non fluidized endo-
where immunocomplexes are embedded this occurs cardial surface. After the process of colonization the
commonly in cases of systemic lupus erythomatosus microorganisms start to multiply. After 3–6 hours
and in rheumatic disease of the heart. Stress as well aggregations of the microorganisms, thrombocytes,
do represent an evident cause of endocardial injury. and fibrin are formed. After 24 hours the infecting
Endocardial injury is manifested by sloughing of vegetation are markedly enlarged. Microorganisms,
the endothelial cells and the exposure of the en- thrombocytes, and fibrin are sandwiched and joined
dothelial basal membrane. The basal membrane is together. Bacteria may accelerate the processor fib-
composed of collagen fibers on which thrombocytes rin formation via activating the blood coagulation
(platelets) can adhere. The process of platelet ad- cascade. the growing bacterial colonies participate
herence is a matter of surface receptors. Each ad- by this way in the formation of fibrin network, that
hered thrombocytes is activated, and many factors contains only few cells having the ability to phagocy-
are released from this thrombocytes, one of them is tose and lose their defensive ability. The whole endo-
ADP. ADP evokes the adherence of other thrombo- cardial surface is continuously washed by blood that
cytes. This procedure is continuously repeated. The contains antibodies and protective monocytes and
platelet adherence will lead to and inflammatory pro- polymorphonuclear leucolyses. Bacterial colonies are
cess in the basal membrane. There will be the forma- protected by the fibrin network. This process can
tion of non bacterial thrombotic endocarditis. It can take place anywhere in the endocardium. The most
be a completely benign process. Thrombocytic micro common sites are the valvular edges.
thrombi can be stabilized by fibrin. Due to unknown Infective endocarditis can cause the most serious
causes, in patients suffering from cachexia and ma- changes in the valvular apparatus of the heart. It
lignancies there might be the formation of non bac- is commonly a problem that concerns the whole or-
terial thrombotic endocarditis, which is marked as ganism. the classical picture of infective endocarditis
marantic endocarditis. has the following parameters: fever, cardiac murmur
Endocardial injury is the first condition for the oc- which changes very fast, petechiae on the skin, con-
currence of infective endocarditis. Consequently we juctiva, and oral mucus membrane. The cooperation
may say that infective endocarditis is connected to of the whole organism is caused by the continuous
the non bacterial thrombotic endocarditis. The mi- spread of the infected micro emboli and immuno-
croorganisms get into the circulation during many complexes to the whole organism. Apart from fever
diagnostic and therapeutic procedures. These might there is anorexia, loss of weight, lumbar pain, night
be genitourinary diagnostic procedures such as in- sweating, the appearance of new changing murmurs,
travenous pyelography (IVP), and even some dental petechiae, positive haemoculture, increasing erythro-
procedures. There is a great opportunity for the en- cyte sedimentation, abnormal urine exam and usu-
trance of the microorganisms during haemodyalisis. ally a quick onset of the disease.
In long lasting intravenous infusions and in surgical Infective endocarditis can affect the conductive
152 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

system of the heart. We can then notice different ing through the capillaries of each tissue, or organ per
types of atrioventricular heart blocks. Atrioventricu- a time unit is fair enough to keep the homeostasis of
lar blocks, bundle branch blocks or fascicular blocks. that organ, so that it can perform its function ade-
The displaced vegetation can reach the coronary ar- quately. the blood flow per minute via the capillaries
teries, and then evoke a picture of acute myocardial of the given tissue or organ is the most important pa-
infarction. rameter of the blood flow (haemodynamics)
The process of treatment can be obtained by an- The vessels from the functional point of view can
tibiotics to destroy the bacteria. Macrophages then be devided into:
remove the destroyed and useless material. Fibrob-
last form new collagen and in few weeks or few 1. Compliance vessels, that form the large and in-
months time the endocardial surface is covered with termediate arteries. Their function is to provide
epithelium. Even through we may find later during a continuous flow of blood. Ensure a fast trans-
transplantation of values the presence of microorgan- port of blood to the peripheries.
isms on those injured valves. The affected valve is
usually thickened and calcified. During endocarditis 2. Resistant vessels are the major determinants of
the affected valve can be perforated. the general peripheral vascular resistance and
The most frightening complication is heart fail- by this even the regional blood flow.
ure. It occurs nearly in 75 % of the affected individ- The whole peripheral vascular resistance is an
uals. The second serious complication is meningoen- important factor upon which the intermediate
cephalitis and cerebral embolism. Renal disorders arterial blood pressure depends. It includes:
are mainly caused by the embedded immunocom- The elastic resistance in the arterial system, the
plexes in the basal membrane of the glomerular capil- peripheral resistance of the resistant vessels, and
laries. In the acute form of infective endocarditis the the resistance which is imposed by the pre cap-
patient is threatened by a huge distraction of the af- illary sphincter. We recognize two types of the
fected valves, including perforation. In long-lasting resistant vessels:
intensive use of drugs there might be a progression to
a sub acute form of infective endocarditis. After the (a) pre capillary resistant vessels – small arter-
replacement of a valve (implantation) infective endo- ies and arterioles – which form about one
carditis occur within 60 days. During pregnancy in- half of the value of the peripheral vascular
fective endocarditis may follow infections in patients
resistance.
having already some kind of congenital heart disease.
The untreated infective endocarditis is always a fatal (b) post capillary resistant vessels – venules
disease. and small veins That form a small part
of the resistance. The participate in the
changes of the potential volume of the ca-
pacity field.

3. precapillary sphincter is that part of the vessel

3.13 Pathological changes of that regulates blood flow into the capillaries and
selectively distributes blood into those capillar-
the blood pressure ies. By opening and closing these segments we
can determine the number of transition capillar-
ies in a given organ or tissue. The pre capillary
sphincter under goes systemic and local effects.
That determine the metabolic of the tissue or
3.13.1 Functional anatomy of the cir- organ.
culation
4. capacitance vessels (volume) are mainly the
The circulation can perform its basic function in an large systemic veins. They represent the reser-
optimal way only when the amount of the blood flow- voir for heart filling.
3.13. Pathological changes of the blood pressure (H. Sapáková) 153

5. exchange vessels are the true blood capillaries. The total peripheral resistance in the arterioles,
They mediate the contact between the blood but partially even in the larger arteries, capillar-
field and the interstitial place. ies, and venules = total peripheral resistance.
6. shunt vessels of the arterio- venous shunts. The minute cardiac output is regulated by four
These vessels provide a fast flow of blood from factors:
the arterior to the venous side without passing
through the capillaries i.e. (bypassing the capil- 1. The end diastolic volume of the left ventricle
laries). They exist in certain tissues such as skin (the preload)
and lungs.
2. The myocardial contractility
The primary function of the cardiovascular sys-
tem is to provide adequate flow of blood through 3. The resistance against which the left ventricle
different tissues. The power that provide this is the pumps the blood (the after load)
mean arterior pressure. There is a physical relation 4. The frequency of the heart.
between the mean arterial pressure, the minute vol-
ume of the heart, and the total peripheral resistance. All these factors affecting the minute cardiac out-
This relation is similar to the relation between the put are affected by the autonomic nervous system:
tension (E), the electrical current intensity (I) and that activated adrenergic receptors in the SA node,
the resistance of the electric conduction (R) which is the myocardium, the smooth muscle in the arterial
determined by Ohm’s low: wall, venules, and veins.
Regulation of vascular tonus. The value of the
E tonus depends on the structural and functional char-
R=
I acteristics of the individual vessels. This value is
The resistance is directly related to the tension and under the effect of many systemic and local factors.
in indirect relation with the intensity. The tension Systemic factors regulating the vascular tonus are
is then equal to the intensity multiplied by the re- mainly nervous mechanisms, sympathicoadrenal sys-
tem, system rennin-angiotensin-aldosteron, and the
sistance. For the arterial pressure the relation looks
vasopresin system.
like this:
Local factors can be devided into three groups:
the mean arterial pressure = minute volume multi-
plied by the total peripheral resistance. 1. the vascular myogenic reaction to the tension
By increasing the minute volume we lower the to-
2. chemical factors having metabolic origin
tal peripheral resistance and vise versa, by decreas-
ing the minute volume, the peripheral resistance in- 3. humoral factors.
creases, so that the pressure remains unchanged.
1) The caliber of the blood vessels is determined
by two physical antagonizing (acting against each
3.13.2 Regulation of the blood pres-
other) factors. These are the transmural distend-
sure ing pressure and a tangentially acting tension on the
Under the headline the arterial (systemic) blood vascular wall. In the state of equilibrium the relation
pressure we understand, the lateral hydrostatic pres- between these two and the diameter of the vessel is
sure that acts on the arterial wall during the ven- defined by Laplace low:
tricular systole. The perfusion of organs and tissues r
is dependent upon the mean arterial pressure. The T he vascular wall tension = P ·
value of which depend on: h
P . . . the distending pressure, r . . . the vascular diam-
1. The volume of blood pumped by the left ventri-
eter, h . . . is the wall thickness
cle in a time unit. The cardiac output.
2. The resistance to the blood flow laid down by According to this low the smaller is the vascular
the vessels in the peripheries of the vascular field diameter the lower is the pressure needed to close
154 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

the vessel. This is why as soon as the pre capillary other large arteries, in the upper chest. Any increase
sphincter starts to contract and its translucency is in the arterial blood pressure stimulate the barore-
decreased (the wall thickness increases) the tendency ceptors, these will depress the activity of the vaso-
of this sphincter to close the vessel is increasing. This motor center that is followed by lowering the sympa-
magic circle tends to close the vessels completely. thetic tonus: resulting in peripheral vasodilatation
2) An increase in the tissue metabolism is accom- lowering the cardiac activity and normaliyation the
panied by an increase in the regional blood flow, blood pressure. An opposite effect could be achieved
which is known as functional hyperemia. The re- when there is initial drop in the blood pressure.
gional vascular tonus is decreasing and the blood flow 2) Chemoreceptors react to changes in the pO2 of
is increasing. Contraversly in non functioning organs blood flowing towards the aortic and carotid bodies
or tissues the blood flow drops down. and they exert their action on the blood pressure
Functional hyperemia is related to the effects of that ranges between 40–100 torr. When there is a
local chemical factors, either by the accumulation dicers in the blood flow there is a consequent drop
of metabolic products or by the depletion of nutri- in the oxygen supply and a resulting conduction of
ents. Intensive hyperemia occurs during muscular activity to the vasomotor center will aim to return
exertion: there is a marked dilatation of the pre cap- the pressure back to its original level.
illary and post capillary resistant vessels.
3) Reaction of CNS to ischemia is a defensive
According to the vasodilatatory theory the vas-
mechanism against the extreme drop of the blood
cular tonus is regulated by factors that originate
pressure. This is about a mechanism that ensures an
during the exertion in the contracted muscle fibers,
adequate blood flow to the brain. When the blood
released to the intersitium and can affect the vas-
pressure drops down or the brain is badly perfused
cular tone directly: CO2 , lactate, other carbohy-
due to other reason, the vasomotor centrum suffers
drate metabolites, decreased in the pH, acetylcholin,
and starts to be exclusively active. It starts to send
(ATP) that evoke active vasodilatation such as his-
sympathetic vasoconstricting impulses to the vessels
tamin and bradykinin, and eventually leading to an
and cardiac accelerating impulses to the heart. This
increase of the capillary permeability. According to
mechanism is activated only when the arterial blood
the oxygen theory – vascular vasodilatation in active
pressure drops below 60 torr.
tissues is caused by inadequate O2 .
Attention is given mainly to three factors: Hy- The vasomotor center is mainly controlled by the
poxia, a regional increase of the extra cellular con- hypothalamus, which posterolateral part increases
centration of kalium, and regional hyperosmolarity. the activity of the vasomotor center, the anterior
Changes in the extra cellular concentration of kalium part inhibits it.
and of the osmolarity probably influence the vascular Central and peripheral sympathetic nervous
tone via the Ca2+ influx into the muscle fiber. systems regulate cardiovascular function via the
3) Humoral factors: a group of vasoactive sub- adrenoreceptors. The mediator is noradrenalin,
stances – kinins, that have the character of local which is produced by the nerve endings. Sym-
hormones. Their main function is the regulation pathetic vasoconstricting agents (eg. psycho emo-
of micro circulation. These are mainly: acetyl- tional stress) stimulate the chromafin system of
cholin, histamin, 5-hydroxytryptamin - serotonin, the adrenals as well, that will lead to the produc-
prostaglandin, endothelium - derived relaxing factor tion of adrenalin and low amounts of noradrenalin.
EDRF, endothelin. Direct regulation of blood pres- Adrenalin leads to an increment in the cardiac out-
sure is provided by three reflexes. put, evoke tachycardia, and increases the systolic
blood pressure. The total peripheral resistance is ba-
1. baroreceptor reflex sically not changed. Noradrenalin increases the sys-
tolic and diastolic blood pressure by increasing the
2. chemoreceptor reflex
peripheral vascular resistance. Catecholamins lead
3. ischemic reaction CNS (Cushing reflex) to a decrement of the vascular blood flow through
the kidneys, and hence a decrement of sodium and
1) Baroreceptors are situated in the carotid sinus, water excretion by the kidneys. There is also activa-
aortic arch, pulmonary arteries and less frequently in tion of rennin-angiotensin system.
3.14. Systemic arterial hypertension (H. Sapáková) 155

Renin-angiotensin system is composed of a multi- rect only changes ranging between +30 % till -15 %
step cascade of on each other dependent substances. of the blood volume.
The key substance and a limiting factor is the en- Long lasting regulation of the blood pressure is
zyme rennin. This enzyme is produced in the jux- obtained mainly by the kidneys as an organ. Aldos-
taglomerular apparatus of the kidneys. Rennin- teron limits water and salt loss.
angiotensin system exists in other tissues too. This The renal mechanisms of sodium and water excre-
extrarenal system is subjected to an intensive study tion have the greatest importance for the long lasting
mainly in the vessels. regulation. With the raising blood pressure there is a
Angiotensin II binds to the cellular membrane re- consequent raise of the perfusion pressure in the kid-
ceptors and stimulate Ca2+ influx, but do not acti- neys and sodium and water excretion in the urine.
vate adenylcyclase. Angiotensin as well stimulates A raise in the blood pressure that results from a
the biosynthesis and proliferation of smooth muscle. raise in the cardiac output (for e.g.: in cases of ex-
It causes a constriction of the systemic arterioles (by pansion of the body fluids) when normal renal func-
its direct effect on the pre capillary resistant ves- tion will evoke pressure diuresis and natriumuresis
sels). During the physiological conditions there is a and hence decreasing the volume and the blood pres-
dynamic equilibrium between the pressor and the de- sure. In renal function disturbance e.g. in low blood
pressor mechanism, this equilibrium keeps the blood flow through the kidneys which result from the gen-
pressure in the optimal range. (Arterial hypertension eral drop of the blood pressure, or from a loss of
can be the consequence of a disorder of the men- functional kidney parenchyma there will be sodium
tioned equilibrium being either due to the relative and water retention in the organism that will con-
or the absolute excess of the pressing factors or the sequently lead to raise in the venous return, cardiac
absolute excess of the pressing factors or the inade- output, and blood pressure.
quacy of the depressing factors). There will be an establishment of a new state of
Differing from the nervous regulatory mechanisms, equilibrium that characterizes most of the hyperten-
that can react within few seconds, other regulatory sion cases. A high blood pressure, a high peripheral
mechanisms need longer time for exerting their ef- resistance, normal cardiac output, and a normal vol-
fect. ume of body fluids. This condition modifies the func-
tion of baroreceptors, sympatico adrenergic mecha-
1) Transcapillary shift of fluids (the flow of fluid nisms, rennin-angiotensin system, mineralocorticoids
out of the capillaries or into the capillaries): With and other factors.
blood pressure change there will be a change in the
capillary pressure. When the arterial blood pres-
sure drops down there will be a consequent drop of
the fluid filtration through the capillary membrane
into the interstitial space and hence increasing the
amount of the circulating blood. Contraversly, in
cases of the increased blood pressure there will be 3.14 Systemic arterial hyper-
fluid escape into the interstitial space. This mecha-
nism reacts slowly.
tension
2) Mechanism of vascular adaptation: For exam-
ple after a massive blood transfusion there will be
an initial raise in the blood pressure, yet after some- Systemic arterial hypertension is a long-lasting,
time – 10 min. till one hour – and due to a vascu- usually permanent elevated blood pressure (BP) in
lar relaxation the blood pressure returns to the nor- the systemic circulation. It might usually concern
mal even though the blood volume increase by nearly only of the systolic BP, and respectively only of the
30 % over the normal level. Contraversly post a mas- diastolic blood pressure, or it might concern both of
sive bleeding this mechanism can lead to a vasocon- them at the same time.
striction enclosing the remaining blood volume and Increase of BP can be determined:
by this keeping the normal haemodynamic. This
mechanism has its restriction by which it can cor- a) by the increase of the cardiac output or by the
156 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

increase of total circulatory blood volume – vo- • a disturbed renal function – proteinuria,
lume hypertension; possibly a slightly raised creatinin in the
plasma (this stage can be characterized as
b) by the increase of the total peripheral vascular the stage of a cardiovascular hypertrophyas
resistance – resistance hypertension; well).
c) by the decrease of the vascular compliance or III. Organ injury is manifested by same subjective
elasticity – so called a compliance hypertension. and objective signs:
Some physical factors of the blood like high viscos- • left ventricular insufficiency;
ity, etc. might play a supporting role in the develop- • hemorrhages into the brain, the cerebel-
ment of arterial hypertension. The blood pressure lum, or the brainstem, hypertensive en-
within a population in the physiological conditions cephalopathy;
has wide inter individual, and even intraindividual
differences. Inter individual variability of the BP • hemorrhages and exudates into the retina
is affected by the age, (in children the blood pres- (the III stage could be characterized as the
sure is low and it raises with age), sex, body con- stage of a cardiovascular injury).
stitution, body weight, and by other factors. The This classification reflects the fact that, the sys-
blood pressure is changing during the day in every temic arterial hypertension – no matter what the
normal individual. It is usually lowest in the early etiopathogenic mechanism is - is not merely a raise of
morning hours, and it is at its highest level in the the blood pressure but it is a disease where the whole
afternoon and in the evening. Based on epidemio- cardiovascular system is affected, with the affection
logical data of the world health organization (WHO) of other vital organs, mainly the brain, and the kid-
three bordering values of BP for the adult individ- neys. These changes may combine, so that many
ual were estanlished. The value of 160/95 mm Hg organs can be affected simultaneously and elsewhere
(21,3/12,7 kPa) is regarded as a border of the abnor- the main pathology is in the only one organ affection.
mally high blood pressure. The most dangerous stage (III) may turn into a
The normal blood pressure of adults is de- malignant form of a disease (called malignant or
fined by the upper border of the systolic BP accelerated hypertension). What characterizes this
140 mm Hg (18,7 kPa) and a diastolic blood pres- type is the changes in the diastolic blood pressure
sure of 90 mm Hg (12,0 kPa). The BP between the that may reach 130 mm Hg (17 kPa), some compli-
values of which are considered as normal and the cated retina changes and a rapidly progressing renal
value 160/95 mm Hg, there is a line of values that failure, cerebral failure, and heart failure. In the non
are known as the suspicious values (boderline val- treated individuals this malignant form ends within
ues). 1–2 years by exitus. The malignant progression is
The professionals in the commitee of the WHO caused by these three mechanisms:
have accepted the classification of the systemic arte-
rial hypertension according to the value of BP and 1. An abnormal raise of the blood pressure
the extent of the organ injury into three stages:
2. Activation of the rennin angiotensin system
I. A raised blood pressure without any objectively 3. Microangiopathic hemolytic anemia.
present signs of organ injury.
An abnormal raise of the blood pressure will cause
II. The presence of at least one of these signs of changes of the permeability of the arteriolar endothe-
organ injury: lium, that leads to a leak of some plasma particles
– including fibrinogen – into the vascular wall. We
• a left ventricular hypertrophy (proven may prove the presence of some tears on the reti-
by radiography, electrocardiography, or nal vessels by special techniques. The rennin an-
echocardiography); giotensin (RA) system is accomplished mainly by its
• a generalized or focal arterial narrowing of prominent vasoconstrictive effect. The activation of
the retina vessels; this system by the abnormally high loss of Na+ and
3.14. Systemic arterial hypertension (H. Sapáková) 157

hence loosing body fluids due to the pressure diuresis regulatory disturbances of the BP, which might have
will lead to a vicious circle formation. various causes of development and therefore different
Although a new balance is established by loos- pathogenic mechanism. Most of the theories which
ing the excessive amounts of fluid, yet the vasocon- try to explain the pathogenesis do agree on that there
strictive effect of angiotensin and hence the BP is is an disoirder in the blood pressure regulation (this
still raising. The microangiopathic hemolytic ane- disturbance may probably affect any parts of the reg-
mia that develops during the malignant transforma- ulating chain), that is due to some internal (endoge-
tion of hypertension can occur due to a mechanical nous) or external (exogenous) factors.
injury of the erythrocytes during the micro circula- The endogenic factors are multifactorial, including
tory disturbance – erythrocyte haemolysis and due genetic ones. The exogenous factors are the realiza-
to the release of the coagulatory factors that result tors of the genetic propensity, and they include pri-
from the raised blood pressure in the arterioles. Yet marily a high salt intake, high energy provision and
we may deal with a case of a primary coagulation some psychogenic factors.
disturbance that is the formation of intramural and
intraluminal thrombi in the small renal arteries – as 3.14.1.1 Genetic and familiar affects
a result of accumulation of the stimulated thrombo-
cytes on the vascular wall and a consequent alter- It is known, that hypertension usually affects more
ation of the erythrocytes and their haemolysis. than one member of the family. The blood pressure,
At last, the third criteria recommended by the similarly as other quantitative constitutional signs,
WHO in the classification of hypertension is accord- is to a certain limits similar in all members of the
ing to the etiology. Most commonly (90–95 % ) the same family.
cause of the high systemic blood pressure is unknown The decisive factor yet is considered to be the in-
and that is why we call this type of hypertension as heritance of those factors that have some importance
the essential hypertension (primary or idiopathic). in the etiology and the pathogenesis of the essential
And on the other hand a hypertension that is ac- hypertension. It was proven that some biochemical
companying a known primary disease is known as and other markers, and even some reactions to differ-
the secondary (symptomatic). By this way the sec- ent stimuli – that are present in people with essential
ondary hypertension is usually joined to many re- hypertension – can be noticed also in still healthy
nal diseases, cardiovascular, endocrine, and nervous normotensive members of hypertensive families:
system diseases. The highest proportion of diseases • There might be some genetically conditioned
that are associated with the secondary hypertension changes of the metabolism and the release of
is given to renal diseases. catecholamines.

3.14.1 Essential hypertension • Fast release of (NE) noradrenalin from the

thrombocytes, can be one of the genetic markers
Is the most common form of hypertension. Accord- (the place of NE storage are even the thrombo-
ing to some statistics it forms nearly 90–95 % of all cytes).
hypertension cases. This disease affects about 15 %
of the world population. • Low contents of kalicrein (a depressor factor)
Etiology and pathogenesis of essential hyperten- was found in some children of hypertensive fa-
sion is only partially understood. Due to a large milies.
number of factors and pathogenic mechanisms, that • Apart from the discovered high systolic and di-
participate in the development and progression of hy- astolic blood pressure as well as the body weight
pertension their pathogenesis is rather complicated. in children of the hypertensive families, the have
The heterogenesity of the factors which lead to the also a significantly low level of plasma aldos-
eventuall effect – increasing the systemic arterial teron.
blood pressure – is the cause of the fact that its has
not been unified yet. It seems that it is not even • There is also a genetically based high sensitivity
possible, because according to the newest informa- to Na+ expected in the essential hypertensive
tion essential hypertension is a common name for the people.
158 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

• There might be a genetic factor that is expressed possibility is a primary increase of the peripheral re-
even due to stress (e.g. the normotensive people sistance. During an abnormally high natrium intake
react differently to various psychogenic stimuli there will be an increase of natrial concentration in
by increasing the blood pressure and a long last- the muscle cells of the vascular wall, that will con-
ing increment of the BP. sequently result in the retention of more Ca2+ ions
leading to higher vascular wall sensitivity to vaso-
• Meanwhile there is an intensive study about constricting agents.
some enzyme transport systems, mainly for According to the latest studies concerning the
Na+ , K+ , Ca2+ (in the kidneys and the vascular pathogenesis of essential hypertension the genetic de-
wall, in erythrocytes, leukocytes, and lympho- fect of kidneys to excrete salt plays a very important
cytes). The genetic determinant of these trans- role. Yet, the exact mechanism that results in in-
port abnormalities in the patients suffering from creasing of the blood pressure is still not exactly un-
the essential hypertension was shown. derstood or proven. One of the possible explanations
that are accepted nowadays are the changes of the
The question of genetic markers is very important cation transport across the cellular membrane. To
for the practical field – mainly for the future. As maintain a constant low Na+ concentration of Na+
markers blood and serum groups are being studied intracellularly, the Na+ has to be expelled out across
before all. Meanwhile it is the HLA system and other the cellular membrane using these active transport
systems that influence the immunity. For hyperten- mechanisms:
sion they are important only for its familiar predilec-
tion and also for prognosis of atherosclerosis develop- 1. Na+ –K+ pump: actively expels Na+ extracellu-
ment and its complications. The hereditary factors larly against the concentration gradient. The
basically participate in the variability of the blood needed energy for this active process is sup-
pressure and in the genesis of the essential hyperten- plied from the hydrolysis of ATP with the aid
sion. The type of inheritance is most probably by of the Na+ , K+ dependent ATPase. The activ-
a polygenic, additive and it further more interacts ity of the Na+ –K+ ATPase is a measure of the
with exogenic factors. natrium pump activity. From the quantitative
point of view natrium pump is responsible for
about 80 % of the active transport of natrium
3.14.1.2 Factors of the external environment from the cell, the action of which is inhibited by
SALT The relation between the salt and hyperten- ouabain or digoxin.
sion development has been known since the begin- 2. Na+ –K+ cotransport mediates a simultaneous
ning of this century. Its role in the pathogenesis is
unidirectional transport of Na+ , and K+ and
based partly on many epidemiological studies (from
may be also chlorides intra– or extracellularly.
different regions of the world), from which it was
clear that the prevalence of hypertension is directly In physiological conditions these and other trans-
related to the amount of salt intake. And partly due port systems from an optimal electrolyte composi-
to some clinical studies, that refer to that lowering tion of the intracellular fluid. A disorder of these
the blood pressure is parallel with decreasing the ex- transport mechanisms can decrease the active trans-
tra cellular fluid that may be accomplished by diet port of natrium from the cell. This means that
containing markedly low quantities of salt or by con- during an unchanged passive intracellular transport
tinuous diuretic therapy. the content of intracellular Na+ will raise. This
Increasing the salt intake will result in increasing raise of the intracellular Na+ concentration causes a
the volume of extra cellular fluid. This fact results in raise of the concentration of free intracellular Ca2+
a larger venous return to the heart, that will conse- as well (due to the fact that there is close relation
quently cause an increase the cardiac output and due between the intracellular Ca2+ concentration and a
to autoregulation peripheral vessel resistance will be transmembrane Na+ gradient due to the presence of
secondarily increased. According to Guyton the pe- Ca2+ –Na+ exchange mechanism. Even a slight raise
ripheral tissues protect themselves in this way from of the intracellular natrium concentration leads to an
high perfusion, if they are not functioning. Another increment of Ca2+ transport intracellularly.)
3.14. Systemic arterial hypertension (H. Sapáková) 159

These transport systems do exist even in the a high K+ intake is protective against hypertension
formed blood elements such as erythrocytes, leuko- and maybe even against other hurtful effects of high
cytes, and lymphocytes. This provides us with the natrium intake. High kalium intake results in drop
chance to study the activity of those transport sys- of the blood pressure. (Individuals that consume
tems for Na+ also in human and not only in exper- mainly vegetarian food have a low blood pressure).
imental animals. The activity of Na+ –K+ ATPase The combination of low Na+ intake and higher K+
was proven to be low in erythrocytes, leukocytes, intake is more effective than low Na+ intake alone.
and even lymphocytes of patients with essential hy- There are many possibilities of the hypotensive ef-
pertension. fect of kalium:
Low Na+ –K+ ATPase activity is more prominent
1. It causes diuresis and hence lowers the plasma
in patients with high or normo rennin essential hy-
volume
pertension (according to the plasma rennin activity
we classify hypertension as: low-, normo-, and high 2. In patients treated with K+ there is a drop in
rennin hypertension). Upon increasing the volume of the body weight and there is a decrease of Na+
extracellular fluid and hence increasing the extra cel- content in the organism
lular Na+ content the organism will compensate this
by increasing the level of natrium uretic substances, 3. It inhibits the plasma rennin activity
mainly, the atrial natriuretic peptide (ANP), which
4. It can cause vasodilatation due to a direct effect
is formed in the cardiac atria and its function is re-
on the arteriolar smooth muscle.
alized in the kidneys ANP increases the excretion
of Na+ by increasing the glomerular filtration and
inhibiting its tubular reabsorption. It also lowers MAGNESIUM (Mg2+) It was found that adding
the aldosteron production. The other of the natrium Mg2+ (in the form aspartate hydrochloride) increases
uretic substances is a natrium uretic hormone that the depressor effect of the diuretics. Any disturbance
inhibits Na+ –K+ ATPase, which will consequently of Mg2+ metabolism may result in generalized mus-
lead to a limited transport into cells or to expulsion cular contraction and hence affecting the blood pres-
of Na+ outside the cells, and hence to an increase sure. Mg2+ is Na+ –K+ ATPase activator and it is
of the intra cellular Na+ content followed by an in- Ca2+ antagonist. When the level of Mg2+ is low it
crease of intracellular Ca2+ content as well (as ex- causes an increase of the intracellular Ca2+ concen-
plained previously). It is not clear yet whether the tration and hence promotes vasoconstriction.
natrium uretic hormone and digitalis like endogenous
substances (digitalis – like compounds) are the same OBESITY Practically all the epidemiological
and the only Na+ –K+ ATPase inhibitor. studies point to that there is a direct relationship be-
tween the level of the blood pressure and the body
As a consequence of all we mentioned is that there
weight. This relationship concerns the primitive as
might be a congenital primary defect of the trans-
well as the developed polulations, and also concerns
membranous Na+ transport caused by a high level
both the children and the adults.
of a humoral substance – that is supposed to be na-
To explain the relationship between the obesity
triuretic hormone.
and the blood pressure we noticed that the obese
What is more important here is that during the people, that expend more kJ need as well a higher
mentioned exchange mechanisms intracellular Ca2+ expenditure of salt per day. In obese people there
concentration increases, which is then a trigger mech- might be hyperinsulinemia and as well as insulin re-
anism for muscular contraction of vessels. By this sistance. Insulin enhances the retention of natrium
mechanism the increased Na+ concentration in the in the kidneys. Too much eating is also accompanied
myocytes of the vascular wall could lead to an by an increase of the sympathetic tonus and an in-
increased susceptibility for vasoconstriction stimuli creased noradrenalin turnover.
and by this to become an important pathogenic
mechanism for the development of hypertension. PSYCHOEMOTIONAL STRESS In the interac-
tion with other mechanisms the neurovegetative sys-
KALIUM (K+ ) There is a lot of evidence that tem also takes part in the regulation of blood pres-
160 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

sure. Also its function arises from the basic circula- most important one in the stressory situations is the
tory functions – in any case to ensure the supply of adrenocorticotropic hormone (ACTH).
oxygenated blood under the required blood pressure The accepted fact meanwhile is that a high blood
to all organs and tissues according to their actual pressure is associated with certain personality char-
needs. acters as well as with the type of occupation. Apart
The CNS reacts to exogenous stressory factors from this in about 30 % of hypertensive people we
(stressors of the outside environment) actually via a are dealing with a hypertension that is only present
dual efferent stereotype which affects also the blood at work (white coat office hypertension). From this
pressure: point of view there are some interesting studies, that
classify people according to their behavior and re-
1. Activating the sympathetic system that leads to activity into two types: type A and type B. Type
the release of catecholamines from the adrenal A people – who are predisposed to hypertension are
medulla and this is characterized by some known characterized by high agility, ambition, psychologi-
reactions. cal instability that might turn into aggressively and
impulsive behaviour, the person is despotic and ego-
(a) fight (associated with vasodilatation in all centric. People of type B are characterized as phleg-
limbs) matic, psychologically stable, with no personal am-
(b) flight (vasodilatation only in lower limbs) bitions.

2. Activating of the adenohypophysis and via the 3.14.1.3 Haemodynamic changes in essential
adrenocorticotropic hormone the stimulation of hypertension
the adrenal cortex.
During the initial stage of the essential hyperten-
In the initial phase of stress there will be an activa- sion the cardiac output is increased and tachycar-
tion of antidiuretic hormone (ADH), that is formed dia is present. The causes and the mechanism of
in the hypothalamus. After its release from the neu- an increased cardiac output in hypertensive patients
rohypophysis (where it is only stored) into the circu- with the initial stage of EH are due to an increased
lation, it acts on the distal and the collecting tubules sympathetico-adrenal activity. It acts directly on the
of the kidneys. Its action lies in enhancing the reab- heart and the vascular structure, where there is an
sorption of water. Apart from this it shares in the increased tension of the vascular wall in the resis-
modulation of blood pressure. In the beginning of tant and the capacitance (venous) field. Narrowing
the stress situation and as a result of the peripheral the venous field will increase the preload and could
vasoconstriction there will be a lowered renal per- be the primary cause of the increased cardiac output.
fusion, that leads to the activation of the rennin – But more marked haemodynamic changes can be
angiotensin I, II, III – aldosteron system. seen in people with the essential hypertension during
Aldosteron increases the volume of body fluids by the physical activity. During the early stages of the
the reabsorption of Na+ and hence water in the distal hypertension there will already be a drop in the car-
tubules. Angiotensin II is a pressor factor. It stimu- diac output due to the drop of the systolic output.
lates vasoconstriction via a direct mechanism. It en- However, the resistance of arteries increases. In the
hances the synthesis and the release of noradrenalin late stages the signs of hypokinetic situation due to
from the nerve endings and it also blocks its uptake the subnormal systole become even more prominent.
by the nerve terminals. Apart from this it stimulates In patients with long lasting hypertension the high
adrenaline and aldosteron release from the adrenals blood pressure is the result of a high peripheral re-
as well as the vasopressin from the neurohypophysis, sistance in case of a low functioning myocardium,
what will consequently lead into increasing the vas- or a marked cardiac insufficiency. The first change
cular susceptibility to vasoconstricting agents. occurring in the vessels can be a functional vasocon-
Along with the stimulation of the sympathetic ner- striction or some structural changes in the vascular
vous system and the adrenal medulla, there will be wall.
also the release of hormones of the anterior lobe During vasoconstriction that is caused by a high
of the pituitary (adenohypophysis), from which the sympathetic tonus, concentration of Na+ , Ca2+ and
3.14. Systemic arterial hypertension (H. Sapáková) 161

water content in the vascular wall also increase. more than others. They mainly affect the coronary
Later on there will be some structural changes in the arteries with the consequence of ischemia and my-
wall of the vessels. A thickening due to the hypertro- ocardial infarction. The brain vessels are also very
phy of the media and a hyperplasia of the collagen often affected, where their closure, or the hemorrhage
fibers. That is a cause of the changes in the relation from a ruptured artery causes distraction of the brain
between the thickness of the vascular wall and its lu- tissue. A branch of the medial cerebral artery is of-
men. The narrowing of the lumen alone can increase ten affected and is known as Charcot artery of the
the peripheral resistance. In the patients with a de- sudden death, that supplies that part of the brain
veloped hypertension (II. stage) the high peripheral through which the main pyramidal tract is passing.
resistance is caused by vasoconstriction and by the Due to ischemia or due to hemorrhage in this region
structural changes in vascular walls. there will be a resulting hemiplegia - which is a ple-
The arteriolar vasoconstriction and the vascular gia that affects the contra lateral half of the body.
resistance do not occur in all the organs equally in As a result of vascular injury in the eye there will
the essential hypertension. The most affected are be some degenerative changes on the retina (hem-
vessels of the skin and kidneys, whereas the skeletal orrhage and exsudates), with the possibility of its
muscles are perfused normally. ablation – ablatio retinae. From the practical point
of view the retinal blood vessels can be subjected to
3.14.1.4 The consequences of the hyperten- examination and so they can provide us with valu-
sion for the organism able information about the state of the brain vessels.
Due to the injury of renal blood vessels there might
Hypertension basically has two injurious conse- be degeneration of the renal parenchyma, nephroscle-
quences for the organism: rosis resulting in worsening of the hypertension. If
the renal injury exceeds a certain limit, the kidneys
1. It causes an overload on the left ventricle
stop to perform their basic function and uremia de-
2. Causes some degenerative changes in the arter- velops.
ies.
3.14.1.5 Complications of hypertension
1) The left ventricle must continuously pump
blood against an increased resistance, which means The prognosis of patients with EH depends on the
that it must perform a compensatory hyperfunction. early diagnosis, on the appropriate treatment, and on
The left ventricle becomes gradually hypertrophied the speed of development of atherosclerotic changes
and its weight might markedly increase. The hy- in the arterial system and on the secondary injury
pertrophied left ventricle can compensate this pro- of individual organs. Nearly 20 % of patient having
cess for a long time. It depends on a level of the so called juvenile hypertension (the increase of blood
mean arterial pressure, and on the state of the my- pressure in the age of 15–18 years) turns to become a
ocardium. If the blood pressure is no more increas- chronic hypertension in the adulthood. Basically we
ing, still the myocardium becomes gradually worn may say that at present we do not know how to treat
out. Cardiomyofibrosis might develop and this might essential hypertension. Today’s therapeutic possibil-
result into the left ventricular failure. ities however have essentially improved the prognosis
2) If the hypertension last for a long time, there in patients because they delay the occurrence of or-
will be degenerative changes in the vascular wall ganic complications and life is prolonged in 80–85 %
(sclerosis, atheromatosis, hyalinosis, and fibrinoid of the patients.
degeneration). In about 15–20 % hypertensive patients the illness
These changes, which are provoked, or the forma- is resistant to the therapy and the progression of the
tion of which gets faster by the action of continual organic complications is proceeding and here occurs
high blood pressure on the vascular wall, will them- an accelerated or malignant hypertension. It is char-
selves be the cause why hypertension becomes fixed acterized by a continuous elevation of the diastolic
because they make the vascular lumen narrower and blood pressure over 130 Hg prominent changes in the
on the other hand they decrease the elasticity of the retinal blood vessels, fast progression of the renal in-
vessels. The vascular changes affect some regions sufficiency, some predisposition for encephalopathic
162 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

attacks and for the development of left ventricular can explain the characteristic morning headaches in
insufficiency. the hypertensive people. The serious life threatening
complications of the essential hypertension can be:
The occurrence of complication markedly affects
the prognosis of the patients. The acute complication • left ventricular failure leading to pulmonary
might be hypertensive crises – being a sudden raise oedema
of the blood pressure over the values 220/130 Hg and
a fast development of the signs and symptoms of hy- • acute myocardial infarction
pertensive encephalopathy: severe headache, nausea • cerebral hemorrhage
and vomiting, epileptic convulsions, aphasia, disori-
entation, somnolence, and finally coma. The opthal- • dissection aneurysm of the aorta
moscopic examination reveals papillary oedema and
retinal hemorrhages and exudates. The morphologi- • progressing renal insufficiency.
cal substrate of this syndrome are multiple thrombi
in the small cerebral arteries and brain oedema. The
main reason for the occurrence of hypertensive en-
cephalopathy is the failure of the normal autoregu-
latory mechanism of the cerebral blood flow. It was
found out that as a result of the high blood pres-
sure in the systemic circulation in the hypertensive
3.15 Secondary arterial
patients there will not be an autoregulatory condi- hypertension
tioned drop of the cerebral blood flow, but on the
contrary, the cerebral blood flow will be increased.
This will increase the capillary hydrostatic pres-
The secondary hypertension usually accompanies
sure and as a consequence there will be an increase
diseases of the kidneys, cardiovascular system, en-
of transudation of fluid from the intravascular space
docrine and nervous systems.
into the interstitium and by this mechanism cerebral
oedema occurs. Since the brain is enclosed in an un-
expandable skull, the capacitance blood vessels are 3.15.1 Renal hypertension
compressed as a result of additional transudation of It occurs as a result of the primary injury of the
fluid into the interstitium. These changes in intersti- functional renal parenchyma – nephrogennic hyper-
tial space will compress the cerebral capillaries and tension, or it is due to some anomalies and changes of
therefore the blood flow via the brain decreases. The the renal vasculature – renovascular (vasorenal) hy-
wall of the cerebral arterioles that are affected by the pertension. The pathogenesis of the arterial hyper-
atherosclerotic changes and thickened become poorly tension is in those patients explained by two mecha-
adaptable to the changes of the systemic blood pres- nisms: volumetric or resistance.
sure. At the physiological conditions an increase
of the systemic blood pressure induces vasoconstric-
3.15.1.1 Injury of the renal parenchyma
tion, whereas the decrease of the systemic blood pres-
sure causes vasodilatation of the cerebral blood ves- Hypertension during parenchyma injury is one of the
sels. Brain hypoxia occurs in he normotonic people most common types of the secondary hypertension.
when the mean arterial blood pressure is 40 mm Hg An increased blood pressure is mostly the first sign
(5,5 kPa), and in hypertonics when the pressure is of the original renal disease.
70 mm Hg (9,3 kPa). The hypertensive patient is not One of the pathogenic factors to which is related
able to respond to the hypercapnia and acideamia in the cause of the occurrence and the maintenance of
the cerebral vessels by vasodilatation and can not re- the hypertension is a drop in the Na+ excretion. The
spond to hypocapnia and alkalosis by vasoconstric- increased volume of the circulating blood will lead to
tion as well, as it is in physiological conditions. The an increased venous return into the heart. That is
relative hypercapnia and cerebral hypoxia with the why the central venous pressure is increasing and the
corresponding changes of the brain haemodynamic ventricular filling is increased as well. As a result of
3.15. Secondary arterial hypertension (H. Sapáková) 163

these changes there will be an increment of the car- substances with vasopressor effect and natrium ure-
diac output and the systemic arterial blood pressure tic effect, i.e. prostaglandins and kalikrein-kinin sys-
– this is known as a volume hypertension. tem.
The volume hypertension occurs in acute glomeru- Lowering the vasopressory function of the kid-
lonephritis. It is usually transient – and after the ney explains the hypertension that accompanies
acute stage the blood pressure returns to normal val- renal diseases, which are presented with promi-
ues. But hypertension may manifest later, after sev- nent destruction of the renal medulla, which pro-
eral years when additionally to the glomerular lesions duces the depressor substances (prostaglandins):
some changes in the arteries and the arterioles arrive. chronic interstitial nephritis, pyelonephritis, obstruc-
In such cases there is already a combination of the tive uropathies, and polycystic kidneys.
volume and the resistance hypertension.
In patients with the tubulointerstitial diseases of 3.15.1.2 Renovascular hypertension (vasore-
the kidneys, the hypertension is less common as that nal hypertension)
in the glomerulonephritis. The cause lies in the lower Renovascular hypertension results from a narrowing
ability of the reabsorption of water based on the pri- of the renal artery. The cause of its narrowing lays
mary injury of the tubules. in many pathological processes, most commonly they
Another mechanism, by which the renal disease are atherosclerosis and fibromuscular hyperplasia.
can result in an increased blood pressure is the resis- As a result of the classical experiments with hy-
tance mechanism. The mechanism of the resistance pertension in animals it was considered sure till re-
hypertension is explained as the result of the effect of cent time that the cause of hypertension in those
the pressor and depressor substances that are formed animals was due to renin – angiotensin system, that
in the kidneys. One of the pressor substances that is is activated by renal ischemia (i.e. by the lower pres-
incorporated in the regulation of the blood pressure sure amplitude in the renal vascular area) caused by
in the physiological but mainly in the pathological the drop in the kidneys perfusion. However, later on
conditions is the renin–angiotensin–aldosteron sys- there appeared many pieces of evidence which deny a
tem. direct relationship between this system and a chronic
The decisive role of the renin–angiotensin system clinical or experimental hypertension.
(RAS) in the pathogenesis of hypertension is as- The course of renovascular hypertension is similar
sumed in renal infarction, and in unilateral renal to the course of the essential hypertension, however
affection, and it is absolute and very aggressive in it is usually more serious and a malignant deterio-
cases of renal tumor that secretes rennin. In cases ration is frequent. What is specific for this type of
of bilateral parenchymal diseases of the kidneys, the hypertension is a progressive ischemic post stenosis
level of the plasma rennin activity (PRA) is only renal atrophy. From the mentioned above it is clear
slightly increased, or it might even be normal, what that two mechanisms share the pathogenesis of the
on the other hand does not exclude the role of this renal hypertension.
factor in the pathogenesis, mainly when we are deal- The volume (hyporenin) mechanism and the re-
ing with a consequent increase of the plasma volume. sistance (hyperrenin) mechanism. According to the
In 5–10 % patients with chronic renal failure that are type of renal disease, the anatomical and functional
treated by dialysis the hypertension does not subside renal injury, and the stage of this disease both those
after the normalization of the content of Na+ and mechanisms can alternate with each other or inter-
fluids in the organism. The finding increased PRA act with each other. In certain cases one of them has
as well as the normalization of blood pressure after the primary role, that will promote the whole mech-
nephroctomy prove that the RAS is the determining anism, in other cases it is the factor that maintains
factor in the pathogenesis of hypertension (known the hypertension.
as renin-dependent hypertension). RAS also plays Apart from the mentioned factors the haemody-
an important role in the maintenance of vasocon- namic changes caused by anemia play an important
striction and of a high blood pressure in malignant role in the pathogenesis of renal hypertension that
hypertension. A certain role in the pathogenesis of accompanies chronic renal insufficiency.
some types of the renal hypertension can play the For maintaining of hypertension an important role
164 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

is played by the adapting mechanisms of neural reg- overproduction (or inversely – an insufficiency) of
ulation of the circulation and also by the secondary some hormones of the adrenal cortex.
morphological changes of the cardiovascular appa- There are three types of hypertension that are
ratus (atherosclerosis and mainly its renal form- caused by an adrenocortical dysfunction:
nephroangiosclerosis).
1. Primary hyperaldosteronism. It is a disease
caused by an primary overproduction of al-
3.15.2 Endocrinal hypertension dosteron in the adrenal gland (benign ade-
It is a hypertension caused by an absolute or a rel- noma, malignant tumors, bilateral hyperplasia),
ative abundance of hormones with pressor effect or which differs from the secondary hyperaldos-
by an abnormality of the hormonal balance, that af- teronism, that occurs as a result of an over-
fects some components of the regulatory mechanisms stimulation of the renal cortex by the system
which influence the blood pressure. renin – angiotensin and by other primary dis-
eases (e.g. nephrotic syndrome, liver cirrhosis,
PHEOCHROMOCYTOMA (chemodektom). It is cardiac insufficiency, an advanced essential and
a disease caused by an autonomic overproduction of renal hypertension). An overproduction of al-
catecholamines by the chromaphin cells tumor of the dosteron in primary hyperaldosteronism is re-
sympatoadrenal system. These are usually benign sponsible for all the clinical and the laboratory
tumors. characteristics of the disease, which become nor-
Most of the pheochromocytomas produce nora- mal after its removal. A long lasting overpro-
drenalin and adrenaline. In nearly 90 % of cases the duction of aldosteron can be manifested by:
tumor is situated in the adrenal medulla; in the re- • Arterial hypertension, and by increase of
maining 10 % it is situated in the area of the ab- the extracellular Na+ content with a pre-
dominal aorta, and less common in other places. disposition for hypernatriemia
Adrenaline stimulates mostly the beta-receptors and
increases the minute cardiac output. Noradrenalin • Hypokaliemia with alkalosis (a result of a
via the alpha receptors increases the peripheral vas- long lasting kalium depletion are some neu-
cular resistance. romuscular changes such as spasm, and the
With regards to the fact that in most patients with development of kaliopenic nephropathy).
pheochromocytoma the overproduction of both hor- The raise of Na+ content and of the ex-
mones is mixed in various quantitative relations, the tracellular volume leads to (by a feed back
circuatory changes are markedly variable. Hyperten- mechanism) the lowering of the plasma
sion can be manifested in three different forms: renin activity, however not to a point that
causes a clinically manifested oedema. And
1. As a permanent hypertension (in nearly half the so in arterial hypertension caused by the
patients) primary aldosteronism there are:
2. As a permanent hypertension with paroxysms of – increased of Na+ content and of the
increasing values of the blood pressure extracellular volume
– high level of aldosteron in the plasma
3. As paroxysmal hypertension (with otherwise and urine
normal blood pressure). – suppression of the plasma renin activ-
The course of permanent hypertension is very ity
much similar to the course of essential hypertension. Since the description of primary hyperaldostero-
The paroxysmal forms of the disease threaten the nism in 1955 by Conn, it was shown that it is
patients with the corebrovascular accidents, myocar- not a unified syndrome, but this disease has at
dial infarction, and heart failure. least three subtypes:

ADRENOCORTICAL DYSFUNCTION. It is a • The classical Conn’s syndrome, when the

case of hypertension with an absolute or a relative aldosteron overproduction is caused by an
3.15. Secondary arterial hypertension (H. Sapáková) 165

aldosteron producing adenoma, less com- disturbed biosynthesis of cortizol, but also an-
mon by a carcinoma affecting one adrenal drogens and estrogens, the mineralocorticoid hy-
gland. pertension is usually accompanied by hypogo-
• Idiopathic hyperaldosteronism – in cases nadism.
of micro- or macronodular hyperplasia of
both adrenals. PRIMARY HYPERRENINISM. It is a rare dis-
• Dexamethazon – suppressible hyperaldos- ease, caused by renin overproduction by renal or ex-
teronism (Murlow’s). It is a rare overpro- trarenal tumors. These are most commonly originat-
duction of aldosteron by hyperplastic or ing from the juxtaglomerular apparatus of the kid-
normal adrenals in children. Hypertension neys. Hypertension is caused by renin overproduc-
in this case can be stabilized only by suple- tion, that leads to the formation of large quantities
mentation of Dexamethazon, that will in- of angiotensin II and so to a secondary hyperaldos-
hibit the overproduction of aldosteron by a teronism.
feed backmechanism.
HYPERTENSION THAT ACCOMPANIES
2. Cushing syndrome. Hypertension results from OTHER ENDOCRINOPATHIES
the overproduction of glucocorticoids and some-
times also the mineralocorticoids. They could 1. Acromegaly. It is due to the overproduction of
be produced by tumors or hyperplasia of the growth hormone most commonly in cases of ade-
adrenal cortex, and also by adenoma of the ade- noma of the adenohypophysis. Apart from the
nohypophysis. The clinical and the laboratory morphological and biochemical changes which
picture is given by the ratio of overproduction are characteristic for the acromegaly, this dis-
ease is accompanied by the hypertension which
of the glucocorticoids and mineralocorticoids. In
other words the hypertension is a result of the does not differ from the essential hypertension.
overproduction of glucocorticoids, that increase The cardiomegally corresponds with the level of
the sensitivity of the vascular wall to endoge- hypertension.
nous pressor factors and most probably they also 2. Hyperparathyreoidism. An increased produc-
change the contractility of the myocardium and tion of parathormone can be most commonly
so increase of the cardiac output. seen in cases of the parathyroid glands adenoma.
Cortizol also stimulates the formation of an- The early renal complications that occur in hy-
giotensinogen in the liver and that is the rea- perparathyreoidism can play an important role
son why there is an increase of the plasma an- in the development of hypertension.
giotensin concentration. Apart from this it in-
crease the vascular wall sensitive to the pressor 3. Hyperthyroidism. An overfunction of the thy-
substances. The overproduction of mineralocor- roid gland can also be accompanied by hyperten-
ticoids promotes its effect via the Na+ retention. sion. In cases of hyperthyroidism it is usually a
systolic hypertension with a high cardiac output
3. Adrenogenital syndrome with hypertension. (volume hypertension). Hypertension as well as
They are rare congenital abnormalities that oc- other common cardiac complications are caused
cur as a result of a disturbed formation and by the direct effect of the thyroid hormones on
hence production of steroids. Hypertension the myocardium.
is accompanied by hypokaliemic alkalosis, by
a suppressed plasma renin activity and by a 4. Diabetes mellitus. The relation between hy-
disturbed sexual maturation and development. pertension and diabetes is well known for over
The inborn insufficiency of the enzymes needed 60 years. The presence of hypertension is
for normal steroidogenesis causes stimulation of more common in cases of non insulin depen-
the formation of deoxycorticosteron (DOC) and dent diabetes (type II) where it correlates with
hence deoxycortizol and androgens. That is why age, obesity, and with the drop in the re-
a mineralocorticoids hypertension is accompa- nal function. Pathogenesis of this hyperten-
nied by the increased virilization. In case of a sion is quite. Many factors play a role here:
166 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

e.g. renal factors, macro- and microangiopathy, blood pressure what is the result of the increased
renin- angiotensin-aldosteron system and cate- cardiac output. The blood flow passes by the ar-
cholamines. terioles and the capillaries and that is why the
diastolic blood pressure decreases. As an exam-
ple of this is the systolic hypertension in cases of
3.15.3 Hypertension in cardiovascu-
multiple arterio-venous aneurysms in the skele-
lar diseases ton as it is in Pagets disease (chronic osteitis
1. Coarctation of aorta. It is an inborn narrowing deformans – processes of new formation as well
of the aortic isthmus, i.e. of the section between as bone resorbtion are faster and the blood sup-
the ostia of the subclavian artery and the attach- ply is increased).
ment of the ductus arteriosus. In broader sense 4. Increase of the minute cardiac output and tachy-
of the coarctationof aorta its stenosis might be cardia at hyperkinetic syndrome. It occurs at
localized along the whole aorta, proximal and disfunction of the vegetative nervous system
distal from the isthmus itself.In aortic coarcta- which is due to an increased sensitivity of the
tion the adequate blood flow and pressure in cardiac or blood vessels beta adrenoreceptors.
the lower half of the body is obtained via three The positive effect of beta blockers strengthens
mechanisms: this hypothesis. We consider a hyperkinetic cir-
• by increasing the systolic blood pressure in culation also states with an increased cardiac
the proximal segment of the aorta output at rest and they are accompanied by a
normal blood pressure (e.g. anemia). In cases of
• by arteriolar vasoconstriction that main- juvenile hypertension and also in early stages of
tains a high diastolic blood pressure the essential hypertension the peripheral vascu-
• by a collateral circulation and possibly by lar resistance is not able to adapt itself to this
the opening of ductus arteriosus. high blood flow and so the blood pressure in-
creases. So the hypertension here does not start
The blood pressure measured in the upper limbs as a generalized vasoconstriction, rather as an
shows an increased systolic, diastolic, and mean inadequate ability of the peripheral vascular bed
arterial blood pressure, while the systolic blood produce effective dilatation. This is considered
pressure is measured in the lower limbs it is in all to be so called relatively increased peripheral
cases low, and the diastolic pressure is increased. vascular resistance.
The mean arterial blood pressure in the lower
limbs is always low, however it is kept at the 5. Decrease of elasticity of the large arteries with a
value arround 50 mm Hg (6,6 kPa), what is the restriction of aortic elasticity. It is usually an ac-
minimal pressure needed for adequate function companying feature of a generalized atheroscle-
of the kidneys. rosis. The systolic blood pressure is usually
slightly increased. The rigid arteries do not ex-
2. Aortic valve insufficiency. It will cause a raise pand during systole. The diastolic blood pres-
in the systolic blood pressure, by the fact that sure is normal or lower that normal, because the
a part of the systolic cardiac output flows back impedance strength which pushes the blood to
into the left ventricle at the beginning of the sys- the periphery during diastole cannot be applied.
tole and hence increases its diastolic filling. The This type of hypertension is called elasticity hy-
left ventricular systolic volume gets larger as the pertension.
regurgitation volume increases. The diastolic
blood pressure becomes lower due to the faster
blood flow from the aorta. The total peripheral
resistance is lower as a result of the adaptation 3.15.4 Hypertension in diseases of the
to the increased cardiac output. nervous system
3. Large arteriovenous fistulae (congenital or ac- The hypertension might occur in patients with brain
quired). They cause the increase of the systolic tumors, cerebral hemorrhage, encephalitis, or menin-
3.15. Secondary arterial hypertension (H. Sapáková) 167

gitis and also after cerebral accidents. Its occurrence flow increases by about 50 % and also increases
is explained by: glomerular filtration. When approaching the end of
the gravidity both those values return to normal.
• increase of the intracranial pressure

• cerebral ischemia Pathogenesis of the hypertension in gravidity is

complicated. It is most probable that its pathogen-
• lesion of the vasomotor centers. esis is shared between the volume and resistant fac-
In cases of acute cerebral ischemia (e.g.: stenosis tors. One of the hypothesis provides us with the
of the carotid artery) the blood pressure is promptly following explanation: During pregnancy the total
increasing by so called Cushing’s reflex. The brain body fluid volume is increased by at least 8,5 l. From
this total volume the plasma volume during the gra-
ischemia is an enormously strong stimulus for the
activation of the central components of the sympa- vidity increases by nearly 1,5 l above the normal. By
thetic nervous system and hence a factor leading to this the appropriate conditions for the congestive cir-
the raise of the systemic arterial blood pressure. The culation and for the occurrence of volume hyperten-
reaction of the cerebral blood vessels to this incre- sion are created. Apart from this the postural char-
ment of systemic blood pressure is vasoconstriction, acteristics of the pregnant women also have a certain
that will lead to the closure of a vicious circle. Hy- rolein the pathogenesis of this hypertension. In the
pertension often accompanies the atherosclerosis of late stages of pregnancy the pressure of the gravid
main vessels of the brain. uterus on the inferior vena cava in the horizontal
position decreases the venous return from the lower
Another mechanism that can play a role in the oc- limbs, what leads to a marked drop of the cardiac
currence of the hypertension is the disinhibition of filling during diastole. As a result of this lowering of
higher centers of the brain as a result of a mechanic, the cardiac filling the cardiac output decreases what
inflammatory, degenerative or toxic affection of the is compensated by vasoconstriction in the splanch-
peripheral neurons in polyneuropathies (e.g.: alco- nic vascular bed and in the skin blood vessels. The
holic neuropathy), in diphtheria, porphyria, thallium lower blood flow via the kidneys is a very important
intoxication, lead intoxication, phosphorus intoxica- factor which leads to the activation of the renin –
tion, etc. . Hypoxia and hypercapnia have a share in angiotensin – aldosteron system.
the pathogenesis of hypertension.
Low sensitivity of baroreceptors can be the cause Recently many hypothesis which tried to explain
of the systemic blood hypertension when there is a the pathogenesis of hypertensionin gravidity come
low pressure in the bulbus caroticus and the aorta out of the fact that in some gravid women the renin
which is characteristic for Takayasa disease (syn- – angiotensin – aldosteron systemis activated. In the
drome of the aortic arch known as an inversed steno- first gravidity preeclampsia state usually occures af-
sis of the aortic isthmus). What predisposes to hy- ter 20th week of the gravidity. It is characterized
pertension here is also brain hypoxia and a lower by a rapid gain of weight, the formation of oedema,
aortic elasticity. proteinuria and by the hypertension. The opthal-
moscopic examination of the retina reveal vascular
spasms and sometimes papillary oedema. The renal
3.15.5 Hypertension in gravidity
blood flow as well as the glomerular filtration are
Hypertension together with oedema and proteinuria being worsened. In the inadequately perfused uterus
form the basic trias of the late pregnancy eclamp- renin is formed. Angiotensin then causes vasodilata-
sia. During the gravidity the blood pressure is tion in the placenta by its effect on prostaglandin
slightly lower than normal and this is why its increase E release, but in other places of vascular bed an-
by 30/15 mm Hg (4/2 kPa) or over 140/90 mm Hg giotensin causes vasoconstriction. The glomerular
(19/12 kPa) is considered as hypertension. Vasodi- filtration decreases and thesefore the natrium re-
latation in pregnancy is caused most probably by the tention and the extracellular fluid volume increase.
higher secretion of progesterone and prostaglandins. Those changes together with vasoconstriction lead to
During the first months of gravidity the renal blood the increase of the systemic blood pressure.
168 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

3.15.6 Hypertension caused by drugs were on a long lasting treatment with conjugated and
and toxic substances synthetic estrogens, or synthetic gestagens. Natural
progesterones inversely have an antihypertensive ef-
The arterial systemic hypertension can occur as an fect.
unwanted side effect that accompanies treatment The mechanism of the development of hyperten-
with some drugs. From the etiopathogenic point of sion here is similar to that occurring post the use
view drugs may lead to hypertension via three mech- of oral steroid contraceptive agents. There will be
anisms: retention of Na+ via either direct natrium retention
• due to their natrium retention effect – similar to mechanism (estrogens or synthetic progesterones) or
mineralocorticoids via the activation of rennin – angiotensin – aldos-
teron system(estrogens).
• due to their effect on the biosynthesis, secre-
tion or metabolism of the pressoric humoral sub- 3. Glucocorticoids and mineralocorticoids.
stances During the therapy with adrenocortical steroids
previously some coarse extracts of the adrenal cor-
• by their direct vasoconstrictive effect tex were used and so hypertension was a common
side effect of the treatment with corticosteroids. To-
1. Hypertension resulted from the use of steroid day it is a rare complication during the substitution
peroral contraception.The steroid peroral contracep- therapy of hypofunction syndromes.
tive agents increase blood pressure in long term use
During the use of mineralocortid substances, hy-
even in otherwise healthy women. Yet chronic hyper-
pertension is accompanied by hypokaliemia, alkalo-
tension develops only in some women. We usually
sis, and a suppressed plasma renin activity
find hypertension in those females with a positive
family history of hypertension in gravidity, in obese 4. Monoaminooxidase inhibitors. The treatment
women, and in woman with a higher predisposition of depressive states by the use of monoaminooxidase
for Na+ retention and the formation of edema, as inhibitors (MAOI) lead into often hypertensive crises
well as in women with chronic pyelonephritis. in these patients after the uses of fermented drinks
The mechanism of the peroral contraceptive agents and food. MAOI causes hypertension via two mech-
that leads to hypertension is complex and depends on anisms:
estrogen content. Estrogens have a direct natrium re-
tention effect and they activate renin – angiotensin – • by inhibiting the intracellular MAO and hence
aldosteron system via a higher angiotensinogen syn- an increase in the level of monoamines due to
thesis in the liver. their low turnover (break down)
The result of all this will be:
• by interfering with tyramine deamination. In
• a higher plasma renin activity till three folds normal cases tyramine is quickly oxidized, yet
more than normal with the presence of MAOI it cumulates in the
• more angiotensin II that via tissues. Tyramine then releases adrenaline and
noradrenalin from their reservoir in the nerve
• the stimulation of aldosteron leads into a sec- endings. Apart from this it has a direct pressor
ondary hyperaldosteronism and hence into effect. A higher release of catecholamines and
their lower break down is observed after meals
• an increased Na+ retention which contain the tyramine (some cheese, alco-
hol drink, meat extract from cans, chocolate.In
The synthetic progestrones in contrast with the
patients treated with MAOI (or α methyldopa)
natural progesterones have also a mineralocorticoid
these meals causes a progressive increase in the
natrium retention effect.
plasma concentration of catecholamines and a
2. Other substances with estrogen and proges- prominent hypertensive crises.
terone activity A relatively common occurrence of
hypertension was described in those patients who 5. Lecorice – Na carbenoxolon.
3.16. Systemic arterial hypotension (D. Maasová) 169

A chronic use of lecorice (like in some expectorants adrenal function (Addison’s syndrome), malabsorb-
or sweets) can cause hypertension that is combined tion syndrome, heart failure, aortic stenosis and con-
with hypokaliemia, alkalosis, and suppressed renin. strictive pericarditis.
This is caused by a natrium retention effect of the
ammonia salts of the glycyrhinic acid, contained in
the lecorice extracts. In other words they act simi- 3.16.1 Orthostatic (postural)
larly to mineralocorticoids. hypotension
6. From the toxic effects hypertension can be The blood vessels are relatively elastic and perme-
caused by acute porphyria, lead, thallium, carbon able pipes. Upon taking the upright position, and
monoxide, mercury poisoning, and experimentally due to the effect of gravity there is a tendency for
cadmium poisoning. The pathogenic mechanism the blood to cumulate in the distendable veins below
is probably a centrally conditioned stimulation of the heart level and also to the escape of plasma into
adrenergic activity. the interstitium. This transient blood distribution
would be the cause of a sudden drop of the venous
7. Postradiation hypertension. Occur in those pa- return, leading to a decrease of the arterial blood
tients treated by radiotherapy. Those are patients pressure with the consequent lower cerebral perfu-
with abdominal tumors probably due to the occur- sion. In normal conditions when taking the upright
rence of so known radiation nephritis. This hyper- posture there are reflex compensatory mechanisms
tension might inquire a malignant character. keeping the arterial blood pressure within a certain
limit of range. In the human organism the most
important are the baroreceptor areas mainly those
situated in the vessels above the heart level. Upon
standing up the blood pressure above the heart level
drops. This change is registered by the barorecep-
tors where the final effect is the reflexly increased
3.16 Systemic arterial sympathetic tonus of the vasomotor fibers that will
hypotension provide vasoconstriction in the resistant vessels (a
compensation of the lower systolic output) and even
in the capacitance blood vessels (lower blood acum-
mulation and hence a larger venous return). Despite
A permanently low systolic blood pressure below the narrowing of the resistant vessels, the hydrostatic
13,3 kPa (100 mm Hg) and a diastolic blood pressure pressure in the lower limb capillaries in orthostasis
below 8,0 kPa (60 mm Hg) in different positions (ly- would be over 13 kPa (100 mm Hg), what consider-
ing, sitting, standing) is marked as chronic arterial ably exceeds the colloidal osmotic pressure of blood
hypotension. It is not considered as a disease con- protein. There would be a prompt plasma diffusion
dition, the hypotensive patients usually reach older into the interstitium. The protective mechanism here
ages than the normotonics. The cause of the contin- is represented by the contraction of the precapillary
uously low blood pressure is not exactly understood. sphincters. An abnormal vessel dilatation will, at
From the theoretical point of view the hypotonics the same time, be prevented by the muscular con-
are on the opposite side than the hypertonics in the tractions that push the venous blood towards the
curve that determines the role of hereditary factors heart.
on a level of blood pressure. It might be a sign of a The muscle contraction and muscle massage of the
generalized asthenia in vagotonics. It course is usu- vessels in the lower limbs can be out of function in
ally asymptomatic with the exception of the frequent case of the passive tilting. During this examination
sleeping or an increased tiredness. Cases of a tran- the patient’s position is changing on a mobile bed,
sient hypotension (syncope and shock) are described to which the patient is tightened. According to the
elsewhere. level of blood pressure during the passive changing
Arterial hypotension might occur in many dis- of the patients position, we might evaluate the ac-
eases. It is the accompanying sign of inadequate tivity of the sympathetic vasomotor reflexes with-
170 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

out any side effects. Changes of the blood pressure tion a patient is unable to keep the normal values of
during the passive tilting in healthy people do not the systolic and diastolic blood pressure. The low-
exceed 1,3 kPa (10 mm Hg). Orthostatic hypoten- ering of blood pressure might be so serious that an
sion (orthos – upright, statio – standing, being or- inadequate cerebral blood flow leads to syncope and
thostaticus means occurring while upright standing) even loss of consciousness. Putting the patient to a
is a condition, that is characterized by a drop in the horizontal position will improve his condition very
systolic and even the diastolic pressure by 2,6 kPa quickly.
(20 mm Hg) when taking the upright standing posi-
tion. In complicated situations the sitting alone may 3.16.1.2 Secondary orthostatic hypotension
cause an evident drop of the blood pressure.
Since hypotension might occur in positions other An inadequate response to gravitation might be an
than the upright position, we might use a wider term accompanying sign of many diseases. The most com-
– postural hypotension. Apart from the usual picture mon cause is again a disturbance of a sympatho-
we might include here some rare situations such as adrenal system at any level – it occurs in pa-
hypotension in the late trimester of gravidity, where tients with neurological diseases (multiple sclerosis,
the heavy gravid uterus will press in the veins upon diabetic and alcoholic neuropathy, peripheral neu-
laying on the back an causes hypotension that might ropathies), after administration of sympatholytic or
lead to syncope. following surgical sympathectomy. After a long lying
Another rare condition might arise from the pres- down, and in the cosmonauts after the long lasting
ence of atrial myxoma or a pendulous intraatrial loss of gravitation there is a developing orthostatic
thrombus during which hypotension might result hypotension, that signalizes a slower or inadequately
upon sitting due to the low ventricular filling in this responding sympathetic nervous system to the effect
position. of gravity to which the patient was not exposed for
a long time. A short lasting training is enough to
make the symptoms of orthostatic hypotension fade
3.16.1.1 Idiopathic orthostatic hypotension out. Another cause of orthostatic hypotension might
Idiopathic orthostatic hypotension affects men more commonly be the varicose syndrome. The failure of
often than women. It is characterized by clear signs valves to close in the wider veins can be so serious,
and symptoms caused by a disturbed or inadequate that an adequate venous return can not be main-
activity of the autonomic nervous system – postu- tained upon standing upright even with the maximal
ral hypotension, low sweating and fixed (unchanged) activation of the sympathicus.
heart rate. Bradbury and Eggleston were the first The signs of postural hypotension are also not un-
who described this syndrome as a triad of a grad- common in patients with cerebrovascular diseases,
ually progressing postural hypotension, anhydrosis in whom syncope might occur upon coughing, a tir-
that affects the whole body surface and impotence. ing defecation, most probably due to the failure of
The exact cause of this condition is yet unknown, the reflex vasoconstriction with a low venous return
some hypothesis suggest a disturbance of biosynthe- (Valsalva maneuver).
sis of catecholamines in the sympathetic ganglia and Inversely a sudden drop of the arterial systemic
neurons. The level of catecholamines in plasma and blood pressure can cause focal neurological injury in
urine is often lower than normal. During the pas- patients suffering from atherosclerosis, intracranial
sive tilting there won’t be normal reaction (a higher vessel occlusion, carotid occlusion, or the vertebral
elimination of catecholamines by the urine). In some artery occlusion.
patients there is a lower reactivity effect of renin – an-
giotensin – aldosteron system. Hypovolemia is found
quite frequently. In cases of lower sympathetic ac-
tivity, the pumping function of the heart depends
mostly on the venous return. As long as the veno-
constriction is inadequate and a compensatory tachy-
cardia doesn’t occur, the cardiac output during the
orthostasis will drop by one fourth. In this posi-
3.17. Syncope (D. Maasová) 171

up by syncope: a disturbance at the level of heart

itself (cardiac syncope) and an extracardial distur-
3.17 Syncope bance in the regulation of the circulation and venous
return (vasomotor syncope).

3.17.1 Cardiac syncope

Syncope is a transient disturbance or loss of con-
sciousness, caused by a sudden lowering of the cere- The basic of its occurrence is the sudden drop in
bral blood flow as a result of the low arterial blood the cardiac output. This occurs commonly during
pressure. The syncope differs from shock in that in some serious disturbances of the cardiac rhythm. It
case of syncope there is no systemic disturbance in might be also provoked by paroxysmal tachycardia,
the micro circulation. ventricular ectopics in runs, paroxysmal atrial fib-
Brain utilizes mainly glucose and has no ability rillation (in the period between the decrease of sys-
to store substrates of the metabolic energy. It has tolic cardiac output and the following reflex vasocon-
got a relatively stable rate of oxygen utilization, and striction). A typical cardiac syncope is the Stokes-
its function depends only on adequate cerebral blood Adams attacks, during which the ventricular con-
flow. The main factor, that determine the amount traction stops till the accessory ventricular rhythm
of the cerebral blood flow are: the systolic cardiac takes over. As this pause last for few seconds there
output, the perfusion pressure and the vascular re- will be a transient loss of consciousness.
sistance. The cardiac syncope can occur even in some cases
The perfusion pressure in the cerebral blood field of haemodynamic disturbances of the heart, mainly
depends on the difference between the mean arterial when the body activity requires a sudden increase
and the mean venous blood pressure.Upon changing of the cardiac output, that can not be obtained by
the position from horizontal to vertical the pressure the injured heart. This might occur in cases of valve
above the heart level decreases and the drop of the diseases (aortic stenosis, mitral stenosis) where the
venous pressure is more pronouced than arterial one. syncope occurs due to inability of the heart to obtain
The increase the pressure gradient will prevent the an increased output upon physical activity. In cases
lowering of the cerebral blood flow. of congenital heart diseases with left-to-right shunt,
The resistance in the cerebral blood field increases syncope is mainly the result of the low oxygen satu-
upon increasing the systolic cardiac output and in- ration in the arterial blood.
versely upon lowering the cardiac output it becomes The clinical picture of the cardiac syncope is char-
less. This feedback regulation is more prominent in acterized by a sudden loss of consciousness occur-
the cerebral circulation than in the systemic. It is ring without any prodromal vegetative symptoms.
one of the mechanisms, by which an adequate blood Its length doesn’t exceed one minute and the gain
flow via the brain is maintained despite the common of consciousness will return the patient to his nor-
deviations of the systemic arterial blood pressure. mal condition. If the loss of consciousness lasts for
The most important mechanism that regulates the longer that 3 min. there might occur an ischemic
cerebral blood flow is the intracerebral regulation injury of the brain. Therefore if the cardiac syncope
of the vascular tonus. The local metabolic effects doesn’t end spontaneously it is necessary to start up
and mainly those of pCO2 and pO2 have a domi- with resuscitation (a hit to the cardiac apex, cardiac
nant role in the adaptation of the cerebral vessels to massage, artificial breathing).
the changing haemodynamics in the systemic circula-
tion. The local hypercapnea or hypoxia as well, that
3.17.2 Vasomotor syncope
occur upon a lower blood flow via the brain will re-
sult in a vast cerebrovascular dilatation. Changes in The primary cause of vasomotor syncope is the drop
the vegetative tonus, that are realized via the sym- of blood pressure and an inadequate brain perfusion
pathetic and the parasympathetic nervous endings caused extracardially – most commonly we are deal-
have a minor role in the maintenance of the cerebral ing with a disturbance of the reflex adaptation of the
blood pressure. organism to orthostasis with an inability to maintain
There are actually two basic mechanisms that end the postural tonus.
172 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

3.17.2.1 The vasodepressoric syncope 3.17.2.2 Syncope due to the primary failure
of venous return
The causative factor is a transient low activity of the
sympathicus and a consequent dilatation of the pe- The primary failure of venous return can cause syn-
ripheral vascular field. The typical representative is cope upon venous stasis in the large dilated veins,
the vasovagal syncope. Occurs in some people upon during gravitational overload and during an in-
fear, pain, and psycho emotional stress (venopunc- creased intrathoracic pressure.
tion, the sight of blood etc.). A predisposing fac- Orthostatic syncope is always characterized by an
tor is an upright posture and a residence in an op- inadequate response of the sympathetic nervous sys-
pressive environment. The cause is a reflex depres- tem to the change of position from horizontal to ver-
sion of the vasomotor center that causes dilatation tical. The typical orthostatic syncope occur upon a
of the peripheral vessels. The syncope is preceded sudden standing upright in those people with inade-
by malaise, nausea, pallor, sweating, hyperventila- quate reactivity of the sympathetic nervous system,
tion, confusion, blurred vision and tachycardia, that in patients treated with antihypertensive drugs, and
will change into bradycardia during the synchope. also in cases of diseases of the central and peripheral
Putting the patient to the horizontal position the nervous system (atherosclerosis of the CNS, diabetic
loss of consciousness will fade away and the patient neuropathy). Long standing may predispose to syn-
returns to normal soon after. cope in patients with tendency to cumulate blood in
the lower limbs due to the insufficiency of the venous
Carotid sinus syndrome occurs in normal condi- valves.
tions upon massaging or exposing pressure on the
Gravitation syncope occurs with increasing the
carotid sinus that will lead to bradycardia and hy-
gravitation, and here it depends on the intensity of
potension. In some cases and mainly in sick peo-
this increase, its direction (from head to feet), and
ple with hypertension or atherosclerosis, loss of con-
upon previous experiences. In sensitive patients it
sciousness occurs upon a very slight stimulation of
might occur in elevators or upon a fast start. It oc-
the carotid sinus (a narrow tight collar, pressure
curs within 2–4 seconds after the beginning of grav-
upon shaving, turning the head). Cardiac, vasomo-
itational overload and it gets soon to normal.
tor, and cerebral factors all share in the pathogenesis
Syncope during cough: Syncope occurs in the case
of its occurrence. That is why the sick carotid sinus
of heavy cough in patients with airway obstruction
syndrome might present in three variable types:
or pulmonary emphysema, where the increasing in-
trathoracic pressure will prevent the venous return.
• the hypersensitive type, characterized by a This case as well might occur in troublesome defeca-
prominent hypotension without changing the tion – in old patients can a prolonged Valsalva ma-
heart rate neuver be the cause of the transient lower venous
return with the occurrence of syncope.
• the cardioinhibitory type in which there is a
prominent bradycardia without any change in
the blood pressure

• a cerebral type where collapse occurs with no

change in the heart rate or in the blood pres-
3.18 Shock states
sure, that indicate a disturbance in the higher
regulatory centers
The heart ensures blood flow via the vascular sys-
Syncope during miction occurs in men and it is tem. The speed of blood flow depends on the ar-
mainly nocturnal after the intake of a large amount terial pressure, that has to reach a certain value to
of fluids. It is most probably a case of some reflex obtain adequate perfusion via the large capillary net-
mechanism (emptying the overfilled urinary bladder, work. The value of the blood pressure in the central
Valsalva maneuver). area of the vessels is determined by two factors. The
3.18. Shock states (I. Hulı́n) 173

first factor is the blood volume that is pumped per tive nervous system obtains the information about
minute time. The second factor is the resistance to the actual state of pressure via the baroreceptors
the blood flow imposed by the peripheral blood ves- (receptors sensitive to the pressure and distention).
sels. The resistance changes according to the muscle The do present mainly in the carotid sinus, in the
tension in the arterioles as well as according to the arch of aorta, heart ventricles, and in the lungs. In-
length of the vessels and the blood viscosity. The formation from the baroreceptors are transferred to
main determinant of the resistance is the total cali- medulla oblongata. There are connections among the
bre of the vessels. From the below mentioned values sympathetic and the parasympathetic nuclei. From
in tab. 3.1 we might notice that venules and small medulla oblongata the information might be trans-
veins together have a 5 folds larger calibre than the ferred to the cerebral cortex and the hypothalamic
arteries and arterioles and that is why this part might nuclei. By this way is the nervous regulation inter-
be a reservoir of a large volume of blood. connected into the humoral regulation till the pitni-
tary (hypophysis).
The permanent tension of the vascular wall con-
tinuously stimulates the baroreceptors. This infor-
aorta 2,5 cm2 mation is processed centrally and according to the
need it modulates the circulatory state.
small arteries 20,0 cm2 A severe sudden lowering in the arterial pres-
sure decreases the stimulation of baroreceptors, that
arterioles 40,0 cm2 causes changes in the sympathetic information and
depresses the parasympathetic activity at the same
capillaries 2500,0 cm2 time.The result is constriction of the smooth mus-
cle of the arteriolar wall and venous wall and an in-
venules 250,0 cm2 creased myocardial contractility.
Consequently there will be an increased hormonal
small veins 80,0 cm2 secretion from the adrenal cortex, the release of
ADH, ACTH, renin and following aldosteron. Other
vena cava 8,0 cm2 substances share the regulation and those are some
metabolites with vasodilatatory effect such as adeno-
sine, kinins, and prostaglandins. Changes in the vol-
umes and in the electrolytes also take place in the
Table 3.1: Area of the calibres of different vessels of process of maintaining the optimal blood pressure.
the circulation The neural and humoral changes aim to renew the
optimal level the blood pressure, to stay within an
The blood volume is not stationary, it might easily controllable and easily regulated range.
change accordingly with the actual needs. This
change might occur via the neural or the humoral
regulatory intervention only. Apart from those fac- 3.18.1 The adapting and compensa-
tors other constituents might be quite important for tory mechanisms activated by
the blood flow but they are considered to be sec- the low tissue perfusion during
ondary. shock
The cardiac output is modulated and controlled
by many factors, that are realized via the changes of Shock is an emergency, that is characterized by its
the end diastolic volume of the ventricles, the quality variable clinical presentation. It can be treated and
of contraction and via changing the heart rate. managed successfully. Yet for this we need a clear
The arterial blood pressure is largely monitored by appropriate medical care and a prompt and accurate
the vegetative nervous system. This has a prominent monitoring of the haemodynamics.
effect on the cardiac output and on the level of con- The etiology of shock may be heterogenouse. It
striction of the resistance vessels (arterioles) and the is substantial, that in every case the circulation is
capacitance vessels (veins and venules). The vegeta- deteriorated. Common sign of all shock types is the
174 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

disturbance of microcirculation. Impairment of the Increase in the heart rate is the first compensatory
circulation system leads to decreased tissue perfusion change appearing during the fall of the systemic ar-
and deterioration in cell function. terial pressure. The heart rate change is modulated
For understanding the pathophysiology and the by the autonomic nervous system. Increase in heart
treatment of the shock is necessary to know the prin- rate leads commonly to the cardiac output elevation.
ciples of the circulation functions and of the control In heart rate elevation above 180/min., however, the
mechanisms involved in the shock development hav- diastole shortens so far that the phase of rapid ventri-
ing the role of adaptation and compensation mecha- cle filling becomes also shortened. During this heart
nisms. rate the output volume is reduced owing to the heart
filling decrease, and so does the output volume per
3.18.1.1 Haemodynamic adaptation and minute. This situation results in the blood pressure
compensation fall. The condition may be very infavourable, e.g. in
acute myocardial infarction. The ventricular tachy-
The fundamental function of the circulation is the cardia or the atrial fibrillation result in reduced car-
oxygen and nutrient supply for the tissues and the diac output, which is already decreased owing to the
metabolic products removal from the tissues. This myocardial infarction itself. (the necrotic part of the
function of circulation is in all shock types insuffi- ventricle does not contract).
cient. The degree of this disturbance determines the
shock development nd its clinical manifestation. This might result in the occurrence of cardiogenic
shock, that is a very common dramatic situation with
The perfusion of tissues is regulated by very com-
a lethal outcome. In this case the state of the haemo-
plicated processes. There are some tens of determi-
nants involved in the perfusion regulation: cardial dynamics is getting worse due to the higher heart
rate. Sinus tachycardia alone is a useful compen-
and vessel factors, and factors at the microcircula-
satory mechanism. Yet it depends on the situation
tions level. The perfusion of organs depends on the
of its occurrence. It is a useful compensatory mech-
systemic arterial blood pressure, on the resistance
anism during febrile states, in anemia, or upon an
of vessels in the relevant organ, and on the state of
capillaries inside of the organ. acute blood loss. This is how we can explain tachy-
cardia and the pathophysiology of its occurrence.
The systemic arterial pressure depends of the car-
It wouldn’t be right to aim to treat a useful com-
diac output of all vessels resistance. The resistance
pensatory mechanisms in every situation. On the
of vessels is determined by their lumina, which are
contrary bradycardia can also occur during a sud-
influenced by neural, humoral and muscular factors
den drop of the cardiac output or during a sudden
regulating the tension of vessels smooth muscle. The
hypotension. This condition occurs mainly in situ-
blood supply of every organ depends on the heart
ations where the low cardiac output and hypoten-
function, on blood vessel wall tension and on the
sion lead into hypoxia of the regulatory centers in
calibre of resistent vessels and the vessel bed in the
the medulla oblongata. Bradycardia can occur upon
organ itself. The exchange of substrates between the
treatment with many medicaments especially those
tissue and the circulating blood depends of the mi-
leading to hypotension or upon blood loss. Brady-
crocirculation. Hence, the capillary network forms
cardia yet occurs even after myocardial infarction or
the interface between the circulation and the cells.
in situations that lead to severe hypotension. This is
The left heart ventricle pumps five liters of blood
not uncommon in cases of a sudden atrioventricular
each minute into the arterial circulation. The right
block.
ventricle pumps an equal volume of blood into the
pulmonary circulation. If the cardiac output falls Another factor that determines the state of haemo-
under 2 liters/min/m2 of body surface the shock de- dynamics is the stroke volume. It is the amount
velops with all consequences. Particularly rapid is of blood expelled by the ventricle during each con-
the development of shock if the fall of the cardiac traction. Low stroke volume can be the result of
output occurs rapidly. a low heart filling (preload), or a weak contractil-
The heart can pump the blood with great vari- ity (a negative inotropic state of the heart) and a
ability of the frequency. It is able to maintain the high afterload. Preload is defined as the tension of
output volume per minute between 40 to 180/min. the sarcomer at the very beginning of the ventricu-
3.18. Shock states (I. Hulı́n) 175

lar contraction. Clinically the preload represents the tolic pressure at the beginnig of the aorta depend
ventricular filling at the end of the diastole. Preload on the total peripheral resistance, on the viscoelas-
shares in the determination of cardiac contraction ticity of the arteries and on the volume of blood in
by the means of Starling law. Preload is clinically the aorta at the beginning of systole. The resistance
measured as a pressure and not the filling of ventri- in this case is the sum of factors that try to prevent
cle at the end of diastole. Yet we have to consider the blood to flow out of the ventricle. These are
that the relationship between the pressure and vol- the continuation, the viscosity, the resistance, and
ume is represented as compliance (dispensability) of the compliance. The resistance is shown by the dy-
the ventricle. Compliance represents the ratio be- namic relationship between the pressure changes and
tween the volume changes and the pressure changes. changes of the blood flow clinically it is only possi-
(The inversion of the value of compliance is known ble to count the resistance but not to measure all
as ventricular tension). its constituents. The calculated resistance can be
The most important factor, that determines the expressed as the systemic vascular resistance. We
preload is the total volume of the circulating blood. subtract the mean pressure in the right atrium from
The volume of the circulating blood can decrease rel- the mean systemic blood pressure and the difference
atively or actually. An actual decrement in the blood is devided by the cardiac output.
volume – hypovolemia – occurs upon the loss of blood In normal condition the contraction of the atria
or fluids. A worsening hypovoleamia is the cause plays a neglegable role in ventricular filling. Their
of hypovoleamic shock. Such a state occurs during share does not exceed 5–10 %. In diseases of the
bleeding, exhausting vomiting, diarrhea, burns, ab- heart the atrial contraction share about 40–50 %
normal loss of water by the kidneys, and upon an of the ventricular filling and that is why in aortic
excessive sweating with no fluid intake. Hidden loss stenosis or cardiomyopathy, the atrial fibrillation will
of fluids occur in peritonitis, pancreatitis, intesti- worsen the heart failure.
nal obstruction, splanchnic ischemia with necrosis, The inotropic state of the heart determines the
in haemoperitoneum, and in fractures with muscular speed and the amount of the muscular contraction
bruising. in the physiological conditions no matter how long
It is unbelievably important to realize that, the was the sarcomer at the end of diastole. From the
normal yet unchanged total blood volume is still not clinical point of view it is the power of contraction
an indicator of an optimal haemodynamic. The vol- that is determined by multiple factors. Among those
ume of blood has to be properly distributed in the factors are the mass of the functioning myocardium,
organism so that the preload would be good enough the myocardial perfusion, the controlling mechanism,
for the required stroke volume. The main factors and humoral factors. In some shock types we expect
that determine the distribution are the body posi- that the myocardial depressing factors has a certain
tion in relation to the gravity force, venous tension, role, that affects the contractility of the myocardium
intrathoracic and intrapericardial pressure and the will result in a state where the heart can not maintain
pumping of blood in veins by the skeletal muscles. the cardiac output on the required level.
Cardiac compression for example in pericardial tam- An important determinant of the myocardial con-
ponade can limit its filling. Low venous return due tractility is the state of the sympathetic nervous sys-
to the abscence of the negative intrathoracic pressure tem, that is realized via the activation of β – recep-
can occur in pneumothorax. A relative lowering of tors in the heart. The result is a higher contractility
the blood volume can occur when loosing the vas- of the heart and its frequency. This effect is ob-
cular tonus. This occur during anesthesia, injury to tained by the effect of the efferent sympathetic fibers
the medulla oblongata, and some disturbances of the of the myocardium, as well as the effect of the cate-
vegetative nervous system. cholamines produced by the adrenal medulla.
Afterload be easily understood as the sum of The cardiac activity depends on the relation be-
forces, that has to be by the ventricle, to expel blood. tween the myocardial requirements and the oxygen
Afterload is first of all determined by the diastolic supply. The supply of oxygen to the myocardium
arterial pressure at the beginning of aorta, the size depends on its perfusion, that is prominently deter-
of the ventricle, and vascular resistance. The dias- mined by the arterial diastolic pressure and the state
176 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

of the coronary arteries. The state of the coronary ing function of the heart and lowering the peripheral
arteries can be permanently changed by atherosclero- vascular resistance.
sis of the coronary arteries or the change might be the Arterial baroreceptors in the carotic sinus in the
result of a transient spasm. A prominent fast drop of aortic arch are a high pressure mechanoreceptors,
the diastolic pressure can cause myocardial ischemia, that are activated when increasing the arterial pres-
the consequence of which is a lower cardiac output. sure. The activation of receptors is like an afferent
If the coronary arteries are changed as well (narrow- inhibition of the vasomotor centers. Next the ef-
ing in any segment by the atherosclerotic process), ferent sympathetic stimulation will be inhibited and
there will be vasodilatation after the constricted seg- hence the occurrence of vasodilatation and brady-
ment. It is caused by the accumulated metabolites, cardia. On the other hand when the blood pressure
that have vasodilitatory effects. In this situation the becomes low the afferent inhibition from the arte-
arterial blood pressure becomes a factor, that deter- rial baroreceptors on the vasomotor centers is. That
mines perfusion via the collateral arteries or via the is the reason why the sympathetic effect increases,
narrowed coronary arteries. resulting in vasoconstriction and tachycardia.
Both the mentioned systems are inhibitory. Apart
3.18.1.2 Nervous regulation from them there is a peripheral excitatory system,
that makes use of the chemoreceptors that are local-
An important part of the nervous regulation are the ized in the carotic area. They are activated in shock
receptors, that are placed in strategic areas. The when hypoxia takes place. Their activation has an
most important are the arterial baroreceptors in the excitatory effect on the medulla oblongata by means
carotid sinus area, in the aorta, the cardiopulmonary of the increased sympathetic activity and vasocon-
baroreceptor, chemoreceptor, and receptors of the striction. The other excitatory system is formed by
skin and muscles. The vasomotor centers in the the somatic receptors. These are actually metabolic
medulla oblongata are under the control of higher receptors that are activated by the metabolic prod-
centers in the central nervous system. By this the ucts in the working muscles.
sympathetic and parasympathetic regulation is mod- The excitatory effect on the medulla oblongata re-
ulated from the central nervous system. semble the sympathetic stimulation in the muscles,
The heart doesn’t only work as a pump of blood that yet effects merely the functioning muscles. The
even if this function is principally the most impor- result is a useful redistribution of blood. In case
tant one. The heart is a periphery sensory and en- of circulatory disturbances many reflex mechanisms
docrine organ. Baroreceptors are localized mainly might become interconnected. If eg. hypovolaemia is
in the posterior wall of the left ventricle. They are combined with hypoxia more mechanisms are acti-
activated as mechanoreceptors upon the relaxation vated. The result is not necessarily useful for the
and the contraction of the myocardium. When the organism, because there might be the activation of
preload is increased the ventricular relaxation recep- opposing mechanisms. That is why in myocardial
tors are activated and work as an afferent inhibitors infarction due to the loss of a part of the contractile
on the cardiovascular centers in the medulla oblon- myocardium and a low cardiac output there will be
gata. That is why the efferent sympathetic stimula- hypotension. This hypotension will act on the ar-
tion is decreased in these centers. On the contrary terial baroreceptor systems. At the same time there
during hypovolemia or upon the standing position will be diskinesia in the infarct area, that might cause
the afferent inhibition affect of the ventricular recep- a wrong information that signalizes a higher preload.
tors on the centers in the medulla oblongata is sup-
pressed. This is the reason why the afferent sympa-
3.18.1.3 Humoral regulation
thetic activation is promoted, and this will result in
vasoconstrictriction, tachycardia, and the release of For optimizing the haemodynamics even humoral
renin. The ventricular relaxation receptors can sig- factors play an important role. Renin, primary syn-
nalize incorrectly during myocardial infarction that thesized in the juxtaglomerular apparatus and regu-
the tension in the ventricular wall is high. lated by different stimuli, mainly the pressure in the
The outcome of this there will be an inhibition afferent arteriole, the concentration of Na+ in the
of the cardiovascular centers, worsening the pump- region of macula densa, the stimulation of the renal
3.18. Shock states (I. Hulı́n) 177

sympathetic fibers, the circulating angiotensin II and that are present in the vascular wall. Prostacy-
the concentration of electrolytes in plasma. Renin as clin is vasodilitatory agent that inhibits aggregation
a proteolytic enzyme converts angiotensinogen to an- of thrombocytes and vasoconstriction. The forma-
giotensin I. In the lungs angiotensin I is converted to tion of prostacyclines and thromboxan arises from
angiotensin II and III by the effect of angiotensin the arachidonic acid, that is a part of the mem-
converting enzyme. There are powerful vasocon- branous phospholipids. The trigger for its release
striction agents, that also facilitate a fast release might be a very slight injury. In the first phase
of noradrenalin from the sympathetic nerve termi- there is the formation of cyclic endoperoxid from
nals. Vasoconstriction aims to increase the blood which later prostacyclines and thromboxanes with
pressure. Angiotensin II increases the release of al- their mentioned effects of thrombocytes aggregation
dosteron with the resulting retention of Na+ and wa- are formed.
ter. Haemodynamics during trauma and shock is af-
During hypovolemia and upon increasing the os- fected even by neuropeptides. The most effective
molarity vasopressin is released from the posterior are endogenous opiates (β–endorphin), thyreotropin
lobe of the pituitary. Its vasoconstriction and an- releasing hormone and ACTH. β–endorphin and
tidiuretic effect is prominent during shock. Vaso- ACTH are readily formed in the hypophysis and they
pressin stimulates the release of ACTH and cortisol. are usually released during stress. They modulate
The release of vasopressin ceases upon stimulating the function of the vegetative nervous system. β–
the sensitive baroreceptors in the left ventricle, in endorphins are usually of importance during hemor-
hypervolemia, and arterial baroreceptors in hyper- rhage and septic shock. They most probably have a
tension. On the contrary the level of vasopressin is direct or an indirect modulated depressor effect on
markedly increased in cases of hypotension. Lower- the myocardium. Thyreotropin releasing hormone
ing the blood volume by 10 % its volume is a strong that is released during shock will improve the car-
stimulus for the release of vasopressin. The vaso- diorespiratory function.
pressin release is promoted by the central nervous Its function is probably an opposite to the β–
system as well after the higher angiotensin level. It endorphins function.
is very important to know that the release of vaso- Catecholamines are important modulators of the
pressin is stimulated by hypoxia and nausea as well cardiovascular function. Noradrenalin increases my-
and morfin. Catecholamines inhibit the release of ocardial contractility and the heart rate via the ac-
vasopressin. tivation of β–adrenoreceptors. That is why its func-
tion lies in the increase of the cardiac output. Nora-
To maintain the haemodynamics many other
drenalin however has mainly an α–adrenergic func-
polypeptides with local vasodilatatoray effect are of
tion and causes vasoconstriction in the skin vessels,
value. These polypeptides are formed by the ef-
muscles, splanchnic area but at the same time it has a
fect of some proteolytic enzymes on plasma protein
β2 –adrenergic mechanism and causes the vasodilata-
precursors. The classical prototype of this group
tion in coronary arteries. Adrenaline has got both
of endogenous peptides is bradykinin. The role of
α, β1 , β2 effects, it causes a mild increase in the car-
these peptides is the modulation of local perfusion
diac output.It causes redistribution of blood to the
via some organs. Their effect is very prominent in
muscles.
case of inflammatory processes, that are accompa-
nied with hyperemia. During shock they mainly in-
fluence the blood flow via the kidneys and pancreas. 3.18.1.4 Autoregulation of perfusion and
Renal kinins can increase diuresis and natriumuresis. changes in the microcirculation
During shock serotonin is released from the Autoregulation of tissue perfusion is most important
thrombocytes and histamine from mast cells. They in the cerebral vasculature, in the coronary field, and
affect the local circulation. What is important is that in the renal vessels. Its function lies in maintaining
they affect the capillary permeability. During hy- the adequate perfusion even in cases where the arte-
poxia that results from shock some substances might rial blood pressure is markedly low. In those vascular
be released and affect the formation of thrombi. areas there are no specific mediators. The tension
Prostacyclin is synthesized from the endoperoxides of the vascular wall is regulated by a combination
178 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

of changes of oxygen concentration, CO2 concentra- the micro circulation and the whole haemodynam-
tion, pH, osmolarity, the level of adenosine and other ics.
metabolic substances.
The most difficult problem in the pathogenesis of 3.18.1.5 Hypoxia and acidosis
shock is microcirculation. Every shock type is ac-
A very unfavorable factor that accompany shock is
tually the outcome of microcirculatory failure. The
hypoxia and acidosis. Tissue hypoxia and its degree
redistribution or shift of an adequate volume of blood
during shock is the factor that determines the clinical
into a certain organ is not the guarantee that all parts
manifestation of the individual organ injury. It is yet
of this organ and the capillaries will be perfused ac-
natural that the degree of hypoxia also depends on
cordingly to their metabolic needs. Blood in certain
the perfusion. Tissue hypoxia can not be separated
situations can leave a part of that organ without per-
from the value of oxygen saturation of the blood.
fusion. The total blood flow via the kidneys might
The O2 saturation in the arterial blood can be within
be only slightly reduced. Blood can only flow via the
the normal range and still the tissue hypoxia might
medullary part and that is why some serious changes
occur (e.g. during a prominently low cardiac output).
might occur in the cortex. Apart from this, blood
Hypoxemia whether (arterial or tissue) causes va-
flow is regulated via the capillary sphincters. Those
sodilatation in both the heart and the brain. Hypox-
sphincters are actually smooth muscles of the vascu-
emia activates chemoreceptors sensitive to low O2 .
lar wall, that is under the influence of many neuro-
The result will be sympathetic vasoconstriction in
humoral factors. In hypovolaemic shock the blood
the vessells of the skeletal muscles, skin, and in the
pressure drops and the activation of the sympathoa-
splanchnic area. Due to this vasoconstriction there
drenal system will result in vasoconstriction of the
will be redistribution of blood toward the vital or-
precapillary resistant vessels. As the result of all this
gans, that have a high requirement for O2 supply.
the intracapillary pressure will reduce as well and
Arterial hypoxemia with the secondary cellular hy-
hence fluid flows from the tissues intramuscularly.
poxia causes myocardial depression in many shock
If this condition lasts for longe time, vasoconstric-
types. Acidosis is the result of anaerobic metabo-
tion will gradually become weaker. It is caused by
lism with the cummulation of lactate and organic
the fact that in the tissue becomes acidosis. At the
acids due to the low renal perfusion.
same time the postcapillary resistance increases. In
this stage fluid escapes from the intravascular spaces Acidosis lowers myocardial contractility and the
into the tissues (interstitium). This condition might vasoconstriction caused by many endogenous and ex-
be caused by catecholamines. ogenous neurohumoral substances. We also have to
think about the fact that the treatment of shock by
Changes of the precapillary and postcapillary re- using many substances can have other effects: their
sistance affect the shift of fluids between the in- metabolism and excretion from the organism for ex-
travascular space and the interstitium. Along with ample might be changed.
this it affects some colloid osmotic pressure changes
that consequently change the capillary permeability.
That is very important in some organs. Any change 3.18.2 Shock
in the capillary permeability is sometimes so impor- Shock is a state of the circulation, in which there is
tant that it causes escape of the plasma proteins into an acute and marked low tissue perfusion. Initially
the extravascular spaces. These changes play an im- this state is reversible but later after its prolonga-
portant role in the development of pulmonary shock. tion and worsening it becomes an irreversible cellu-
During this shock there might be erythrocyte, lar damage. The low tissue perfusion is the primary
leukocyte or thrombocyte agglutinations. These factor that results in other changes. During shock
might obstruct capillaries and small arterioles. there are some changes that develop in the cardio-
Thrombocytes activated by catecholamines can form vascular system, and metabolism, and these changes
individual clusters. Hypoxia causes injury to the en- occur in a certain sequence and they are of different
dothelial cells, that will aggregate the accumulation degrees. Almost in every case we can find a severe
of micro thrombi. Endothelium forms free oxygen drop of the blood pressure and a low cardiac output.
radicals. These changes might worsen the state of All this will consequently end up by an inadequate
3.18. Shock states (I. Hulı́n) 179

blood flow through the tissues. Tissue hypoxia leads

to acidosis and some complex hormonal and humoral
changes.
The most important causes of shock are blood loss,
trauma, dehydration, burns, toxemia, gastrointesti-
nal perforation, myocardial infarction, anaphylaxis,
septicemia, peritonitis, pancreatitis, plureal punc-
tion and hydrocentesis (evacuation of large amounts
of ascitic fluid).
The classical picture of shock is rather typical.
There might be some consequence disturbances – ir-
ritability, apathy, confusion and coma. The skin is
usually pale, covered with cold sweat. The periph-
eral pulls is weakly palpable or thready. There is
usually tachycardia and a very weak unmeasurable
blood pressure, oliguria or anuria.
The low cardiac output is the cause of low organ
perfusion. Hypo perfusion might damage the heart
alone or the cardiovascular apparatus as whole. A Figure 3.18: Development of the shock
vicious circle would be closed by which the cardiac
hypo perfusion worsens its own function and by the
inadequate heart function hypo perfusion is getting
more prominent and so on. From this point of view
we might differentiate two different states of shock,
the progressing state, and the non progressing shock
state. See fig. 3.18 on page 179. (Blood transfu-
sion performed in cases of irreversible shock state will
only have a transitional haemodynamic effect but it
cannot prevent the circulatory failure).
The development of shock can be prevented ini-
tially. Here we are talking about the reversible stage
during which we can reverse the condition. But in
cases where the tissue hypoperfusion already caused
necrosis of cells in vital organs, shock is turning to
become irreversible. In this stage there is cardiac in-
jury as a result of the hypo perfusion with simultane-
ous hypoxia of the regulatory centers. Any approach, Figure 3.19: Acute decrease of blood pressure. The
or even the removal of the shock cause cannot in this haemodynamic’s fall down – see three bottom curves
stage prevent death. See fig. 3.19 on page179.
The low minute cardiac output is presented clin-
ically as a decrease in the arterial blood pressure. centile drop of the minute cardiac output. In case
There is a certain relation between the blood pres- we don’t respect this fact, we could overlook or mis-
sure measured in torr (i.e. in kPa) and the minute judge the hypo perfusion state as long as his arterial
cardiac output. This relation is true and can only blood pressure is within the absolute physiological
be applied for the diastolic values of the blood pres- range of values. In hypertensive people shock may
sure before the occurrence of shock. See fig. 3.20 on develop when there is lowering in the blood pressure
page 180. by about 40 torr. That is why we consider measur-
From the picture we can see, that the percentile ing arterial pressure the fastest and the most easily
decrement of the blood pressure is equal to the per- approachable parameter in determining the develop-
180 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

peripheral vascular spaces are actually filled with a

large volume of blood. And in this condition blood
does not return back to heart in adequate quantities.
The circulation is failing due to incorrect distribution
of blood. Sometimes there is a combination of septic
and hypovoleamic shock. It is a very complicate sit-
uation, from the etiologic as well as the therapeutical
point of view.

3.18.2.3 Cardiogennic shock

It is basically a normovoleamic shock which forms
a separated condition because it differs from other
types of normovolemic shocks. The basic difference
lies in the fact that in cardiogennic shock the left ven-
tricular filling pressure is increased. It occurs in my-
ocardial infarction (MI) when due to necrosis more
than 40 % of the left ventricular muscle mass is not
Figure 3.20: Relationship between % of blood pres- contractible. The left ventricle as a pump is failing.
sure decrease and stroke volume of the heart This condition may occur not only in cases of infarc-
tion, but even in acute myocarditis, depression of
myocardial contractility, in cardiac arrest, and post
ment of shock state. To understand all the changes
a long lasting cardiosurgical insult. Cardiogennic
that occur in the organism during shock it is neces-
shock occurs when, due to cardiac causes there is an
sary to differentiate among individual types of shocks
acute drop down of the blood ejection to the aorta.
according to their etiology.

3.18.2.4 Extra cardiac obstructive shock

3.18.2.1 Hypovolemic, oligeamic shock
Bleeding, or a heavy loss of fluids during vomit- We are dealing with a type a shock, that develops
ing, diarrhea, burns, and cases of dehydration cause during the pericardial tamponade. The low cardiac
volume is in this case caused by the inability of the
decrement in the blood volume. That is why there
ventricle to expand and be filled during the pres-
will be low venous return and ventricular filling.
ence a tamponade. Another type of the extra car-
This condition then shows itself, in form of low end-
diastolic volume and pressure in both ventricles. The diac obstructive shock is a shock during a massive
lowered preload results in lowered cardiac output. pulmonary embolism.
This is the most basic cause of many changes in the
organism, which aim is to remove this unfavorable 3.18.3 Some common signs of the in-
situation. dividual types of shock
A common danger or risk of every shock is the cel-
3.18.2.2 Normovolemic, distribution shock
lular death. When a certain number of cells in vital
Here the shock condition occur without any drop in organs (brain, heart, kidneys) are affected the shock
the blood volume. An example for this is the trau- is irreversible even when we remove its basic causes.
matic shock, which triggering mechanism is pain. The irreversible distraction of such a number of cells
Another type of distribution shock is the anaphylac- in this organ will lead to the failure of its function.
tic and septic shock. In cases of distribution shock This idea is very important mainly from the prac-
is the anaphylactic and septic shock. In cases of dis- tical point of view as we want to prevent the irre-
tribution shock the characteristic event is an enor- versibility of the shock. Another common sign of the
mously fast and markedly expressed lowering of the different types of shocks is lowering of the minute
peripheral resistance in the resistant vessels. The cardiac output. No matter what the causative agent
3.18. Shock states (I. Hulı́n) 181

is, shock starts to develop, when the perfusion of the contractility and tachycardia. Catecholamins are
life essential organs is low. At the very beginning released from the adrenals, mainly adrenalin.
thanks to the compensatory mechanisms the arterial A powerful vasoconstriction mainly in the cortical
blood pressure is kept within its normal levels. As area of the kidneys leads to low glomerular filtration
the cause of shock is not removed, after a certain eventually resulting in higher water and electrolyte
time the compensatory mechanisms become ineffec- reabsorbtion in the tubules. What favors this con-
tive. Here there will be wide clinical manifestation of dition is the increasing level of aldosteron and an-
a shock. When the shock lasts for long there will be giotensin caused by the high rennin release. Due to
cellular death and patient is in the irreversible stage the stimulation of osmoreceptors and vollumerecep-
of shock. tors there will be a release of ADH, that has itself a
The progression of hypovoleamic shock depends role in the water reabsorbtion in renal tubules. From
upon the volume of blood loss and the time pe- the previous mentioned facts the final result might
riod during which the loss occurred. Large volume be oliguria and anuria. Vasoconstriction is gener-
loss during short time has unfavorable prognosis. alized. Yet brain and heart are spared. Due to a
The effect of compensatory mechanisms depends on marked vasoconstriction there is not enough clear-
whether we are dealing with a young healthy, or an ance of acidic metabolites, that are formed in the
older sick individual. tissues during hypoxia.
The clinical signs of shock appear after a blood In the initial state of shock there will be an incre-
loss that is 20–25 % of the total blood volume. De- ment of the precapillar resistance, which effect lies
spite an intensive vasoconstriction the minute car- in the resulting low filtration pressure and fluid reab-
diac output drops down and hypotension appears. sorbtion into the capillaries. Later and due to the ef-
In this situation the cardiac and brain perfusion is fect of local products of anaerobic metabolism of his-
enfavoured and spared representing a marked com- tamin and kinin the precapillary resistance remains
pensatory mechanism. In some tissue the level of unchanged. This situation is shown as an increase
vasoconstriction is so intensive that it might result in in the filtration pressure with the consequences es-
tissue destruction and hens leads to ischemic necro- cape of fluids into the tissues. The capillary wall is-
sis. This might occur in the intestine, and the distal chemia do further help the already present fluid loss
parts of limbs. During further progression of shock across the capillary walls. As a result of this there
there will be a fast appearance of ARDS (adult respi- will be very low oxygen transfer to the tissues. As a
ratory distress syndrom), an acute renal failure, DIC result of the previous facts the erythrocyte concen-
(disseminated intravascular coagulation) and multi- tration is increasing. Small thrombotic loci are easily
ple organ injury. In this case we can not prevent formed. Their formation amplifies a slow blood flow
death. The mechanism leading to the final event of and thrombocyte aggregation.
heart failure is yet unknown. We may refer it to In cases of a serious injury, that causes no blood
the effect to metabolites of ischemic tissues, that has loss shock might develop after few hours. This usu-
some depressive effect on the myocardium. The car- ally happens after skeletal muscle and bone injury.
diac arrest might as well be the result of inadequate There might be loss of consciousness. The haemody-
coronary blood flow, acidosis, and the failure of reg- namic changes are similar to changes of distribution
ulatory center. in the normovolemic shock. A heavy trauma causes
Lowering the minute cardiac output is always a po- pain and this pain has its inhibitory effect on the
tent stimulus for baroreceptors. The basic effect lies CNS and it inhibits the vasomotor center. As a re-
in lowering the arterial filling no matter what is the sult of vasomotor center inhibition, the vascular field
evoking factor. Noradrenalin is produced from the capacity increases. And as a result there will be low
nerve endings. It stimulates a receptors in the arte- venous return, and cardiac output. The progression
rial and venous blood field. a receptors are mainly of shock is accelerated by the production of toxic
situated in the splanchnic area, the kidneys, and the substances from the necrotic tissues.
in skin. This is why vasoconstriction is most promi- A locus of infection is usually a predisposing factor
nent in these areas. The simultaneous stimulation for the occurrence of septic shock. Micro emboli of
of b receptors in the heart has an effect of increasing microbes are liberated from these loci. Other factors
182 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

released are histamin, kinins, prostaglandins, endor- of view we deal with an increased vascular capac-
phins, TNF (tumor necrosing factor), interleukin 1 ity. Moreover plasma leakes out from the vessels
and interleukin 2 that cause vasodilatation. Va- so the hypovolemia becomes even more prominent.
sodilatation overwhelms despite the fact that some This condition develops within few seconds or min-
prostaglandins and leucoteriens cause vasoconstric- utes post allergen application. First of all there will
tion. The heart reacts on this situation by an be itching, generalized edema, later there might be
increased cardiac output. Later acidosis develops headache, dyspnoe, stridor, nausea, vomiting and ab-
through the high cardiac output. This is most likely dominal pain. The course of symptoms is very fast
caused by the vasodilatation and elsewhere vasocon- and dramatic which may many times end by excitus.
striction that is caused by the circulating mediators.
At the beginning of the septic shock the cardiac 3.18.4 Clinical manifestation of shock
output is high, which may appear on the first sight as
a good functioning ventricles. Yet the ejection frac- Some clinical manifestation of shock are similar for
tion is small and the ventricles are dilated. A high all types of shock. Clinically the most reachable pa-
ventricular filling (preload) provide a normal cardiac rameter is the blood pressure as a value, that has a
output even in case of low ejection fraction. This certain relationship to the cardiac output. Yet we
is combined with tachycardia, and the result might have to keep in mind the fact that the mean arterial
be an increment of the cardiac output. The ejection blood pressure has an informative value only when
fraction is still decreasing and the ventricles become we already knew this value prior the occurrence of
even more dilated. Gradually there is a myocardial shock. Different mean arterial blood pressure dur-
injury accompanied with the situation and this is ing shock can be found in a normotonic individual,
most probably caused by some kind of myocardial a hypertonic, or a chronic hypotonic. For normo-
depression that results from a circulating myocardial tonic and hypertonic individual can a drop of blood
depressant factors the blood. pressure for about 40 mm Hg be considered to be a
manifestation of hypotension.
If the septic shock still continues, the peripheral
Another common signs of shock are tachycardia,
vascular abnormalities becomes combined with the
oliguria, disturbances of consciousness, as well as
myocardial injury. In these cases the mortality rate
cold extremities with numbness due to the reduction
might exceed 50 %. Death is caused by hypoten-
of blood flow. There is also metabolic acidosis.
sion and organ injury. Hypotension is usually severe
Other clinical symptoms are specific for individual
and mostly irreversible. Myocardial depression and
types of shock. Patients with cardiogenic shock have
the drop of the cardiac output worsen the already
the usual symptoms of a heart disease. They might
present hypotension. Renal, cerebral, and hepatic in-
have an increased filling pressure, gallop rhythm,
sufficiency occur in this stage. Apart from the men-
and signs of acute heart failure when the cardiogenic
tioned changes we sometimes notice neutrophilic ag-
shock results from mechanical causes, there will be
gregation, thrombus formation, and endothelial cell
the presence of some cardiac murmurs. This con-
injury. The result will be a prominently disturbed
dition usually occurs in cases of acutely developing
micro circulation and perfusion.
mitral regurgitation, or a ventricular septal defect.
A vast cellular death of important vital organs, Patients with pericardial tamponade can have pul-
shock becomes irreversible and despite all the care sus paradoxus. Patients suffering of hypovoleamic
given the patient dies. (oligemic) shock show an evident blood loss, com-
Anaphylactic shock occurs as a result of a general- monly in cases of a gastrointestinal blooding. There
ized reaction of antigen with antibody. This leads to might be a clear loss of fluids in cases of diarrhea or
reaction of antigen with antibody. This leads to com- vomiting. Patients with a distribution shock (in case
plement activation. The cascade system of comple- of sepsis) have signs of infection, fever, vasoconstric-
ment activation leads to the release of many media- tion, and shivering.
tors of the anaphylactic reaction namely the anaphy- Shock is a serious acute situation that requires
latoxins C3 and C5. Even histamin is released. And treatment and hospitalization. Everything should
the end result is a vast vasodilatation and high vas- aim to prevent the irreversible injury of the vital
cular permeability. From the haemodynamic point organs. That is why we first of all have to know the
3.19. Septic shock and septicemia (I. Hulı́n) 183

causative factor and the degree of shock. Initially we of infections caused by the gram-negative bacteria.
have to prepare an X-ray of the chest, ECG, pO2 , Staphylococci, pneumoccoci, streptococci, and other
pCO2 of the arterial blood and the pH. Yet the only gram-positive microbes are a less common cause of
way to determine the state of haemodynamics is by septic shock. Some viruses, mycobacterium, fungi
performing the cardiac catheterization. Generally in and protozoa play a particular role in developing of
every shock state we should provid e an adequate septicemia. It is not easy to prove the presence of
flow of blood via the coronary field, the kidneys, the microorganisms the blood by (haemoculture). Even
liver, the nervous system, and the lungs. To reverse in a fully manifested septicemia haemoculture might
the progression of shock it is necessary to keep the not reveal any microorganisms in the blood.
mean arterial blood pressure 60 mm Hg or more. The According to trustful statistics, during one year in
lactate value should be below 22 mmol/l. USA there is around 500 000 cases of septic shock
In case of the cardiogenic shock the situation is caused by gram- negative bacteria. Mortality rate
always very serious. The mortality rate in patients raches about 20 %. We are usually dealing with
with cardiogenic shock during myocardial infarction patients suffering of diabetes mellitus, liver cirrho-
reaches 90 %. Apart from the basic steps to handle sis, alcoholic patients, patients with leukemia, lym-
shock we have to solve the problem of myocardial phoma, and disseminated carcinoma. Further they
contractility and perfusion. The cardiac rhythm dis- are patients - who undergo cytostatic and immuno-
turbances are other undesirable complication. supressive treatment and patients with neutropenia.
It might as well occur in patients who are on the
parenteral nutrition, in those having urinary tract in-
fections and gastrointestinal infections including the
gallbladder and the billiary tract. Another predis-
posed groups for septicemia are the new born and
3.19 Septic shock and septice- the elderly. Gram positive bacteria appear during
the long lasting or repeated cathetarization and with
mia long lasting antibiotic or glucocorticoid therapy. Pre-
viously there was a high incidence of post abortive
and post puerperal sepsis as a result of endometrial
and its surrounding structures invasion by strepto-
When microorganisms and products of the inflam- cocci. This condition was usually complicated by
matory process reach the blood flow they might end septic thrombophlebitis of the pelvis, peritonitis, or
up as a state known as sepsis (septicemia). Sep- the formation of abscess.
ticemia is characterized by fever, rigor, tachycar-
The clinical manifestation of septicemia and sep-
dia, tachypnoe, vasodilatation, and disturbances of
tic shock are based on the simultaneous action of
consciousness at different levels. When simultane-
microorganisms with the immune and the mediator
ously with this there is a developing hypotension
systems of the concerned organism. At the level of
and hypo perfusion of organs we name this condi-
micro circulation a vicious circle develops between
tion as a state of septic shock. It has a very dra-
the decreasing tissue perfusion and the worsening of
matic clinical symptomatology. Hypoperfusion is a
the endothelial quality. This results is tissue injury.
result of a low vascular resistance, a low pumping
If we don’t interrupt this vicious circle the condition
function of the heart, and a disturbed micro circula-
usually ends by death.
tion. Changes in the cardiac output in septic shock
are known as the adapted compensatory mechanisms Among the most important microbial factors,
of shock. Hypoperfusion will lead to a diffuse cellu- that initiate the changes of septic shock are the
lar and tissue injury. Upon reaching a certain value lipopollysacharides of the gram-negative bacteria,
the signs of multiple organ injury and failure become specifically lipid A and peptidoglycans of the gram-
manifested. In this case and despite all the care given positive bacteria. Even polysaccharides and extra
death can not be avoided. cellular enzymes or toxins such as streptokinase and
Septicemia may result from all acute infections. staphylococcal endotoxins can be manifested.
Septic shock on the other hand usually occur in cases The mediators of the injured organ play a very
184 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

distinguished role in the pathogenesis of the septic proven clinically that there is a close correlation be-
shock. Those are mainly the active metabolites of the tween the value of TNF, and the serious of shock
complement, kinin, and coagulation systems. Medi- and the mortality. Yet the correlation between the
ators such as cytokines, TNF (tumor necrosis fac- TNF value and the IL-1 level is less prominent. TNF
tor), interleukin-1, enzymes and oxidants from the and IL-1 act synergeously even in the experimental
polymorphonuclear leukocytes, vasoactive peptides, conditions.
products of arachidonic acid metabolism are released They liberate lipids from the adipose tissue and
from the stimulated immunocompetent cells. they cause hyperlipidaemia. They stimulate hep-
To antagonize the destructive action of the previ- atic glycogenolysis and gluconeogenesis. Further-
ously mentioned factors there will be a release of anti- more they inhibit the synthesis of albumin and hence
coagulants, catecholamins, angiotensin, hypophysial leading to hypoalbuminaemnia. TNF and IL-1 lib-
hormones, insulin, and glucagon. erate glucagon and insulin from the pancreatic cells,
Lipopolysacharides (LPS) of the gram-negative ACTH from the hypophysis as well as beta endor-
bacteria activate both the complement, kinin, and phins, growth hormone, and ADH.
the coagulation systems at the same time (see In experimental conditions it was found that by
fig. 3.21 on page 185). inhibiting cyclooxygenase or thromboxan synthesis
The coagulation system and kinin system activa- it is possible to inhibit the progression of the septic
tion accomplished via the activation of Hageman endotoxic shock. The level thromboxan B2 (TXB2 )
factor. The cascade of coagulation then continues. and the end product of the prostacyclin metabolism
Hageman factor changes prokalikrein to kalikrein 6-keto-prostaglandin F1 alfa, found to be high in
(scheme). Bradykinin and other kinins increase the patients with sepsis. Thromboxan produced by ac-
capillary permeability. The complement system ac- tivated thrombocyte and polymorphonuclear leuko-
tivation takes place via the alternative way and re- cytes act as thrombocyte aggregating substance, and
sults in C3a and C5a formation. These factors cause apart from this they stimulate pulmonary vascula-
an increase of the capillary permeability and vasodi- ture vasoconstriction. Prostacyclines produced by
latation. Lipopolysacharides increase thrombocyte the endothelial cells antagonize the effect thrombox-
aggregation and their adhesion to the endothelial ans. Prostacyclines act as vasodilatation agents and
cells. Furthermore they enhance the release of the they increase capillary permeability. The formation
lyzozyme enzymes, and they activate the formation of these substances as well as the formation of clas-
of super oxides. sical prostaglandins of the E series by different cell
might be induced by interleukin-1 and TNF or even
Lipopolysacharides together with other bacterial
LPS. Circulating PGE2 act as a vasoconstrictor and
products during sepsis stimulate the formation and
it potentiate and increase the gastrointestinal motil-
the release of interleukin-1 (IL-1) and tumor necro-
ity.
sis factor (TNF) from macrophages, endothelial cells,
and most probably from some other cells of the or- LPS has a direct effect on polymorphonuclear
ganism. IL-1 is responsible for the high body tem- leukocytes, thrombocytes, macrophages, and most
perature (fever) during sepsis due to affecting the hy- cells. They increase the formation of leukotriens
pothalamic thermoregulation. It was shown experi- and platelet activating factor (PAF) in these cells.
mentally that the application of TNF to experimen- Leukoteriens may predispose to pulmonary edema.
tal animals evokes similar changes to those changes PAF cause thrombocyte aggregation, vasodilatation,
accruing in septic shock. After the application of and increases the permeability of the capillaries.
TNF we will notice the appearance of hypotension, Endothelial cells and microcirculation are buffers
an injury to the lungs and pulmonary circulation for the released substances and the on going de-
with the formation of leucocytic and thrombocytic structive processes. This is provided by pre cap-
thrombi, intestinal haemorhagic necrosis, acute renal illary blood shunts and post capillary venule ob-
failure, metabolic acidosis and animal death. Gluco- struction by polymorphonuclear leukocytes, throm-
corticoids block the effect of TNF and even the effect bocytes thrombi, and fibrin deposits. A gener-
of IL-1. In normal subjects we notice the appearance alized condition known as the fenestrated capil-
of TNF in the plasma post LPS application. It was lary syndrom is usually manifested by pulmonary
3.19. Septic shock and septicemia (I. Hulı́n) 185

Figure 3.21: Effect of lipopolysacharides in septic shosk

oedema. Kinins, C3a, C5a, histamin, arachidonic tion and renal and hepatic failure prominently wors-
acid metabolites, protease and oxygen radicals all ens lactic acidosis. Hypoxia becomes deeper even
take part on the vasomotor injury of the large vessels due to pulmonary complications. There will be for-
and capillaries. Tissue hypoxia and cellular death is mation of pulmonary edema, hemorrhages, and cap-
the end result of the micro circulatory disturbance. illary thrombi.
The cardiovascular changes in septicemia and sep- Thrombocytopenia is a common accompanying
tic shock differ from the cardiogenic hypovoleamic symptom of septicemia. It results from a direct LPS
shock by the fact, that in septic shock the periph- action, and thrombocyte activation (aggregation).
eral (vascular) resistance is low whereas the minute The simultaneous activation of Hageman factor has
cardiac output is high. The disturbed microcircula- its share in the formation of disseminated intravas-
tion on the non rational distribution of blood are the cular coagulation.
result of many simultaneously acting vasodilatatory Renal hypoperfusion can end up by acute renal
and vasoconstricting factors. The capillary leak of failure. The renal injury is initially presented as olig-
fluid ends up by hypovolemia. A refractory hypoten- uria, azotemia, and proteinuria. The development of
sion and a continuously low peripheral vascular resis- tubular necrosis may occur later on.
tance worsens the already present acidosis this even- Loci of necrosis may be formed in the myocardium
tually leads to multiple organ injury and finally death and they may lead to heart failure. In the intestines
occurs. The pulmonary circulation changes accord- there might be some haemorhagic necrosis. In the
ingly depending on the level of pulmonary edema, end stage hepatic necrosis develops. The clinical
the degree of hypoxia and acidosis. The destruction manifestation of septic shock were mentioned pre-
reveals ARDS (adult respiratory distress syndrom). viously. Fever and chills are not a condition in the
The plasma concentration of lactate increases from clinical manifestation of the septic shock. In some
the beginning of sepsis. Lactate is produced by hy- patients a raise in temperature is not found at all
poperfusion tissues. The progressing vasoconstric- (anergia). These are usually elderly patients, alco-
186 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

holics, and uremic patients. This condition always conditions for the mural trombus formation. This
carries bad prognosis. trombus gets organized with time but with the re-
Septicemia with disseminated intravascular coag- peated occurence of this process it in fact extends
ulation is usually accompanied by acrocyanosis and and progressively narrows or acutely occludes the
necrosis of the peripheral sites of the body. In some artery.
patients we may notice an initial nausea, vomiting, In advanced stages of atherogenesis the athero-
diarrhea or ileus. An upper GIT bleeding may ap- matous plaques undergo some relevant changes, e.g.
pear. disruption ulceration (cell necrosis on the top of the
If septic shock takes place in patients with another plaques), or intraplaque haemorrhage and intramu-
serious disease the prognosis is always bad. Mortality ral haemorrhage into the surrounding artery wall.
due to septic shock is about 25 %. The highest mor- Plaque disruption and ulceration considerably in-
tality occurs within the first 48 hours, and is caused crease the disposiotion to the formation of super-
by the irreversible shock with all its drawbacks. ficial thrombi. Intramural haemorrhage also pro-
duces acute narrowing of the artery lumen. Ad-
vanced plaques affected by these changes, i.e. calcifi-
cation, ulceration, haemorrhage and thrombosis are
so-called ”complicated atheromatous lesions”. Only
3.20 Etiopathogenesis in this stage of atherosclerosis a clinically significant
occlusion of the artery followed by ischaemia of the
of atherosclerosis supplied region originates. Complicated atheroma-
tous lesions may crumble and the pulpy fat-tissue
debris and other constituents of the plaques may get
loosened into the lumen of the artery and may be a
In the last 40 years cardiovascular diseases are in source of microembolisation.
all economically developed countries of the world the
major cause of morbidity and mortality. Their sub- Atherosclerosis affects mostly aorta, elastic and
stantial part is due to atherosclerosis. In our country elastic-muscular type of arteries (large and medium
the number of these diseases continues to increase in size arteries). Atherosclerotic lesions may develop
contrast to countries such as USA or Sweden where separately only in one vessel region (e.g. in aorta,
this number has been already decreasing for several in coronary carotid, cerebral, legs, renal, or mesen-
years. The consequences of atherosclerosis in our terial arteries), or it may be a diffuse affection of
country cause about 56 % of all deaths in the age be- the whole arterial system (generalized atherosclero-
tween 35 to 65 years, i.e. in the working productive sis). The affections of the coronary (ischaemic heart
population. Furthermore, their occurence is shifting disease followed by myocardial infarction), cerebral
towards younger age groups. From the point of view (haemorrhage or encefalomalacy) and lower extrem-
of pathological anatomy the basis of atherosclerosis ities (gangrene) arteries are the most frequent occu-
is a focal accumulation of lipid substances and an rances with serious clinical consequences.
increased amount of connective tissue components In conclusion, atherosclerosis is a long-term, very
within the arterial intima resulting in a subsequent complicated and complex pathological process caus-
oringin of focuses of pulpy fat-tissue debris known as ing lesions of the arterial wall. It is asymptomatic
atheromatous plaques. These plaques protrude into for a long period of time and gets clinically manifest
the arterial lumen and cause its narrowing. Within only when complicated atheromatous lesions occur.
the atheromatous calcium salts may be deposited Clinical consequences of atherosclerosis appear par-
later (calcificated plaques). The consequence is a ticulary because of the occlusion of the corresponding
substantial loss of the arterial wall elasticity so that artery, or sometimes because of the aneurysmatic di-
the arteries are no more able to allow for an increased lation of the artery (an atheromatous lesion of the
blood flow during higher oxygen demands of the tis- arterial wall leads to its weakening, which causes an
sues. aneurysm formation). Clinical symptoms differ ac-
The endothelium damage and the blood flow tur- cording to the affected organ, or part of the vascular
bulence in the place of atheromatous plaques create region.
3.20. Etiopathogenesis of atherosclerosis (L. Zlatoš) 187

In the past as well as at the present time great at- endothelial function causes increase of transcellular
tention was focused upon the research of the patho- transport of plasma lipoprotein macromolecules and
genesis of atherosclerosis. According to present may be manifested by:
knowledge atherosclerosis is not caused only by one
pathogenetic stimulus, but undoubtedly by more fac- 1. An increasing number of pinocytic vesicles in the
tors of the internal and external environment which endothelial cells.
participate in its origin and development. Thus, 2. Formation of bigger pinocytic vesicles at the lu-
atherosclerosis has a multifactorial genesis. Accord- minal pole of the endothelial cells.
ing to the currently accepted hypothesis the first
step at the beginning of the long-term developing 3. Joining of the vesicles in the endothelial cell cy-
process of atherogenesis is the damage of the en- toplasm and forming big transport vesicles.
dothelial layer of the arterial wall (the hypothesis
of a repeated or chronic microtrauma of the en- 4. Forming transcellular channels after the fusion
dothelium). The most important atherogenic fac- of pinocytic vesicles at the luminal and basal
tors today are considered to be hemodynamic stress, ends poles of the endothelial cells.
low-density lipoproteins (LDLs), very low-density
There are also several types of disorders of the
lipoproteins (VLDLs), vasoactive substances (mainly
endothelial morphological integrity:
catecholamines and angiotensin), immunocomplexes,
endo- and exo-toxins, hypoxia and viruses. The 1. A partial damage of compact intercellular junc-
atherogenic factors may act separately or in com- tions caused by intensive endothelial-cell con-
bination. Their atherogenicity is multiplied by in- traction (vasoactive substances provoke the con-
creasing their number. They damage the endothe- traction of actin fibres in endothelial cells), or by
lium of the arteries by their mechanical, cytotoxic or the the direct demage of intercellular material
metabolic effects. by the atherogenic factor itself. Plasma is cu-
Focal endothelial damage provokes in the place of mulating in these gaps and its components get
its origin two processes which have very important into the cells by endocytosis not only through
role in atherogenesis: the luminal pole of the endothelial cells but also
through their side wall.
• increased endothelial permeability to plasma
macromolecules, especially lipoproteins (LDLs 2. A complete opening of the intercellular junc-
and VLDLs), which are increasingly transported tions. Blood components get straight into the
into the intima. subendothelial space through these intercellular
ductuli, but also by endocytosis through the side
• response of the arterial wall, which leads to
wall of the endothelial cells.
interactions between cellular blood elements
(platelets, leucocytes, monocytes and lymfo- 3. Death of the endothelial cells (necrosis and
cytes) and the arterial wall. desquamation). At the beginning there is a
From the pathogenetic point of view the most im- higher transport of plasma components through
portant are adhesion and aggregation of platelets in the anatomically damaged cells. Later, after
the place of endothelial damage, and adhesion and their desquamation, there is a straight connec-
penetration of circulating monocytes into the intima. tion between blood and the subendothelial tis-
So the atherosclerotic lesion develops as a reaction sue.
of the arterial wall to endothelial damage. This re- 4. Endothelial cells can flatten, and so, because of
sponse has many signs of an inflammatory process a path shorthening, an increase of transcellular
(increased permeability, neutrophils and monocytes transport of plasma macromolecules may occur.
adhesion, monocytes migration).
The atherogenic factors can cause several types of Many observations from the last years showed
a focal injury of the arterial endothelium. There are that the relationship between endothelial injury and
conected with breaking of the functional or morpho- atherogenesis is not as simple and straight as it had
logical integrity of the endothelium. A disorder of been believed initally. It was concluded that for the
188 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

origin and development of the atherosclerotic lesion more platelets, damage endothelial cells, increase en-
the status of the morphological integrity of the en- dothelium permeability, iniciate the inflammatory
dothelium is not so decisive as the actual functional reaction of the damaged arterial wall and stimu-
status of the endothelial cells. Crucial is the func- late the migration and proliferation of media smooth
tional integrity disorder of the endothelium, i.e. a muscle cells. From the platelet factors the most im-
dysfunction of endothelial cells. When trying exper- portant for atherogenesis are:
imentally to deendothelize the artery it was found
that in places with a new endothelial layer there 1. ADP and tromboxan A2 – powerful potentiating
was a thicker intima and an accumulation of larger factors of platelets aggregation.
amount of lipids in the subendothelial space than
2. Serotonin, which increases the permeability of
in those parts of the artery wall which were still
the endothelium.
noncovered by the endothelium. This means that
at the beginning of reendothelization the function of 3. Lysosome enzymes – destructing the surround-
the new endothelium is not fully recovered. So, for ing tissue and thus further increasing the en-
the lipid accumulation in the intima the endothelial dothelial permeability.
functional status is more important than its anatom-
ical presence. That shows that for atherogenesis the 4. The platelet-derived growth factor which is of
transcellular transport of plasma lipoprotein macro- the greatest importance for the patogenesis of
molecules into the intima of the artery is more im- atherosclerosis. It iniciates migration of smooth
portant than their intercellular transport. It means muscle cells from the media through the open-
that it is not the absence of the endothelium, but ings in internal elastic lamina into the intima
rather its dysfunction that will cause a higher lipid and also stimulates their proliferation.
accumulation in the intima and its thickening.
There is evidence that vascular myocytes prolifer-
Although we gained much new information there
ation is stimulated also by some plasma components,
is still missing an exact definition of the endothelial
which get into the subendothelial area because of the
dysfunction, the presence of which is a crucial condi-
endothelium permeability disorder. These are low
tion for the development of arterial wall atheroscle-
density lipoproteins (LDLs), fibrinogen and insulin.
rotic lesion. It seems that the dysfunction may mani-
It seems though that the platelet-derived growth fac-
fest itself not only by a higher transendothelial trans-
tor plays a crucial role in the initial state of atheroge-
port of lipoprotein macromolecules, but also by de-
nesis. It acts as a starter of myocytes migration and
creased prostacyclin synthesis, increased synthesis of
proliferation. The above-mentioned plasma compo-
the endothelial cells growth factor, glycosaminogly-
nents cumulating in the intima below the place of
cans and by decreased tissue plasminogen activator
the endothelium damage have only a supporting role
synthesis in endothelial cells. The presence of other
in stimulating of the proliferation of migrated my-
changes of metabolism and function of endothelial
ocytes.
cells are also presumed.
What is the role of monocytes in the pathogenesis
In the place of endothelial damage (caused by of atherosclerosis – that was the question mainly for
atherogenic factors) adhesion and aggregation of intensive recent studies. It was demonstrated that
platelets and the release of the content of their gran- on the luminal surface of the artery, at the place of
ules occur immidiately. This is the next important endothelial damage, margination and adhesion of cir-
step in pathogenesis of atherosclerosis. There is ev- culating monocytes occur very soon. It is followed by
idence that the adhesion of platelets can occur also their penetration between the endothelial cells and
on a morphologically intact surface of endothelium, so they become localized subendothelialy where they
e.g. during a decreased synthesis of endothelial cell undergo conversion into macrophages.
prostacyclin (PGI2 ) and an increased synthesis of The migration mechanism of blood monocytes into
platelets tromboxan A2 (TXA2 ), which result from the subendothelial space of the arterial intima is not
hypercholesterolemia and hyperlipoproteinemia. exactly known yet. It seems that their adhesion to
The substances released from the granules of the vascular endothelium is initiated by platelets,
the activated platelets potentiate the agreggation of which are the first from the blood cells ahering to
3.20. Etiopathogenesis of atherosclerosis (L. Zlatoš) 189

the arterial wall in the damaged part of endothe- of atherosclerotic lesion development. The interac-
lium. The platelet-derived growth factor is chemo- tion between blood monocytes and neutrophils, and
tactic not only for media smooth muscle cells, but the arterial endothelium already from the first hours
also for circulated monocytes. It is presumed that after endothelium damage as well as the following ac-
in migration of blood monocytes also participate the cumulation of monocyte-macrophages in the intima
chemotactic factor of the damaged endothelial cells, below the damaged place are signs of inflammatory
the smooth muscle cells chemotactic factor and the mechanisms participating in atherogenesis.
chemotactic factor of macrophages cumulated in the
A subject for intensive studies is also the role of
intima. In the last years the attention of experts is
participation of the endothelial cell growth factor in
concentrated especially on the oxidized LDLs. They
the proliferation of arterial wall myocytes. Beside the
study not only their participation in monocytes mi-
fact that this factor is released from the undamaged
gration but mainly their role and mechanisms of ac-
cells around the place of the endothelial desquama-
tion in the pathogenesis of atherosclerosis. During a
tion (the aim is the reendothelisation), its production
long-lasting hypercholesterolemia and hyperlipopro-
can probably be stimulated also when a dysfunction
teinemia the molecules of plasma LDLs circulate for
of endothelial cells due to hypercholesterolemia and
a longer time, so there is a higher probability that
hyperlipoproteinemia occures.
their molecules will be oxidized, acylated, or oth-
erwhise modified. Oxidized LDL molecules are not In connection with the participation of arterial
only very cytotoxic, but when transported into the wall myocytes in atherogenesis it is important to
intima they can be chemotactic for monocytes and mention the hypothesis of benign neoplastic origin of
in that way induce their migration. the myocytes population with the autonomous pro-
Clinical and experimental studies have shown that liferation in the atherosclerotic lesion. Several meth-
monocyte – macrophages may participate in athero- ods have shown that myocytes of the atherosclerotic
genesis by several mechanisms the most important of lesion have a monoclonal origin (are derivated from
which are: one cell or one clone of myocytes). This hypothesis
presumes that it is a reaction of media myocytes to
1. Synthesis and release of the growth factor, which unnown mutagenic factors, e.g. chemical substances
stimulates the proliferation of myocytes in the or viruses. On the other hand there are some find-
arterial wall. ings showing that early atherosclerotic lesions are not
monoclonal but polyclonal. And so it seems that
2. Accumulation of lipids followed by formation
the monoclonal lesions develop only later due to the
of macrophage-derived ”foam cells” of the
selection of cell subpopulations during the develop-
atherosclerotic lesion.
ment of atherosclerotic lesion. Some scientists see
3. Production of reactive forms of oxygen. the basis for monoclonal origin of atherosclerotic le-
sion myocytes in the fact that some media myocytes
4. Release of some types of proteases. are tetraploic or more polyploic. It is especially this
genoma instability which is brought into relationship
5. Modulation of the arterial wall imune reaction.
with the greater proliferation readiness. The hypoth-
6. Chemotactic factor production. esis of monoclonal origin of atherosclerotic lesion my-
ocytes is not in contradiction to the hypothesis of
It seems that in the proliferation of arterial wall the crucial role of endothelial dysfunction and growth
myocytes the macrophage-derived growth factor is factors production in atherogenesis. It is only its sup-
at least as important as the platelet factor. Platelets plementation - though in another type of the mecha-
adhesion to the arterial wall and the release of the nism of arterial wall myocytes proliferation. Smooth
content of their granules is most intensive in the first muscle myocytes of the arterial wall have preserved
24 hours after the endothelial damage. Therefore, the characteristics of multipotent mesenchyma cells.
some authors presume that a continuous presence of After the myocyte migration from the media into
monocyte-macrophages in the intima below the dam- the intima their contractile status changes to a syn-
aged endothelium could be important not only at thetic status. After having migrated into intima and
the beginning, but mainly in the subsequent phases having lost their contact with other media myocytes
190 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

they get very sensitive to the effect of growth fac- of the early atherosclerotic lesion myocytes prolif-
tors, which stimulate them to intesive proliferation. eration and production of connective tissue com-
In the intima proliferated accumulated myocytes be- ponents continue. The intimal myocytes accumu-
gin an intensive synthesis and a production of con- late large amounts of lipids, mainly cholesteryl es-
nective tissue matrix, i.e. collagen, elastin and gly- ters. This process of intracellular lipids deposition
cosaminoglycans, mainly dermatan sulfate and hep- is followed by formation of myocyte-derived ”foam
aran sulfate. There is evidence that a higher content cells”. However, in progressing atherosclerotic le-
of glycosaminoglycans in the subendothelial space is sions lipids are mainly accumulated in mono- cyte-
caused by their higher synthesis and production by macrophages of the intima and these are transformed
damaged endothelial cells. Glycosaminoglycans and into macrophage- derived ”foam cells”. The amount
mainly dermatan sulfate have a high affinity to low- of foam cells in intima is progressively increasing.
density lipoproteins and together they create a non- Later many of these lipid overloaded foma cells rup-
soluble complex. That is why their higher production ture and necrotize and release their lipids droplets
is supposed to play an important role in lipoprotein into the surrounding extracellular space. So besides
accumulation in arterial intima. the continuous intracellular lipid accumulation there
Smooth muscle cell multiplication, and collagen, is present also their extracellular deposition. These
elastin and glycosaminoglycans accumulation in the progressing atherosclerotic lesions of the arterial wall
intima result in the formation of the fibromuscular are spreading and deepening. This process results
plaque which is considered to be an early atheroscle- in the formation of advanced atherosclerotic lesions
rotic lesion. called ”atheromatous plaques”. The core of this ad-
vanced plaques contains fat-cellular debris (necrotic
Recent imunohistochemic studies have shown
foam cells, extracellular lipid droplets, cholesterol
that not only in the early but also in the ad-
crystals and later also deposits of calcium salts).
vanced atherosclerotic lesions T-lymphocytes and
This central core of atheroma is at the luminal side of
imunocomplexes are often present beside monocyte-
the artery covered by a fibromuscular layer (collagen
macrophages. Their presence in an atheroscle-
and elastin fibrils and smooth muscle cells), called a
rotic lesions hints at imune mechanism participa-
”fibromuscular cap”.
tion in atherogenesis. An accelerated development of
atherosclerosis was observed in patients with a high As mentioned above, the terminal stage of athero-
concentration of circulating imunocomplexes and genesis results in complicated atheromatous le-
also in patients with a heart transplantation (a very sions. Their characteristics are ulceration, superficial
fast development of coronary arteries atherosclero- thrombosis, haemorrhage and/or calcification. Only
sis). these complicated lesions cause the origin of serious
From the early stages of atherogenesis, i.e. when clinical symptoms of atherosclerosis.
a fibromuscular plaques aris, the arterial wall lesions
may continue to develop in two directions. If the Recently the investigators have focused on the
atherogenic factor will not be effective any more study of the mechanism of lipid accumulation in
the endothelial cells will regenerate and restore their monocyte-macrophages and their transformation
normal function. The result of the previous lesion into foam cells of the atherosclerotic lesion. It is well-
is only a mild local thickening of the intima having known that under physiological circumstances there
one ore two layers of myocytes. Smooth muscle cells is a continuous transendothelial lipid transport from
are normally not present in the intima there. During blood into intima and media, and so the nutrition of
the lifetime the vascular system of everyone probably these two layers is provided directly from the vessel
undergoes many such microtraumas of the endothe- lumen. On the contrary, the nutrition of the adven-
lium. Under favourable circumstances these always titia is provided by its own capillaries – vasa vaso-
regenerate and the result is only a cellular fibrous rum. Under physiological conditions there is a bal-
thickening of the arterial intima. ance between the supply and the consuption of lipids
On the other hand, if the effect of the athero- in vessel cells, respectively their removing from arte-
genic factor operates repeatedly or continuously, rial wall. One of the crucial pathogenetic mechanism
the atherosclerotic process progresses. In the place of atherogenesis is breaking this balance followed by
3.20. Etiopathogenesis of atherosclerosis (L. Zlatoš) 191

lipid accumulation in intima cells (macrophages and great amount of lipids (mostly cholesteryl esters) be-
myocytes). cause these receptors do not respond to the feedback
The most important plasma cholesterol-carriers regulation. It leads to their transformation into fat-
are LDLs. LDLs transport cholesterol mainly from laden foam cells.
the place of its synthesis (in the liver) to tissues Thus, it can be concluded that pathologically in-
(also to the arterial wall), and that is why they are creased modification, especially the oxidation of LDL
such an atherogenic factor. High density lipopro- molecules plays the key role in the development of in-
teins (HDLs) contain less amount of cholesterol than tima foam cells and, therefore, also in pathogenesis
LDLs, and they are the main transport system of of atherosclerosis. Oxidized LDLs may be involved in
cholesterol from the extrahepatic tissues (that means atherogenesis also due to their cytotoxic effect upon
also from the arterial wall) to the liver, where choles- endothelial and smooth muscle cells of the arterial
terol is degraded into bile acids. To a certain extent wall.
HDLs protect the arterial wall from the devepolment In recent years a great deal of scientifical activ-
of atherosclerosis and so they are called ”antiathero- ity has been focused on the study of the role of
genic lipids”. long-chain polyunsaturated fatty acids in atheroge-
Most tissues, including arterial wall smooth mus- nesis. There are several experimental and clinical
cle cells can take up plasma LDLs with the help of observations, which indicated that the esential fatty
membrane LDL-receptors. After a LDL-molecule acids participate in the development of atheroscle-
links with a cell receptor, an endocyte vacuole arises rotic lesions, as well as in their thrombotic compli-
and is hydrolysated by lysosome enzymes. LDLs cations. It was shown that cause of low mortality
are catabolised according to the needs of the cell. from ischaemic heart disease in Eskimos and partly
The interaction between LDLs and membrane LDL- also in Japanese is due to a regular consuming of
receptors has the basic influence on intracellular large quantitis of sea fish. In the fish oil there is a
cholesterol metabolism. An increase of intracellular high ratio of polyunsaturated fatty acids to saturated
cholesterol concentration inhibits its synthesisin the fatty acids. Further it was found that among the
cell, increases its esterification and inhibits the num- polyunsaturated fatty acids of seafood the majority
ber or the activity of the membrane LDL-receptors. is represented by omega-3 (eicosapentaenoic acid –
This LDL catabolism regulation through a feedback C20:5 ,n-3 and docosahexaenoic acid – C22:6 ,n-3) and
mechanism protects cells against uncontrolled uptake not omega-6 fatty acids (linoleic acid – C18:2 ,n-6,
and intracellular cumulation of cholesterol. A dis- arachidonic acid – C20:4 ,n-6 and docosapentaenoic
ability of cells to degrade LDLs is due to a com- acid – C22:5 ,n-6). There is evidence that omega-3
plete lack or a great insufficiency of membrane LDL- fatty acids have a protective effect in atherogene-
receptors, as it is e.g. in familial hyperlipoproteine- sis. Meals prepared from fish (mainly mackerel and
mia (type II.). carp) are highly recomended as an important part of
In various pathological conditions the plasma level the anti-atherogenic diet. On the contrary, vegetable
of oxidized or otherwise modified LDLs can in- oil contains mainly omega-6 fatty acids, in particu-
crease. In contrast to native LDLs, modified LDL- lar C18:2 ,n-6 and C20:4 ,n-6. But some vegetable oils
molecules are not well recognized by membrane LDL- (walnut, rape-seed, soya beans and flax-seeds) con-
receptors. Therefore their catabolism is not regu- tain also a bigger amount of linolenic acid (C18:3 ,n-3)
lated by the feedback mechanism, but by compen- which is one of omega-3 fatty acids.
satory way, when especially monocyte-macrophages It was found that the eicosapentaenic acid
come into play and these become progressively trans- (C20:5 ,n-3) is a false substrate for prostaglandins
formed into foam cells. The alternative way of tak- synthesis. Instead of TXA2 which is (synthetized
ing up chemically modified LDLs is provided via a from C20:4 ,n-6) and causes aggregation and vasocon-
mediation of monocyte-macrophages specific mem- striction, in platelets is syntetized TXA3 which has
branereceptors, known as scavenger receptors (acyl- reduced platelet aggregatory effect. On the other
LDL-receptors). Owing to the mediation of these hand, the arterial wall endothelial cells synthesize
receptors, but also to beta-VLDL-receptors the ar- from eicosapentaenoic acid prostacyclin PGI3 that is
terial intima macrophages are able to accumulate a biologically fully active – antiaggregating and vasodi-
192 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

lating features are the same as those of PGI2 which of foam cells and extracellular lipid deposition
is synthesized from arachidonic acid – C20:4 ,n-6. occur which result in the origin of the athero-
PGI3 so increases the total antiaggregating activity matous plaque.
of prostacyclins. Besides that, it seems, that eikos-
apentaenoic acid competitively inhibits cyclooxyge- 5. The origin of complicated atheromatous lesions
nase, which also results in the reduced TXA2 pro- (ulceration, superficial thrombosis, calcification
duction. Recent observations showed that omega-3 and haemorrhage) which are conected with the
fatty acids have also other beneficial effects. They manifestation of serious clinical symptoms of
reduce triacylglycerides and VLDLs plasma concen- atherosclerosis.
trations, they inhibit the production of reactive oxy-
gen forms in neutrophils and monocytes, they in- 3.20.1 Atherosclerosis of important
hibit the production of the growth factors in trom-
bocytes, endothelial cells, monocytes and fibroblasts,
vascular regions
they mildly decrease blood pressure, they signifi- 3.20.1.1 Atherosclerosis of lower extremities
cantly inhibit the synthesis of an important inflam-
matory mediator – leukotriene LTB4 (synthetized Atherosclerotic changes in vessels may cause a steno-
from arachidonic acid) and stimulate the production sis (narrowing) or an obliteration (complete closure)
of LTB5 , which has a much smaller inflammatory of the vessel lumen.
effect. From the therapeutic point of view and espe- In the stenotic portion there is acceleration of the
cially from the point of prevention of atherosclero- blood flow with laminar flow changing to turbulent
sis the presented results of experimental and clinical (this is the basis for a vascular murmur). Also the
studies pointed out the importance of regular intake endothelium distal to the stenosis is being damaged.
of substances inhibiting the oxidized-LDLs produc- The collagen thrombogene structures are naked, a
tion (antioxidants). These characteristics are already thrombus arises and further deteriorates the arterial
known in vitamines E,C and A, but there is an inten- stenosis.
sive search for other such substances. An adequate From the clinical point of view we distinguish a
regular fish meal consuming has also protective ef- proximal stenosis or obliteration - above the popliteal
fect. From the clinical point of view it may be use- artery branching (to this group belong also patients
ful to look for specific growth factor antagonists, or with ischaemic disease of the lower extremities due
drugs that could inhibit their production in platelets, to an affection of the iliac arteries or the abdomi-
monocyte-macrophages and endothelial cells of the nal aorta), a distal stenosis (the affected place is be-
arterial wall. low the popliteal artery branching) and a combined
Finally, according to the present knowledge, the stenosis, when both areas are affected. Distal and
process of atherogenesis comprises 5 main stages: combined occlusions of the limb have a much worse
prognosis and risk of a gangrene. If atherosclerosis
1. A disorder of functional and/or morphological gets manifested after 45 years of age, more often a
integrity of the endothelium (the origin of en- proximal affection occurs, with a better prognosis.
dothelial dysfunction). A more progressive stage of the atherosclerotic
process is characterized by a complete arterial oc-
2. Cumulation of cells (myocytes, monocyte-
clusion. As the whole process takes usually a long
macrophages, T-lymphocytes) in the intima of
time, during the continuous artery narrowing there
the artery wall.
is enough time to develop a collateral system to pro-
3. Production of connective tissue components vide at least a limited blood supply behind the com-
(collagen, elastin, glycosaminoglycans) in the in- plete occlusion of the main artery. Patients with a
tima which leads to the origin of the fibromus- complete arterial stop is typically suffered from in-
cular plaque. termittent claudication. The pain appears when the
blood flow through the narrowed artery is insufficient
4. Accumulation of lipids in the intima monocyte- to cope with the metabolic demands of the working
macrophages and myocytes, and their successive muscles. This pain is sharp or blunt and relieves af-
transformation into foam cells. Later, necrosis ter 2 or 3 minutes of rest. A lower pain intensity
3.20. Etiopathogenesis of atherosclerosis (L. Zlatoš) 193

depends in some cases on the ability of the circu- The closure of the internal carotid in its extracra-
lation to increase hyperaemia in the affected limb nial part plays a major role in 1/3 of cerebral strokes.
and to eliminate the substances which are causing
pain. According to the pain location we can predict
3.20.1.5 Closure of the subclavian artery
the level of the arterial occlusion. Later on, nerve
and the upper limb arteries
trunks hypoxia develops resulting in ischaemic neu-
ropathy with resting pain, in supine position, or at The subclavian artery closure is manifested as the
night. In later stage of the disease trophic defects, ischaemic disease of the upper limb. If the occlusion
mainly painful ulcerations and gangrene, appear on is located before the origin of the vertebral artery a
the skin. They often result from minor injuries. so called ”steal” phenomenon may occur. The CNS
The absence of the pulse on one of the limb ar- circulation receives less blood, while this is flowing
teries and the decreased skin temperature of the af- according to a pressure gradient through the verte-
fected area can be very helpful for estimating the bral artery to a vasodilated upper limb circulation
diagnosis. Important are the functional tests of the (the vasodilatation as a result of ischaemia). Clini-
blood flow in lower extremities, the reflectory vasodi- cal signs are headache, sight disturbance, vertigo or
latation test, the measurement of the distal pressure syncope during working with the upper limb.
with Doppler ultrasound method and angiography. Atherosclerotic occlusions of the upper limb itself
are extremely rare.
3.20.1.2 Closure of the abdominal aorta
is usually caused by atheroma located in the aor- 3.20.1.6 Acute arterial closures
tic bifurcation followed by thrombosis. This process
sometimes has its origin in the iliac artery and is Acute arterial closures are sudden events. The limb
continuing to the abdominal aorta and also to the survival, but often also patient’s life depends on the
contralateral iliac artery. earliest possible therapeutic intervention.
It may be manifested by pain in the thigh and in Most often they are caused by thrombosis or em-
the gluteal muscles. The closure of the abdominal bolism, more rarely by dissecting aneurysm or by
aorta can continue proximally and may lead to an ileofemoral venous thrombosis.
occlusion of the renal or mesenteric arteries causing Acute arterial thrombosis usually develops in the
abdominal angina. place of intimal damage, most often due to a sclerotic
To verify the diagnosis translumbal aortography is process.
needed. About 50 % of patients feel a pain like a lash of a
Similar clinical signs may be observed when a clo- whip. The affected limb is pale and cold. After the
sure of the iliac artery is present, however the pain in vasospasm remission the pain relieves and changes
the thigh and in the gluteal muscle may be one-sided. to ischaemic neuralgia with paresthesia. The colour
A vasculogenuous impotence may be present. of the extremity changes to marbly with ecchymoses.
Ischaemia of the nervous trunks may cause limb ple-
3.20.1.3 The aortic arch syndrome gia and anesthesia. A gangrene may follow.

The aortic arch is the most frequent location where

atherosclerotic lesions occur. A closure of the arte- 3.20.2 Aorta diseases
rial branches arising from the aortic arch can also be
found, manifesting with clinical signs of the upper The aorta as an outflow vessel is heavily loaded with
changing blood pressure depending on heart output.
limb, face, central nervous system or the eyes.
Aorta is an elastic vessel. During the systole it dis-
tends according to the blood output volume, in dias-
3.20.1.4 Closure of carotid arteries
tole it recoils to its previous position so that blood is
The affection of the external carotid is manifested ejected to the periphery. Aortic damage most often
by claudication pain of the chewing muscles, face occurs in places of the greatest mechanical stress.
atrofia, severe paradentosis. An isolated closure is The most common aorta diseases are pathological
rare. dilations – aneurysms. It is a dilation of a particular
194 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

aortic segment. The real aneurysm is a pathologi- tending slowly in both directions. The presence of
cal dilation of all three aortic layers. In a pseudo- symptoms depends upon the development of collat-
aneurysm there is a tear in intima and media, while erals.
adventia is dilated. In a fusiformed aneurysm the Syphilitic aortitis is the best known inflammatory
aorta is dilated all around its circumference. In a process of the aorta. The ascending aorta and the
saccular aneurysm only a part of the circuit is af- aortic arch are affected most often. An aneurysm
fected. Aneurysms of the aorta are usually caused often occurs. Sometimes a rheumatic aortitis may
by atherosclerosis. The most common location is develop.
the abdominal aorta. The ascending aorta is af-
fected by cystic medial necrosis. Aortic aneurysms
are most often clinically silent. Sometimes pain oc-
curs. Troubles may be caused also by compression or
by erosion of the surrounding tissues. In the dilated
area thrombi may occur and may cause a periph-
eral embolisation. Aneurysms may get perforated.
3.21 Coronary circulation dis-
A perivascular bleeding is accompanied with a pain turbances
and tension feeling.

3.20.2.1 Atherosclerotic aneurysms

The heart has the action of a valvular pump. This
are usually located in the abdominal aorta below means that the pumping of blood takes place by fill-
the origin of the renal arteries. Most often they are ing and expulsion in the direction determined by its
asymptomatic. During abdominal palpation a pulsa- anatomic structure and the functioning valves. The
tion may be discovered. The ultrasound examination physiological outcome of the heart function is the
will establish the diagnosis. The prognosis depends cardiac output. Both the ventricles have the same
on the extent of the aneurysm. One half of the very cardiac output otherwise there will be an accumu-
big aneurysms end-up lethally in two years when not lation of blood ahead from the ventricle that expels
treated surgically. less blood. The cardiac function is both pressor and
Cystic medial necrosis is a degenerative process volumetric work. This work is provided when the
when collagenous and elastic fibres of the aorta heart changes the speed of blood flow, which takes
change into a mucoid matherial. Affected is the prox- place from the heart to vessels. The cardiac output
imal aorta. A fusiformed aneurysm develops. It of- is expression of the heart function, and its effective-
ten occurs in Marfan’s syndrome but also in pregnacy ness. We may have an idea about the cardiac func-
and with hypertension. tion by measuring its energetic expenditure. The
Intimal disruption of the aorta. It’s origin is not requirement of O2 in the myocardium per minute
exactly known but basicaly it occurs in places of the equals three times the O2 needed by the brain and
greatest mechanical load. Most often the external ten times the O2 needed by the skeletal muscles. As
part of the aortic arch is affected. The disruption blood flows through the myocardium the oxygen is
continues to the descending aorta. Under the dis- maximally extracted from it. That is the reason why
rupted intima a false duct can be found. The predis- the difference between the arterial and the venous
posing factors are hypertension, cystic medial necro- oxygen is the largest in the body. The exchange of
sis and congenital defects of the aortic valve. In the substances in the heart takes place in aerobic con-
latter case the disruption begins near the valve. The ditions. The heart cannot work with oxygen deficit
clinical sign is pain between the scapulae. With a (debt.), and that is why it needs a very effective ar-
dramatic onset fatigue, dyspnea and syncope may terial blood supply.
occur. Aortic regurgitation may result in pulmonary The myocardial blood supply is provided by the
edema. The prognosis is very bad. coronary arteries. The coronary circulation actually
Atherosclerotic occlusion of the aorta begins most represents a junction between the aorta and the right
often in the distal part of the abdominal aorta below atrium. It is hence the shortest circulation in the
the origin of the renal arteries. The occlusion is dis- body with the highest pressure gradient. The coro-
3.21. Coronary circulation disturbances (I. Hulı́n) 195

nary circulation is very variable. Yet originally we sult in a marked reduction of the coronary flow, that
have to agree with the opinion that says that the left might even lead to ischemia of the myocardium.
coronary artery supplies the left ventricle and the The coronary field, and mainly the intramural re-
right coronary artery supplies the right ventricle. sistant arterioles has a great ability to provide all the
The coronary arteries run on the epicardial sur- needed blood and oxygen in every and even extreme
face of the heart. The branches to the myocardium situation (a tiring task for the human). It is very
branch from the coronary arteries at a right an- important to regulate the coronary blood flow ac-
gle. Under the endocardium (subendocardially) they cording to the metabolic needs. Apart from this the
form an interconnected network. The myocardium coronary flow autoregulation renders the coronary
possesses a rich capillary supply. There is between flow suitable for other physiological or pathological
2 000 till 4 000 capillaries per 1 mm2 of the my- conditions. The epicardial arteries as well has the
ocardium, value which is ten times more than in the ability to contract and relax. They are considered to
skeletal muscles. be distributing vessels. The intra mural arteries have
The venous blood collected from the areas sup- the ability to change their wall tension fast, and this
plied by the left coronary artery is then directed to is why they are considered to be resistant vessels.
the coronary sinus. A small amount of blood col- In case of coronary artery narrowing, the blood
lected by some veins flows directly to the right ven- flow depends on the pressure gradient. The flow
tricle. From the area supplied by the right coronary becomes limited when the stenosis exceeds 75 % of
artery blood flows directly to the right atrium. the vascular lumen. The vascular field distal to the
Around 200–250 ml of blood is flowing via the stenosis becomes dilated. This leads to a raise in the
coronary field per 1 minute. This represents about pressure gradient. If stenosis continues in progres-
80 ml/min/100 g myocardium. In case of a heavy sion, the flow might only be increased by increasing
load on the heart the blood supply may increase 5 to the pressure of blood in the pre stenozed area. If the
7 times. In normal conditions the coronary field has cardiac need is high the blood flow becomes insuf-
a very high pressure gradient. The blood flow varies ficient. The myocardial need of oxygen is increas-
rhythmically with the pulse pressure changes. Apart ing linearly with the increment of the cardiac action.
from this it changes accordingly with the contraction The oxygen extraction is at its maximum in a rest-
cycle of the heart. The flow of blood across the coro- ing stage. That is why a higher oxygen need by the
naries is affected by the coronary vascular resistance myocardium can only be obtained by a higher blood
to the blood flow, this is regulated by the cardiac flow through the myocardium. For the blood supply
neuronal mediators. It is as well regulated by some to be adequate all the time its regulated according to
direct myocardial factors locally and the amount of the actual needs. When the metabolic needs of the
O2 supply of the blood. heart are increasing, the coronary artery branches
The flow of blood across the coronary arteries is react by vasodilatation, that ensures a high blood
not continuous. Along the isometric phase and due flow. The main regulating factor is adenosine. In
to the high myocardial tension the flow of blood be- cases of a relative hypoxia, that results from the in-
comes slow. As the ventricular contraction during creasing myocardial demand, in the endothelial cell
systole is stronger, the flow of blood via the coronar- membrane is adenosine produced. Adenosine reaches
ies becomes less. Sometimes it may stop completely. the interestitium, where it acts as a vasodilatatory
By the end of the ventricular ejection it becomes agent by its direct action on the adenosine receptors
markedly faster. And during the fast ventricular fill- in the smooth muscle cells of the vascular wall. The
ing phase the coronary blood flow is at its maximal high blood flow washes away adenosine. Using of this
level. Here the conditions are most favorable for my- mechanism may increase up blood flow to five times.
ocardial blood flow. The amount of blood flowing The process of auto regulation is very complicated
across the coronary field depends upon the diastolic and it needs many other factors.
pressure in the aorta and the length of the diastole. The ideal function of the pump – namely the cir-
The shortening of diastole in case of tachycardia or a culatory flow of blood depends upon the circulating
drop in diastolic pressure in aortic regurgitation re- blood in the pump itself – namely the coronary field.
196 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

The epicardial coronary arteries in the human

organism are the site where atherosclerotic process
3.22 Ischaemic heart disease loves to occupy. The dysfunction of vascular en-
dothelium and an abnormal interaction with the cir-
culating monocytes and thrombocytes that leads to
abnormal storage of fat in the subintimal space, as
Low blood flow through the large coronary vessels well as some cells and other substances. The result
can be expressed clinically only when their narrow- is the formation of atherosclerotic plaques in differ-
ing exceeds 75 %. Here the blood pressure decrease ent segments of the coronary arteries and narrowing
behind the obstruction, and the blood flow becomes of their translucency. In translucency decrement to
lower. In such a case ischemia develops in the sup- 25 % the coronary arteries no more can provide the
plied area of the myocardium. Under the term is- increasing myocardial demand for blood and oxygen.
chemia we understand a low perfusion of tissues, When the translucency drops to only 20 % its original
which most important outcome is inadequate oxy- level or more, the coronary blood flow will reduce.
genation, caused by the inadequate perfusion. This reduction results in myocardial ischemia with
Ischemic heart disease is a condition having the clinical manifestation. The atherosclerotic process
most variable causes. Yet each and every time the doesn’t always progress so much to cause a promi-
cardiac function is disturbed as a result of the loss nent decrement of the translucency of the vessels.
of balance between the oxygen supply and its re- The preformed atherosclerotic plaque may be dis-
quirements. The most common cause of ischemia turbed, or sloughed and at this site the formation of
is atherosclerosis of the coronary epicardial arter- a thrombus begins. It is only natural that the clin-
ies. Their low translucence due to the atherosclerotic ical manifestation and the patient’s state as well as
process leads to a low myocardial perfusion during the condition of his heart depends on the localization
the normal requirements for cardiac function, possi- of the affected artery and on its degree of narrowing.
bly it allows a small blood flow increment when the The progressing narrowing of the coronary artery is
functional requirement becomes higher. The coro- usually connected with the development of the col-
nary flow may suffer further lowering of blood flow lateral vessels, which provide a better coronary blood
due to the formation of thrombi, a spasm, and oc- flow at least in the resting patient.
casionally an embolus. Rarely we may find an ab-
In the post stenotic area the resistant vessels are
normal branching of the coronary artery from the
dilated. In case of maximal dilatation the coronary
pulmonary artery. Myocardial ischemia may occur
blood flow depends upon the pressure, which is distal
even in cases where the requirement for oxygen are
to the stenosis. In that case the state of hypoxia
abnormally high. This happens is case of excessive
depends on the myocardial requirement, possibly the
left ventricular hypertrophy as a result of hyperten-
tendency for arterial spasm, but not their dilatation
sion or aortic stenosis. The signs of angina pectoris
which is already in its maximum.
will appear and these cannot be differentiated from
angina pectoris that resulted from coronary arteries Low supply of oxygen caused by the coronary
atherosclerosis. In cases of an extreme drop of the atherosclerosis will lead to transitional disturbances
transport capacity of blood for oxygen myocardial of the mechanical, biochemical and the electrical
ischemia may also occur. Yet the combination of function of the myocardium. A fast developing is-
high oxygen requirement caused by the left ventric- chemia usually causes an immediate disturbance of
ular hypertrophy and the simultaneous presented of contraction, and relaxation of the myocardium in a
atherosclerosis of the coronary arteries very common. certain section. A decreasing perfusion of the suben-
As we mentioned previously, the size of the coro- docardial area leads into a prominent ischemia in the
nary blood flow is subjected to the myocardial con- corresponding area of the heart ventricle. Ischemia
trol, and its metabolic level. This is mainly because, of a large area can reveal a condition of a transitional
that the myocardium can obtain a higher O2 sup- left ventricular failure. When ischemia affects the re-
ply when needed by a higher blood flow but not by gion of papillary muscles, mitral regurgitation may
an increased oxygen extraction because the oxygen result. Coronary atherosclerosis is not equally dis-
extraction is already at its maximum during rest. tributed. Due to this reason the change in contrac-
3.22. Ischaemic heart disease (I. Hulı́n) 197

tility may affect only a certain segment of the left 3.22.1.1 Chronic stable angina pectoris
ventricle. In case of a long lasting ischemia necrosis
Is basically a syndrom caused by a transitional my-
may result, that is represented as an acute myocar-
ocardial ischemia. Patients complain of a chest pain
dial infarction. The typical clinical picture yet is not
with different shadowing. In the typical case the
necessarily present.
pain is retrosternal. That might radiate to the up-
With normal oxygen supply of the heart fatty acids per limbs and even to some less usual sites such as
and glucose are metabolized into CO2 and H2 O. In the neck, or teeth. According to the type of the pre-
case of a prominent drop of oxygen supply, fatty disposing factors we may describe different types of
acids cannot be oxidized. The only left metabolic stable angina pectoris.
event that supplies energy is the anaerobic glycolysis,
during which glucose is broken down to lactate and a • Angina d’effort – evoked by physical activity
relatively small number of ATP is formed. The intra-
cellular pH becomes low. The oxygen insufficiency • Postprandial angina – after eating
is then changing the membrane function. Kalium
• Emotional angina pectoris – during excitement
escapes out of the cells and sodium is accumulated
intracellularly in large amounts. The difference be- • Angina decubitus – after laying in bed
tween the needs of the myocardium for oxygen and
the oxygen supply and length of hypoxia determines • Angina pectoris inversa (Prinzmetal) – steno-
the extent of myocardial injury. cardia occurring at rest, physical activity is not
Ischemia affects the transport of ions via mem- a causative agent
branes and the course of the electrical activation in
• Status anginosus – is the commutation of at-
individual myocytes in the heart as whole. Changes
tacks.
the electrical function of the heart during ischemia is
shown on the electrocardiogram on the T wave and Nearly half the patients with angina pectoris have
ST segment. A transitional depression of the ST normal ECG at rest. The other half have some non-
segment is a picture of a subendocardial ischemia. specific ECG changes at rest such as changes of the
Elevation of the ST segment is usually caused by ST segment and the T wave, these changes can be
a prominent transmural ischemia. Ischemia in any evoked by loading test.
heart segment can produce a marked electrical insta- During the treadmill test we control the electro-
bility, a result of which is usually ventricular tachy- cardiogram and blood pressure prior the test, during
cardia or fibrillation. Patients who died of sud- it, and after finishing the physical load. ST segment
den cardiac death due to myocardial ischemia are depression that is larger than 0,1 mV compared with
through to suffer from malignant ventricular arrhyth- the primary ECG reading is considered to be the
mia. sign of the induced ischemia. The ST depression last
for more than 0,08 seconds and it has a horizontal
or a descendant course. It is logical that even the
T wave changes or the appearance of ventricular ex-
3.22.1 Angina pectoris trasystolies, or paroxysmal tachycardia are a proof
of myocardial ischemia. Similarly the drop of blood
Angina pectoris means anxiety (pain) on the chest. pressure is an indicator of ischemia and a non over-
This name was used prior to the knowledge about comed load. In this case a drop in the ejection frac-
the association of pain with the diseased coronary tion during the loading test is a prominent indicator
vessels. Angina pectoris is actually a syndrom pro- of myocardial ischemia, and usually even a sign of
voked by a transitional myocardial ischemia. Chest the affection of more tan one coronary artery.
pain is commonly the only symptom of the disease. The anatomy of the coronary vessels has a very
It is of short duration and is typically localized ret- important place in understanding the ischemic dis-
rosternally. Depending on other symptoms we may ease of the heart. Viewing the coronary arteries can
differentiate two main forms of angina pectoris and provide us with information about, of or to what ex-
their further more specific types. tent are the coronary arteries narrowed by the effect
198 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

of the atherosclerotic process. The coronary arteri- performed by the percutaneous transluminal coro-
ography can show of it is possible to perform the nary angioplasty (PTCA). This method is quite suit-
percutanneous transluminal coronary angioplasty as able for stenosis of the coronary roots or the proxi-
a treatment for the condition, whether we have to mal stenosis of its main branches. The more distal
perform an aortocoronary bypass. Cardiac catheter- stenosis are necessarily solved by other techniques.
ization is performed to find out any increase in the Revascularization can be provided even by a sur-
end diastolic pressure and the enddiastolic volume gical formation of a new vascular junction between
and mainly of there is any reduction of the ejection the aorta and a section of a coronary artery which
fraction. These three parameters are very important lies distally to the stenosis. In patients with ischemic
from the prognostic point of view in cases of ischemic disease of the heart, the aortocoronary bypass do not
diseases of the heart. A high enddiastolic pressure decrease the risk of myocardial infarction occurrence.
with a high enddiastolic volume and a low ejection Yet it improves the vascularisation and the actual
fraction carries a very bad prognosis. Sclerosis of state of the myocardium. It decreases the mortality
the left coronary artery root is considered to be the in patients with left coronary artery lesion that is
highest risk for patients suffering from the ischemic affecting all the three main vessels.
disease of the heart.
A high end diastolic volume and pressure render
the coronary blood flow unfavorable. The applica- 3.22.1.2 Unstable angina pectoris
tion of nitrates causes vasodilatation. And that is
why there will be lowering in the left ventricular Is another painful form of the ischemic heart disease.
wall tension during diastole and the flow is improved. It has a very marked beginning of the attack and the
Apart from this nitrates are know to cause dilatation spasm occurs at least 3 times per day. Under this
of the epicardial coronary vessels. The result is an type of angina we may put patients suffering of the
improvement of the coronary blood supply even via chronic stable angina pectoris, in whom a worsening
the collateral in the left ventricular wall. of attacks occurred with an increase of their number.
Blocking β–adrenoreceptors is another important The attacks usually last for more than 20 min.
factor to influence the ischemic disease of the heart. A primary unstable angina pectoris represents
Substances with such effect decrease the myocardial a condition, in which we do not find any factors
requirement for oxygen, they inhibit increasing heart that may lead into worsening of ischemia in pa-
rate and contractility that is caused by the adrener- tients suffering from this angina. Among the fac-
gic stimulation. Lowering the heart rate, the ejection tors that cause worsening of myocardial ischemia are
volume and pressure at rest are only partially edged anemia, fever, infection, tachyarhythmia, emotional
by these substances. Sometimes we may notice a stress, and hypoxemia. Unstable angina may develop
prominent bradycardia, disturbances of electric acti- shortly after the occurrence of myocardial infarction.
vation and signs of left ventricular failure. The unstable angina pectoris with attacks occurring
Calcium chanel antagonists have vasodilatatory ef- at rest is a sign of risk for acute myocardial infarc-
fect on the coronary arteries. Apart from this they tion.
decrease the myocardial requirement for oxygen, de- The unstable angina pectoris with evident electro-
crease the contractility, and the arterial blood pres- cardiographic changes during the attacks is always
sure. Yet they might lead into some conduction dis- combined with the stenosis of one or more coronary
turbances in the heart and hence bradyarhythmia. arteries. During the attack spasm might cause some
A negative inotropic effect and worsening of the left microscopical changes of the endothelial surface of
ventricular function or even its failure can appear the atheromatous plate and hence might lead to a
when use β–adrenergic blockers. thrombocytic plug. This is why we usually give hep-
Ischemic heart disease is the problem of oxygen arin in case of such attack.
requirement and supply. Improving the blood and In patients with unstable angina pectoris cathetri-
oxygen supply might be solved not only pharmaco- sation is necessary as well as coronarography. Then
logically but even by mechanically by revasculariza- a decision for PTCA or a surgical revascularization
tion. Recently the mechanical revascularization is takes place.
3.23. Acute myocardial infarction (J. Murı́n) 199

3.22.1.3 Asymptomatic (silent) ischemia sis is not very prominent and the occurrence of
myocardial infarction is caused by a rupture of an
During the treadmill test in patients with various cir- atherosclerotic plaque or the formation of a thrombus
culatory disturbances we may uncover patients with (plug) in this locality. In some cases we are dealing
ischemic heart disease. Apart from the treadmill with a coronary spasm (what is known as obstructive
test results these patients are usually diagnosed by form). It is usually compelled with coronary sclero-
the use of longitudinal ECG examination with judg- sis. In what is known as the non obstructive form
ing the ST segment shape on the ECG. It is a fact we noticed an increased tone of the large coronary
that these patients have no symptoms of the ischemic artery, or an increasing tonus of the distal coronary
heart disease. Their long lasting monitoring showed field. An important factor for coronary artery clo-
that the occurrence of sudden death is common in sure is an intimal injury. In the following years it
this group, as well as myocardial infarction or the was found out that the endothelium plays a very im-
manifestation of non stable angina pectoris. The pro- portant role in the coronary artery obstruction. The
gression might be judged only individually. About endothelium modulates the function of the vascular
the prognosis the decisive factors are the left ventric- smooth muscle via the liberation of substances that
ular function, the state of the coronary arteries, the control local constriction and relaxation of the ves-
effect of pharmacological therapy, and the possibility sels. Haemodynamics factors (increasing the coro-
of revascularization and even its contraindication nary blood flow) and some substances (serotonin,
acetylcholin) can activate the liberation of some en-
dothelial relaxing factors - EDRF Endothelium De-
rived Relaxing Factor. In a normally functioning
artery with intact endothelium, the release of EDRF
causes vasodilatation. Apart from this it has an
3.23 Acute myocardial infarc- antithrombotic effect on the luminal surface of the
endothelium. In the presence of the atherosclerotic
tion plaque or an injured endothelium no EDRF is formed
or released and so its mentioned functions do not ap-
pear. When thrombocytes aggregate on the endothe-
lial surface they will release thromboxan that cause
Acute myocardial infarction is a dynamic state, in further vasoconstriction and further thrombocyte ag-
which a stopped myocardial perfusion leads to my- gregation. Endothelial dysfunction occurs quite of-
ocardial irreversible injury. Acute myocardial infarc- ten due to some minor insults. It might be an ac-
tion is an anemic necrosis most commonly caused by tivation of the vascular smooth muscles, that is not
a closure of a coronary artery or one of its branches so prominent so that to cause a serious arterial oc-
affected by an atherosclerotic process. The causes clusion. The endothelial injury is the most probably
of the coronary artery closure might be some obvi- due to a faster flood flow in the area of the partial
ous morphological changes (thrombus based on the functional stenosis. Later on there will be a depo-
atherosclerotic changes), it might also be coronary sition of thrombocytes on the injured endothelium
artery spasm that occurred with or without the pres- and a formation of non occlusive micro thrombi. The
ence of the atherosclerotic changes in the affected atherosclerotic process doesn’t only lead into a lower
vessel. The area affected by necrosis can not be translucency of the coronary vessels. During this
changed or drown smaller. It is surrounded by a process a monocellular infiltration, foam cells and
hypoxic myocardial area of various sizes. In exper- leukocytes can release many factors (thromboxan,
imental conditions necrosis (death) of the myocytes leukotriens, 5-hydroxytryptamin), these result into
occur within 15–40 min following the stop of blood thrombocyte aggregation, an increased predisposi-
flow and a complete coronary artery or its branch tion for blood coagulation, stimulation of migration
occlusion. and proliferation of other cells. Apart from this they
The cause of myocardial infarction is most com- have other affects on the distal segments of the coro-
monly an acute thrombotic closure of the coronary nary system. The clinically known triggering factors
artery affected by atherosclerosis. Sometimes steno-
200 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

for myocardial infarction act through disturbing the 2. Embolisation of the coronary arterial system:
atherosclerotic plaque (rupture of the plaque) or via
increasing the oxygen requirement in patients with a • infective endocarditis
considerable stenosis (see table 3.2). • left atrial or ventricular thrombosis
• rheumatic process in the mitral value with
atrial fibrillation
Factors Examples • artificial heart valves
• cardiopulmonary bypass (thrombocyte ag-
Environmental Smoking, emotional
gregation, air)
stress, exposure to cold
• coronary angiography.
Associated diseases Anemia, thyreotoxico- 3. Non atherosclerotic changes of the coronary ar-
sis, hypertension, teries:
arrhythmia, infection,
polycythemia, fever • arteritis (Takayasu disease, infective and
nonspecific arteritis, polyarteritis nodosa,
Vasoconstricting Amphetamines A lupus erythomatosus, and primary chronic
agents polyarteritis
• Thickening of the coronary artery wall in
Sudden withdrawal nitrates, nifedipin, cases of metabolic diseases or in cases
anti angina pharma- betablockers of intimal proliferation (homocystinuria,
cotherapy Fabry’s disease, amyloidosis, hyperplasia of
the intima coupled with the use of contra-
ceptive steroids or connected with post de-
livery state, disease of the small coronary
Table 3.2: Triggering factors for the occurrence of arteries (of a diameter 0,1–1,0 mm known
acute myocardial infarction as small vessel disease)
The less common causes are: • Narrowing of the coronary artery lumen
by other mechanisms (dissection of the
1. Acute coronary thrombosis without the presence coronary artery, spasm of the coronary
of the atherosclerotic process in the coronary ar- artery after the withdrawal of nitroglycer-
teries ine’s, a spasm due to a vasoconstriction
(Prinzmetal) angina pectoris and normal
2. An embolic closure of the coronary artery
coronary arteries.
3. Coronary artery stenosis that resulted from an • Congenital anomalies of the coronary ar-
inflammatory process in the coronaries (coro- teries (abnormal origin of the left coronary
naritis) artery from the pulmonary artery).
Myocardial infarction might occur without any The extent of the coronary spasmus as an etiolog-
atherosclerotic changes in the coronary arteries: ical factor is yet not clear. It seems that it can only
occasionally be the main primary cause of a sudden
1. Normal coronary arteries:
cornary artery occlusion. Yet it has a great value
• unknown etiology as a cofactor. We may induce the coronary spasm
experimentally by many substances, for example by
• myocardial contusion
the use of ergonovin, acetylcholin, or histamin. It
• a state of no equilibrium between the re- is hence possible to expect that spasm may be not
quirement of oxygen and its supply (aor- caused by blocking a certain kind of a receptors, but
tic stenosis, aortic insufficiency, carbon it may occur by affecting a certain mechanism that
monoxide intoxication, thyreotoxicosis) regulates the vascular contractility. Meantime there
3.23. Acute myocardial infarction (J. Murı́n) 201

is an intensive study about the effect of endothe- area. The size of the infarct area is determined by
lin, which is a substance with a prominent vasocon- the following factors:
stricting effect. It is 21 amino-peptide, that has the
most potent vasoconstrictory action among all the 1. The size of the area nourished by the occluded
known substances, biological poisons and toxins. It coronary artery.
is most probably produced by the vascular wall en- 2. The period of coronary closure.
dothelium. A question whether this substance leads
3. The oxygen requirement by the myocardium
to vasoconstriction directly or it only sensibilities the
during the coronary occlusion. It was found ex-
vasculature for otherwise non effective vasoconstric-
perimentally that the time period between 10–
tory stimuli is not yet solved.
20 minutes post coronary artery occlusion is
The assume that there will be an irreversible coag- very important. If at this time there is a high
ulation necrosis of a part of myocardium is through myocardial requirement for oxygen (for e.g.: due
to result from a critical restriction of perfusion of a to a present tachycardia), a large infarction will
concerned part of cardiac muscle (myocardium) for a develop. Pharmacologically, for example due to
relatively long time. In experimental coronary liga- the use of betablockers it is possible to reduce
ture there will be an irreversible myocardial necrosis the oxygen need of the myocardium. This pro-
within 15-40 minutes. The development of necrosis tection yet last for only 2–3 hours. If we do not
can be influenced in individual cases by many factors, open the occluded coronary artery the resulting
that affect the oxygen supply of the myocardium infarction will be large as well.
(the remaining perfusion in case of a heavy coronary 4. The extent of the resting coronary perfusion via
stenosis or perfusion by the collateral circulation in the collateral arteries. This is evidently the most
case of total obliteration of the coronary artery). The important factor that will decide the myocardial
time needed for the necrosis to develop, is affected sparing. The presence of collaterals is very vari-
by the oxygen requirement of the heart (the presence able among different individuals. The collateral
of a morphological factor for e.g.: myocardial hyper- circulation is important not only for the mini-
trophy, or the presence of some function factors, for mal oxygen supply, but even for the removal of
e.g.: tachycardia, a high left ventricular wall tension, metabolism products, that are an osmotic load
a high contractility – all these conditions increase the on the myocardial cells.
oxygen utilization in the myocardium). The critical
time for the development of necrosis can be affected 5. Variable ischemia toleration of the myocardium.
by the combination of the previously mentioned fac- It is very important to the development of acute
tors. infarction into two phases, the early phase, and the
On the other hand the thrombotic closure of the phase of adaptation.
coronary arteries can occur without a necessary fol- The acute phase of myocardial infarction. From
lowing myocardial infarction. Usually in these cases the periodical point of view it includes the first
coronary artery stenosis develops very slowly till its six hours from the developing signs and symptomps
final closure. This slow stenotisation will provide ad- of the disease. Its main characteristic lies in that
equate time for a network of collateral circulation to the therapeutical intervention in this period of time
develop, and these collaterals will ensure an adequate has the greatest possibility of achieving a favourable
perfusion of tissues that are supplied by the stenozed change in the course of the disease.
artery. During the acute phase there are very serious vas-
cular changes in the infarct area. Atheromatous ma-
Any stop of the coronary perfusion causes necrosis terial and mixture of thrombocytes and fibrin can
of the cardiomyocytes over a certain period of time. act as an embolizing material in the vascular field.
Individual parts of the myocardium have different The endothelial cells become odematous due to hy-
sensitivity for hypoxia. The subendocardial area is poxia. Thrombocytes, leukocytes, and fibrin occlude
the most sensitive and the subepicardial area is the the small vesseles. As a result of this there will
most resistant. Even the infarct as a rule is progress- be capillary compression which worsens the function
ing form the subendocardial area to the subepicardial and the effectivness of the collateral circulation. In
202 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

this situation the capillary permeability increases till A delayed remodelation of the left ventricle.
a point where hemorrhage may occur Means a gradual ventricular dilatation, that occurs
The phase of cardiac adaptation during the acute in a healthy myocardium, meaning an area or a seg-
myocardial infarction. From the periodical point ment of the left ventricle not affected by the infarc-
of view it includes the myocardial events, that take tion. It is a process that, from the functional point
place after the sixth hour of the appearance of signs of view stands for or is compensating the decrease of
and symptoms. In this phase the heart (left ventri- the left ventricular function which follows the infarc-
cle) undergoes a geometrical rebuilding of its archi- tion for example, via the Frank-Starling mechanism.
tecture, what is known as remodelation. This pro- From the pathophysiological point of view it is nec-
cess is for more complex than previously thought. essary to explain two important terms:
We can define two general processes, that lead to
changes of the shape (geometry) of the left ventricle 1. The myocardial stunning phenomena (stiff my-
after the infarction. The first process is known as ex- ocardium). In certain cases a prominent my-
pansion of the infarct area and the second is known ocardial ischemia can produce a complicated
as the late remodelation of the left ventricle. myocardial dysfunction with no proven necro-
Expansion of the infarct area Marks the ventric- sis. This dysfunction persist for a long time af-
ular dilatation, that occur as a result of an acute ter the equilibrium between the myocardial re-
stretching, thinning and dilatation of the injured my- quirement for oxygen and its actual supply has
ocardial segment. This process has got a very impor- been established. So despite the renewed estab-
tant role in the development and the final result of lishment of perfusion the functional, ultrastruc-
the infarction. tural, and biochemical abnormalities in the my-
It concerns nearly 15 % of acute myocardial infarc- ocardium persist, and this lasts for days or even
tion cases. And later on, depending on this there weeks, for the myocardial function to be fully
might be a permanent dilatation, aneurysm forma- regenerated.
tion (that means a persistent local expansion of the
left ventricular wall in the region of the overcomed 2. Phenomena of the hibernating myocardium
infarction), rupture of the interventricular septum or (means cold or frozen myocardium). It develops
the free wall of the left ventricle. Expansion of the during the chronic reduction of perfusion or in
myocardium and its rupture often occur in cases of cases of an increase of the oxygen requirements
transmural infarcts (known as the Q infarcts, which that in turn causes a mild, yet a persistent hy-
is a classification that depends upon the electrocar- poxia. The myocardium then is down regulated,
diographical findings, and this corresponds with the meaning that it decreases its function to a level
hypothesis that we are dealing with a transmural in- which corresponds with its oxygen supply. The
farction) in patients who have the infarction for the remodeling or down regulation stands against
first time and in hypertensive patients. the hypothesis that says ”the myocardium com-
Many times we use terms like extension of the in- mits suicide” i.e. necrotizes, and this happens
farction or reinfarction. These terms do often inter- when its supply of blood is reduced for a long
change or one of them is thought to mean the other. time. With this down regulation there will be
They mark a further injury of the left ventricular my- setting of a new equilibrium, and this will not
ocardium. Extension of the infarct area (expansion progress to a state of necrosis. This equilibrium
of the necrosis) Is expanded on the base of a new is however very labile and any further worsening
raise of MB isoenzymes of creatinin kinase in the in the supply of oxygen or an increase in oxygen
blood (this fact stands for the myocardial necrosis). requirement will eventually lead into the pro-
Extension of the infarct clearly raises the patients gression of necrosis. The myocardial segment
mortality. It is quite understood, because it is about with dysfunction (e.g. hypokinesis), that have a
an increment in the region of the infarction. Previ- reduced perfusion but are metabolically active,
ously an overcomed infarction was increasing the risk will eventually loose their dysfunction after a
of extension. successful reperfusion (renewal of the perfusion
in the coronary field) with the help of a surgi-
cally created bypass. The evidence about the
3.23. Acute myocardial infarction (J. Murı́n) 203

presence of induction and control of down regu- Inadequate perfusion (hypoperfusion) of a part of
lation of the myocardial function does provide us the myocardium leads quickly to its abnormal con-
with some attractive therapeutical approaches traction. Only few seconds after an experimental
for patients with an acute myocardial infarction. closure of the coronary artery hypokinesis develop
(meaning a drop of the systolic contraction), akinesis
The loss of integrity of a myocardial myocyte in the
(no systolic contraction) or dyskinesis (paradoxical
acute phase of infarction produces a prominent elec-
systolic contractions) of that part of the myocardium
trophysiological changes, that are usually the cause
which lacks the required perfusion. The final results
of arrhythmia.
on the general function of the heart as a pump de-
During the course of an acute myocardial infarc-
pend on:
tion we usually notice the presence of a marked sym-
pathetic nervous system stimulation. This is as well 1. The size of the area, that is affected by the loss
produced by increasing the number of baroreceptors of contractility
in the ischemic myocardium, and this occurs shortly
post the occurrence of the coronary occlusion (as 2. The functional state of the intact myocardium,
proven in an experiment provided on animals). being the part, that is not affected by the in-
The local presence of catecholamins are yet ar- farction.
rhythmogenic, and as they increase the inflow of cal-
cium ions into the cell via the stimulation adenylcy- These facts take place mainly in the haemody-
clase. A partial inactivation of the fast Na+ chan- namic results of the acute infarction in the human
nels (due to the drop in the membrane potential) being. From the view of functional status definition
leads to a slow conduction of stimuli in the region of the heart as a pump the following parameters or
of infarction. These facts are very important from quantitative changes were defined.
the arrhythmogenic point of view in the acute my- • The reduction of ejection fraction, and the drop
ocardial infarction. In this situation there is an in- of the stroke volume
crease in the number of the spontaneous ectopic de-
polarization and a prominent non homogenity of the • The reduction of dp/dt max. and the calculated
electrical characteristics of the myocardium. This Vmax (dp/dt max = the speed of change in the
condition occurs inside the infarction area, yet it is intraventricular pressure in the left ventricle per
mainly in the borderline (being a zone between the time measured by the non invasive manometric
non infarction and the ischemic myocardial area). In technique).
experiments done on animals we could detect some
other metabolic changes, that might have a certain • The end diastolic volume of the left ventricle is
role in the arrhythmogenesis of the acute infarction. mostly raised. At the beginning, the end di-
This is mainly about these: astolic volume even when the compliance is in-
creased, might be still normal. It rises later on
• The raise in lactate production shortens the du- as a result of the continuous worsening of the
ration of action potential (shortening the refrac- ventricular compliance.
tory period) with a simultaneous drop of the
resting membrane potential. In the course of few days the area of infarction be-
comes hard as a result of the deposition of fibrous
• Phase 4 TAP (the spontaneous depolarization)
tissue in this region of the heart. And the result-
is usually faster
ing reduction of compliance will eventually lead to
• Free fatty acids in the presence of hypoxia or is- the disappearance of the infarct dependent dyskine-
chemia might simultaneously decrease the rest- sis. This will eventually cause an improvement of
ing membrane potential and accelerate phase 4. the ventricular function. In the next there will be an
There is a relation between the level of the free establishment of a slow change in the ventricular ge-
fatty acids in the serum of a person suffering ometry (remodelation) with the enlargement of the
from an acute myocardial infarction and the in- ventricular volume. This change, as well as the raise
cidence of ventricular disturbances of the car- of the diastolic pressure in the ventricle will result in
diac rhythm (see fig. 3.22 on page 204). a raise of the myocardial oxygen requirement.
204 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.22: Pathogenesis of ischemic arrhythmias

From this point we would like to remind the stu- farction replaced the old term (the subendocardial
dent of the electrocardiographical classification of infarction). In the clinical practice we noticed that
the infarction, that is referred to in the chapter of the the number of patients with the non Q infarction is
electrical function of the heart. In cases of acute my- increasing. This might be due to the improvement
ocardial infarction a useful classification was made of the diagnostic methods, as well as the new ther-
depending on what is known as the Q wave. We apeutical procedures (calcium antagonists, nitrates,
classify the infarction into Q infarction type (where beta blockers), that limit the progression of necrosis.
we see a pathological Q wave on the electrocardio- These patients appear electrocardiographically as if
gram) and the other type is the non Q infarction they have undergone a partial perfusion. They have
(where the Q wave does not develop). The term smaller infarcts and a lower early mortality than the
Q infarction replaced the old term (transmural in- patients with the Q infarction. Yet these patients
farction). The morphological studies couldn’t prove have a higher risk of developing an early infarction
the specificity of the Q wave in that sense that it with its possible complication. Myocardial infarction
is the marker of the infarction which affects all the might very rarely affect the atria or the right ventri-
layers of the myocardial wall. The term non Q in- cle (this might occur in cases of their hypertrophy
3.24. Pathophysiology of the brain circulation (B. Mladosievičová) 205

which is the result of another primary disease). 3. Attempts made in the region of infarction heal-
ing. The modern moleculo-biological methods
Pathophysiological aspects in the therapy of acute in animal experiments proved by the use of a
myocardial infarction cardio-specific genes to stimulate the cardiomy-
ocytes to devide. It is hence possible to hope
1. From the awareness of the pathogenesis of the
for the regeneration of the vascular system of
acute myocardial infarction we conclude, that
the myocardium.
an important therapeutic step lies in the reper-
fusion of the coronary field by the help of 4. The hit in protecting the myocardium is what is
thrombolysis (via a chemical way, e.g. strep- known by preconditioning. In life the prevention
tokinase as an infusion or a mechanical way must be sleep and glycosides, that can keep a
e.g. PTCA = percutaneous transluminal coro- high ATP level in the myocardium.
nary angioplasty).
2. Application of betablockers (intravenously or
orally) is very useful mainly because they lead
to a decrement in the oxygen requirement by the
myocardium.
3. The use of an antiaggregatory substances (sali- 3.24 Pathophysiology of the
cylic acid alone or in combination with dipyri-
damol) as a prevention of reocclusion of the
brain circulation
coronary artery.
In the region of a palliative therapy the greatest
attention is given to:
Vascular supply of the brain
1. The reconstruction of the diseased coronary ar-
Brain is supplied by blood through 4 large vessels
teries (meanwhile the main problem is to over-
– 2 carotids and 2 vertebral arteries. The left carotid
come the restenotization of the artery in the re-
artery (a. carotis communis sinistra) is branching
gion of the attempt, for example through the use
right out of the aortic arch, the right (a. carotis com-
of cellular proliferation inhibitors).
munis dextra) is branching from the brachiocephalic
2. Changing the myocardial tolerance to the is- trunk. The carotid sinus lies at the level of C3 –C4
chemia. Only recently it was found that, the where the common carotid artery branches into the
myocardial tolerance to ischemia can be changed internal and external carotid arteries. This sinus
not depending on the perfusion at rest that is has special receptors for pressure changes (barore-
obtained by the collateral arteries. This toler- ceptors) and the afferent impulses travel through the
ance could be trained by short occlusions of the glossopharyngeal nerve into the vasoregulatory cen-
coronary circulation (for 5-15 min.). It actually ters. A. carotis interna enters the intracerebral cav-
delays the occurrence of necrosis yet it does not ity at the base of the skull through the carotid canal,
prevent it. It was found that by this way it is then forms the S shape and passes through the sinus
possible to raise the gene expression for a whole cavernosus. A. opthalmica which is the first branch
series of proteins HSP 70, that have a protec- of the internal carotid artery anastomosis with the
tive function during many insults (such as heat, a. carotid externa. Another branch of the internal
radiation). A high tolerance for ischemia is pos- carotid artery is a. communicans posterior. The in-
sible to imagine by the help of substances that ternal carotid artery ends as a bifurcation into ante-
are activated by the ischemia that would com- rior and median cerebral arteries.
pletely exclude the contractile apparatus of the 85 % of the blood supply of the brain is pass-
myocardium during the earliest signs of ischemia ing through the carotids and the rest through the
(e.g. when pH drops). The spared oxygen will 2 vertebral arteries. The vertebral arteries in their
be then disposed for keeping the integrity of the extravertebral course (after branching from a. sub-
myocardium. clavia) are in close relation to the neck vertebrae.
206 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

The vertebral arteries run in the foramena costo- sympathetic fibers and the vasodilatatory parasym-
transversaria of the cervical vertebrae C6 and above. pathetic fibers are in the cranial nerves III., VII., X.
The left and right vertebral arteries are united at the
lower end of the pons and form a. basilaris. A. basi- Regulation of the brain blood flow
laris is then devided into 2 aa. cerebri posteriores at
the upper end of the pons. They are connected to The human brain represents nearly 2–3 % the com-
the carotid field by joining aa. communicantes pos- plete weight of the organism. Yet for the oxida-
teriores. The communicans anterior artery connects tion that takes place in the brain nearly 20 % of the
both anterior cerebral arteries. whole oxygen is needed. The neurons cannot work
with low oxygen supply. The damage of the neurons
By this vascular anastomosis circulus anteriosus
may result also from the depletion of glucose, phos-
Willisi is formed and through this circle it is possi-
phates rich with energy, some aminoacids, vitamins
ble to compensate the obliteration of any mentioned
and other substances. Nearly 15 % of the minute
artery. The deep structures of the brain are sup-
blood volume is passing through the brain. This is
plied by short perforating arteries. The superficial
750 ml/min. (Compared to the myocardium where
structures of the cortex are supplied by long arter-
it is 250 ml/min). This amount represents a large
ies. Three main arteries emerged from the circle of
circulatory reserve. During the childhood the blood
Willis being: anterior cerebral artery, medial cerebral
flow through the brain is twice as much as the flow
artery, and posterior cerebral artery which commu-
in elderly when it is usually the least.
nicate by anastomosis. The amount of blood supply
The brain utilizes oxygen merely for glucose oxida-
is more in the gray matter than the white matter,
tion. The gained energy is largely transformed into
this is related to the intensity of the metabolic rate.
macroenergetic phosphate bonds. The total oxygen
There is what is called haematoencephalic barrier
store of the brain is 315 mmol/g and is mostly con-
(blood brain barrier – BBB). The importance of this
tained in the brain vessels and with a sudden in-
lies in that the exchange of material in the brain
terruption of the oxygen supply by blood this store
vessels is markedly different from other parts of the
enables the survival of the neurons for only 8 min-
body where the capillary supply is usually present.
utes. The dysfunction of the neurons takes place
The speed of exchange is very slow and in the normal
after nearly 10 sec. The brain of the newborns can
situation many substances cannot pass through the
tolerate anoxia more than in the adulthood.
BBB from the blood to the brain. But this perme-
The oxygen supply is 1/4–1/2 larger than the ac-
ability changes during some diseases.
tual amount utilized.By this way the brain is pro-
The veins of the brain are devided into the super- tected against the oxygen depletion which takes place
ficial (which carry the blood into the sinuses of dura during blood pressure changes.
mater) and into deep veins (which empty into the in-
The basis of the adequate oxidation of the brain
ferior or the great cerebral vein that in turn empties
tissue is the perfusion pressure which is given in the
into the rectus sinus).
following relation:
The intracranial venous sinuses (s. sagittalis su-
perior and inferior, rectus, transversi, sigmoidei, cav- CRP = M AP − (CP P + CV P )
ernosus) are placed between the lists of dura mater
and all flow into the v. jugularis interna.
where: CP P – cerebral perfusion pressure
There are no lymphatics in the brain, the perivas- M AP – median arterial pressure
cular spaces take the function of lymphatics. ICP – intracranial pressure
The collateral blood supply is present in some ar- CV P – central venous pressure
eas of the brain, but in other areas, such as internal
capsule, basal ganglia, the thalamus only few anas- The intracranial space is strongly limited by the
tomosis are present. bony parts and filled with 3 noncompressible com-
The sensory inervation of the brain vessels comes ponents - the brain tissue, blood, liquor (the cere-
from the V., IX., X. cranial nerves and the upper brospinal fluid or CSF). The change of volume in any
cervical roots. of these components is accompanied by the change
Vasoconstriction is mediated through the cervical in ICP which ranges physiologically between 0,9–
3.24. Pathophysiology of the brain circulation (B. Mladosievičová) 207

1,9 kPa. When ICP reaches over 6,6 kPa the brain tioned levels leads to the failure of autoregulatory
circulation will stop. mechanisms. Carbon dioxide can affect the brain
The venous pressure in the brain is only 0,7 kPa. vessels in 3 manners:
In normal conditions the CPP ranges between 6,6– • through the pCO2 level in the arterial blood
20 kPa. The critical level of the MAP needed to keep
the blood flowing through the brain is about 8 kPa. • indirectly acting on the vasomotor center in the
Any decrease below this level, specially if sudden, medulla oblongata
can lead to failure of the brain circulation. • through pH changes in the tissue which may
Another condition for normal functional activity of have an influence on contractile elements in vas-
the brain is an intact BBB. As well as other criteria, cular wall
such as enough glucose supply.
Hypercapnia leads to vasodilatation of the brain
The normal blood flow through the brain is about
vessels, acidosis in the perivascular space and in the
50–60 ml/100 g tissue/min. When this is lowered
smooth muscle cells in the vascular wall leads to va-
to 20 ml/100 g tissue/min, the functional activity
sodilatation as well.
of the neurons decreases and this is presented very
The metabolic results of hypoxia (decrease in the
fast in the cerebral cortex. The structural changes
hydrogen ions concentration, increase K+ and Ca2+
in the brain neurons take place after few minutes
concentration, increase the level of catecholamins,
when the blood flow level is decreased to 10 ml/100 g
and adenosin level increase in the tissues surrounding
tissue/min. The most sensitive are the neurons, then
the arterioles) may lead to vasodilatation.
the glial cells and finally the endothelial cells of the
On the other hand hypocapnia, alkalosis, and hy-
brain vessels.
peroxia have a blocking effect on the vasodilata-
During the passive changes in the systemic arterial tion and have vasoconstrictory effect. Some other
pressure the brain circulation is not affected due to substances with vasoconstrictory effect are acetyl-
the autoregulatory compensatory mechanisms. choline, norepinephrine, dopamin, serotonin, his-
Yet those regulatory mechanisms do not start tamine, thromboxan A2 , haemoglobin, prostaglandin
working immediately after the drop of blood pres- E2 etc.
sure, but with a 1–2 min latency, during which The neurogenic regulation is less prominent than
the blood pressure may get below the critical level the chemical regulation in the brain circulation and
needed to keep the CPP. In hypertensive and it has an adjusting action. The outcome of this reg-
atherosclerotic patients has been noticed that the ulation comes from the baroreceptors in the aortic
critical level needed to keep the CPP is relatively arch and the carotic sinus. These are stimulated by
higher than in normal individuals. Decrease in blood any change in the diameter of the vessel where they
pressure to 70 % of its original level in hypertonic pa- are located. The role of the sympathetic nerves lies
tients may have serious outcomes. in protecting the brain against any sudden increase
The brain vessels are very much adapted to deal in the blood pressure. The stimulation of the sym-
with any decrease in the brain perfusion by an ad- pathetic fibers leads usually to vasoconstricion simi-
equate vasodilatation. At the same time vasocon- larly to the stimulation of the a-adrenergic receptors,
striction takes place of the peripheral structures and on the contrary the stimulation of the b -adrenergic
by this mechanism a redistribution of blood supplies receptors leads to vasodilatation.
adequate amounts of blood to the brain. The mech-
anism which leads to vasodilatation in the brain ves- 3.24.1 Stroke – acute cerebrovascular
sels is yet unknown but many opinions point to the
role of carbon dioxide and its effect on the brain ves- accident
sels. Cerebrovascular accident – CVA (apoplexia, ictus) is
On the other hand when there is an increase in the a localized cerebral damage which results from a sud-
blood pressure (for instance an increase in the MAP den drop of blood perfusion in a certain area of the
up to the level of 20 kPa) the arteriol field reacts brain tissue (local brain ischaemia) or a sudden dis-
by increasing the vasoconstriction. Any deviation of traction of the brain tissue by a haemorrhage which
pressure changes above or below the previous men- is localized in a certain area (cerebral haemorrhage).
208 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

3.24.1.1 Localized ischaemia of the brain • mitral valve diseases

Is a condition of decreased perfusion in a limited • others
area of brain tissue resulting from cerebrovascular
Lowering the heart function in these cases leads to
insufficiency. Cerebrovascular insufficiency can oc-
the decrease in the amount and the speed of cerebral
cur, when cerebrovascular resistance increases with blood flow.
a normal haemodynamics (eg.atherosclerotis or oblit-
Generally there are some hypoxic factors which
erations) or the resistance is unchanged but the
correlate with other factors predisposing to the acute
haemodynamics are decreased (eg. hypotension).
regional brain ischaemia.
The decrease in the brain perfusion by 30–50 % can
These are: increased blood viscosity, anaemia,
pass with no neurological signs and with no switch-
polycythaemia, change in blood temperature, coag-
ing on of the regulatory mechanisms, yet any further
ulation disorders, disorders in glucose utilization, li-
reduction in the brain circulation leads to switching
paemia, cytotoxic changes in the cells, haemoconce-
on of compensatory mechanisms.
tration, respiratory disorders.
Yet, when the cerebrovascular insufficiency leads
The most effective factor among them is diabetes
to a perfusion decrease of about 20 ml/100 g/min,
mellitus (DM), with bad glucose tolerance and uti-
then the compensatory mechanisms are not capable
lization. Diabetic microangiopathy of the brain ar-
any more to deal with the perfusion drop in the brain.
teries may cause their dysfunction and respectively
So the cerebral blood flow is no more sufficient for the
the failure of their autoregulatory function. Poly-
adequate oxygen and nutrition supply of the brain
cythaemia may lead to high blood viscosity which in-
and the clearance of the metabolic products. Here
creases the cerebrovascular resistance and decreases
an area of a permanent ischaemia is formed (with the the cerebral blood flow.
changes of pH of the perivascular fluid, and the re-
Anaemia with a low haemoglobin concentration
sulting pathological vasodilatation, hyperaemia and
worsens the brain supply with oxygen. In lipaemia
brain oedema).
there is also an increase in blood viscosity. Another
Brain ischaemia can occur as well during an ab-
hypoxic factor is an increase in the thrombocyte ag-
normal increase in brain function beyond the physi-
gregation, which leads to a microcirculatory failure.
ological ability where the compensatory mechanisms
A localized atherosclerosis in regions of branching,
are no more capable of adapting the increasing re-
bifurcations, and bendings of carotid, vertebral and
quirements.
cerebral vessels is the most common cause of the
Brain ischaemia can occur due to acute hy-
cerebrovascular failure. It causes chronic stenosis
potension specially in patients with cardiocircula-
and represents also one of the pathogenic factors in
tory insufficiency with hypertension, atherosclerosis
acute brain ischaemia.
or other pathological disorders. In these patients
Atheromatous changes lead to the narrowing of
even a physiological drop of the blood pressure in
the vascular lumen and hence they become less
such conditions as rising up, long standing, after
translucent. The endothelium is destroyed and then
meals, after hypotensive therapy, may lead to brain
sloughed during the process of atherosclerosis lead-
ischaemia.
ing eventually to a marked loss of vasoconstricting
Localized brain ischaemia can occur as well with a
endothelines, which more over induces the loss of
pathological drop of the blood pressure e.g. in shock,
thromboxanes being another effective vasoconstrict-
haemorrhage, MI, Adam’s stroke syndrom, narcosis.
ing agents present in the platelets. Atheromatous
bn The cerebrovascular insufficiency may be a re-
lesions may also lead to microembolization.
sult of the circulatory failure in cardiocirculatory dis-
The atherosclerotic changes are usually found on
eases:
the extracerebral part of the carotid arteries.
• myocardial infarction (MI) The vascular anomalies such as (absence of a ves-
sel, their tortuosity, etc.) occur mainly in the regions
• cardiac arrhythmias of the vertebrobasilar and carotid vessels. The cere-
• heart failure brovascular insufficiency arises from the slow blood
flow through the abnormal vessels mainly in the el-
• cor pulmonale with decompensation derly. There are also some other mechanical factors
3.24. Pathophysiology of the brain circulation (B. Mladosievičová) 209

that affect the circulation (for example the vertebral malatia pseudocyst being a cavity filled with serous
artery is closely related to the bodies of the verte- fuild.
brae, to the intervertebral discs and to the spinal Between day 7 and day 30 of the CVA a defect
nerves). Thus change in the position of the head in the blood brain barrier is noticed. The hypoxia
together with additional factors may play a role in not only affects the neurons and the glia but as well
cerebrovascular insuffuciency. destroys the vascular endothelium. The damage of
The cerebral arteries (with the exception of the the blood brain barrier during the ischaemia is an
circle of Willis) have a very weakly developed tu- important factor in other 3 processes being :
nica muscularis media and hence a weak ability to 1. The passage of the serum proteins extravas-
contract. Apart from this penetrating cerebral arter- cularly lead to the formation of extracellular
ies loose the periarterial inervation when penetrating oedema.
the brain tissue and as a result they loose the neu-
rogenic regulation of their contraction. 2. The abnormal permeability of pharmacologi-
The ischaemic tissue from the pathological point cally active substances leads to a change in the
of view contains devitalized central areas (where the vascular smooth muscle cells reactivity.
blood flow is below 10 ml/100 g of tissue/min) as 3. There is a disturbed permeability for some tis-
well as vital peripheral parts in which the perfu- sue metabolites and some local toxic products to
sion reaches about 10-20ml/100 g /tis/min but these vascular lumen (this leads to the accumulation
parts due to their dysfunction are also considered of lactic acid in the interestitium and hence an
”lost” parts. increase in the water binding capacity).
The initial functional change is the loss of neuronal
membrane polarity. The initial structural change af- Brain oedema is an increase in the water content
ter few minutes of ischaemia is the enlargement of the in the brain tissue. Since the brain is contained in
mitochondria (and hence the damage of their mem- limited and closed intracranial space, this phenom-
brane) which is essential for the oxidative phosphory- ena is very dangerous. The increasing brain volume
lation). In the nucleus there is loss of proteosynthe- leads to deformation of the brain ventricles and other
sis, free oxygen radicals are released as well. These liquor filled spaces, a deviation of the midline and
radicals react with some phospholipids in the cell even herniation of the brain tissue to intracranial
membrane leading to it dysfunction. After few hours spaces like to foramen occipitale magnum.
of ischaemia due to the rupture of the cell membrane Ischemic oedema marks the hyperhydratation of
the hydrolytic enzymes are spread into the intersti- the infarcted area which results from the tissue hy-
tium. poxia. It starts as intracellular hyperhydration and
later the vasogenic oedema takes place. The effect of
The first morphologically detected change in the
oedema on the nervous tissue lies in the formation of
ischaemic area is the intracellular oedema. Hypoxia
bad condition for neuronal transmition. Global hy-
leads to the depletion of ATP due to low aerobic gly-
poxic damage of the brain can be the end result and
colysis. This eventually leads to the dysfunction of
this is manifested as a state of deep coma after the
Na+ –K+ pump in the cell membrane. There is an
cardiopulmonary resuscitation. The picture of this
influx of Na+ intracellularly leading to intracellular
state is a multicentric necrosis.
oedema. Ca2+ plays a key role in cell damage hence
it flows intracellulary and activates the phospholi-
pase enzymes. Free oxygen radicals represent other 3.24.1.2 Brain haemorrhage
factors in the cellular damage. The basis of brain haemorrhage is a gush of blood
Later the tissue necrosis develops. The patho- through a vascular rupture into the brain tissue, or
logicanatomical picture of the necrotizing area is into the cerebrospinal fluid (CSF) of a ventricle or
malatia alba, less frequent is malatia rubra being a the leptomeningeal cisternae.
haemorhagic infarct which occur when there is ve- The degenerative vascular changes render the ves-
nous stasis in the cerebral circulation. The final pic- sels liable for rupture. The usual site is the internal
ture which is the result of the macrophage action capsule and the most common artery affected is the
after weeks and months is what is known as post- Charcots artery.
210 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

The etiopathogenesis lies in a lower local resistance in a weakened area of the vessel wall. It can be con-
of a given artery in combination with a sudden or a genital, traumatic, arteriosclerotic or inflammatory.
continuous increase in a cerebral arterial blood pres- Congenital and traumatic aneurysms are the com-
sure. An arterial spasmus can precede the haemor- monest causes of the subarachnoid haemorrhage.
rhage causing a functional distraction to the vessel Besides the congenital aneurysms there are also
wall and then its easy rupture in case of any increase the required ones usually due to mycotic embolisa-
in the blood pressure. A decrement in the mechani- tion. Some aneurysms have elastic wall and their
cal strength of the cerebral arteries is mostly caused rupture occur very rarely. So they are manifested
by the atherosclerotic changes. by their pressure on the brain tissue or the cranial
At the moment of the arterial wall rupture the nerves.
blood gushes out, and the pressure is markedly
decreased intravascularly leading to the vascular
smooth muscle contraction. The narrow lumen leads 3.24.4 Generalized arteriosclerosis of
to thrombus formation. The flow of blood continues the small cerebral arteries
till the decreasing intravascular pressure is in equi-
librium with the increasing intracranial pressure. The pathologicanatomical finding of the cerebral ar-
Haemorrhage causes a disruption in the brain tis- teriosclerosis is the picture status verminosus of the
sue along the axons can completely destroy the tis- cerebral cortex (being the extinction of the ganglion
sue despite its anatomical structure. The increase in cells due to ischaemia), status cribrosus of the basal
the intracranial pressure leads to the failure of the ganglia being a widening of the perivascular spaces,
venous return and hence venous congestion leads to and status lacunaris (being small cavities or post
malacia rubra. malatia pseudocysts).
In the elderly the brain tissue is subjected to
a diffuse slowly progressing arteriosclerosis. The
3.24.2 Subarachniod haemorrhage arteriosclerotic changes seems to develop gradually
reaching the small vessels. During life a gradual
Is a spontaneous intracranial haemorrhage which hyalinization of the vessels takes place, particularly
spreads in the leptomeningeal space between the in hypertensive individuals, which is followed by fi-
arachnoid and pia mater. Frequently it is associ- brosis and necrosis. Thus the vessels loose their elas-
ated with a cerebrovascular haemorrhage which is ticity and the ability of dilatation.
the primary event and the passage of blood to the
The illness usually starts as pseudoneurosthenia
leptomeningeal space is the secondary event. The
being (tiredness, irritability, apathic behavior). We
vascular aneurysms are the usual source of the sub-
can notice some memory problems, emotional liabil-
arachnoid haemorrhage. This condition usually oc-
ity, and some sleep disturbance.
curs suddenly and hence the term ictus.
The clinical picture of the subarachnoid haemor-
rhage is usually pain as a dominating symptom which 3.24.5 Thrombosis and thrombophle-
is frequently accompanied by alteration of conscious- bitis of the cerebral veins and
ness. The location of the pain usually corresponds
to the site of rupture. Meningeal syndrom develops
sinuses
6–12 hours later when the meningies respond to the Venous obliteration can result from inflammation of
presence of blood by a sterile inflammation. In cases the venous wall and disturbances of the haemody-
where the aneurysmal blood affected the surround- namics with venous stasis.
ing brain tissue, here a loss of individual functions Thrombophlebitis results from a generalized or a
may occur. localized inflammation such as sinusitis, otitis media
etc.
3.24.3 Aneurysms On the other hand, phlebothrombosis is mainly
caused by a disturbance in the haemodynamics. It
Intracranial aneurysm is an abnormally located di- can manifest itself in patients with an increased
latation of a cerebral artery which usually develops haemocoagulation and in cases of venous stasis.
3.25. The basis of the electrical action of the heart (I. Hulı́n) 211

Thrombophlebitis and thrombosis of the cerebral the out–flow is know as efflux. The passive transport
venous system lead to a picture of pseudotumorous takes place along the electrochemical gradient and
encephalopathy (being an elevated intracranial pres- depends on the concentration gradient of the solutes.
sure with no proved expanding process). Thrombosis The active transport occur against the electrochem-
and thrombophlebitis have a relatively higher inci- ical gradient, still not all the power sources taking
dence during gravidity and puerperium. The reason place in the active transport are known. The active
of this is the higher heamocoagulability, arterial in- transport needs energy supply which is mainly from
fections of the genitalia which is common in these the ATP. Most probably the active transport is the
situations as well as the possible migration of the result of no equilibrium of ions and electric charges
thrombophlebitis from the pelvic area intracranially on both sides of the membrane. Na+ and Cl− are
through the vertebral plexuses. predominantly extracellular ions whereas K+ is main
The clinical manifestation of this condition is usu- intracellular ion. Nernst equation shows the state of
ally headache, symptoms of a space occupying lesion equilibrium:
(SOL) in the brain, signs of an elevated intracranial
pressure, and possibly signs of infection. 1 ioni
Vx = −61, 5 · · log
z ione

ione = extracellular concentration of the ion;

ioni = intracellular concentration of the ion;
z = the ion charge, e.g.: +1 for K+ , +2 for Ca2+,
-1 for Cl− )
3.25 The basis of the electrical Vx = the equilibrium state (tension) for choice ion.
action of the heart
The ATP-ase enzyme is unequally distributed in
the cell membrane and it can change its position.
When the ATP-ase is directed intracellularly (to the
The cell is a structural unit in all living organ- inside) it has a high affinity to Na+ . When it is di-
isms. The cellular membrane has an important role rected to the outside it has a higher affinity to K+ .
in all the electric events that precede the contraction. The Na+ –ATP-ase binding leads to ATP-ase hydrol-
Cellular membranes are complicated structures that ysis which first step is the enzyme phosphorilation.
protect the intracellular environment. They have The following conformation change rotates the en-
special systems which have the ability to recognize zyme along with the bound Na+ to face the extra-
structures being that is known as massangers. These cellular fluid, in this condition the affinity to Na+
can carry information to internal organelles. Mem- decreases with a simultaneous increase in the affin-
branes are lipid structures or layers which are in- ity to K+ . The phosphorilated enzyme then makes
terrupted by protein molecules. Soluble substances an exchange by giving Na+ and taking K+ instead.
in the extra cellular space can pass intracellulary by Then another conformation change will rotate the
simple diffusion or active transport where the protein K+ –ATP-ase to face intracellularly where the K+ ion
receptors in the cell membrane take part. Phospho- is exchanged by Na+ . This process continues and the
lipids are the building units apart from them are the in-flowing Na+ is expelled extracellularly when on
neutral fat and glycolipids. The lipids form polar the other hand the lost K+ ions are returned back into
hydrophilic heads and non polar hydrophobic ends. the cell. Yet this process is not equivalent because
The membrane proteins are arranged asymmetri- for pumping 3 Na+ moles extracellularly only 2 K+
cally. Sometimes they surround lipid rings and hence moles are returned back and one mole of ATP is used.
form some non specific hydrophilic configurations This mechanism is known as the Na+ –K+ pump.
which act as channels through which electrolytes can Many living cells make use of the differences in the
pass. Some membrane protein are mobile, they can electric charge across the membranes in regulating
rotate or change their position in the membrane. physiological functions. Muscle fibers and neurons
The transmembrane transport (flux) can be active make use of the electric charge of their membranes
or passive. Influx means the in–flow of solutes and in the regulation of their permeability, releasing neu-
212 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

rotransmitters, Ca2+ release for contraction, and in others. Ca2+ is very important for the regulation
the secretion of some substances. of myocardial contractility. In the resting state of
With the appropriate stimulation the neurons and the cell the Ca2+ ions are expelled out of the cell by
muscle fibers have the ability to change their elec- Na+ –Ca2+ transport mechanism. This mechanism is
trical characteristics – A wave of excitation can take voltage depended. During the plateau of the action
place in the membranes or the near by cells which will potential the transporting mechanism is changed into
eventually lead to a change in the electrical character a pump which enables a faster Ca2+ ions influx to the
of these membranes. As a result there is an influx of cell.
the positive charged particles (Na+ and K+ ) into the
cells. The influx of these ions is mediated by special
sensors for voltage changes. The polar molecules in 3.25.1 The resting (membrane) po-
the membranes represent those sensors and they have tential
high charge resp. high dipole moment. These polar
highly charged molecules change their conformation In the living cells the ions are unequally distributed
as a response to the electric changes. on both sides of the cell membrane. As a result of this
fact a potential difference is formed between both
Channels present in the cell membrane by which sides of the membrane, this is known as the resting
the Na+ influx takes place are known as the fast potential. It is negative on the internal side of the
channels. These channels are regulated by 2 gates membrane. Many factors share the task of keeping
being the m and h gate which are localized one be- this potential. The active Na+ –K+ transport (Na+
hind the other. At rest the gate h is opened end gate is transported to the outside and K+ to the inside) is
m is closed. When the cell is stimulated and the one of the most important factors and as a result of
potential reaches -60 mV (-40 mV) (this is known as the action of Na+ –K+ pump the K+ concentration
the threshold potential) the gate m opens fast mean intracellulary is 40 times higher than extracellularly
while the gate h starts to close. The closure of gate and the Na+ concentration is intracellularly 15 times
h is 3-4 times slower than the gate m opening and lower than extracellularly. In the resting state the
due to this there will be a small portion of time when membrane permeability for Na+ ions is very small.
both gate m and gate h are opened so that the Na+ This means that even the Na+ conduction (g Na)
ions enter the cell due to the electrochemical gradi- is very small and hence the concentration gradient
ent. It is very likely hat the gate system is in a con- for Na+ can not be turned by the passive diffusion
tinuous transitional state, all the time moving from of Na+ back to the cell. The proteins on the other
active to inactive and back to the active state and so hand are carriers of the negative charge intracellu-
on, and hence the resulting state of the membrane larly and they similarly to H2 PO− 2−
4 and HPO4 can
depends on the total number of the opened channels not leave the cell because of the low permeability
in a given time. The gate m is an activatory gate and of the cell membrane to these molecules. The cellu-
the gate h is an inactivatory one. The channel is ac- lar membrane permeability for K+ ions is relatively
tivated when gate m is opened and it is inactivated high. The difference of the K+ concentration is con-
when gate h is closed. In conclusion the channel can sidered the generating power for this ion diffusion.
exhibit 4 different states according to the position of K+ ions have the tendency for increasing the posi-
the gates and the channel is considered to be open tive charge on the outer side of the membrane but
only when both gate h and m are opened (see fig. 3.23 this positive charge will return the positive charged
page 213). particles back to the cell. Both the opposing electric
In some excitable cells there are similar channels power and the concentration gradient (which act in
for Ca2+ ions and other ions which have a similar opposite directions) are equal for the K+ ion when
diameter to the Ca2+ ions (e.g. Ba2+ , Mn2+ , Mg2+ ). it is in the state of equilibrium. Nernst equation
These channels are controlled by 2 gates known as d applies in the equilibrium state and the K+ voltage
and f. They are known as the slow channels and a in the equilibrium state equals –100 mV. Using the
continuous supply of energy is needed to keep them Nernst equation we can calculate the voltage of other
active. In addition another ions can pass through ions in the equilibrium state. So for Na+ it is VNa
the slow channels such as Ba2+ , Mn2+ , Mg2+ and = +60 mV and for Ca2+ it is VCa = +100 mV. So
3.25. The basis of the electrical action of the heart (I. Hulı́n) 213

Figure 3.23: Influx of ions in cell via the slow and fast channels

the current size for any ion (Ix ) is determined by the tion the resting potential starts to change. This ad-
membrane conduction for this ion (gx and the driving equate stimulation may be an electrical stimulation
voltage can be obtained by calculating the difference from the outside or an activation which is transmit-
between the actual voltage on the membrane (V) and ted from a neighbouring cell, on the other hand a
the given ion voltage in state of equilibrium (Vx ). mechanical or a chemical stimulation can be an ad-
All the living membranes have their resting po- equate impulse or stimulus is followed by a change
tential but only the muscle fibers and the neurons in the membrane permeability and a change in the
have the ability to change their permeability upon state of the gates in the membrane channels. The
the stimulation. By this some large potential depend membrane activation icreases the membrane perme-
on the activity of the Na–K pump and the higher is ability for Na by opening the m gates in the fast Na+
the pump activity the higher is the resting potential. channels and by this Na+ ions can flow freely along
their electrochemical gradient entering the cell (Na+
influx) INa . The Na influx causes the extinction of
3.25.2 The action potential the Na gradient between the intra and extracellular
Upon stimulating the myocardial cell a characteris- spaces. The Na influx cancels potential difference of
tic change takes place, this change is known as the the membrane. This process is very fast lasting only
bn action potential. The resting potential in these 2–4 ms and hence its name being the fast depolariz-
cells ranges round –90 mV. Upon adequate stimula- ing influx If or Iqi (fast, quick). On the transmem-
214 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

brane action potential curve this change (the fast change in the membrane potential. The myocardial
depolarization) is shown as phase 0. The Na+ influx cells mainly are concerned with this process. (See
changes the membrane potential which further leads fig. 3.24 page 215). During the phase 0, 1, 2 it is not
to opening of the Na+ channel. So there is a pos- possible to stimulate the cell membrane by any im-
itive connection in which an increasing Na+ influx pulse or stimulus because stimulating the membrane
will fascilitate even more Na+ influx. This relation in other words means its depolarization. Because we
is known as the regenerative depolarization. The po- cannot depolarize a depolarized membrane. That
tential changes its value to become near 0. Usually is why these phases are called the absolute refrac-
there is an overshooting of the potential value reach- tory phase. At the end of phase 3 the membrane
ing +20 mV. This overshoot will cause the Na+ influx renewes its excitability (ability to be excited, sensi-
inactivation. The sharp change in the potential in 0 tivity to stimuli) due to its partial repolarization. So
phase is known as the steep edge of the action poten- we can stimulate the cell by an impulse which is over
tial. So the steepness of the curve decides the quality threshold and we can achieve a depolarization which
of spread of the action potential to the neighbouring is slower than the normal repolarization. This period
cells. is known as the relative refractory period or phase.
During the membrane fast depolarization by the The membrane potential should be -45 mV at least
Na+ influx the Ca2+ channels will open when the and the depolarization in this situation (with over
membrane potential reaches -40 mV. This will facil- treshold impuls) is achieved by the slow Ca2+ influx.
itate the Ca2+ ions to flow or (influx) along their In pathological conditions repolarization is not
electrochemical gradient. This ion flow is known as necessary completed in phase 3 so the membrane
the slow inward influx ISI. . potential doesn’t reach the level -70 mV to -90 mV
as it is suppose to be but it only reaches -30 mV
So influx of the Ca2+ ions join the influx of Na+ to -40 mV. In this condition a new depolarization
ions in the process of membrane depolarization. The (phase 0) can be obtained by stimulating the cell
K+ ion escape from the cell occurs simultaneously membrane by under threshold impulse. This process
with the continuation of the membrane depolariza- takes plase when there are membrane abnormalities
tion and by this the process of repolarization actually or when there is an abnormal potential which is usu-
begins. The fast K+ ion efflux starts with the over- ally localised in the vicinity of the ischemic regions.
shoot to +20 mV, and a quick K+ repolarization Iqr . In this situation the difference in the potential lev-
This is known as phase 1. In this phase the Na influx els of the two neighbouring zones leads to a partial
slows down whereas the Ca2+ influx continues. Here depolarization of the attached cells. Due to the ef-
the membrane potential doesnt change because the fect of some substances there is an increase in the
Ca2+ influx equalizes the K+ efflux. This equilib- speed of Na+ and Ca2+ influx and a dicrease in the
rium represents a process of remedy, or rectification. K+ efflux. A situation similar to the mentioned can
Because the K+ ion efflux is opposed by a high re- occur when the cells are overfiled with Ca2+ ion due
sistence, the Ca2+ flow stops at the end of phase to different causes.
2.
In phase 3 only the K+ flow remains. This is
3.25.3 Automatic cells
known as the late K+ flow Ix1 and later flow Ix2 .
This condition could be reffered to as the late (true) In automatic or rythmogennic cells phase 4 doesn’t
rectification. The membrane potential gradually re- represent the preciously described isoelectric inter-
turns to the original value at the end of phase 4. val. In the sinoatrial cells similarly to other cells in
Yet the ion balance is markedly different from the the conducting system of the heart upon reaching
original state. There is a surplus of Na+ and Ca2+ the maximal diastolic potential its negativity starts
ions with a depletion of K+ ion. The correction of to decrease it gradually i.e. if –70 was its maximal
the ion levels start after reaching the original poten- diastolic potential it gradually reaches –60). This
tial. Ca2+ ions are exchanged by Na+ ions ( the change is marked as the spontaneous diastolic depo-
action of Na–Ca pump) and the Na+ ions surplus larization which is caused by Na+ ion influx. This is
is then corrected by the Na–K pump. So during due to Na+ inadequate pumping out which is caused
phase 4 there is an intensive exchange of ions with no by a low Na-K pump performance. The SA node
3.25. The basis of the electrical action of the heart (I. Hulı́n) 215

Figure 3.24: Transmembrane action potential of cardiomyocyte

cells have the steepest (fastest) diastolic depolariza-

tion. After reaching the threshold potential (–40 to
–30 mV) phase 0 takes place (fast depolarization).
The following phase (phase 1) is not as steep as in
the myocardial cells. In the SA node cells the depo-
larization (phase 0) results from the Ca2+ ion influx
and only partially due to the Na+ ion influx. The
overshooting usually doesn’t occur, plateau usually
doesn’t exist. The SA node cells don’t need Ca2+
for contractions (an obvious plateau is present in the
contractile cells). So in the action potential curve
phase 1 is directly followed by phase 3.

The diastolic potential can only reach (–50 mV) –

(–70 mV). The potassium potential is low. The spon-
tanuous diastolic depolarization takes place in phase Figure 3.25: Transmembrane action potential of
4. The in-flowing Na+ ions cause the membrane sinoatrial node
potential to reach the threshold levels upon which
phase 0 takes place (see fig. 3.25 page 215). The
whole process is repeated approximately 70 times per in this case phase 4 takes longer time. An impulse
minute. A similar process can occur in other ryth- wave coming from the activated part of the conduc-
mogenic cells in the conductive system of the heart, tive system of the heart reaches the myocardial cells
216 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

before they reach the threshold potential and here current waves, where as the time constant stands for
phase 0 starts. The refractory phase lasts for the the time needed to change the membrane potential.
whole action potential. This fact prevents the SA It is not easy to determine the time and space con-
node from an immature activation as a consequence stants for the cardiac conductive system or for the
of activated atria. The spontanous depolarization myocardium. The Purkinje and myocardial fibers
of the SA node cells is not depended upon the Na+ microstructure facilitate a longitudinal progress of
and K+ concetration in the extracellular fluid. Yet activation. The intensity of the local current waves
the Ca2+ flow can affect the automacity. The speed depends on the speed of the regenerative depolariza-
of the diastolic depolarization determines the heart tion, which in turn depends on the membrane resting
rate. Many substances achieve their action on the potential. So in conclusion the intentsity of the local
heart through changing the SA cells membrane per- current waves as well as their speed depend on the
meability and hence change the length of phase 4. membrane resting potential.
From the electrophysiological point of view we can The space constant of the myocardium and the
devide the heart cells into those having the ability to conductive system is 1–2 mm. Local currents can
spontaneously depolarize, and those which need ac- then generate depolarization in the myocardial tis-
tivation from the nearby cells to depolarize. The ac- sue. This depolarization can reach the distance of
tion potential of one cell shifts the resting potential few millimeters. This will guarantee the progress of
of the neighbouring cell to the level of the thresh- activation even in case of some inadequate cell func-
old potential (by the ionic flow) and then the pro- tion to conduct stimulation with the myocyte length
cess of depolarization takes place as previously de- about 100 mm. The local currents can even stand
scribed. The action potential of an activated cell is for a cable defect which is the representation of non
the impulse which causes depolarization of the neigh- functional myocytes.
bouring cell, its effect is incresing with increasing its
The activation of the heart doesnt progress de-
speed. That is why it is very easy for the steep 0
pending marely on the physical principles because if
phase of the action potential to spread. It is very
the conduction progresses by a cable mechanism only
important to realize that after reaching the thresh-
it would be gradually weaker and weaker. Yet the lo-
old potential through activating the cell by an ac-
cal current waves induce depolarization in the neigh-
tion potencial of another cell, the coninuity of the
bouring cells which means that each cell generate an-
event does not depend on the activating action po-
other stimulus (when it depolarized). In other words
tential but on electrophysiological properties of the
the myocardial and the conductive system cells act as
activated cell.
amplifieres of a continuously weakening stimulus and
that is why activation is spread without any decrea-
3.25.4 The progress of activation ment. Moreover, the cellular activation (the process
of action potential) presents the backward process of
Stimulation passes from one cell membrane to the
activation due to the refractivity phenomen.
neighbouring cell membrane in the form of local
electric currents which are generated between the The transfer of activation from cell to cell depend
polarised and the depolarized areas. These currents on the cellular membrane characteristics and on the
form circles on the still polarised cell membrane lead- time at which activation took place. When the im-
ing to the decrease of the membrane potential. And pulse reaches the cell in phase 3 with no renewed di-
then decrease the resting potential to the threshold astolic potential, the Na+ channel doesn’t open. Yet
level. The local currents are generated during repo- another slow chanel opens and a regenerative depo-
larization as well, yet they are weak and inadequate larization takes place. In this case the membrane
for activating cells which reached the relative refrac- depolarization is slow and that is why phase 0 hasn’t
tory phase. The spread of the local current waves is got a steep angle, the intensity of the local currents is
affected by the characteristic of the conducting sys- lower, and the activation is progressing slowly. The
tem as well as the characteristics of the myocardium spread in this case can dicrease gradually and the
which could be described as cable characters. We steepness of phase 0 is decreasing also till is finally
mainly deal with two constants being time and space. dies out.
The space constant determines the extent of the local The absolute and fast transmission of activation
3.25. The basis of the electrical action of the heart (I. Hulı́n) 217

ensures a high and steep action potential and a po- 3.25.5 Anatomy and physiology of the
larised membrane with a low potential threshold. conductive system of the heart
Na+ channel disfunction can eventually lead to a con-
duction error. This effect could be achieved by us- The awarness of the conductive system function and
ing some antiarrhythmmic drugs. So the weak Na+ structure is crucial for understanding the basis of the
current will cause the activation decreament and re- electrophysiological processes in the heart and hence
spectively its end. a right interpretation of the electrocardiogram.
In the heart there is a special conducting system
A condution block occurs when the stimulus
which provides the automatic formation and propa-
reaches a depolarized membrane, considering that a
gation of the excitatory process in a way by which
continuous depolarization can be caused by a high
the heart can perfectly perform its pumping function.
K+ concetration intracellularly. In this case the nor-
The conductive system of the heart differs function-
mal impulse or stimulus is below the threshold level
ally, histologically and evolutionally from a working
needed and by this there is a complete block of con-
myocardium. The automatic formation of a stimulus
duction. When the injury is less there wil be a con-
occurs in the sinoatrial node (SA node). The excita-
ductive delay. The block can present only in one
tion spreads through the atria to the atrioventricu-
direction and hence the impulse conduction to other
lar node (AV node). From this point the activation
than the main side doesn’t have to be blocked.
progress to the bundle of His, right and left bundle
In some cases a functional block can occur and is branches, to the Purkinje fibers and finally to the
usually caused by a continuous depolarization of the myocardium.
membranes. This continuous depolarization can be SA node The SA node develops during the em-
kept in some areas due to a repeated activation. bryonal period together with the compact AV node
An abnormal conduction can occur during an in the region where the right superior cardial vein
increased membrane sensitivity of stimuli usually is united with the sinus venosus. The AV node mi-
caused by catecholamines. In this case the slow Ca2+ grate internally to its definitive position whereas the
channel is activated spontaneously and a slow wave SA node remains in its original position. It is situ-
of depolarization spreads to the membranes. This ated in the vicinity of the enterance of superior vena
spread is due to the action potentials of the Ca2+ cava to the right atrium, along the crista terminalis.
channels. This condition occurs in the ischemic zone Its internal end lies subendocardially. The SA node
of the myocardium and a conductive deffect can be is 1–2 mm in width, 10–20 mm in length and it is
furtherly complicated by the fact that the ischemia pyramidal in shape, and cross section is triangular
shortens the refractory phase. The short refractory which base is directed towards the antrum of the
phase when coupeled with a slow conduction is most right atrium. There is a small artery in the center of
dangerous. As a result of these facts, the slow con- the triangle. This artery gives many small branches
duction can reactivate the areas which have short to provide the SA node with nutrition.
refractory phase and a returning or (back going) ac- Besides the pacemaker function, the SA node
tivation occurs. This is known as (reentery) phe- monitors the central aortic pressure and the pulse.
nomena. In some cases the returning activation is The SA node artery is the first branch of the right
progressing cross the Purkinje fibers and the my- coronary artery. The substances that increase the
ocardial fibers as well. The tract could be so long SA node activity cause dilatation of the SA node
that it is possible to see the myocardial contraction artery and vise versa, the substances which depress
in front of the stimulating wave and behind it, this the SA node activity cause constriction of the SA
is a case of macroreentery. Usually the returning node artery. This feedback mechanism will provide
activation (circulating wave) progresses in the same stabilization of the SA rythm.
manner. In other situations the stimulus breaks up The fundamental skeleton of the SA node is thick
and the circulating wave moves in small circles, this callagenous connective tissue which surronds the cen-
is a case of microreentrery. A high susseptibility of tral artery. It seems as the central artery adventitia.
the myocardium for micro and macro reentery ren- This connective tissue is composed of on irregularly
ders the myocardium instable (an electric instable distributed collagen fibers which forms a layer which
myocardium). encircles the central artery. On the edges of the node
218 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

the cells join to form the efferent pathways. The not yet certain. There are three main conductive
amount of collagen in SA node increases with age. pathways, the anterior, the middle and the poste-
The centre of the SA node contains large number rior, which provide internodal conduction between
of nerve endings, and cholinergic ganglia are found on the SA node and the AV node. These pathways not
the peripheries. The afferent nerve fibers to the node only possess specialized cells but they are not con-
join the nodal cells. The parasympathetic supply tinuous with each other (in other words they are in-
originate from the right vagus n. and the adrenergic terrupted). The cells in these pathways contain less
supply comes from the post ganglionic sympathetic myofillaments, yet they use multiple nexuses for con-
nerves. nection (junction).
There are at least 2 types of specialized cells in the In normal conditions the task of the pathways be-
SA node. The first type are small cells being round ing conducting stimuli to atrial muscles is not clear.
or oval in shape. The shape of the cells simulate It is possible that these tracts or pathways conduct
the primitive myocardial cells having few organelles activation during the pathological conditions and it
and pale cytoplasm. They are reffered to as P cells was found that the posterior pathway has an im-
(pole cells) and contain large amount of glycogen. portant task during the shortening of P–Q interval.
They are situated in the central area of the SA node Those pathways don’t have to exist as an exactly de-
and are organized into clusters. These cells are in fined structures. They could be composed of groups
direct contact with each other and they form the in- of cells having different electrophysiological charac-
tercalated disks in areas of contact. Yet these are teristics. These pathways are possible to be the basis
no nexuses which have the function of low resistence for the reentery circles which occur during the car-
conection of the differentiated cells. The P cells pre- diac arrythmias.
served the ability to generate impulses endogenously The activation of the atria reaches the atrio-
from embryonal period. vetricular junction which is a more complicated
Apart from P cells in the SA node there are structure and could be anatomicallly divided into 4
also long thin myocytes with a longitudinally ori- parts.
ented myofibriles and multiple intercellular conec-
1. The atrionadal region (junction) being a transi-
tions. These cells are refered to as transitional cells.
tional zone
They form a network of fibers and are mainly found
on the SA node peripheries. They are attached to
2. The compact AV node
the P cells on one side and to the myocardial cells
in the atria on the other side. By this way it is pos-
3. The penetrating bundle (the proximal part of
sible to provide the transmission of activation from
bundle of His)
the SA node to the atrial myocardium.
The main characteristic of the P cells is their 4. The branching bundle (the distal part of bundle
automacity, being the ability to depolarize cellular of His)
membrane till reaching the threshold level without
any external stimulation. This character is unique The mentioned parts in 1,2,3 are refered to as the
for the P cells being the fastest among the conductive junctional area. The branching bundle together with
system cells which have the ability to spontaneously the bundle branches is referred to as the subjunc-
depolarize the cellular membrane. And as a result of tional area. (see fig. 3.26 on page 219).
this they are known as the pacemaker cells. SA node The atrionodal region The atrionodal region or
is primary pacemaker. junction or what is known as the transitional zone is
It is possible that automacity can occur in other composed of groups of cells which are found between
conductive system cells. But in the normal condi- the atrial myocardium and the AV node. These cells
tions the automacity of these cells doesnt express (the transitional cells) are smaller than the active
itself because of the dominance of the primary SA myocardial cells. They form tiny clusters which are
node activity. separated by a conective tissue septi. These transi-
The ways for the SA activation spread through tional cells enter the superficial and the deep part of
the atria to the atrioventricular node (AV node) are the compact AV node.
3.25. The basis of the electrical action of the heart (I. Hulı́n) 219

Figure 3.26: Sodium and calcium channels

The compact AV node The compact AV node is work when they reach the N area. The N area is con-
located in the posterobasal part of the interatrial sep- sidered to be the area of the slowest activation con-
tum. It is found between the isthmus of the coronary ducion. The atrionodal fibers can enter the SA node
sinus and the medial cusp of the tricuspid valve. It’s in this part. The NH part is composed of elongated
area is nearly 10 x 6 mm. From the electrophysiolog- cells which simulate the cells that form the bundle
ical point of view the AV area is divided into AN of His. The area where the AV junction crosses to
/atrionodal area), N (nodal area), and NH (nodal – the fibrous ring is considered to be the beginning of
His area). The AN area is composed of cells orga- bundle of His.
nized in a parallel way which gradually form a net- Autonomic nerve fibers are found in the compact
220 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

AV node. They are in the vicinity of the arteries supplied by blood from the septal branch of the
and veins. The parasympathetic n. fibers come from right coronary artery. The right bundle branch and
the left vagus n. and the sympathetic come from the the anterior fasciculus of the left bundle branch are
postganglionic neurons. The blood supply is from supplied by blood through the descending branch of
the fibrous ring arteries. the left coronary artery. The terminal parts of the
The bundle of His The penetrating part and the branches are supplied by blood through the right
remaining part of the branching bundle after giving coronary artery.
its branches will pass through the annulus fibrosus
as the continuity of the compact node then it passes 3.25.5.1 Atrial activation
through the membranous part of the interventricular
septum. It starts to branch at the lower part of the As mentioned above the excitatory process begins
membranous septum. The bundle of His is formed in the SA node and from the SA node the activation
by parallel muscle fibers which are separated by con- spreads radially and continuously across the atrial
nective tissue into a number of stripes. Its diameter myocardium. In the beginning and after the rising
can reach 3 mm and length 12 to 40 mm where its of activation from the SA node, the right atrium is
penetrating part forms about 8–10 mm. the first to be activated. Shortly afterwards the ac-
tivation proceeds to the atrial septum and the left
Branching of bundle of His starts at the lower
atrium respectively. For simplicity we can follow
edge of the membranous part of the interventricu-
the atrial activation using three vectors, each one
lar septum. The right bundle branch is the continu-
of them starts on the SA node. The initial vector of
ity of bundle of His, and its similar to it histologi-
the atrial activation represents the activation of the
cally. The proximal part of the right bundle branch
right atrium and its direction is inferior, anterior and
is situated in the vicinity of the aortic and tricuspid
slightly to the right. The second vector represents
valve. The distal part on the other hand is situated
the activation of the right and left atrium and it is
subendocardially near the septal papillary muscle,
directed inferiorly, to the right, and slight anteriorly
and it continues its pathway till reaching the apex of
or posteriorly. The terminal vector represents the
the right ventricle. The anatomical division of the
activation of the left atrium and is oriented to the
bundle of His into right and left bundle branches is
left, inferiorly, and posteriorly. The relation among
referred to as pseudobifurcation. The reason of this
these vectors on one plane is shown in fig. 3.27 on
lies in that the bundle of His fibers are divided before
page 221.
the anatomical bifurcation, so they differ in function
The first half of the P wave is a picture of the
yet they still pass alongside together for a small dis-
right atrial activation whereas the second half of the
tance. Analogical situation to this are present in
P wave stands for the activation of the left atrium
the anterior (superior) and the posterior (inferior)
mainly. The average direction of maximal vector of
branches of the left bundle. Their division already
the P wave is +60o in the frontal plane. The P wave
occurred in the bundle of His. So they run in the
being normally positive in leads I, II, AVL, but in-
left bundle branch but they differ in their function.
vered in the AVR lead. It is usually the highest in
In some cases a third (branch) fasciculus is discribed
lead II. In the horizontal plane the maximal vector
to be present in the left bundle branch. The division
lies between 0o and +60o . The vector that represents
of the bundle branches is very variable. There are
the right atrial activation is partially anteriorly ori-
some junctions between the branches. The bundle
ented whereas the vector that represents the activa-
branches pass to Purkinje fibers at the apical part.
tion of the left atrium is partially posteriorly directed
Purkinje fibers Purkinje fibers represent the pe- and that is why the P wave is commonly biphasic in
ripheral branching of the bundle branches. They leads V1 and V2 , being initially positive with a neg-
form an subendocardially situated network. Purk- ative terminal part. The positive part represents the
inje fibers contain myofibrils and are divided by col- activation of the right atrium whereas the negative
lagen fibers so that to prevent the side way spread part represents the activation of the left ventricle.
of activation. The Purkinje fibers spread among the In the chest leads which are close to the heart the
fibers of the ventricular muscle fibers. P wave is usually higher. In the left precordial leads
The compact AV node and the bundle of His is the P wave is positive.
3.25. The basis of the electrical action of the heart (I. Hulı́n) 221

Figure 3.27: Activation of the atria and relationship between some vectors (left, right and maximal)

3.25.5.2 Atrial repolarization negative wave (q wave) on the leads V5 and V6 .

The repolarization of atrial muscle fibers is related The progression of activation of the septal and api-
to its depolarization and it is represented as the Tp coanterior parts of the right and left ventricles (0,02)
deviation (also referred to as Ta ). It is usually not During this phase the intervetricular septal activa-
shown on the ECG and the reason is that the repo- tion continues from both sides. The electrical power
larization starts simultaneously with the ventricular are partially similar but a larger part of the septum
depolarization and hence the two processes occur at is depolarized from the left side. So the net direction
the same time. On the ECG the atrial repolarization of the septal activation will be from the left ventricle
Tp is masked by the ventricular QRS complex. The to the right vetricle. The septal activation spreads
direction of the Tp usually opposes the P wave. The from the apex to the heart base, and from the ante-
atrial repolarization can cause pseudo depression of rior to the posterior part simultaneously meanwhile
the ST segment in the J point (see fig. 3.28 page 222). the activation could spread fast to both ventricles.
The apex of the heart, the lateral wall of the right
ventricle, and the anterior apical part of the left ven-
3.25.5.3 Ventricular activation tricle are mainly activated during this phase. The
The activation of the ventricles can be divided into sum of the dipoles in the left ventricle is higher than
4 phases for the purpose of which is an easy under- in the right ventricle and that is why the vector of ac-
standing of the ECG process yet actually the ven- tivation is directed slightly anteriorly, to the left and
tricular activation is one continuous event. Basically partially inferiorly. There will be a positive wave in
each deviation during the process of activation is the chest leads as a result.
shown immedialtedy as a projection on the corre- The complete activation of the interventricular
sponding axis of the lead. septum, the right ventricle, and the larger part of
The initial septal activation (0,01 s) The interven- the left ventricle (0,04–0,06 s) In this phase the acti-
tricular septum in the cavity of the left ventricle is vation of the septum and the right ventricle except its
the first to be activated during the activation of the posterobasal part is completed. Most of the left ven-
ventricles. The interventricular septum is nearly par- tricle is activated as well. Even in this phase the to-
allel to the frontal plane of the human body. That is tal sum of the potentials in the left ventricle is higher
why the initial vector that represents the septal acti- than in the right ventricle, and hence the resulting
vation is directed anteriorly, slightly to the right and vector is large and left oriented, slightly backwards
superiorly or inferiorly. The projection of this vec- and inferiorly. This vector plays role in determining
tor on chest lead axis will form the positive (r wave) the final direction of the resulting QRS vector. The
on the right chest leads (V1 and V2 ) and a small projection of this vector on the chest leads will even-
222 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.28: Ta wave

tually result in recording the shortest S wave in lead the complexes recorded by medial precordial (chest)
V1 and highest R in left chest leads. leads will be equiphasic. During the ventricular ac-
Activation of the basal part of the interventricular tivation we can register the loops representing the
septum and the posterobasal part of the left ventri- QRS complex from different planes. These loops are
cle (0,06–0,08 s) This is the last event by which the recorded in the frontal, horizontal and left sagittal
activation of ventricles is completed (see fig. 3.29 on planes.
page 223 and fig. 3.30 on page 224).
At this time the activation of the pulmonary conus
3.25.5.4 Ventricular repolarization
takes place yet its role in the activation is negligible.
The terminal vector of the activation is backward Ventricular repolarization starts immediately after
directed and to the left or slightly to the right. This the completion of their activation. The direction of
vector is the cause of the descending part of the R repolarization is generally opposite to the direction
wave and the terminal part of the S wave in the left of activation, and that is why the resulting T vector
chest leads. Sometimes a small deviation is recorded in the adults is relatively parallel with the resulting
being a normal variation in the lead V1 it is usually QRS, or it is only slightly deviated. This means that
found in young people and it refers to the activation in the ECG recording T wave is positive except in
of crista supraventricularis. lead V1 . In the new-born and in children the result-
In Eithoven bipolar leads and in the unipolar limb ing T vector is oriented to the left and posteriorly,
leads the ECG deviation are recorded as the picture and that is why T wave is negative in the leads V1 ,
of the projection vectors on the frontal plane accord- V2 , and V3 . The direction of the T complex is usu-
ing to the corresponding phases. There is a certain ally similar to that of the QRS complex in each of
variability in the ECG recording yet this variability the three used planes.
is considered to be normal. Arythmology is a new study concerned with the
In conclusion during the ventricular activation the different mechanisms which take place in cardiac ac-
right precordial (chest) leads will record negative tivation, whereas in the area of long monitoring of
ventricular QRS complexes. On the other hand ECG there is the intensive development of the elec-
3.25. The basis of the electrical action of the heart (I. Hulı́n) 223

Figure 3.29: Vector representation of ventricular activation

trocardiograph, pacing, and some special methods the QRS complex there is only negative wave which
which can detect the cardiac activation and mark- is followed by a positive wave it is then known as the
ers of electrical instability. Recording the electrical S wave. Other waves of R or S are known as R’ and
activity of the heart can afford the most valuable in- S’ waves. T wave represents the ventricular repolar-
formation about the defect and the mechanisms that ization and sometimes is followed by U wave. The
occur during the cardiac activity. That is why it atrial repolarization is represented by Ta wave, this
is very important to be aware of the principles of wave can occur in the PR interval. The section from
the ECG because the ECG recording can provide the end of the QRS complex till the beginning of T
us with information that can not be substituted re- wave is known as the ST segment. It is the segment
garding the cardiac activity and arrythmology, the between the ventricular depolarization and its fast
pathophysiology of the heart, together with the elec- repolarization. The PR or (PQ) interval is the in-
trocardiographic studies and explains some cardiac terval between the beginning of the P wave and the
disorders and that is why were going to go through beginning of the QRS complex, it usually lasts for
some of its most important principles. 0,12–0,20 sec. The QRS complex takes about 0,04–
Electrocardiogram The P wave represents the 0,10 sec. The QT represents the approximate refrac-
atrial activation (depolarization). The QRS complex tory period of the ventricles.
represents the ventricular activation. The Q wave is
a negative wave representing the initial stage of the
QRS complex. R wave is the initial positive wave
that immediately follows the Q wave. The S wave is
a negative wave following the R wave. If instead of
224 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.30: Time course of ventricular activation

3.25.6 The electrocardiographic voltage reaches the value of S wave, or there may be
changes in cardiac disorders a normal R wave with a flat S wave in the lead V2
with an obvious terminal S in the leads V5 and V6 .
3.25.6.1 The electrocardiographic changes in
ventricular hypertrophy

The left ventricular events are the dominating events The left ventricular hypertrophy is usually pre-
shown in the ECG. During the ventricular hypertro- sented as a high voltage in the leads that show the
phy the left ventricular activity and its share in the left ventricle. The R waves can exceed 2,0 mV in the
cardiographic changes is more obvious and clearly standard leads meanwhile there is a tendency for a
expressed. shift in the electrical axis of the QRS complex to the
The right ventricular hypertrophy will shift the left in the frontal plane till -30 degrees. In leads V1
cardiac axis (the main direction of activation) from or V2 there is a deep S wave exceeding 2,5 mV. In the
being backwards and to the left to become forwards V5 or V6 leads there are R waves exceed 2,5 mV. It is
and to the right. On the ECG these changes are very interesting that in young, thin and healthy peo-
shown as a high R wave in the lead V1 it may reach ple the voltage criteria of left ventricular hypertrophy
0,5 mV or even exceed it. At the same time there is can be found without actual hypertrophy. Usually
an abnormal S wave in leads V5 or V6 which may there are no changes in the ST segment or T wave
reach or exceed 0,7 mV. The QRS axis in the frontal changes, and that is why their changes are the de-
plane is directed to the right, usually is more than cisive criteria upon which we can say if there is left
110 degrees. In a mild right ventricular hypertrophy ventricular hypertrophy not in cases which are very
there is a deep S wave in V1 , and R wave, which suggestive of the left ventricular hypertrophy.
3.25. The basis of the electrical action of the heart (I. Hulı́n) 225

3.25.6.2 The electrocardiographic changes in The right ventricular MI is rare. It is usually

acute myocardial infarction (MI) combined with inferior wall infarction or MI of the
posterior wall of the left ventricle. During the acute
From the pathological point of view an acute MI is MI of the right ventricle the most typical changes are
a necrotic area which is surrounded by an ischemic those occurring in leads V6 R, V5 R and V6 R.
zone which separate the necrotic zone from the sur-
rounding healthy myocardium. The ischaemia is usu-
ally presented by certain changes in the T wave and 3.25.6.3 The electrocardiographic changes in
the ST segment whereas necrosis is shown as changes chronic ischemic heart disease
in the QRS complex. During the development of An important finding is the pathological Q wave of
acute myocardial infarction the signs of ischaemia a previous MI. Other ECG changes are not specific.
are the first to be shown as a high peaked T waves, The patients usually use drugs which can markedly
later these waves become inverted and symmetrical. affect the ECG findings. Apart from this usually,
The progressing ischaemia will lead to electrical in- those patients have a left ventricular hypertrophy
tegrity disorders of the cellular membranes. These which is shown on the ECG adding to this are some
are shown as the ST segment elevation in correspond- ST segment and T waves changes. A horizontal ST
ing leads which face the ischaemia and as ST seg- segment depression or S depression in the J point is
ment depression in the leads opposing the ischaemia. an important landmark as well.
In case of transmural infarction the pathological Q
wave will occur in leads where no Q wave was present
before and it becomes very clear. 3.25.6.4 The ECG changes during the intra-
ventricular conduction disorder
In myocardial infarction of the anterior wall most
of the changes take place in leads AVL, V2 , V3 The conducting system of the heart and the my-
whereas an inverted picture (ST depression) occur ocardium could be the cause of intraventricular dis-
in leads II, III and AVF. The deepening of the Q order of conduction. The basic disorder is slow ven-
wave is most obvious in leads AVL, V1 , V3 . The Q tricular activation which could accompany a diffuse
wave stays the same (see fig. 3.31 page 226). or local disorder. The diffuse disorders of the ac-
In the posterior wall MI the ECG changes are ex- tivation progression is usualy caused by ventricular
actly the opposite of those changes in the anterior hypertrophy cardiomyopathy, or some metabolic dis-
wall infarction. Instead of the Q wave, ST segment orders. On the other hand the local disorders of the
elevation, and T wave inversion there is a tall R wave, activation progression is related to a partial or total
ST segment depression and positive T waves. This block of the activation conduction in the left or right
type of infarction is usually combined with infarction bundle branches of the bundle of His.
of the inferior wall. In right bundle branch block the activation is pro-
In the inferior wall myocardial infarction the most gressing normally in the beginning. Yet the block of
obvious changes are seen in those leads which picture activation transmission in the right bundle branch or
the inferior wall of the left ventricle. These are the the right ventricle is obvious in the terminal part of
leads II, III, and AVF in which the Q wave appear the QRS complex. There will be a wide S wave in
combined with ST segment elevation, and T wave in- lead I, AVL, and V6 . R wave occurs in V1 and it
verssion. The opposite changes being (ST depression is the picture of septal activation, it is then followed
and high T waves) are shown in the AVL. by S wave and R’ wave. In cases of incomplete right
If the infarct locus lies only in the subepicardial bundle branch block there will be what is known as
or subendocardial area there will be all signs of MI rSR’ yet the QRS interval lasts for less than 0,12 sec.
in the ECG except the Q wave which will be absent (see fig. 3.32 page 227).
because Q wave is considered to be pathognomic to During the left bundle branch block the QRS in-
the transmural infarction. This ECG discovery is not terval is prolonged as well. The progress of acti-
totally corresponding with the post morten findings vation is disturbed immediately and simultaneously
in dead patients due to MI, nevertheless we classify with the septal depolarization. And that is why there
the MI according to the presence or absence of the is no Q wave in leads I, AVL, and V6 . R wave could
Q wave. be absent or very small in lead V1 . There might be
226 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.31: Myocardial infarction of vetricular septum and anterior left ventricular wall

some QRS changes (notches) in lead I and V6 . Sec- terval is prolonged due to intrinsic wave formation in
ondary changes can occur in the T wave and the ST leads V5 or V6 the QRS complex then is shorter than
segment and this is the reason why it is very difficult 0,12 sec and here we are talking about incomplete left
to differentiate the ischemic heart disease changes bundle branch block (see fig. 3.33 on page 3.33).
from those of left bundle branch block. When the in-
As the left bundle branch block is accompanied
3.25. The basis of the electrical action of the heart (I. Hulı́n) 227

a right axis deviation. there are no specific criteria

for the posterior hemiblock and we usually reach the
diagnosis by exclusion (excluding all other reasons
of right axis deviation), and when no reason is found
the finding is then considered a posterior fascicular
block. The left fascicular blocks are frequently com-
bined with a right bundle branch block. In this case
we are talking about a bifascicular block. A trifasci-
cular block on the other hand occur when the acti-
vation conduction is slow in each of the left branch
Figure 3.32: Right bundle branch block
fascicles and the right bundle branch.

3.25.6.5 The electrocardiographic changes in

pericarditis
Acute pericarditis is presented by an isolated devia-
tion of the ST segment in nearly all the leads. The
ST segment deviation is not shown in the lead AVR
and V1 . In a long lasting pericarditis the ST eleva-
tion could be normalized but an inversion of the T
wave can appear. T wave inversion and other ab-
normalities can last for a very long time. Electrical
alternations can occur when a large quantity of excu-
date is formed in the pericardial cavity. There might
Figure 3.33: Left bundle branch block
be a drop in the voltage in all complexes and waves
in all the leads.
with a marked left axis deviation, we can usually no-
tice a clear left ventricular dysfunction. The left bun- 3.25.6.6 The electrocardiographic changes in
dle branch gives many diffuse small branches, from myocarditis
these we can differentiate two parts. One is known The electrocardiographic changes occurring in the
as the anterior fasciculus and the other part is known late stages of pericarditis. The ECG changes which
as the posterior fasciculus. If a block occur in these point out to a myocardial injury are usually found
fasciculi it is the known as a hemiblock. in many infectious diseases as viral hepatitis, infec-
In the left anterior fascicular block the activation tious mononucleosus (IMN), mumps, influenza, and
conduction slows down in the upper part of the left others. Only some of these are presented with his-
ventricular wall and this is usually shown as QRS tological findings and the ECG changes are usually
prolongation and a left axis deviation. It is not easy non specific. In a clinical case of myocarditis there
to differentiate between the fascicular block and a are symmetrically inverted T waves in the standard
left ventricular hypertrophy. The hypertrophy of the leads and left chest leads. Different conduction disor-
left ventricle usually doesn’t result in left axis devi- ders could appear, and arrhythmias are not unusual.
ation over –30 degrees in the frontal plane yet in the
frontal hemicblock the deviation of electrical axis is
3.25.6.7 The electrocardiographic changes in
-60 degrees or more. The ventricular QRS complex
cardiomyopathies
is usually typical. There is a mall Q wave in leads I,
AVL and there is a small R and a deep S wave in Signs of left ventricular hypertrophy are the most
lead II, III, and AVF. common signs of ventricular hypertrophic cardiomy-
In the left posterior fascicular block the progres- opathy. There might be an abnormal Q wave in leads
sion of activation slows down in the posterior and I, AVL, V5 and V6 and a tall initial R wave in V1 in
inferior part of the free wall of the left ventricle. We cases of the asymmetrical hypertrophy of the inter-
can notice a prolongation of the QRS complex and ventricular septum.
228 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

In congestive cardiomyopathy it is possible to no-

tice an abnormal conduction in the ventricles which
leads to some abnormalities in the QRS complex. 3.26 The electrophysiological
We can notice the presence of some nonspecific ST
segment and T wave changes as seen in other car-
basis in the generation
diomyopathies. In restrictive cardiomyopathies we of cardiac arrhythmias
can notice a low voltage QRS complex and disap-
pearance of progression in the precordium.

3.25.6.8 Electrocardiographic changes The term arrhythmia constitutes all changes of

in metabolic and electrolyte the cardiac rhythm that render the rhythm different
disorders from the normal sinus rhythm. The sinus rhythm
is initiated in the SA node. The activation is pro-
The cardiac tissue is electrically active, and that is gressing then from the atria to the ventricles having
why the electrolyte changes can affect its electrical a normal PR interval that doesn’t exceed 0,20 s and
activity. the heart rate in adults ranges between 60–100 /min.
In hyperkalaemia the appearance of tall T waves The development of electrocardiology and espe-
and a prolonged ventricular complex which becomes cially the intracardial electrophysiological study and
mated with the T wave to form one peak. P wave is the Holter monitoring could influence many opinions
small and PR interval is prolonged. about cardiac arrhythmias. Many findings were used
In hypokalaemia T waves become flattened or in- to explain changes in the conventional electrocardio-
verted. Whereas the U wave becomes very clear and graphy.
the QT interval is markedly prolonged. Its prolon- From the histological and functional point of view
gation is partly due to the U wave which is mated we can differentiate two types of cardiac cells: con-
into the T wave. These signs signalize the possible tractile cells, which duty is to provide the pumping
occurrence of arrhythmias especially when digitalis function of the heart and specialized cells for the for-
or antiarrythmic drugs (group 1) are applied. The mation and conduction of activation. The contractile
ECG changes in hypokalaemia are similar to those cells have the ability to perform mechanical works
of hypocalcaemia. Hypocalcaemia prolongs the ST and conduct electrical impulses from cell to cell.
interval as well as the T wave, this will lead to QT The myocardial cells are connected to one another
interval prolongation. Hypocalcaemmia on the other by intercalated disks by which they form intercon-
side is not as dangerous as hypokalaemia in generat- nected muscle fibers. The intercalated disks serve
ing cardiac arrhythmias. Non specific ECG changes the conduction of mechanical energy, yet they have
occur in hyperthyroidism, hypothyroidism, diabetic electrical characteristics which render the activation
ketoacidosis, and of course after the use of antiarry- conduction from cell to cell much easier.
thmic drugs. The prolongation of PR and QT in- The intercalated disks are formed by union of
terval as well as some non specific changes in ST plasma membranes of the neighboring cells. It is
segment and T wave are the most commonly seen. actually a doubled plasma membrane. The junction
is step, shaped with the alternation of areas oriented
vertically and horizontally to the disk plane. This
leads to an increment of the total surface area of
the membranous contact. There are special junction
structures in the intercalated disks being: The fascia
adherens, macula adherens (desmosom), and a nexus
(gap). Fascia adherens is the most common struc-
ture which form both plasmatic membranes which
are wavy and inserted to each other. They run
in a parallel manner and are separated by a 20–
30 nm wide slot. Fascia adherens on the other side
is the place where myofillaments are inserted. The
3.26. The electrophysiological basis in the generation of cardiac arrhythmias (I. Hulı́n) 229

desmosom or macula adherens is a structure having tion in the AV node is partially caused by the absence
0,2–0,5 micrometer diameter in which the neighbor- of the intercalated disks.
ing plasma membranes are situated parallel to each The transitional cells form a heterogeneous group
other. Nexus or the gap is a special structure which of cells which are present among the P cells, Purk-
is found in the longitudinal segments of the inter- inje cell, and myocardial fibers. Purkinje cells are
calated discs. The electrochemical impulse spreads mainly present in the branches of His bundle and in
through the gap from cell to cell. It is composed the Purkinje network. If we compare them with the
of tight junctions of the neighboring plasma mem- contractile cells we will find that they have less mito-
branes. The membrane is structurally different in chondria and linearly situated myofibrils. These cells
these areas. The gaps contain small channels 2– are also composed of many intercalated disks with a
2,5 nm in diameter through which small ions can simple T system which might be absent. This system
diffuse from cell to cell. Gaps and desmosomes do might be the basis of fast conduction of activation.
present even in the lateral surfaces of the neighbor- From the conductive point of view the contractile
ing cells. elements are less effective. The Purkinje cells and
According to other electrophysiological character- similar contractile cells are on the other hand con-
istics we can differentiate what is known as fast and sidered to be electrophysiological.
slow cells. The fast cells are characterized by a large The basic electrophysiological characteristics of
diameter and high speed of conduction. Their resting the heart cells are automacity, excitability, and con-
potential is –90 mV. The ascending edge of the action ductivity. Automacity is the ability of some cardiac
potential is very steep. On the action potential curve cells to generate impulses which can spread to the
we can see the overshoot to positive values and the surrounding area. Excitability is the ability of all the
plateau is very clear as well. Purkinje cells and func- cells in the heart to respond to an effective impulse.
tioning cells of the myocardium have the characteris- In case of repeated impulses these cells need a certain
tics of the fast cells. The resting potential of the slow time for recovery (refractory period). Conductivity
cells is between –50 and –70 mV. Even the threshold is the ability of the cell to conduct impulses. The im-
potential is low (–30 till –40 mV). The stimulation pulse conduction is related to the electrical phenom-
of slow cells starts endogenously by increasing the ena of the transmembranous transmission but it is
membrane potential (from –70 to –40 mV) to reach as well related to the heart as whole. The mentioned
the threshold level. The ascending part of the ac- electrophysiological characteristic could be disturbed
tion potential curve is not steep and there is no over and might lead into a disturbance of cardiac rhythm.
shooting. There is no plateau on the action potential This is the reason why we explain them in relation
curve. These are the characteristics of both SA node with the generation of arrhythmia.
cells and AV node cells.
From the functional point of view we can find two 3.26.1 Automacity
types of cells, the myocardial functioning cells and Automatic cells (slow cells) are characterized by di-
cells of the cardiac conductive system. The main astolic transmembranous potential which is modifi-
function of the conductive system of the heart is the cated by spontaneous diastolic depolarization (grad-
generation of impulses and their conduction form the ual change in membrane potential in phase 4). The
SA node where they are usually generated to the diastolic transmembrane potential is not horizontal
atrial and ventricular myocardium. According to as in the contractile cells but is slow ascending, till
the ultrastructure we can differentiate three types of it reaches the threshold potential. In the contractile
cells: the P cells, the transitional cells, and Purkinje cells (fast cells) the formation of transmembrane ac-
cells. tion potential is the result of impulse affect, which
P cells or the pacemaker cells present in large was formed in the pacemaker cells.
number in the AV junctional area. These cells gener- The impulse leads to an electrical flow which pro-
ate impulses and hence are marked as the automatic gresses across the cellular membrane. This electrical
cells. Comparing those cells with the contractile cells flow will reduce the diastolic transmembrane poten-
they contain small number of mitochondria, and less tial of the regional contractile cells (in phase 4) to
developed sarcoplasmic reticulum. The slow conduc- the threshold potential. The change of the mem-
230 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

brane potential to the threshold potential and the The structures of the conducting system have
beginning of phase 0 will stimulate an electrical flow the duty of impulse conduction to other structures.
which spreads across the membranes and its origin Apart from this they have the ability to generate im-
is in the automatic cells. pulses which in certain conditions can be propagated
The automatic cells have even with no external to the surrounding regions. Automacity can generate
interference the ascending phenomena in phase 4. in the cells of A-V junctional area, but even in the
This event proves that a slow diastolic depolarization bundle of His and Purkinje system where fast cells
takes place on the membranes. During diastole the are found. But this automacity is smaller (slower)
continuous Na+ or Ca2+ flow is evident. It is marked and normally the sinus automacity is the dominant
as the IBi which is equalized by the K+ efflux IK2 or one.
IP flow (see fig. 3.34 page 230). The automatic cells reach the threshold potential
fast. That is why cells which need the shortest time
for reaching the threshold potential dominate over
others and they become the center of impulses. The
time taken by the diastolic depolarization to reach
the threshold potential is basically determined by
three factors.
1. The ascending speed of diastolic transmembrane
potential (phase 4). The fast and soon reached
threshold potential determines high automatic-
ity
2. Level of the threshold potential. When
more negative level of the threshold potential
with same ascending speed of diastolic trans-
membrane potential the threshold potential is
reached sooner. The final result is a faster auto-
maticity meaning that a more negative thresh-
old potential will increase the heart rate and vice
Figure 3.34: Ascend phase 4th of transmembrane versa.
action potential of an automatic cells
3. Level of the diastolic transmembrane action po-
Inactivation of the potassium efflux explains the tential (DTP). As this level is more negative on
formation of transmembranous action potential, the beginning of phase 4 more time is needed
when sodium and calcium influx overwhelms or ex- for the spontaneous diastolic depolarization to
ceeds the potassium efflux. IP inactivation is on the reach the level of the threshold potential. The
other hand responsible for the diastolic depolariza- speed of impulse formation is hence decreased.
tion of the SA node cells, and the IK2 inactivation is Contraversly when the starting DTP is not very
responsible for diastolic depolarization of the Purk- negative the threshold potential is reached very
inje cells. In normal conditions phase 4 is faster in soon and the speed of impulse generation is
the SA node than in the Purkinje cells. The reason is faster.
that the IP is inactivated faster than the IK2 . From
the mentioned facts we can learn that automacity has 3.26.2 Automacity disturbances
its origin in the changes of ionic flow. Automacity
is produced when there is an excess in permeability Decrement of the SA node automaticity can happen
and conductivity of K+ , Na+ , and Ca2+. Transmem- due to the following causes:
branous action potential (phase 0) in the automatic 1. Lowering of the DTP speed
cells grows more slowly and reaches less values due
to its generation from lower values of the diastolic 2. Increment of the maximal diastolic potential
transmembrane potential. (e.g.: due to hyperpolarisation)
3.26. The electrophysiological basis in the generation of cardiac arrhythmias (I. Hulı́n) 231

3. Decrement of the threshold potential (reaching 3.26.3 Excitability disturbances

the 0 level)
Excitability is the ability of all cardiac cells to re-
sponse on stimulus.
These causes can occur in combination (see Cardiac cells need a certain time to renew their
fig. 3.35 page 232). own excitability. The period needed for their ex-
Increment of the SA node automaticity can hap- citability renewal corresponds with the final part of
pen due to opposite causes of the mentioned above. the TAP (voltage dependent excitability renewal).
When the SA node automaticity is decreased it Slow cells need a longer period to renew their
could be compensated for by the automaticity of excitability (time dependent excitability renewal).
the AV junctional area and its frequency is only be- This means that those cells don’t have their excitabil-
tween 20–40/min. If the automaticity in the AV area ity renewed, when in phase 3 they reach a certain
was disturbed either, a pacemaker will generate in level of potential. Their excitability will be renewed
the subjunctional area and its frequency is only be- after some time of the TAP ends. Potential renewal
tween 20–40/min. During certain structural condi- of excitability corresponds with the transmembrane
tions with slower activity the SA node automaticity action potential. The relation of excitability with
can not be interfered. These structures are depolar- TAP can be devided into 5 periods (phases) (see
ized with every excitation and they start to repeat fig. 3.37 page 231):
the cycle of renewing the membrane potential, which
starts to get slower during any given disturbance.
Impulses which start to generate as a result of the
reduced automacity of the SA node, can be single or
repeated. These impulses from AV junctional area
or from the ventricles are referred to as escape im-
pulses when they are repeated they may generate an
independent rhythm (escape rhythm).
In some case the ectopic, atrial, the AV junctional,
or the ventricular automacity can increase so much
that it exceeds the sinus rhythm. In these cases we
are not dealing with a defensive but with a hyperac-
tive rhythm. Impulses generating from an increment
of automacity can be isolated or can be repeated.
Isolated impulses, which activate the heart do not de-
pend on the original rhythm, they stimulate what is
known as parasystole. Isolated impulses which occur
in relation with the original rhythm generate what is Figure 3.37: Relationship of excitability to TAP
known as extraxystole. Impulses can originate from
in one or more centers.
It was proved experimentally that depolarization 1. Complete refractory period. In this period
is sometimes incomplete or delayed. After reach- the cellular membrane is absolute refractory to-
ing the membrane potential –50 till –70 mV an early wards any impulse. Absolute Refractory period
post potentials can occur and depolarization may ARP (see fig. 3.37 page 231)
start again. Delayed post potentials (see fig. 3.36 2. Period of local response. It is a very short pe-
page 232) are the result of oscillating diastolic de- riod in which some local changes of potential can
polarization. Arrhythmias caused by post potentials occur, yet the potential can not be propagated.
are marked as trigger arrhythmias. They differ from The effective refractory period ERP consist of
arrhythmias caused by a disturbance in the automac- the ARP and a period of local response
ity. Trigger activity is noticed with arrhythmias that
occur post acute coronary occlusion in its late stages 3. Period of partial excitability. Consist of the last
(see fig. 3.36 page 232). part of phase 3. The response is obtained only
232 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.35: Automacity decrease in SA node

Figure 3.36: Early and late postpotentials

by an above threshold stimulus and it can be 3.26.4 Conduction disorders

propagated. This phase is marked as the relative
refractory period (RRP) The impulse which generates in the SA node is prop-
agated through a special conductive system to the
atria and to the ventricles. The progress of acti-
4. Period of normal excitability. The cell responds vation is basically an electrochemical change, which
to any stimulus which has the threshold inten- takes place on the cellular membranes. This is real-
sity. ized without chemical mediators, but the speed of the
activation progress can be changed by material which
usually affect the TAP (those are catecholamins,
5. Period of supernormal excitability. In this short acetylcholin and anti arrythmic substances).
section at the end of phase 3. The cell responds The cytoplasm of muscle fibers and interstitial
to a sub threshold stimulus. fluid have a low resistance and are good electric
3.26. The electrophysiological basis in the generation of cardiac arrhythmias (I. Hulı́n) 233

transmitters. Cellular membranes are structures The result is that there is shortening of the com-
with high resistance and they seperate these 2 me- plete activation progressing time. Another gap phe-
dia. The conduction is different in the fast and slow nomen is noticed with antigrade and retrograde con-
cells. For fast cells the regenerative conduction is duction. Differentiation could only be obtained by
typical. For slow cells in the junctional area, mainly intracardial electrocardiologic monitoring.
the AN and H ones the decremental conduction is Conduction via abnormal pathways. These con-
typical. The speed of conduction in different cardiac ductions are mainly shown in WPW (Wolf Parkin-
structures is: son White) syndrome and in short PR interval syn-
drome. It cold occur even with other disorders. In
• atria 1–2 m/s these cases the activation is progressing via unusual
pathways which might or might not be histologically
• AV node 0,05 m/s
evident.
• His–Purkinje system 1,5–4 m/s Slowing of conduction. There are many types of
slow conduction. It could only concern a certain part
• Ventricles 0,3 m/s of conductive system of the heart. In the electrocar-
diologic terminology we use the term block. We can
The speed of conduction is determined by 2 basic distinguish many types of blocks. First degree heart
factors: block. This term refers to a condition when impulses
are constantly created but their propagation is some-
1. How fast the TAP level is reached (dV/dt how a bit slower than normal.
phase 0)
Second degree heart block It is marked as Mob-
itz I. A classic picture are Wenckebach periods dur-
2. Ultrastructural characteristics
ing which the P-Q interval is gradually prolonging
Thin fibers (contractile and transitional cells) and till they reach a state where no impulse is propa-
those not having intercalated disks (P cells) con- gated anymore. When the relation is not strong the
duct activation slowly. Thick fibers with intercalated block is marked as Mobitz II.
disks (Purkinje cells) conduct activation fast. Third degree heart block This type occurs when
In the sinoatrial junction and AV junction area the no impulse is conducted to the ventricle. Atria
activation is progressing slowly. This is caused by the and ventricles have an independent activity on each
presence of large number of P cells and transitional other. The AV dissociation can be caused by an ex-
cells. In these structures conduction disturbances tremely long refractory period of the AV junction. It
can be in form of supernormal conduction, gap phe- can be a picture of complete block. In this case no
nomena, slow conduction, and a hidden conduction impulse is transmitted from atria to ventricles. In
and reentry mechanism. case of incomplete block and AV dissociation some
Conduction faster than normal. An early impulse impulses can be conducted from atria to ventricles.
can be blocked during propagation. Sometimes an In other cases it is possible that a fast activity in the
ectopic impulse is created even earlier and this im- junctional area could be transmitted in a retrograde
pulse could be propagated. On one side we are deal- direction back to the atria. There is formation of
ing with a supernormal excitability of the surround- AV dissociation with interference. Sinoatrial block
ing cells but on the other hand there is a supernor- is a condition during which no impulse is conducted
mal conduction. This could be the result of tran- from the SA node to the atria. Usually in these cases
sitional hyperpolarisation of cellular membranes. It there is the formation of a substitute impulse in the
was shown experimentally that a supernormal con- AV–junctional area.
duction can be time or tension dependent. During Aberrant Ventricular Conduction. Is formed as
pre- mature stimuli the supernormal conduction may a result of differences in the refractory period be-
lead to gap phenomena. Premature impulse slows tween some parts of the transitional abnormal dis-
the progression of activation. The earlier impulse tribution of supra ventricular impulses. We can see
comes the slower. The activation reaches the distal ventricular complexes which have abnormal shapes.
zones outside of refractory period. The condition can occur as a result of prolongation
234 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

of the refractory period in one of the branches or these facts three types of reentry can occur
when the impulse reaches the ventricle through an
accessory pathway. In physiological conditions the 1. enclosed conductive circle
refractory period is longer in the right arm. The 2. unidirectional block
classical aberrant conduction in ventricles depends
upon the length of diastole. It could be seen dur- 3. a proper speed for conducting activation.
ing extrasystolia or with tachycardia. Electrocardio-
graphic picture of wide QRS with a supra–ventricular An enclosed reentry circle can have many types.
tachycardia may disappear with a certain drop in the It can occur in the atria with or without participa-
heart rate. During fast heart rate the impulses in tion of the junctional area. In His-Purkinje system
the right branch of bundle of His are in the refrac- a vicious circle could occur either in the peripheral
tory phase. The picture of aberrant conduction can Purkinje fibers or at the level of junction of Purk-
occur even when the cycle is prolonged. It is caused inje fibers with the contractile myocardium. In this
by an increased diastolic depolarization, or when the case the vicious circle is very small. It is a typi-
threshold potential reaches near 0 levels, or by some cal example of microreentery. It is usually the basic
hidden conductive pathway, or by a combination of reason for ventricular extrasystolies and hyperactive
many factors. Aberrant conduction occurs even with ventricular rhythm. (see fig. 3.38 on page 235). An
normal cycle of an intermittent ventricular block. It enclosed circle could be formed in the branches and
can occur with incomplete depolarization in a cer- the fascicles which have parallely situated fibers. The
tain area of a conductive system of the heart or with proper conditions for the circle closure occur when
incomplete production of TAP. two independent waves of activation are progressing
Concealed Conduction Could be a partial depolar- simultaneously. This condition is known as reentry
ization which can not be differentiated using the elec- with summation of activation.
trocardiogram. Concealed conduction is the cause of A closed circle can happen in AV junctional area
a large number of phenomena in arrythmology. Usu- (see fig. 3.39 on page 235). Reentry phenomen
ally it is concerned with AV junction or branch of then leads to the appearance of junctional reciprocal
bundle of His. tachycardia. It is a regular supraventricular tachy-
Reentry disorders of conduction are sometimes cardia. Reentry cycle can exist with the participa-
dealing with a certain area. We can talk about an tion of intranodal structures, or with the participa-
extra bundle branch or local block. In the surround- tion of juxtanodal structures.
ing tissue the activation can be conducted normally. Intranodal circle can have a pathway with a short
A block in such a place could be unidirectional. This refractory period and a prolonged conduction, or it
means that activation can reach this area from the can take the b pathway with a long refractory pe-
opposite side. In this case activation can spread re- riod and a shortened conduction. Sometimes there
peatedly via same pathways. The progress of activa- might be formation of a pathway in the extranodal
tion is slow. structures which have the character of specialized ab-
normal pathways. Reciprocal tachycardia with AV
We are talking about classical reentry phenomena.
The obstacle of the spread of activation doesn’t have junctional area participation can have:
to be an anatomical structure. When a circular ac- 1. slow antigrade and fast retrograde conduction
tivation is formed the conditions will be in favor of
slow progress of activation and of shortening the re- 2. fast antigrade and slow retrograde conduction.
fractory period.
Unidirectional block. In this case the determinant
A. reentry with normal conductivity and uni- is that a part of tissue can be activated from the
directional block tissue which is in the area of block. Overmore if
the myocardium is not in the refractory period it
This type occurs in slow cells during some ab- could be reexcited. A small circle could be formed,
normal conditions. In this case extrasystolies are (a microreentery) or a large circle could be formed, a
formed. These extrasystolies have constant interval macroreentery, which has the character of intra and
after the previous systole. Basically depending on extra nodal circle. When it is intranodal it has the
3.26. The electrophysiological basis in the generation of cardiac arrhythmias (I. Hulı́n) 235

Figure 3.38: Unidirectional block of one Purkinje fiber

Figure 3.39: Closed circuit in AV junctional region

characteristic of B pathways. The impulse can be vated. As a result of this the reentry continues with
transmitted form the atria via the A pathway to- the participation of both pathways.
wards the ventricles and can be transmitted retro- When the cycle consist of atria, AV-junctional
gradly back to the atria. The atria may be reacti- area, and ventricular myocardium it is very difficult
236 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

or even impossible to determine the exact place of drop in the cardiac output. There might be no im-
the unidirectional block. pulse formation in the SA node (sinus arrest) or there
A proper speed of conduction. When a reentry might be a block of the SA node. Sometimes the SA
of this type is formed the progress of activation can node dysfunction occurs together with AV dysfunc-
not be very fast, otherwise it hits a zone which is in tions. Elsewhere the SA node disfuction and arrest
the refractory period. It also can not be very slow. is manifested by syncope and a possible junctional
Because of the mentioned the atria would be then rhythm. Yet more often the SA dysfunction is shown
activated first by the SA node. as an inability to increase cardiac frequency during
situations which are usually accompanied by tachy-
B. Reentery resulting from disturbance of re- cardia. The SA node dysfunction can appear after
fractory period the use of pharmaceutics which usually don’t affect
the heart rate in healthy individuals.
In this case some zones with shortened refractory
Sick sinus syndrom has a very wide range of symp-
period may occur. In neighboring zones the refrac-
toms. It is manifested by bradycardia, sinoatrial
tory period is prolonged or different (non homoge-
block, or sinus arrest. Atrial tachyarhythmia as
nous). This situation usually occurs in areas where
well as fibrillation and flutter are usually joined
slow and fast cells exist. During fibrillation there
with tachyarhythmia and bradyarrythmia. Sinoa-
may be a microreentery in different areas of the my-
trial block of first degree presents a prolonged pro-
ocardium.
gression of activation from the SA node to the sur-
rounding tissue. When the atrial activation (P wave)
3.26.5 Sinoatrial node dysfunction is the first to be shown in the ECG, the first degree
block can not be diagnosed from the electrocardio-
SA node is the dominant pacemaker of the heart be- gram. Only by a special examination being an in-
cause it is the fastest one to reach the threshold po- tracardiac registration if possible.
tential level. The speed of diastolic depolarization
Second degree sinuatrial block is a disorder, during
is under the control of vegetative nervous system
which some impulses from the SA bundle are not
i.e. (autonomic nervous system). It is getting fast
transmitted to the surrounding tissue. It is expressed
during activation of the organism and slows down
as the abscence of one P wave and the related QRS
during sleep and rest. The increment in impulse for-
complex.
mation at rest is usually obtained by sympathetic ac-
tivation via the B adrenergic receptors. Slowing on Third degree sinuatrial block is actually a com-
the other hand is realized through the activation of plete sinuatrial block. It cannot be differentiated
parasympathetic fibers via the muscarinic receptors. from sinus arrest on the ECG. This disorder could
Sinus rhythm in the adults reaches a frequency be- be registered by the use of intracardial registration
tween 60–100 beat/min. In children the frequency is bradycardia.
higher, in newborn it is about 120–140/min. Trained Tachycardia syndrom is shown as tachyarhythmia
individuals (athletes) have a frequency which is be- on the ECG. In this case the retrograde progression
low 50/min, most probably as a result of an incre- of activation from the atria can lead to SA node sup-
ment in parasympathetic tonus. pression. The most important thing is to recognize
The normal SA node function can be disturbed the relation between the SA node dysfunction and
due to decrement in the direct vascular supply of other symptoms from which the patient suffers.
the SA node. This usually happens in coronary Very important is the 24 hour monitoring of the
sclerosis, mainly the right coronary artery. An- electrical function of the heart. By pharmacological
other type of dysfunction is senile amyloidosis of tests it is possible to influence the autonomic nervous
atrial myocardium. Sinus bradycardia occurs in hy- system, to find out if there is a primary error in the
pothyroidism, hypothermia, liver diseases, brucel- SA node. By using a complete chemical (pharma-
losis, vasovagal syncope, hypoxia, hypercapnia, aci- cological) block of the autonomic nervous system it
dosis, acute hypertension, and in other conditions. is possible to prove the SA node dysfunctions caused
If bradycardia occurs quickly, it can evoke haemo- by the autonomic nervous system and to exclude pri-
dynamic changes, which are manifested as an acute mary SA node dysfunction. An effective method is
3.26. The electrophysiological basis in the generation of cardiac arrhythmias (I. Hulı́n) 237

the intracardiac registration with complete pharma- known to occur in trained individuals with a marked
cological block, so that it is possible to measure the vagotonia. The AV junctional area as well as the
refractory time for the SA node. First we provide AV node changes during many diseases. AV blocks
the atrial pacing and after that we notice how much can occur even as congenital defects. The progress
time is needed for the activity of the node to oc- of activation across the AV area can be changed in
cur. The SA node recovery (refractory time) is less myocardial infarction of the posterior wall or in right
than 550 ms, its prolongation is a sign of SA node coronary artery spasm. The AV junction is affected
dysfunction. The carotid sinus syndrom can be ver- by many drugs, mainly digoxin, beta blockers, cal-
ified by short massaging of this area and monitoring cium blockers, and some toxic substances. The AV
the ECG. Patients with SA node dysfunction may conduction disorders are seen in some viral infections
or may not have various symptoms in relation with like viral myocarditis, in rheumatic fever, infectious
this dysfunction. In the asymptomatic SA dysfunc- mononucleosis, in amyloidosis, and in neoplastic dis-
tion it is not necessary to do the electrocardiological eases of the heart. AV block can occur simultane-
monitoring or cause any trauma to the patients by ously with the bundle branch block. This usually
other examinations. SA node dysfunction often oc- occur in sclerotic fibrosis of the cardiac skeleton, aor-
curs together with AV conduction defects. Here the tic and mitral valves. Sclerodegenerative changes of
haemodynamic symptoms are mostly caused by the the AV junctional area can occur in an isolated man-
AV conduction disorder and not by the SA node dys- ner. Hypertension and aortic or mitral stenosis are
function alone. In these cases it is necessary to pro- diseases, which usually accelerate the degeneration of
vide a complete electrocardiographical examination the conductive system, or may cause its calcification
together with the electrocardiographic registration and fibrosis.
of the His bundle and a programmed atria R and First degree AV block. Often marked as the pro-
ventricular stimulation. In patients with SA node longation of AV conduction. There is prolongation
dysfunction, which is connected with haemodynamic of the PR interval for more than 0,20 s on ECG. This
outcomes a permanent pacemaker is very likely the interval represents the progress of activation through
best solution. In a disorder which is manifested only the atria, AV bundle and His -Purkinje system. The
during a paroxysm or during an attack it is better prolongation can occur in any of these parts. The
to use ventricular or biventricular or even atrial on QRS complex is normal. When the PR interval is
demand pacemaker (this pacemaker paces only when changing the error usually lies in the AV bundle. In
needed). case the error is more distal in the His-Purkinje sys-
tem, it is always accompanied by QRS prolongation.
Only by using the intracardiac electrography it is
3.26.6 Disturbances of AV conduc- possible to locate the exact place of the error.
tion
Second degree AV block. Also known as the in-
There is a morphologically defined structure between termittent AV block. In this case some impulses are
the atria and ventricles. This structure provides the not conducted to the ventricles. On the ECG we
transmission of activation from atria to ventricles. can notice a gradual prolongation of the PR inter-
Apart from activation conduction the atrioventric- val, untill one ventricular systole doesn’t occur. This
ular junction shares in the cardiac action coordina- is also known as Mobitz 1 second degree AV block.
tion by slowing down the conduction of activation, Before this the disorder was known as Wenckebach
so that to enable the atria and ventricles to work in a periods or Wenckebach block. The error is usually
coordinate manner from the haemodynamical point localized in the AV node. The QRS complex is usu-
of view. ally unchanged. This block may occur in myocardial
The AV junction is composed of structures to- infarction, in digitalis intoxication, post b blockers
gether known as the AV junctional area. It is com- and calcium antagonists. The seriosity of this lies
posed of the AV compact node, which is supplied in the haemodynamic changes. When there are no
by sympathetic and parasympathetic fibers. The haemodynamic changes, the prognosis is excellent
progress of activation is influenced by the autonomic (see fig. 3.40 page 238).
nervous system. Slow transmission of activation is Sometimes the impulse is not conducted to the
238 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.40: AV block of 2nd type, Mobitz type I.

ventricles without prolongation of the PR interval. ing the complete AV block. The last mentioned de-
This is known as Mobitz type 2 second degree heart mand is the most important one. The resulting pic-
block. The primary error is usually localized in the ture of the complete AV block depends if there is or
His-Purkinje system. Often there is prolongation if there is not a substitutive rhythm, and the type
of the QRS complex. The most important thing is of this rhythm. In good conditions the substitutive
to know whether the error progresses to a complete rhythm can generate in His bundle. Here the fre-
block or not. It is usually found in the anteroseptal quency reaches 40–60/min. Because the progress of
infarct, or in sclerodegenerative or calcificating dis- activation is usually normal, the ventricular complex
orders of the fibrous skeleton of the heart. In what is is not deformed. Yet when the activation is gener-
called a higher degree block, two or more successive ated in distal parts of the conductive system e.g. in
impulses are not expressed in the ventricles. If the Purkinje fibers, the frequency is about 25–45/min.
resulting haemodynamics is affected a pacemaker is The progress of activation in the ventricles is abnor-
necessary (see fig. 3.41 on page 238). mal, and shows itself as a wide QRS complex.

Figure 3.41: AV block of 2nd type, Mobitz type II.

Third degree heart block, also known as complete

AV block. No impulse is transmitted from atria
to ventricles. If there is a ventricular substitutive
rhythm, the frequency reaches 40–55/min. Com-
plete congenital AV block originates in the AV bun- Figure 3.42: AV block of 3rd type
dle. The main error is usually localized in the His
bundle (see fig. 3.42 on page 238). This complete AV dissociation represents a disorder in which the
AV block causes syncope and ventricular arrest. But control of the ventricles is separated from the control
usually this block is preceded by some mild dysfunc- of the atria. This error doesn’t have to be combined
tion. That is why it is important to define them, with the complete AV block. AV dissociation can
know their progression, and if possible determine the occur in extreme sinus bradycardia. It can also oc-
probability of a substitutive rhythm occurrence dur- cur when there is an ectopic junctional or ventricu-
3.27. Tachyarhythmia (I. Hulı́n) 239

lar pacemaker that has a higher frequency of impulse

formation than the SA node. Here an interference in
the rhythms can occur. This condition occurs in case 3.27 Tachyarhythmia
of accelerated junctional or ventricular rhythm, in is-
chemic disease of the heart, in myocardial infarction,
or after cardiac surgery.
AV blocks that have haemodynamic symptomatol- All kinds of tachyarhythmias can be devided into
ogy can be solved by the use of pacemaker. Prior to two types depending on their origin. A group of
this it is necessary to perform an intracardiac electro- tachyarhythmias which cause are changes in the
cardiographic examination. The obtained results en- spread, and progression of activation. Another group
able us to understand the pathophysiological mech- is caused by a defect in the formation of stimuli.
anism of the disorder. Valuable information are ob- The electrophysiological bases of conduction distur-
tained from the electrocardiographic registration of bances were considered in the previous chapter. The
the bundle of His, and from programmed stimula- reentry mechanism is the most common of cardiac
tion. Electrocardiography is necessary in patients dysarhythmias. With no detailed electrophysiologi-
with syncope and a bundle branch or a bifascicu- cal differentiation it is shown that the following four
lar block the His bundle electrocardiography is nec- conditions are needed for the reentry to occur:
essary. If the HV interval is longer than 100 ms,
1. An electrophysiological nonhomogenesity of two
this means that there is an infra–His disorder, which
or more areas in the heart, which are activated,
should be solved by pacemaker. In AV block we
or can be activated following each other, and
should differentiate between the intra or infra–His
hence they can form a potentially morphologi-
block, or finally if there is block in the His-Purkinje
cal base for a close conductive circle. This non-
System.
homogenesity results from the difference in the
It is possible to use a trans venous insertion of
conductivity of these structures or the difference
catheter electrodes to the apex of the right ventri-
in their refractory period.
cle with an external monitoring to handle a com-
plicated case of atrioventricular conduction distur- 2. A unidirectional block means, that there is part
bance. Electrodes for permanent pacing is usually of the conductive loop that can be activated
placed in the right atrium or right ventricle via the from the neighboring area, which is part of the
subclavian vein. The source of power is fixed sub- conductive loop and part of the block.
cutaneously in the sub clavicular area. Epicardial
electrodes are used when, due to other reasons tho- 3. The refractory period should be shortened to
racotomy is performed. The pacemaker can have a a level that permits reexcitability on repeated
fixed frequency or it can work on demand, it may also activation.
be rate adaptive. The electrodes can be connected 4. Re excitation leads to the formation of loop ac-
to atrium or ventricle or it can be connected to both tivation.
arteries or ventricles. From the pathological point
of view it is not easy to simulate the optimal func- The repeated circulation of an impulse can form
tion of the conductive system of the heart. Pacing the basis for the formation of arrhythmia’s. These
can cause haemodynamic changes in the atria and arrhythmia’s can be initiated repeatedly. Yet they
the atrioventricular valves. Such change can mani- can end as an extra systole or as a fast stimulation.
fest itself as marked difficulties for the patient. The This characteristic renders them different from the
combination of symptoms is known as the pacemaker trigger arrhythmias.
Syndrom. Arrhythmias that are generated from disturbance
in the impulse formation, can be further devided
into, those caused by automacity change, and those
resulting from triggered activation. Normally the
myocardial cells lack the pacemaker action of the
SA node, in other words this activity is very low in
them. The pacemaker activity is obtained due to the
240 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

speed of the spontaneous diastolic depolarization. In individuals. More sensitive individuals could notice
the originally rhythmogenic cells its duration is very palpitation. The occurrence of atrial and supra ven-
long and it is always disturbed by the coming ac- tricular tachycardia can be evoked by alcohol, smok-
tivity from the neighboring areas. Increment in the ing and adrenergic stimulation.
automacity of the potential pacemaker cells can af- Atrial extrasystoles are based on extra stimulus
fect the following conditions in the heart: which can form at any time in the atria. On the
ECG these extrasystoles are shown as a morphologi-
1. An increment in the endogenous and exogenous
cally changed P wave during sinus rhythm. The more
catecholamins.
the ectopic center is away from the SA node the more
2. Electrolyte changes. distinguished is the P wave. The activation starting
in the ectopic locus reaches the AV node and spreads
3. Hypoxia or ischaemia. to the ventricles via the usual pathway. That is why
the QRS complex is unchanged. Sometimes the acti-
4. An increment in the muscle fiber tension (dilata- vation may come from the atria to the AV node very
tion). quickly. AV node may still be in the refractory pe-
5. The effects of some substances. riod. In such case the PR interval is prolonged and
the QRS complex has a different morphology com-
The high automacity may lead to tachycardia, pared with the normal non extra systolic complexes
which is initiated from an ectopic excitatory locus. (see fig. 3.43 page 240).
Tachycardia resulting from an ectopic automacity
can not be initiated neither stopped by pacing.
Trigger activity phenomena can be provoked on
isolated cells, when there is an increment of the lo-
cal concentration of catecholamins, in hyperkalemia,
hypercalcemia, and in toxic effect of digitalis. In all
these cases there will be an intracellular accumula-
tion of calcium, which is caused by depolarization.
This is marked as early depolarization (after depolar-
ization). If the amplitude is high enough a repetitive
activation will occur. For the initiation of the trig-
ger activity it is necessary that a normal activation
occurs first. That is why trigger activation can be
caused by pacing. To give an exact definition of the
mechanism of defect formation we have to perform
an intracardial registration of the activation progres- Figure 3.43: Supraventricular extrasystole
sion, and a programmed stimulation. The result of
this examination is useful for proper treatment. AV junctional extrasystole. AV junction includes
many morphologically defined structures. The com-
pact AV node is composed of cells that have no pace-
3.27.1 Extrasystole maker activity. That is why the extrasystoles can
Extrasystole is known as that cardiac systole which have its origin in all other structures of the AV junc-
occurs early and disturbs the original heart rhythm. tional area apart from the compact AV node. The
We can divide the extrasystole depending on many most common place for extra stimulus generation is
principles. One of these is according to the location in the bundle of His.
of the impulse formation which is the main cause of The AV junctional extrasystole is less common.
the extrasystole formation. They occur in heart diseases. The activation spreads
Atrial extrasystole can occur in totally healthy in an anti grade manner to the ventricles, but also in
people. Those individuals usually don’t know about a retrograde manner from the ventricles to atria. On
this condition. The 24 hr monitoring could prove the ECG the QRS complexes have normal configu-
the existence of extrasystole in nearly 60 % healthy ration, yet the interval between the beginning of the
3.27. Tachyarhythmia (I. Hulı́n) 241

P wave and the QRS complex is shorter. During the

retrograde activation the P wave could be inverted
in lead II, III and AVF. The P wave can either oc-
cur after the QRS complex or it can disappear in the
QRS complex (see fig. 3.44 page 241).

Figure 3.45: Ventricular extrasystole

no strong relation (i.e. the distance between the nor-

mal systole and extrasystole have different duration)
then we have to count the distance between the in-
dividual extrasystoles, and if this distance is one of
Figure 3.44: AV junctional extrasystole the multiples of the same distance here we are deal-
ing with what is known as parasystole (see fig. 3.46
on page 242).
Ventricular extrasystole. Occurs relatively often.
It was found that in nearly 60 % of adults was re- In the ventricles there is a locus with an abnormal
vealed individual ventricular extrasystole during the automacity and this locus is protected against the
24 hour monitoring. What is important to know is normal coming activation. The function of this locus
whether these extrasystoles occur in a healthy or in is regular, and that is why the distances between the
a diseased heart. In a healthy heart the individual extrasystoles has the same relation.
extrasystoles are not considered a risk factor, which Ventricular extrasystoles are either isolated or re-
means an increased morbidity or mortality. The ex- peated (see fig. 3.47 on page 242).
trasystoles occur in 80 % of patients who suffered Bigeminy is a condition in which each normal sys-
with myocardial infarction. It is important to know tole is followed by an extrasystole, whereas trigeminy
whether we are dealing with individual extrasystoles is a case where each two normal systoles are followed
or not and how often they occur. If their number by an extrasystole.
is more than 10 per hour and if they occur in clus- If one systole is followed by another one here we
ters, they are usually connected with an increased are talking about a coupled extrasystoles. When
mortality in these patients. The mortality though is three or more extrasystoles occur together we are
related to the present, and markedly noticed ventric- dealing with a cluster of extrasystoles or ventricular
ular dysfunction. Ventricular dysfunction might lead tachycardia. If the extrasystoles originate from one
to heart failure as a pump. Ventricular tachycardia place they are known as monomorphic, because they
or fibrillation is once again very dangerous because have similar shapes. On the other hand extrasys-
they may lead to sudden death. toles which have different shapes originate from dif-
Ventricular extrasystole are easy to recognize on ferent areas, and so are called polymorphic or multi-
the ECG due to their wide and morphologically morphic. Ectopic activation of the ventricles doesn’t
changed shape of the QRS complex. Apart from this spread in a retrograde manner to the atria. This is
there is no P wave preceding the QRS complex (see why the SA node is not exhausted by this activity.
fig. 3.45 on page 241). The activation from the SA node reaches the ven-
Ventricular extrasystoles are usually strongly re- tricle in the refractory period. So the next impulse
lated to the preceding normal complex. If there is coming from the SA node is effective. The inter-
242 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.46: Parasystolia

of activation. Ventricular extrasystole can occur as a

result of a marked sinus bradycardia but here there
will be no retrograde spread or compensatory pause.
This is a case of interpolated extrasystole. If the ex-
trasystole occurs very shortly after the last complex
it is known as the R on T phenomena, it might be a
risk factor in the ventricular fibrillation occurrence.
Individual ventricular extrasystoles do not require
any treatment. In otherwise healthy heart treatment
is questionable. Treating ventricular arrhythmia’s
don’t seem to affect the risk of the occurrence of
sudden death. Moreover the antiarhytmic drugs may
cause lethal arrhythmias. The situation is of course
different in patients with MI where the ventricular
tachycardia may proceed into ventricular fibrillation.

3.27.2 Tachycardia
Under the term tachycardia we mean tachycardia
Figure 3.47: Recurred extrasystoles which occur suddenly and reaches over 100/min.
Paroxysmal tachycardia starts by atrial or ventric-
ular extrasystole. They occur on the base of reentry
val following the extrasystole is longer than normal mechanism. Only in case of intoxication they occur
and it is called the compensatory pause. The in- as a result of trigger activity.
terval preceding the extrasystole together with the Paroxysmal (attack) tachycardia can be an acute
compensatory pause equals two RR intervals. Occa- and dramatic situation which starts suddenly and
sionally the activation may spread to the atria. Here ends suddenly. The important factor here is the
a negative P wave can appear in lead II, III and AVF. haemodynamic state. If the haemodynamic state
The compensatory pause will be shorter because the is stable we can provide a longer ECG monitoring.
sinoatrial node is now exhausted. Sometimes the ac- On the ECG we consider the shape of P wave and
tivation reaches only the AV node, so in the following its presence, the morphology of the QRS complexes,
normal systole there will be prolongation of the PR the relation between atrial and ventricular activation
interval which proves the hidden retrograde spread and possible differences between the sinus rhythm
3.27. Tachyarhythmia (I. Hulı́n) 243

and tachycardia. In case of good haemodynamic ter intoxication by alcohol or during life threatening
state we may try to perform carotid sinus massag- situations. It more often occurs in patients with car-
ing, or any other vagal reflex. Affecting the auto- diopulmonary diseases, in acute hypoxia, hypercap-
matic nervous system can sometimes end the tachy- nia, or in metabolic disorders. It occurs in rheumatic
cardia. Yet, massaging the carotid sinus can in this fever, mitral valve diseases, hypertension, atrial sep-
case evoke asystolia or ventricular fibrillation. The tal defect and in thyrotoxicosis.
electrocardiologic monitoring during the presence of Atrial fibrillation with a high ventricular fre-
a flexible stimulating electrode situated in the oe- quency can lead to hypotension or syncope. Atrial
sophagus can give us some valuable information and fibrillation may lead to thrombus formation in the
we can also try a vagomimetic maneuver. atria and these thrombi may reach the lungs or the
greater circulation If this condition is long lasting
3.27.2.1 Sinus tachycardia it might lead to heart failure. Together with mitral
stenosis it may lead to lung oedema (see fig. 3.48
Sinus tachycardia is not classical or primary arrhyth- page 243).
mia. It is basically an extremely high cardiac fre-
quency. It occurs in stress situation, fever, blood
loss, anxiety, during work, during thyrotoxicosis, hy-
poxemia, hypoxia, and in heart failure. It usually
starts insidiously and ends gradually. We can notice
signs of sinus rhythm on the ECG even if they are
sometimes slightly changed. Massaging the carotid
sinus terminates or at least decreases the tachycar-
dia.

3.27.2.2 Atrial fibrillation

The primary cause of atrial fibrillation is a chaotic
activation of atrial myocardium in very small sec-
tions. Atria are dilated and it is possible to see non
coordinate contraction of small sections if we look to Figure 3.48: Atrial fibrillation
the atrial surface. It is not possible to see P waves
in any of the 12 leads of ECG. We can see many
deviations between the QRS complexes. These de- 3.27.2.3 Atrial flutter
viations are of different shapes and sizes. Their fre-
quency reaches about 300–600/min. The atrial ac- Ectopic activation is the usual cause of atrial flutter
tivation reaches the AV node in large numbers but and this activation leads to 250–350 contraction/min
it dies out at the AV node because of the long re- in the atria. This condition usually occurs in patients
fractory period of the AV node, or sometimes due with cardiac diseases, pericarditis, acute respiratory
to a hidden conduction. The activation reaches the insufficiency, and after cardiosurgery. The thrombi
ventricles irregularly, but in large numbers. The ven- are formed less frequently. The ECG shows a typical
tricular irregularity is totally irregular. On auscul- picture of saw-toothed waves between the ventricular
tation with simultaneous pulse examination we can complexes, the ventricular complexes on the other
notice a pulse deficit. The cause of which is what hand have normal configuration. Only part of the
is known as a non systole outcasting ie. due to the impulses are transmitted form atria to the ventricles.
short diastole there is not enough time for the ven- This is the reason, why the ventricular contraction
tricular filling and when the ventricle contracts there is regular, and usually without tachycardia.
will not be opening of the semiluminar aortic valves Detailed electrocardiological studies revealed that
and hence the pulse wave doesn’t occur. Atrial fibril- atrial flutter is maintained depending on the prin-
lation can come in paroxysms or can be a continuous ciples of the reentry mechanism (see fig. 3.49 on
process. It can occur following cardiosurgery, or af- page 244).
244 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

toles occur, they spread towards the AV junction.

They cannot continue spreading via the β pathway
because it is still in the refractory period of the pre-
vious activation, and this refractory period is quite
long. So this is why the activation continues its pro-
gression via α pathway. The progression of activa-
tion via this pathway is so slow, that there is quite
enough time for the β pathway to recover from its re-
fractory period. The activation reaches the ventricles
via the β pathway and via the same pathway there
will be atrial echo and so tachycardia continues. For
the tachycardia to continue an optimal coordination
between the refractory period and the speed of ac-
tivation in the AV bundle is necessary. Ventricular
Figure 3.49: Atrial flutter and atrial activation occur simultaneously. That is
why P waves are imbedded in the QRS complex (see
fig. 3.50 page 244).
3.27.3 Paroxysmal supraventricular
tachycardia
Nearly in all cases we are dealing with the mech-
anism of reentry. The close cycle of activation is
running via the SA node to the atria, the AV node
and then back to the SA node. This circle can some-
times be formed of the AV area with an anti grade
progression of activation and a retrograde pathway
for activation progression via a by-pass tract. The
anti grade by-pass tract is present in the WPW syn-
drome. Yet we more often deal with a hidden retro-
grade by-pass tract.

3.27.3.1 AV nodal reentry tachycardia

Figure 3.50: Supraventricular tachycardia
is the most common form of the paroxysmal
supraventricular tachycardia. It is characterized by
narrow ventricular complexes. Tachycardia is initi- 3.27.3.2 AV reentry tachycardia
ated by atrial extrasystoles, which have a prolonged
PR interval. During the tachycardia P waves may A determinant factor for this supraventricular tachy-
differ in their relation to the QRS complex. Yet their cardia is a by- pass tract that is incorporated in
position during the tachycardia is stable. Prolonga- the loop activation and this AV-by-pass tract can
tion of the PR interval is caused by the prolongation conduct activation strictly in a retrograde direction.
of AH interval which is shown on the electrogram of The activation progresses from the atria via the AV
bundle of His. This is most probably caused by a node and His-Purkinje system to the ventricles and
doubled conduction through the AV node. β path- from there by a retrograde direction via a hidden
way is characterized by a fast conduction with a long by-pass tract back to the atria. In this paroxysmal
refractory period. α pathway on the other hand is tachycardia unlike in the WPW syndrom the hidden
characterized by slow conduction and a short refrac- (concealed) by-pass tract cannot transmit or conduct
tory period. During the sinus rhythm only the β activation an anti grade direction when there is si-
(fast) pathway is used, and this is why the PR inter- nus rhythm. Tachycardia starts by atrial or ventric-
val is normal (not prolonged). When atrial extrasys- ular extrasystole. P waves occur after the QRS com-
3.27. Tachyarhythmia (I. Hulı́n) 245

plexes. The electrocardiographic mapping of atrial 2. Nodal – ventricular junctions, that join the atri-
activation have a great value in determining the ori- oventricular myocardium
gin of this arrhythmia. The main proof of presence of
a hidden by-pass tract is the fact that we can activate 3. Fasciculo–ventricular junctions, that join the
the atria by activating the ventricles by a stimulus in penetrating bundle with the ventricular my-
time when the His bundle is in the refractory period. ocardium
This defect can be treated by surgical ablation.
4. Atrio–fascicular junctions, that join the atria
3.27.3.3 Sinoatrial reentry tachycardia with the pearcing bundle.
This paroxysmal supraventricular tachycardia starts
by atrial extrasystoles. P waves are similar as in the 5. Intranodal by-pass tract that is located in the
sinus rhythm, but there is prolongation of the PR AV node.
interval. By this it differs from the sinus tachycardia,
in which the PR interval is shorter. If the reentry is Its existence was not proven histologically, but
intraatrial P waves have different configuration and electrophysiologically. Ventricular activation occurs
the PR interval is prolonged. via the normal pathway, only sometimes via the ac-
cessory pathways. When the activation reaches the
ventricles via the accessory pathway there will be
3.27.3.4 Atrial tachycardia without reentry
shortening of the PR interval and delta wave at the
They occurs in cardiac and pulmonary diseases, hy- beginning of the QRS complex. The QRS duration is
pokalaemia and after the application of some sub- prolonged. The resulting activation is fusion of the
stances. We are commonly dealing with that is normal activation and activation via the accessory
known as multifocal tachycardias. They are charac- pathway.
terized by different P wave morphology. This com- The term WPW (Wolf-Parkinson-White) syndrom
monly occurs after overdosing with digitalis. is used in cases where there is preexcitation on the
ECG with the presence of paroxysmal tachycardia.
3.27.3.5 Preexcitation syndrom In atrial paroxysmal tachycardia the activation trav-
els anterogradely via the accessory pathway (the by-
Impulse propagation from atria to the ventricles oc- pass tract). In WPW syndrome it is very important
curs over the exactly anatomically determined struc- to reach the exact diagnosis and location of the ac-
tures. Sometimes, some accessory pathways may ex- cessory pathway. It is also important to know its role
ist in the heart by which the impulse can pass much in the occurrence of arrhythmia and the probability
faster than through AV junctional area and AV node. of life-threatening situation during the fatal distur-
The impulse, which is conducted via the accesory bances of the rhythm. Pharmacological treatment,
pathways by-passes AV node to activate the ventri- pacing, or surgical treatment is usually required.
cle. Therefore, there is no physiological slowing of
conduction in the AV node. The activation, which
travels via the accessory pathway, reaches the ven- 3.27.3.6 Junctional non–paroxysmal tachy-
tricles earlier that the activation that travels via the cardia
normal pathway. Thierefore, this activation is called
as premature (preexcitation syndrom) see fig. 3.51 Junctional non-paroxysmal tachycardia can result
page 246). from increased automacity or trigger activity in the
The existence of aberrant pathways was proved AV-junctional area. Its occurrence is very common
histologically. The terms, such as Kent, Mahaim, in setting of intoxication with digitalis, in associa-
James bundles are not currently used. The accessory tion with posterior myocardial infarction, myocardi-
pathways are anatomically devided into: tis, after catecholamines, in rheumatic fever, and
in valvular cardiosurgery. The highest frequency is
1. Accesory atrioventricular junctions, which are 150/min. The QRS complexes are similar as during
situated away from the AV junction sinus rhythm.
246 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.51: W–P–W syndrome

3.27.3.7 Sustained ventricular tachycardia

Sustained ventricular tachycardia is defined by last-

ing more than 30 seconds or causing haemodynamic
collapse. It may occur in setting of structural heart
diseases with altered myocardial architecture. It oc-
curs commonly in patients with chronic ischaemic
heart disease in the setting of healed myocardial in-
farction. It can be present in patient with cardiomy-
opathies without ischemic heart disease, metabolic
disorders, toxic cardiac disorder, in prolonged QT
interval. Sustained ventricular tachycardia is some-
times not secundary to any cardiovascular disorders.
The sustained ventricular tachycardia is almost al-
ways associated with haemodynamic deterioration or
with the development of acute myocardial ischaemia. Figure 3.52: Ventricular tachycardia
The acute myocardial ischaemia can facilitate the
development of ventricular fibrillation. Many cases
of ventricular fibrillation are initiated as ventricular attention is focused on detection of markers for life
tachycardia. The typical findings in patients with - threatening ventricular tachycardia. These mark-
ventricular tachycardia are shown as wide QRS com- ers are: wide QRS complexes that occur during the
plexes. Heart rate is over 100/min. The rhythm is sinus rhythm, uniform QRS complexes from the pre-
usually regular. The atria have own rhythm or they cordium, and unexplainable electric axis deviations
can be activated in a retrograde direction. The on- of ventricular axis. Using programmed stimulation,
set of tachycardia is usually sudden and sometimes it premature ventricular stimuli can initiate sustained
might be insiduous. The configuration of QRS com- ventricular tachycardia in 95 % patients, who present
plexes can be monomorphic if the ectopic impulses with this clinical arrhythmia. This type of stimu-
origin from the same locus (see fig. 3.52 page 246). lated tachycardia is identical with the spontaneous
The QRS morphology of ventricular tachycardia tachycardia. Occasionally, polymorphic ventricular
can be also polymorhic, with changing loci of the tachycardia or ventricular fibrillation is provoked us-
ectopic impulses. In case of a bidirectional tachycar- ing programmed stimulation. It is possible that us-
dia the QRS complexes have two configurations and ing of programmed stimulation or fast pacing we can
they origin from two different loci. Paroxysmal ven- also terminate the uniform ventricular tachycardia.
tricular tachycardia usually starts with ventricular If the tachycardia persists after this, cardioversion
premature complexes. It is very important to dif- is required. The ability to terminate tachycardia by
ferentiate between the supraventricular tachycardia the programmed stimulation provides us with the
and the aberrant intraventricular conduction from possibility of using antitachycardia pacemaker for
ventricular tachycardia. Comparing between a rest long treatment of the ventricular tachycardia. The
ECG recording and ECG during the attack of ven- use of such pacemaker is not without risk.
tricular tachycardia may be helpful. Meantime much Haemodynamic problems associated with ventric-
3.27. Tachyarhythmia (I. Hulı́n) 247

ular tachycardia depends on the heart rate and on occurs in association with hypokalaemia, hypomag-
the cardiovascular state. Patients with high frequent nesaemia, therapz with chinidin, phenothiazides, and
ventricular arrhytmias and myocardial dysfunction tricyclic antidepressant agents, during intracranial
are at risk of syncope. The most serious problem processes, and in complete AV block. This polymor-
represents the sustained ventricular tachycardia in phic tachycardia can be accompanied with syncope,
post- myocardial infarction patients. ventricular fibrillation and sudden death.
Patients with ventricular tachycardia occuring After the termination of tachycardia, it is impor-
within the first six weeks after the acute myocar- tant to remove factors causing QT prolongation. The
dial infarction have a very poor prognosis. It this application of magnesium is also effective in sup-
group of patients is about 85 % mortality within one pressing the tachycardia. Polymorphic tachycardia
year. Patients with sustained ventricular tachycar- with normal QT interval in patients with ischemic
dia have a three fold higher risk of sudden death heart disease occur after very early ventricular pre-
than patients with myocardial infarction without mature complexes (R on T phenomenon). This form
ventricular tachycardia. The problem of ventricu- of tachycardia has completely. So here we are dealing
lar tachycardia is very difficult. It is important to with tachycardia of completely different substrate.
consider risk / benefit ratio in every treating proce-
dure, because of some antiarrhythmic drugs instead
of arrhytmia prevention can paradoxically provoked 3.27.3.9 Accelerated ventricular rhythm
arrhythmia. Patients with ventricular tachycardia This tachycardia is marked as slow ventricular tachy-
without underlying heart diseases or a haemody- cardia. It is seen in acute myocardial infarction and
namic symptoms should not be treated. Whereas mainly with thrombolitic procedures and treatment.
patients with sustained ventricular tachycardia, even It can also occur post cardiosurgery, rheumatic
if they are without clinical symptoms, should be fever and cardiomyopathies it doesn’t cause any
treated because this tachycardia is not without marked haemodynamics problems, because its fre-
haemodynamic outcomes. Ventricular tachycardia quency ranges between 60 and 120/min.
have to be immediatedlly terminated in patients
with haemodynamic deterioration, underlying or-
ganic heart disease, myocardial ischaemia, heart fail- 3.27.4 Ventricular fibrillation
ure or CNS hypoperfusion. Progammed stimulation and ventricular flutter
may be helpful for the best choice of antiarhytmic
drug. Antitachycardial pacing should be employed, if Ventricular fibrillation and ventricular flutter are
the tachycardia is resistant to pharmacotherapy. Re- cardiac rhythm disturbances, which lead to an im-
cently there have been used automatic implantable mediate drop of blood pressure and a reduction of
cardioverter defibrillators (AICD) in patients with the cardiac output ”to zero”.
non-stable ventricular tachycardia. Endocardial and They both occur suddenly. There will be loss of
peroperative mapping lead to development of new consciousness, and if there is not immediate resus-
surgical techniques, which allow treatment of the citation, the patient dies. These arrhythmias usu-
ventricular arrhythmias. Mapping of activation ally occur in patients with ischaemic heart disease.
spread allows to localise side of origin of tachycar- They can also occur in WPW syndrome, after the
dia. It is common recently to provide ablation of use of antiarrhythmics for QT interval prolongation,
the morphological arrhythmogenic substrate based or after an electric shock. Studies showed that 75 %
on accurate mapping by specialized experts. of deaths occuring during Holter monitoring were
caused by either ventricular fibrillation or flutter.
3.27.3.8 Torsades de pointes Ventricular fibrillation or flutter are usually initiated
with ventricular extrasystoles. Couplets of ventricu-
Torsades de pointes is ventricular tachycardia that is lar extrasystoles evoke ventricular tachycardia which
characterized by polymorphic QRS complexes with may degenerate to ventricular fibrillation or flutter.
different amplitude and duration. Tachycardia is not In patients with acute myocardial infarction it is usu-
regular and the QRS duration of cardiac cycles is ally the acute ischaemia that leads to the ventricular
variable. QT interval is prolonged. This tachycardia extrasystole, which falls into a vulnerable period (R
248 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

on T extrasystole). See fig. 3.53 on page 248 and The choice of the proper antiarhythmics is quite
fig. 3.54 on page 248. difficult. Antiarrhythmics have some exactly de-
fined characteristics, considering their effect on the
electric process on the cellular membranes. Yet
the doctor does not know how these processes take
place on the patients cellular membranes. He only
knows the result which is arrhythmia. That is
why we recently appreciate testing the effects of an-
tiarhytmics in programmed stimulation. For exam-
ple: in induced ventricular tachycardia we found out
that antiarrhythmics really lead to the prevention of
ventricular tachycardia after stimulation. Yet pro-
grammed stimulation and intravascular catheteriza-
tion are procedures which have some limits due to
many risks.
Antiarrhythmics are agents that affect the depo-
larizing Na2+ and Ca2+ ion currents, the process of
action potential, and cellular automacity. For exam-
ple, if we depress the depolarizing currents, slowing
Figure 3.53: Ventricular flutter in the impulse conduction will be resulted and so we
can terminate arrhythmia by blocking the impulse
conduction in these areas where they are already
slow. Another type of antiarrhytmics lead to the
prolongation of action potential and hence the pro-
longation of the refractory period. These effects are
defined precisely on isolated myocytes. The effect of
antiarrhytmic drug in vivo may differ. Besides the
fact that the heart architecture is very complicated
and we can not calculate with it in using of antiar-
rhythmics. Arrhythmia usually have a morphologi-
cal substrate for a reentry mechanism, in which some
cells or cardiac areas are incorporated. But antiar-
rhythmic drugs effect all cardiac cells equally. There-
fore, it is necessary to reevaluate the proarrhythmo-
genic effects of antiarrhythmics in each individual
Figure 3.54: Ventricular fibrillation patient.

3.27.5 Pathophysiological outcomes

of antiarrhythmic treatment
In antiarrhythmic treatment it is necessary to con-
3.28 Diseases of the venous
sider all the pathological changes, which can cause system
arrhythmia, maintain it, or initiate it. The removal
of these nonsuitable conditions is first aim. Then we
have to consider the fact that antiarrhythmic drugs
have proarrhytmogenic effect. The aim of treatment Veins are capacity vessels which secure the venous
can be to terminate arrhythmia or to prevent its oc- return of blood to the heart. Changes in the venous
currence. return affect the minute heart volume. The entire
3.28. Diseases of the venous system (J. Holzerová) 249

venous circulation is affected to a decisive extent by Dysfunction of these compensatory mechanisms

central venous pressure, i.e. blood pressure in large (insufficiency of venous valves, long lasting immobi-
veins, in clinical practice being measured in the right lization of patients) augments the hydrostatical pres-
atrium (0,8 kPa, event. 6 torr). It is determined by sure in veins and causes the development of venous
the equilibrium between the heart pumping function insufficiency.
and venous return. The most important diseases of the venous system
The low-pressure easily distensible venous system are represented by varices. thrombophlebitis and
contains 60-880 % of the total blood volume. Changes phlebothrombosis. The most serious consequences
in the capacity of this system are conditioned by of these states are chronic venous insufficiency and
passive dilatation (e.g. hydrostatic pressure effect), pulmonary embolism.
as well as active venoconstriction. General venocon-
striction increases the venous return. It is applied in 3.28.1 Varices
situations requiring an increased minute heart vol-
ume, e.g. due to muscle excercise and stress, or due Varices are sack-shaped bulges of superficial veins
to a pathologically decreased minute heart volume, due to which they acquire a tortuous course. They
e.g. due to failure of the left ventricle. are most frequently localized on the lower limbs (var-
ics cruris) and inflict women twice as often as men.
Veins of the lower extremities are formed by su-
Their origin is stimulated by a long-term elevation of
perficial and profound venous systems which are
venous pressure in the lower limbs (professions per-
transconnected by a system of joining veins. Un-
formed in upright position and associated with lifting
der physiological conditions, the venous return leads
of heavy burdens, obesity, wearing compressing sus-
blood from the superficial veins to those profound.
penders, the pressure of a pregnant womb upon large
The superficial veins lead 10 % and those profound
venous trunks, etc.) Primary varices originate due
(the so-called collecting veins) 90 % of blood.
to an inborn weakness of the connective tissue (colla-
In addition to mechanisms which support the gen) in vein walls, which results in loss of resistance
blood flow in veins (changes in intrathoracic pres- against overstrain. Secondary varices originate due
sure, pulsation pressure of arteries upon the venous to impairment of compensatory mechanisms and ve-
wall), the venous return is secured by two compen- nous hypertension, Most frequently, they originate
satory mechanisms which maintain pressure in the due to inflammation of the profound venous system
venous system on a relatively low level. They are after trauma, or due to arteriovenous fistula. Sec-
venous bicuspidal valves, the number of which de- ondary varices represent channels which compensate
creases in the proximal direction, and the muscle- the impairment of the venous return via profound
veins pump which functions on the principle of rhyth- veins.
mic compression and decompression of veins owing to Pathologically, varices are based on venous valvu-
the work of the lower extremities muscles. lar insufficiency leading to severe haemodynamical
Contraction of limb muscles augments pressure changes. Blood flows in an opposite direction as un-
upon the due segment of the profound vein seven der physiological conditions, thus the venous return
fold. The valves under the site of compression close, directs from the profound (collecting) veins towards
those above the compression site open and thus blood the superficial veins. The muscle-vein pump is in
flows toward the heart. During the relaxation phase consequence of valvular insufficiency dysfunctional
the pressure situation reverses. The pressure in the and in such cases gait does not improve circulation.
due segment of the profound vein decreases rapidly; Superficial veins are overfilled, the blood flow dete-
that in the cranial and distal segments, as well as in riorates, venous pressure is not improved by gait, on
the superficial venous system, increases. The valves the contrary, it elevates. Venous hypertension super-
in cranial segments of the profound vein close and venes (mean venous pressure in the dorsum of the
inhibit the backflow of blood towards the periph- foot increases above 4,0 kPa, event. 30 torr) and the
ery. The valves localized more distally, as well as superficial veins distend.
the valves of joining veins and valves of the superfi- The first stage of the disease involves simple di-
cial venous system open and the due segment refills latation of veins without valvular impairment. An
with blood. unimpaired valvular apparatus secures reduction of
250 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

pressure in veins during orthostasis or gait, therefore blood clotting. The predisposition factors of throm-
swellings do not occur. The second stage of the dis- bophlebitis include the following: surgical interven-
ease merely involves valvular insufficiency of super- tions, injuries, infectious diseases, intravenous injec-
ficial veins. The venous pressure does not decrease tions, lasting immobilization, obesity, and hereditary
during gait or orthostasis. It is reduced only due to dispositions.
obviation of filling of superficial veins with blood due According to its ethiology, thrombophlebitis can
to compression of the limb, namely cranially from be of primary or secondary character. The pri-
the inflicted site. The third stage supervenes when mary thrombophlebitis includes idiopathic throm-
valves of the profound venous system become also bophlebitis which occurs in healthy people without
inflicted and thereby the venous pressure does not an obvious reason, and thrombophlebitis migrans
decrease due to muscular contraction during gait or which represents the initial symptom of thrombangi-
orthostasis. In the fourth stage, valves of the join- itis obliterans. The secondary thrombophlebitis oc-
ing veins, and/or in the ostia of v.saphena magna or curs more often. It can be of local, superficial or
v.saphena parva are insufficient. Decompensation of profound character.
the venous system supervenes and chronical venous Superficial thrombophlebitis occurs most fre-
insufficiency develops, manifesting itself by a picture quently. It manifests itself by the reddening and
of varicose complex: swelling of the limb, hyperpig- warming of the skin, swelling, tension and pain along
mentation of the skin, subcutaneous inflammation the inflicted vein. It represents the least serious pro-
with a subsequent induration, eczema, and the most cess. When there are no complications, there is no
severe complication 8- ulcus cruris. threat of embolization.
Varices occur also in the rectum (nodi haemor- Profound thrombophlebitis is more serious, as it
rhoidales externi et interni). They originate in con- disables drainage from a larger area and endangers
sequence of the development of a collateral circuit. the patient by the possibility of occurence of throm-
Their origin is stimulated by sedentary mode of life, boembolic complications. Most frequently it inflicts
constipation, or on the contrary, by diarrhoea. Por- veins of the lower limbs, it may though occur in other
tal hypertension often brings about, due to the devel- sites. The visceral thrombophlebitis is also known
opment of collateral circuits, the oesophageal varices. to occur (in kidneys, spleen, liver, intestines, uterus,
Their rupture usually results in fatal bleeding. prostate, cerebral hemispheres, eyes, etc.)

3.28.2 Thrombophlebitis 3.28.3 Phlebothrombosis

Thrombophlebitis is inflammation of the venous wall Phlebothrombosis is an intravital blood coagulation
secondarily accompanied by formation of throm- within veins. It inflicts the veins of the profound sys-
bus. The thrombus firmly adheres to the vessel wall tem. In contrast with thrombophlebitis, the thrombi
and causes its partial or total occlusion. Throm- in phlebothrombosis are formed primarily, and not in
bophlebitis inflicts prevailingly the veins of the su- consequence of inflammation. The thrombi are loose,
perficial venous system. It is three times more fre- later they may, often only partially, adhere to the ve-
quent in women than in men and its incidence in- nous wall. They can evoke a reactive inflammation,
creases with age. Embolization is rare. and the profound phlebothrombosis can turn during
Pathogenetically, phlebitis is caused by irritation several hours or days into thrombophlebitis. These
of the venous wall and subsequent inflammation, facts represent the reason why it is often impos-
the irritation being of chemical, microbic, mechan- sible to distinguish phlebothrombosis from throm-
ical, or other character, eventually by pervasion of bophlebitis and vice versa in clinical practice. The
the inflammatory process from the surrounding tis- most feared complication of phlebothrombosis is mi-
sues (periphlebitis). In the consequence of inflam- gration of the torn off thrombi into the lungs, thus
matory impairment of the vascular endothelium, the causing pulmonary embolism. Phlebothrombosis oc-
blood corpuscles get into contact with subendothe- curs more frequently in women than in men and its
lially layed collagen fibrils which in turn stimulate incidence increases with age.
blood coagulation. Haemocoagulation is enhanced Since 1856, the main ethiological factors of the
by the slowing of the blood flow and changes in phlebothrombosis origin are being considered to be
3.28. Diseases of the venous system (J. Holzerová) 251

three compounds of the Virchow’s triade: slowing and abdomen. Emboli from the right chambers of
down of blood flow, vessel wall lesion, and changes the heart originating due to arrhythmias, especially
in blood coagulation. Aggregation of thrombocytes due to fibrillations of atrii also occur. The supporting
and their adhesion to the vessel wall takes place at factors of pulmonary embolism include inactivity and
the beginning of thrombosis, though minute thrombi immobilization, especially in older patients, those
adhering to the vessel are dissolved by the fibrinolytic with tumours or hemiplegias, after surgery, pro-
system. Later, the balance between the coagulation tracted parturitions, severe injuries, massive bleed-
and fibrinolytic systems becomes disturbed and phle- ing, etc. . Embolization often takes place after an
bothrombosis is at its onset. The origin of phleboth- abrupt change of a recumbent to an erect position
rombosis is usually evoked by participance of the (after prolonged confinement in bed), or at defeca-
following factors: surgical intervention, bone frac- tion. Pulmonary embolism often represents the first
ture, tissue contussion, bleeding, lasting immobiliza- symptom of venous thrombosis. In some patients
tion, parturition, abortion, infectious diseases, ma- neither repeatedly performed examinations make it
lign neoplasms, etc. . The predisposition factors of possible to discover the particular source of emboliza-
the phlebothrombosis origin include: obesity, ageing, tion.
lack of excercise, disturbances of lipid metabolism, Embolization of a.pulmonalis may be clinically
and cardiac decompensation. manifested in an acute or chronic form. The acute
The veins obstructed with thrombi disable form includes massive pulmonary embolism and mul-
drainage from the due area, subsequently transsuda- tiple embolism. The course of the chronic form of
tion of fluids into the surrounding tissue supervenes embolism of a. pulmonalis bears the character of pul-
and edema originates. The status can be deterio- monary microembolization.
rated by reflex spasms in the surrounding veins. The The primary event in massive pulmonary em-
healing is secured by spontaneous fibrinolysis which bolism is the occlusion of one or both main branches
leads to a partial or entire recanalization of the vein. of a.pulmonalis, thus excluding more than 50 % of
The healing though, is not absolute, the valves re- the pulmonary vascular network. Such a state im-
main permanently impaired and the disease leads to minently endangers life. 50 % of such cases result in
a chronic venous insufficiency (postthrombotic syn- sudden death, in the rest of them the clinical pic-
drome). ture is severely dramatic (severe dyspnoe, retroster-
Many cases of profound phlebothrombosis are clin- nal pain, cough, hemoptysis, tachycardia, anxiety,
ically latent, and they often become clinically mani- restlessness, cyanosis and cardiogenic shock). Mas-
fested later by pulmonary embolism. sive pulmonary embolism often immitates the picture
of acute cardiac infarction.
3.28.4 Pulmonary embolism Multiple pulmonary embolism inflicts some lobal
Pulmonary embolism is a pathophysiological and and segmental branches of a.pulmonalis. It repre-
clinical status which is inaugurated by occlusion of sents the most frequent form of pulmonary embolism.
a.pulmonalis vascular network. It originates most It manifests itself as pulmonary infarction. It origi-
frequently along with the thromboembolic disease, nates due to insufficiency of nutritive bronchial cir-
the cause of occlusion being the embolus originating culation in consequence of pulmonary venostasis or
in the venous system by thrombus liberation. Less a major decrease of the systemic pressure.
frequent etiologic factors of pulmonary embolism in- Microembolization of the lungs manifestats itself
clude drops of fat, air bubbles, aggregations of leu- as a chronic form of a.pulmonalis embolism. It
cocytes, or loosened pieces of neoplasms, eventually involves the occlusion of arterioles and capillaries
amnionic fluid, etc. . Pulmonary embolism represents of the pulmonary vascular network. It occurs in
the third most frequent cardiovascular disease. cases of succesive multiple embolization of the lungs,
Etiopathogenesis of the thromboembolic disease is which leads to gradual obturations of the peripheral
partially described in the article dealing with phle- branches of a. pulmonalis.
bothrombosis. Emboli have their source prevailingly Respiratory, hemodynamic and metabolic acute
in the profound venous system of the lower limbs manifestations are very variable and depend on the
(90 %), less frequently in plexuses of the small pelvis severity of the disease. Though the part of the lungs
252 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

behind the site of obstruction in pulmonary em- thromboses of the profound veins (the so-called
bolism is ventilated, it is not perfused. Ventilation of post8thrombotic syndrome), less frequently after in-
the nonperfused pulmonary region does not fulfill its flammation of the superficial veins (the so-called
function. There occurs an intrapulmonary, so-called post-phlebitis syndrome), or after extensive varices,
dead space. Within this space, bronchioloconstric- often without clear precedent signs of thrombosis or
tion takes place due to alveolar hypocapnia. The phlebitis (the so-called varicose complex).
origin of alveolar collapse and subsequent atelectasis Manifestation of chronic venous insufficiency is
occur later as a consequent of a partaking decrease of composed of three groups of symptoms: swelling
lipoproteins (surfactant) which maintain the alveolar of the limbs, hyperpigmentation of the skin, sub-
surface tension. A 50 % reduction of the pulmonary cutaneous inflammation with subsequent induration,
vascular capacity increases the pulmonary resistance eczema, and the most serious complication – ulcus
and subsequently leads to pulmonary hypertension cruris.
which possibly results in an acute heart failure (cor Pathophysiologically, the chronic venous insuffi-
pulmonale acutum). The acute hypertension over- ciency is based on permanent venous hypertension.
strains the right heart, the pressure in the right ven- At the mean venous pressure being above 6,0 kPa,
tricle elevates at the end of diastola. In consequence eventually 45 torr, the venostasis and venous hyper-
of an insufficient blood inflow towards the left heart, tension increase to such an extent that it interferes
the minute heart expenditure decreases and the sys- also the capillary network. The balanced state be-
temic pressure in spite of tachycardia rapidly drops. comes impaired, filtration prevails resorption, thus
Severe embolization causes a shock or sudden death resulting in edema formation. The origin of such lo-
due to circulation failure or ventricular fibrillation. cal hydrostatic edema is later also affected by partic-
Besides the mechanical obstruction, microem- ipation of capillary permeability alteration which su-
bolization of the lungs involves also vasoconstriction pervenes due to hypoxia. The growth of protein con-
and bronchiololconstriction of the uninflicted area. It tent in the edema fluid is caused also by compression
is not clear if the process involves a reflex mechanism, of lymphatic capillaries, which leads to abrogated
or whether it originates due to humoral stimulation elimination of proteins from the interstice. Hence,
of local mediators arisen from the ischaemic area. in final consequence, the impairment of both venous
Microembolization of the lungs takes place without and lymphatic drainage participate in the edema ori-
any specific clinical symptoms, sometimes symptom- gin in venous diseases.
less and cor pulmonale chronicum develops only after Diapedesis of erythrocytes and macromollecular
repeated embolization. proteins, and stagnation of metabolites lead to sec-
The process of healing of pulmonary emboliza- ondary skin alterations. Hyperpigmentation super-
tion involves two mechanisms, the fibrinolytic pro- venes due to presence of hemosiderin caused by
cess and thrombus organization. The majority of em- break-down of erythrocytes. Macromollecular pro-
boli is relatively quickly dissolved and the occluded teins act as alien material and thus cause sterile
vessels recanalize. Minority is subdued to organiza- imflammation, in turn leading to proliferation of
tion resulting in small mural scars and intravascular the connective tissue, subcutaneous induration, skin
bridges. atrophy, and finally to ulcus cruris. The chronic
Paradoxical embolism supervenes when thrombi venostatic eczema represents a sign of impaired skin
arisen from the venous system cause embolization trophicity.
of the systemic circulation circuit. It may occur in Advanced stages of chronic venous insufficiency
patients with an inborn defect of the atrial septum may display subcutaneous bone metaplasis and re-
during the change of the left-right shunt to the right- striction of anckle movement.
left shunt.

3.28.5 Chronic venous insufficiency

The chronic venous insufficiency may represent con-
sequence, eventually the complication of any of
vein diseases. Most frequently it develops after
3.29. The role of endothelium in the reactivity of the vascular smooth muscle (R. Sochorová) 253

PGI2 (prostacyclin) – is a metabolite of arachi-

donic acid. It stimulates adenylatecyclase and
3.29 The role of endothelium increases the amount of cAMP in cells of vascu-
lar smooth muscle.
in the reactivity of the Endothelium-derived relaxing factor (EDRF) –
vascular smooth muscle is being synthetized from L-arginine in endothe-
lium cells due to the impact of arginine oxidase.
Chemically, EDRF is nitrogen oxide (NO) or
other labile nitroso compounds (R-NO). EDRF
stimulates guanylatecyclase and increases the
Contractility of vessels is regulated by nervous,
amount of cGMP in the vascular smooth mus-
hormonal, but also local humoral regulatory mech-
cle. EDRF is released under basal conditions
anisms. The sympatic adrenergic nervous system is
and stimulation. The variety of physiological
regarded as the main regulatory mechanism of the
stimulations capable of evoking the augmenta-
vascular tonus. Activation of this system which lo-
tion of EDRF liberation includes the throm-
cally releases a neurotransmitter (in particular nora-
bocytes products (serotonin, ADP), thrombin,
drenaline), leads to contraction of the smooth vascu-
hormones, neurotransmitters (acetylcholine),
lar muscle.
changes in partial oxygen tension and increased
Currently, great attention is paid to the study of
blood flow. The release of EDRF owing to the
vascular endothelium cells which play an important
increased blood flow plays an important role in
role in modulation of the vascular tonus.
alteration of the size of arterial lumen. Rapid el-
Endothelial cells are responsible for a variety of
evation of intraluminal pressure stimulates the
physiological functions, as for example uptaking and
EDRF release or leads to an increased release
metabolism of noradrenaline or serotonin, conversion
of EDCF (endothelium-derived contracting fac-
of angiotensin I to angiotensin II, bradykinin meta-
tor).
bolism, prostacyclin (PGI2 ) biosynthesis. They af-
fect the vascular wall permeability, blood coagula- 2. Vasoconstricting factors are produced by en-
tion, and throbocytes activity. dothelial cells (EDCFs). They function as inter-
Since the discovery of prostacyclin Mondacom, mediaries of endothelium-dependent vasocon-
great attention has been paid to vasoactive sub- striction. It has been experimentally confirmed
stances produced in the vascular wall. The Furch- that the removal of endothelium reduces con-
gott’s discovery of the role of vascular endothelium striction caused by antagonists. Endothelium-
in vasodilatation induced by acetylcholin (1980), and dependent vasoconstriction can be stimulated
evidence that this response takes place due to par- by naturally present substances (noradrenaline,
ticipation of a substance called endothelium–derived arachidonic acid (AA), thrombin, prostaglandin
relaxing factor, stirred interest and attention to the H2 ), by pharmacological substances (nico-
forthright role of endothelium in modulation of vas- tine, increased K+ ions), physical stimuli
cular responses. (stress, pressure) and hypoxia (see fig. 3.55 on
Endothelium cells produce vasodilatatory and page 254).
vasoconstrictive factors. EDCFs which modulate the endothelium-
dependent vasoconstriction include three cate-
1. Vasodilatatory factors include:
gories:
• PGI (prostacyclin) (a) EDCF1 – vasoconstricting matabolites of
• Endothelium–derived relaxing factor arachidonic acid or oxygen radicals (e.g. su-
(EDRF) peroxide anion)

• Endothelium–derived hyperpolarizing fac- (b) EDCF2 – which is released due to hypoxia.

tor (EDHF) Its chemical structure has not yet been
identified.
254 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

Figure 3.55: Endothel and some other vasoconstrictors

(c) EDCF3 – endothelin – substance which in covered in cells of nonvascular type, as for example
contrast to the rapid contraction caused by in kidneys, lungs and other tissues. ET-2 and ET-3
other EDCFs, causes a long-term slowly are contained in tissues of the brain, lungs, kidneys,
developing vasoconstriction adrenal glands, and small intestine.

Endothelin – is a peptide comprising 21 amino- 3.29.1 Effects of endothelin

acids. It has a strong vasoconstricting effect. A sig-
nificant resemblance between endothelin and sarafa- Endothelin had been formerly identified as a strong
toxin which is a compound of snake venom has been vasoconstricting substance, later a wider spectrum
revealed. Sarafatoxins, similarly as endothelin, have of its effects was discovered.
a strong coronaconstricting, hence cardiotoxic lethal
1. Vasoconstricting effects of endothelin - in de-
effect.
pendence on dosage endothelin evokes contrac-
Three different endothelin genes, and consequently
tions of arteries and veins, already in doses of
three different endothelins were confirmed in man.
10−11 − 10−8 , regardless of anatomical localisa-
Endothelin 1 (ET-1 in pigs, human endothelin),
tion of blood vessels. In general, the veins are
endothelin 2 (ET-2 differs from ET-1 by two
more sensitive to endothelin than arteries. The
aminoacids) and endothelin 3 (ET-3 differs from ET-
onset of the coronary vessels response to the ET
1 by six aminoacids).
constricting effect is slow and of prolonged du-
Endothelin 1 is formed from a precursor protein, ration (several hours).
the so-called big endothelin by the effect of endothe-
linconvertase. ET-1 is the only endothelin contained 2. Pressoric and depressoric ET effects – intra-
in vascular endothelium cells, additionally it was dis- venous administration of endothelin causes a
3.29. The role of endothelium in the reactivity of the vascular smooth muscle (R. Sochorová) 255

short-term (0,5–2 min.) depressoric response parenchyma organs (heart, kidneys, lungs, small in-
which is followed by elevation of arterial pres- testine, suprarenal glands, brain). Endothelin effect
sure dependently on the dosage. The mecha- is based on the increased influx of Ca2+ via calcium
nism of the initial depressoric response can be canals in target cells.
explained by the fact that endothelins, mainly It can also mobilize Ca2+ from intracellular depot
ET-1 and ET-3, induce a release of prostacyclin sites by induction of the phosphatidylinositol system.
or EDRF from the vascular endothelium. The The evidence of endothelin effects, other than
pressure elevation in the vascular network lasts vasoconstrictive, as well as of endothelin receptors
for 2–3 hours. This extremely prolonged effect existence in various nonvascular tissues, draws at-
represents one of the most important vascular tention to the fact that endothelin affects regula-
effects of endothelin. tory functions of various cardiovascular and non-
cardiovascular tissues. Endothelin participates in
3. Contraction of nonvascular smooth muscles – regulation of the systemic arterial pressure and lo-
endothelin causes contraction of the small in- cal blood distribution, formation and composition
testine, tracheal and bronchial smooth muscles. of urine, release of circulating hormones (e.g. re-
The endothelin effect is comparable with that of onin, ANP, adrenaline) from kidneys, atrium and
histamin and exceeds that of leucotrien D4 . suprarenal glands, tonus of bronchial smooth mus-
cles, small intestine motility, various CNS functions
4. Endothelin has a positive inotropic and including autonomous regulation and higher func-
chronotropic effect on myocardium. tions.
There are two different models of endothelin for-
5. Endothelin stimulates secretion of atrial natri-
mation in relation to the cardiovascular system reg-
uretic peptide (ANP) in myocardium
ulation:
6. Renal effects – endothelium participates in regu- 1. Endothelin participates in maintainance of the
lation of renal functions by inhibiting the release systemic and local circulation under physiologi-
of renin in kidneys. It decreases renal blood flow cal conditions. It functions similarly as a num-
accompanied by reduction of glomerular filtra- ber of vasoactive substances, e.g. catecholamins,
tion, urine volume and excretion of Na+ and K+ angiotensin II, vasopressin and ANP. Plasmatic
by the kidneys. concentration of endothelin in man is in average
cca. 1 pmol·l−1, which is a too small amount
7. Endothelin decreases aggregation of thrombo-
for it to be classified as a circulating hormone.
cytes, assumedly by cAMP decreasing.
It is quickly eliminated from circulation by the
8. Proliferation of smooth muscle cells lungs. Endothelin has a local impact. Inhibi-
tion of renin-angiotensin system by means of en-
In addition, endothelin has trophic effects on the dothelin, as well as stimulation of ANP secretion
smooth muscle cells of vessels, the effect being of (strong vasorelaxing factor) represent examples
importance in regard to its role in both pathogenesis of negative feedBback between endothelin and
of atherosclerosis and vascular hypertension, and in other hormonal systems.
elevated blood flow.
2. A greater amount of endothelin is produced in
damaged tissues due to their lesion or protec-
3.29.2 The mechanism of endothelin tive reactions (e.g. healing of wounds, inflamma-
effect tion), its formation being induced by thrombin.
Endothelin can be released due to the effect of va- Abrogation of regulatory mechanism which partic-
sopressin, adrenaline and thrombin. It is active via ipate in endothelin formation, leads to various patho-
endothelin receptors of several subtypes, whilst the logical states, e.g. coronary and cerebral vasospasms,
affinity of ET-1, ET-2 and ET-3 to these receptors bronchospasms, atherosclerosis and hypertension.
is variable. The binding loci for endothelin are situ- Endothelin is to a greater extent produced within
ated in the media of variously calibrated vessels and the site of endothelial impairment and has contrac-
256 Chapter 3. Pathophysiology of the cardiovascular system ( I. Hulı́n, F. Šimko et al.)

tile and proliferative effects on cells of the vascular in people with essential hypertension, vasospastic
smooth muscle representing the pathogenic factors angina pectoris, and in acute myocardium infarction
of atherosclerosis and vasospasm pathogenesis. (IM).
Undoubtful is the role of endothelin especially in From the clinical point of view, the changes in plas-
the pathogenesis of cardiocascular diseases. An in- matic ET concentration could be regarded as indices
crease of plasmatic ETB1 concentration was observed of IM course.
Chapter 4

Pathophysiology of kidneys and

urinary system

haemodialysis, peritoneal dialysis and transplanta-

tion gained in last time important success. These
4.1 Introduction therapeutic procedures are very expensive, therefore
they can not be the main method of renal disease
treatment. The transplantation of kidney can be the
solution only in 4-6 per cent of patients.
Disorders of renal functions may be manifested by
Pathophysiology of kidneys and the urinary sys-
many various clinical symptoms and laboratory find-
tem is one of the most important topics of contem- ings which can be understood only when the func-
porary pathologic physiology and of medicine in the
tion of kidneys is well known. Kidney can be consid-
most general aspect. It reflects the very important
ered to be a mysterious house, about which we know
role of kidneys in the maintenance of the organism
who enters and leaves it, and from these facts we
existence and in ensuring its crucial functions.
have to conclude what happens in it. Understand-
Renal diseases are frequent. They can lead to al- ing the pathologic physiology of uropoietic system
terations in the organism, affecting so the functions can influence considerably the therapeutic approach
of other organs and systems considerably. Very im- to the unfavorable development of uropoietic system
portant fact is, that diseases of uropoietic system diseases and therefore it has a most important ex-
(the urinary tract infections, interstitial nephritis,
traordinary importance for clinical praxis.
nephrolithiasis and others) are often hidden and may
lead in their terminal stage to uraemia, and uraemia
uses to be lethal. 4.1.1 Important tasks of uropoietic
Renal diseases can be the underlying cause of sys- system
temic arterial hypertension with all its consequences
and cause other serious alterations in organism. Re- The functions accomplished in organism by uropoi-
nal impairment can be secondary, developing owing etic system contribute considerably and rather irre-
to an other basic illness (e.g. long-lasting hypoten- placeably to maintenance of homeostasis. The home-
sion, in shock, in endocrine and metabolic disorders, ostasis regulation concerns the maintenance of cer-
in cardiovascular diseases). Renal impairment can tain physiologic constants: the stability of body fluid
be caused often by toxic substances and drugs. Kid- volume (isovolaemia), concentration of electrolytes
neys can be in fact, the ”perpetrator” causing very (isoionia), of osmotic active substances (isosmia),
serious alterations of organism, or to be the ”victim” and of hydrogen ions (isohydria). It does not mean
of other organ and system lesions. the maintenance of an unchangeable, stationary state
In contrast to other organs, the functions of kid- in a closed system, but the maintenance of a dynamic
neys can be compensated or replaced by trans- steady-state in a complex, integrated open system –
plantation. Modern therapeutic procedures – the the living organism. With this dynamic steady-state

257
258 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

correspond relative stationary values of volume and

composition of body fluid, varying in admissible lim-
its.
These particular functions of kidneys are per-
formed by its excretory capability based on elim-
ination of useless substances. The needless, even
harmful substances are exctreted by mechanism of
glomerular filtration and by tubular mechanisms.
Kidney is in fact the only way how to excrete the
waste products, the molecules containing nitrogen
and sulfur. The most important substances are the
products of protein metabolism (urea, aminoacids,
uric acid, creatinine, creatine etc.). In renal fail-
ure the retention of these substances in organism fol-
lowed by elevation of their concentrations in blood is
developing.
In addition to this excretory function, kidney per-
formes important functions, which could be thought
to be endocrine. Kidney is not only the effector organ
of several hormones (aldosterone, ADH, parathor-
mone, angiotensin, prostaglandins etc.), but kidney
is also the site of production of substances with hor-
monal or enzymatic activities (renin, renal erythro-
poietic factor, prostaglandins, kallikrein-kinin sys-
tem).

Figure 4.1: Longitudinal section of the kidney

reaching the calyces renalles. Medulla renalis con-

4.2 Basic anatomic notes sists of 8-20 pyramidal formations separated by cor-
tical projections. The tops of pyramids are oriented
towards the renal hilus. Each pyramid with adjacent
cortical layer forms the renal lobe – lobus renalis.
Kidneys lies in the abdominal cavity retroperi- A. renalis enters kidney through the hilus divid-
toneally and paravertebrally, between the twelfth ing into 2–3 branches. Accesory arteries with an
thoracal and third lumbar vertebra. The right kid- irregular course can be found sometimes, they can
ney lies slightly lower than the left. In adult subjects enter the kidney outside the hilus. After entering
each kidney weighs 120 to 170 g or more. Kidneys the kidney the branches of renal artery divide into
are covered by a thin, but firm fibrous caspsule, ad- arteriae interlobares passing between the pyramids
herent to the vessels and renal pelvis in the hilus. into their bases where they branch and join in an
The capsule consists mostly of collagenous and less arch-like shape, forming the arteriae arcuatae. They
of elastic fibres. In this net of fibres some smooth lie at the border between the cortex and medulla.
muscle cells are found. Kidneys are surrounded by From the arcuate arteries are derived the interlob-
a lipid ”cushion” - the panniculus. See figure 4.1, ular arteries – arteriae interlobulares – crossing the
page 258. cortex to its surface. From interlobular arteries arise
Renal cortex is about 5 to 15 mm thick, not vertically short afferent arterioles into the glomeruli.
sharply demarcated from the medulla. The corti- According their localization two types of glomeruli
cal substance forms longitudinal projections – colum- can be distinguished in kidneys. Most of them are
nae renales, penetrating the medullar substance and localized superficially, designated as glomeruli corti-
4.2. Basic anatomic notes 259

cales. Nearer to the medulla are the glomeruli jux- 4.2.1.1 Glomerulus
tamedullares. From the cortical glomeruli arise the
vasa efferentia (vessels of arteriolar type) forming the The mean diameter of glomerulus is close to 200 µm.
peritubular capillary network, from where the blood It is a tuft of capillaries inserted into the mesangium
is flowing into the venae stellatae corticales and fur- and lying in the Bowman’s capsule. Glomerular cap-
ther into the venae interlobulares. At the margin illaries have a rather simple structure: the inner layer
between the cortex and medulla the venae interlob- consists of endothelial cells, the medial layer of base-
ulares join into the vv.arcuatae, further with vv. in- ment membrane and the outer layer oriented towards
terlobares, forming finally v. renalis. the Bowman’s capsule consists of epithelial cells –
podocytes. The space between the capillaries is filled
From juxtamedullar glomeruli arise the vasa effer- with mesangial cells and mesangial extracellular sub-
entia with a larger luminal diameter. They do not stance - the matrix. The parietal part of Bowman’s
form such a capillary network like around the corti- capsule consists of basement membrane and flattened
cal glomeruli, but they form some smaller branches epithelial cell lining oriented towards the glomerulus.
only. Greater part passes into the vasa recta (arteri- (See the figure 4.2, page 260).
olae rectae medullares spuriae) entering the medulla
Endothelial cells The thickness of the endothelial
and returning from medulla as thin venulae to the
cells measures only 50-60 nm and their nuclei bulge
cortico-medullar margin, where they drain the venae
into the capillary lumen. The layer of endothelial
arcuatae. The peritubular capillaries have a simi-
cells is not continuous, it is breached in intervals by
lar structure as the glomerular capillaries, but they
holes and covered with a very thin mucopolysaccha-
do not contain the podocytes. Vas efferens of jux-
ride membrane - forming membrana fenestrata. The
tamedullar glomerulus branches into the capillaries
whole surface area of human glomerular capillary en-
which can supply several different nephrons. Lym-
dothelium measures approximately 1,5 m2 .
phatic vessels are present in the capsule and in renal
Basement membrane is the basis of the capillary
parenchyma. They drain into the lymph nodes along
wall. Basement membrane of glomerular capillar-
the vena cava inferior.
ies is in fact the continuation of vas afferens base-
Sympathetic, parasympathetic and sensitive nerve ment membrane. It is continuous with the basem-
fibres enter the kidney innervating mainly the affer- net membrane of vas efferens and of basement mem-
ent arterioles. Glomeruli have no special innervation. brane of Bowman’s capsule. At several sites it is con-
nected with mesangial cells and mesangial substance.
Basement membrane consists of glycoproteins and of
collagen, measuring about 300–330 nm in thickness.
4.2.1 Nephron Three layers can be observed in basement membrane:
the medial, the inner and the outer layers. The me-
Basic functional unit of kidney is the nephron. Each dial layer is the thickest and the most consistent of
kidney contains about 1 200 000 nephrons. Nephron them - lamina densa. The layer lying under the en-
consists of glomerulus, Bowman’s capsule, proximal dothelial cells is the - lamina rara interna and the
tubule, the loop of Henle and of distal tubule. The layer under the podocytes is - the lamina rara ex-
glomeruli lie in the renal cortex, the tubules in the terna.
cortex and in the medulla. The system of collect- Podocytes are the epithelial cells covering the ex-
ing and discharging ducts crosses the medulla and ternal surface of the basement membrane. Under
lead into the papillary apices as canaliculi renales. great and spatial magnification they have a octopus-
Nephrons are separated from each other by only a like shape with thick foot processes branching into
thin layer of interstitial tissue. Glomeruli of the less-sized pedicels attached to the basement mem-
cortical nephrons lie in cortex, their loops of Henle brane by fine fibrils. Network of these pedicels
reach the medulla. Glomeruli of the juxtamedullar forms a variable interpedicular split (pores) which
nephrons lie at the margin between the cortex and can vary or disapear. They are permeable for smaller
medulla (near to medulla). The loops of Henle of molecules than those passing through the membrana
these nephrons course deeply into the medulla, or to fenestrata. The penetration of molecules through the
the papillae. capillary membrane is determinated, besides their
260 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

Figure 4.2: Structure of glomerulus (A – cross-section through glomerulus; B – capillary wall; C – connection
between the podocytes; from McCance KL, Huether SE: Pathophysiology, 1990)

size, also by electrical charge of molecules. The sialo- stance. They are more numerous at site where the
proteins form a polyanionic gel covering the cytoplas- arterioles enter and leave the glomerulus. Here they
mic membranes of pedicels and are present in the have a closer connection with the the juxtaglomeru-
peripedicelar splits. This polyanionic gel suppresses lar apparatus. Mesangial cells are star-shaped cells
the penetration of negatively charged molecules of with several thin processes penetrating the surround-
albumin (See figure 4.3, page 261). ing tissue.
Mesangial cells and mesangial substance fill the The parietal wall of Bowman’s capsule consists of
space between the glomerular capillaries. Mesangial basement membrane with identical structure as the
substance is similar with the basement membranes. basement membrane of glomerular capillaries. The
Mesangial cells are dispersed in the mesangial sub- epithelium covering the parietal wall of Bowman’s
4.2. Basic anatomic notes 261

Figure 4.3: Glomerular capillary (P – podocytes; from Kissane JM: Anderson’s Pathology, 1985)

capsule passes at the vascular pole to the podocytes. tein membrane enables a selective choice and transfer
of various substances. The lipid component of the
4.2.1.2 Tubules membrane acts as isolating layer, being permeable
for liposoluble substances.
The basic structure of tubules is the basement Convoluted portion of proximal tubule (pars con-
membrane which in fact, is a continuation of the voluta) continues in the straight portion (pars recta)
Bownam’s capsule basement membrane. forming the beginning of Henle’s loop. The proximal
Proximal tubule is about 15 mm long and its di- convoluted tubule is lined by low cells provided with
ameter measures 5 mm. It is lined by a single layer brush border at their apical surface. It continues in
of cuboidal cells containing numerous elongated mi- descending limb of Henle’s loop. The nephrons de-
tochondria and enzymes of anaerobic metabolism. rived from glomeruli lying in outer renal cortex have
Numerous processes at the basal portion of tubular short loops of Henle, while the nephrons derived from
cells increase the surface area and forms a labyrint juxtamedullar glomeruli have long Henle’s loops ex-
at the basement membrane which contains a great tending to the medullary pyramids. The thin seg-
amount of canaliculi communicating with extracel- ment of Henle’s loop having a lenght of 2 to 14 mm
lular space. The border between the tubular epithe- continues in the thick segment of ascending limb be-
lium and the epithelial cells of peritubular capillaries ing about 12 mm in lenght.
is formed only by the basement membrane of simi- The distal tubule is only 5 mm in lenght. The
lar qualities as the basement membrane of glomeru- ascending part of Henle’s loop and the convoluted
lar capillaries. The proper intercellular dividing line part of distal tubule have a nearly identical micro-
is formed by cytoplasmic membrane provided with scopic structure. The cells are shorter than in prox-
brush border at the apical cell surface. This lipopro- imal tubule, the brush border is absent, the basal
262 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

Figure 4.4: The epithelial cells of the tubules (from Berne RM, Levy MN: Physiology, 1988)

labyrinth is not so pronounced. They are cuboid in The entire nephron with the collecting tubule is
their shape and have few processes covered by acid about 45-65 mm in lenght (see figure 4.4, page 262).
mucopolysaccharide. In the luminal portion of these
cells numerous vesicles can be found. They contain 4.2.1.3 The juxtaglomerular apparatus
fewer mitochondria and enzymes than the cells of
ascending limb of Henle’s loop. The juxtaglomerular apparatus is located in the re-
gion where vas afferens enters the glomerulus. It is
Macula densa is a portion of the distal tubule spacially confined by afferens and efferens glomerular
closely adjacent to the glomeruli at the vascular pole. arterioles and the wall of distal tubule. The centre of
The collecting tubules are about 20 mm in lenght. this triangle is filled with special cells being related
The lining of the collecting tubules consists of rela- with smooth muscle cells of arterioles and connected
tively large cells named the light and dark cyllindri- through the vascular pole with glomerular mesangial
cal cells. At their basal site are numerous pseu- cells. In afferent arterioles occur the juxtaglomerular
dopodia and many enzymes of anaerobic metabo- cells having properties of myoepithelioid cells. A few
lism. Several collecting tubules join the neighbouring dispersed cells of this type occur also on other parts
ones to form finely papillary ducts which drain at the of renal arteries. Juxtaglomerular cells contain nu-
papillary tips of kidneys. merous ribosomes, well developed Golgi complexes
4.3. Peculiarities of renal blood flow 263

and endoplasmic reticulum and secretory granules. physiologic capacity is variable, it varies about
Some of these granules are considered to be specific 300 ml. The urinary bladder wall consists of three
secretory granules containing renin the other gran- muscle coats, the lining of a superfiacial layer of flat
ules do not contain renin, but it is suggested, that cells, and a deep layer of cuboid cells. In the region
renin could be deposited in these cells in a non gran- of trigonum vesicae urinariae is an inner sfincter.
ular form. The man urethra is divisible into three portions:
In the juxtaglomerular triangle cells called lacis prostatic, membranous and cavernous. The female
cells occur designated also as extraglomerular mesan- urethra is short. It’s lining consists of pavement ep-
gial, or Goormaghtig’s cells. They have numerous ithelium.
microvilli forming a fine network.
The interstitium consists of cells and cell-free sub-
stance. Interstitial cells resemble in their struc-
ture to fibroblasts. They contain lipoid drops of
prostaglandin precursors and a system of fibrils,
probably identical with elastic fibrils. The thicker
4.3 Peculiarities of renal
fibres cross the juxtaglomerular cells entering the blood flow
Bowman’s capsule and the podocytes.

4.2.2 The urinary outflow tract Concerning the blood flow the kidneys are exep-
Urine from collecting ducts is excreted into the renal tional organs. The peculiarity of renal haemody-
pelvis, passing calyces renales minores et maiores. namics is a consequence of the fact, that the kid-
From the renal pelvis is the urine transported into neys have 100 times greater blood flow than other
the urinary bladder by the contractive activity of organs and tissues in human organism. The arteri-
ureters. The wall of the urinary excretory system ovenous difference in blood oxygen content is low in
has in all its segments almost the same structure. It renal blood vessels. In healthy adult man at rest the
cosits of three coats: mucous, muscularis nad fibrous. renal blood flow is about 1200 ml per minute repre-
The mucosa is lined by transitional epithelium. In senting 25 per cent of cardiac output. In fact, almost
the proximal parts of urinary outflow tract 2-3 cellu- the whole blood flows through the glomeruli, only 5-
lar layers in the more distal portion 5-7 layers can be 10 per cent of it courses trhough the paraglomerular
found. Lamina propria mucosae lying beneath the anastomoses.
epithelium consists of collagenous connective tissue. It was found that the blood pressure whitin the
The middle coat of urinary tract excretory system glomerular capillaries is about 50-60 per cent of the
consists of an inner longitudinal and an outer cir- blood pressure in systemic arteries – 10 kPa (80 torr).
cular layer of smooth muscle. Calyces renales have The blood pressure in peritubular capillaries is about
two muscle layers enabling contraction waves wich 1,9 kPa (15 torr) and in vena renalis about 0,8 kPa
aid the urine transport into the renal pelvis. The re- (6 torr). The glomerular capillary network can be so
nal pelvis has the same structure, consisting of two considered to be a high – pressure capillary network
muscle layers. The distal third of ureters consists of in contrast to the low – pressure peritubular capillary
three muscle coats – the thirth, outer coat is formed network. The striking difference in pressure between
of longitudinally oriented smooth muscle layer. The the glomerular and peritubular capillaries is caused
peristaltic waves of ureter occur 1-5/min. shifting by the high resistance within the vas efferens.
the urine towards the urinary bladder. The stim- The high-pressure region of cortical glomerular
ulus initiating these movements is not understood network resembles the arterial end of capillaries. In
till now. It could be a certain filling pressure in re- the low-pressure peritubular capillary network pre-
nal pelvis. The oblique ”entrance” of ureters into vails the retrograde diffusion of fluids according to
the urinary bladder inhibits the urine reflux, though Starling’s law, thus the peritubular capillary bed
ureters are not provided with sfincters at their ter- functions as the venous end of capillaries. Blood
minal portion. flowing through the peritubular capillary network is
Urinary bladder is the reservoir for urine. Its deprived of the water volume which has been filtered
264 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

in glomeruli, thus its osmotic pressure is high, and wall of vas afferens, stimulated by tension changes
thereby it has the ability to reabsorb the water. affecting the vessel wall. If this tension is dimin-
The rate of blood flow within the perilobular ar- ished e.g. during reduction of blood flow through
teries is relatively high, hence the erythrocytes move kidneys the renin secretion by these cells rises and
mainly in the centre of this flow. Vasa afferentia are vice versa. The second type of receptors (chemore-
derived from the aa. interlobulares in a nearly rectan- ceptors) is found in the wall of distal tubules in their
gular direction, therefore more plasma than erythro- portion lying near to glomeruli: - the granular cells of
cytes flow in them. Owing to this fact the cortical macula densa. They respond to changes in sodium
glomeruli are supplied with blood containing more concentration of tubular fluid. The stimulation of
erythrocytes than plasma. renin secretion occurs if the NaCl concentration in
The arrangement of two successive capillary net- the vicinity of macula densa cells decreases. On the
works is very important concerning urine production contrary, an augmented NaCl content in this area
and its concentration. For understanding the disor- supresses renin release. Renin is releases from cells
ders arising in kidneys during glomerular blood flow into the intersticium and from there it gets into the
alterations is very important to know these facts. capillaries. Renin is a specific endopeptidase con-
The blood distribution in kidneys is uneven. Al- verting angiotensinogen. A glycoprotein present in
blood plasma - to angiotensin I which is converted by
most 80 per cent of renal blood perfuses the outer
converting enzyme to a substance with very strong
cortical regions. This is why all changes in blood
vasoconstrictive activity - the angiotensin II.
flow will be reflected in alterations of this region.
The blood flow in renal medulla does not depend of Renin-angiotensin system is one of the key sys-
systemic arterial blood pressure. tems regulating the blood pressure. Despite of ex-
Blood flow through the juxtamedullar glomeruli tensive research projects, all facts concerning the re-
enables to maintain the blood flow in renal medulla lease and regulation of this very important factor are
to the detriment of cortical glomeruli, especially not known in detail till now. The baroreceptor and
when the blood supply of kidneys is diminished, or chemoreceptor mechanism explaining the triggering
the systemic arterial pressure falls considerably. off this system is in principle accepted.
The high blood flow through the renal cortex The mechanism of angiotensin action is not well
responds sensitively to blood volume and pressure understood. Angiotensin II stimulates the calcium
changes. An important fall of blood pressure or vol- uptake and the calcium release from celullar or-
ume can elicit development of ischaemia, even of ganelles in target cells. Angiotensin II induces vaso-
necrosis in outer cortical layers. Inflammatory al- constriction of renal vessels, above all in vas efferens.
terations in the renal cortex can vice versa affect the In vas afferens is its vasoconstrictive action probably
blood flow through the medulla renalis. masked by vasodilatation due to prostaglandins, syn-
Oxygen consumption in cortical region is 9 ml per thesis of which is stimulated by angiotensin. During
minute, it is about 20 times higher than in medullar decreased blood flow the constriction of vas efferens
region (0,4 ml per minute). Thus, the renal blood ensures the glomerular filtration. This vas efferens
flow supplies the organ with oxygen and nutriments constriction causes blood pressure fall in peritubular
for its own metabolic processes and it ensures simul- capillary network leading further to improvement of
taneously the processes of ultrafiltration of plasma fluid resorption in proximal tubule. The angiotensin
and thereby of urine formation. Kidneys are there- receptors are situated also on mesangial cells within
fore provided with several mechanisms enabling the the glomeruli. These cells may influence the per-
adaptation of blood flow according the given require- meability of glomerular capillaries. Enhanced an-
ments of organism. giotensin level suppresses by feedback mechanism the
The autoregulation of renal blood flow is accom- renin release from juxtaglomerular apparatus. But
plished by nerves and humoral factors. The most the suppression of renin production can be induced
important regulation is accomplished by the renin- by an other pathway – by aldosterone release, sodium
angiotensin system. There are two types of in- reabsorption and by its increased concentration in re-
trarenal receptors recording stimuli for renin release: gion of macula densa.
the first type are the baroreceptors localized on the The renin-angiotensin system is involved not only
4.3. Peculiarities of renal blood flow 265

in regulation of renal functions but it plays a very tion of vasoconstrictive substances is the result of en-
important role in control of systemic arterial blood hanced sympathetic activity. In this situation have
pressure. Angiotensin II by its strong vasoconstric- the prostaglandins a protective influence upon the
tive effect increases the peripheral resistance of ves- renal circulation.
sels and maintains so the blood pressure on appro- The natriuretic hormone is very probably sub-
priate desired level. Apart from this, angiotensin II stance with low molecular weight, produced in brain,
stimulates the sympathetic activity and facilitates mainly in hypothalamus. In experiments it inhibits
the noradrenaline release from peripheral endings. the sodium transport through the frog skin. The
Angiotensin II indirectly promotes the sodium and mechanism of this effect is the inhibition of the trans-
water retention in organism. By its action is aldos- porting enzyme Na+ –K+ –ATP–ase activity. Natri-
terone released from suprarenal glands ensuring the uretic hormone enhances the contractility of smooth
tubular reabsorption of sodium. It also stimulates musle cells in the vessel wall. Increased sodium ex-
the vasopressin release and induces the dipsogen ef- cretion induced by natriuretic hormone is explained
fect in central nervous system (CNS). This complex by inhibition of the sodium pump in proximal tubule
action results in correction of disproportion between and in other parts of tubular system. Elevated natri-
the capacity and filling of the vessel system during uretic hormone activity was found in patients with
arterial hypotension and hypovolaemia. The correc- chronic renal failure, with essential hypertension and
tion is performed by renin-angiotensin-aldosterone with low renin hypertension. Nevertheless, in pa-
system that induces vasoconstriction, increase of wa- tients with heart failure and in patients with oedemas
ter intake with reduction of its elimination, and en- of various origin a zero activity of natriuretic hor-
hancement of sodium retention. mone was observed. These facts indicate that natri-
In the regulation of renal blood flow participates uretic hormone regulates the volume of extracelullar
the nervous system. The adrenergic fibres of sym- fluid under physiological circumstances and in patho-
pathetic system come from Th 10 to Th 12 segments logic conditions. The chemical structure of natri-
and a part of them in Th 12 to L2 segments. These uretic hormone was not identified till now.
fibres enter the kidneys with renal arteries and pass On the other hand, the atrial natriuretic peptide
along them. They innervate afferent and efferent ar- (factor) was identified in heart atrial tissue. It is
terioles, intrarenal veins and tubules. Parasympa- a peptide with a molecular weight of 2 500 to 3 000
thetic fibres were found in the same areas. Applica- daltons. Applied to experimental animals it induces
tion of alfa-adrenergic agonists (e.g. noradrenaline) acceleration of renal sodium excretion without in-
elicits vasoconstriction of a. afferens and a. effer- hibition of Na+ –K+ –ATP–ase, thus it is not an in-
ens resulting in blood flow decrease through kidneys. hibitor of this enzyme and it does not exhibit vaso-
Only minor changes of glomerular filtration arise constrictive activity, but has vasodilating effects. Its
thereby. Also hypoxia can be the stimulus triggering release into the blood is initiated by expansion of cir-
the renal vasoconstriction mediated by chemorecep- culating blood volume, by enlargement of heart atria
tors. and enhanced plasmic sodium concentration. The
Activity of the sympathetic system is low under mechanism how the natriuretic factor increases the
basal circumstances. Renal flow is therefore not con- renal sodium excretion is not fully understood. It
siderably increased by adrenergic receptor blocking is known at present that it enhances the glomeru-
agents or by renal denervation, but it can be raised lar fitration and causes vasodilatation in kidneys.
under the influence of vasodilating agents which can Glomerular filtration is increased by influencing vas
reduce the myogenic tonus of vessels. This is ac- efferens and vas afferens, resulting in elevation of fil-
cepted at present, although the myogenic theory does tration pressure and thereby of sodium and water
not explain the renal blood floow changes. load in tubules. Sodium is not completely absorbed
Adrenergic stimuli induce in kidney the vasodilat- in tubules, but the water reabsorption influenced by
ing prostaglandin PGE2 and PGA2 release. They an- vasopressin is unchanged leading to natriuresis.
tagonize the vasoconstrictive adrenergic stimuli. In- Thanks to regulating mechanisms remains the re-
creased level of noradrenaline or angiotensin II trig- nal blood flow relatively constant even during mean
gers the prostaglandin release. Increased concentra- arterial pressure fluctuations in extent of 10 to 24 kPa
266 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

(80 to 180 torr). The ability of autoregulation is per- urine) contains few proteins (maximally 150 mg/l),
sisting even following denervation (renal transplan- non-electrolyte substances with low molecular weight
tation), indicating that neural mechanism does not (glucose, aminoacids, urea etc.), monovalent ions
play an important role in renal blood flow regulation. (sodium, potassium, chlorides etc.) approximately
Mechanisms of autoregulation fail only in conditions in the same concentration as in plasma. As the pro-
where the blood pressure is extremely low occuring teins of plasma are not diffusible, the rules of Gibbs-
in massive bleeding when the renal blood flow is con- Donnans distribution governs the process of monova-
siderabily restricted. Global blood flow falls also in lent diffusible ions distribution. Small differences in
anatomic restriction of vessel bed, e.g. in chronical concentration are due to Gibbs-Donnans effect, ow-
renal disease and in all renal diseases connected with ing to which is the cation concentration in ultrafil-
shrinkage of renal parenchyma. trate lower by about 5 per cent and the concentration
of anions by about 5 per cent higher than in plasma.
In severe paraproteinaemia and hyperlipidaemia is
the concentration of these lowmolecular substances
higher in ultrafiltrate than in plasma. The diva-
4.4 The urine formation lent ions concentration (calcium, magnesium) and
the concentration of organic acids and bases, con-
cerning their binding to the plasmic proteins, is sub-
stantionally lower in ultrafiltrate than in plasma.
Urine formation is a very complex process includ- Should a substance pass from blood into the pri-
ing glomerular ultrafiltration, tubular resorption and mordial urine it has to cross three barriers:
excretion (see figure 4.5, page 267).
1. the endothelial layer with pores-fenestrations on
the inner surface of glomerular capillaries
4.4.1 Glomerular filtration
180 l of plasma is daily filtered through glomeru- 2. the basement membrane composed of three lay-
lar capillaries and 120 ml of ultrafiltrate is produced ers. The central layer is the proper filtering
each minute. The glomerular filter is permeable for membrane. It consits of thin collagenous fi-
substances in a manner as if it would be provided by bres arranged in a three-dimensional network
pores with diameter measuring 10 nm. Substances inserted in a homogenous matrix provided by
with molecular weight under 70 000 daltons appear in pores of 30 to 60 nm in diameter
glomerular filtrate depending on the molecular con-
figuration. The plasmic globulines with molecular 3. the layer of epithelial cells (podocytes) with nu-
weight of about 90 000 daltons are not at all filtered, merous foot processes spanning the outer wall
but few amounts of albumines (m. w. 69 000 dal- of glomerular capillaries. At the surface of
tons) is filtered and reabsorbed in proximal tubules. podocytes is a layer of acid mucopolysaccha-
Glomerular filtration does not differ substantially rides (glycocalyx) filling the gaps between the
from filtration process occuring at arterial end of podocytes. The permeability of capillaries is af-
capillaries anywhere in the body. The driving force fected also by electric charge and the configu-
of ultrafiltration is the hydrostatic pressure of blood ration of particles permeating into the ultrafil-
ensured by heart action. Ultrafiltration of blood trate.
plasma does not require local energy supply. In com-
parison with capillaries in striated muscles is the per- Concerning the electrolyte and fluid metabolism
meability of glomerular capillaries 400 times greater is the glomerular filtration extremely important. It
and the pressure considerably higher. The resulting follows from the fact that kidney filter daily a four-
effective filtering pressure is given by the difference fold volume of the entire body fluid, the fifteenfold
between hydrostatic blood pressure, the oncotic pres- volume of extracelullar fluid, and sixtyfold volume of
sure of plasmic proteins and the pressure inside the blood plasma.
Bowmans capsule. The effective filtrations pressure Glomerular filtration is affected by following fac-
is about 3,3 kPa (25 torr). The ultrafiltrate (primary tors:
4.4. The urine formation 267

Figure 4.5: Glomerular filtration and the tubular function (from Thibodeau GA: Anatomy and Physiology,
1987)
268 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

Figure 4.6: Mechanism for concentrating and diluting urine (from McCance KL, Huether SE: Pathophysiology,
1990)

1. changes of systemic arterial pressure or anatom- infants. In men is the glomerular filtration, calcu-
ically restrained blood supply for glomeruli ated to the body surface higher. Glomerular filtra-
(e.g. in renovascular diseases) tion falls with age. This finding is a general informa-
tion on biologic age of an individuum. Glomerular
2. changes of intrarenal tissue pressure (in obstruc- filtration varies also during the day up to 30 per cent.
tions of ureters, in oedema of kidneys, in per-
inephritis)
4.4.2 Tubular functions
3. changes in oncotic pressure of plasma (e.g. in
Changes occuring in tubules adjust the definitive vol-
dehydration)
ume and composition of urine so, that it complies
4. reduction of filtration surface (involution of with given conditions of organism. The role of the
glomeruli, partial nephrectomy) tubules is the excretion of useless and harmful sub-
stances and to retain the usefuls. The tubular func-
Glomerular filtration depends on age, stage of tions are accoplished by comlex processes of reab-
body hydratation and on body surface. In first sorption and secretion (see figure 4.6, page 268).
four days after the birth are renal functions reduced.
Glomerular filtration is restricted to only 25-50 per
4.4.2.1 Mechanisms of tubular absorption
cent of the filtration values in adults. The concen-
tration ability, the excretion of water, NaCl, phos- Absorption of filtered proteins is performed by
phates and the formation of ammonia are decreased, pinocytosis. Protein molecules enter the tubular cells
thus the newborn tends to have lower plasmic values through celullar membrane. At the cell surface there
of pH and bicarbonates. The tubular apparatus is are stereospecific receptors capable to catch a part of
less efficient and less sensitive to ADH the formation filtered proteins. Other substances pass by passive
of which is reduced. In spite of restrained renal func- diffusion in direction of chemical and electrical gradi-
tions in sucklings and infants, they remain sufficient ents and by active transport against the chemical and
under normal circumstances, especially in breast-fed electric gradients. There is oxygen consumption dur-
4.4. The urine formation 269

ing the active transport (aerobic oxidation). Both, etc.) and potassium into the urine. Hydrogen ions
the active and the passive transports are dependent are secreted by active mechanism exhibiting limita-
on presence of carriers. tion by gradient and probably by time. In proximal
The majority of solutes occurring in ultrafiltrate tubule occurs the secretion of hydrogen ions in large
and being absorbed in tubules are strong or weak amount against a low concentration gradient, and in
electrically charged electrolytes. In absorption of collecting tubules it occurs in small amount against
these substances their size and the transtubular elec- a high concentration gradient.
trical potential play an important role.
Water, chlorides and urea moving passively in di- 4.4.2.3 Maintenance of extracelullar milieu
rection of electrical gradient without need of imme- stability
diate energy supply.
Actively absorbed are: Na+ , K+ , PO3− 4 , amino-
Kidneys maintain the stability of extracelullar mi-
acids, glucose, creatine, sulphate, uric acid and ke- lieu, creating so optimal conditions for the in-
tonic substances. Existence of different transporting tracelullar milieu.
systems for single aminoacids was found. The sodium amount determinates a priori the vol-
ume of extracelullar fluid, because it represents 80 to
90 per cent of osmotic active substances in plasma
4.4.2.2 Mechanisms of tubular secretion
and in interstitial fluid.
Renal transport of substances does not occur only Kidneys perform, in this respect, an irreplace-
from tubular fluid into the interstitium. During the able function in excreting the sodium excess and,
complex excretion process of substances from the on the contrary, if it is needed, retaining it in the
body occurs in kidneys also the transport of sub- body. This function is accomplished in cooperation
stances from peritubular fluid into the tubules. This with endocrine system by mineralocorticoids, pro-
process is termed tubular secretion. Tubular secre- duced in suprarenal cortex. The main ”represen-
tion participates substantially in regulation of acid- tative” of mineralocorticoids is aldosterone ensuring
base balance and in maintenance of isotonia. the sodium economy in kidneys and by it the body
The tubular secretion can be accomplished: fluid volume regulation.
The aldosterone receptors are found in several
1. actively with limited transport maximum (Tm) cells along the entire nephron. The maximal number
of aldosterone receptors occur probably in cells of
2. actively with transport capacity limited by gra-
collecting tubules. Aldosterone stimulates in collect-
dient and time
ing tubules the sodium reabsorption and the potas-
3. passively sium excretion. It is named: the aldosterone de-
pendent sodium resorption and potassium excretion.
The active mechanisms limited by Tm or by gra- This process occurs mainly in medullar portion of
dient and time need energy supply for substance collecting tubules. The aldosterone effect is not sus-
transport from blood into the urine. The passive tained, it operates only according the needs of or-
secretion is accomplished without direct energy sup- ganism. The secretion of aldosterone is governed by
ply, but the concentration and electric gradients are the renin-angiotensin-aldosterone system.
dependent on energy supply. Profoundly investi- A further important hormonal system afecting
gated is the mechanism with limited Tm in case of the renal functions is the kallikrein-kinin system.
paraaminohippuric acid (PAH) excretion. Its excre- Kallikrein is produced in cells of distal tubules, where
tion by glomerular filtration and tubular secretion the highest activity of kallikrein-synthetase has been
raises proportionally with elevation of its concentra- found. Kallikrein converts plasmatic kininogens into
tion in plasma. By exceeding a certain level remains kinis (bradykinin, lysyl-bradykinin, methionyl-lysyl-
the tubular secretion constant and independent of brady-kinin) by proteolysis. It is interesting, that
plasmatic concentration. For that reason is PAH the same enzyme converting angiotensin I to an-
clearence used for determination of renal blood flow. giotensin II desintegrates also the kinins. Generally
By tubular secretion come weak acids and bases is the effect of kinins opposite to the angiotensin ef-
(ammonia, salicylic acid, phenobarbital, penicilin fect. Kinins are potent vasodilators i and in kidneys
270 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

they stimulate the prostaglandin release (PGE2 ). interstitium and intracelullar space has a lower per-
They reduce the vasoconstrictive and antidiuretic ac- meability. Here actually occurs the active sodium
tion of angiotensin. Kinin dilate vas afferens and vas transport by sodium pump.
efferens. Active transtubular sodium transport begins with
Sodium secretion is affected by glucocorticoids, passive sodium transport across the luminal mem-
namely the cortisol, (but also by progesterone). Glu- brane of proximal tubule cells, owing to the electro-
cocorticoids enhance the sodium reabsorption and, chemical gradient between tubule and tubular cell.
to the contrary to mineralocorticoids, they increase Sodium is transported alone or with HCO− 3 anion,
the glomerular filtration. The glomerular ultrafil- or in cotransport with aminoacids phosphates, glu-
trate volume diminishes in absence of glucocorticoids cose, uric acid and other substances. The cotrans-
and under the water loading the excretion of exces- port with sodium enables some substances to cross
sive water is decreased, owing to the enhanced per- the luminal membrane even against the concentra-
meability of distal tubules to water. Progesterone tion gradient leading to their increased celullar con-
is an antagonist of tubular effects of aldosterone. It centration. They move subsequently in direction of
increases the sodium excretion by spirolactone mech- concentration gradient by passive transport entering
anism. It reduces the aldosterone effect directly in the peritubular space and the peritubular capillaries.
renal tubules. The decreasing Na+ gradient between the tubule and
Sodium reabsorption with its accompanying ion the tubular cell is caused by sodium pump, the en-
(mainly Cl− ) occurs in proximal tubule followed zyme Na+ –K+ –ATP-ase, converting the high-energy
by water since epithelium is permeable to water. binding of anorganic phosphorus in ATP to electro-
Sodium salts represent 80 per cent of solutes in ultra- chemical gradient. By the hydrolysis of one ATP
filtrate. In addition, the sodium reabsorption func- molecule three Na+ are transported from the cell and
tions as pumping system for transport of other sub- two K+ into the cell. So a low celullar sodium ion
stances. About 60 to 75 per cent of sodium filtered concentration is maintained in the cell in comparison
in proximal tubule is reabsorbed with accompanying with the sodium concentration in tubule (chemical
ions, chiefly with chlorides and bicarbonates. It is an gradient) and high concentration of K+ which flows
isoosmotic process occuring with equivalent volume from the cell according its chemical gradient. Ow-
of water. Thus, the tubular fluid is in the entire prox- ing to this, becomes the cell inside electronegative
imal tubule isonatraemic and isoosmotic with plasma against its surroundings (-70 to -90 mV).
(sodium concentration equals 140 mmol/l, osmolality By the transtubular sodium and relevant anion
about 300 mosm/l). If poorly resorbable but osmoti- transport (Cl−, HCO− 3 , aminoacids, etc.) into the
cally active substances, e.g. mannitol enter the tubu- intercelullar space and the peritubular labyrinth the
lar fluid, the sodium and water reabsorption contin- so called stationary osmotic gradient is created. But,
ues, but a part of water is retained in the tubular it is immediately disturbed by retrograde diffusion
fluid to keep this fluid isoosmotic with the interstitial through intracelullar space into the tubule and by
fluid. By this way can be the sodium concentration water diffusion into the peritubular space. Following
in tubular fluid reduced even to one half. the primary active solute reabsorption an appropri-
According the filtered sodium load, concomit- ate volume of water is reabsorbed, hence the osmotic
tantly occurs its reabsorption in tubules. During concentration in tubule or in peritubular space does
larger changes of glomerular filtration is this com- not change. The hydrostatic pressure rises in per-
pensation usually not sufficient (glomerulo-tubular itubular space owing to the water accumulation. The
dissociation). As mentioned above, sodium is fluid is absorbed from the peritubular space into the
transported passively from tubules independently of peritubular capillaries. This process depends on the
metabolic energy, its active transport is dependent hydrostatic and the colloidal osmotic pressure ratio.
of energy supply. The cells of proximal tubules are The filtered potassium is almost completely reab-
functionally polarized: the permeability of luminal sorbed in proximal tubule. Proximal tubule is, in
membrane portion is more permeable to the passive addition, the site of active resorption of other sub-
sodium flow from the tubular lumen into the cell. stances (calcium, magnesium, glucose, aminoacids
The portion of cell membrane oriented towards the etc.) and from pharmacological point of view the
4.4. The urine formation 271

site of important carrier mechanisms for acids and sors of vitamin D active form are synthesized in
bases. skin, or supplied by food intake, and hydroxyl-
Calcium reabsorption occurs at the same sites as ized in the liver to 25-hydroxycholecalciferol. Fur-
the sodium reabsorption: mainly in the proximal ther hydroxylation occurs in kidneys, resulting in l,
tubule. About a half of plasmatic calcium only is 25-dihydroxychole-calciferol formation. This active
soluble and filtrable, the rest is bound to plasmatic form of vitamin D stimulates phosphate and calcium
proteins. In ultrafiltrate and in plasma an equal ratio absorption from the gut and the bone resorption.
between calcium and sodium ions is maintained. The 1,25-dihydroxycholecalciferol inhibits probably
the phosphaturic effect of parathormone in renal
Total plasmatic calcium concentration is 2,25 to
tubules. The vitamin D hydroxylation may be af-
2,75 mmol/l. A part of it is bound to proteins, an-
fected in renal disorders.
other part is present in diffusible form as free Ca2+
ions and its compounds like phosphates, citrates and Total plasmatic magnesium concentration is 0,7
bicarbonates. About 0,5 to 5,0 per cent of filtered to 0,9 mmol/l. About one third of this amount is
calcium loading is excreted by urine. Tubular reab- present in undiffusible form. The diffusible portion is
sorption depends on filtered calcium loading. Cal- present in form of free magnesium ions, Mg2+ . From
cium is actively transported across the peritubu- 3 to 6 per cent of filtered load is excreted by urine.
lar membrane by Ca2+ –Na+ –ATP-ase. Parathor- The magnesium excretion is increased by parathor-
mone enhances the reabsorption in the distal tubule. mone, calcitonin, vitamin D and glucocorticoids.
Thyreocalcitonin and cortisol decrease the calcium Substances completely reabsorbed in proximal
reabsorption. Parathyroidectomy leads to enhanced tubule are designated as treshold substances, if their
calcium excretion by urine. Thyroxine stimulating supply in the glomerulus does not exceed a certain
the bone tissue metabolism induces hypercalciuria. value (threshold). They include glucose, aminoacids,
Under physiological circumstances about 90 per phosphates, etc. Really true threshold substances
cent of filtered phosphate is reabsorbed in proxi- and true substances without renal threshold do not
mal tubules. Parathormone enhances phosphate ex- exist. Glucose is a typical threshold substance.
cretion by inhibition of its reabsorption. Increased Its reabsorption occurs almost quantitatively in the
parathormone secretion may cause that less than proximal tubule. Glucose is almost completely re-
15 per cent of phosphates is reabsorbed. Optimal absorbed, without residue, if its tubular load and so
phosphate excretion is achieved by progressive reduc- its plasmatic concentration do not exceed the renal
tion of phosphate reabsorption in proximal tubules. treshold for glucose. When the glucose plasmatic
Rise in parathormone release during decrease in concentration has normal value (90 mg per cent, or
nephron number is the major regulating factor of cca 5 mmol/l) about 110 mg (0,6 mmol) of glucose is
phosphate excretion. Inspite of perfect regulation a reabsorbed per minute.
transitory rise of plasmatic phosphates occurs caus- The amount of reabsorbed glucose can be calcu-
ing a slight diminution of ionized calcium level and lated from glomerular ultrafiltrate volume and glu-
a rise of parathormone release. A balance is at- cose concentration in plasma (GF.P g). Tubular cells
teined, and disturbed again by increase of plasmatic are able to reabsorbe as much as three times more if
phosphate level. This repeated process results in all nephrons are working at maximal capacity. Most
nearly permanent increase of parathormone level. of glucose is reabsorbed in the first half of proximal
Progressive loss of nephrons leads to an insufficient tubule. Glucose threshold, that means the maximal
parathormone degradation in kidneys. Finaly, when amount which could be reabsorbed by tubule back
the glomerular filtration falls under 25 ml/min., the into the blood is termed the transport maximum
phosphates begin to be retained in organism. Sec- (Tmg ). It can be calculated from the difference be-
ondary parathyroidism develops, associated with re- tween the amount of filtered glucose and the amount
nal osteodystrophy. Destruction of functional re- of glucose excreted by urine.
nal parenchyma impairs the phosphate, calcium and
bone metablism. Tmg = (GF.P g) − (V.U g)
Kidneys play an important role in conversion of
vitamin D to its active metabolites. The precur- GF is the amount of glomerular ultrafiltrate, P g and
272 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

U g are the glucose concentrations in plasma and in dissociated form. If the pH falls up to 4,7 only 5 per
urine, and V is the urine volume per minute. cent of uric acid is dissociated. In these conditions
Tmg provides ionformation about the total func- may the uric acid undergo the process of crystal nu-
tional capacity of tubular cells to transport glucose. cleation and urate stones formation. Urate crystals
The determination of Tmg is technically rather dif- (calculi) are formed from uric acid easier when the
ficult because such a glucose concentration has to sodium concentration is higher. The uric acid prae-
be attained and maintained which leads to glyco- cipitation can be prevented and inhibited by water
suria. Renal threshold is changing indirectly with diuresis.
the glomerular filtration and directly with Tmg . The most important end-product of protein meta-
bolism is the urea. Urea is per se not very toxic
There is a linear relation between the glucose for the organism. During uraemia is its level an
transport and sodium reabsorption in proximal indicator of concomitantly retained toxic products
tubule. This relation can be observed also in re- of metabolism. Its plasmatic level is usually not
absorption of some aminoacids. The sodium reab- stable, depending on food protein intake and its
sorption in proximal tubule depends more upon the metabolic turnover. Under normal circumstances
glomerular filtration than on reabsorption of glu- can the plasmatic urea level vary from physiologic
cose. In the case when the tubular sodium load is value (4,5 mol/l) up to twice higher values. Clear-
larger, the proximal tubule reabsorbes more sodium. ance of urea in healthy subjects is about 50 to 60 per
As mentioned above, the reabsorption capacity of cent of filtered urea amount. The clearance of urea
tubules is so large, that the tubular load must exceed is evidently influenced by glomerular filtration and
three times the filtrated load to saturate the tubu- by the rate of tubular fluid flow. During the dehy-
lar reabsorption capacity to such a degree, that the dration and owing to the decreased diuresis falls the
excess of glucose could leak into the urine. The trans- clearance of urea much more than the inulin clear-
port maximum of glucose depends partly of sodium ance. For that reason can the urea clearance be
and water reabsorption. As the glomerular filtra- an approximate indicator of renal function distur-
tion increases, so raises the sodium, water and glu- bances. Nevertheless, it does not enable to discern
cose reabsorption. But, if the tubular glucose load between the haemodynamically caused disorders and
markedly rises owing to the high plasmatic glucose renal disturbances. The urea reabsorption is con-
level, its reabsorption increases considerably, even sidered to be a passive process and is explained by
in comparison with water and sodium reabsorption. the mechanism of retrograde diffusion or by solvent
But, if the Tmg is attained, the glucose excretion drag. The urea reabsorption depends not only of its
into the urine begins. The mechanism of glucose concentration in tubular fluid and of transtubular
excretion is not well understood. It could be very retrograde water diffusion, but also of tubular per-
probably performed by active transport. The fact meability to urea and of tubular fluid volume. The
that cyanides, acidosis and hypoxia inhibit the glu- major factor is problably the concentration gradient
cose transport might be evidence of this assumption. of urea between the tubular fluid and surrounding
Kidneys play an important role in the uric acid ex- interstitium. If the membrane of tubular cells is in-
cretion although the uric acid constitutes only 5 per tact, urea diffuses isoosmotically together with wa-
cent of the global amount of nitrogenous substances ter. The same mechanism works probably also with
metabolism products. The uric acid excretion is other substances.
especially important in hyperuricaemic syndrome.
Uric acid is freely filtered in glomeruli like other or- 4.4.2.4 Na+ and Cl– reabsorption in the loop
ganic acids. In addition it is secreted in proximal of Henle by counter-current multipli-
tubule and further partly reabsorbed. In compari- cation system
son with inulin and creatinine clearance is the clear-
ance of uric acid low, only 12 ml/min. (clearance of In the process of urine concentration participate,
creatinine is about 120 ml/min.). Of practical im- above all, the descending and ascending limbs of
portance is the fact, that undissociated uric acid is Henle’s loop, the collecting tubule and vasa recta.
poorly soluble. The solubility of uric acid is reduced The driving force of the urine concentration process
by acidosis. At pH 7,4 is 98 per cent of uric acid in is the active sodium transport from the ascending
4.4. The urine formation 273

Figure 4.7: Bicarbonate exchange

limb of Henle’s loop into the surrounding intersti- the counter-current system, thus a concentration dif-
tium. Because this segment of nephron is imperme- ference arises increasing gradually towards the bend
able to water, water can not diffuse with sodium. of the loop and atteining multiple values of single
The descending limb of Henle’s loop is in presence partial effects. From thermodynamic point of view
of ADH permeable to water. Provided the concen- this is a process of extraordinary economy, requiring
tration gradient is present, water is sucked up into minimum of energy in comparison with the energy
the interstitium. The osmotic gradient between the amount which would kidneys expend during the pro-
ascending and descending limbs of Henle’s loop resp. cess of the urine concentration to its definitive con-
the interstitium may constitute only a small part of centration performed in a single step.
the concentration gradient between the plasma and
the definitive urine providing it operates along the At the end of ascending limb of Henle’s loop be-
entire loop of Henle. The tubular fluid is flowing comes the fluid again hyposmotic, its sodium concen-
namely in both limbs of Henle’s loop in opposite di- tration being in comparison with the plasmatic con-
rection, thus the water diffuses permanently from the centration (140 mmol/l) by 100 mmol/l lower. This
ascending limb of Henle’s loop into the interstitium fluid enters the distal tubule with its wall again per-
being always little more hyperosmotic. This is main- meable to water, enabling to attain the osmotic bal-
tained despite the low osmotic gradient owing to the ance, that means, equilibrating the osmotic concen-
permanent water diffusion and a progressive increase tration gradients at the end of the distal tubule be-
of tubular fluid osmolality towards the papilla. On tween the tubular fluid and the isomotic interstitium.
the contrary, the fluid flowing in the ascending limb The water diffusion and further sodium reabsorption
of Henle’s loop has always a little higher osmolality result in decrease of tubular fluid volume by a half in
than the surrounding interstitium. This fact sup- comparison with the volume in loop of Henle. Tubu-
ports (stimulates) sodium transport into the intersti- lar fluid flows then in collecting ducts towards the
tium. Many of these partial effects are multified in papilla, passing regions with rising sodium concen-
tration in interstitium. This hyperosmotic milieu,
274 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

in presence of ADH, sucks the water from collecting Sufficient supply of hydrogen ions to the exchange
tubule untill the appears of osmotic balance. reaction requires considerably higher rate of CO2 hy-
In addition to the counter-current exchange sys- dratation than is the rate during the spontaneous
tem contribute also the vasa recta to diluting and course of this reaction. The needed hydratation rate
concentrating functions of kidneys. As their wall is ensured in the cell by action of the enzyme car-
is permeable to water and osmotically active sub- bonic anhydrase.
stances a water transfer (shift) from the lumen into During the bicarbonate reabsorption is H+ ex-
the interstitium occurs in the descending portion of changed for Na+ . In the tubular cell Na+ conju-
these capillaries. In their ascending part move water gates with HCO− 3 and returns into the blood in form

and osmotically active substances in opposite direc- of NaHCO3 .

tion. The counter-current diffusion is diminished in Hydrogen ions react in urine with HCO− 3 and the

vasa recta when the medullar blood flow raises. This created H2 CO3 is rapidly decomposed to CO2 and
situation may be induced by application of drugs water. CO2 rediffuses from urine and is used by tubu-
causing vasodilation in medullar vessels. This is ob- lar cell for H2 CO3 formation or is exhaled by lungs.
served also in shock when the glomerular filtration The exchange of hydrogen ions for sodium ions con-
decreases but the medullar blood flow remains un- tinues even when the entire amount of bicarbonate
changed. Under physiological circumstances the effi- is exhausted.
ciency of counter-current diffusion in vasa recta can During metabolic processes the phosphoric acid is
be diminished when the osmotic concentration gra- formed and neutralized to neutral salts. The excre-
dient between renal cortex and medulla becomes de- tion of phosphates in form of neutral salts might lead
creased. to sodium depletion and owing to this to HCO− 3 de-
crease. The hydrogen ion reacts in urine with the
The H+ secretion in exchange for Na+ occurs prob-
buffer system, mainly with Na2 HPO4 changing in
ably along the entire tubule. This process is extraor-
NaH2 PO4 . Na+ reacts in the cell again with HCO−
dinary important for homeostasis and it results in 3
and increases the alkali reserve of the organism.
bicarbinate reabsorption, in acidifying of urine and
In absence of bicarbonate and phosphate buffers
excretion of fixed anions in combination with NH+ 4
is H+ exchanged for Na+ of a neutral salt (NaCl
instead of Na+ . Tubular cells secrete hydrogen ions
above all). The HCl formed would acidity urine (rise
which are simultaneously exchanged for other cations
the hygrogen ion concentration) to such a degree to
on the luminal poles of cells. For each hydrogen
make the further exchange impossible (the hydrogen
ion enters one sodium ion the cells. In proximal
ion transport can surmount maximally a difference of
tubules are daily about 4 000 mmol H+ and in the
about 3 pH units). Another mechanism however be-
distal tubule concomitantly further 500 mmol of hy-
gins to operate. The renal cells sythesize ammonia,
drogen ions secreted. This amount of hydrogen ions
mainly from aminoacids and from glutamine. Am-
is daily secreted in excess. If 60 mmol of free acids in
monia is easily soluble in lipids and therefore freely
1,5 l is excreted daily, its pH value would fall to 1,4.
crosses the cell membrane. It enters into the tubu-
The pH value of urine never falls below 4,5.
lar fluid by the mechanism of non-ionic diffusion and
From this point of view is the role of kidneys in bi- forms here with H+ ammonium NH+ 4 . The ammo-
carbonate resorption very important (see figure 4.7, nium ions are poorly liposoluble, thus they do not
page 273). The filtered bicarbonates are actively, rediffuse, but are excreted by urine. So H+ as well
almost completely, reabsorbed in proximal tubules. as NH3 disappear from urine and further exchange of
The bicarbonate renal threshold is identical with hydrogen ion for sodium ion is again possible, as well
their plasmatic concentration, being under normal as further NH3 diffusion into the urine. In this way
conditions 22 to 25 mmol/l. The source of hydrogen the renal cells resorb a considerable amount of Na+
ions exchangeables for sodium ions is the carbonic originating from neutral salts of urine and retake it
acid in the tubular cell. It is formed by following into the blood in form of bicorbonate.
reactions: Anions of strong acids in tubular fluid are excreted
in form of ammonium salts with concomitant sparing
H2 O + CO2
H+ + HCO−

H2 CO3 3 the sodium and bicarbonates.
4.5. Disturbances of glomerular functions 275

The most outstanding is the rise of plasmatic concen-

tration of substances with renal excretion depending
4.5 Disturbances of glomeru- chiefly on their filtration (urea, creatinine). Between
the clearance value of creatinine and its plasmatic
lar functions concentration is not a linear, but a hyperbolic rela-
tion. If the glomerular filtration values are low, even
a small further decrease of filtration results in rela-
tive high creatinine plasmatic concentration. Thus,
in progressive renal failure yet a small reduction of
4.5.1 Decrease of glomerular filtra- filtration leads to a rapid raise of creatinine plas-
tion rate matic concentration. Vice versa the normal value
of creatinine plasmatic concentration does not ex-
Reduced glomerular filtration rate is one of the most
clude disturbance of glomerular functions. Similar
important consequences of glomerular function dis-
relation between the glomerular filtration and plas-
turbances. Decreased glomerular filtration rate oc-
matic concentration counts also for urea. If the
curs mainly:
decrease of glomerular filtration is caused haemo-
1. during the fall of systemic arterial blood pres- dynamically the urea plasmatic concentration raises
sure (anatomic restriction of blood flow to more rapidly than the creatinine concentration. In
glomeruli e.g. in renovascular diseases) addition, the urea plasmatic concentration depends
more on protein turnover than the creatinine concen-
2. when the intrarenal tissue pressure is elevated tration. During the protein katabolism rises the urea
(during the obstruction of ureters, oedema renis, plasmatic concentration already when the glomerular
in perinephritis with stiffened capsula renis etc.) filtration rate has yet normal values and vice versa
in patients with chronic renal failure during low pro-
3. when the oncotic pressure of plasma is increased
tein intake may the plasmatic urea concentration de-
(during dehydratation)
crease without alterations of glomerular filtration.
4. if the filtration surface is reduced (destruction Therefore is the plasmatic creatinine concentration
of glomeruli, partial nephrectomy) a better indicator of glomerular filtration than the
urea concentration.
Decrease of glomerular filtration rate of renal ori- When the glomerular filtration decreases more
gin is usually due to destruction of glomeruli being than to one quarter of the normal value, in addi-
replaced by connective tissue. During the progressive tion to the progressive creatinine and urea retention,
glomerular destruction (chronic glomerulonephritis, phosphate retention, and in terminal stage occurs
pyelonephritis, nephroangiosclerosis etc.) functional also retention of sodium, chlorides, sulphates, mag-
and morphologic compensation is developing by the nesium, potassium, uric acid, phenols and other sub-
hypertrophy of remaining functioning nephrons. De- stances.
crease of glomerular filtration rate can occur ow-
ing to the fall of effective filtration pressure even if
the number of functioning nephrons is not reduced. 4.5.2 Alterations of glomerular mem-
This functionally caused reduction of glomerular fil- brane permeability
tration rate is distinguishable from the anatomi-
cally caused decrease of glomerular filtration con- Glomerular disturbance can be manifested by in-
nected with irreverisible elimination of a larger num- creased permeability of glomerular membrane. Un-
ber of glomeruli. During the glomerular filtration der physiological circumstances less than 200 mg of
decrease from functional causes are the fluctuations proteins are excreted daily by urine. The very small
of glomerular filtration values usually retained. The amount of proteins leaking across the glomerular
fluctuation of glomerular filtration values during the capillary wall into the ultrafiltrate are removed in
day is a physiologic sign of well functioning kidneys. tubules by pinocytosis. One part of proteins oc-
Decreased glomerular filtration rate is manifested curing in the definitive urine originate directly from
by retention of nitrogenous substances in organism. kidneys. In the cells of Henle’s loop a glycoprotein
276 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

(uromucoid), an alfa-globulin with molecular weight filtration of plasmatic proteins or by a transient in-
more than 70 000 daltons is formed. 25 mg of this crease in glomerular membrane permeability due to
protein are excreted into the urine in 24 hours. It hypoxia. In these cases is the composition of protein
is produced also in cells of distal tubules and col- fractions in urine similar with that in plasma. This
lecting tubules. This glycoprotein (Tamm-Horsfall’s type of proteinuria can be observed following hard
mucoprotein) constitutes the main component of uri- physical exertion, long lasting exposure to cold and
nary casts occuring under pathologic circumstances. after s.c. vegetative crises (colics, epileptic seizures
When the permeability of glomerular membrane is etc.). A transient, reversible glomerular damage and
increased larger amount of plasmatic proteins passes proteinuria may occur during febrile conditions.
into the urine than the tubules are capable to reab- Preglomerular proteinuria is a condition without
sorbe. This is the way the proteins are passing into presence of renal disturbance. The underlying cause
the urine, first albumins, and if the impairment of is the filtrating of atypical proteins with smaller
glomerular basement membrane is more severe the molecular weight which may appear in blood (myo-
globulins. globin, haemoglobin, products of fibrin degradation
The glomerular permeability to proteins is deter- etc.). In multiple myeloma the light chains of im-
mined by the structure of single capillary layers. munoglobulins occur in urine, exhibiting positive re-
Substances with molecular weight less than 70 000 action in protein determination in urine by boil-
daltons can cross the glomerular capillaries. The ing (s.c. Bence Jones protein with molecular weight
basement membrane operates as a gross filter and 45 000 dalton).
the epithelial cells as fine filter. In addition to this
The lowmolecular proteinuria occurs also in amy-
the permeability of glomerular filter to a given sub-
loidosis. Proteinurias due to haemodynamic alter-
stance depends not only on its molecular weight, but
ations are considered to be of preglomerular charac-
also on the configuration of its molecule. So can
ter, because of true renal disturbance absence (pro-
some polysaccharides cross the glomerular filter and
teinuria in heart failure). Also the haemoglobin can
get into the urine, if they are sufficiently flexible.
be excreted by urine without presence of pathologic
The electric charge of these structures participates,
alterations in glomeruli. The renal threshold for
to some degree, in the filtration process in glomeruli.
haemoglobin is about 150 mg/dl. By exceeding this
The endothelial cells, basement membrane, epithe-
plasmatic concentration haemoglobin passes into the
lial cells have in the region of pores a strong negative
primordial urine. During a massive damage of ske-
charge repulsing the negatively charged proteins.
latal muscles myoglobin may occur in urine.
The glomerular permeability is partly influenced
by the glomerular filtration rate. If the glomerular Glomerular proteinuria. The underlying cause of
fitration rate is decreased the contact time of pro- this type of proteinuria are disturbances of glomeru-
tein molecules with the capillary wall becomes pro- lar filter. If they are not severe only proteins with
longed. Decrease of filtration pressure may cause en- lower molecular weight pass into the urine. The oth-
largement of pores through which the blood plasma ers are not filtered. Thus in this condition mainly
ultrafiltration occurs. In pathologic alterations can the albumin is in urine. In clinical praxis is this
these factors concomitantly exert their influence, or type of proteinuria usually named the selective pro-
can combine with furhter factors. teinuria. When the damage is more severe proteins
with high molecular weight are filtered into the urine
(e.g. IgG with molecular weight 150 000 daltons).
4.5.2.1 Proteinuria Glomerular proteinuria occurs most frequently in all
The condition where the amount of proteins appear- forms of glomerulonephritis. The filtered proteins
ing in urine exceeds 0,2 g daily is named proteinuria. are partly reabsorbed in the tubules, however the
This finding signalizes a potential renal disease and filtered amount exceeds the absorptive capacity of
initiates a thorough examination of renal functions. tubules, hence the protein passes into the definitive
Nevertheless, the proteinuria per se need not indi- urine.
cate a renal disease. It may be observed also in Tubular proteinuria The tubular proteinuria is a
healthy subjects. These so called functional or in- pathologic condition where the tubules are incapable
nocent proteinurias and are explained by enhanced to reabsorbe the small amount of proteins with low
4.5. Disturbances of glomerular functions 277

molecular weight filtered in glomeruli. More fre- derlying mechanism of this type of proteinuria could
quently however, the underlying cause of the tubular be the compression of inferior vena cava by the liver
proteinuria is a direct impairment of tubules (toxic against the lordotic spine, with retrograde condution
lesions of tubular cells caused by heavy metals) or a of this pressure to the renal veins causing renal con-
congenital defect of enzymatic system participating gestion and proteinuria; or leaking of lymph into the
in protein tubular reabsorption. urine, are not longer accepted. In most cases, how-
An intensive reabsorption of proteins with low ever, minute lesions of glomerular membrane can be
molecular weight takes place in tubules, whereby the observed by electron microscopy, hence the ortho-
kidneys participate significantly in the metabolism of static proteinuria is thought to be rather the conse-
polypeptides and protein hormones (e.g. angiotensin, quence of glomerulonephritis.
insulin, etc.).
Under pathologic circumstances in proteinurias of
Tubular proteinuria is usually not very substantial. renal origin glomerular basement membrane lesions
The protein loss does not exceed 2 to 3 g/24 hours. are found by electron microscopy. The portion of
During chronic renal insufficiency a combined form proteins with low and high molecular weights in urine
of proteinuria occurs. The postrenal proteinuria is depends on the type of morphologic lesions. If the
the condition in which proteins from renal intersti- electrophoretic, or immunoelectrophoretic findings of
tium appear in the definitive urine. It occurs usually protein fractions do not differ from the plasmatic
during peylonephritis when the proteins of inflam- protein fractions – the condition is considered to be
matory exudate are present in urine. the nonselective proteinuria (e.g. in membraneous
Proteinuria need not to be a permanent sign of glomerulonephritis). In selective proteinuria more
renal impairment. In clinical praxis is rather a tran- portions of proteins with lower molecular weight
sient proteinuria observed being usually not associ- are found in urine (e.g. in lipoid nephrosis in chil-
ated with a persistent renal impairment. Apart from dren). The above mentioned functional proteinurias
the mentioned causes, proteinuria may be due to in- are also of selective type.
fectious diarheic diseases with dehydratation. The
underlying cause is probably the direct renal damage The concomitant finding in proteinuria of any ori-
by microbial toxins combined with haemodynamic gin is usually the presence of hyaline cylinders (cylin-
changes due to dehydration. Proteinuria can be ob- druria). The casts (cylinders) are formed by protein
served also during viral or staphylococcal infections. praecipitations in distal tubule where the process of
The febrile proteinuria usually disappears after the urine concentration occurs. The acidity of urine fa-
primary disease is healed, or when the fever falls to cilitates the change of filtered protein in tubules into
normal values. its colloidal form. Thus, the cylinders are de facto
Proteinuria can be seen also following hard phys- the casts of tubules. Cylinders are the single ele-
ical exertion and exposure to extreme cold. The ments in urine originating certainly in kindneys, not
occurence of proteinuria after vegetative crises is in urinary outflow tract.
almost regular (colic, epileptic seizure, myocardial Under physiological circumstances the proteins
infarction). It appears also during hypertension, with low molecular weight are filtered into the
and pregnancy associated with various complications glomerular ultrafiltrate. Their molecular weight
(pre-eclampsia, eclampsia, abruptio placentae etc.). is usually lower than 40 000 daltons, most fre-
Decreased renal blood flow and the renal hypoxia is quently the microglobulins (with m.w. 11 600 dal-
most probably the underlying cause of proteinuria in tons), lysozyme (with m.w. 14 000 daltons) or light
heart failure. chains of proteins (m.w. 22 000 daltons) are very eas-
If a persistent proteinuria is found with further ily filtered, yet they are absent in the definitive urine,
pathologic renal findings, it indicates usually a severe or only trace-amounts of them are found, because
renal lesion. they are very efficiently reabsorbed in tubules. Dis-
Proteinuria observed in connection with upright eases affecting selectively more the tubules than the
position is the orthostatic proteinuria. It occurs in glomeruli lead to an excessive excretion of small pro-
younger subjects usually when a higher degree of teins into definitive urine, without enhancing the al-
lumbar lordosis is present. Suggestions, that the un- bumin excretion.
278 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

4.5.2.2 Haematuria or oval fatty corpuscules. In all inflammation pro-

cesses affecting the nephron leucocytes and epithelial
The term haematuria designates the presence of cells can appear in definitive urine. These cells may
blood in the definitive urine. According to blood form cylinders (casts).
amount it can be micro- or macrohaematuria distin-
guished. 4.5.3 The involution of nephrons
Isolated haematuria. Bleeding from urinary tract Renal diseases frequently lead to the involution of
is termed isolated haematuria. In isolated haema- nephrons manifested by decrease of glomerular fil-
turia, appart from erythrocytes, no other cells are tration rate. Despite of this fact certain balance
found in urine, proteinuria and renal casts are not can be preserved between the sodium intake and
present. If during the urination blood appears at its excretion. This can be ensured only when some
the beginning, it is usually of urethral or prostatic compensatory mechanisms are employed. When the
origin. glomerular fitration rate is decreased because the
Very frequently the underlying cause of isolated number of nephrons has been reduced and when
haematuria is the nephrolithiasis, neoplastic pro- the excretion of sodium amount is maintained – this
cesses, trauma, tuberculosis of urinary tract and pro- can be achieved only if every ”healthy” nephron fil-
statitis. It occurs also in primary renal diseases. If ters more sodium. It means that during decreased
the isolated haematuria is observed it is necessary to glomerular filtration, the sodium excretion, calcu-
exclude the haemocoagulation disorders, the throm- lated for one nephron, raises.
bocytopenia and the infections of urinary tract. The involution of functional nephrons does not re-
Haematuria in renal diseases The haematuria in main without consequences in interstitium. The hy-
urinary tract infections is accompanied usually with drostatic and oncotic pressures can not act as under
pyuria (finding of pus in definitive urine). The acute normal circumstances. This results in suppression of
cystitis or urethritis in women use to be accompa- sodium and water reabsorption in tubules. The rise
nied with rather massive haematuria and a moderate of hydrostatic pressure in peritubular capillary net-
pyuria. work may reduce the reabsorption in proximal seg-
The blood can get into the urine from any part ments of nephrons. This can be preceded by sys-
of nephrons. The erythrocytes may form cylindric temic arterial hypertension – a frequent finding in
shapes in tubules, being a convincing evidence that renal failure.
they originate in an haemorhage in nephrones. The When the glomerular filtration is reduced by invo-
haemorhage from nephrone combined with glomeru- lution of nephrons the urea, creatinine and organic
lar proteinuria is always evidence of a very severe acids accumulation develops. These substances are
renal disease. The renal diseases where both haema- excreted by glomerular filtration and tubular secre-
turia and proteinuria are not present or if protein- tion. When the decrease of glomerular filtration is
uria alone, without haematuria is found, have a bet- severe the rise of organic acids level is considerable.
ter prognosis than conditions where both symptomes Organic acids can pass into the proximal tubules by
are present simultaneously. osmosis. The increased urea concentration in ultra-
It is always necessary to exclude an other causal filtrate may lead to the osmotic diuresis.
relation of haematuria with proteinuria. There is During the osmotic diuresis the sodium excretion
however a possibility of both disorders combination is enhanced by reduction of its reabsorption. Some
without mutual correlation. Thus, nephrosclerosis forms of chronic renal failure are associated with
with hypertension can be the cause of proteinuria a considerable loss of salt. It occurs in nephropa-
and the present haematuria can be of extrarenal ori- thy, chronic pyelonephritis, tubulointerstitial dis-
gin. It can originate in urinary outflow tract, not in eases. These diseases are associated with a large de-
kidneys. In urine examination however, occur both struction of renal medulla and interstitium and with
findings in simultaneously although the underlying a minor impairment of cortex renis and of glomeruli.
mechanisms are different. Nevertheless, the tubular reabsorption is consider-
Following a severe albuminuria or dehydration the ably impaired, less sodium is reabsorbed from the
hyaline casts can appear in definitive urine. They can filtrated amount, hence the sodium loss of organism
combine with lipoid particles forming fatty cylinders becomes larger.
4.6. Acute renal failure 279

direct action of ethanol on muscles might be father

causes of myoglobin release. The myoglobin itself is
4.6 Acute renal failure not nephrotoxic. To the development of acute re-
nal failure contribute the myoglobin praecipitation
in tubules and concomitant hypotension.
The intravascular haemolysis may result in acute
Use to be defined as a rapid impairment of re- renal failure. Haemoglobin is not a nephrotoxic sub-
nal functions leading to accumulation of nitrogenous stance. In the pathogenesis of acute renal failure
substances in the body. The underlying causes can have more importance substances released from the
be prerenal or renal, originating in parenchymal le- erythrocyte stroma and the concomitant hypoperfu-
sions, and postrenal. According to the occurence, sion of kidneys.
these conditions are most frequently associated with From point of view of pathogenesis the acute re-
renal hypoperfusion, with obstructive uropathy or nal failure can be divided into tubular and vascu-
with the renal disease per se. This situation develops lar type. In the tubular type the cylinders and the
in acute glomerulonephritis. The acute, reversible re- wastage are considered to be the underlying cause of
nal failure occurs rather frequently following surgical urine outflow obstruction. The pressure in tubules
intervention or trauma. Renal failure is usually asso- rises, is transferred into the glomeruli and reduces
ciated with the drug treatment of an other disease. or stops there the filtration process. In the vascular
It occurs rarely during the pregnancy. The most fre- form a considerable constriction of afferent arteri-
quent underlying cause is renal ischaemia following oles is suggested. It can be induced by stimulation
a rapid haemorrhage, during a severe fall of circulat- of nerves, by angiotensin II, or by catecholamines. In
ing blood volume, hypotension during surgery, car- this case the decrease of glomerular filtration would
diogenic shock, during surgical intervention with in- dominate. In fact such isolated disturbances do not
terrupted renal blood flow. The duration of renal occur. However, it is to realize, that principally two
hypoperfusion is the limiting factor. The hypoperfu- most important pathogenic factors exist, determin-
sion can result in acute tubular necrosis. ing the course and outcome of acute renal failure:
Several nephrotoxic substances may be the un- the vascular and the tubular factor.
derlying cause of acute renal failure: heavy metals The histological findings support the conception
and organic solvents – occuring in our milieu and of two most important pathogenetic factors. The le-
many drugs. At present is the acute renal failure sions observable by microscope are of various degree
observed after treatment e.g. with aminoglycosidic and considerably variable. Tubular necrosis, tubu-
antibiotics. Usually is the nephrotoxic effect of these lar cylinders, interstitial oedema, interstitial cellular
antibiotics associated with concomitant application infiltration, enlarged or narrowed tubules can be ob-
of other nephrotoxic substances and with very effec- served. The histological alterations may be of two
tive diuretics. Some anaesthetics and contrast media types:
used in radiological investigation of kidneys and its
outflow tract can lead to acute renal failure. Their 1. Diffuse necrosis of proximal tubules with intact
effect is malignant, chiefly in patients with diabetic basement membrane
nephropathy or in dehydrated patients (where they 2. Minor necrotic alterations occuring along the
are absolutely contraindicated). entire nephrons
The acute renal failure may be the result of an ex-
cessive myoglobin release in the blood. The underly- Most outstanding changes are found in distal
ing mechanism is often the rabdomyolysis following tubules on the margins between cortex and medulla
the trauma (crush syndrome). Non-traumatic rab- renis. Disruptions of basement membrane can be ob-
domyolysis may lead to acute renal failure during served. Between the histological alterations and im-
the heat shock, after extreme physical exertion, in pairment of renal functions do not exist almost any
hypokalaemia, hypophosphataemia, during the hy- correlation. After healing some minute alterations in
perlipidaemia, treatment by fibrates, or in genetic histological picture may be found.
defects. The ischaemia in muscles results in myo- As mentioned at the beginning, the impairment
globin release. Overdosage of some drugs, infections, of renal functions can be induced by praerenal, re-
280 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

nal causes, or postrenal causes. The most frequent The acute renal failure leads to the impair-
praerenal cause is the hypoperfusion and the most ment of erythropoiesis resulting in normocytic nor-
frequent postrenal cause is the urinary outflow tract mochromic anaemia. The number of leucocytes rises
obstruction. The glomerulonephritis and interstitial owing to the tissue damage. The number of thrombo-
nephritis may also lead to the impairment of renal cytes falls concomitantly with erythrocytes because
functions and to acute renal failure. The elimination of bone marrow depression and absence of erythro-
of extrarenal cause leads to recovery of renal func- poietin. The disturbance may impair considerably
tions. Every obstacle in urine outflow can result and can result in haemorrhagic diathesis. Dissemi-
in impairment of renal functions. The chronic re- nated intravascular coagulation is not frequently ob-
nal failure in its terminal stage can impair to such a served.
degree, that it can imitate the acute renal failure. The cardiovascular complications are outstanding.
Uraemic osteodystrophy, neuropathy and anaemia The most important are – the hypertension, arrhyth-
can be found. mias and pericarditis. The overload of circulation
Hyaline casts, epithelial cells, erythrocytes and is due to sodium and water retention. The hyper-
polymorphonuclear leucocytes are found in urine. tension is not outstanding, it appears during the
The finding can be very heterogeneous. It depends 2nd week of renal failure duration and its main un-
from the primary disease. derlying cause is the fluid retention. Supraventric-
The first sign of acute renal failure is the oliguria ular arrhythmias occur rather frequently and may
being the cardinal symptome, nevertheless it does complicate the severe condition of the patient. The
not occur in all patients. Azotaemia can occur also underlying mechanism is constituted by a complex of
in patients without oliguria. The duration of olig- factors – the most important of which is congestion
uria may be 10 to 14 days, but also several hours of circulation, changes in electrolytes, pericarditis,
only or some weeks. In oliguric patients the creati- anaemia.
nine and urea plasmatic level raises. Hyponatraemia, Metabolic alterations in acute renal failure lead
oedema and pulmonary congestion develop. The hy- to neurologic disorders, above all in elderly pa-
ponatraemia is the consequence of water retention tients. Sometimes psychical disturbances are ob-
and the oedemas are due to sodium retention. served: lethargy, somnolence, confusions. Nearly
During acute renal failure the potassium excre- in all cases gastrointestinal disorders are observed
tion decreases. The hyperkalaemia can occur also in most frequently – anorexia, nausea, vomoting, ileus
other disturbances in organism e.g. as consequence and diffuse abdominal pain. Haematological disor-
of tissue destruction or by potassium shift from cells ders and alterations in gastrointestinal tract can be
during acidaemia. When the potassium level exceeds complicated by gastrointestinal haemorrhage.
6,5 mmol/l electrocardiographic alterations appear: During acute renal failure infections often occur –
deviation of heart electrical axis to the left, pointed they are very severe complications ending frequently
T waves, prolonged duration of QRS and PQ and de- lethally. The most common are the infections of res-
pression of P wave. Bradycardia and cardiac arrest piratory system and of urinary tract.
can occur. In acute renal failure appears hyperphos- In favorable conditions an increased diuresis and
phataemia due to decreased phosphate excretion. It glomerular filtration can be observed after the olig-
does not attain extreme values. Concomitantly with uric period. It is a sign of recovery. Neverthe-
hyperphosphataemia, hypocalcaemia and hypermag- less, the complications as the gastrointestinal haem-
nesaemia are observed. The underlying mechanism orrhage, electrolyte alterations and cardiac dysfunc-
is not well understood. tion may persist. The recovery can begin fallowing
In acute renal failure develops the metabolic acido- 1 to 2 weeks. The improvement of altered functions
sis. The retention of organic acids leads to decrease may last by one year following the acute renal failure.
in plasmatic bicarbonate concentration. Minute renal functional alterations and hypertension
Hyperuricaemia is due to decreased uric acid renal can persist.
excretion. The excretion of amylase is also reduced, The acute renal failure may appear at the begin-
its plasmatic level rises only moderately, unlike in ning of pregnancy, but more often during the last
pancreatitis. trimester and post partum. Following an unsterile
4.7. Chronic renal failure 281

abortus it uses to be associated with sepsis, so with dition can persist during variably long time. Later, a
disseminated intravascular coagulation. Acute renal further decrease of nephron number occurs, anaemia
failure after the delivery occurs as consequence of and hypertension becomes more severe, renal failure
acute haemorrhage. In some cases diffuse necrosis becomes manifest, the metabolic acidosis, gastroin-
is found in renal cortex accompanied usually with testinal, cardiovascular and nervous disturbances ap-
disseminated intravascular coagualtion. pear. Even in this situation are the kidneys capable
The impairment of renal functions can appear also to excrete potassium. Clinically important hyper-
during hepatic diseases in absence of known renal kalaemia does not occur.
or other cause. It is manifested by oliguria associ- It has been known long ago that the serum from an
ated with a modest finding in urine sediment. It uraemic patient has toxic effects on many biological
occurs usually during the liver cirrhosis associated systems. This fact led to searching after responsible
with icterus, ascites and hepatic encephalopathy. toxins. Substances with toxic effect are protein- and
aminoacid-metabolites. Lipids and carbohydrates
are metabolized to CO2 and H2 O and easily excreted
by exhalation and through the skin. The waste prod-
ucts of protein metabolism, however, are excreted
4.7 Chronic renal failure almost exclusively by kidneys. In patients with
chronic renal failure urea represents about 80 per
cent of nitrogen excreted by urine. The guanidine
compounds are on the second place of importance
Renal diseases are dangerous because of de- among the nitrogenous substances being the end -
product of protein metabolism: guanidine, methyl-
structive process progression resulting in lost
of nephrones. These are: glomerulonephritis, and dimethyl-guanidine, creatinine and guanidine-
tubulo-interstitial diseases, diabetic nephropathy, succinic acid. Further, the metabolites of nucleic
nephrosclerosis and futher renal diseases leading to acids and derivates of aromatic aminoacids as tryp-
an extensive reduction of renal nephrones and re- tophan, tyrosine and phenylalanine exhibit toxic ef-
fects. It is not possible to decide which substance
sulting in chronic renal failure with clinical picture
termed uraemia. This term emphasizes the most is responsible for a given symptom. The plasmatic
important finding: the increased plasmatic level of level of urea reflects, to some degree, appearing of
urea. Nevertheless, it implies the deterioration of anorexia, malaise, nausea, vomiting and headache.
several mechanisms, causing alterations in the whole Very probably not urea alone is the underlying cause
organism. The resulting condition depends on ex- of these symptomes. The guanidine-succinic acid
tent of nephron reduction and on the speed of its impairs the thrombocyte functions by affecting the
progression. thrombocyte factor 3. Some metabolites are not di-
rectly toxic (e.g. creatinine), they can however influ-
Kidneys have the capability to maintain body
ence other substance which change under their influ-
functions unchanged also during decreased glomeru-
ence into the toxic ones.
lar filtration rate. This can be decreased to 35 to
55 per cent of the physiologic values and the pa- In uraemia are nitrogenous substances with high
tient will be asymptomatic. Except for glomeru- molecular weight retained in the body. Analysing
lar filtration decrease no other changes have to be the plasma of uraemic patient, however, molecules
found. However, when the glomerular filtration falls of intermediate size were prevailing. The kidneys
to 20 to 35 per cent of physiological values, the azo- catabolise many plasmatic proteins and polypep-
taemia appears with other pathologic signs signal- tides. When the functional parenchyma is lost,
izing the renal failure manifestation. Systemic ar- plasmatic levels of polypeptide hormones: parathor-
terial hypertension and anaemia are appearing first mone, insulin, glucagon, growth-hormone, luteiniz-
and most frequently. Later, carbohydrate intoler- ing hormone and prolactin raise. Not only the re-
ance, hyperuricaemia, hypertriglyceridaemia and in- nal impairment participates in this increase of pro-
ability to concentrate the urine may be observed. teins, but also the elevated secretion of mentioned
Polyuria and nycturia appears thereafter. This con- hormones during chronic renal failure.
282 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

4.7.1 Cell – organ – and metabolic al- membranes is proportional to the basal energy pro-
terations due to uraemia duction. An inverse relation between the body tem-
perature and azotaemia is due to the inhibition of
Uraemia is associated with changes in intracellular sodium pump mechanism by accumulation of toxic
and extracellular fluids. These alterations affect the substances during uraemia.
ion transport mechanisms across the cell membranes.
The capability to metabolise the exogenous glu-
It is very probable that the transport of ions across
cose load is in uraemic patients impaired. The dis-
the membranes is impaired by uraemic toxins. At
turbance becomes manifest by slower decrease of glu-
the first place is the sodium transport. Sodium is
cose plasmatic level after glucose intake. The fasting
permanently present in higher concentration in ex-
plasmatic level of glucose is normal or moderately
tracellular than in intracellular space. The cell re-
elevated. Hyperglycaemia and ketosis are commonly
quires energy and oxygen to maintain this state. The
present in uraemia. The glucose intolerance do not
sodium efflux is necessary for the maintenance of
require specific treatment. During uraemia the secre-
membrane resting potential, by this process is con-
tion of total insulin impairs, resp. its degradation is
cominantly also the potassium influx ensured. The
also impaired. Therefore the plasmatic insulin level
uraemic toxins inhibit sodium efflux. Most out-
is moderately increased. The glucose load, on the
standing alterations can be found in erythrocytes,
other hand, leads to delayed return of glucose level
leucocytes, skeletal muscles but also in other tissues.
to the initial value. The glucose intolerance is caused
The changes in sodium efflux and potassium influx
by insensitivity of peripheral tissues to insulin effects.
are, of course, mainly affecting the membrane po-
tentials of excitable tissues. During uraemia a fall Intracellular potassium deficiency contributes to
in Na+ –K+ –ATP-ase activity has been observed in the carbohydrate intolerance. A similar condition
several types of cells. This is why the transport of can be induced in patients by treatment with thiazide
mentioned ions falls. diuretics. The carbohydrate intolerance is impaired
As mentioned, uraemia causes the sodium efflux by metabolic acidosis. Disorders of acid-base balance
decrease from the cells. Impaired sodium transport inhibit the glycolysis and the glucose utilisation and
out of the cell leads to an elevated sodium concen- influence the peripheral insulin effect. The plasmatic
tration in cells. Sodium causes consequently osmotic glucagon level uses to be elevated in chronic renal
hyperhydrations of cells. This alteration can affect failure. Glucagon plays a role in hepatic glycogenol-
all cells, of course, it can be developed to various de- ysis. Hyperglucagonaemia depends from the func-
gree. During uraemia progression, untill the terminal tional parenchyma of kidneys. The reduced nephron
stage, a tendency of sodium and water retention per- number results in impaired glucagon excretion. In
sists. The successful haemodialysis is manifested by the pathogenesis of glucose intolerance participate
an outstanding fall of body weight – due to decrease also catecholamines, growth hormone, prolactin and
of cells hyperhydration. The success of transplanta- further potential toxic substances.
tion becomes evident by very important body weight In chronic renal failure the renal capability to ex-
gain caused by regeneration of body mass and of lipid crete nitrogen and products of protein metabolism
deposits reaching the status before the uraemia. is extremely reduced. This condition can be desig-
The potassium concentration in uraemia can be nated also as protein intolerance. The retention of ni-
unfavorably affected by diet, vomiting, diarhea and trogenous substances is the cardinal underlying cause
diuretics. The potassium loss can be increased in of uraemic symptoms. In addition the hypertriglyc-
uraemic patient if the volume of excreted urine re- eridaemia with simultaneous decrease of HDL level.
mains relatively normal, in addition, it can rise due The plasmatic cholesterol level is usually normal. It
to high aldosterone level in uraemia. Aldosterone is not clear if uraemia induces an increased triglyc-
can increase the potassium loss into the colon. In eride production in liver and in intestine. Insulin
spite of the low cell potassium level kalaemia is usu- could participate in triglyceride synthesis. As men-
ally normal or increased due to metabolic acidosis tioned, the plasmatic level of insulin during uraemia
inducing the potassium efflux from cells. is increased. Its lipogenetic effect could contribute
In uraemia, urea and other toxic substances cause to the hypertriglyceridaemia. Insulin enhances the
hypothermia. The active sodium transport across synthesis of triglycerides and inhibits the lipoprotein
4.7. Chronic renal failure 283

lipase. The metabolic alterations concerning lipids ditions differing significantly from each other. The
are irreparable by haemodialysis. Thus, in patients uraemic osteodystrophy comprises osteomalacia, os-
with chronic renal failure cardio-respiratory distur- teosclerosis, osteofibrosis and growth disorders in
bances appear as consequence of atherosclerosis. children. Clinical symptoms of these disturbances
are present in about 10 per cent of uraemic patients
with advanced chronic renal failure. Histological al-
4.7.2 Pathophysiology of symptoms terations in bones are nevertheless found in 35-95 per
in uraemia cent of uraemic patients. Renal osteodystrophy oc-
curs more frequently in children with renal anoma-
Chronic renal failure and its terminal stage – uraemia lies, mostly with a slow progression of renal failure.
– represent a very complex disturbance affecting al- The underlying causes are the elevated parathyroid
most, every organ or system. In all patients with hormone production, disturbance of vitamin D me-
uraemia retention of sodium and water occur. Ex- tabolism, chronic metabolic acidosis and severe cal-
pansion of the extracellular fluid volume needs not to cium losses by stool. Renal osteodystrophy can be
be evident. The sodium retention contribute to de- classified according radiological skeletal findings. In
velopment of heart failure, systemic arterial hyper- patients spontaneous fractures may occur without
tension, ascites and oedemas. Hyponatraemia can tendency to heal. Joint pain can dominate, caused
be observed if the water retention prevails. No other by calcium deposits in bursae and periarticular struc-
symptoms are present in this situation. Decrease of tures. A severe pain of bone or joint is sometimes ac-
extracellular water volume (during fever, vomiting, companied with proximal myopathy. Following renal
diarrhea) impairs the still preserved renal function transplantation with secondary hyperparathyroidism
and gradates the manifestations of uraemic symp- aseptic femoral necrosis can occur. Responsible for
toms. it could be the disturbance of vitamin D metabo-
Potassium level is moderately changed in the ini- lism and the treatment with corticoids. Extraosseal
tial phases of uraemia owing to adaptation of distal metastatic calcification appears in middle sized ves-
tubules and colon. Aldosterone and other factors in- sels, in joints and periarticular structures, in my-
crease the potassium excretion. In this situation can ocardium and in lungs.
oliguria lead to hyperkalaemia. The fall of blood pH The progression of chronic renal failure is accom-
can result also in hyperkalaemia. Acidosis leads to panied with elevated plasmatic levels of uric acid and
the potassium leak from intracellular space into the magnesium.
extracellular fluid. Between potassium and pH val-
ues is a reciprocal relation.
Concentration of phosphates in plasma raises if 4.7.3 Consequences of alterations oc-
glomerular filtration becomes impaired to such a de- curing in chronic renal failure
gree, that its value falls to less than 25 per cent of
normal value. Increase in plasmatic phosphates facil- Fluid retention represents a large preload for the
itates the intake of calcium into the bones, leading to heart. Pulmonary congestion occurs not inevitably
hypocalcaemia. The hypocalcaemia induces the rise accompanied with overload of circulation. Pul-
of parathyroid hormone plasmatic level. In chronic monary oedema is developing during normal intrac-
renal failure is hypocalcaemia caused by incapability ardiac and pulmonary pressure. Radiological exam-
of kidneys to synthesise the active form of vitamin D ination of uraemic lungs reveals a peripheral, vascu-
(1,25 dihydroxycalciferol). When the level of active lar congestion in shape of butterfly wings. Uraemic
vitamin D is low, the reabsorption of calcium from lungs and cardiopulmonaly alterations associated
gut is reduced. In patients with very advanced renal with preload of circulation recover quickly following
failure is the resorption of calcium salts from bone by haemodialysis.
parathormone reduced. In spite of various causes of A very frequent complication of end-stage renal
hypocalcaemia the hypocalcemic tetania and similar diseases, including chronic renal failure is the sys-
syptoms are not observed in uraemic patients. temic arterial hypertension. The absence of hyper-
In uraemia severe bone diseases like uraemic os- tension may have several underlying causes: the pa-
teodystrophy are appearing. This term includes con- tient receives antihypertensive drugs, or the patient
284 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

has evidently large fluid losses through gastrointesti- The deterioration of all types of leucocytes is caused
nal system. Diuretic treatment can lead to fluid loss, by toxins present in uraemic serum. The chemotaxis
and so does a salt wasting renal disease with chronic of leucocytes is also depressed. The reactions to in-
pyelonephritis. The major cause of hypertension in fection are in uraemic patients reduced, even during
uraemic patient is the hypervolemia. In spite of this severe infection the fever does not rise to substantial
the blood pressure improves during the haemodialy- degree. This can lead to underestimation of infection
sis even without regulation of circulating blood vol- severity. In addition, the resistance towards infection
ume. of uraemic patients is impaired, due to leucocytes
Systemic arterial hypertension can be present also deterioration. The presence of acidosis, hypergly-
in absence of salt and water retention. Under these caemia, azotaemia and the decreased immunoglobu-
circumstances, elevated renin plasmatic activity is lin and complement level contribute to infection de-
found almost regularly. More seldom, but not ex- velopment progression.
ceptional is the progression of the hypertension to At the initial stage of uraemia only moderate dis-
so-called malignant hypertension. The systolic and orders of central nervous system are found: minor
diastolic blood pressure is elevated, plasmatic renin sleep- and behavioral disturbances. Lack of concen-
activity use to be increased, the hypertensive en- tration, amnesia and signs of neuromuscular irritabil-
cephalopathy is developing, retinal alterations and ity appear later. Hiccups, convulsions, twitchings of
oedema of optic papilla appear. Haemodialysis large muscles mainly are frequently present. Periph-
and drug treatment have no effect. Only bilateral eral neuropathy affecting more the lower than the
nephrectomy results in a rapid fall of elevated blood upper extremities arises being the sign of severe im-
pressure. Progressive uraemia is often accompanied pairment and progression of disease. It uses initiate
with pericarditis. In chronic renal failure atheroscle- the treatment by haemodialysis or renal transplan-
rosis is developing, in spite of successful haemodial- tation. These interventions are evidently not risk-
ysis, affecting coronary, cerebral and peripheral ar- less. At the beginning of dialysis the plasmatic urea
teries. More accelerating factors participate in the level falls rapidly. This fall use to be associated with
atherosclerosis progression: hypertension, hyperlipi- nausea, vomiting, headache and cramps. The under-
daemia, glucose intolerance and metastatic vascular lying cause of these symptoms are rapid changes in
calcifications. extracellular fluid. Retarded sequential alterations
Chronic renal failure progresses to such a degree in intracellular space follow. Cerebral oedema may
that kidneys are unable to synthesize erythropoi- develop. During chronic dialysis, the syndrome of
etin, thus a normochromic, normocytic anaemia de- dialysis dementia occurs. It is thought to be related
velops. Its appearence is facilitated by erythropoiesis with elevated aluminium level and is manifested by
depression induced by retained toxins, in addition, dysarthria, myoclonus and dementia. In addition,
to above mentioned absence of erythropoietin. Toxic the patients are threatened with viral infections, as
substances induce premature haemolysis of erythro- hepatitis B or AIDS.
cytes. Certain amount of blood is lost through the Anorexia, frequently singultus, nausea and vom-
gastrointestinal tract. The heparin administration to iting occur in patient with uraemia. High plasmatic
haemodialysed patients potentiates the blood loss. level of urea leads to its excretion by saliva. Urea is in
Larger haemorhage into the gastrointestinal tract, saliva decomposed to ammonia causing the uraemic
pericardial cavity; subdural and intracerebral bleed- foetor ex ore. Along the whole gastrointestinal sys-
ing may be observed. In chronic renal failure the tem mucosal ulcerations, or extensive, less demar-
bleeding time is prolongated, caused by diminished cated lesions termed uraemic gastritis can appear.
thrombocytic factor 3 activity which corresponds Ulcerations and enteritis lead to blood loss from gas-
with the rise of guanidinylsuccinic acid plasmatic trointestinal tract. Peptic ulcers are particularly fre-
level. quent, occuring in every forth uraemic patient. Gas-
In chronic renal failure the production and func- tric hyperacidity, enhanced gastrin secretion or the
tion of leucocytes becomes deteriorated. Lymphope- secondary hyperparathyroidism could contribute to
nia and atrophy of lymphatic tissue appear. The their formation.
neutrophils are less affected, being more resistent. In chronic renal failure anaemia associated with
4.8. Inflammatory processes of kidneys due to immunopathogenic mechanisms 285

urochrome retention cause the typical coloration of In the third type the autoantibodies are involved,
the skin. Urea is excreted also by sweat and may arising following streptococcal, staphylococcal, or
contribute to the uraemic itching. pneumococcal infections or following malaria. The
The patients, if in good care, die most commonly most frequent cause are the streptococci of group A.
of cardiovascular complications (50 per cent) and of In contrast to the rheumatic fever the poststrepto-
sepsis (25 per cent). coccal glomerulonephritis is not caused by all, but
only by some serotypes. These nephritogenic cocci
produce a lipoprotein with a molecular weight of
about 120 000 daltons, which is an component of cy-
toplasmatic membrane and is an efficient immuno-
gene. Antibodies produced against this lipoprotein
4.8 Inflammatory processes of can cross-react with antigenic determinants of re-
kidneys due to immunopa- nal tissue, mainly of the basement membrane. Fol-
lowing this interaction arise histologically well iden-
thogenic mechanisms tificable immune complexes activating the comple-
ment. The basement membrane, or other tissues are
than damaged by cytotoxic effects of terminal com-
plement, components and of neutrophil leucocytes
Etiopathogenesis of several inflammatory pro- attracted by chemotactic factors produced during
cesses in kidneys is due to immune mechanisms ac- complement activation. Above all, the free oxygen
tivation. Immunopathologic mechanisms may result radicals and hydrolytic lysosomal enzymes released
in inflammatory process of kidneys by three ways: from neutrophiles have cytotoxic effects. Apart from
neutrophils, the macrophages and monocytes may
1. by heterologue antibodies against the basement
membrane participate in this process by mechanism of ADCC
(antibody-dependent cell-mediated cytotoxicity).
2. by soluble immune complexes not containing the Recently, a further autoimmune mechanism sig-
renal antigen originating in kidneys, but a dif- nificantly participating in the pathogenesis of hu-
ferent antigen man glomerulonephritis was described, represented
by autoantibodies against some lysosomal enzymes
3. by autoimmune mechanism following strepto- of neutrophiles, especially against myeloperoxidase
coccal (group A), or other infection. and elastase.

In the first type is the underlying cause the re-

action between the circulating antibodies and the 4.8.1 Renal damage due to antibodies
antigen in kidneys. The antigen may be a natural against basement membrane
constituent (component) of kidneys, or it can be an
antigen bound with the tissue by biological or im- This type of renal damage is in men uncommon.
munological reactions. The primary components of Under experimental conditions a model of this dis-
immune-pathological mechanism leading to the dam- ease may be elaborated. The nephritis induced
age of tissue are the antigens in the basement mem- by nephrotoxic serum may be considered to be the
brane of glomerular capillaries or renal tubules and prototype of this disease. In the classical experi-
the antibodies against basement membranes. ment (Masugi’s nephritis) the antibodies against the
In the second, more frequent type, the macro- glomerular basement membrane of rabbits are ob-
molecular immune complexes composed of antigens tained by immunization of ducks. The nephrotoxic
and antibodies are deposited in kidneys, mainly in serum is than injected into rabbits. The heterologous
glomeruli. In this case are kidneys a passive partici- antibodies are rapidly bound to relevant antigen in
pant, a victim of this process which can start at any glomerular basement membrane. The antigen is a
time. The antigen can be of autologous or heterol- glycoprotein evenly dislocated in the basement mem-
ogous type. It is never a component, or constituent brane of glomerular capillaries. On immunofluores-
of kidneys. cent examination the reactive immunoglobulin will
286 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

be therefore equally dispersed in the capillary wall stituent of glomerular basement membrane with high
of glomeruli. If a sufficient amount of heterologous content of sialic acid, fucose, mannose, galactose
antibodies has been applied and they were bound and glucose is the most frequently occuring antigen.
to the antigen, various mechanisms and reactions Its molecular weight is about 26 000 to 58 000 dal-
will be activated. First, are the complement and tons. The highest concentration of this antigen is
the haemocoagulation cascade activated. Vasoac- found in lamina rara interna of the glomerular base-
tive polypeptides, polymorphonuclear neutrophiles ment membrane. Less is found in tubular basement
and macrophages are activated subsequently. The membranes and in Bowman’s capsule. The antigen
phagocytes and some lymphocytes may operate by is equipped with epitopes similar to the basement
mechanism termed antibody-dependent cytotoxicity membrane of lungs, eye, cochlea and plexus chori-
(ADCC). By action of these factors is the functional oideus epitopes. The antigen of basement membrane
and anatomic integrity of capillary wall deteriorated termed nephritogenic antigen is excreted by urine.
to such a degree,that proteinuria appears. The pro- The underlying cause, giving rise to of glomeru-
liferation of cellular elements in capillaries appears lonephritis is thought to be the penetration of this
simultaneously resulting in development of progres- antigen into the circulation and its contact with
sive capillary obstruction. Reduction of capillary lu- immunocompetent cells. Some conditions facilitate
men leads to reduced renal blood flow and glomeru- these processes: viral infections, toxins, drugs and
lar filtration rate. Released local hormones can cause renal ischaemia. The helper T-cells distinguish the
the disintegration of glomerular capillary basement released nephritic nephritogenic antigen. Primarly
membrane. Macromolecular substances - like fibrino- activated T-cells produce interleukin-2 (IL-2) and
gen and cellular elements as macrophages and ery- create new receptors for it. Binding of IL-2 on re-
throcytes may get from capillaries into the Bowman’s ceptors stimulates lymphokines production and the
capsule. If the injury of glomerular capillary walls is proliferation of specific clones of helper T-cells which
severe extracapillary proliferation also appears. It is releasing activating factors stimulate the specific B-
dependent on fibrin polymerisation in the Bowman’s cell clones. These activated B-cell clones begin to
capsule. The complement activation enhances the produce specific antibodies. These antibodies bind-
injury induced by chemotactic and cytolytic effect. ing with antigen cause its destruction. Together with
The glomerular damage however, can develop also amplification systems of immunity they destruct also
independently from the complement activation. the relevant tissues. Antibody - mediated glomeru-
This phase of glomerulonephritis is termed the het- lonephritis appears. The basement membrane de-
erologous phase. The antibodies bound to the base- struction leads to further antigen release. A circu-
ment membrane operate, at the same time, as anti- lus vitiosus develops – being the underlying cause of
gen. Therefore anti-antibodies against it begin to rapid progression of this type of glomerulonephritis.
be produced. The duration of their production is 1 The antibodies against glomerular capillary base-
to 2 weeks. They affect subsequently the antibodies ment membrane can bind to the cross-reacting epi-
already bound to the basement membrane. The so- topes of other organ capillary membrane antigens. In
called autologous phase begins. Virtually, only now the Goodpasture’s syndrome the antibodies bind to
the condition becomes to be glomerulonephritis. the pulmonal capillaries. Haemoptysis appears with
rapidly progressing glomerulonephritis.
Several drugs have the ability to bind on re-
nal structures, forming conjugated antigens. This Antibodies against glomerular capillary basement
is e.g. penicillin. This could be considered to be membrane IgG are bound to antigen determinants.
an analogy to the heterologous phase of nephro- They activate the phagocytosis and the complement
toxic nephritis. Later, the production of antibodies system. The chemotactic components of comple-
may begin. A similar situation may occur following ment attract the leucocytes, the neutrophils, above
the renal transplantation. Some structures of renal all. The neutrophils bind to the glomerular struc-
transplant may become antigenic for the recipient. tures and release the lysosomal enzymes like pro-
In a classical case the glomerulonephritis induced teases, collagenases and other hydrolases. The
by antibodies is developing according the follow- activated leucocytes, in the same time, produce
ing principle. A component of non-collagenous con- toxic oxygen metabolites, mainly the hydroxyl rad-
4.8. Inflammatory processes of kidneys due to immunopathogenic mechanisms 287

icals (OH), superoxid anion (O− 2

) and the hydro- cytoma (multiple myeloma), DNA in lupus erythe-
gen peroxide (H2 O2 ), arachidonic acid metabolites matosus nephritis and the tubular antigen in Hey-
(prostaglandins and leukotriens) kinins, angiotensin mann nephritis.
II and histamine. These processes occur with par- The immune complexes are usually, immediately
ticipation of complement, mainly its components after their appearence, bound to the complement
– C5a6789 forming the membrane attacking com- which solubilises them and enables their transport to
plex (MAC). The MAC perforates the biologic mem- the cells of phagocytic and macrophage-system. Here
branes and thereby disturbs their selective perme- are immune complexes continously decomposed. Im-
ability. The perforation of the cellular cytoplas- mune complexes are transported mainly by erythro-
matic membrane may result in the cytolysis. Owing cytes. Every disturbance of immune complex decom-
to these processes are the endothelial cells of cap- position results in immune complex-mediated dis-
illaries damaged. The capillaries are narrowed and ease. In this way can arise the immune complex-
obstructed by cells and thrombi. The integrity of mediated glomerulonephritis.
the basement membrane is considerably impaired. Soluble circulating immune complexes without
In basement membrane and the capillary walls ap- any relations to the glomeruli may be retained
pear perforations. This impairs the blood flow and in glomerular capillaries. This form of glomeru-
enhances the permeability of glomerular capillary lonephritis may be induced, experimentally, by intra-
walls. The plasmatic proteins including fibrinogen venous application e.g. of bovine serum albumin to
and other coagulation factors penetrate through the rabbits immunised before by this antigen and having
perforated capillary walls into the Bowman’s cap- circulating antibodies against it. Antibodies of recip-
sule. The negative charge of Bowman’s capsule ep- ient are bound to antigen and the immune complexes
ithelial cells induces the Hageman factor activation. formed are deposited in various tissues, including the
Through the gaps penetrate into the Bowman’s cap- glomerular capillaries - where they activate the com-
sule also the monocytes containing prothrombinase, plement. This induces the chemotactic effects of C5a
activating the thrombin. This all results in rapid ac- and C3a complement fragments to neutrophylic leu-
tivation of haemocoagulation processes during which cocytes. The leucocytes release proteolytic enzymes
fibrin polymers are produced. The epithelial cells of and kinins and with complement components dam-
glomeruli and the monocytes phagocytise the pro- age the basement membrane in glomeruli, breaches
duced fibrin. The phagocytised fibrin stimulates the arise in it and system of haemocoagulation becomes
cell proliferation. The extracapillary space is there- activated. The inflammatory mediators are released
fore rapidly filled by cells. In addition, the mono- and the glomerulonephritis is developing.
cytes release mitogenic factors for fibroblasts. It re-
When the immune complexes are deposited in
sults in collagen deposition and forming of scars, re-
glomerular capillaries develops most frequently the
placing the functional renal parenchyma.
chronic proliferative glomerulonephritis.
The specific configuration of kidneys facilitates
4.8.2 Renal damage induced by im- the deposition of immune complexes. In glomeru-
lar capillaries, in comparison with other capillar-
mune complexes
ies, the blood pressure is higher. In addition, there
The deposition of circulating immune complexes in takes place only the filtration, the reabsorption oc-
kidneys is the underlying cause in more than 75 per curs at another site. An important contribution
cent of all renal disturbances induced by immuno- has the state of immune system. If it is perfect,
pathologic processes. The immune complexes may the immune complexes are completly removed, by
circulate in blood and form subsequently deposits in the monocyte-macrophage system in the liver, spleen
the basement membrane. The antigen component and other organs. Immune system defect can be
of immune complexes may be of exogenous origin – manifested also by forming of small, soluble immune
e.g. the antigens of some bacteria, hepatitis B virus, complexes, which are most dangerous for causing
foreign proteins. The endogenous antigens of im- glomerulonephritis.
mune complexes are most commonly the components The glomerular basement membrane is negatively
of tumors, myeloma immune complexes in plasma- charged, hence repelling the majority of protein
288 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

molecules, including the immune complexes. The 4.9.1 Acute glomerulonephritis

loss of electric charge may be the cause of immune
complex deposition in glomeruli and vice versa – the Acute glomerulonephritis is characterised by an
immune complex deposition leads to the loss of base- abrupt onset. Haematuria and proteinuria associ-
ment membrane electric charge. This may be one of ated with azotaemia appear, due to reduced glomeru-
proteinuria causes. lar filtration. Retention of salt and water is present.
If it is considerable, oliguria arises. The salt and
In Heymann nephritis the immune complexes pass
through the basement membrane and form deposits water retention causes congestion of circulation, hy-
at its outer side. These immune complex deposits pertension and oedemas. The fluid retention is the
lead to forming the epithelial cell processes. consequence of glomerular filtration decrease and of
exaggerated water and salt absorption, mainly in the
The circulating immune complexes are not per se
distal renal tubules. Oedema is located at sites with
the cause of pathologic process in kidneys. They
low oncotic pressure (e.g. periorbital oedema), but if
occur in circulation without any renal alterations.
it progresses it can lead to ascites or pleural exsuda-
In some cases the antibodies against the antigens tion. The congestion of circulation is manifested by
of epithelial cell pedicles may be produced. These elevated systemic arterial or pulmonal blood pres-
antibodies pass through the glomerular basement sure associated with normal or enhanced ejection
membrane and can be bound to antigen. Immune volume per minute and with shortened circulation
complexes are formed which are situated outside the time. If ischaemic heart disease or valvular defect
basement membrane. are not present it is not probable that the right ven-
tricular failure will develop. If the filling pressure
in the left heart atrium rises considerably, pulmonal
oedema may develop. The arterial diastolic hyper-
tension is caused by several factors: increased vol-
ume of extracellular fluid, enhanced heart volume
4.9 Glomerulopathies per minute and moderate increase in peripheral resis-
tance. The plasmatic renin activity, aldosterone and
the activity of the sympathetic nervous system are
rather depressed. The systemic arterial hypertension
If the integrity of glomerular capillaries is struc- may be, mainly in younger children associated with
turally or functionally damaged disturbances of re- encephalopathy.
nal functions may appear. The renal function al- The most frequent and very remarkable symp-
terations are the underlying cause of findings occur- tom of acute glomerulonephritis is the macroscopic
ing isolated or in combination: haematuria, protein- haematuria. The microscopic haematuria can be
uria, reduction of glomerular filtration rate and hy- overlooked. In this case, the fluid retention and hy-
pertension. From pathophysiological point of view pertension may be incorrectly considered to be symp-
some disturbances of glomeruli may be distinguished toms of a different disease. Haematuria is often asso-
relatively well: acute forms of glomerulonephri- ciated with occurence of erythrocytic casts in urine.
tis, rapidly progressive glomerulonephritis, chronic In the definitive urine are found frequently leucocytes
glomerulonephritis, nephrotic syndrome and asymp- and leucocytic cylinders. They are the evidence of
tomatic abnormalities. The clinical classification by inflammatory processes in glomeruli. The degree of
itself is considerably variable. It was several times proteinuria varies according the glomerular damage
changed untill the contemporary classification has extent. Proteinuria may be sometimes severe. In
been elaborated by WHO (World Health Organiza- persistent severe proteinuria the nephrotic syndrome
tion) which takes into consideration mainly the clin- is developing.
ical aspects. Thus, the effort of morphologists to The course of glomerulonephritis depends on the
adapt it to the morphologic classification is not sur- character of glomerular lesion. In some cases the
prising. The description of single clinical pictures fluid retention and systemic arterial hypertension
and the precise classification is left to the clinicians. may improve. In other cases renal failure develops
4.9. Glomerulopathies 289

rapidly. This condition is termed rapidly progressive monocytes is commonly present. The capillary wall
glomerulonephritis. is thin. In some glomeruli extracapillary prolifera-
tion can be observed. Erythrocytes and erythrocytic
4.9.1.1 Acute poststreptococcal glomeru- casts are present in tubules.
lonephritis In immunofluorescent microscopic examination
granular deposits of IgG with C3 component of com-
Is observed following infections of upper airways and plement and properdin are found in capillary loops,
skin. Infections are caused most frequently by beta- at circumference of glomeruli and in mesangium.
haemolytic streptococci of group A. These, poten- Less frequently the complement components C1q and
tially nephritogenic streptococci possess in their su- C4 are observed. These deposits represent probably
perficial membrane an antigen, the M-protein. the immune complexes.
Typical for this type of nephritis is the latent pe- In some cases the acute proststreptococcal
riod between the onset of infection and appearence glomerulonephritis leads to lethal end. The un-
of first nephritic symptoms. For correct diagnosis of derlaying cause is mainly the renal failure. Com-
poststreptococcal glomerulonephritis is necessary: monly complete recovery occurs. The urine findings
normalisation lasts long time, sometimes weeks or
1. To obtain information about the presence of
months, nevertheless it is not seldom, that the nor-
beta-haemolytic streptococci of A group
malization of urine finding lasts years.
2. If this is not possible, it si necessary to look Persistent proteinuria or haematuria and slowly
for evidence of the immunity reaction to ex- progressing glomerulosclerosis are an unwanted out-
oenzymes of streptococci. Determination of come of glomerulonephritis. This progression of dis-
anti-streptolysine O, antistreptokinase, anti- ease use to be associated with hypertension.
deoxyribonuclease B, anti-nicotinamid adenin
dinucleotidase and anti-hyaluronidase 4.9.1.2 Acute non – streptococcal glomeru-
lonephritis
3. Low plasmatic levels of C3 complement com-
ponent are regularly observed; moderately de- This type of glomerulonephritis ressembles to the
creased components C1q and C4 are also found above mentioned. It is caused by another infection
(non-streptococcal). It may occur also following vi-
In advanced glomerulonephritis a transient cry- ral and parasitic infections. In this type of glomeru-
oimmunoglobulinaemia, positive tests demonstrat- lonephritis the circulating immune complexes have a
ing the presence of immune complexes and of fib- determinant importance. Decrease of C1q, C4 and
rinogen complexes with high molecular weight are C3 components of complement is observed. Tests
found. Sedimentation of erythrocytes use to be el- detecting the circulating immune complexes are pos-
evated. Moderate anaemia and hypoalbuminaemia itive.
due to fluid retention and circulating blood dilu-
tion are observed, and significant hypoalbuminaemia
may be the consequence of a massive proteinuria 4.9.2 Rapidly progressive glomeru-
of non-selective type. Fibrin degradation products lonephritis
and C3 complement component are later found in
It is in fact an acute glomerulonephritis without
urine. In azotaemic or oliguric patients hypona-
tendency to recovery. On the contrary, it leads to
traemia, hypokalaemia and metabolic acidosis are
the renal failure in relatively short time. Exten-
observed. The sodium concentration in urine is usu-
sive extracapillary glomerulonephritis with crescents
ally low, due to its effective reabsorption in distal
dominates the histological picture. Three types of
part of nephrons. Moderate pulmonal congestion
glomerulonephritis can be distinguished:
and enlargement of cardiac shadow are found in ra-
diographic examination. 1. Renal complications of hidden, or subacute in-
The bioptic examination reveals diffuse endocap- fections
illary proliferative glomerulonephritis. Glomerular
infiltration by polymorphonuclear leucocytes and 2. Renal complications of systemic diseases
290 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

3. Primary or idiopathic disease of glomeruli 3,5 g (2,5 to 10,0 g) during 24 hours/1,73 m2 body
surface and are considered to be the underlying cause
The first type has been described in the preced- of nephrotic syndrome. Protein loss large like this
ing section, the second type will be described in a has never been observed in other renal diseases. Per-
separate section and the third type will be analysed sistent severe proteinuria is associated with hypoal-
here. buminaemia, stimulating the hepatic albumin syn-
thesis. The plasmatic albumin level falls to such a
4.9.2.1 Idiopathic rapidly progressive degree, that it leads to changes of Starling forces in-
glomerulonephritis volved in fluid exchange in capillaries. It results in
interstitial oedema formation. It occurs in tissues
Azotaemia develops rapidly in this type of glomeru- with low oncotic pressure. The process of filtration
lonephritis. Therefore weakness, nausea and vom- at the arterial end of capillaries is not affected. Be-
iting appear soon. In addition oliguria, abdominal cause of hypoalbuminaemia the oncotic pressure at
pain and haemoptysis often occur. The systemic ar- the venous end of capillaries is low. The filtered wa-
terial blood pressure is rather moderately elevated. ter can not be reabsorbed into the capillaries, be-
Haematuria occurs and erythrocyte casts are found cause the force (albumins) retracting (pulling back)
in urine. Proteinuria is always present. It may be the water into the capillaries is absent. These con-
massive, and it is always nonselective. Products of ditions accelerate or stimulate the mechanisms caus-
fibrin degradation occur in urine. ing the plasma volume expansion. It is the renin-
An extensive extracapillary proliferation with angiotensin-aldosterone system, increase in ADH se-
characteristic crescents is present in glomeruli. The cretion, stimulation of the sympathetic system and,
endocapillary proliferation may also be present, but probably, decreased secretion of natriuretic hormone.
it is rather a typical feature for the presence of im- The effect of these mechanisms leads to water and
mune complexes. The basement membrane is perfo- sodium retention. The extent of oedemas reflects
rated. In about one third of cases linearly arranged the degree of hypoalbuminaemia, respectively of the
IgG often together with C3 component of the comple- protein loss by urine. The present condition (status)
ment occur. This finding confirms the presence of an- of the heart and circulation participate partly in the
tibodies against the basement membrane. The com- formation of oedemas.
plement level in plasma is usually unchanged. Oc-
curence of haemoptysis is observed (Goodpasture’s Decreased oncotic pressure of plasma stimulates
syndrome). The prognosis of rapidly progressive the synthesis of lipoproteins in the liver. Therefore
glomerulonephritis is unfavorable. Treatment with is the hyperlipidaemia often observed in nephrotic
glucocorticoids in combination with anticoagulants syndrome. The low density lipoproteins (LDL) and
and cytostatic drugs might bring some hope. The cholesterol are raised most frequently. During a very
haemodialysis will save the live but not the kidneys marked fall of the oncotic pressure of plasma the
per se. Renal transplantation is not very hopeful, in very low density lipoproteins (VLDL) and the tri-
these cases, because the rapidly progressive glomeru- acylglyceroles raise. The plasmatic protein factors
lonephritis may soon affect the transplant. The an- regulating the system of lipoproteins are also lost by
tibodies against the basement membrane may circu- urine. This might participate in hyperlipidaemia de-
late in the blood of recipient. The bilateral nephrec- velopment. The above mentioned alterations may ac-
tomy before the transplantation might be a solution. celerate atherosclerosis development in patients with
nephrotic syndrome. Lipid casts can be found in
urine.
4.9.3 Nephrotic syndrome
Not only albumins but also other plasmatic pro-
The typical nephrotic syndrome is characterized by teins may be lost by urine. If, e.g. the thyroxine bind-
albuminuria, hypoalbuminaemia, hyperlipidaemia ing globulin (TBG) is lost the turnover of thyroxine
and oedemas. These alterations are the consequence and T3 can be stimulated. Loss of cholecalciferol-
of plasmatic protein losses by urine. Severe protein- binding protein may lead to vitamin D deficiency, to
uria is the main symptome of nephrotic syndrome. secondary hypoparathyroidism and to renal bone dis-
Protein loss can be considerable, reaching values of ease (renal osteodystrophy). Hypocalcaemia and hy-
4.9. Glomerulopathies 291

percalciuria appear. The loss of transferin can result Lipoid nephrosis is sometimes developing in pa-
in hypochromic microcytic anaemia resistent to iron tients with Hodgkin’s disease. It is supposed, that
therapy. The antithrombin III (heparin cofactor) loss the lymphocytes play the major role in the pathogen-
can be presented by hypercoagulation of blood. This esis of this disease. Neither a rapid fall in glomeru-
condition can be compensated by loss of coaguation lar filtration rate, nor acute renal failure occur in
factors. The haemocoagulation disorders may result this condition. Since the pathogenesis is unknown,
in thrombosis of renal veins. the treatment is only symptomatic. Glucocorticoids
The complement components can be excreted into nevertheless, may induce improvement.
the urine and lost, causing so possibly a defect in Focal and segmental glomerulosclerosis In this
opsonization of bacteria. Sometimes a severe loss of type of nephrotic syndrome are some, but not all
IgG is observed. glomeruli affected by sclerosing lessions and hyalin-
Oedema in nephrotic syndrome is a complicated ization. Rather a part of demarkated glomeruli uses
component of the disturbance the beginning of to be affected, often the juxtamedullar glomeruli.
which, respectively the main underlying cause of Concomitant tubular and interstitial lessions occur.
which - the proteinuria - is seemingly simple. The
On immunofluorescence deposits of IgM and C3
reduction of oedemas by application of drugs increas-
at sites of segmental sclerosis are found. On elec-
ing the diuresis can reduce the circulating plasma
tron microscopy lesions of basement membrane and
volume. The decreased volume of plasma becomes
epithelial cells are present. Less than 80 per cent
the cause of decreased glomerular filtration, which
of glomeruli are affected by these alterations in
finaly may result in acute renal failure. Systemic
glomerulosclerosis. In the segmental glomeruloscle-
arterial hypotension due to reduced plasma volume
rosis are the glomeruli only partially damaged.
contributes to this process.
Owing to the increased tendency to haemocoagula- Systemic arterial hypertension, decreased glo-
tion thromboembolic complications occur frequently. merular filtration, altered tubular functions and
Thrombosis of pulmonary arteries and veins may de- pathological findings in urine are often observed.
velop. Thrombosis can attack also the renal veins Nonselective proteinuria is usually present. The
manifested by massive haematuria and assymetric global condition of the patient and the degree of hy-
renal function. poalbuminaemia are determined by proteinuria ex-
tent. About one half of patients die in ten years.
The concomitant systemic arterial hypertension and
4.9.3.1 Idiopathic nephrotic syndrome azotaemia worsen the prognosis.
Comprises several forms, classification of which Membranous glomerulopathy is characterized by
needs renal biopsy. This is important also from point irregular protein deposits at the outer side of base-
of view of rational therapy. ment membrane under the epithelial cells. These de-
Lipoid nephrosis and minimal abnormalities of posits consist mainly of IgG. In this condidtion are
glomeruli In this type of nephrosis any alterations almost all glomeruli damaged rather uniformely. The
should not be observed in light microscopic exami- progressive apposition of deposits leads to the thick-
nation. In immunofluorescent microscopy irregular, ening of the glomerular capillary wall. Towards the
nonspecific deposits of immunoglobulins a comple- Bowman’s capsule spike-shaped protrusions appear,
ment components might be visible. This type of typical features of this condition. Moderate prolifer-
nephrosis occurs usually in boys from 8 years of age. ation of endothelial and mesangial cells is observed.
These patients have normal blood pressure, mod- In later stages tubulointerstitial atrophy occurs. The
erate decrease of glomerular filtration and some of systemic arterial blood pressure, glomerular filtra-
them have a microscopic haematuria. IgM level is tion rate and urinary sediment remain relatively long
usually elevated. In some cases immunization is es- time normal.
tablished in anamnesis, or the upper airways infec- The membranous glomerulopathy can occur dur-
tion. Prevalence of HLA-B12 is stated, associated ing certain chronical infections, solid tumors,
frequently with atopy. Disease improves sponata- melanoma, pulmonary and colon carcinomas but also
neously without apparent causes even for a long time. following penicillin application.
292 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

Membranous proliferative glomerulonephritis 4.9.4 Isolated asymptomatic renal

The most characteristic features in this condition are disorders
the proliferation of mesangial cells and increase in
mesangial matrix, in addition, irregularly thickened In these conditions proteinuria of non-nephrotic
walls of glomerular capillaries can be found. The character associated with haematuria is found, or
basement membranes become also thicker. This type isolated haematuria without oedemas, hypertension
of glomerulonephritis belongs in fact to the mesan- and decreased glomerular filtration. These alter-
giocapillary or tubular glomerulonephritis group. ations can be persistent or intermittent, interrupted
Several types of proliferative membranous glomeru- by asymptomatic intervals.
lonephritis can be distinguished :
4.9.4.1 Idiopathic renal haematuria
(Berger’s IgA nephropathy)
1. Subendothelial deposits are present; C3 compo-
nent of the complement in granular form is al- Characteristic of the disease is reccurrent micro-
most regularly found or macrohaematuria. The microscopic examina-
tion reveals large deposits of IgA in mesangium and
in glomeruli. Haematuria is often associated with
2. Lamina densa of basement membrane is ex- rather moderate proteinuria. The level of IgA in
tremely dense; therefore is this condition termed serum is increased. In skin examination the IgA,
the dense deposit disease. The basement mem- C3 component of the complement and fibrin deposits
brane of Bowman’s capsule and of tubules are are ofen observed in skin capillaries. Similar skin al-
damaged, deposits of C3 component of com- terations occur in Henoch–Schönlein purpura. The
plemet and a few IgM are present. Berger’s IgA nephropathy might be in fact a form
of this purpura. The biopsy shows a wide range of
changes in glomeruli. The most frequently are such
The systemic arterial pressure is usually increased,
alterations present which are typical of the segmen-
the glomerular filtration decreases. Fibrin degrada-
tal proliferative glomerulonephritis. The progression
tion products and the C3 component of complement
of disease is slow. It results about in a half of cases
are present in urine. The C3 plasmatic level falls. In
in renal failure.
the first, above mentioned type of disease, circulating
Histological changes in kidneys are sometimes not
immune complexes are found. Similar alterations as
observed, apart from IgM and IgG deposits. In this
in type I occur in haemolytic uraemic syndrome, in
case is the prognosis of disease favorable.
transplant rejection and in chronic hepatitis. Nearly
60 per cent of patients die over a ten-years period of
renal failure. 4.9.4.2 Isolated glomerular proteinuria
Other forms of idiopathic nephrotic syndrome of non-nephrotic type
This group may include conditions with not very Proteinuria does not exceed 3,5 g of proteins / 1,73 m2
clearly defined rather modest bioptic findings as of body surface per day. It is usually not associated
the mesangial proliferative glomerulonephritis, or the with renal alterations and the urinary sediment use
crescentic glomerulonephritis, or finaly the segmen- to be normal. The orthostatic proteinuria is the most
tal proliferative glomerulonephritis. Deposits of IgA common type of this proteinuria.
and IgM may be present and haematuria with pro-
teinuria use to occur.
4.9.4.3 Chronic glomerulonephritis
Nephrotic syndrome can develop also during or fol-
lowing treatment with some sort of drugs. Drug- Chronic glomerulonephritis presents persistent pro-
induced nephropathy occurs frequently after the teinuria and/or haematuria and progressive deterio-
therapy of patients with rheumatic arthritis with ration of renal functions. The condition leads to the
gold containing drugs. Idiopathic nephrotic syndrom hypertension of shrunken kidneys and renal failure.
may be induced also by application of antiserum dur- The terminal stage is preceeded by changes which
ing infection diseases. could form three groups of typical processes:
4.9. Glomerulopathies 293

1. Proliferative processes: as in endo and extracap- 4.9.5.1 Systemic lupus erythematosus

illary proliferative glomerulonephritis, focal and
segmental proliferative glomerulonephritis The underlying cause of lupus erythematosus is till
now unknown. The serum of patients suffering from
2. Sclerosing processes; focal and diffuse glomeru- systemic lupus erytematosus contains large amount
losclerosis of antibodies against DNA, nucleoproteins, and sev-
eral components of nuclei. These antibodies are
termed in common: antibodies against nuclear anti-
3. Membranous processes; are the most frequently
gens (ANA antibodies to nuclear antigens). The an-
occuring
tibodies per se do not damage living cells providing
they do not penetrate the cell membranes. ANA
The so-called chronic nonspecific glomerulonephri-
tis may exceptionally be included. Chronic glom- form complexes with their specific antigens. DNA
erolonephritis is not a specific nosologic unit. It rep- and the antibodies to DNA, nuclear proteins, anti-
resents, in fact, a group of diseases with various eti- bodies to nuclear proteins and the components of the
complement are observed in the basement membrane
ology, pathogenesis, course, morphological and clin-
of glomerular capillaries, but also in basement mem-
ical pictures. The chronic glomerulonephritis is not
presented by typical strictly defined clinical features, brane of other capillaries.
thus it is diagnosed usually by different ways: The pathological process in glomeruli leads to mas-
sive haematuria and proteinuria associated with ful-
1. by appearence of pathologic urinary finding, im- minant inflammatory alterations. Impairment re-
paired renal functions and systemic arterial hy- sults in renal failure. Of the large number of variable
pertension in subjects with moderate clinical glomerulonephritis forms associated with lupus ery-
symptomatology thematosus some clinical pictures may be defined on
the basis of glomerular morphologic changes.
2. by statement of renal disease progression and Mesangial lupus glomerulonephritis is presented
impairment with appearence of hypertension by proliferation of mesangial cells or by mesan-
and anaemia gial sclerosis.Immunofluorescent examination reveals
IgG, IgM, IgA immunoglobulins and C1q, C4 and C3
3. by determination of glomerulonephritis exacer- components of the complement forming outstanding
bation during viral or bacterial diseases electrodense deposits. Glomerular filtration use to
be normal at the beginning. Occurence of hyper-
Some symptomes dominate the clinical picture of tension is not constant. The development of disease
chronic glomerulonephritis. The most important are: depends on disturbances of other organs.
symmetric shrinkage of kidneys, severe proteinuria Focal lupus glomerulonephritis In this condition
and pathologic finding in urine sediment. In sedi- focal and segmental distribution of cell proliferation
ment prevail the erythrocyte casts. is observed, often associated with necrosis and diffuse
The chronic glomerulonephritis could be virtually mesangial hypercellularity. The glomerular deposits
limited in time. It can be, in fact, any type of se- of immunoglobulins and complement components are
vere glomerulonephritis in the period before the renal larger than in mesangial form. The mesangium and
failure. glomerular capillary loops are involved. Subendothe-
lial deposits are observed. Impairment can lead to
nephrotic syndrome. The glomerular filtration rate
4.9.5 Glomerulopathies in other is usually not changed. The disease may progress
diseases like diffuse proliferative glomerulonephritis.
Diffuse proliferative lupus glomerulonephritis Dif-
Glomerular damage is observed in several systemic fuse proliferation of mesangial and endothelial cells
diseases. It may be the dominant finding in is typical of this disease. In addition focal cellular
metabolic disturbances (diabetes mellitus), neoplas- necrosis is found. Subendothelial and subepithelial
tic processes, genetic disorders, in diseases where dif- deposits and extracapillary proliferation are present.
ferent immune processes are the underlying cause. Nearly in all glomerular loops granular deposits of
294 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

immunoglobulins and complement components are sity. Even gastrointestinal haemorhage with perfora-
observed.In this type of glomerulonephritis the pa- tion may occur. The renal damage is manifested by
tients have severe proteinuria and progressively im- haematuria and proteinuria. The disturbance may
pairing renal functions. progress rapidly in form of nephritis or nephrotic
Membranous lupus glomerulonephritis is similar syndrome. The beginning of disease may be pre-
or rather identical with the idiopathic membranous sented as postinfectious glomerulonephritis. About
glomerulopathy. In addition mesangial deposits and in one half of patients is the IgA level in serum in-
proliferation of mesangium are observed. The walls creased. Renal biopsy reveals a wide range of al-
of glomerular capillaries are thickened in subepithe- terations. Diffuse proliferation of mesangial cells or
lial region by deposits of immunoglobulins and com- focal segmental proliferative glomerulonephritis can
plement components. Nearly in all patients a mas- occur. The picture of diffuse proliferative glomeru-
sive proteinuria with signs of nephrotic syndrome is lonephritis may also occur, associated sometimes
present. The glomerular filtration rate progressively with extracapillary proliferation. Granular deposits
diminishes. Disease results in renal failure. Rapid of IgA, IgG, C3, properdin and fibrinogen are usually
obliteration of capillaries occurs in some nephrons. present. It is supposed, that the Henoch-Schönlein
Owing to this glomeruli undergo sclerosis. This is purpura may be very probably caused by immune
usually the last stage of disease. complexes containing IgA. The origin of antigen is
not known. The IgA nephropathy (m. Berger) could
4.9.5.2 Goodpasture’s syndrome be considered to be a form of Henoch-Schönlein pur-
pura.
The characteristic features are pulmonary haemor- The course of disease may be benign, in some pa-
hage, glomerulonephritis and presence of antibod- tients however, it can result in renal failure.
ies to basement membrane antigens. The pulmonary
haemorhage may be of various severity. During the 4.9.5.4 Renal lesions in various types of sys-
cough might the haemoptysis become very dramati- temic vasculitis
cal. Otherwise it can be mild but longlasting, leading
to sideropenic anaemia. The haemoptysis can be as- Glomerular disturbances use to be associated with
sociated also with renal failure, systemic lupus ery- diseases manifested by inflammatory vascular le-
thematosus, Henoch–Schönlein purpura, cryoglobu- sions. The most typical are: the macroscopic and
linaemia, pulmonary embolia Legionnaires’ disease microscopic polyarteritis nodosa and the Wegener’s
and further conditions. The extracapillary prolif- disease.
eration is often present.Renal failure might develop Macroscopic polyarteritis – typical features in this
rapidly. The histologic examination shows typical condition are the inflammatory lesions of large ves-
linear deposits of antibodies to basement membrane, sels. Occlusions of renal vessels and renal infarctions
associated sometimes, with C3 deposits. may occur. Deposits of immune complexes are found
In peripheral blood of 90 per cent of pacients, pres- in vessels. These immune complexes are in some
ence of circulating antibodies against the glomerular cases in connection with hepatitis B in anamnesis
basement membrane, alveoli and tubules is stated. of the patient. The level of circulating immune com-
The levels of these antibodies do not provide a pre- plexes use to be increased, hypertension associated
cise information on the severity of the condition and with microangiopathic haemolytic anaemia is often
on the degree of the damage. present. Fever, abdominal pain, skin alterations and
disorders of nervous system and coronary vessels oc-
cur occasionally.
4.9.5.3 Henoch–Schönlein purpura
Microscopic polyarteritis affects small vessels of
Presence of nonthrombotic purpura, arthralgia, ab- kidneys and other organs. The pulmonary vessels are
dominal pain and glomerulonephritis are the char- often involved. Antibodies to basement membrane
acteristic features of this condition. The underlying are often present. During the pulmonary vessels in-
cause of purpura is the vasculitis in the skin, domi- volvement eosinophilia appears. The picture of seg-
natly in the vicinity of low extremity joints. Arthral- mental or diffuse capillary necrosis is observed in kid-
gia and abdominal pain may be of various inten- neys. In affected glomeruli deposits of IgG and IgM
4.9. Glomerulopathies 295

are found. Some patients with macroscopic or mi- is the deposition of circulating immune complexes
croscopic polyarteritis may have rheumatoid arthri- composed of tumor antigens and antitumor antibod-
tis. The prognosis depends on glomerulonephritis ies. Lymphomas and leukaemias are also associated
progression. with glomerulopathies. Proliferative and sclerosing
Wegener’s granulomatosis is a vasculitis dissemi- glomerulopathy is dominant in the histological pic-
nated in upper airways and kidneys. In lungs, kid- ture.
neys and other organs sclerosing vasculitis can be
seen due to the deposition of immune complexes. 4.9.5.8 Renal disorders in rheumatoid
The origin of the antigen is unknown. arthritis
can develop as consequence of gold therapy or peni-
4.9.5.5 Cryoglobulinaemia
cillamine treatment. The clinical picture may be
This disturbance is associated with the presence similar to the amyloidosis, or to the disturbance
of circulating immuno-globulins praecipitating re- described in systemic lupus erythematosus. Dur-
versibly when exposed to cold. They consits usually ing rheumatic fever proliferative glomerulonephritis
of IgG and IgM. Purpura, necrosing cutaneous le- may occur. Chronic hepatic diseases are often con-
sions, arthralgia, fever and hepatosplenomegaly may nected with renal disturbances. In chronic active
occur. The condition can be due to hepatitis B, hepatitis membranous proliferative glomerulonephri-
bacterial, viral mycotic and other diseases. Cry- tis with deposits of immune complexes occur. Hep-
oimmunoglobulins may be found in serum also dur- atic cirrhosis use to be accompanied with glomeru-
ing several further diseases. The cryoimmunoglob- losclerosis. In alcoholic cirrhosis deposits of IgA can
ulins praecipitate in glomerular capillaries, thus the be found in mesangium.
clinical picture of acute renal failure or of rapidly
progressing glomerulonephritis, or of nephrotic syn- 4.9.5.9 Diabetic nephropathy
drome can develop. The complement level in serum
is often reduced and circulating immune complexes All renal disturbances appearing in diabetic pa-
are regularly present. The picture of diffuse prolif- tients are termed diabetic nephropathy. Glomeru-
erative glomerulonephritis with circulating cryoim- losclerosis, arterionephrosclerosis, chronic interstitial
munoglobulins may develop. nephritis, papillary necrosis and various tubular dis-
orders are observed most commonly. The diabetic
nephropathy use to be associated with several clinical
4.9.5.6 Plasmacytoma (multiple myeloma)
syndromes, mainly with asymptomatic proteinuria,
The most frequent renal damage in plasmacytoma nephrotic syndrome, renal failure and hypertension.
is the amyloidosis. Amyloidosis however, may occur The diffuse diabetic glomerulosclerosis is the most
in several pathologic conditions. The celullarity in frequent type of renal damage in diabetics. Mod-
glomeruli is reduced and glomeruli are progressively erate enlargement of mesangial matrix and thicken-
infiltrated by amorphous amyloid deposits. Amyloid ing of glomerular capillary basement membrane are
is a protein with typical ultrastructure. The renal observed. Degenerative process in form of hyaline
amyloidosis is a persistently progressing disease. arteriosclerosis affects vasa afferentia. In diabetes
where the antibodies to the Langerhans’ islet cells are
present, intercapillary nodes are formed in kidneys
4.9.5.7 Neoplastic diseases
(intercapillary glomerulosclerosis) and enlargement
Glomerular lesions may appear in various neoplastic of mesangial matrix occurs. The nodes do not con-
conditions. Adenocarcinoma of lung, colon, stomach tain cells. In other cases may occur, on the contrary,
and breast, especially, can lead to the development of the picture of membranous proliferative glomeru-
idiopathic membranous glomerulonephritis. The fo- lonephritis. Pathogenesis of diabetic nephropathy
cal or segmental proliferative glomerulonephritis or is not well understood, nevertheless it depends, in
amyloidosis dominates the histological picture. The a considerable degree, on metabolic compensation of
disturbance is clinically presented by nephrotic syn- diabetes.
drome. The underlying cause of glomerular lesion Diabetic nephropathy is clinically presented by
296 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

moderate and asymptomatic proteinuria. Even be-

fore proteinuria appears carbohydrate intolerance is
almost in all cases present. The glomerular filtration 4.10 Infections of the urinary
rate is normal or increased. tract
When the proteinuria appears during the diabetes,
glomerular filtration begins to decrease. Very exact
regulation of glucose level in peripheral blood can sig-
nificantly delay the appearence of diabetic nephropa- In most cases of urinary system infections is bac-
thy. teriuria present. Bacteriuria is a condition where
in the midstream urine more than 105 bacteria are
4.9.6 Hereditary glomerulopathies found. Less amount of bacteria may also indicate in-
fection if the urine was obtained by catheterization or
4.9.6.1 Alport’s syndrome (hereditrary by suprapubic aspiration. Bacteriuria however, migt
nephritis with deafness) be absent in some cases, thought the urinary system
Pathogenesis of this condition is not known ex- infection is evident. This situation may occur follow-
actly. There is a disorder of glycoprotein, non- ing or during the antibiotic treatment, during high
collagenous components of glomerular and tubular urea concentration in urine and when the pH of urine
capillary basement membrane synthesis. The clini- is low.
cal manifestation is haematuria and proteinuria. The
microscopic picture shows commonly focal and dif- 4.10.1 Cystitis, acute pyelonephritis,
fuse glomerular proliferation with segmental sclero- urethritis
sis.
Various types of microbes might be the underlying
4.9.6.2 Fabry’s disease (hereditary dystopic cause of these diseases. Ninety per cent of acute
lipidosis) urinary tract infections are caused by Escherichia
coli. Further Gram-negative microbes, as Proteus,
is an inherited disorder of glycosphingolipid meta- Klebsiella, Enterobacter and Pseudomonas may be
bolism with accumation of trihexosylceramide in the responsible for urinary infections. They participate
tissues of eye, skin, cardiovascular system and kid- in nosocomial infections. Among the Gram-positive
neys. In glomeruli, tubules and in renal interstitium cocci the enterococci and staphylococcus saprophyti-
typical foam cells are found with lipid vacuoles and cus occur most commonly. The viral infections may
excentric location of nucleus. Clinical manifestation be the cause of cystitis and pyelonephritis.
of disease are: haematuria and proteinuria with pro- Under physiological circumstances the urinary
gressive development, resulting in renal failure. tract cannot be settled by micro-organisms. The
urine dispose of direct antibacterial effects. The high
4.9.6.3 Congenital nephrotic syndrome urea content and the high osmolarity of urine kill di-
rectly the pathogenic germs. The prostatic secretion
is a fatal hereditary disease, inherited as an auto-
has also antibacterial activity. The polymorphonu-
somal recessive trait, manifested by nephrotic syn-
clear leucocytes in the urinary bladder wall also have
drome in first weeks of life. The synthesis of glomeru-
a protective function.
lar and tubular basement membrane components is
Favorable conditions for infection arise if obstruc-
pathologically altered. Large amount of proteins
tion occurs. Tumors of urinary tract, urinary cal-
cross the impaired basement membrane. The pro-
culosis and hypertrophy of prostata may lead to hy-
teinuria of non-selective type is very massive. The
dronephrosis and urinary tract infections. In these
disease leads to renal failure. Concomitant infection
cases the concomitant infection accelerates the renal
is commonly fatal.
tissue destruction.
Vesicoureteral reflux facilitates sometimes the de-
velopment of infection. The reflux of urine may at-
4.10. Infections of the urinary tract 297

tain ureters or even renal pelvis. Reflux occurs most function. Patients with chronic pyelonephritis have
commonly in anatomic aberrations. a history of frequent, repeated urinary outflow tract
Renal disturbances raise the possibility of infec- infections with impaired renal functions. Their urine
tions appearence. It is not known if renal hyper- contains pus, leucocyte casts and bacteria. Alter-
tension accelerates the infection occurence. The dia- ations of renal pelves can be detected by excretion
betic nephropathy has, however, a very close relation urography. In other cases this finding can be absent
to the urinary tract infections. During the diabetic in spite of chronic pyelonephritis presence.
nephropathy the chronic pyelonephritis occurs most Kidneys are of uneven magnitude, with irregu-
frequently and necrosing papillitis is easily develop- lar, rugged surface. The pathologic process be-
ing. Renal papillae and medulla are very receptive gins usually in renal interstitium, in medullar re-
to pathogenic microorganisms. gion and in renal papillae. Fibrous tissue, lympho-
Infections of urinary tract can clinically occur as cytes and plasma cells replace completely the inter-
strictly defined diseases. Bacteriuria per se occurs stitium and the tubules. In the interstitium, mainly
also in completely asymptomatic patients. Cystitis in the medulla renis are foci of inflammation. In some
has a rather strict clinical symptomatology. Acute tubules leucocyte casts occur, in others large amount
pyelonephritis may include the symptomes of the cys- of eosinophilic material and colloid casts are found.
titis and further signs as fever attacks, nausea, vom- These tubules are dilated. Proliferative arteritis may
iting, diarhea and tachycardia. Leucocyte casts and be present. None of these alterations is pathognomic
purulent matter are found in urine. Bacteriuria and for chronic pyelonephritis. The finding in kidneys de-
pyuria may persist longtime. Haematuria is present scribed above may appear during diabetic nephropa-
only at the beginning of disease. During urethral thy and many different nephropathies.
syndrome dysuric troubles are dominant. Infections The chronic pyelonephritis does not have any typ-
of urinary tract in hospitalized patients occur namely ical clinical manifestation. Systemic arterial hyper-
in connection with catheterization. tension is commonly found stimulating the search
for the underlying cause. Patient usually visits the
4.10.2 Prostatitis doctor only when the first signs of renal failure ap-
pear: fatigue, malaise, nausea, tendency to suffusion
Prostatitis includes various types of inflammatory formation, anorexia, body weight loss, polyuria and
processes comprising acute and chronic inflamma- nycturia. The progression of pyelonephritis is accom-
tions caused by specific bacteria. Clinical manifes- panied with decreased glomerular filtration rate an
tations are: sacralgia, and peritoneal pains. Some- reduced renal blood flow. The picture of uraemia is
times testicular dyscomfort and moderate dysuria developing. Proteinuria raises to 2 g/day. The renal
are experienced. In additions, microscopic pyuria ability to concentrate urine decreases. Presence of
and haematuria are occasionally observed. bacteria, leucocytes, leucocyte casts in urine may be
The underlying cause of acute prostatitis use to only intermittent. Renal biopsy can be completely
be the Gram-negative bacterial flora or Staphylococ- normal.
cus pyogenes aureus. It is difficult to diagnose the Chronic pyelonephritis need not cause dyscomfort
chronic bacterial prostatitis, because the symptomes and troubles to patients until the renal functions do
are often inapparent. In uric sediment excessive leu- not impair substantially. Hypertension makes the
cocyte numbre may be found. The bacteriologic ex- prognosis of patient worse. During acute infection
amination however, might be negative. Dysuric dis- or dehydration the renal functions may become es-
orders appear when infection reaches urinary blad- sentially impaired. The impairment can result even
der. in uraemia. At the beginning is the impairment usu-
ally reversible.
4.10.3 Chronic pyelonephritis
4.10.4 Papillary necrosis
This term indicates the condition developing follow-
ing renal infections. It can occur under the influ- Renal papillae play a very important role in the
ence of predisposing factors as obstructions, vesi- pathogenesis of chronic interstitial nephritis. Renal
coureteral reflux and disorders of urinary bladder papillae have high affinity to bacterial infection. It is
298 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

very probable that first occurs the papillary damage that only some of these alterations might be caused
and the chronic interstitial nephritis develops later. by infection. In tubulointerstitial disturbances are
Papillae may be damaged during arthritis urica, and non-bacterial factors involved, as: exogenous toxins,
diabetes mellitus. Relatively frequently the papillary immunologic and metabolic disorders.
lesions occur during treatment with various drugs. Tubular disturbance is manifested by impaired
Some substances attain just in papillae high concen- capability of concentration of the urine, by de-
trations affecting with toxic action papillae and the creased reabsorption of filtered solutes, especially
surrounding area. The effect of phenacetin – a com- of amoinoacids, phosphates, sodium, chlorides and
ponent of analgesic tablets is well known. It is not potassium. Tubular alterations appear at the begin-
understood exactly which substances can damage re- ning separatly, later they become concomitant. The
nal papillae. It is suggested however, that the uri- structural alterations lead to the progressively re-
nary tract infections might cause papillary lesions. duced glomerular filtration rate. Tubulointerstitial
Papillary necrosis appears when the infection is damage causes secondary glomerular disturbances of
retained in renal pyramids. Participation of a fur- glomeruli and their involution.
ther factor is necessary to give rise to the papillary Kidneys have to excrete unnecessary substances,
necrosis. These factors are often: diabetes mellitus, toxins or drugs from the body. This is why these sub-
chronic alcoholism and blood vessel diseases. stances cummulate in urine. Various medicaments,
Clinical manifestations of papillary necrosis are: the antibiotics above all, can damage the renal inter-
back pains, abdominal pains, and fever. Acute renal stitium.
failure with oliguria or anuria can occur occasionally.
A sudden impairment of renal functions in patients
with diabetes mellitus or with obstruction of ureters 4.11.1 Nephropathies
signalizes almost in every case the papillary necrosis.
If so, fever or pains are not present. 4.11.1.1 Phenacetin nephropathy (Analgesic
nephropathy)

It is known that in persons taking large amounts

of analgesics lesions of renal interstitium and pap-
illar necrosis frequently are developing. Especially
4.11 Tubulointerstitial phenacetin and acetylosalicylic acid can cause papil-
renal diseases lary necrosis.
Analgesic nephropathy is characterized by pap-
illary necrosis and tubulointerstitial inflammation.
The papillary necrosis occurs usually following
A large group of diseases exists affecting both the tubulointerstitial inflammation which causes
kidneys simultaneously, in which morphologic alter- glomerular filtration rate decrease.
ations in interstitium and in tubules are present. Papillary damage following phenacetin intake is
Also the functional disturbances are limited rather due to its metabolite acetaminophen. Its concen-
exclusively to the tubules and interstitium. tration in papillae is ten times higher than in re-
Glomeruli and the renal vessel system are usually nal cortex. High water intake reduces papillary ac-
not involved. Interstitial edema prevails in acute etaminophen concentration and protects the papil-
form of these diseases, associated often with corti- lae from necrosis. Acetylosalicylic acid inhibits the
cal and medullar infiltration by polymorphonuclear synthesis of renal prostaglandins which are impor-
leucocytes. Here are the foci of celullar necrosis. In tant vasodilating factors. Thus, the acetylosalicylic
chronic forms more outstanding interstitial fibrosis, acids acts simultanously by its toxic and by indirect
mononuclear inflammatory infiltration with signs of vasoconstrictive effects increasing so the possibility
atrophy are observed. The tubular lumen is dilated of renal damage appearing.
and the basement membranes are thickened. In past Analgesic nephropathy is developing usually if the
was this morphologic finding considered to be the daily intake of phenacetin, lasting 1 to 3 years, is 1
picture of chronic pyelonephritis. We are aware now, to 2 g.
4.11. Tubulointerstitial renal diseases 299

In analgesic nephropathy is the patients condition an inflammatory process with lymphocytic infiltra-
impaired by repeated renal colics caused by frag- tion. Fibrosis develops in medullar and papillary
ments of necrotic tissue. The colic is usually accom- regions. Systemic arterial hypertension, hyperlipi-
panied with haematuria. Proteinuria is rather mod- daemia and degenerative alterations of renal arteri-
erate. Kidneys of patients with analgesic nephropaty oles are commonly obeserved in patients. Owing to
lose the capability to concentrate maximally the the renal interstitium lesions the capability of urine
urine. Anaemia and systemic arterial hypertension concentration is diminished. The interstitial fibrosis
are developing proportionally with azotaemia. Dis- progresses and leads usually to renal failure.
ease may progress rapidly resulting in renal failure.
Even when the progression is slow the disease leads 4.11.1.4 Hypercalcaemic nephropathy
to renal failure.
The cause of nephropathy is the chronic hyper-
4.11.1.2 Nephropathy due to lead intoxica- calcaemia. Persistent, chronic hypercalcaemia ap-
tion pears during primary hyperparathyroidism, sar-
coidosis, multiple myeloma, vitamin D intoxication
Chronic lead intoxication is always associated with and metastatic skeletal processes. The tubulointer-
renal tubulointerstitial damage. The lead accumu- stitial damage arises first, resulting in renal failure.
lates in cells of proximal tubules and induces de- The persistent hypercalcaemia causes at the begin-
generation of these cells. The tubular degenera- ning damage of cells of Henle’s loop, distal tubules
tive alterations are accompanied with ischemic al- and collecting ducts. The cell damage is very se-
terations of glomeruli and fibrosis of small arteries vere and leads to necrosis. The cell necrosis may be
in cortical region. Azotaemia develops and tubu- the underlying cause of tubular system obstruction
lar functions impair. The renal glycosuria and resulting in intrarenal urine stasis and calcium prae-
aminoaciduria may appear. In patients with this cipitation. During this disturbance are the kidneys
type of nephropathy the hyperuricaemia is always usually affected by infection.
present due to enhanced uric acid reabsorption. Hy- The tubular cell necrosis and destruction of
pertension, peripheral neuropathy and encephalopa- nephrons due to their obstruction, leads to intersti-
thy appear later. tial fibrosis, mononuclear leucocytic infiltration and
Further toxic substances like heavy metals, radio- interstitial calcium deposition. This condition has
graphic contrast media and antibiotics may induce been termed in past nephrocalcinosis. Calcium de-
similar clinical picture of nephropathy. posits may occur in glomeruli and in blood vessels.
Kidneys lose the ability to concentrate the urine.
4.11.1.3 Hyperuricaemic nephropathy Collecting ducts lose partly the capability to re-
sponse to ADH. The glomerular fitration rate falls.
During overproduction of uric acid may the hyperuri- In long lasting hypercalcaemia nephrolithiasis arises.
caemia cause acute renal failure termed sometimes
– the hyperuricaemic nephropathy. This condition
4.11.1.5 Hypokalaemic nephropathy
does not develop during classic hyperuricaemia. The
acute hyperuricaemic nephropathy may arise during Potassium depletion leads in relatively short time
treatment of lymphoproliferative or myeloprolifera- to severe morphologic and functional alterations in
tive diseases by cytotoxic substances. In hyperuri- kidneys. Alterations of tubular epithelial cells with
caemic nephropathy the deposits of uric acid crys- typical excessive vacuolization may appear. The
tals are formed in collecting ducts, renal pelves and glomerular cells are usually not affected. Clini-
ureters. They may cause obliteration and acute renal cal symptomes of hypokalaemic nephropathy appear
failure characterized by oliguria and rapid increase of before the morphologic changes become apparent.
creatinine concentration. Crystals of uric acid can be Polydipsia, polyuria and nycturia are typical signs
found in urine. Haematuria occurs frequently. of longstanding potassium depletion. Enhanced in-
During long lasting hyperuricaemia the nephropa- trarenal prostaglandin production contributes to the
thy can develop. Uric acid and monosodium urate renal alterations. Prostaglandins antagonize the os-
deposits are formed in renal parenchyma, inducing motic effects of ADH in collecting ducts. It is how-
300 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

ever not well understood to which extend the mani- 4.11.1.10 Balkan nephropathy
fested pyelonephritis might participate in these alter-
ations. Therapeutic management of hypokalaemia This condition occurs in the watershed of Danube.
and the best adjustment of potassium levels in serum Its occurence is endemic and the underlying cause
leads within several months to functional and mor- unknown. The histological examination shows tubu-
phologic renal improvement. lar atrophy, interstitial oedema and diffuse intersti-
tial fibrosis. Disease can result in renal failure.
4.11.1.6 Neoplastic processes
In malignant processes renal alterations with vari-
ous manifestation are observed. Postmortal studies
revealed histological renal alterations in about 50 per 4.12 Renovascular diseases
cent of patients. Not only the metastatic process by
itself, but also metabolic disturbances due to the ba-
sic primary disease cause renal damage.
This group of diseases comprises renal distur-
4.11.1.7 Tubulointerstitial reaction due to bances related to renal blood supply. The primary
drugs disorder is in fact of non-renal origin. Disturbances
occuring during stenosis and occlusion of renal arter-
Many drugs may be the cause of tubulointerstitial
ies, nephrosclerosis, polyarteritis nodosa, haemolytic
renal damage. In addition to sulphonamides, the
uraeamic syndrome, scleroderma, and prae- eclamp-
antibiotics and diuretics may be nephrotoxic. The
sia may be included. Renal damage depends on the
renal lesions are observed interstitium. Oedema and
speed of occlusion development determining the ex-
polymorphonuclear leucocytic infiltration of intersti-
tent of ischaemia.
tium is frequently found. In extensive damage the
necrosis of tubular cells is observed. As already mentioned, the renal blood flow
In addition the drugs attach to the basement through kidney, calculated per gram of tissue is the
membrane whereby it becomes antigenic. If this highest in the whole organism.It exceeds many times
occurs the disturbance will present clinically two the heart, liver and brain blood flow. The purpose of
weeks after the drug administration in form of acute this arrangement is not only the oxygen supply but,
glomerunephritis. above all, the glomerular plasma filtration. Kidneys
have at disposal several mechanisms to ensure ap-
propriate filtration of plasma and a proper sodium
4.11.1.8 Sjögren’s syndrome
economy. Nevertheless, these mechanisms may influ-
Dry keratoconjunctivitis and lesions of mucous mem- ence other systems, mainly the circulation and act at
branes of salivary and lacrimal glands are due to their expense. Extremely reduced glomerular filtra-
immunological disturbance, accompanied sometimes tion can result in renal failure.
with rheumatic arthritis. Renal impairment may be
found. Histologic examination shows lymphocytic 4.12.1 Diseases related to the blood
infiltration in tubulointerstitial region of kidneys.
supply
4.11.1.9 Irradiation nephropathy 4.12.1.1 Acute renal artery occlusion
Nephropathy due to irradiation is developing several This term includes acute occlusion of the renal
weeks following exposition to radiation. Glomeru- artery, or occlusion of its main intrarenal branch.
lar hyalinization, tubular atrophy, interstitial fibro- The acute occlusion may be caused by trauma or em-
sis and hyalinization of media of renal arteries are bolia. Embolus can occur in stenosis of mitral valve,
found. The underlying cause of these alterations is is- in bacterial endocarditis, myocardial infarction or
chaemia due to irradiation damage. Azotaemia, sys- atherosclerosis of aorta. The embolus might be, of
temic arterial hypertension, anaemia and proteinuria course, of various size and according to it, it can oc-
are rapidly developing. clude small or larger branches of renal artery. The
4.12. Renovascular diseases 301

resulting coagulation necrosis is located in the region 4.12.1.4 Sclerodermia

supplied by occluded artery. The clinical manifesta-
Is an uncommon disease caused by autoimmune le-
tions depend on the necrosis extent. A restricted
sions of blood vessels and of connective tissue. The
infarction located in renal cortex might not be clin-
alterations are usually present in the skin, lungs, and
ically apparent. A large infarction induces an im-
especially in kidneys and oesophagus. The intralob-
mediate, intense and permanent lumbal pain accom-
ular arteries in kidneys are notably narrowed, some-
panied with fever leucocytosis and haematuria. It
times completly occluded by fibrinoid alterations and
is to realize, that the occlusion of renal artery main
deposits of fibrin and mucopolysaccharides. In other
branch need not lead to evident alterations in blood.
cases fibrin thrombi and fibrinoid necrosis are ob-
If the functions of the other kidney are preserved the
served. The condition may lead to systemic arterial
urea and creatinine plasmatic levels are not elevated.
hypertension. When concomitant oliguria occurs,
sclerodermia progresses rapidly to the fatal end.
4.12.1.2 Renal artery stenosis
Partial occlusion (stenosis) of renal artery or of its 4.12.1.5 Nephropathies in condition with
main branch is commonly due to atherosclerotic nar- abnormal haemoglobin types
rowing or to fibromuscular dysplasia of the vessel.
Presence of abnormal haemoglobins (e.g. of hae-
The main consequence of stenosis is the hyperten-
moglobin S) is relatively frequently accompanied
sion. Intrarenal pyelography and radionuclid renog-
with morphologic and functional renal disorders.
raphy may reveal the cause of hypertension. The af-
The best known disease of this group is the sickle cell
fected kidney is notably smaller. Arteriography pro-
anaemia. Sudden, unexpected haematuria appears
vides the definitive distinction.
without preceding trauma or other overt cause. Re-
nal urinary concentrating ability use to be impaired.
4.12.1.3 Arteriolar nephrosclerosis Vascular lesions are most notable in vasa recta. If
the proteinuria is severe, this condition may develop
Alterations of small renal vessels are considered to
like nephrotic syndrome. The underlying cause are
be in relation to systemic arterial hypertension. This
the microscopic infarctions in kidneys,commonly lo-
conception could be accepted with some reservations.
cated in papillae and in renal cortex. Infarctions are
Alterations of small renal vessels have been found in
due to hypoxia and elevated osmolality of blood of
subjects with normal values of blood pressure ,de-
these patients.
seased in age more than 60 years. Signs of ischaemic
atrophy and glomerular sclerosis associated with al-
terations of small vessels are present in patients with 4.12.1.6 Haemolytic-uraemic syndrome
hypertension. The most important symptomes are: the haemoly-
The alterations in small vessels are sometimes sis, decreased numbre of thromocytes and intravas-
thought to be a concomitant sign of aging. They cular coagulation. Combination of acute renal failure
explain the reduced glomerular filtration rate occur- with haemolytic anaemia and thrombocytopenia oc-
ing in elderly. curs commonly in children. The prothrombin time
In essential hypertension the acceleration of is usually prolonged and fibrin degradation products
nephrosclerosis may appear, leading to malignant appear in serum. It is not well understood how are
hypertension. This reversal can arise also dur- the kidneys involved in this complex disturbance.
ing secondary hypertension including hypertension
in glomerulonephritis, pyelonephritis, pheochromo-
4.12.1.7 Thrombosis of renal veins
cytoma and in other diseases. In kidneys petechiae,
fibrinoid necrosis of afferent arterioles and the hyper- Commonly occurs during membranous glomeru-
plastic endarteritis occur. lonephritis. It may apper during the vena cava
The clinical picture is completed by hypertensive thrombosis, trauma, or hypernephroma and extreme
encephalopathy, progressive uraemia and heart fail- dehydration. Morphologic alterations and the clin-
ure. Proteinuria and haematuria are present. Plas- ical picture will depend on the occluded vein cal-
matic levels of urea and creatinine are elevated. ibre and on the collateral blood flow. Complete
302 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

thrombotic occlusion is manifested by intensive pain, prae-eclampsia or eclampsia are the candidates for
haematuria, oliguria and renal failure. If the renal later developing of hypertension.
functions recover a massive proteinuria appears.

4.14 Hereditary renal diseases

4.13 Prae-eclampsia and
eclampsia

4.14.1 Polycystic kidney disease

In the last trimester of pregnancy sometimes ab-
normalities occur chacterised by trias of symptomes: Is inherited as an autosomal dominant trait. It is
systemic arterial hypertension, oedemas and protein- relatively uncommon, occuring in 5 per cent of all
uria. This condition is termed prae-eclampsia. In terminal renal conditions.
some cases unconsciousness and convulsions with im- Globular cysts of various dimmensions, with di-
paired hypertension may occur. This condition is ameter measuring from 1 mm to some cm, occur in
termed eclampsia. kidneys. Among the cysts are islets of normal tis-
In kidneys a generalized oedema is present. The sue. The cysts are pressing the nephrons and cause
thickened glomerular capillary basement membrane so intrarenal obstruction. The cysts may occur also
and narrowed capillary lumen due to enlargement in other close, or distant organs.
of endothelial cells occur. This finding is some- The disease becomes clinically manifest in adults
times termed glomerular endotheliosis. In addi- by lumbosacral pains or haematuria appearing fol-
tion, between and under the endothelial cells fib- lowing trauma or physical exertion. The condition
rinoid deposits are observed. In patients deceased is in many cases associated with hypertension and
in this stage of disease necroses in renal tubules, leads to the progression of renal failure. Proteinuria
liver cells, petechial haemorrhage in brain accompa- is present very frequently. Acute renal failure may be
nied with signs of disseminated intravascular coag- due to the obstruction, resp. compression of ureters
ulation are found. The pathogenesis of this condi- by large cysts.
tion is not clear. Attention is focused mainly on One form of polycystic kidney disease is combined
renin-angiotensine-aldosterone system and sodium with congenital hepatic fibrosis and portal hyper-
balance. It is generally accepted,that during the tension; it is a relatively severe hepatic disturbance,
pregnancy sodium is retained expanding the vol- therefore the hepatic symptoms prevail.
ume of circulating blood. When the symptoms of
prae-eclampsia appear the volume of the plasma is
lower in comparison with nornal pregnancy. It is 4.14.2 Disturbances of tubular func-
not well understood why the plasmatic volume is re- tions
duced. In this condition the signs of utero-placental 4.14.2.1 Bartter’s syndrome
ischeamia are stated. It is generally known that in
uterus the renin and prostaglandins are synthesized. This condition is characterised by hypokalaemia due
Thus, it could be supposed,that the renin production to potassium loss induced by renal disturbances.
in uterus might be responsible for the hypertension. Renin plasmatic acitivy and aldosterone secretion
The hypertension is accompanied with oedemas and are elevated. The pressor reaction following an-
later with proteinuria. giotensin II administration and the cellular hyperpla-
If seizures appear induced termination of gravidity sia in juxta-glomerular apparatus are evident. Weak-
becomes inevitable. This is the most effective thera- ness and polyuria appear in patients. Histological
peutic intervention. All disorders disappear in some examination reveals hyperplasia of interstitial cells
weeks. It is not univocally clear if the women with producing prostaglandins E and F in renal medulla.
4.14. Hereditary renal diseases 303

Decreased NaCl reabsorption in proximal tubules hereditary origin, type 3 is a combination of type 1
and in ascending limb of Henle’s loop are thought and 2. Type 4 is characterised by insufficient urine
to be the cause of above mentioned alterations. The acidification and concomitant hyperkalaemia. Hy-
sodium transport may be disturbed also in erythro- perkalaemia is caused by hyporeninaemic hypoaldos-
cytes and skeletal muscles. The sodium loss due to terinism, or by insensitivity of distal tubules to cir-
decreased reabsorption is associated with water loss. culating mineralocorticoids.
These alterations stimulate the juxta-glomerular ap- Type 1 – the collecting tubules enables the redif-
paratus to increased renin production leading to rise fusion of hydrogen ions from lumen into the blood,
in aldosterone secretion. The sodium reabsorption or the ability to transport the hydrogen ions against
increase is slight and the potassium is lost. The pres- electrochemical gradient into the lumen is decreased.
sor effect of angiotensin II can not be asserted. The Chronic acidosis reduces the tubular calcium re-
angiotensin II intravenous infusion has no effect, its absorption. Hypercalciuria and secondary hyper-
blood level being already extremely high. The PGE 2 parathyroidism appear. In children leads this dis-
production may be due to hypokalaemia or to high turbance to growth retardation.
angiotensin II level. Type 2 – in this type a defective bicarbonate re-
Pharmacologic inhibition of aldosterone effect can absorption is present in proximal tubules. Plasmatic
prevent further potassium loss. bicarbonate level decreases. Bicarbonates are lost
by urine in form of potassium salts. Hypokalaemia
4.14.2.2 Nephrogenic diabetes insipidus is developing.

Distal tubules and collecting tubules do not react 4.14.2.4 Phosphaturia

to the antidiuretic hormone. It is usually a drug-
induced disorder, (e.g. by lithium treatment) and Reduced reabsorption abitily of proximal tubules
only rarely it can be an inherited disturbance. The causes an excessive excretion of phosphates in the
patients urinate large volume of hypotonic urine. urine resulting in plasmatic hypophosphataemia.
Polyuria and the resulting water loss are the cause Patients may have no symptoms. Relatively fre-
of polydipsia and hypertonic dehydration. Decrease quently osteomalacia with all consequences is devel-
in cAMP production in collecting tubules epithelial oping.
cells might be the cause of irreactivity to antidiuretic
hormone. Another possibility could be the inability 4.14.2.5 Cystinuria
of cAMP to increase the permeability of collecting
In this condition the transport of cystine and of other
ducts to water. Both disorders might be combined.
aminoacids having a common transport mechanism
If the symptoms are present from the first week
(lysine, arginine and ornithine) is defective. The dis-
of life, the permanent dehydration, hypernatraemia
turbance leads to an excessive urinary excretion of
and hyperthermia may produce brain damage lead-
mentioned aminoacids. Cystinuria is clinically man-
ing to mental retardation.
ifested by urolithiasis with cystine hexagonal concre-
ments.
4.14.2.3 Renal tubular acidosis
Can be an inherited defect, or it can develop fol- 4.14.2.6 Renal glycosuria
lowing various diseases, like: chronic interstitial Is a defect of tubular glucose transport. Glycosuria
nephrosis, hydronephrosis, polycystic renal disease, appears therefore during normal glycaemia values.
kaliopenic and hypercalcaemic nephropathy. Glycosuria does not depend on diet. Patients with
Metabolic acidosis is due to excessive accumula- this disturbance have a normal results of glucose tol-
tion of hydrogen ions in blood. The excretion of erance test and normal carbohydrate utilisation.
other ions is not impaired. The kidneys reabsorb
an extremly large amount of chlorides to maintain
4.14.2.7 Fanconi syndrome
the electroneutrality of extracelullar fluid. This re-
sults in hyperchloraemic acidosis. Four types of re- The transport defect in this condition is concerned
nal tubular acidosis are known. Type 1 and 2 are of with aminoacids, monosaccharides, sodium, potas-
304 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

sium, calcium, phosphates, bicarbonates, uric acid tant for concrement formation in urine depends on
and proteins. The impaired transport may lead to water rediffusion in tubuli and on filtered amount
aminoaciduria, glycosuria, salt wast, hypercalciuria, of these substances. Thus, increased diuresis re-
hypophospataemia, proximal tubular acidosis and duces the concentration of stone-forming substances
tubular proteinuria. Inherited disturbance occurs in urine. Among further important factors belongs
commonly. Similar condition may develop in adults urine stasis, commonly accompanied with infections
owing to the renal disorders and dysproteinaemia. In of urinary outflow tract, enhanced excretion of stone-
Wilsons type amyloidosis and in Love’s type a com- forming substances and changes of urine colloidal
plex of occulo-cerebro-renal alterations occur. qualities. The stasis of urine and the concomitant
infection create favorable conditions for formation of
concrements. The calculi commonly originate by a
process of crystal nucleation in tubules,or in bends
of renal calyces. The crystal nucleation occurs fre-
quently in renal papillae, but they can be formed
4.15 Urolithiasis also in renal pelvis, urinary bladder or elsewhere.
The changes in excretion of stone-forming substances
appear in metabolic disorders or in primary tubu-
lar disturbance in reabsorption of stone-forming sub-
Urolithiasis is a relative common disease occur- stances. Supersaturation of urine with stone-forming
ing in about 1 per cent of inhabitants, mainly in substance constitute favorable conditions for crys-
men. In one tenth of cases is the nephrolithiasis di- tal nucleation. Further layers of the concrement are
agnosed during their life. In remaining cases is the formed around it by apposition of stone-forming salts
nephrolithiasis asymptomatic. and organic substances.
The calcium salts are the basis of urinary con-
The hypothesis of colloid protection significance
crements. 75 to 85 per cent of urinary calculi con-
supposes an imbalance between mineral substances
tain calcium oxalate and calcium phosphate. Apart
and organic substances, termed protective colloids
from the calcium salts the uric acid and cystine
in urine. When the balance has been disturbed by
contribute to the concrement formation. Uratic
an excess of mineral substances or by defficiency of
calculi occur commonly in patients with hyperuri-
protective colloids the concrements arise.
caemia. Magnesium- ammonium- phosphatic concre-
ments appear during urinary tract infections. Uri- The mucoprotein occuring in urine has some qual-
nary calculi are formed when the balance becomes ities identical with the mucoprotein in bone. The ori-
impaired between the water volume and excreted gin of urinary mucoproteins is unknown. They can
crystal forming material. Under physiological cir- be products of tubular cells or of the substance oc-
cumstances the calcium salts do not form crystals. If curing among the epithelial cells. The mucoprotein,
urine is supersaturated with calcium salts the crys- at last could originate in basal osseous mass. Fol-
tallization can start. The supersaturation of urine lowing the parathyroid hormone application depoly-
is considered to be the main mechanism responsible merisation of bone mucoproteins occurs. The prod-
for concrement formation. Another important fac- ucts of depolymerisation are subsequently filtered
tor is the pH of urine. Alkaline urine contains more in glomeruli and reabsorbed in proximal tubules
urates and dissociated phosphates. The calcium ox- Calcium binds with mucoprotein forming microlith,
alate solubility however, does not depend on pH of which can pass the renal outflow tract. This mecha-
urine. The third important factor is the dehydra- nism may explain the concrement formation during
tion, and the fourth is the overloading of organism hyperparathyroidism.
with some substance which could become the basis The pathogenesis of urolithiasis is not well un-
for stone forming. derstood. The mechanism of concrement formation
Kidneys release several lyotropic protective sub- might not be the same for each type of stone. Ac-
stances preventing the stone formation: citric acid, cording their composition the concrements are di-
glucuronic acid, magnesium, glycine and other sub- vided into oxalate-, urate-, phosphate- carbonate-,
stances. The concentration of all substances impor- xantine and cystine stones. The succession in the list
4.16. Urinary outflow tract disturbances 305

indicates the incidence of individual concrements.

Oxalate concrements contain predominantly cal-
cium oxalate. In the proper form they occur rarely. 4.16 Urinary outflow tract
Commonly the contain also the salts of uric acid –
the urates. They are hard and of whitish colour and disturbances
of mulberry form. Oxalates are poorly soluble and
can arise in acidic as well as in alkalic urine. Oxalate
stones are formed in concentrated urine, during in-
sufficient water supply, in urine stasis, and during After its excretion in the renal papillae is the urine
dehydration. They arise only sporadically owing to transported by peristaltic contractions of renal ca-
the enhanced oxalate excretion in oxaluria – a sel- lyces smooth muscles towards the urinary bladder.
dom metabolic disturbance with deposits of oxalates The lumen of renal pelves and ureters is adjusted
in various tissues of other organs. to some degree to the volume of urine. Single peri-
Urate concrements arise in supersaturation of staltic waves with frequency of 2 to 5 per minute
urine by urates. The salts of uric acid are poorly increase the pressure in ureters towards the urinary
soluble in urine with low values of pH. Their prae- bladder. The peristaltic activity can be seen on
cipitation occurs therefore in acidic urine. Oxalate roentgenograms as fusiform local dilations of ureters
concrements may occur in hyperuricaemic syndrome following contrast medium application. In children
and after consumption of food with high purine con- they can imitate even a pathologic dilation of ureters.
tent. The idiopathic urate concrements arise how- In acute inflammations of renal outflow tract with-
ever mostly either without observed increase of plas- out urine discharge disturbances, spastic constric-
matic uric acid concentration, or its enhanced uri- tions of urinary ”ways” with enhanced peristalsis can
nary excretion. Urate lithiasis is encountered also in be observed. In chronic inflammatory processes of
conditions with increased uric acid excretion due to renal outflow tract are the urinary ”ways” atonic,
tumorous diseases and cytostatic treatment polycy- The smooth muscle action of renal pelves, ureters
taemia. and of urinary bladder is coordinated. Following
Phosphate concrements contain magnesium am- transversal ureter cross-section a transient disorder
monium phosphate. They occur during infections of urinary outflow tract peristalsis usually occurs.
caused by urease producing microbes. This enzyme In complete acute obstruction of ureters, e.g. by
cleaving urea into CO2 and NH3 elevates the urine ligation, the peristaltic movements disappear with-
pH and enables the phosphate precipitation. Phos- out dilation and pain and the urine production stops.
phate concrements are found also in occurence of for- The partial obstruction of ureters e.g. by a concre-
eign matter (corpus alienum) in renal outflow tract. ment causes, at the beginning, an elevation of the
Carbonate as well as oxalate stones occurence ap- basal pressure in ureters and increase in peristaltic
pears in relation with calcium metabolism disorders. frequency with concomitant lowering of peristaltic
Elevated glomerular filtration of calcium due to hy- amplitudes; subsequently the activity of ureters dis-
percalcaemia enables the concrement formation. appears. Colics occuring during this condition are
Nephrocalcinosis may develop owing to the hy- not due to hyperperistalsis, but to the rise in ureter
percalcinaemia. Nephrocalcinosis is chacterised by and renal pelves tension. The dilatation of upper
calcium salts deposition into the renal parenchyma, parts of urinary outflow tract occurs in longstanding
mainly in the papillary region. Hypercalcaemia with incomplete obstruction.
the consequent stone formation may appear also in Complete or partial obstruction of renal outflow
increased calcium resorption from the gut and in en- tract leads to morphologic and functional alterations
hanced calcium release from bones. According to the in kidneys - termed - obstructive nephropathy. The
concrement location nephro- uretero- cysto- urethro- pressure in the renal outflow tract raises above the
and prostato-lithiasis may be distinguished. site of obstruction and is transferred to the tubules
and glomeruli. The glomerular filtration rate falls
and so does the renal blood flow. In obstructive
nephropathy functions of distal tubules, the concen-
trating ability, the acidifying tubular activity and the
306 Chapter 4. Pathophysiology of kidneys and urinary system ( I. Hulı́n )

renal reactivity to antidiuretic hormone are mainly lesions. Reflux of urine occurs also in central ner-
affected. vous system lesions. Severe inflammatory of the uri-
Azotaemia develops only in bilateral, more severe nary collecting system alterations with subsequent
obstruction. Unilateral obstruction with intact con- fibrosis, e.g. in tuberculosis of collecting system re-
tralateral kidney does not cause the retention of ni- sult in the loss of their motoric function. The uri-
trogenous substances because of compensatory hy- nary ”ways” are changed into rigid tubes without
pertrophy. After the urinary outflow tract obstruc- any peristaltic movement and antireflux function. In
tion removal a transient polyuria with subsequent children the vesicoureteral reflux occurs commonly
dehydration and salts loss usually occurs.Polyuria in renal outflow tract infections, where an organic
reaches as much as 15 l daily and salt loss of 5 g cause always should be considered. Each reflux re-
daily. The underlying cause are: the endogenous tards or even abolishes the peristaltic movements of
osmotic diuresis, tubular irreactivity to antidiuretic urinary ”ways” and the retrograde overpressure with
hormone effects and specific disturbances of tubular severe consequences in renal parenchyma.
sodium reabsorption. A special group of of urinary tract disturbances
When the renal outflow obstacle is early removed a comprises disorders of urinary bladder discharge,
complete recovery of renal functions can be expected the congenital disorders of miction, above all. The
in 10 to 20 days. Longer persisting obstructions re- underlying cause is the functional insufficiency of
sult in irreversible lesions of renal parenchyma. The urinary bladder smooth muscles. This group in-
stasis of urine in dilated urinary collecting system en- cludes the so-called myogenic atony, or the achala-
ables arise of infections. Chronic bacterial infection sia of sphincter, a condition with increased tonus
usually results in interstitial nephritis. of sphincter and failure to relax. Owing to the hy-
Apart from the mechanic obstructions, inherited potony and decreased contractility of urinary bladder
dynamic disorders of miction (urine discharge) oc- muscles the bilateral vesicoureteral reflux arises: the
cur, being due to a disproportion between the force syndrome of megaureter megacystis occuring in cen-
of urinary collecting system smooth muscle contrac- tral nervous system lesions. If the urinary bladder
tion and the tonus of sphincters. . Dynamic urine sphincter is hypertonic the bladder muscles become
outflow disturbances are encountered e.g. in congen- hypertrophic. In the urinary bladder failing to dis-
ital nephroses with spastic constriction of ureteral charge completely residual urine remains.
upper orifice and subsequent pelvis dilatation. An- The underlying causes of acquired miction disor-
other example is the so-called megaureter caused by ders are commonly the hypertrophy of prostata, car-
spastic constriction of some part of the ureter. Inher- cinoma prostatae, strictures in urinary collecting sys-
ited neuromuscular dysplasia is considered to be the tem or acquired hypertony of urinary bladder sphinc-
cause of these dynamic disorders of urine discharge. ter. In these cases the vesicoureteral reflux is not ob-
The dilation of upper parts of urinary collecting served. The basal tonus of ureters is usually normal,
system affects about one third of pregnant women. the ureter peristalsis however, is reduced.
Functional alterations of renal outflow system during Disorders of miction are frequently due to various
pregnancy are due to hormonal effects, to the ureter central nervous system diseases. In this group are
compression by enlarged uterus, or to neuromuscular included: urine incontinence, urine retention (inabil-
disturbances of outflow ducts during infections. ity to discharge the urinary bladder in response to
In the pathogenesis of pyelonephritis, above all, an appropriate, normal stimulus). In these neuro-
has the reflux of urine a great importance. Every genic disorders of miction is the balance between the
retrograde urine flow should be considered to be a sphincter tonus and urinary bladder muscle contrac-
pathological phenomenon. The so-called primary re- tility impaired.
flux of urine is thought to be an inborn valve mech- Transverse lesion of spinal cord induces complete
anism disorder in the region of ureter orifices. The urinary bladder atony with inability to discharge.
secondary reflux occurs commonly in congenital dis- The so-called upper lesion (above the sacral medulla)
turbances of urine discharge. It can be due to the leads to urinary bladder automatism. The urinary
valve presence in ureters, to fibroelastose of the uri- bladder filling elicits stimulus spreading towards the
nary bladder orifice, or eventually to the spinal cord medullary centre. About 100 ml of residual urine
4.17. Tumors of urinary tract 307

remain in bladder. In so-called lower lesion (below Intermittent fever may occur without overt in-
the 11th thoracic vertebra) are the nervous pathways fection. Anaemia is present in about 50 per cent
in sacral medulla eliminated and so are the affer- of patients. Occurence of polyglobulia is rather
ent pathways leading from urinary bladder,and the exceptional. It is induced by erythropoietin pro-
medullar centre with efferent pathways. duced in tumor cells. It is very important to re-
In the state of automatism is the urinary bladder alise that the renal carcinomas can produce many
atonic. Irregular contractions of m.detrusor single various hormones or hormone-like substances. It
fibres appear, induced by stimuli arising from intra- is frequently the parathyroidal hormone, prolactin,
mural ganglia. The urinary bladder can be evacu- prostaglandins, gonadotropins and glucocorticoids.
ated only by use of abdominal press and the volume Thus, it is not surprising, when a condition devel-
of residual urine exceeds 300 ml. ops with dominant Cushing’s syndrome.
In kidney arterio-venous fistulae may arise, which
can create conditions for heart failure with increased
minute cardiac volume. Tumor may occlude v.cava;
induce severe liver deterioration and changes in
4.17 Tumors of urinary tract blood flow through the splanchnic region.
In children occurs malignant nephroblastoma
(Wilms’ tumor). It is composed of various types
of cells: epithelial, muscle-, cartilage-, bone cells. It
Benign renal tumors originate in parenchyma and grows to large dimensions and occurs bilaterally. The
are usually small. The adenomas reach 5 to 10 mm most frequent symptoms are haematuria, pains, fever
in diameter. They can cause recurrent haematuria and hypertension.
without pains. Malignant transformation of adeno- Except for kidneys, tumors of urinary tract can
mas is exceptional. The hamartomas can be uni- arise from renal pelves, ureters and urinary bladder.
or bilateral. They contain vessels, adipose tissue, Tumors of the urinary bladder prevail. The tumors
smooth muscle. Benign tumors may arise also from of renal pelvis and ureters use to be accompanied
capillaries adjoining the juxta-glomerular apparatus. with renal colics. The carcinomas of urinary bladder
They are producing renin. are manifested by painless haematuria, nycturia and
Malignant renal tumor (adenocarcinoma, hyper- sacral pains.
nephroma) becomes clinically manifest by haema- Carcinoma of prostata can stay long time asymp-
turia, lumbar pains and palpable resistance. The tomatic. Its incidence raises. The prognosis is favor-
most important symptom is the haematuria. Tu- able if the extent of the tumor is small. This type of
mor penetrates the renal capsule and renal veins, tumor penetrates later the lymphatic nodes, bones
therefore haematuria can be very dramatical. It and lungs.
may spread into the peritoneal lymphatic tissue and Benign hypertrophy of prostata can lead to alter-
liver. Metastases are found mainly in lungs, brain ation due to partial obstruction of urinary collecting
and bones. system.
Chapter 5

Pathophysiology of endocrine system

well as by normal concentration of this hormone

(these hormones) in circulating blood. Some-
5.1 Types of endocrine disor- times, however, other symptoms referring to ex-
istence of eufunctional endocrine syndrome can
ders be present.

According to the place of endocrine disorder ori-

gin, the following types of endocrine disorders can be
Endocrine disorders can be classified according to distinguished:
the intensity of hormonal activity and according to
the place of endocrine disorder origin. From the 1. In endocrine glands regulated by the hypothala-
point of view of intensity of hormonal activity of en- mic-pituitary system the following disorders can de-
docrine gland we can distinguish: velop:

1. Hyperfunction of endocrine gland, which is A. Primary (peripheral) hypofunction or hyper-

characterized by increased secretion of its hor- function. The cause of the disorder of hor-
mone (hormones) as well as by increased con- monal secretion is in peripheral (target) en-
centration of this hormone (these hormones) in docrine gland.
circulating blood.
B. Secondary (central adenohypophyseal) hypo-
2. Hypofunction of endocrine gland, which is char- function or hyperfunction. The cause of the
acterized by decreased secretion of its hormone disorder of hormonal secretion of peripheral en-
(hormones) as well as by decreased concentra- docrine gland is in the adenohypophysis (the an-
tion of this hormone (these hormones) in circu- terior pituitary).
lating blood.
If endocrine gland produces several kinds of hor- C. Tertiary (central hypothalamic) hypofunction
mones (e.g.,adenohypophysis) the symptoms re- or hyperfunction. The cause of the hormonal
sulting from hyperproduction or hypoproduc- secretion disorder of peripheral endocrine gland
tion of more kinds of hormones may develop, is in the hypothalamus.
respectively, at the same time the symptoms of
hyperfunction resulting from overproduction of 2. The cause of the origin of primary hyperfunction
one kind of hormones and the symptoms of hy- or hypofunction of those endocrine glands, which
pofunction due to a deficiency of other kind of are not regulated by the hypothalamic-pituitary
hormones can develop. system, is also in the endocrine glands them-
selves, but their secondary hyperfunction is caused
3. Eufunction of endocrine gland, which is in the by extra-glandular (non-hormonal) stimulus, e.g.,
time of medical examination characterized by secondary hyperaldosteronism or secondary hyper-
normal secretion of its hormone (hormones) as parathyreoidism.

308
5.2. Etiology of endocrine disorders 309

3. Some hormones can be produced also in the The common characteristic of the APUD cells is
cells of organs which do not belong to the glands ability of secretion of polypeptide hormones with lo-
of internal secretion. It is an ectopic production of cal or general effects, in less extent also ability of se-
hormones, which is autonomous and causes the ori- cretion of biogenic amines, and in special cases also
gin of ectopicly conditioned endocrine hyperfunction ability to produce prostaglandins and kinins. A neo-
(ectopic endocrine syndrome). As a rule it is the plasm of the APUD system (apudoma) can produce
consequence of production of hormones from non- not only larger amount of hormone, but usually also
endocrine neoplastic tissue, and, therefore, this clin- more kinds of hormones which cause a variety of the
ical syndrome is also called paraneoplastic endocrine clinical picture of this disease.
syndrome (paraneoplastic endocrinopathy).
4. In unique cases, an endocrine disorder can arise
in the consequence of a defect of hormonal transport
from the place of its origin to the place of its action.
This disorder is caused by deficiency or by abundance 5.2 Etiology of endocrine dis-
of a plasma transport protein for the hormone or it is orders
due to the defect of hormone binding to the specific
carrier protein.
5. The endocrine disorder can also originate as the The causes of endocrine disorders can be acquired
consequence of a defect in target tissue for the hor- or genetic.
mone or in the place of hormone degradation. This
endocrine disorder can be due to: 1. Acquired causes
A. Tumors of endocrine glands. Adenomas
A. A change of number or function (structure) of
(benign neoplasms) are one of the main
receptors for individual hormones.
causes of hyperfunctional endocrine syn-
B. A presence of antibodies against receptors for drome. They occur more frequently than
individual hormones. malignant neoplasms. Adenomas may also
cause combinated endocrine disorder char-
C. A defect on the level of postreceptor effector acterized by the excess of one hormone
mechanisms for individual hormones. and by the deficiency of other hormones
(e.g., adenoma arising from one type of
D. An accelerated or slowed conversion of prohor- cells of adenohypophysis causes destruc-
mone to active hormone. tion of other types of its cells). Malig-
nant neoplasms of endocrine glands are less
E. A defect of inactivation (degradation) of hor- frequent. The production of hormones by
mone in peripheral tissues. malignant tumors depends on the degree
of differentiation of their cells. If the cells
The above mentioned defects on the level of target are insufficiently differentiated they usually
(peripheral) tissues are called pseudohypofunctional lose their hormonal activity.
or pseudohyperfunctional endocrine disorders (pseu-
B. Inflammatory lesions of endocrine glands.
doendocrinopathies).
There are a very frequent cause of hypo-
6. Adenomas or carcinomas originated from the cells functional endocrine syndromes. Etiologi-
of disperse endocrine system, known as Amine Pre- cal factor of these lesions may be autoim-
cursor Uptake and Decarboxylation (APUD) system, mune process or viral and bacterial infec-
are called multiple endocrine neoplasia (MEN). Ade- tion.
nomas or carcinomas can be found in several en- C. Disorders of nutrition. The most fre-
docrine glands or other endocrine structures. They quent cause is the deficiency of iodium
are typical familial diseases with autosomal domi- needed for the synthesis of thyroid hor-
nant type of heredity. mones. The increased strumigene intake
310 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

in food, which inhibits synthesis of thyroid of various hormones (hypothalamic releasing hor-
hormones, may be also a cause of endocrine mones, hypothalamic inhibiting hormones or factors,
disorder. antidiuretic hormone, and oxytocin). Hypothala-
D. Iatrogenic causes. Endocrine disorders mus, therefore, has an important role in the reg-
may occur as a complication of various ulation of endocrine system as well. In the hier-
kinds of therapy (e.g., surgical interven- archy of endocrine glands hypothalamus has a role
tion, radiotherapy, inadequate hormone of a control centre and along with hypophysis it
treatment, or therapy with some non- forms a functional unit. In the consequence of its
hormone drugs). organic or functional disorder, a hypothalamic syn-
drome develops. In the clinical picture of this syn-
E. Primary hyperplasia of endocrine gland
drome only endocrine symptomatology is present,
cells. As its consequence, a hyperfunc-
or its endocrine symptomatology may be combi-
tional endocrine syndrome develops.
nated with neurovegetative symptomatology. These
F. Other acquired causes. They are rather disorders are usually distinguished as: disorders of
rare. They include, e.g., destruction of hypothalamic-neurohypophyseal system and disor-
endocrine cells by hormone inactive neo- ders of hypothalamic-adenohypophyseal system.
plasma, various kinds of vascular disorders
(mostly aneurysm or hemorrhage), cyst,
trauma, degenerative process, metabolic 5.3.1 Pathophysiology of hypothala-
defect, and by toxic influences. mic-neurohypophyseal system
2. Genetic causes Antidiuretic hormone (ADH, vasopressin) and
Relatively frequent genetic causes of endocrine oxytocin are the hormones of hypothalamic-
disorders are defects of various enzymes (enzy- neurohypophyseal system. They are produced in
mopathies) taking part in a hormone biosynthe- the nuclei of the front hypothalamus, i.e., in nucleus
sis. The other inherent cause can be the synthe- supraopticus and in nucleus paraventricularis. They
sis of a defective prohormone or hormone or the are transported to neurohypophysis via the axons of
disorder of conversion of prohormone to active the cells of these nuclei, where they are stored and
hormone. The existence of genetic disorder of released into the circulation when needed. Clinical
cell receptors for hormones is assumed as well. symptoms of deficiency or overproduction of ADH
Inborn causes of endocrine disorders can also in- are known only in human being. Disorders of oxy-
clude hypoplasia or aplasia of endocrine gland as tocin secretion are unknown at present.
well as chromosome anomalies concerning X or
Y chromosomes (gonosomes). 5.3.1.1 Central diabetes insipidus
Central diabetes insipidus (neurogenic diabetes in-
sipidus, diabetes insipidus verus) is a rare disease
caused by partial deficiency or total absence of ADH.
The kidneys of a patient, therefore, are not able to
5.3 Pathophysiology of hypo- produce hypertonic urine and thus to prevent exces-
sive loss of water from the organism. Most often it
thalamic-hypophyseal sys- develops in the consequence of the damage of front
tem hypothalamus, namely of nucleus supraopticus, e.g.,
by severe head trauma, intracranial tumors (cran-
iopharyngioma, Rathke’s pouch tumor, germinoma,
pinealoma, pituitary adenoma, and metastatic tu-
Hypothalamus has an important integrative in- mors), cysts, inflammatory lesions, vessel lesions
fluence on the function of vegetative nervous sys- (hemorrhage or aneurysm), sarcoidosis, or by sur-
tem and also it is a place of various vital cen- gical intervention in the area of hypothalamus. Di-
tres. It has a key role in regulation of basic bi- abetes insipidus, which is due to any organic lesion
ological rhythms and it is the place of production mentioned above, is called symptomatic (secondary)
5.3. Pathophysiology of hypothalamic-hypophyseal system 311

diabetes insipidus. However, in about 45 % of cases frequently, however, urine volume is only moderately
the cause of ADH deficiency is not found out. It is increased (from 3 to 6 litres per day).
idiopathic diabetes insipidus. In rare instances, cen- Polyuria is the most expressive objective symp-
tral diabetes insipidus may be inherited as an iso- tom, and excessive thirst is the main subjective
lated defect (autosomal dominant inheritance) or as symptom. Polydipsia provides an adequate compen-
a part of an autosomal recessive syndrome (Wolfram sation for large volumes of excreted water. The slight
syndrome) consisting of diabetes insipidus, diabetes rise in serum osmolality, resulting from hypotonic
mellitus, optic atrophy, and deafness. polyuria, stimulates thirst. Large volumes of fluid,
From the point of view of etiopathogenesis pe- therefore, are imbibed, and cold drinks are preferred.
ripheral diabetes insipidus (nephrogenic diabetes in- For the patient excessive thirst is hard to control,
sipidus) can be also distinguished. It originates as a and due to that he often awakes throughout night.
consequence of reduced sensitivity even of insensitiv- During the sleeping hours he often drinks and mic-
ity of the distal tubules and mainly of the collecting turates (nycturia). Interrupted sleep may cause the
ducts to ADH. It is caused by disorder or lack of cell origin of neuroasthenic syndrome. If the patient did
receptors for this hormone. Peripheral diabetes in- not take adequate quantity of fluids he would de-
sipidus is hypofunctional pseudoendocrinopathy. It velop severe dehydration, hypernatremia, plasma hy-
may be inborn or acquired. Hereditary nephrogenic perosmolality, fever, psychic disturbances, prostra-
diabetes insipidus is the disease with X chromosome- tion, collapse, and towards the end oligemic shock
linked inheritance. The abnormal gene is localized and death may occur.
on the long arm of this chromosome. It is trans-
mitted by heterozygous women and clinically man- 5.3.1.2 Syndrome of inappropriate ADH se-
ifested in man. Acquired nephrogenic diabetes in- cretion
sipidus has heterogeneous etiology. It may develop,
e.g., due to chronic hyperkalemia, chronic renal in- The syndrome of inappropriate ADH secretion
sufficiency, nephrocalcinosis caused by chronic hy- (Schwartz-Bartter syndrome, primary vasopressin
perparathyroidism, amyloidosis, multiple myeloma, excess) is the term applied to persistent production
or due to long-lasting therapy by some drugs, such as of ADH or ADH-like peptide despite body fluid hy-
demeclocycline, methoxyflurane, and lithium (drug- potonicity and an expanded effective circulating vol-
induced nephrogenic diabetes insipidus). ume. These peptides are syntethized and released
autonomously, i.g., independently from plasma os-
Pathophysiology and clinical features. Diabetes molality. There is sustained release of ADH in the
insipidus refers to the passage through the body of a absence of either osmotic or nonosmotic (volume-
large quantity of dilute fluid. This state of excessive mediated) stimuli. It means that simple feedback
water intake (polydipsia) and hypotonic polyuria is control mechanism between plasma osmolality and
due to failure of vasopressin (ADH) release in re- ADH secretion is broken (osmoreceptors of the front
sponse to normal physiologic stimuli (neurogenic di- hypothalamus lost or cannot realize their control
abetes insipidus) or due to inability of renal tubules function).
to respond to ADH (nephrogenic diabetes insipidus). The syndrome of inappropriate ADH secretion
Polyuria, excessive thirst and polydipsia are primary originates by numerous causes. Its most fre-
symptoms almost invariably present in the patients. quent cause is an ectopic ADH or ADH-like pep-
Characteristically, they are sudden in onset. The tide production from neoplastic tissue (small cell
patient may recall the precise day or hour when bronchogenic carcinoma, pancreatic carcinoma, lym-
polyuria and thirst began. phosarcoma, Hodgkin’s disease, reticulum cell sar-
Urine osmolality is below that of the serum (less coma, thymoma, and carcinoma of duodenum or
than 290 mmol/kg). A urine specific gravity is from bladder), and from lung cells during inflamma-
1.001 to 1.005. Persistent hypostenuria is the hall- tory pulmonary diseases (tuberculosis, lung abscess,
mark of diabetes insipidus. In severe cases, the urine pneumonias, empyema). In other cases the cause of
is pale color, and the volume may be immense (up this syndrome is organic disorder of hypothalamic-
to 16–24 litres per day), requiring micturition every neurohypophyseal system (skull fracture, subdural
30 to 60 minutes through the day and night. More or subarachnoid hematoma, cerebral vascular trom-
312 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

bosis, encephalitis, and purulent meningitis). Such serum osmolality and dilutive hyponatremia. Hy-
cases are, however, very rare. ponatremia is paradoxically connected with in-
The symptoms of permanent inadequate antidi- creased excretion of natrium by urine (inadequate
uresis may also result from drug therapy. Some natriuresis), so that urine osmolality is higher
drugs, such as vincristine, cyclophosphamide, clofi- than plasma osmolality. In paradoxically increased
brate, carbamazepine, metoclopramide, and beta- glomerular filtration rate, decreased aldosterone se-
adrenergic agents, may stimulate excessive ADH re- cretion and increased production of atrial natriuretic
lease from the neurohypophyseal system, and other peptide take part. These changes arise secondary to
drugs, as chlorpropamide and nonsteroidal anti- increased plasma volume.
inflammatory agents, potentiate the antidiuretic ac-
tion of ADH, what is the result of increase of sensi- 5.3.2 Pathophysiology of hypothala-
bility of renal tubule receptors to ADH. In this sec- mic-adenohypophyseal system
ond case it is, however, hyperfunctional pseudoen-
docrinopathy. From the knowledge regarding the role of the hy-
The persistent production of ADH or ADH-like pothalamus in regulating anterior pituitary func-
substances, or increased sensibility of renal tubules tion, it seems likely that some diseases may actually
to ADH result in excessive retaining ingested wa- be due to disordered function of the hypothalamus
ter and in the excretion of concentrated urine. The rather than at the level of the adenohypophysis or the
excretion of concentrated urine (urine osmolality is target endocrine gland. Therefore, from the point
usually over 300 mmol/kg) exists despite of subnor- of view of pathophysiology of hypotalamic-pituitary
mal plasma osmolality and decreased plasma sodium system we distinguished between disorders of hy-
concentration. In a patient, the dilution of extra- pothalamus with endocrine symptomatology and en-
cellular fluid develops. And so, the ADH excess is docrine disorders of adenohypophysis.
considered to be inappropriate because it occurs in
the presence of plasma hypoosmolality. Water re- 5.3.2.1 Disorders of hypothalamus with en-
tention and consequent dilution of body fluids lead docrine symptomatology
to hypotonic hyperhydration. The patient becomes
Some of the disorders of hypothalamus are connected
hyponatremic, modestly volume expanded, and his
with endocrine symptomatology because hypotha-
body weight increases by 5 to 10 %. In spite of hy-
lamus regulates secretion of adenohypophyseal hor-
pervolemia there is no hypertension and no edema
mones by means of releasing hormones (liberins) and
(for an unknown reason).
by means of inhibiting hormones or factors (statins).
Because of permanently increased concentration of As hypothalamus has a key role also in regulating of
ADH in circulating blood superfluous water cannot basic biological rhythms, it takes part in regulation
be excreted by the kidneys as free water (without of the onset of puberty and also of sexual functions,
solutes). Therefore, by urine only water linked to endocrine disordes may also originate as the conse-
solutes excretes because ADH has no influence upon quence of changes of these regulatory functions of
this water. In the clinical picture, therefore, symp- the hypothalamus. Hypothalamus is sexually differ-
toms of water intoxication and symptoms of blood entiated and regulates the sexual functions through
dilution are dominant. its own biorhythm, which regulates secretion of go-
Symptoms of water intoxication. The extracellu- nadotropins (it is a monophasic type of their secre-
lar hypotonicity, mainly if it is severe or acute at the tion in a man, but cyclical one in a woman). Hy-
onset, leads to intracellular edema. Therefore, espe- pothalamus plays an important role in regulation of
cially severe symptoms of cerebral edema and fol- lactation, too, which starts by combination of nerve
lowing intracranial hypertension occur and become and several hormonal influences.
predominant. They include nausea, vomiting, rest- From the point of view of etiology the disor-
lessness, irritability, headache, desorientation, confu- ders of hypothalamus with endocrine symptomatol-
sion, letargy, somnolence, convulsions, and coma. ogy can be divided to functional or organic, and in-
Symptoms of blood dilution (hemodilution). The born or acquired. Most often they are manifested by
most expressive of these symptoms are reduced various disorders of hypothalamic-pituitary-gonadal
5.3. Pathophysiology of hypothalamic-hypophyseal system 313

axis. As for intracranial organic disorders the fol- stantly involved in each other’s problems. Although
lowing are most frequent: tumors (craniopharyn- family structure appears to play a primary role in
gioma, pinealoma, glioma, meningioma, metastases), the genesis of anorexia nervosa, cultural issues and
cyst, traumatic lesions, lesions after neurosurgical occupation are also important.
interventions, inflammatory lesions (meningitis, en- How the psychodynamic dysfunction is translated
cephalitis, tuberculosis), sarcoidosis, and vascular le- into biological disease remains a mystery. Numer-
sions (ischemic lesions, local hemorrhage, aneurysm) ous neurotransmitter systems may play a mediating
in hypothalamus or in its neighbouring region. role. The role of hypothalamus, in which centres of
controlling food intake are situated, and which is the
A. Anorexia nervosa (anorexia mentalis) place of gonadotropins releasing and inhibiting hor-
Anorexia nervosa is an eating disorder of young, pre- mones as well, in the pathogenesis of anorexia ner-
viously healthy women who develop a paralyzing fear vosa is not known. We do not know whether there
of becoming fat. The driving force is the pursuit of is a certain predispose weakening of hypothalamic
thinness, all other aspects of life being secondary. function (its latent dysfunction), or it is only a dys-
This aim is achived primarily by radical restriction function of various internal interactions of the hy-
of caloric intake, the end result being emaciation. pothalamus evoked by the influence of external fac-
Anorexia nervosa is psychoneurosis, or rarely it is tors.
purposeful reaction. It is connected with remark- The patients permanently refuse food intake
able lowering of body weight and with amenorrhea. (drastically restrict their own food intake) and later
This disease occurs primarily in young women (to they gradually lose appetite. Sporadic dieting usu-
25 years of age), mainly in neurotic adolescent girls. ally begins about a year before the start of the proper
The most common time appearance is 4 to 5 years disease, often at the point at which maximal weight
after menarche. was reached. If social circumstances require them
In etiology of this disease the combination of psy- to eat more than usual, vomiting is induced as soon
choemotional factors and behavioral characteristics as possible, often in a public restroom. As noted,
of the patient (e.g., mentally unbalanced personality, episodic binge eating may occur and also followed
anxiety, depression, perfectionism, inadequate ambi- by emesis. The patient secretly self-induces vomit-
tion) takes place. The onset of the desease frequently ing most often by putting her fingers or tooth-brush
follows a stressful event in the subject’s life. The fre- into the pharynx, later she vomits reflexively. She
quent cause of its origin is psychical stress, bad rela- may use enormous doses of laxatives. In the conse-
tion between mother and daughter, improper family quence of this considerable loss of body weight may
relations, inappropriate and frequent comments on be seen, as a rule from 15 to 25 % of the original body
body weight or body proportions. It may be also weight. In spite of significant cachexia the patient is
an abnormal reaction to adolescence (a refusal of the often physically and psychically overactive, and ritu-
role of adult woman and at the same time demand alized excercise is common. Despite profound weight
for independence from the family influence and par- loss patients deny hunger, thinness or fatigue.
ent’s authority). Its prevalence is 0.5–1.5 per 100 000 From the point of view of endocrinology anorexia
inhabitants (involves approximately 1 % of girls and nervosa is manifested by secondary amenorrhea
young women between ages 14 and 25, generally from (menstruation was present for a variable time and
middle to upper socio-economic families). then ceases), which is one of its basic and an almost
The causes and pathogenesis of anorexia nervosa constant symptoms. It is now generally accepted
are not fully explained. It has been argued that hy- that the primary cause of its origin is localized in
pothalamic dysfunction is primary, but the evidence the hypothalamus and operates via impaired (insufi-
appears persuasive that the disorder is a psychiatric cient) secretion of luteinizing hormone-releasing hor-
one. The psychodynamic mechanisms are not clear mone (LHRH deficiency), also termed gonadotropin-
and in fact may not be fixed. Whatever other fac- releasing hormone (GnRH). Functional gonadotropic
tors operate in the genesis of the disease, the fami- hypopituitarism is formed. Why the hypothalamus
lies tend to be ”enmeshed”: they are blurred gener- is unable to release LHRH is not known, although
ational boundaries so parents and children are con- abnormalities in norepinephrine and dopamine me-
314 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

tabolism in the central nervous system (CNS) have B. Hypothalamic amenorrhea

been postulated. All types of amenorrhea of the hypothalamic origin,
with the exception of amenorrhea at anorexia ner-
In the origin of secondary amenorrhea psychoe- vosa, rank among this titlle. They are secondary
motive stress and significant body weight loss take amenorrheas caused by various functional or organic
part. About one half of patients with anorexia ner- disorders of the hypothalamus, which result in disor-
vosa develop amenorrhea consominant with the onset der of LHRH secretion.
of dieting. However, up to 40 % of girls cease menses Among functional amenorrheas of the hypothala-
before significant body weight loss. The latter one mic origin are included:
points out to the fact that amenorrhea origin is likely
not to be only a simple consequence of malnutrition. • psychogenic amenorrhea after psychic stress;
Presumably, early amenorrhea is due to emotional
stress antedating clinical illness. • amenorrhea at false pregnancy (pseudocyesis,
pseudogravidity);
Plasma levels of follicle-stimulating hormone
(FSH), luteinizing hormone (LH), and estrogens are • exercise-induced amenorrhea, which is associ-
low. However, there is no evidence for primary dys- ated with intense and prolonged physical exer-
function of the pituitary gland or gonads. Plasma tion, such as long-distance running, swimming,
prolactin level is usually normal. Female secondary gymnastic, and ballet dancing. The patients are
sexual characteristics (breasts and pubic hair) are always below ideal body weight and have low
properly developed. stores of fat. The mass of fat may be a regula-
tor of LHRH secretion;
In the consequence of long-lasting malnutrition
anemia, hypoproteinemia and hypokalemia may be • long-term starvation;
developed. Anemia and occasional pancytopenia ap-
pear to be due to hypocellularity (hypoplasia) of the • amenorrhea at hyperprolactinemia mediated by
bone marrow. Later peripheral edema (mainly on decreased hypothalamic dopamine (prolactin-
extremities) may apear. It is due to a failure to inhibiting factor – PIF). Hyperprolactinemia
mobilize the normal extracellular fluid volume pro- causes amenorrhea by inhibition of LHRH re-
portionately with body mass during starvation and lease.
probably due to hypoalbuminemia. If vomiting is Organic causes of hypothalamic amenorrhea can
severe and prolonged, hypochloremic alkalosis may be head trauma, tumor, inflammatory lesion and
occur. Basal metabolic rate is decreased. vascular lesion in the hypothalamic gonadotropin-
By clinical examination bradycardia (persistent regulating area.
resting pulse of 60 beats per minute or less), arterial
hypotension (less than 70 mmHg systolic), bradyp- C. Hypothalamic disorders of the onset of pu-
nea (less than 15 breaths per min), hypothermia, and berty
cold intolerance are found. These changes develop as Some functional or organic disorders of hypothala-
a response of circulation to cachexia. Skin is usually mus may cause true precocious puberty or true de-
pale and dry, hands and feet are cold. Anorexic pa- layed puberty. Puberty is considered precocious if
tients may develop excessive vasoconstriction, and the symptoms of sexual maturity begin to apear prior
Raynaud phenomenon has been noted. Hair is dry to age 8 in girls and age 10 in boys. Puberty is con-
and soft. The patients often suffer from obstipation. sidered delayed if its spontaneous beginning appears
Sometimes also psychical depression occurs. In the in both sexes by age 16 or older.
consequence of long-term and severe malnutrition, True precocious puberty (pubertas praecox vera).
various complications may develop (symptoms of vi- In girls this type of puberty has mostly functional
tamin deficiency, osteoporosis and intercurrent in- origin (primary hypothalamic). The cause of the
fections). If the treatment is delayed till the body precocious onset of hypothalamic regulatory mech-
weight falls under 50 % of patient ideal weight, this anisms (precocious secretion of LHRH), and thus
disease may end lethally. Mortality is about 4–7 %. also precocious gonadotropic hormone secretion from
5.3. Pathophysiology of hypothalamic-hypophyseal system 315

adenohypophysis is not known (idiopathic true pre- Besides obesity, Fröehlich syndrome is charac-
cocious puberty). In boys true precocious puberty terized by symptoms of hypogonadotropic hypog-
occurs more rarely than in girls. Its cause is usu- onadism (sexual infantilism) and by shortness of
ally organic, especially hypothalamic tumors (e.g., stature. Gonadotropic deficiency is due to LHRH
hamartoma) or tumor of epiphysis (pinealoma), in- deficiency, which is caused by damage of crucial area
ternal hydrocephalus or consequences of encephalitis. of hypothalamus that regulates synthesis and secre-
True delayed puberty (pubertas tarda vera). In tion of gonadotropins. In the patient some of the
boys and girls it is mostly constitutional deviation symptoms caused by compression of the hypotha-
with familiar occurence in some members of the fam- lamus and its surrounding structures may occur,
ily (constitutional delayed puberty). By the age of e.g., epileptic attacks, visual field defects, diabetes
18 it is usually spontaneously settled. It is caused by insipidus, and headache. This compression is sec-
the delayed onset of hypothalamic mechanism (de- ondary to expansive growing tumor.
layed secretion of LHRH, and thus by delayed go-
nadotropic hormone secretion of adenohypophysis. E. Laurence-Moon-Biedl-Bardet syndrome
This syndrome is an inborn disease with autosomal
D. Adipose genital dystrophy (Babinski-Fröe– recessive type inheritance. It is characterized by a
hlich syndrome) set of various abnormalities and anomalies, e.g., hy-
Adipose genital dystrophy is a rare organic disor- pogonadotropic hypogonadism (delayed puberty and
der of hypothalamus affecting mostly boys. It is sexual infantilism), obesity, short stature, retinitis
characterized by obesity and by symptoms of hypog- pigmentosa (visual impairments or blindness), men-
onadotropic hypogonadism. This disorder may be tal retardation, polydactyly, syndactyly, and defec-
caused by a wide variety of organic lesions of the hy- tive hearing even deafness. The basis of the origin of
pothalamus, such as tumors, various degenerative or the above mentioned abnormalities is diencephalo-
inflammatory changes in hypothalamus and its sur- reticular degeneration. Hypogonadism and obesity
rounding area. are thought to be hypothalamic in origin.
Besides this organically conditioned, so called true
adipose genital dystrophy, also so called benign type F. Kallmann’s syndrome (dysplasia olfacto-ge-
of adipose genital dystrophy (false adipose genital nitalis)
dystrophy, Fröehlich like type), which occurs more This disease is a rather rare form of isolated hypog-
often, is known. It develops in boys in the con- onadotropic hypogonadism with familiar occurence,
sequence of wrong regimen (inadequate alimentary which is connected with impaired sense of smell and
and locomotor habits, inappropriate upbringing in a sometimes also with other anomalies. It is a het-
family, i.e., overeating, mainly sweets, drinking sweet erogenous genetic disorder with X-linked as well as
juices and limonades, not sufficient physical activ- autosomal inheritance with incomplete exppressivity
ity, and too much protective influence from mother). (it affects boys).
The course of puberty in boys with benign type of Kallmann’s syndrome is characterized by congen-
adipose genital dystrophy is usually spontaneously ital hyposmia or anosmia (central type), due to the
settled when regimen becomes normal. On the other olfactory bulb disorder (hypoplasia or agenesis). The
hand, in organically conditioned true adipose genital olfactory bulbs (rhinencephalon) and the hypothala-
dystrophy the disorder of the hypothalamus is per- mic defects originate in embryonic life and are due
manent without surgical therapy and its prognosis is to failure of olfactory receptor neurons and LHRH-
serious. synthetizing neurons migration from the olfactory
Dominant symptom of Fröehlich syndrome is obe- placode, where they arise, into the brain, along with
sity with typical deposition of fat mostly in the sub- the olfactory and other nerves. Hypogonadotropic
cutaneous tissue of abdomen, thighs, and gluteal hypogonadism is due to LHRH deficiency. In this
area. Fat can deposit also in the subcutaneous tissue disorder, the young males fail to undergo puberty.
of chest and suras. The presence of obesity implies They enter adulthood with an eunuchoid habitus and
that there is damage of the food-regulating region of other evidences of androgen lack, such as immature
the hypothalamus. genitalia (hypogenitalism), cryptorchidism (the size
316 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

of testes correlates with the extent of the LHRH de- thy), which may sometimes be similar to those at
ficiency), gynecomastia, imperfect or absence of fa- schizophrenia.
cial hair, feminine body contour, and the absence of If hypothalamic hyperprolactinemia occurs in
libido and potentia. Plasma FSH, LH, and testos- young women, who are not and have never been preg-
terone levels are below the normal male range. The nant, it is defined as Ahumad-de Castill syndrome
secretion of other pituitary hormones is normal. Less (some authors call it Forbers-Albright syndrome).
commonly, these patients may have other congenital
anomalies, such as cleft lip, cleft palate, deafness,
and daltonism. H. Other hypothalamic disorders of adenohy-
pophyseal regulation
As a result of primary disorder of production of hy-
G. Hypothalamic hyperprolactinemia pothalamic releasing or inhibiting hormones or fac-
Hyperprolactinemia of hypothalamic origin is rare. tors is the origin of increased or decreased function
It arises in the consequence of decreased secretion of adenohypophysis. This disorder is defined as cen-
of prolactin inhibiting factor (dopamine) or due to tral hypothalamic hyperpituitarism or central hy-
disorder of its transport from hypothalamus to ade- pothalamic hypopituitarism. However, if the disor-
nohypophysis. Weakening or absence of inhibitory der of adenohypophyseal hormone production is not
influence of dopamine causes permanent production the result of the change of production of hypotha-
of prolactin by anterior lobe of pituitary. lamic releasing or inhibiting hormones, but it is the
Hypothalamic hyperprolactinemia has many cau- result of a pathologic process which affects adeno-
ses. It can be organic lesion in the hypothalamic hypophysis primarily, central adenohypophyseal hy-
area or pituitary stalk (e.g., by tumor, inflammatory perpituitarism or central adenohypophyseal hypopi-
or vascular lesions, trauma, sarcoidosis, and by stalk tuitarism develops. It is rather difficult to make the
section) or hypothalamic disorder caused by long- difference between the primary hypothalamic disor-
lasting drug therapy (phenothiazines, thioxanthenes, ders and the primary adenohypophyseal disorders.
metoclopramide, methyldopa, reserpine, cymetidine, Primary hypothalamic and primary adenohy-
estrogens, oral contraceptives, and opiates). This pophyseal endocrinopathies may be manifested ei-
disease may be also of unknown origin (an idiopathic ther by the disorder of production of one type
form of the disease). of adenohypophyseal hormones (isolated hyperpitu-
In women hypothalamic hyperprolactinemia is itarism or hypopituitarism), or by the disorder of
manifested by non-puerperal galactorrhea (contin- production of several types of adenohypophyseal hor-
ual milk secretion in non-puerperal period), by sec- mones (combinated hyperpituitarism or hypopitu-
ondary amenorrhea, and by atrophy of gonads and itarism). These combinated primary hypothalamic
uterus. The set of these symptoms is called hyper- endocrinopathies are, however, very rare.
prolactinemic syndrome. From the point of view of The cause of primary hypothalamic endocrine dis-
endocrinology the clinical picture is the same as at order may be hypothalamic adenoma overproducing
adenohypophyseal hyperprolactinemia. And, there- one of the releasing hormones, hormonally nonfunc-
fore, its detailed description is given in the chapter tioning tumors situated in the surroundings of hy-
on endocrine disorders of adenohypophysis. pothalamus, or a disorder of production of one of the
If hypothalamic hyperprolactinemia develops post releasing or inhibiting hormones of unknown etiology
partum, it is so-called Chiari-Frommel syndrome. It (idiopathic primary hypothalamic endocrinopathy).
is defined as galactorrhea and amenorrhea persist- Following four types of isolated primary hypotha-
ing more than 6 months post partum in the absence lamic endocrine disorders may be distinguished:
of nursing and without an evident pituitary tumor.
Some of these patients probably harbor occult mi- 1. Isolated TRH deficiency. Undersecretion of
croadenomas stimulated by the hormones of preg- thyrotropin-releasing hormone (TRH, thyroliberin)
nancy that may later become radiologically evident. leads to decreased thyroid-stimulating hormone
In about half, menses eventually return over a period (TSH, thyrotropine) synthesis by the pituitary and
of months or years. This syndrome is often connected thus gives rise to the syndrome of hypothalamic hy-
with psychotic symptoms (depression and somnipa- pothyroidism, also called tertiary hypothyroidism.
5.3. Pathophysiology of hypothalamic-hypophyseal system 317

Its clinical picture is usually milder than the one of of growth hormone-releasing hormone (GHRH, so-
primary hypothyroidism. matoliberin, somatocrinin) in childhood causes hy-
pothalamic hyposomatotropic nanism. GHRH defi-
2. Isolated CRH oversecretion. Corticotropin-
ciency, resulting in the growth hormone (GH, soma-
releasing hormone (CRH, corticoliberin) causes the
totropin) deficiency, appears in most patients with
origin of tertiary hyperglucocorticoidism (Icenko-
idiopathic dwarfism. The hypothalamic hyposoma-
Cushing’s disease). Some authors assume that CRH
totropic nanism is sometimes combined with hy-
overproduction is probably the cause of Nelson’s syn-
pothalamic hypogonadotropic hypogonadism. The
drome development, which appears in about 10–15 %
clinical picture of hypothalamic hyposomatotropic
patients with hyperglucocorticoidism after bilateral
nanism is the same as that of adenohypophyseal hy-
total adrenalectomy realized for the purpose of the
posomatotropic nanism.
therapy of hyperglucocorticoidism. Despite perma-
Special cause of isolated GHRH deficiency ori-
nent adequate substitute glucocorticoid therapy in
gin may be emotional (psychosocial) deprivation
patients with Nelson’s syndrome, significant ACTH
of a child. It is mostly secondary to insufficient
(adrenocorticotropin hormone) oversecretion hence-
care of the child in a family with improper rela-
forth continues and increasing skin pigmentation is
tions. Decreased production of GHRH results in
present. This presence of ACTH excess is caused by
hyperplasia or adenoma (Nelson’s adenoma) of corti- STH deficiency. Compared to his/her age group,
the child’s growth is, therefore, retarded (psychoso-
cotrope cells of the pituitary gland. This hyperplasia
cial dwarfism). If the psychosocial relations in the
or even adenoma develops secondary to permanent
family improve, the child begins to grow evidently
stimulation of corticotrope cells by CRH. Production
faster and the growth retardation is gradually com-
of CRH in hypothalamus is primarily autonomously
increased, and, therefore, feedback inhibition of its pensated.
secretion by exogenic cortisol, administrated for the 4. Isolated GHRH oversecretion. It is now
purpose of substitute therapy, is not realized. Some known that excess GHRH can be induced (though
other authors assume that exogenic cortisol is not rarely) by neurogenic tumors of the hypothala-
equivalent to endogenic cortisol, therefore, its in- mus (GHRH-secreting gangliocytomas, gliomas, and
hibiting influence upon the CRH secretion via feed- hamartomas), or by non-endocrine neoplastic tis-
back mechanism is weaker. This fact is considered sue (most common by GHRH-secreting tumors of
to be the cause of continual CRH overproduction, as the bronchi or pancreas, by medullary thyroid carci-
well as Nelson’s syndrome. noma, and by carcinoids of small intestine and thy-
Nelson’s adenomas sometimes grow more rapidly, mus). In the latter case it is ectopic GHRH produc-
are frequently invasive, and some of them even bor- tion.
der malignity (agressive ACTH-secreting pituitary GHRH hypersecretion causes somatotropes hyper-
adenomas). In the clinical picture progressive skin plasia and thus excessive secretion of growth hor-
hyperpigmentation (similar to that of Addison’s dis- mone. GH overproduction, dependent on the pa-
ease) dominate. ACTH and MSH (melanocyte- cient’s age in which arises, causes gigantism or
stimulating hormone) partake in its origin. Stimu- acromegaly of hypothalamic origin. But, they
lative ACTH effect on skin melanocytes equals 1/3 are clinically indistinguishable from gigantism and
of MSH effect. It is due to the fact that the sequence acromegaly of primarily adenohypophyseal origin.
of the first seven amino acids of ACTH and MSH
molecules is identical. Besides that, the cells of the
adenohypophyseal adenoma along with ACTH over- 5.3.2.2 Endocrine disorders of adenohy-
secretion usually also overproduce MSH. pophysis
In the clinical picture visual disturbances and vi-
From the point of view of intensity of hormonal ac-
sual field defects (due to compression of the optic
tivity endocrine disorders of adenohypophysis can be
chiasm by adenoma), severe headache, respectively
classified as adenohypophyseal hyperfunction (hy-
further symptoms of intracranial hypertension often
perpituitarism) and adenohypophyseal hypofunction
apear.
(hypopituitarism). They are clinically manifested by
3. Isolated GHRH deficiency. Undersecretion endocrinological symptoms, which are conditioned
318 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

by the change of secretion of one or more adeno- Permanent GH overproduction gives rise to the ex-
hypophyseal hormones. If they are caused by the tu- cess growth of long bones of extremities, and thereby
mors in the area of Turkish saddle (sella turcica), in accelerated and excessive linear body growth in the
the clinical picture local symptoms, resulting from youth, as well as overgrowth of soft tissues. After
compression of intrasellar or parasellar structures puberty, respectively in adulthood it results in ex-
which is secondary to expansive tumor growth, may cessive growth of acral parts of the body.
occur. Manifestation of these local symptoms de- Dependent on the age in which GH oversecre-
pends on speed, range, and direction of tumor ex- tion occurs two clinical forms of somatotropic hy-
pansion. perpituitarism originate. They are gigantism and
acromegaly.
I. Adenohypophyseal hyperfunctions Gigantism – It is the clinical form of soma-
Hypersecretion of one or more hormones of the ante- totropic hyperpituitarism characterized by statural
rior lobe of the pituitary gland is called as hyperpitu- overgrowth (giant’s growth), eunuchoid proportions
itarism. There is usually isolated hyperpituitarism resulting from lower concentrations of gonadotropins
which originates by oversecretion of only one ade- and thereby lower concentrations of sex hormones.
nohypophyseal hormone (monohormonal hyperpitu- Atrophy of gonadotrope cells caused by expansive
itarism). Isolated somatotropin oversecretion, iso- growth of somatotrope adenoma partakes in de-
lated prolactin oversecretion, and isolated adreno- creased secretion of gonadotropins and sex hormones.
corticotropin oversecretion most often occur. Iso- If STH overproduction starts at the onset of puberty
lated thyrotropin hypersecretion, and isolated go- and continues also in adulthood, epiphyseal closure
nadotropin (FSH or LH) hypersecretion are very is delayed and finishes around the age of 30. There-
rare. In some cases combinated hyperpituitarism, fore, by the end of 3rd decennium, besides the giant’s
e.g., simultaneous hyperproductions of STH and stature also acromegalic features begin to apear and
prolactin (PRL), or simultaneous hyperproductions the clinical picture of gigantoacromegaly originates.
of ACTH and MSH (bihormonal hyperpituitarism), The increased GH concentration does not influence
may develop. longitudinal growth of bones directly, but through
A. Somatotropic hyperpituitarism the stimulation of insulin-like growth factor I (IGF I,
also called somatomedin C) production in liver (its
This disorder is relatively rare and mostly caused
main source), kidneys, muscles, chondrocytes, and
by primary acidophilic (eosinophilic) adenoma (so-
may be also in other tissues. IGF I (a 70-amino acid
matotrope adenoma), or less frequently by chromo-
basic peptide) is the important mediator of GH ac-
phobic adenoma of adenohypophysis. These adeno-
tion. It stimulates deposition of chondroitin sulphate
mas have autonomous STH secretion. Over 99 % of
in epiphyseal cartilage of long bones, and so increases
cases of somatotropic hyperpituitarism result from a
chondrogenesis followed by longitudinal growth of
primary pituitary adenoma. As a rule this adenoma
bones.
grows slowly. Whether development of somatotrope
adenoma is primarily a pituitary disease or the result In the clinical picture of gigantism some local
of hypothalamic dysregulation is unresolved. How- symptoms (secondary to compression of intracranial
ever, the majority of evidences suggest that it is a structures) induced by expansive growth of adenohy-
primary pituitary disease. STH overproduction may pophyseal tumor (expansive adenoma) can be also
be caused also by hyperplasia of acidophilic cells (so- observed. Prognosis of the disease, especially if it
matotrophs) of the anterior pituitary. It is assumed develops in the early childhood, is usually bad. If
that somatotropic hyperpituitarism caused by hyper- the patients are not given a successful therapy, they
plasia of somatotrophs has a hypothalamic origin. mostly die prematurely, in the first years of adult-
In fact it is hypothalamic somatotropic hyperpitu- hood. However, today, gigantism has become van-
itarism caused by isolated GHRH overproduction in- ishingly rare.
duced by a tumor or by other organic lesion in the Acromegaly – It is a clinical form of somatotropic
hypotalamic region. In rare instances ectopic GHRH hyperpituitarism characterized by enlargement of
secretion has been described. Ectopic STH produc- acral parts of the body, and by overgrowth of in-
tion is very rare. ner organs (generalized organomegaly). It is the en-
5.3. Pathophysiology of hypothalamic-hypophyseal system 319

largement of the acral parts that gives the name to ges thickening followed by their degenerative chan-
this disease. It develops if STH overproduction be- ges.
gins during adulthood, i.e., after epiphyseal growth Hypersecretion of GH induces insulin resistance
plates are closed. Therefore, excessive GH produc- and glucose intolerance in about 50 % and diabetes
tion does not induce exessive longitudinal growth of mellitus in about 20 % of patients.
bones, but causes only widening of bones by periostal In some patients, more often in acromegalic
apposition, and overgrowth of soft tissues, especially women, combination of hypersomatotropinemia and
of skin, subcutis, and inner organs. hyperprolactinemia is present. The cause of this
combinated endocrine disorder may be the presence
In the clinical picture the enlargement of acral
of somatotrophs and lactotrophs in adenohypophy-
parts of the body dominates. The result of widened
seal adenoma, respectively adenoma consists of bi-
phalanges, and skin and subcutis thickening is grad-
hormonal somatolactotrophs. Probably, in the con-
ual enlargement of fingers and toes, and hands and
sequence of antagonistic effect of hyperprolactinemia
feet, leading to the need of larger gloves, rings, and
to gonadotropin production, in men decreased libido,
shoes. The increased hand and finger size may cause
and impotence, gynecomastia, and galactorrhea may
difficulty with performing fine task, e.g., picking up
occur. In acromegalic women gonadal dysfunction
a pin. Head size increases because of the increase
is manifested by loss of libido, oligomenorrhea, even
in both soft tissue and skull mass (the need of a
secondary amenorrhea, and infertility.
larger hat). The mandible enlargement is man-
ifested by expressive protrusion of the lower jaw At progressive adenoma expansion some of the lo-
(prognatism), and by increased spaces between the cal symptoms secondary to compression of intracra-
teeth. Supraorbital ridges, and cheek bones are made nial structures may gradually appear, too. These
more expressive. Physical examination demonstrates symptoms are: chronic cephalalgia usually accom-
the typical facial appearance with soft tissue thick- panied by nausea and vomiting, diminished visual
ening, greasiness of skin, increased breadth of the acuity, diplopia, visual field defects, sometimes even
nose, enlarged ears, protruding chin, and thicken- complete blindness, symptoms resulting from nerve
ing of the lips. These changes gradually lead to damage of oculomotor muscles, changes in eyeground
coarsening of the facial features. In patients gen- from optic nerve compression (paleness of optic nerve
eralized organomegaly is usually present, including papilla, respectively even papilloedema), parosmias,
enlargement of the tongue (macroglossia), and in- epileptic attacks, and symptoms from damage of hy-
ner organs (visceromegaly), mainly enlargement of pothalamic centres (disorder of body temperature
heart (cardiomegaly), liver (hepatomegaly), spleen regulation, somnipathy, obesity, emaciation). In x-
(splenomegaly), and kidneys (nephromegaly). La- ray film changes of size or configuration of sella tur-
ryngeal hypertrophy, vocal cords thickening, and si- cica can be seen.
nus enlargement result in a characteristically deep,
resonant, and hollow-sounding voice. B. Prolactic hyperpituitarism
The patients with acromegaly have a gradual pro- Prolactic hyperpituitarism (adenohypophyseal hy-
gression of all above mentioned symptoms. Thus the perprolactinemia) is the most frequent among hy-
diagnosis is often delayed for as many as 15–20 years. perpituitarism. The cause of its origin are almost al-
The symptoms usually begin inconspiciously and in- ways lactotrope adenomas (prolactinomas), belong-
sidiously, therefore, they are unnoticed until compli- ing among the most often occuring hypophyseal tu-
cations develop. mors (30–40 % out of their total number). Women
are affected 5–8 times more often than men. The
Along with bone thickening, osteoporosis (prob- adenomas can appear at any age, however, the most
ably as a result of hypogonadism) also develops. It frequently from 20 to 40 years of age. If they occur in
gives rise to bone deformations. The disease is, there- children, their puberty is delayed. In women simulta-
fore, associated with dorsal kyphosis or kyphosco- neous occurrence of more small adenomas (microade-
liosis. Joint pain resulting from accelerated os- nomas) are prevailingly present. In men mostly one
teoarthrosis may also be the presenting symptom. larger adenoma (macroadenoma) occurs, which gives
The osteoarthrosis is secondary to articular cartila- rise to local symptoms from its expansive growth.
320 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

The cause of prolactinomas is not known. Primary disease is mostly caused by corticotrope microade-
hypothalamic disorder in the sense of insufficient pro- nomas (in 90 % of patients) and by a corticotrope
duction of prolactin-inhibiting factor (PIF), or dis- macroadenoma in most of the rest. Microadeno-
order of its transport to adenohypophysis are con- mas and macroadenoma autonomously overproduce
sidered. In unique cases prolactic hyperpituitarism ACTH resulting in hyperplasia of adrenal cortex.
may arise as a result of decreased perception of lac- Therefore, the adrenal glands overproduce glucocor-
totrophs to PIF. But, this disorder is associated with ticoids, mainly cortisol. The microadenomas are of-
pituitary lactotroph hyperplasia. ten small (3 to 6 mm or less) and may be difficult to
The clinical picture of prolactic hyperpituitarism find.
is characterized especially by the symptoms of hy- Central adenohypophyseal hyperglucocorticoidism
pogonadism and by galactorrhea. It is diferent in (secondary hyperglucocorticoidism) represents 90 %
both sexes. of the total number of cases of central hypergluco-
In women the main symptom is a disturbance of corticoidism, and the rest 10 % represents central
menstruation (oligomenorrhea or secondary amenor- hypothalamic hyperglucocorticoidism (tertiary hy-
rhea) which is accompanied by infertility. Concen- perglucocorticoidism). The result of ACTH excess,
trations of estrogen and progesterone in blood are de- which is common phenomenon of the both forms of
creased. Galactorrhea is present in 30–80 % of these the central hyperglucocorticoidism, is the origin of
women and may be related to the duration of gonadal hyperplasia of adrenal cortex (mainly zona fascic-
dysfunction. Women with long-standing amenorrhea ulata), and thus the origin of glucocorticoid over-
are less likely to have galactorrhea, which proba- secretion with its subsequent clinical symptoms. The
bly reflects prolonged estrogen deficiency. In some cause of origin of ACTH-secreting pituitary adeno-
women patients (20–30 %) other features of estrogen mas is not known.
deficiency may occur, such as decreased libido, vagi- Cushing’s disease is seldom (5–10 %) caused by ec-
nal dryness, dyspareumia, mastalgia, and hirsutism topic ACTH production (ectopic ACTH syndrome).
and tendency to obesity may be also present. A unique possibility of ectopic CRH production is
In men hyperprolactinemia is manifested by de- also admitted. Ectopic production of both these hor-
crease or loss of libido, partial or complete im- mones is usually caused by malignant tumors, mostly
potence, disorder of spermatogenesis (oligospermia by lung carcinoma, thymic carcinoma, duodenal car-
or azoospermia), and decreased plasma testosterone cinoma, pancreatic carcinoma, thyroid medullary
level, sometimes by gynecomastia, and rarely galac- carcinoma, and rarely bronchial carcinoid or neurob-
torrhea. As to the fact that in men the cause lastoma.
of adenohypophyseal hyperprolactinemia is mostly Cushing’s disease occurs 4 times more in women
macroadenoma, in the clinical picture also local than in men, prevailingly from 25 to 45 years of age.
symptoms from its expansive growth are present. Pathophysiology and clinical features of Cushing’s
In both sexes the hypogonadism associated with disease (secondary hyperglucocorticoidism) are al-
hyperprolactinemia appears to be due to inhibition of most the same as those of the primary hyperglucocor-
hypothalamic release of LHRH by hyperprolactine- ticoidism (Cushing’s syndrome). Therefore, they are
mia, resulting in decrease of LH and FSH secretion. detailed in the chapter on pathophysiology of adrenal
Besides that, hyperprolactinemia decreases the ef- cortex. They differ from Cushing’s syndrome only by
fect of gonadotropins at the gonad level (hypofunc- the presence of skin hyperpigmentation, which orig-
tional pseudoendocrinopathy). The damage of pitu- inates because the corticotrope adenomas, as well as
itary gonadotrophs by macroadenoma compression the cells of malignant tumors with ectopic ACTH
may be also considered. secretion, also produce MSH. The moderate stimu-
lative effect of ACTH on skin melanocytes also par-
C. Adrenocorticotropic hyperpituitarism ticipates in the origin of the skin hyperpigmentation.
Adrenocorticotropic hyperpituitarism (central a-
denohypophyseal hyperglucocorticoidism, Cushing’s
disease) is the most frequent form of hypergluco- D. Other types of hyperpituitarism
corticoidism. It represents 75 % of the total num- The occurrence of gonadotropic hyperpituitarism
ber of the cases of hyperglucocorticoidism. This is unique. It is caused mainly by macroadenoma of
5.3. Pathophysiology of hypothalamic-hypophyseal system 321

gonadotrophs (gonadotropic adenoma), which over- totally absent. In about one third of cases it is an
produces gonadotropins (usually FSH or FSH in con- isolated GH deficiency. However, in the rest of the
junction with LH, rarely LH alone). It can be ob- patients the deficiency of GH is combinated with the
served before puberty more often than in adulthood, deficiency of gonadotropins.
five times more frequent in girls than in boys. In both In adults, STH deficiency is usually cryptic. Its
sexes it results in true precocious puberty. Although presence in adults does not seem to be inevitable.
in men LH plasma concentration is elevated, testos- But, the consequences of STH deficiency and re-
terone level is often low. The reason for this subnor- placement in adults are still being explored. Phys-
mal serum testosterone concentration is unclear, but iological production of GH is needed only in chil-
by some authors it is attributed to secretion of bio- dren during the whole period of body growth, i.e.,
logically inactive gonadotropins. In postmenopausal till the epiphyseal growth plates are closed. Insu-
women with macroadenomas, it may be difficult to ficient STH production in childhood or youth be-
ascertain whether the increased plasma gonadotropin fore epiphyseal closure leads to impaired growth and
concentration is due to normal menopause or due to short stature, respectivelly gives rise to the origin
a gonadotropin-secreting adenoma. of hyposomatotropic dwarfism (pituitary dwarfism,
Thyrotropic hyperpituitarism (pituitary hyper- pituitary nanism). However, it is more often a con-
thyroidism, secondary hyperthyroidism) is very rare. sequence of hypothalamic GHRH deficiency than a
It is caused by macroadenoma (thyrotropic ade- consequence of primary disorder of STH production
noma) of thyrotrophs which overproduces TSH by pituitary somatotropes.
(TSH-induced hyperthyroidism). In the patients the There are two forms of hyposomatotropic
clinical symptoms of thyrotoxicosis are present, how- dwarfism: hypothalamic and pituitary. Hypothala-
ever, they are usually milder than in primary (pe- mic dwarfism is usually caused by isolated STH defi-
ripheral) hyperthyroidism. ciency, while pituitary dwarfism is mostly character-
ized by combinated disorder, e.g., by STH deficiency
and gonadotropin deficiency.
II. Adenohypophyseal hypofunctions
The cause of the both mentioned forms of hypo-
Decreased ability of the anterior lobe of the pituitary
somatotropic dwarfism can be found only in about
gland to produce one or more tropic hormones is
35 % of affected children. It may be an organic dis-
called hypopituitarism. Insufficient secretion of only
order, e.g., tumor, cyst, aneurysm, trauma, or other
one pituitary hormone (isolated hypopituitarism,
pathological process endamaging the cells of compe-
monohormonal hypopituitarism, monotropic hypopi-
tent endocrine active tissue of hypothalamus or ade-
tuitarism) occurs seldom and it is mostly STH defi-
nohypophysis. In about 65 % of patients the cause
ciency. Dependent on the cause, the monohormonal
of GH deficiency can not be found (idiopathic hypo-
hypopituitarism can be sometimes gradually changed
somatotropic dwarfism).
to plurihormonal hypopituitarism (combinated hy-
The both forms of hyposomatotropic dwarfism are
popituitarism). However, the most frequent form
necessary to differ from those forms of dwarfism in
of adenohypophyseal hypopituitarism is the disor-
which plasma GH concentration is normal or even
der manifesting insufficient secretion of all adenohy-
increased. The following forms of dwarfism must be
pophyseal hormones. This condition is called panhy-
distinguished:
popituitarism. If the adenohypophyseal hypofunc-
tion orriginates as a result of the pathological process 1. Nanism caused by long-term severe nutritional
of gradually destroying cells of its hormonally active insufficiency.
tissue, isolated or combinated hypopituitarisms are
only incipient phases of panhypopituitarism. Panhy- 2. Nanism caused by some chronic diseases, e.g.,
popituitarism may occur also suddenly, without the malabsorption or chronic inflammatory intestine
two phases mentioned above. disease, chronic renal disease (renal nanism), se-
vere congenital heart disease (cardial nanism),
A. Somatotropic hypopituitarism severe pulmonary disease, and severe hemato-
logical disease.
In the patients with the somatotropic hypopitu-
itarism STH deficiency is present or this hormone is 3. Dwarfism caused by insensitivity to GH at the
322 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

level of GH receptors. This disorder is due to ab- pubertal development. Plasma concentrations
sent or defective GH receptors. It is also widely of STH and IGF I are usually normal. Familial
known as Laron-type dwarfism, which probably short stature is a physiological variant of growth
represents only one form of insensitivity to STH distance in which the velocity of bone age is nor-
(familial form of short stature). Due to STH re- mal, whereas constitutional delay in growth and
ceptors disorder IGF I (somatomedin C) is not adolescence is a disorder of growth and bone age
produced in hepatocytes and in cells of other tempo that secondarily impairs growth distance.
tissues. The serum IGF I concentration is low Of course, some children may have a combina-
and does not increase in response to injection of tion of genetic short stature and constitutional
human GH. Abnormalities of DNA restriction delay in growth and puberty.
fragment length in some of these patients are
consistent with defects in the gene encoding the Pathophysiology and clinical features of hyposo-
GH receptor. matotropic dwarfism. The most expressive symptom
of this disease is a disorder of body growth. Chil-
4. Constitutional delay in growth and puberty. dren with hyposomatotropic hypopituitarism are of
Healthy individuals, who spontaneously enter a short stature and exhibit growth curves that devi-
puberty after the age of 12 for girls and 14 ate progressively from normal. In idiopathic hypopi-
for boys, have constitutional delay in growth tuitarism, growth failure may not be obvious until
and adolescence. The syndrom of growth re- patients are 2 to 4 years old. In retrospect, however,
tardation with delayed puberty accounts for a it is often possible to establish that growth failure
high proportion of referrals for growth evalua- began in the first few months of life. The growth
tion, particularly in boys. Height and bone age disorder is most evidently manifested at the onset
are usually delayed by 2 to 4 years, and onset of puberty when the psychical problems from short
of pubertal development is delayed by 2 years stature of the pacient may appear.
or more. In the patients adrenarche and go- Retardation or precocious cessation of body
nadarche occur later than in their classmates growth is the result of longitudinal bone growth dis-
for years. However, the patients undergo spon- order, while epiphyseal growth plates are open for
taneous puberty. longer than usual. Therefore, in the patient the slow
GH secretion before the actual onset of puberty growth may be prolonged until age 30–40 years. A
in these patients is suboptimal. However, their bone age retardation in relation to chronological age
STH secretion and growth velocity return to (delayed skeletal maturation) is evident. Closure of
normal after the onset of puberty. There is an the fontanelles and eruption of permanent teeth are
interaction of IGF I and gonadotropins in the delayed.
testis, and the relatively low secretion of GH The final height of hypophyseal dwarf varies from
(and presumably intragonadal IGF I) may im- 120 to 150 cm. The stature is, however, usually pro-
pair the gonadal response to gonadotropins. Af- portional (the patients exhibit normal body propor-
fected boys seem to be more distressed by short tions). Overall look, especially facial appearance is
stature than by delay in sexual development. infantile for quite a long time. On the contrary, in
Final adult stature, which may not be reached adulthood the facial appearance is progeric (preco-
until age 20 or more, is often in the low-normal ciously senile). There is no significant deviation of
range, and sexual development and fertility are the patient intelect. In the first several years of life,
normal. Anamnesis can show, that delay in approximately 10 % of children with somatotropic
growth and in pubertal development may have hypopituitarism have hypoglycemic convulsions. An
occurred in the father and other male relatives. additional 10 % or more have asymptomatic fasting
This diagnosis of constitutional growth delay hypoglycemia. Hypoglycemia is usually secondary to
should be made only after the exclusion of other combined deficiencies of cortisol and GH.
causes of delayed growth and puberty. Somatotropic hypopituitarism in children is usu-
ally associated with gonadotropin deficiency (com-
5. Familial (genetic) short stature. The patients binated hypopituitarism). In that case along with
with familial short stature do not have delayed dwarfism also sexual infantilism occurs. When
5.3. Pathophysiology of hypothalamic-hypophyseal system 323

the hyposomatotropic dwarfism is due to expansive ing of the voice does not occur and facial appear-
growing tumor, in the clinical picture of the disease ance remains infantile for a long time. Develop-
also local symptoms from the damage of the sur- ment of muscles is insufficient and sometimes
rounding intracranial structures can be present. gynecomastia is present. The testes are small
In adults the clinical syndrom due to STH defi- and soft, and scrotum is not pigmented. Some-
ciency is not known. In the patients only tendency times cryptorchism may be present. Spermio-
to hypoglycemia resulting from the increased sensi- genesis is absent what leads to infertility. The
tivity of tissues to insulin is observed. GH is insulin size of the penis remains the same as in child-
antagonist, and, therefore, its deficiency is connected hood. If STH production is normal (isolated go-
with the increased sensitivity of tissues to insulin. nadotropic hypopituitarism), epiphyseal fusion
is retarded, and growth of long bones of ex-
B. Gonadotropic hypopituitarism tremities continues also after 20 years of age.
Forms and intensity of symptoms of gonadotropic Therefore, eunuchoid body proportions (exces-
hypopituitarism (gonadotropic hypogonadism, sec- sive and disproportional body growth, charac-
ondary hypogonadism) depend not only on the de- terized by too long extremities in relation to the
gree of gonadotropin deficiency, but also especially trunk) develop in the patient. But, if STH secre-
on the age and sex of a patient in the time of the ori- tion is decreased (combinated disorder) not only
gin of gonadotropin deficiency. Isolated type of go- sexual infantilism, but also hypophyseal nanism
nadotropic hypogonadism is very rare. Combinated appears in the patient.
gonadotropic hypogonadism, characterized by simul-
taneous deficiency of gonadotropins and GH, is more 2. Prepubertal hypogonadotropic hypogonadism
frequent. in girls
Isolated gonadotropic hypogonadism is usually in- In affected girls any symptoms of spontaneous
born (see Kallmann’s syndrome). However, it is a onset of puberty are absent, sexual infantilism
primary hypothalamic disorder (deficiency of GnRH continues. The main symptom of the disease is
secretion). It can be caused also by a functional dis- primary amenorrhea. Neither primary nor sec-
order, mainly in the female, e.g., by chronic psychoe- ondary sexual organs are being developed like
motional stress. in women. Also secondary sexual characteris-
Combinated gonadotropic hypogonadism, i.e., si- tics are not developed. If STH secretion is nor-
multaneous gonadotropin and GH deficiency, is more mal, epiphyseal closure is retarded leading to
often caused by organic disorder (see somatotropic disproportional body growth (eunuchoid habi-
hypopituitarism). This organic disorder destroys the tus). But, if in the patient STH deficiency oc-
hypothalamic cells producing GnRH and GHRH, or curs, hypophyseal dwarfism originates.
destroys adenohypophyseal gonadotrophs and soma-
totrophs. 3. Postpubertal hypogonadotropic hypogonadism
The clinical picture of secondary hypogonadism in men
depends on sex and the age of a patient in the time
of the origin of this disease. Prepubertal or postpu- This disorder is very rare, and sometimes it can
bertal hypogonadotropic hypogonadism can be dis- be the first symptom of development of panhy-
tinguished. Their clinical picture depends on the sex popituitarism. It is manifested by gradual re-
of a patient. Therefore, the following four types of gression of secondary sexual characteristics, di-
hypogonadotropic hypogonadism may occur: minished libido and impotence appear. Axil-
lary and pubic hair becomes thinner, and growth
1. Prepubertal hypogonadotropic hypogonadism of facial hair decelerated. Moderate atrophy of
in boys. epididymides may occur, spermatogegenesis be-
In an affected child the sexual development comes insufficient and leads to infertility. Mus-
ceases, the symptoms of spontaneous onset of cle flaccidity and atrophy are present, female like
puberty do not appear. Secondary sexual char- type of subcutaneous fat distribution appears.
acteristics are not developed (sexual infantil- Chronically untreated hypogonadism may result
ism). Axillary and pubic hair is missing, break- in the origin of osteoporosis. Some psychical
324 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

changes may appear as well, e.g., loss of aggres- Pathogenesis of Sheehan’s syndrome is not exactly
sivity. known. But, mainly spasm of arterioles of portal
vessel bed during obstetric posthemorrhagic shock
4. Postpubertal hypogonadotropic hypogonadism is supposed to participate in the origin of adenohy-
in women pophyseal necrosis. Other pathogenic mechanism,
Postpubertal hypogonadotropic hypogonadism however, may be involved, such as intravascular
is more frequent in women than in men. It thrombosis or increased sensibility (vulnerability) of
may be only the initial phase of gradually de- the anterior lobe of pituitary gland to hypoxia in
veloping panhypopituitarism. The most evident parturient women.
symptoms of hypogonadotropic hypogonadism Other causes of sudden origin of panhypopitu-
in women are the secondary amenorrhea and in- itarism are: adenohypophyseal hemorrhage (pitu-
fertility. Gradually the symptoms of different itary apoplexy), severe head trauma, hypophysec-
degree of defeminization (atrophy of the breast, tomy, and ionizing irradiation applied in the area
uterus and ovaries) appear. Inhibition of orgas- of sella turcica.
mic function may appear. When hypogonadism The cause of gradually developing panhypopitu-
is untreated for a long time, the symptoms of itarism may be expanding adenohypophyseal tumor
osteoporosis may be gradually developed in the (mainly from chromophobic cells), craniopharyn-
patients. gioma, pinealoma, large artery aneurysm, metas-
tases, cyst, infiltrative diseases, infectious diseases,
and lymphocytic hypophysitis (autoimmune pitu-
C. Other types of hypopituitarism
itary destruction). Because the functional capacity
Due to primary disorder of adenohypophysis iso- of the adenohypophyseal tissue is rather large, pitu-
lated TSH deficiency or isolated ACTH deficiency itary hypofunction is unlikely to be manifested un-
can occur very rarely. Damage of thyrotropes or cor- til at least 75–85 % of anterior lobe is destroyed. In
ticotropes is more frequently present in the patients most instances, there is destruction of 95–99 % of the
with panhypopituitarism, when also other trope cells anterior lobe. Secondary to chronic deficiency of ade-
are damaged. Secondary hypothyroidism as well nohypophyseal tropic hormones, atrophy of individ-
as secondary hypoglucocorticoidism have essentially ual target endocrine glands (multiglandular atrophy)
the same pathophysiology and clinical features as gradually develops.
primary hypothyroidism or primary hypoglucocor- The clinical picture of panhypopituitarism de-
ticoidism. The symptoms of secondary hypothy- pends on the age and sex of the patient in the time
roidism are, however, usually milder than the symp- of the origin of this disease, and also on the degree
toms of primary hypothyroidism. of deficiency of individual adenohypophyseal hor-
mones. Prepubertal and pospubertal panhypopitu-
D. Panhypopituitarism itarism can be distinguished.
The term panhypopituitarism signifies a deficiency
of all anterior pituitary hormones. Its symptoms Prepubertal panhypopituitarism
originate either suddenly or are developing gradu- This disease is manifested especially by the symp-
ally (even several years). It is caused by various or- toms resulting from STH and gonadotropic hormone
ganic disorders of adenohypophysis. Sudden form deficiency. Deficiency of STH prior to epiphyseal fu-
of panhypopituitarism in the past often occured in sion leads to retardation in bone age and in body
some women as a result of postpartum necrosis of growth resulting in pituitary dwarfism. Central ade-
adenohypophysis (pituitary infarction at the time nohypophyseal hypothyroidism may to a certain ex-
of delivery), the clinical picture of which is known tent also participate in the body growth disorder.
as Sheehan’s syndrome. Adenohypophyseal necro- GTH deficiency leads to absence of pubertal devel-
sis induces sudden occurrence of symptoms of pan- opment (sexual infantilism), the clinical picture of
hypopituitarism. This syndrome usually originated which depends on sex of the patient. As there is a
in women with a long-lasting and complicated de- certain spontaneous basal production of the thyroid
livery accompanied by excessive blood loss as a se- hormones, TSH deficiency in the dwarfish children
quel of hemorrhagic shock at the time of delivery. is not usually expressively manifested. Therefore,
5.4. Pathophysiology of thyroid gland 325

mental retardation is not a common clinical symp- ciency (to a certain extent also ACTH deficiency) is
tom. ACTH deficiency in children with panhypopi- manifested by hypopigmentation or depigmentation
tuitarism results in the tendency to hypoglycemia of the skin, which is expressive mainly in physiolog-
and neuroglycopenic attacks. Besides insufficient ically hyperpigmentated areas of the body (breast
production of glucocorticoids, ACTH deficiency also areolae, perigenitally, perianally), and by decreased
leads to a decreased secretion of sex hormones of tolerance to sunshine.
adrenal cortex, which together with GTH deficiency If panhypopituitarism is caused by intrasellar or
participates in the origin of hypogonadism. extrasellar expanding tumor, in the clinical picture
also local symptoms resulting from compression of
Postpubertal panhypopituitarism surrounding structures are present.
The peripheral manifestations of panhypopituitarism In the past, gradually developing panhypopitu-
in adults are mostly the consequences of deficiency of itarism was called Simmond’s cachexia, because
five tropic hormones: gonadotropins (LH and FSH), in the clinical picture of this disease extreme loss
TSH, ACTH, and MSH. Characteristically, evidence of body weight and atrophy of organs dominated.
of target gland deficiencies appears in the above men- Those were the patients with severe total insuffi-
tioned order, i.e., gonadal, thyroidal, and cortical de- ciency of adenohypophysis without longterm substi-
ficiency. tution therapy. Due to present day system of health
The early symptoms of developing panhypopitu- care, the patients do not reach such progressive phase
itarism are usually the symptoms of gonadotropin of the disease, and, therefore, expressive cachexia
deficiency. GTH deficiency in female leads to sec- does not occur in them.
ondary amenorrhea and diminishing libido. In
women with Sheehan’s syndrome the failure to lac-
tate and resume menses after delivery are the most
common initial clinical symptoms. In men loss of 5.4 Pathophysiology of thy-
libido and impotence appear.
TSH and ACTH deficiencies are manifested by roid gland
the same clinical symptoms as at primary hypothy-
roidism and at primary hypoglucocorticoidism. The
symptoms of secondary hypothyroidism are, how- The thyroid gland is the largest classic endocrine
ever, less intensive than at primary hypothyroidism. organ. Its disorders are very frequent. If diabetes
Loss of the thyroid function causes dry skin, cold mellitus, which regularly ranks among metabolic dis-
intolerance, somnolence, bradycardia, and constipa- eases, is not considered, the thyroid gland disor-
tion. However, at secondary hypothyroidism typi- ders make about 4/5 of the total number of en-
cal myxedema usually does not originate. Secondary docrinopathies. The thyroid gland disorders are
adrenal insufficiency results from the lack of ACTH much more frequent in women than in men (7:1).
stimulation of the adrenal cortex, and, therefore, af- They can be classified as follows:
fects only adrenal steroids under predominant ACTH
regulation, namely cortisol and adrenal androgens. 1. Simple goiter
Mineralocorticoid secretion, primarily regulated by 2. Hypothyroidism
renin and angiotensin, is preserved, although it may
not be optimal. More common symptoms of glu- 3. Hyperthyroidism
cocorticoid deficiency are malaise, anorexia, weight
4. Inflammations of the thyroid gland (Thyroiditis)
loss, hypoglycemia or hypoglycemia-induced seizure,
hypovolemia, postural hypotension, and orthostatic 5. Thyroid neoplasms
dizziness. ACTH deficiency results also in abnormal
response to stress, and a higher mortality rate. A de- 5.4.1 Goiter (struma)
crease of adrenal androgen production causes in both
sexes gradual thinning even loss of axillary and pubic Goiter is a clinical and morphological term signifying
hair (in men there is a coexistent GTH deficiency). any enlargement of the thyroid gland situated in situ
In men also facial hair may diminish. MSH defi- or ectopic. The goiter placed in situ can be diagnosed
326 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

by palpation or visually. The size of the goiter can phy. Hot nodule (toxic, hyperfunctional) accumu-
be objectively determined by ultrasonographic volu- lates a radioactive isotope of iodine in a higher ex-
metric measurement of the thyroid gland. Ectopic tent. Scintigraphic cold nodule (afunctional, inac-
struma (struma lingualis, struma mediastinalis, or tive) does not uptake radioiodine and is always sus-
struma ovarii) is rare and may be diagnosed only by pect of malignity. If the nodular goiter is caused
scintigraphy. by neoplasia, according to the character of neoplas-
From the morphological point of view enlargement tic process, which leads to the origin of the nodular
of the thyroid gland can be caused by: goiter, benign goiter and malignant goiter can be
distinguished.
a) Hypertrophy and hyperplasia of the epithelial
According to the number of population affected by
cells of follicles;
goiter in a certain geographic region, sporadic goiter
b) Increased coloid accumulation in the follicles; or endemic goiter are known.
Most goiters cause neither functional nor mechan-
c) Inflammation process (inflammatory infiltration
ical problems. At the beginning it may be only a
and augmentation of connective tissue);
cosmetic defect. If the thyroid enlargement is con-
d) Neoplastic process. siderable, the symptoms resulting from displacement
or compression of surrounding structures may ap-
From the functional view-point the term goiter pear, mainly of the esophagus, the trachea, the re-
(struma) does not explain the actual functional state current laryngeal nerve, and the superior vena cava.
of the thyroid gland, i.e., what is the production of Compression of the esophagus or the trachea leads
thyroid hormones in relation to demands of organism to dysphagia, a choking sensation, and rarely to in-
tissues. spiratory stridor. Superior mediastinal obstruction
Goiter may be characterized from several view- may occur with a large retrosternal goiter. Narrow-
points. Goiter may be associated with normal, de- ing of the thoracic inlet may compromise the venous
creased, or increased hormone secretion. Therefore, return from the head, neck, and upper limbs suf-
according to the state of functional activity of its tis- ficiently to produce venous engorgement. This ob-
sue, eufunctional goiter, hypofunctional goiter, and struction is accentuated when the patient’s arms are
hyperfunctional goiter are distinguished. From the raised above the head (Pemberton’s sign). Suffusion
point of view of functional consequences for metabo- of the face, giddiness, and even syncope may result
lism of organism, toxic goiter (hyperfunctional) and from this manoeuvre. Compression of the recurrent
nontoxic goiter (eufunctional or hypofunctional) may laryngeal nerve leading to hoarseness is rare in sim-
be distinguished. ple goiter, and, therefore, its presence suggests ma-
According to the histopathological process prevail- lignant neoplasm rather than nontoxic goiter. Sud-
ingly leading to the enlargement of the thyroid gland, den hemorrhage into a nodule or cyst may lead to an
parenchymatous goiter, colloidal goiter, and fibrous acute painful enlargement in the neck and may pro-
goiter are known. duce the origin or the enhancement of compressive
The enlargement of the thyroid gland (normally 15 symptoms. The set of introduced symptoms, con-
to 20 g in adults) may be generalized or focal. Ac- ditioned by compression of the neck or mediastinal
cording to that, diffuse goiter and nodular goiter are structures neighbouring the goiter, is called mechan-
distinguished. In the thyroid gland only one (solitary ical local syndrome.
nodule) can be present (mononodular, uninodular Along with the symptoms of mechanical local syn-
goiter), or more nodules may occur (multinodular drome, symptoms resulting from dysfunction of the
goiter). Nodular goiter (struma nodosa) is a clin- thyroid gland (hypothyroidism or hyperthyroidism)
ical term including various morphological changes, may also occur.
e.g., nodular hypertrophy and hyperplasia of the aci-
nar cells, colloido-cystic or fibrous changes, intrathy-
5.4.1.1 Simple goiter
roidal hematoma, adenoma, carcinoma, sarcoma, fi-
brosarcoma, and metastases. Simple goiter (nontoxic goiter) may be defined as
Another classification of nodular goiter is due to any thyroid enlargement that is not associated with
intensity of radioiodine accumulation at scintigra- hyper– or hypothyroidism and that is not the result
5.4. Pathophysiology of thyroid gland 327

of inflammatory or neoplastic process. Hence, it is an often due to a definable cause of impaired thyroid
eufunctional (euthyroid) goiter, the tissue of which hormone biosynthesis, such as iodine deficiency, and
produces sufficient amount of thyroid hormones for ingestion of goitrogens. Sometimes it is due to an
maintaining of euthyroid status. inborn defect in a hormone synthesis pathway, but
Simple goiter is the most frequent endocrinopathy. in some instances its cause is not exactly known.
It occurs much more in women than in men (7:1).
The higher occurrence of simple goiter in women is 1. Iodine deficiency in food and water. Iodine and
associated with the increased demands to the thy- tyrosine are the basic substances for the thyroid hor-
roid hormone production at puberty, adolescence, mone biosynthesis. At present the optimal daily
pregnancy, and lactation. With increasing number iodine intake is considered 150–200 microgrammes.
of deliveries, especially in the regions with iodine However, for eufunctional status of the thyroid gland
deficiency in soil and in drinking water, the occur- minimum daily iodine intake of 100 microgrammes
rence of simple goiter or later also of nodular goiter is needed. If its daily intake falls under this value,
increases. Nowadays, in our country 25 % of mid- the production of thyroid hormones significantly de-
dle aged women are affected. It is even more often creases. Therefore, the compensatory goiter begins
present at puberty or in adolescent girls (pubertal to develop, however, in some people it is being de-
goiter, adolescent goiter). In some patients simple veloped also if daily iodine intake is somewhat more
goiter may later diminish (regresses), in others it may than 100 microgrammes. The compensatory aug-
be present lifelong. But in some young women the mentation of thyroid parenchyma is to secure the
simple goiter may henceforth grow, and change mor- uptake of such total amount of iodine from circu-
phologically, or sometimes change even functionally, lating blood, which in spite of its insufficient supply
due to gravidity and lactation, but also due to the to organism, will be sufficient for securing euthyroid
age if influence of etiological factors recurs. status. The uptake and the content of iodine per
unit of thyroid tissue weight are, however, signifi-
In certain geographic regions simple goiter may
cantly lower.
occur sporadically or endemically. Sporadic simple
Iodine deficiency may be absolute or relative. The
goiter arises as a result of factors that do not affect
absolute iodine deficiency in food and water, and so
the population generally. If in particular geographic
in the organism as well, in the past was often present
localities incidence of simple goiter is more than 10 %
in the geographic regions with incidence of endemic
of the adult population, or more than 20 % of the
goiter. In the noted regions endemic goiter had oc-
children population, it is denoted as endemic goi-
curred in several generations. If the iodine deficiency
ter. Endemic goiter implies an etiologic factor (en-
was severe, in considerable number of the patients
vironmental iodine deficiency is regarded the major
goitrous enlargement was also associated with vary-
etiologic factor), or factors common to a particular
ing degree of hypothyroidism. The incidence of en-
geographic region.
demic goiter has been greatly reduced in many coun-
Endemic goiter is still a problem of vast public tries by the introduction of iodized salt (in Slovakia
health significance and has been estimated to afflict since 1951). In our country table salt is enriched
more than 200 million people throughout the world. with potassium iodide containing 25 mg KI/1 kg.
Except perhaps in North America, it is present on all The relative iodine deficiency may originate
continents and occurs mostly in mountainous areas mainly during those periods of ontogenesis, which
such as Andes, Himalayas, and Alps, where iodine are associated with increased demands to the thy-
deficiency still exists. But endemic goiter also may roid hormone production. In girls it is especially
occur in nonmountainous regions remote from the during puberty and adolescence, in women during
sea, such as Central Africa, where iodized salt is not pregnancy and lactation. The origin of simple goi-
used. ter due to iodine deficiency in boys is rather rare.
At the beginning of 50s of this century incidence of The increased need of the thyroid hormones is as-
simple goiter in Slovakia was very high. In some re- sociated with increased demands to iodine intake.
gions, namely Kysuce, Slovenské rudohorie and Žitný However, if the iodine intake remains at the level be-
ostrov, it was present in 50–80 % of adult women. fore the onset of the above mentioned periods of life,
Etiology of simple goiter is multifactorial. It is it becomes relatively insufficient with respect to the
328 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

increased needs of organism. Therefore, it is neces- iodine intake. Although humans rarely, if ever, eat
sary to increase iodine intake by occasional consuma- goitrogenic foods in quantities to lead to goiter (the
tion of sea fish, respectively by use of iodine medical content of natural goitrogens in the mentioned kinds
drugs. This is important especially for women dur- of vegetables is low), sufficient quantities of goitro-
ing gravidity and lactation because of the demands gens to cause goiter may be present in milk.
of the fetus and newborn for iodine. The other group of natural goitrogens are
flavonoids (polyhydroxyphenols). They are present
2. Increased intake of goitrogens. A wide variety of in groundnut, beans, and soya. However, their most
chemical agents have the capacity to inhibit the syn- important source is millet, a significant food in many
thesis of thyroid hormones. When the effect of such countries.
agents is sufficient to reduce the secretion of thyroid Synthetic goitrogens. The most known synthetic
hormones to subnormal levels, secretion of TSH is in- goitrogens are: chlorates, perchlorates, iodates, peri-
directly increased (via the feedback mechanism), and odates, nitrates, and some medical drugs, e.g., para-
so they induce goiter formation. Hence such agents aminosalicylic acid, para-aminobenzoic acid, thio-
are commonly termed goitrogens (strumigens). barbiturates, phenylbutazone, resorcine, resorcinol,
From the standpoint of the aspect of iodine me- some antidiabetic drugs (sulfonylureas, tolbutamide,
tabolism that they inhibit, goitrogens (antithyroid carbutamide), sulfonamids, and lithium drugs. Goi-
agents) can be grouped into two classes: goitrogens ter originated as a sequel of long-term taking larger
that inhibit iodide transport and thereby reduce sub- doses of pharmacological goitrogens is called struma
strate for hormone formation, and those that inhibit medicamentosa.
the initial oxidation (organic binding) of iodide, de- In the last decades the higher attention is paid
crease the proportion of diiodotyrosine (DIT) rel- to the contaminants occurring widely in the envi-
ative to monoiodotyrosine (MIT), and block cou- ronment (anthropogenic goitrogens). They include
pling of iodotyrosines to form the hormonally active mainly:
iodothyronines.
Increased intake of goitrogens participates in the a) polychlorinated biphenyls used in the plastic
origin of the goiter especially if it is associated with material industry. By their decomposition
mild iodine deficiency in food and water. Increased goitrogenic more effective resorcinols, hydrox-
intake of goitrogens may be applied also in the period ypirimidins, and phtalates originate. From these
of increased needs of the thyroid hormones (puberty, chemical agents goitrogenic dihydroxybenzoic
adolescence, pregnancy, and lactation), respectivelly acids originate;
in the persons with mild hereditary deficiencies of b) polycyclic aromatic hydrocarbons (benzpyrene
enzymes participating in biosynthesis and secretion and methylcholanthrene), which also play an im-
of thyroid hormones (the persons with heterozygous portant role in the carcinogenesis;
form of enzymopathy).
Goitrogens are natural or synthetic chemical c) nitrates;
agents. Natural goitrogens are contained in some
d) insecticides (the most known agent from this
kinds of vegetables, such as cabbage, cauliflower,
group is dichlorophenyl-trichloranthen – DDT,
kale, kohlrabi, Brussels sprouts, turnips, mustard,
which was used mainly in the past); pesticides
cassava, and others belonging to the Brassica and
(parathione and metathione). From the om-
Crucifera plants. They may be also in some animal
nipresent polyvinyl-chloride (PVC) goitrogenic
forage, e.g., clover, rape, and soya. Natural goitro-
phtalate esters and dihydroxybenzoic acids are
gens contained in forage may be successively found
being released by moisture, therefore, those
in milk, and probably even in meat of domestic an-
chemical agents are present in plastic packet
imals, which may so become a source of goitrogens
milk, in the vegetables grown in plastic foil
when they are consumed. Well known natural goitro-
greenhouse, and in other foodstuffs.
gens are: thiocyanate, 1-5-vinyl-2-thiooxazolidone,
and allylisotiocyanate. The role of dietary goitro- Simple goiter may be also caused by chronic ex-
gens in the induction of disease in humans is uncer- cessive iodine intake in food (organic form of iodine)
tain. Their effect may depend on the concomitant or in medical drugs (inorganic form of iodine). The
5.4. Pathophysiology of thyroid gland 329

doses of iodine are supposed to be large (more than ologically active, their reduced blood concentration
10 mg daily). Large iodine intake inhibits synthe- via the feedback mechanism leads to increased secre-
sis of thyroid hormones. Chronic administration of tion of TSH. The increased plasma TSH concentra-
large doses of iodine is seen most commonly in pa- tion results in the origin of goiter.
tients with chronic respiratory diseases, who are of-
ten given potassium iodide as an expectorant. How- 5. Immunoglobulins. Recently it has been assumed,
ever, iodine goiter (iodide goiter) develops in only that in blood of some patients there may exist a class
a small proportion of patients given iodine. In sea- of thyroid immunoglobulins stimulating only growth
side areas, where large quantities of food with ex- of the thyroid gland (thyroid growth immunoglob-
cessive content of iodine are consumed (seafish and ulins – TGIs). TGIs, like TSH, stimulate growth
seaweed), iodide goiter occurs endemically (so called of the thyroid gland by hypertrophy and hyperpla-
seaside goiter). Increased iodine supply in pregnant sia of epithelial cells of follicles. However, unlike
women, e.g., long-term therapy by expectorants con- TSH and thyroid immunoglobulins present in pa-
taining iodine, causes the origin of goiter in newborn tients with Graves-Basedow disease, they do not in-
infants. In such cases, the mother is usually free crease biosynthesis of thyroid hormones. This might
of goiter. It is not known whether iodide goiter in explain why in some persons simple goiter is eufunc-
newborns results from hypersensitivity of the fetal tional already from the very beginning of its origin.
thyroid to iodine or from the fact that the placenta Patients in whom such ”autoimmune nontoxic goi-
concentrates iodide several-fold. ter” is thought most likely are those in whom other
autoimmune phenomena are present in themselves or
3. Hereditary factors. Genetically determined de- in their families.
fects in thyroid hormone biosynthesis are rare and Pathogenesis of simple goiter. The action of one
their share in the origin of simple goiter is not clear or several above mentioned etiologic factors (except
enough. In most instances, the defect appears to TGIs) results in reduction of functional efficiency of
be transmitted as an autosomal recessive trait. It the thyroid gland. As a sequel of this state, the pro-
is supposed, that in some persons with inborn en- duction of its hormones is not adequate to the needs
zyme defect only mild decrease of activity of some of the peripheral tissues. The decrease of plasma
of the enzymes in the pathways of thyroid hormone concentration of thyroid hormone reduces feedback
synthesis is present (heterozygous individuals). Un- inhibition of TSH secretion. The increased blood
like severe hereditary enzymopathy (homozygous in- level of TSH causes hypertrophy and hyperplasia of
dividuals) resulting in sporadic cretinism, the thy- epithelial cells of follicles, and also the increase in
roid gland of heterozygous individuals is, therefore, vascularity of the thyroid gland tissue. The result
eufunctional and normal size. This mild enzymopa- of these processes is diffuse parenchymatous goiter.
thy may, however, participate in the origin of sim- This augmentation of parenchyma is a compensa-
ple goiter if in the affected person increased needs tional process securing increased uptake of iodide
for production of thyroid hormones (puberty, ado- from blood, and thereby normalizing plasma concen-
lescence, pregnancy, and lactation), mild iodine de- tration of thyroid hormones, and normalizing TSH
ficiency, or increased intake of goitrogens occur. secretion as well. The patient becomes again euthy-
roid and eumetabolic, though goitrous. Therefore,
4. Increased concentration of estrogens in blood. the eufunctional goiter may usually remain only a
In the origin of simple goiter in girls at puberty symptom of a temporary deficiency of thyroid hor-
or adolescence (juvenile goiter) , and in pregnant mones, which appeared sometimes in the past.
women, besides increased need of the thyroid hor- If the etiologic factor acts only once and temporar-
mones, also estrogen overproduction could partici- ily, the hypertrophy and hyperplasia of the epithelial
pate. Increased plasma estrogen concentration in- cells may almost disappear. This process of involu-
duces the increase of plasma level of the thyroxine- tion leads to a return of the gland to nearly normal
binding globulin (TBG), and thereby also increase of size if the hypertrophy and hyperplasia are of rela-
its binding capacity. Increased concentration of TBG tively short duration, but probably results in a dif-
may reduce plasma concentration of free thyroid hor- fuse colloid goiter if the hyperplastic phase has been
mones. Because only free thyroid hormones are bi- present for years. In long-standing goiter, repeated
330 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

cycles of hyperplasia and involution eventually lead diseases of the thyroid, it occurs more frequently in
to formation of nodules, and a multinodular goiter women, mainly in the elderly.
results, and it may reach considerable size. Areas of From the etiopathogenetic point of view hypothy-
involution are often interspersed with patchy areas roidism is divided into two groups:
of focal hyperplasia. Fibrosis may demarcate hyper-
plastic or involuted nodules. Nodules often undergo 1. Peripheral hypothyroidism;
hemorrhagic or cystic degeneration and may become 2. Central hypothyroidism.
irregularly calcified.
According to the clinical criteria the simple goiter
1. Peripheral hypothyroidism (primary hypothy-
may be classified as follows:
roidism). The cause of the thyroid gland hypofunc-
1. Diffuse goiter with homogenous hyperplasia tion is in its parenchyma. Decreased plasma concen-
trations of thyroid hormones increase TSH produc-
2. Diffuse goiter with nodular hyperplasia
tion by feedback mechanism followed by the increase
3. Nodular goiter (mononodular or multinodular) of its plasma concentration. According to the size of
the thyroid gland two types of peripheral hypothy-
Clinical features of simple goiter. In patients with roidism are known:
simple goiter, the clinical manifestations arise solely
from enlargement of the thyroid, since the metabolic A. Peripheral hypothyroidism without goiter (thy-
state is normal. A small diffuse goiter does not cause roprivic hypothyroidism, nongoitrous peripheral
any problems, it is only a cosmetic defect. A middle hypothyroidism). It is due to subtotal surgical
size nodular goiter may induce feeling of a tighten- removal of the thyroid gland, or due to lesion
ing of garments worn about the neck and sometimes of its parenchyma, e.g., extensive strumectomy,
feeling of irritation to coughing. A large retrosternal overdose of external therapeutic radiation, ex-
nodular goiter may cause the symptoms of mechan- cessive dosage radioiodine or antithyroid agents
ical local sydrome. The symptoms of this syndrome (iatrogenic hypothyroidism). For this type of
usually occur in the middle age, when evidently en- hypothyroidism also developmental defects of
larged goiter descended behind sternum and became the thyroid gland can be responsible. These de-
firm in consistency (augmentation of fibrous tissue). fects may take the form of hypoplasia or apla-
In the patients with simple goiter also functional sia of the thyroid, or failure of the thyroid to
disorders of the thyroid gland may develop later. descend properly during embryological develop-
In the regions with high incidence of endemic goi- ment (its ectopic location). The loss or atrophy
ter, and with insufficient health education and pre- of thyroid tissue leads to inadequate synthesis
vention, goitrous enlargement also may be associ- of thyroid hormones, despite maximum stimula-
ated with varying degrees of hypothyroidism. On tion of any thyroid remnant by TSH.
the other hand, in older patients with long-standing
multinodular goiter, the ingestion of excess iodide B. Peripheral hypothyroidism with goiter (goi-
(mostly by medical drugs) may result in the devel- trous hypothyroidism). It may develop in the
opment of thyrotoxicosis (jodbasedow phenomenon). patient with Hashimoto thyroiditis or with the
At the scintigraphy hyperfunctional nodules are tumor massively infiltrating the thyroid gland.
manifested as hot nodules. However, in the patients This type of hypothyroidism is always present
with simple goiter the prognosis is prevailingly good. in the patients with heritable defects in thy-
roid hormone biosynthesis (homozygous individ-
uals). Finally, in areas of environmental iodine
5.4.2 Hypothyroidism deficiency, goitrous hypothyroidism can occur
Hypothyroidism is the clinical state resulting from on an endemic basis.
thyroid hormone deficiency. This clinical state origi-
nates if in the consequence of various morphological 2. Central hypothyroidism (trophoprivic hypothy-
or functional abnormalities the production of thy- roidism). This type of hypothyroidism is charac-
roid hormones is lower than the demands of periph- terized by insufficient stimulation of an intrinsically
eral tissues for supply of these hormones. Like other normal thyroid gland as a result of hypothalamic or
5.4. Pathophysiology of thyroid gland 331

pituitary disease. Production of TSH and its plasma TSH absence the atrophied thyroid gland preserves
concentration are decreased resulting in atrophy of certain autonomous function, and, therefore, some
the thyroid gland. It may originate either due to basal production of its hormones persists. As a con-
primary disorder in adenohypophysis (central ade- sequence of that, the thyroid hormone concentration
nohypophyseal hypothyroidism, secondary hypothy- at central hypothyroidism is not so low as that at
roidism, pituitary hypothyroidism), or as a sequel peripheral hypothyroidism. In the clinical picture of
of primary hypothalamic disorder (central hypotha- central hypothyroidism the symptoms of ACTH defi-
lamic hypothyroidism, tertiary hypothyroidism, hy- ciency (mainly tendency to hypoglycemia), and also
pothalamic hypothyroidism). the symptoms of gonadotropin deficiency (amenor-
Pituitary hypothyroidism is rare. Its unique ori- rhea, atrophy of the breast and ovaries) are often
gin may be due to isolated TSH hyposecretion. It is, simultaneously present.
however, more often a part of panhypopituitarism.
The cause of TSH deficiency may be a tumor of 5.4.2.1 Infantile hypothyroidism
the pituitary gland or adjacent region, aneurysm in
this region, or adenohypophyseal necrosis (most com- Infantile hypothyroidism is a disease caused by the
monly postpartum pituitary necrosis). thyroid hormone deficiency which originates in pre-
Hypothalamic hypothyroidism is less common and natal period (congenital hypothyroidism), in peri-
results from inadequate secretion of TRH, which is natal period (neonatal hypothyroidism), or when-
due to the damage of the hypothalamic tissue by ever during the first year of life. According to the
inflammatory process, trauma, or tumor. number of affected children in a geographic region,
Peripheral hypothyroidism (nongoitrous and goi- endemic infantile hypothyroidism and sporadic in-
trous together) accounts for approximately 95 % of fantile hypothyroidism are distinguished. Accord-
cases of hypothyroidism, only 5 % or less being cen- ing to the duration of thyroid hormone deficiency,
tral (trophoprivic, suprathyroid) hypothyroidism. temporary neonatal hypothyroidism and permanent
neonatal hypothyroidism are known. The temporary
The consequences of thyroid hormone deficiency neonatal hypothyroidism requires substitutive ther-
and so the clinical features of hypothyroidism de- apy only for certain time, mainly during the crucial
pend on the age at which undersecretion of thyroid phase of CNS development. Later only regular med-
hormones occurs. They also depend on the degree ical checks of the child are needed. The permanent
and duration (early diagnosis) of thyroid hormone
neonatal hypothyroidism requires long-life substitu-
deficiency, as well as on the promptness of adequate tive treatment.
replacement therapy. If the thyroid hormone de-
The temporary neonatal hypothyroidism may de-
ficiency occurs already during intrauterine life and
velop as a sequel of:
perinatal period, or at least during the first year of
postnatal life, i.e., in the period of the most intensive 1. Insufficient iodine supply during the last
CNS development, the clinical picture of infantile hy- trimester of pregnancy. In a newborn the com-
pothyroidism originates. The origin of the thyroid pensatory goiter is usually present.
gland hypofunction after the first year of life, i.e., af-
ter the CNS development has almost ceased, but in 2. Large doses of iodine during pregnancy, e.g., io-
the period of intensive development of the skeleton, dine medical drugs. In some newborns goiter
results in the clinical picture of juvenile hypothy- may be extremely large and may cause death by
roidism. The origin of thyroid hormone deficiency asphyxiation.
after epiphyseal closure causes the development of
the clinical picture of adult hypothyroidism. 3. Transplacental passage of maternal antithyroid
The clinical picture of peripheral hypothyroidism antibodies, which probably block TSH receptors
is usually characterized by more severe symptoms of (TSH inhibiting immunoglobulins). This type of
thyroid hormone deficiency than that of central hy- temporary neonatal hypothyroidism has a famil-
pothyroidism. At central hypothyroidism myxedema ial occurrence frequently accompanied by irre-
does not occur. The clinical symptoms of central hy- versible CNS disorders originating already dur-
pothyroidism are milder because in spite of the total ing intrauterine development. It seems to be
332 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

analogical, but functionally contrary state like Severe disorder of intellectual development may re-
at Graves-Basedow disease in newborns. sult also from nontreated T4 deficiency, which may
occur whenever in the course of the first year of
4. Transplacental passage of antithyroid drugs or life. Certain degree of milder, but permanent dis-
lithium during therapy of pregnant women. order of mental abilities of the aflicted child may ap-
The permanent neonatal hypothyroidism may oc- pear also when T4 deficiency originates from 12th to
cur as a sequel of: 18th month of postnatal life. If thyroid hormone de-
ficiency develops between 18th and 24th months of
1. Anatomical anomaly of the thyroid gland orig- life its clinical picture merges more with that of ju-
inated due to the disorder of its embryological venile hypothyroidism. Nontreated hypothyroidism
development (hypoplasia, aplasia, or rudimen- originated after CNS development finished (after the
tary ectopic thyroid). second year of life), causes only typical disorders
of bone ossification and linear body growth. Men-
2. Genetically determined defects in thyroid hor- tal disorders associated with hypothyroidism which
mone biosynthesis (disorder of hormonogenesis). originates after the second year of life are reversible.
3. Specific disorder of the thyroid that occurs in These mental disorders result from actual thyroid
regions of severe endemic goiter. hormone deficiency.
The clinical features of infantile hypothyroidism
Severe degree of nontreated infantile hypothy- reflect the degree of thyroid hormone deficiency. At
roidism associated with irreversible CNS disorders, moderate T4 deficiency only very mild symptoms of
as well as with irreversible disorders of bone ossifica- retardation of mental and physical development are
tion, skeletal maturation, and linear body growth is present. They may be found out only after more
termed cretinism. Irreversible CNS disorders are due detailed medical examination of a newborn. More
to deficiency of thyroxine (tetraiodo-L-thyronine, expressive T4 deficiency is manifested by various de-
T4 ), which is essential for the development of the grees of cretinous stigmatization. At persisting se-
central nervous system. It is unconditionally needed vere degree of T4 deficiency, which in the past oc-
for maturation of neurons of cerebral cortex, for the curred quite often in regions with endemic goiter,
growth and myelination of nerve fibres, and for form- the clinical picture of cretinism fully develops.
ing of dendritic connections (synapses). Its defi-
ciency in fetal life or at birth results in retardation of Endemic cretinism. It is a severe developmental
the infantile characteristics of the brain, hypoplasia disorder that in the past occurred in regions where
of cortical neurons with poor development of cellular some inhabitants had the severe endemic goiter dur-
processes, retarded myelination, and reduced vascu- ing several generations. Pathogenesis of its origin is,
larity. If the deficiency is not corrected in early post- however, still not exactly known. Aflicted children
natal life, irreversible damage results. The both thy- were usually born to mothers with nodular goiter,
roid hormones, i.e., T4 and T3 (triiodo-L-thyronine), iodine deficiency, or hypothyroidism. It is generally
are necessarily needed also for maturation of bone accepted that the risk of the origin of foetal hypothy-
tissue, respectively for normal ossification and lon- roidism in the mother with hypothyroidism is essen-
gitudinal bone growth until the period of epiphyseal tially higher than in the mother without hypothy-
growth plates fusion. Therefore, the most typical roidism.
symptoms of the clinical picture of cretinism are re- It is supposed, that long-term severe iodine de-
tardation of mental development and retardation of ficiency in mother plays an important role in the
somatic development. In the past it often occurred origin of foetal endemic hypothyroidism. Produc-
as endemic cretinism. Possibility of the origin of tion of thyroid hormones in mother is low, therefore,
sporadic cretinism still persists. However, thanks to transplacental supply of the foetus by maternal thy-
systematic screening at present the danger of the ori- roxine is insufficient. Transplacental T4 supply is,
gin of sporadic cretinism is minimal, and exists only however, unconditionally needed for the supplement
when screening duty is neglected, hence if the diag- of foetal needs also in healthy mother with normal io-
nosis and therapy of sporadic congenital hypothy- dine intake. Therefore, as a sequel of thyroxine defi-
roidism are very late. ciency during pregnancy irreversible disorder of CNS
5.4. Pathophysiology of thyroid gland 333

development originates already in the foetus. Exces- Clinical features. Presence of the clinical symp-
sive intake of goitrogens in the food of the mother toms of congenital hypothyroidism already at birth
during pregnancy may to a certain extent partici- is very rare. The age in which its symptoms appear
pate in the origin of endemic congenital hypothy- depends on the degree of prenatal and postnatal T4
roidism. Thanks to the introduction of iodized salt deficiency. The newborns with this disease clinically
in our country endemic cretinism does not occur. do not usually significantly differ from healthy new-
Sporadic cretinism. It occurs in one in every 4 borns. Only in about 4 % of newborns with con-
to 5 thousand births. It is due to the morhologi- genital hypothyroidism (a very severe degree of T4
cal anomaly of the thyroid gland in newborn, which deficiency) cosiderable clinical symptoms are present
originates during embryogenesis, e.g., its aplasia, hy- at birth or in perinatal period. Therefore, it is dif-
poplasia, or rudimentary ectopic thyroid gland. The ficult to detect the presence of congenital hypothy-
most frequent form of the ectopic thyroid is lingual roidism during the first two weeks of life only on the
thyroid. It originates if its migration is incomplete, basis of clinical symptoms. Suggestive symptoms,
and, therefore, ectopic thyroid tissue lies at the base which could denote the presence of congenital hy-
of the tongue. The form of the congenital hypothy- pothyroidism already in this early period, usually
roidism which is due to the morphological anomalies include: higher birth weight and body length, en-
of the thyroid gland is called nongoitrous sporadic largement of the posterior fontanelle, delay in the
cretinism. passage of meconium, hypothermia, dry skin, pro-
tuberance of abdomen, slightly protruding tongue,
Genetically determined defects in hormone biosyn-
decreased motility, somnolence, and persistence of
thesis are a rare cause of sporadic cretinism. It is
neonatal jaundice.
hereditary enzymopathy transmitted as an autoso-
mal recessive trait. Individuals with sporadic cre- More evident and typical symptoms of infantile hy-
tinism are homozygous for the abnormal gene. Sev- pothyroidism will develop not earlier as at the end
eral members of a family are usually affected, and, of the first month of life, but more often during the
therefore, it is denoted as familial cretinism. As in second or the third month of life. However, the diag-
patient usually compensatory goiter is present, it is nosis of congenital hypothyroidism, detected on the
called goitrous sporadic cretinism. These hereditary basis of the clinical symptoms appearing in this pe-
defects in hormone biosynthesis are more common riod, is very late. Peristence of T4 deficiency during
in boys than in girls. The goiter may be present al- the first 2–3 months of life has, therefore, permanent
ready at birth or shortly thereafter, and since then and severe consequeces for intellectual and motor de-
it is usually associated with severe hypothyroidism. velopment of an affected child. Substitutional ther-
The absence of goiter in a child does not exclude, apy introduced as late as in this period is able to pre-
however, the presence of hypothyroidism. vent the origin of disorder of somatic development,
Five specific defects in the pathways of hormone but the symptoms of permanent impairment of psy-
synthesis have been identified: iodide transport de- chomotor development of an affected child are usu-
fect, organification defect (peroxidase deficiency), ally present. By clinical examination it is possible to
iodotyrosine-coupling defect, iodotyrosine dehaloge- detect: e.g., decrease of mental capacity, impairment
nase defect (deiodinase defect), and abnormal secre- of psychic concentration, impairment of muscular co-
tion of iodoproteins (defect of thyroglobulin synthe- ordination (mainly fine motor activity), impairment
sis). of speech development, and the like. Therefore, only
the treatment from the first days of life, realized by
At endemic cretinism irreversible CNS disorders
administration of thyroxine in doses adequate to the
usually originate already during intrauterine life.
weight and age of a child, may prevent the origin of
On the contrary, CNS disorders conditioned by T4
permanent conseqences of neonatal hypothyroidism.
prenatal deficiency in sporadic congenital hypothy-
roidism are mild, and after the prompt diagnosis and With regard to the need of prompt diagnosis and
adequate substitutional therapy they are reversible. therapy of neonatal hypothyroidism screening of
In most newborns with sporadic neonatal hypothy- congenital hypothyroidism in all newborns has been
roidism, however, significant thyroid hormone defi- done in our country since 1985. The aim is to secure
ciency originates in the postnatal period only. their normal psychomotor and physical development.
334 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

Screening examination of newborns is the only pos- from the second or the third month of life. De-
sible prevention of permanent consequences of such creased motility and somnolence of a child become
sporadic congenital hypothyroidism, in which signifi- more and more evident. Anorexia causes small incre-
cant T4 deficiency followed by CNS impairment does ment of body weight. The voice of a child becomes
not occur prenatally, but as late as in the first days of deeper and hoarse, the child cries very little. Larger
postnatal life. However, it is generally accepted, that tonque (macroglossia) is gradually protruding from
even a short period (lasting only a few days) of sig- the permanently open mouth. Constipation is more
nificant T4 deficiency in early postnatal period leads evident, muscular hypotony and decreased intensity
to permanent disorders of psychomotor development, of reflexes appear. Umbilical or inquinal hernia often
at least to disorders of perception and coordination. occurs.
By neonatal screening, concentrations of total and The skin becomes evidently cold, dry, and rough.
bound T4 or TSH concentration are measured in It is of yellowish colour and feels rough and doughy.
samples of capillary blood. The samples are taken Hair becomes dry and grow slowly. Nails are brit-
after the heel puncture of a newborn on 3rd–5th day tle and their growth is pure. The facial appearance
of life. The first examination found out only serum of the child gradually acquires myxedematous fea-
T4 concentration. If its level is low, by another ex- tures. The anterior and posterior fontanelles are not
amination of the taken blood sample serum, TSH yet closed. Holding up of the head is delayed. Psy-
concentration is assessed as well. By screening exam- chomotor development and linear growth of the child
ination neonatal hypothyroidism may be diagnosed are also delayed. Nowadays, when the screening of
reliably within the first week of life. congenital hypothyroidism is provided for all new-
In the past the diagnosis was not frequently borns, such stage of infantile hypothyroidism should
made until full-blown signs emerged several weeks or not, however, occur.
months after birth. Fortunately, this delay has been In the next period the clinical picture of non-
largely eradicated by the measurement of blood thy- treated infantile hypothyriodism is characterized by
roxine level in neonatal screening programs. Such delayed eruption of the deciduous teeth, by delayed
programs are highly successful in preventing the origin of ossification centres and successive delay in
mental retardation and other neurological sequelae bone age. X-ray examination reveals decreased num-
that result from prolonged hypothyroidism during ber of obviously followed ossification centres of skele-
early infancy. In the past, when hormonal substi- tal bones as well as their slow enlargement. The
tutional therapy did not exist, every severe neonatal retardation of ossification and longitudinal growth
hypothyroidism resulted in gradual development of of bones originates because thyroid hormone defi-
the clinical picture of cretinism. At present, the term ciency is accompanied by both a decrease in secre-
cretinism is, however, archaic because in our country tion and lessened effectiveness of STH as well as with
thanks to the introduction of iodised salt, endemic insufficient skeletal maturation. STH efficiency is de-
cretinism does not exist at all. Alike in instances of creased probably as a sequel of impaired formation
sporadic congenital hypothyroidism, thanks to the of IGF I production, which influences the cartilage of
screening of newborns and following adequate sub- epiphyseal growth plate. Decreased proteosynthesis
stitutional hormonal therapy, the fully developed participates also in retardation of skeletal develop-
clinical picture of sporadic cretinism does not oc- ment.
cur as well. In spite of this fact, physicians as well The deciduous teeth persist for a long time and
as students of medicine should know the possible permanent dentition is rather delayed. The skull
consequences of not only delayed diagnosis and de- shows a poorly developed base. Delayed closure of
layed therapy of neonatal hypothyroidism, but also the fontanelles leads to a head that is large in rela-
the consequences of nontreated neonatal hypothy- tion to the body. Neck is usually short and wide.
roidism. Both, shortening of the skull base and disorder of
The clinical features of cretinism gradually de- nasal bones development cause pulling the root of
velop from early childhood to adulthood. In a child the nose back. Retardation of mental and physical
with congenital hypothyroidism the typical symp- development is manifested by delay in reaching the
toms of infantile hypothyroidism begin to develop normal milestones of development, such as holding
5.4. Pathophysiology of thyroid gland 335

up the head, sitting, standing, walking, and talk- The facial features of the cretin are considerable
ing. Though epiphyseal plates remain open quite (characteristic). The mucinous edema is responsi-
long, often even longlife, linear body growth is sig- ble for the thickened features and puffy apearance
nificantly retarded and finishes prematurely, what is of the patient. Dull expressionless face, poor mimic,
manifested by a short stature. and permanently open mouth with protruding en-
In the adult, the clinical picture of cretinism is larged tongue are typical. Macroglossia is partially
characterized mainly by various degrees of oligophre- responsible for snuffled speach of the cretin. Lips are
nia (from debility to idiocy), and by thyroid thick. Palpebral fissures are narrowed due to peri-
dwarfism. The severe disorder of mental develop- orbital myxedema and ptosis. Lower forehead, wide
ment is the result of insufficient differentiation and cheek bones, and flat, broad, saddle-shaped, pulled
maturation of cerebral cortex neurons, as well as back nose, along with prognatism and wrinkly skin
of their cut in number. The short stature of an cause peculiar facial appearance of the cretin, de-
adult cretin is characterized by the disproportion- noted as simian (pithecoid) physiognomy. The teeth
ately short limbs in relation to the trunk. Impaired are malformed and readily become carious.
bone ossification gives also rise to the origin of vari- Basal metabolic rate (BMR) of the cretin is signifi-
ous skeletal deformities, which occur especially in the cantly decreased. Therefore, slightly decreased basal
most mechanically loaded spots. Thoracic kyphosis body temperature, cold intolerance, and decreased
and coxarthrosis originate most frequently. Defor- appetite are present. Serum T4 and T3 concentra-
mity and restriction of motion of hip joint cause the tions are low. Serum TSH concentration is increased.
typical waddling gait (duck gait) of the cretin. Concentrations of total cholesterol and low-density
lipoproteins (LDLs) in serum are increased. Anemia
The skin of cretin is dry, coarse, rough, wrinkly,
is often present.
and it often desquamates. It has a yellow tint or even
peculiar wax-orange colour. It feels doughy and cool. Heart rate and respiratory rate are slow (brady-
The secretions of the sweat glands and sebaceous cardia and bradypnea). Cardiac output and cardiac
glands are reduced, leading to dryness and coarse- index at rest are decreased. Decreased heart rate and
ness of the skin. Its peculiar colour is induced by hy- cardiac output reflect the loss of the chronotropic and
percarotenemia and successive deposition of caroten inotropic effects of thyroid hormones. X-ray picture
into the skin. Hypercarotenemia is due to the dis- shows enlarged heart shadow as a result of dilata-
order of caroten transformation to vitamin A in the tion of flabby myocardium, as well as due to effusion
liver. Growth of hair is retarded. The hair is dry, into the pericardial sac of fluid rich in protein and
brittle, lacks luster, unmanageable sparse, and tends mucopolysaccharides. Mucinous effusions may also
to fall out. Special mucinous (jelly-like) material occur into any serous cavity.
consisting of protein complexed with mucopolysac- Cretins are less efficient, they become easily tired.
charides (mainly with hyaluronic acid, or also with Stiffness, cramping, and aching of muscles are com-
chondroitin sulphate), electrolytes, and water is ac- mon complaints. Muscles strenght and tonus are
cumulated in the dermis. This material is responsible slightly decreased. Weakened ligaments cause hy-
for the peculiar edematous look of the patient skin perextensibility of joints and the origin of flat-feet
termed myxedema (mucinous edema). Myxedema (pedes plani). Muscle hypotonia gives rise to an evi-
is a tough edema which on the contrary to normal dent protuberant abdomen, and ptosis of upper eye-
(true) edema does not leave a pit on the skin surface lid. Peristaltic activity is decreased and, together
when an edematous part is pressed on (nonpitting with the decreased food intake, is responsible for
edema). chronic constipation.
Special mucinous material infiltrates also other The symptoms of hypogonadism are often present.
tissues, e.g., tongue muscle, skeletal muscles, my- Sexual maturation is retarded, sexual infantilism and
ocardium, and mucosa and submucosa of pharynx, infertility are usually present. Defective hearing and
larynx, stomach, and intestines. Due to thicken- even deafness are very frequent.
ing of the mucous membranes of the larynx and vo- Perceptive deafness may occur in association with
cal chords, caused by myxedematous infiltration, the congenital hypothyroidism caused by genetically de-
voice becomes deeper and hoarse. termined defect in thyroid hormone biosynthesis,
336 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

mainly by a defect in the organic binding of iodine trunk, therefore, the ratio between the upper body
(Pendred syndrome). Goiter and hypothyroidism segment (head, neck, and trunk) and lower body seg-
are usually milder. This syndrome has autosomal ment (legs) is increased.
recessive inheritance. In the clinical picture of juvenile hypothyroidism
the other symptoms of thyroid hormone deficiency
5.4.2.2 Juvenile hypothyroidism are also present. They are similar to those of adult
hypothyroidism, however, they are present to a vary-
Juvenile hypothyroidism is a disease caused by the ing, but usually milder degree.
thyroid hormone deficiency which originates when- Early diagnosis of juvenile hypothyroidism guaran-
ever in the childhood from the end of the second year tees its very good prognosis, because hormone sub-
of life until epiphyseal fusion. Its most typical clini- stitutional therapy prevents the origin of disorders of
cal symptoms are retardation of somatic and sexual growth and sexual development, and settles psychic
development. Hypothyroidism results also in mental activity and intellectual performance of the child.
slowness but not in permanent mental retardation. Permanent mental disorders do not occur, as CNS
The most common cause of peripheral (primary) development was taking place already in the period
juvenile hypothyroidism is autoimmune thyroiditis when thyroid hormone deficiency was not present.
(Hashimoto disease). Sometimes, it may be the re-
sult of decompensation either of an ectopic (dys- 5.4.2.3 Adult hypothyroidism
genetic) thyroid gland, or of heterozygous type of
genetically determined defect in thyroid hormone Clinical syndrom of adult hypothyroidism (Gull’s
biosynthesis. Its rare cause is subacute or acute thy- disease) is developed if the thyroid hormone defi-
roiditis. In exceptional cases it may originate due to ciency originates as late as the epiphyseal growth
infiltration of thyroid gland tissue in patients with plates are closed. It occurs in about 1 % of adult
histiocytosis and cystinosis. Central juvenile hy- population. It is more common in women than in
pothyroidism is very rare. It may usually occur due men (7:1) and appears most often between the ages
to a tumor in the area of pituitary or hypothalamus, of 40 and 60. Its characteristic manifestations are
most often due to craniopharyngioma. decrease of BMR, fall of all activities of organism,
Clinical features. In a child whose mental devel- and myxedema. At present, with regard to the suffi-
opment and physical growth were normal before the cient health care and therapeutical possibilities, fully
onset of hypothyroidism, the clinical symptoms of developed clinical picture of adult hypothyroidism
thyroid hormone deficiency start gradually appaer. practically does not occur.
Skeletal maturation is markedly delayed. Growth In most instances it is a peripheral (primary) hy-
failure precedes the appearance of other symptoms. pothyroidism, which accounts for 95 % of all cases
The rate of linear growth is characteristically less of hypothyroidism, the remaining 5 % being central
than that of weight gain, which is due to develop- (secondary and tertiary) hypothyroidism.
ment of myxedema. Permanent dentition is delayed, Peripheral hypothyroidism may be either spon-
too. Perception of the child gradually decreases, the taneous (about 65 %) or iatrogenic (about 35 %).
child becomes less bright, and a poor performance at The most common cause of spontaneous primary hy-
school is evident. Poorer psychic activity and intel- pothyroidism is Hashimoto thyroiditis, mainly its fi-
lectual performance of the child result from the ac- nal stage in which goiter is either absent or has gone
tual thyroid hormone deficiency, and, therefore, are unnoticed. The presence of circulating thyroid au-
reversible. toantibodies in up to 80 % of the patients may be
Sexual maturation is retarded and the onset of revealed. Rarely it may occur in later life of the pa-
puberty is delayed. The result of growth and sex- tients with multinodular goiter. Iatrogenic primary
ual development retardation is a patient who ap- hypothyroidism may be postablative (surgery or ra-
pears much younger than his or her chronological dioiodine) or postradiation (e.g., for lymphoma).
age (youthful appearance, infantile appearance). In Central hypothyroidism is most commonly the re-
spite of the delay of epiphyseal union the stature of sult of postpartum pituitary necrosis and less com-
the patient in the adulthood is short and dispropor- monly the result of a tumor of the adenohypophysis
tional. Legs are relatively shorter compared with the or adjacent regions (pituitary hypothyroidism). Less
5.4. Pathophysiology of thyroid gland 337

common is hypothalamic hypothyroidism which re- ten occurs. Constipation may develop or, if present,
sults from inadequate secretion of TRH due to im- become worse. The patients almost do not sweat.
pairment of hypothalamic cells by various destruc- Their skin becomes drier and cooler. Women may
tive processes. complain of menstrual disturbances. Poor libido oc-
The first symptom of developing primary hypothy- casionally occurs in both sexes. At this stage of the
roidism in adults is an increase of serum TSH con- disease the BMR is moderately decreased.
centration. The state of increased serum TSH con- The fully developed clinical picture of adult hy-
centration, however, still without presence of classic pothyroidism is characterized by typical facial ap-
clinical symptoms of hypothyroidism (serum thyroid pearance. Periorbital puffiness, broader and flat
hormone concentration is still normal) has been re- nose, thickened lips, sparce eye-brows, and poor
cently demonstrated as subclinical hypothyroidism. mimic are evident (facies myxoedematica).
Other synonyms for this phase of primary adult hy- Skin ot the patient is dry, coarse, rough, and
pothyroidism are: preclinical hypothyroidism, bio- scurfy. It feels cool and dougher. Skin is pallor with
chemical hypothyroidism, or decreased thyroid re- orange tint. Hair is sparce, dry, and lacks luster.
serve. Some specialists acquire also the presence of Nails are thin, fragile, brittle, and grow slowly.
circulating thyroid autoantibodies for diagnosis of Myxedema is most apparent on the face, the dorsa
this functional state. In some patients with sub- of the hands and feet, forearms, and in supraclav-
clinical hypothyroidism also the presence of the dis- icular fossae. Mucinous material infiltrates also
order of lipid metabolism (increased plasma LDL, other tissues. Therefore, tongue is thick and en-
total cholesterol, apoprotein B, and triacylglycerols larged (macroglossia) causing articulatory (pronun-
concentrations) was proved. From the total number ciational) problems (dysarthria). Dysarthria to-
of the patients with diagnosed subclinical hypothy- gether with slow train of thoughts (bradypsychism)
roidism in about 5 % of cases clinically manifested results in slow speech (bradylalia). Voice becomes
hypothyroidism develops yearly. deeper and husky. Myxedemotous infiltration of mu-
The clinical picture of primary hypothyroidism in cous membranes of Eustachian tube and middle ear,
adults usually develops very slowly. Its first symp- as well as myxedematous changes of cochlear fluid
toms start develop only after destruction of signifi- cause defective hearing.
cant part of thyroid parenchyma. The onset of hy- With progression of the diesease the BMR falls to
pothyroidism is usually so insidious that the clas- its minimal value, usually between –35 and –45 %.
sic clinical manifestations may take months or even The decrease in energy metabolism and heat produc-
years to appear and frequently go unnoticed by per- tion is reflected in the low BMR , decreased appetite,
sons well acquainted with the patient. Therefore, the cold intolerance, and slightly lower basal body tem-
symptoms are often attributed incorrectly by the pa- perature (moderate hypothermia). The rate of ab-
tients and relatives to increasing age. The gradual sorption of glucose from the gut is decreased, there-
development of the hypothyroid state is due to a slow fore, the oral glucose tolerance curve is characteris-
progression of both thyroid hypofunction and the tically flat. The decrease in lipid degradation results
clinical manifestations after thyroid failure is com- in the increase of serum cholesterol, triacylglycerols,
plete. and LDL concentrations. Serum concentration of
The early symptoms of adult hypothyroidism are high-density lipoprotein (HDL) is decreased. These
variable and nonspecific. Cold intolerance, drowsi- changes of serum lipid concentrations usually accel-
ness and slowing of intellectual and motor activities erate the development of atherosclerosis and its com-
may be early manifestations. Increasing tiredness, plications, however, only in the hypothyroid patients
weakness, slowness, and lethargy are common and with the presence of arterial hypertension.
lead to difficulty in performing a full day’s work. The Decreased adrenergic activity, respectivelly de-
patients complain of poor memory and evident som- pressed response of tissues to catecholamines accom-
nolence. They become apathetic and listless, and panies thyroid hormone deficiency. The mechanism
lose interest in work and environment. Their trains underlying the decreased adrenergic responsiveness
of thoughts are slow, they are bradypsychic. De- is uncertain. It is assumed that one of the causes
spite a reduction in appetite, modest weight gain of- could be the decrease of the number of adrenergic
338 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

receptors. The cardiac output and cardiac index at Psychic and motor activities of the hypothyroid
rest are decreased because of the reduction in both patients are slow. The patients are not able to
stroke volume and heart rate, reflecting loss of the in- concentrate to their work. There is loss of initia-
otropic and chronotropic affects of thyroid hormones. tive. One of the characteristic features is a gen-
Peripheral vascular resistance at rest is increased, eral slowing of all intellectual functions, including
and blood volume is reduced. These hemodynamic speech. Slow-wittedness, slowness in answering ques-
alterations result in narrowing of pulse pressure, pro- tions, and memory defects are common. Lethargy
longation of circulation time, and decrease in blood and somnolence are prominent. Dementia may oc-
flow to the tissues. The decrease in cutaneous cir- cur and in the elderly patient may be mistaken for
culation is responsible for the coolness and pallor of senile dementia. Psychiatric reactions are not un-
the skin and the increased sensitivity of the patient common and are usually of the paranoid or depres-
to cold. sive type. The mentioned changes of CNS function
Myocardial contractility is decreased. Dilatation originate due to actual thyroid hormone deficiency,
of myocardium is evident, but signs of myocardial and, therefore, they are reversible after adequate hor-
hypertrophy are not present. The heart is enlarged mone therapy.
owing to the both dilatation and pericardial effu- In the both sexes, sexual activity and reproduc-
sion. Electrocardiographic changes include sinus tive function are significantly decreased. In men, hy-
bradycardia, prolongation of the PR interval, low pothyroidism is usually accompanied by diminished
amplitude of QRS complex, and flattened or in- libido, impotence, and oligospermia. In women, it
verted T waves. Histopathological examination of is commonly associated with diminished libido, dis-
the myocardium reveals presence of interstitial de- orders even failure of ovulation, and irregular men-
posits of mucinous material (interstitial myxedema) strual bleeding (rarely menorrhagia, but more fre-
and swelling of cardiomyocytes, with loss of striation. quently oligomenorrhea even amenorrhea).
The set of introduced signs, concerning myocardium,
respectively heart, has been termed hypothyroid car- The mild normocytic, normochromic anemia of-
diomyopathy (myxedema heart). ten occurs in the patients with hypothyroidism. It is
the result of hypofunction and hypocellularity of the
Skeletal muscles are usually stiff and aching. De- bone marrow. It is the response to the diminished
layed muscle contraction and relaxation are respon- oxygen requirements of tissues and to decreased pro-
sible for the slowness of movement. Tendon jerks are duction of erythropoietin. In about 12 % of patients
also delayed, evidently Achilles tendon reflex. On with primary hypothyroidism pernicious anemia as-
histopathological examination, the muscle fibers may sociated with the presence of an atrophic gastric mu-
show swelling, loss of normal striations, and separa- cosa occurs. In these patients also achlorhydria after
tion by mucinous deposits. maximal histamine stimulation, and achylia gastrica
Thyroid hormone deficiency and successive my- are usually present. The coexistence of pernicious
xedematous infiltration of mucous membranes of anemia with primary hypothyroidism occurs in those
GIT cause decrease of peristaltic activity, as well instances in which autoimmune mechanism plays a
as of intestinal wall tonus. Decreased peristaltic ac- primary role in the pathogenesis of primary hypothy-
tivity, together with the decreased food intake, is roidism. In circulating blood of these patients be-
responsible for the frequent complaint of constipa- sides antithyroid immunoglobulins G (IgG) also au-
tion. These intestinal disorders may be extreme, toantibodies against gastric parietal cells have been
leading to fecal impaction and great distention of found. Immediate cause of pernicious anemia is the
colon (myxedema megacolon). Gaseous distention of deficiency of vitamin B12 induced by its impaired
the abdomen may also occur (myxedema ileus, ady- absorption. Insufficient vitamin B12 absorption is
namic ileus). The effects of hypothyroidism on in- caused by deficiency of intrinsic factor due to atro-
testinal absorption are complex. Although the rates phy of parietal cells. Folate deficiency resulting from
of absorption of many substances are decreased, the malabsorption may also be responsible for a mega-
total amount eventually absorbed may be normal be- loblastic anemia. The both, menorrhagia and inef-
cause the decreased motility of the bowel may allow fective absorption of iron resulting from achlorhydria
more time for absorption to take place. may lead to a microcytic, hypochromic anemia.
5.4. Pathophysiology of thyroid gland 339

In the blood of a patient with primary hypothy- D. Hyperthyroidism due to increased TSH produc-
roidism low T4 and proteine-bound iodine concen- tion
trations, and a high TSH concentration are present.
In patients with central hypothyroidism blood TSH E. Iodine-induced hyperthyroidism
concentration is low.
At present the late stage of fully developed clinical II. Thyrotoxicosis without hyperthyroidism
picture of adult hypothyroidism does not occur. In
the past, when the patients with severe long-standing A. Thyrotoxicosis factitia
hypothyroidism were untreated, they usually died of
B. Transient thyrotoxicosis associated with thy-
the consequences of accelerated atherosclerosis (most
roiditis
frequently coronary or cerebral), less frequently due
to myxedema coma. C. Thyrotoxicosis due to ectopic production of thy-
Myxedema coma. It is a rare acute complication roid hormones
of hypothyroidism, which may be fatal. The factors
predisposing to myxedema coma include cold expo- In the patients with thyrotoxicosis total serum T3
sure, trauma, infection, and administration of CNS and T4 concentrations, as well as free T3 and T4
depressants. It is manifested by significant decrease concentrations are increased. In some patients with
of all metabolic processes, by evident hypothermia hyperthyroidism only serum T3 concentration may
(decrease of rectal temperature to 35–32oC), extreme be extremely increased. Whether this phenomenon
bradycardia, systemic arterial hypotension, thready results solely from the preferential increase in thy-
pulse, and respiratory insufficiency. Extremely som- roid secretion of T3 or whether there is in addition a
nolent patient gradually becomes soporous, and fi- disproportionate increase in peripheral conversion of
nally develops coma. Mortality of the patients with T4 to T3 is uncertain, but the former factor is likely
myxedema coma is high, usually 50–70 per cent. responsible in the majority. The thyrotoxic state re-
sulting from extremely increased serum T3 concen-
tration has been designated T3 toxicosis. The serum
5.4.3 Hyperthyroidism total T4 concentration and free T4 concentration are
The complex of clinical, biochemical, and functional normal or decreased in the absence of a deficiency of
findings that originate when the tissues are exposed TBG. In some patients, T3 toxicosis may be the fore-
to, and respond to, excessive quantities of the thyroid runner of the usual form of thyrotoxicosis in which
hormones is termed thyrotoxicosis. The term hyper- production of both T3 and T4 is increased, whereas
thyroidism is best reserved for denoting only those in other patients it may persist as such. T3 toxicosis
disorders in which sustained hyperfunction of the tends to be more frequent in the elderly population.
thyroid gland (overproduction of thyroid hormones) It may occur in association with Graves-Basedow dis-
leads to thyrotoxicosis. Thus thyrotoxic states can ease, toxic adenoma, or toxic multinodular goiter.
be classified according to whether or not they are Preliminary experience suggests that patients with
associated with hyperthyroidism: T3 toxicosis are more likely to enjoy a long-term re-
mission after withdrawal of antithyroid drug therapy
I. Thyrotoxicosis associated with hyperthyroidism than patients with the usual form of thyrotoxicosis,
A. Hyperthyroidism due to immunogenic thyroid in which production of both T4 and T3 is increased.
autonomy Thyrotoxicosis may sometimes be associated with
a clear elevation of serum T4 concentration, but with
B. Hyperthyroidism due to nonimmunogenic thy- a normal or decreased serum T3 concentration. This
roid autonomy syndrome is termed T4 toxicosis. It occurs most com-
monly in the setting of prior excess iodine exposure
a) Toxic multinodular goiter (iodine-induced thyrotoxicosis) in patients who are
b) Toxic adenoma elderly, ill, or both. Increased iodine intake favors
T4 biosynthesis. In the absence of a history of excess
C. Hyperthyroidism due to nonimmunogenic ab- iodine, the combination of high serum T4 concentra-
normal thyroid stimulator tion and normal serum T3 concentration presumably
340 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

reflects inhibition of peripheral T3 generation from antithyroid antibodies can be present (it is a hetero-
T4 . geneous group of polyclonal antibodies). Until lately
The clinical syndrom of thyrotoxicosis is charac- they were called thyroid-stimulating immunoglobu-
terized by manifestation of symptoms resulting from lins (TSIs), however, recently a preferable nomencla-
affection of several organs or organ systems. The ma- ture is to refer to these immunoglobulins as TSH re-
jor of these symptoms are induced by hypermetabolic ceptor antibodies (TRAbs). This term is preferable
state of organism. Hyperthyroidism and thyrotoxi- because only some of these immunoglobulins after
cosis belong to the most frequent endocrine diseases. binding to TSH receptors have a stimulating effects
They occur in 2–5 % of adult population, much more on epithelial cells (in ways analogous to the normal
often in women than in men (5–7:1). action of TSH). Others, however, inhibit the bind-
ing of TSH to its receptors in thyroid tissue (TSH-
binding inhibitory imunoglobulins – TBIIs). TSH
5.4.3.1 Thyrotoxicosis associated with hy- receptor antibodies are present in more than 90 % of
perthyroidism patients with active Graves-Basedow disease.
Thyrotoxicosis associated with hyperthyroidism en- The thyroid-stimulating immunoglobulins (TSIs)
compasses those diseases that lead to sustained over- after binding to TSH receptors activate adenylate
production of hormones by the thyroid gland itself. cyclase – cyclic adenosine monophosphate system
The most frequently, hyperfunction of the thyroid re- which stimulates the cascade of intracellular reac-
sults from the action of an abnormal (immunogenic tions. These reactions lead to the growth of the
or nonimmunogenic), homeostatically unregulated thyroid gland (via hypertrophy and hyperplasia of
thyroid stimulator of extrapituitary origin, as in epithelial cells), to the increased vascularity of its
Graves-Basedow disease (being the most common), parenchyma, and to the increased biosynthesis and
or in hyperthyroidism associated with trophoblastic secretion of thyroid hormones. TSIs are an immuno-
tumor (being rare). Hyperthyroidism may be also genic abnormal thyroid stimulator. TSIs have essen-
relatively frequent due to the development of one or tially prolonged duration of action relative to that of
more areas of autonomous hyperfunction within the TSH. Their high concentration in circulating blood
gland itself. The hyperfunction of the thyroid gland effects the epithelial cells of the thyroid parenchyma
rarely results from excessive TSH secretion. permanently, while TSH has circadian rythm and a
rather short half-life. Effects of TSIs are, for the
A. Hyperthyroidism due to immunogenic thy- present, the only example for such situation when
roid autonomy (Graves-Basedow disease) autoantibodies do not act destructively.
Graves-Basedow disease is the most frequent form The basic problem of etiopathogenesis of Graves-
of hyperthyroidism. It is an autoimmune disease in Basedow disease is the answer to the question what
which the thyroid gland escapes feedback regulatory is antigenic stimulus for the production of antithy-
influence, and becomes autonomous, i.e., indepen- roid autoantibodies, respectively what causes the ori-
dent from TSH. It is more common in women than gin of clones of thyroid-sensitized T lymphocytes.
in men and appears most often between the ages of There is a hypothesis about random mutations hav-
20 and 40. It is very rare before 10 and after 70 years ing no proofs for the present. But there is a variety
of age. In the English-speaking world this disorder of evidence which links autoimmune thyroid disease
is known as Graves disease and on the continent of to infection with the gram-negative enteric bacte-
Europe as Basedow disease. ria. It has been found out that some bacteria of
Etiology and pathogenesis. There is almost uni- this type contain a TSH binding site that also binds
versal agreement that the cause of this disease is the Graves-Basedow-related IgG. Therefore, the initiat-
origin of immunoglobulins of IgG class. These im- ing event may be the infection with gram-negative
munoglobulins act as antibodies against the thyroid bacteria, mainly by Yersinia enterocolitica and E.
TSH reseptors on the plasma membrane of epithelial coli, that gives rise to antibodies that cross-react
cells of follicles. They are elaborated by B lympho- with components of the human thyroid cell mem-
cytes found directly in the thyroid gland. However, branes. In an individual with the predetermined ab-
in circulating blood of the patient several types of normality in immune surveillance, these antibodies
5.4. Pathophysiology of thyroid gland 341

would persist and give rise to the clinical thyroid there is a distinct familial predisposition to this dis-
disease. Immediate impulse of the clinical manifes- ease. The hereditary factor in Graves-Basedow dis-
tation of this disease may be various external factors, ease also appears to involve its autoimmune aspects.
as e.g., infectious disease accompanied by fever, se- This is suggested by the increased incidence in pa-
vere emotinal stress, some medical drugs, or high tients with Graves-Basedow disease or in members
iodine intake. This hypothesis on cross-reaction of of their families of other autoimmune disorders, such
antibodies, originally elaborated against antigen of as Hashimoto disease, primary thyroprive hypothy-
exogenous pathogenic factor, with self-antigen of or- roidism or pernicious anemia, and probably other
ganism, does not, meanwhile, gives the answer to the diseases with prominent autoimmune features.
question, why antibodies against several antigens of Clinical features. Graves-Basedow disease is char-
thyroid gland simultaneously originate. acterized by four major manifestations:
The hypothesis on the origin of clones of thyroid- 1. Diffuse goiter;
sensitized T lymphocytes would require that sensi-
tized T lymphocytes infiltrate the thyroid and elab- 2. Thyrotoxicosis;
orate stimulatory lymphokines, but an evidence that 3. Infiltrative ophthalmopathy;
this occurs is lacking. This hypothesis presumes that
in patients with chronic autoimmune thyroid disease, 4. Infiltrative dermopathy.
a sustained, genetically determined disorder of im-
In the individual patients these four major mani-
mune surveillance permits the persistence of clones
festations need not appear together. Infiltrative oph-
of thyroid-sensitized immunocytes. This is likely the
thalmopathy and infiltrative dermopathy may occur
result of abnormalities in suppressor T lymphocytes
independently of the presence of goiter and symp-
(disturbance of their function or decrease of their
toms of thyrotoxicosis. Ophthalmopathy and der-
number). Therefore, sensitized helper T lympho-
mopathy are specifically related to Graves-Basedow
cytes start to produce lymphokines which stimulate
disease. Thyrotoxicosis is manifested by hyperme-
the specific B lymphocytes. These activated B lym-
tabolism and by the symptoms resulting from disor-
phocytes begin to produce the specific antithyroid
ders of various organ systems. The first two mani-
IgG.
festations, i.e., diffuse goiter and thyrotoxicosis, are
At present the pathogenesis of infiltrative ophthal- termed diffuse toxic goiter. This term connotes the
mopathy (orbitopathy), which is the characteristic presence of thyrotoxicosis resulting specifically from
part of the clinical picture of Graves-Basedow dis- Graves-Basedow disease.
ease, is not yet clear. The hypothesis on production
of abnormal immunoglobulin is the best accepted for 1. Goiter
the present. This hypothesis assumes that an ab- Almost in all the patients with Graves-Basedow dis-
normal IgG acts in concert with an exophthalmos- ease the thyroid gland is enlarged. But only in about
producing factor composed in part of the beta sub- 3 % of the patients with this disease the thyroid gland
unit of TSH. The result of their effect is the induction is of normal size, however, the symptoms of thyrotox-
of mucopolysaccharide synthesis, edema formation, icosis are usually present. Hyperfunctioning goiter is
and successive infiltrative changes in retroorbital tis- mostly small or middle size, in some cases it may be
sues. There has been no evident progress toward elu- rather large. Enlargement of the thyroid is diffuse
cidation of the pathogenesis of the infiltrative der- and usually symmetrical. Goiter is soft and vascu-
mopathy. In its origin an abnormal immunoglobulin lar, its surface is usually smooth. Enlargement of
may also probably take part. the thyroid may be noted as a fullness in the neck.
In etiopathogenesis of Graves-Basedow disease ge- The rich vascularization of goiter may be sometimes
netic factors play an important role. Population manifested by evident pulsation of the thyroid with
studies reveal an increased frequency of haplotypes a possible thrill and bruit (murmour) over it (struma
HLA-B8 and HLA-DRw3 in whites. Of particular pulsans, vibrans et fremens).
importance is the HLA-DRw3, which significantly in-
crease the risk of Graves-Basedow disease and may 2. Thyrotoxicosis
affect its response to treatment. Not surprisingly, The symptoms of thyrotoxicosis are common for all
342 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

forms of thyrotoxicosis irrespectively of the cause even +100 %). The both, synthesis and degradation
of their origin. However, in the clinical picture of of protein are increased, the latter to a greater ex-
thyrotoxicosis not always all its symptoms must be tent than the former, with the result that there is net
present. Unlike hypothyroidism the clinical symp- degradation of tissue protein. This is evident in nega-
toms of thyrotoxicosis are usually developing dur- tive nitrogen balance, loss of weight, muscle wasting,
ing shorter period, in the course of several days or weakness, and mild hypoalbuminemia. The stimu-
weeks. Only seldom they may develop during sev- lation of energy metabolism and heat production is
eral months. In the patients, emotional stress may reflected in the increased appetite and heat intoler-
be a forerunner, e.g., a car accident, the death of a ance and in the slightly elevated basal body tem-
member of the family, and the like. perature. Cutaneous vasodilatation and excessive
At the onset of the disease mainly subjective sweating (hyperhidrosis) are the protective mecha-
symptoms dominate, e.g., nervousness, irritability, nism against possible origin of hyperthermia. The
emotional tension, emotional lability (inappropriate increased lipid degradation is reflected in a decrease
spells of crying or euphoria), and insomnia. The ini- of plasma cholesterol, LDL, and triacylglycerols con-
tial manifestations also include excessive sweating centrations. The oral glucose tolerance curve is usu-
and heat intolerance. Weight loss is usual despite ally abnormal, often with high amplitude and steep
well-maintained or increased appetite. The patient incline (Gothic type). It is probably due to the stim-
gets tired and out of breath at work very soon. Dys- ulative effect of thyroid hormones to resorption of
pnea and palpitations may occur. Other symptoms glucose in intestine. Pre-existing diabetes mellitus is
of thyrotoxicosis are developing gradually. aggravated by thyrotoxicosis, perhaps as a result of
increased degradation of insulin.
Fully developed clinical picture of thyrotoxicosis
due to Graves-Basedow disease is rather variable be- Cardiovascular symptoms of thyrotoxicosis. They
cause its individual symptoms are not always present are the most frequent and most prominent manifes-
and may occur in various combinations. The most tations of thyrotoxicosis. They are present almost in
common is polysymptomatic thyrotoxicosis, which every patient with Graves-Basedow disease. Hyper-
is manifested by the symptoms resulting from dis- metabolism and increased heat production give rise
orders of various organ systems. It is due to the to the increased demands of tissues for oxygen supply
fact that thyroid hormones affect practically all tis- and thereby also for circulation. These changes lead
sues of organism. Oligosymptomatic thyrotoxicosis to the origin of syndrome of hyperkinetic circulation.
may also appear. The presence of the disease is Thyroid hormones in excess also have a direct car-
only in some organs. Various combinations result- diostimulatory action, possibly mediated by changes
ing from disorders of individual organ systems may in the state of contractile proteins (mainly myosin)
be present. Monosymptomatic thyrotoxicosis is very or in the function of sarcoplasmic reticulum. How-
rare. It occurs mainly in older patients. In its clinical ever, increased cardiac sensitivity to catecholamines
picture disorders of only one organ system dominate. in hyperthyroid subjects is also considered.
The symptoms of alteration of cardiovascular system The most characteristic cardiovascular symptom
(cardial form of thyrotoxicosis), or of skeletal muscles of thyrotoxicosis is sinus tachycardia (pulse rate
(myopathic form of thyrotoxicosis) are present most greater than 90 beats/min). It is almost always
frequently. The origin of these monosymptomatic present, even at rest and during sleep. Respiratory
forms of thyrotoxicosis is likely due to the increased arrhythmia is not present. During excercise heart
sensitivity of tissue of alterated organ system to thy- rate is increasing disproportionately to the degree of
roid hormones. physical load. Also dyspnea usually appears.
Metabolic symptoms of thyrotoxicosis. Overpro- Cardiac arrhythmias are common with thyrotox-
duction of thyroid hormones stimulates metabolic ac- icosis. They are almost invariably supraventricular.
tivity of tissues and gives rise to the state of hyper- In some patients, paroxysmal supraventricular tachy-
metabolism. Excessive activation of oxidative pro- cardia may also occur. Approximately 10 % of the
cesses in cells causes the increased consumption of patients with thyrotoxicosis manifest atrial fibrila-
oxygen per weight unit of tissue mass, what is man- tion. Ventricular arrhythmias are unique. Palpita-
ifested by the increase of BMR (in some instances tions may be rather common subjective symptom.
5.4. Pathophysiology of thyroid gland 343

At rest, peripheral vascular resistance is decreased, appear to be the result of increased adrenergic ac-
and cardiac output is increased as a result of an in- tivity and usually subside when the thyrotoxicosis is
crease in both stroke volume and heart rate. Sys- corrected. It is important to distinguish these ocular
tolic blood pressure is slightly increased due to the manifestations, which occur in all forms of thyrotox-
increased stroke volume. Diastolic blood pressure icosis, from those of the infiltrative ophthalmopathy,
is decreased due to peripheral vasodilatation. The which are characteristic of Graves-Basedow disease.
pulse pressure is widened as a result of both an in-
Skin symptoms of thyrotoxicosis. Thyrotoxicosis
crease in systolic pressure and a decrease in diastolic
leads to a variety of changes in the skin and its ap-
pressure.
pendages. Most characteristic is the warm moist feel
As a result of a direct effect of increased concen- of the skin that results from cutaneous vasodilatation
trations of thyroid hormones on myocardium is long- and excessive sweating as part of the hyperdynamic
term increased oxygen consumption in cardiomy- circulatory state. Skin is, therefore, fine with a vel-
ocytes. Persistence of increased oxygen consump- vety texture. The hands are usually warm and moist,
tion and increased energy consumption (due to in- palmar erythema is common. The complexion is rosy
creased cardiac work) may lead to the origin of hy- and the patient blushes readily. Increased diffuse pig-
poxic changes in the myocardium. Also increased mentation is formed occasionally, which may result
degradation of protein has a negative effect on my- from hypersecretion of ACTH secondary to acceler-
ocardium. Due to the noted hypoxic and metabolic ated turnover of cortisol. Hair is fine and friable,
changes in some patients thyrotoxic cardiomyopathy does not retain a wave and some may fall out. Nails
(cor thyreotoxicum) may occur after a long period of are often soft and friable. A characteristic finding is
persisting of thyroid hormone overproduction. It is Plummer nails, especially on the ring finger. This
clinically manifested by severe forms of arrhythmia term is applied to separation of the distal margin of
and by a congestive heart failure. The response of the nail from the nailbed with irregular recession of
such heart to digitalis is decreased. the junction (onycholysis).
Ocular symptoms of thyrotoxicosis. These symp- Psychic and nervous symptoms of thyrotoxicosis.
toms are a very frequent manifestation of all forms These symptoms are an almost invariable accompa-
of thyrotoxicosis, regardless of the underlying cause. niment of thyrotoxicosis. The patients complain of
Spasm and retraction of the upper eyelids (increased nervousness, irritability, psychic and motor restless-
tonus of musculus levator palpebrae), which lead to ness, anxiety, emotional tension, emotional lability,
widening of the palpebral fissure, are most common. insomnia, and hyperkinesia. Nervousness may man-
These changes of the eyelids are evident as the pres- ifest as a feeling of apprehension and inability to
ence of a rim of sclere between the upper lids and concentrate. Emotional lability and irritability may
the superior margin of the iris (Dalrympl symptom). lead to difficulty in interpersonal relationships and
It is responsible for the bright-eyed, staring appear- to inappropriate spells of crying and laughing, or
ance of the patient with thyrotoxicosis. Accompa- euphoria and depression. The patients are scared
nying lid retraction are the phenomena of lid lag, in without apparent reason. Their speech is fast and
which the upper lid lags behind the globe, exposing exciting, trains of thoughts are accelerated. They
more of the sclera, when the patient is asked to gaze respond quickly to questions or commands. Their
slowly downward. Therefore, the presence of a rim behaviour is hyperactive and they are always in a
of sclera is constant (Graefe symptom). When the hury. During the interview the patient cannot sit
patient gazes slowly upward the globe often lags be- still, drums on the table, taps a foot, or shifts po-
hind the upper lid. The movements of the lids are sitions frequently. Movements are quick, jerky, ex-
jerky and spasmodic. A fine tremor of the lightly aggerated, and often purposeless. Examination re-
closed lids can often be observed (Rosenbach symp- veals a fine rhythmic tremor of stretched finger tips
tom). The patients blink rarely, 1–2/min, while the of the arms stretched forward (it is better inspected
norm is 3–5/min. This infrequent blinking is termed by touch than by sight). The fine rhythmic tremor
Stellwag symptom. Due to the increased lacrimation of put out tongue and lightly closed eyelids is also
in the patients with thyrotoxicosis, expressive shiny present. Tendon reflexes are rapid, mainly Achilles’
eyes can be observed. These ocular manifestations jerk. The physiological basis of the findings refer-
344 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

able to the nervous system is not well understood. due to edema resulting from the increased content of
In part, they may reflect increased adrenergic activ- the glycosaminoglycans and also due to an inflam-
ity. matory infiltrate. Glycosaminoglycans are very hy-
Symptoms of thyrotoxicosis due to alterations of drophilic substances, and, therefore, the water con-
skeletal muscles. Weakness and fatigability are fre- tent in retrobulbar tissues is increased. The inflam-
quent. Often the weakness is most prominent in the matory infiltrate consists of lymphocytes, mast cells,
proximal muscles of the limbs (mainly extensor of and plasma cells. Also augmentation of connective
the legs) and is manifested by difficulty in climb- and fat tissues participates in increased volume of
ing stairs or in maitaining the leg in an extended the orbital contents. The fibres of extraocular mus-
position. The patient is also unable to climb the cles show degeneration and loss of striations, with
chair (Plummer symptom) or to rise from a sitting. ultimate fibrosis.
Thyrotoxicosis may lead to degeneration of skeletal
muscle fibres. The mentioned disorders of skeletal The symptoms associated with infiltrative oph-
muscles are termed thyrotoxic myopathy. thalmopathy are diverse and may appear in vary-
Other symptoms of thyrotoxicosis. The common- ing combinations. The most evident symptom is
est of them are referable to the alimentary tract, protruding of the globe (exophthalmos, proptosis),
mainly those related to bowel function. Diarrhea is which is usually bilateral and frequently asymmetri-
rare. More often stools are less well formed, and the cal, and may be accompanied by a feeling of pressure
frequency of bowel movements is increased. Thyro- behind the globes. The cause of protruding of the
toxicosis is generally associated with increased excre- globes is the increased volume of the orbital contents.
tion of calcium and phosphorus in urine and stool. When exophthalmos is pronounced, the patient may
Excessive loss of mineral is sometimes associated sleep with the eyes partly open (lagophthalmos).
with demineralization of bones and occasionally with Edematous and infiltrative changes give rise to
pathological fractures, especially in elders. Thyro- myopathy of the extraocular muscles. Patients fre-
toxicosis in early life may be associated with delayed quently report that their vision is blurred and that
sexual maturation, although general physical devel- their eyes tire easily. Double vision (diplopia) may
opment is normal and skeletal growth is often ac- occur. Weakness of the extraocular muscles is most
celerated. In adults an increase in libido sometimes commonly evident in an inability to achieve or main-
occurs in both sexes. In women menstrual function is tain convergence (Moebius symptom). Limitation
usually disturbed. The change in menstrual pattern of upward gaze and especially of superolateral gaze
usually takes the form of oligomenorrhea with a vari- may be present. Sometimes the paralysis of some
able intermenstrual period, occasionally progressing extraocular muscles may occur. It is manifested by
to amenorrhea. permanent anomalous position of more often both
3. Infiltrative ophthalmopathy globes, but sometimes only one of them. Various
forms of bilateral or unilateral strabismus originate.
Infiltrative ophthalmopathy (infiltrative orbitopathy, The ocular muscle weakness that results in impaired
exophthalmic syndrome) is characteristic only for upward gaze and convergence and strabismus with
Graves-Basedow disease. It occurs in about 50 % of varying degrees of diplopia is termed exophthalmic
patients and is induced by a specific immunoglobu- ophthalmoplegia.
lin. In some patients it may appear in the course of
thyrotoxicosis, most frequently, however, occurs si- Severe and long-standing lagophthalmos promotes
multaneously with thyrotoxicosis. Occasionally, in- drying and corneal damage with subsequent ulcera-
filtrative ophthalmopathy occurs in the absence of tion of the cornea, keratitis ulcerosa develops. When
diffuse toxic goiter, an entity that is termed euthy- exophthalmos progresses rapidly it is termed pro-
roid ophthalmic Graves-Basedow disease. gressive exophthalmos. In untreated patients infec-
In the patients with infiltrative ophthalmopathy, tious inflammation of all orbital structures may occur
the volume of orbital contents is increased because (panophthalmitis), which may lead to destruction of
of both an increase in retrobulbar connective tis- one or both eyes and thereby to loss of vision (amau-
sue and an increase in mass of the extraocular mus- rosis). Ophthalmopathy connected with such severe
cles. This increase in both retrobulbar tissues is complications is termed malignant exophthalmos.
5.4. Pathophysiology of thyroid gland 345

4. Infiltrative dermopathy hypotensive levels. Mortality of the patients with

It occurs in about 5–10 % of patients with Graves- thyrotoxic crisis is high, usually up to 50 %.
Basedow disease. It is almost always accompanied by
infiltrative ophthalmopathy, usually of a severe de- B. Hyperthyroidism due to nonimmunogenic
gree. Pathological immunoglobulins probably partic- thyroid autonomy
ipate in its origin. Skin is infiltrated by glycosamino- There are two forms of hyperthyroidism due to non-
glycans and by the cells characteristic for chronic in- immunogenic (intrinsic) thyroid autonomy: toxic
flammatory process. This dermopathy is usually lo- multinodular goiter and toxic adenoma. In the past
calized over the pretibial area (pretibial myxedema) both these forms were included in a common term
and over the dorsa of the feet. Rarely it is seen on toxic nodular goiter. With regard to their differ-
the face or dorsa of the hands. The skin of the af- ent pathogenesis and histopathology they are distin-
fected areas is thickened, raised, and has a peau d’ guished as separate nosologic entities.
orange appearance. The indurations are usually dis-
crete, assuming a plaquelike or nodular configuration a) Toxic multinodular goiter
but in some instances are confluent. Toxic multinodular goiter is an occasional conse-
quence of a long-standing simple goiter, although the
Severe complications of Graves-Basedow disease
proportion of cases in which this complication arises
Besides the both, congestive heart failure and ma- is uncertain. The symptoms of hyperthyroidism usu-
lignant exophthalmos already mentioned, the third ally originate after the age of 50 in patients who have
dangerous complication is thyrotoxic crisis. had nontoxic multinodular goiter for many years. It
Thyrotoxic crisis (crisis thyreotoxica) is many times more common in women than in men.
The cause of gradually originating autonomy of
Thyrotoxic crisis is an extreme accentuation of certain areas of thyroid parenchyma (their indepen-
thyrotoxicosis. It is an uncommon but serious com- dence from TSH stimulation), which causes transi-
plication of Graves-Basedow disease. Crisis is al- tion from nontoxic to toxic multinodular goiter, is
most always of abrupt onset and occurs in patients not precisely known. It is probably the result of
in whom pre-existing thyrotoxicosis has been treated functional heterogenity of epithelial cells of follicles.
either incompletely or not at all. It is almost al- Sometimes, hyperthyroidism may appear abruptly,
ways evoked by a precipitating factors, such as in- but this almost always results from exposure to in-
fection, trauma, surgical operations, surgical emer- creased quantities of iodine in the patients with a
gencies, radiation thyroiditis, toxemia of pregnancy, nontoxic multinodular goiter (iodine-induced hyper-
and parturition. The mechanism whereby such fac- thyroidism, jodbasedow). Administration of iodides
tors lead to an accentuation of thyrotoxicosis has
permits autonomous foci to increase their rate of hor-
not been ascertained. It does not appear to be an mone biosynthesis and secretion to truly excessive
acute increase in the severity of thyroid hyperfunc- levels.
tion. Rather, it may represent a shift from protein- From the histopathological and functional view-
bound to free thyroid hormones. It is manifested point two types of toxic multinodular goiter can be
by extreme hypermetabolism and by fulminating in-
distinguished:
crease in all characteristic symptoms of thyrotoxico-
sis. 1. The first type of toxic multinodular goiter is
The clinical picture of thyrotoxic crisis is domi- more common. It is characterized by a diffuse
nated by hyperpyrexia (40–41o C), marked tachycar- small focal (patchy foci) distribution of radioiso-
dia (over 140/min), even tachyarrhythmia associated tope in scintillation scaning. This distribution is
with atrial fibrilation, extreme irritability and rest- not usually altered by administration of exoge-
lessness, diarrhea, vomiting, profuse sweating, and nous thyroid hormone. Histopathological exam-
dehydration. As the crisis progresses, apathy, pros- ination reveals multiple aggregates of small fol-
tration, stupor, and coma may supervene, but with licles with hyperplastic epithelium (micronod-
only slight elevation of temperature. The blood pres- ules), interspersed with variably sized inactive
sure, which initially is well maintained, may fall to nodules. It is very likely that some of these inac-
tive nodules may preserve the ability of hormone
346 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

production. They are inactive because TSH se- b) Toxic adenoma

cretion is suppressed by the increased concentra-
tion of thyroid hormones in circulating blood. Toxic adenoma (Plummer disease) is less common
Thyroid hormones are produced by numerous as toxic multinodular goiter. It occurs in a younger
autonomous micronodules. age group than does toxic multinodular goiter, often
between the ages of 30 and 40. Thyrotoxicosis is usu-
ally caused by a solitary hyperfunctional autonomous
2. The second type of toxic multinodular goiter is nodule (toxic uninodular goiter). Occasionally, two
less common. The accumulation of radioiodine or three adenomas of similar character are present.
is localized only in one or more discrete nodules From the point of view of histopathology it is true
within the gland, the remainder appearing to be follicular adenoma being well encapsulated (demar-
essentially nonfunctional (suppressed). No fur- cated from surrounding tissue). Its pathogenesis is
ther suppresion is produced by exogenous thy- unknown. In anamnesis the patient often reports
roid hormone, but administration of TSH stim- that the nodule (lump) in the neck has grown slowly
ulates accumulation of radioiodine in the areas over many years. The nodule becomes capable to
previously inactive. Histopathological examina- produce thyrotoxicosis if it has achieved a diameter
tion reveals that the hyperfunctioning areas re- of 2.5 to 3 cm. Initially it is present as a small nodule
semble adenomas in being reasonably well de- the function of which is insufficient to disturb hor-
marcated from surrounding tissue. They pro- monal equilibrium, though its capacity to accumu-
duce hormones autonomously. They consist of late radioiodine is evident in scintiscans as an area of
large follicles, sometimes with hyperplastic ep- increased density within the still-functioning extran-
ithelium. The remaining tissue appears inac- odular tissue (warm nodule). With time, the nodule
tive. Zones of degeneration are usually present grows larger, its function increasing until it is suffi-
in both hyperfunctioning and nonfunctioning ar- cient to suppress TSH secretion. Consequently, the
eas. remainder of the gland undergoes relative atrophy
and complete loss of function. The scintiscan re-
Clinical features. The extent of overproduction veals radioiodine accumulation only in the adenoma
of thyroid hormones in toxic multinodular goiter is (hot nodule). At this time frank thyrotoxicosis usu-
usually mild compared with that in Graves-Basedow ally sepervenes. Hyperthyroidism is not caused by
disease. Therefore, the serum T4 and T3 concen- the whole parenchyma of the thyroid gland, as it is
trations are only slightly above normal. TSH secre- in the patients with Graves-Basedow disease, but it
tion is inhibited. The symptoms of infiltrative oph- is induced only by its relatively small encapsulated
thalmopathy and infiltrative dermopathy are never area.
present, because toxic multinodular goiter is not a Clinical features. The clinical picture of toxic ade-
disease with autoimmune pathogenesis. noma is similar to that of toxic multinodular goi-
The clinical picture of thyrotoxicosis due to toxic ter. The peripheral manifestations of thyrotoxicosis
multinodular goiter is usually oligosymptomatic. due to toxic adenoma are also generally milder than
Cardiovascular manifestations tend to predominate, those of diffuse toxic goiter. The symptoms of infil-
possibly because of the age of the patients in which trative ophthalmopathy and infiltrative dermopathy
this form of hyperthyroidism may be often acom- are never present. Cardiovascular symptoms may be
panied by ischemic heart disease. These manifesta- prominent, and their relevance increases with the age
tions may include tachycardia, arrhythmias, atrial of the patient. Toxic adenoma in some patients se-
fibrilation, or congestive heart failure. Weakness, crete T3 predominantly, therefore, serum T4 concen-
tiredness and wasting of muscles are common. The tration is normal and serum T3 concentration alone
nervous manifestations are usually mild or absent, is increased. Relative to its overall rate of occurrence,
but emotional lability may be pronounced. As the toxic adenoma is the most frequent of T3 toxicosis.
thyroid tissue due to toxic multinodular goiter is of Secretion of TSH is suppressed, its serum concentra-
tougher consistency and the goiter is often retroster- tion is low. On palpation, the nodule is usually felt
nal, the symptoms of mechanical local syndrome may as a smooth, well-defined, round or ovoid mass that
be also present. is firm and moves freely on swallowing.
5.4. Pathophysiology of thyroid gland 347

C. Hyperthyroidism due to nonimmunogenic tend to be elderly with the danger of serious cardio-
abnormal thyroid stimulator vascular manifestations thyrotoxicosis should ensue,
This form of hyperthyroidism may be also termed hy- large doses of iodine should not be given to those
perthyroidism due to trophoblastic tumors, because with the multinodular goiter. The jodbasedow phe-
malignant tumors arising from trophoblastic tissue nomenon can seldom occur in younger individuals
(hydatidiform mole, choriocarcinoma, or metastatic with the diffuse goiter, and here thyroid-stimulating
embryonal carcinoma of the testis) may be some- immunoglobulins are often present. Thyrotoxicosis
times accompanied by the symptoms of thyrotoxi- is induced by random administrations of pharma-
cosis. The increased production of T4 and T3 is ceuticals containing iodine, such as expectorants, x-
induced by a circulating thyroid stimulator, which ray contrast media, or any other forms. It seems
is not, however, identical with TSH. It is probably that jodbasedow occurs only in thyroid glands in
human chorionic gonadotrophin (hCG), or a protein which function is independent of TSH stimulation
closely related to it (chorionthyrotrophin). It has and refers to the induction of thyrotoxicosis in a pre-
been found out that alpha subunits of TSH and go- viously euthyroid patients as a result of exposure to
nadotropins are identical. administration of larger doses of iodine. Mechanism
Serum T4 and T3 concentrations are increased of inducing hyperthyroidism by iodine is not exactly
only slightly, serum TSH concentration is decreased. known. In these patients, serum T3 concentration
Thyrotoxicosis is mild, goiter is absent. is quite often normal, but serum total and free T4
concentrations are increased (T4 toxicosis).
D. Hyperthyroidism due to increased TSH
production 5.4.3.2 Thyrotoxicosis without hyperthy-
Rarely, hyperthyroidism and thyrotoxicosis are the roidism
result of sustained hypersecretion of TSH (central Thyrotoxicosis not associated with hyperthyroidism
hyperthyroidism). The cause of overproduction of is rare. It may have a iatrogenic origin, it may be as-
TSH may be TSH-secreting pituitary adenoma, se- sociated with various forms of inflammatory disease
lective resistance of pituitary to thyroid hormones, or of the thyroid gland, or the source of excess of thy-
increased secretion of hypothalamic TRH. All these roid hormones may be outside of the thyroid gland
varietes are associated with a diffuse hyperfunction- itself.
ing goiter. Features of autoimmune thyroid disease
are absent in the patient and in the patient’s family. A. Thyrotoxicosis factitia
Serum TSH concentration, as well as serum T4 and This term designates temporary thyrotoxicosis that
T3 concentrations are increased. In the clinical pic- arises from ingestion, usually chronic, of excessive
ture of TSH-secreting pituitary adenoma some local quantities of exogenic thyroid hormone (exogenous,
symptoms, secondary to compression of surrounding iatrogenic thyrotoxicosis). It occurs rarely. The
structures, may be present. symptoms are typical of thyrotoxicosis and may be
Hyperthyroidism due to ectopic (paraneoplastic) severe. If thyrotoxicosis is induced by an excessive in-
production of TSH is extraordinarily rare. Its pro- take of T4 , its symptoms persist several weeks after
duction in bronchogenic carcinoma is most common. the intake of this hormone has been finished. How-
ever, after finishing of an excessive intake of T3 ,
E. Iodine-induced hyperthyroidism the symptoms of thyrotoxicosis will disappear much
For some time it has been known that administra- more faster. Due to long-standing intake of exo-
tion of supplemental iodine to subjects with endemic genic thyroid hormone, endogenous thyroid function
iodine-deficiency goiter can result in overproduction is suppressed and thyroid parenchyma may become
of thyroid hormones. This response has been termed atrophic (serum TSH is decreased, therefore, the
jodbasedow. It usually occurs in the patients with stimulation of thyroid parenchyma is suppressed).
nontoxic multinodular goiter, some areas of which
have autonomous function. This autonomous ar- B. Transient thyrotoxicosis associated with
eas of its tissue, however, has not appeared be- thyroiditis
fore administration of iodine. Since such patients The symptoms of thyrotoxicosis may appear in the
348 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

early phase of subacute thyroiditis. The episode of tonomous adenoma of this ectopic thyroid tissue.
thyrotoxicosis may also occur in the patient with
a painless form of thyroiditis in which biopsy of
the thyroid reveals the histopathological changes of 5.4.4 Inflammations of the thyroid
chronic lymphocytic thyroiditis that, however, dif- gland (thyroiditis)
fers from that of Hashimoto thyroiditis. Circulat-
ing antithyroid antibodies, when present, are in low Inflammations of the thyroid gland (thyroiditis) are
titer. This form of thyroiditis has been variously des- rather common. From the etiological point of view
ignated as painless thyroiditis, silent thyroiditis, or several forms of thyroiditis are distinguished. Thy-
chronic thyroiditis with spontaneously resolving thy- roid biopsy and histopathological examination of ob-
rotoxicosis. At present the term chronic thyroiditis tained specimens has an important role in the di-
with transient thyrotoxicosis is preferred. agnosis of their certain types. The most common
are lymphocytic thyroiditis, chronic thyroiditis with
In the both above mentioned forms of thyroiditis
transient thyrotoxicosis, and subacute thyroiditis.
the thyrotoxicosis is usually of a mild degree, only
They are notable for their different clinical courses
in some instances its symptoms may be severer. The
and for the fact that each can be associated, at one
clinical features of thyrotoxicosis reflect the extent of
time or another, with an euthyroid, thyrotoxic, or
elevation of serum T4 and T3 concentrations. It is
hypothyroid state. Acute thyroiditis, chronic fibros-
supposed not to be induced by the increase biosyn-
ing thyroiditis, and the other types of thyroiditis are
thesis and secretiom of thyroid hormones. The cause
rare.
of its origin is presumably larger destruction of thy-
roid parenchyma (disruption of follicles) which ap-
pears suddenly in the course of inflammatory pro- 5.4.4.1 Acute thyroiditis
cess. Due to the disruption of a large number of fol-
licles the extensive nonregulated depletion of thyroid Acute thyroiditis (pyogenic thyroiditis) is rare. It
hormone stores into circulating blood occurs. Low is due to an infection of the thyroid gland by pyo-
or undetectable serum TSH concentration (suppres- genic microorganisms, most frequently by staphylo-
sion of its secretion by the increased concentrations cocci, streptococci, or pneumococci. Less commonly
of thyroid hormones in blood), as well as decreased it may be due to salmonellae or E. coli. Infectious
accumulation of radioiodine in the thyroid gland are agents may come from infectious focus located in the
the evidence of this assumption. Later, as glandular close area of the thyroid and get into it by lymphatic
hormones are depleted, the patient may pass through or vascular vessels. Sometimes it may be the result
a hypothyroid phase, in which serum T4 and T3 con- of hematogenous dissemination from distant primary
centrations are low and serum TSH concentration is septic foci, or it may be the complication of infec-
increased. After this hypothyroid phase, duration of tious disease. If pyogenic thyroiditis is nontreated
which is several months, the patient usually returns abscesses may develop in the thyroid.
to an euthyroid state. Clinical features. The clinical picture of acute
thyroiditis is characterized by sudden origin of ev-
idently painful goiter. Usually only one lobe of the
C. Thyrotoxicosis due to ectopic production thyroid gland is enlarged. The overlying skin is red
of thyroid hormones and warm. The goiter is tender and painful spon-
The symptoms of thyrotoxicosis may be rarely in- taneously and on palpation. The pain is aggravated
duced by hyperfunctioning distant metastases of thy- by swallowing (dysphagia is present), yawning, and
roid carcinoma (mostly follicular carcinoma) in lung by turning the head. On the affected side, the pain
or bones. Ectopic thyroid tissue may also be present characteristically radiates to the ear, jaw, or occiput.
in teratomas, especially in the ovary. About 3 % of Fever, malaise, leukocytosis, and increased erythro-
the whole number of ovarian teratomas are hyper- cyte sedimentation rate are present. Serum thyroid
functioning. The tissue of such teratomas produces hormone concentration is normal. In scintiscan ab-
thyroid hormones, and, therefore, it may evoke mild scess, if present, is usually manifested as a cold nod-
thyrotoxicosis (struma ovarii). A severer degree of ule. In circulating blood antithyroid antibodies are
thyrotoxicosis can appear due to the origin of au- not present.
5.4. Pathophysiology of thyroid gland 349

5.4.4.2 Subacute thyroiditis only rarely. On palpation, the enlarged thyroid is

firm and often nodular.
Subacute thyroiditis (de Quervain thyroiditis) is con- The origin of painful goiter is usually accompanied
sidered viral in origin (viral thyroiditis). The specific by fever, but in some cases the body temperature
virus which would be the cause of its origin, however, in the morning is increased only slightly. The most
has not been found out. The viral infection of the striking laboratory finding of subacute thyroiditis is a
thyroid gland usually follows a cataral upper respi- high erythrocyte sedimentation rate (usually>100).
ratory infection, or influenza. A tendency to a sea- The leukocyte count is normal or, at most, mod-
sonal and geographic aggregation of cases has been erately increased. Antithyroid antibodies are not
noted. The mumps virus, influenza virus, Coxackie present.
B viruses, echoviruses, and adenoviruses are consid- In the early phase of subacute thyroiditis in some
ered the etiological agents of subacute thyroiditis. patients the clinical symptoms of mild transient thy-
Women are more frequently affected than men. The rotoxicosis (e.g., tachycardia, palpitation, nervous-
maximal incidence is in the fourth and fifth decades. ness, lassitude, and weakness) may occur. They are
In about 70 % of the patients the leukocyte antigen evoked by depletion of larger quantities of preformed
HLA-Bw35 is present, what indicates possibility of thyroid hormones due to the disruption of a larger
existence of genetic predisposition to this disease. number of follicles. The thyrotoxic phase lasts about
Histopathological examination reveals that the one month and results in spontaneous withdrawal
parenchyma of affected area is infiltrated with cells followed by return of serum thyroid hormone con-
predominantly of the mononuclear type. Many of centrations to normal (the phase of transient euthy-
the follicles show disruption of epithelium with par- roidism). Duration of this phase is about 1–3 weeks.
tial or complete loss of colloid. The colloid is found in Later in the disease serum thyroid hormone concen-
the interstitium and is surrounded by the multinucle- trations sometimes decrease below normal level. The
ate giant cells (giant cell thyroiditis). The follicular hypothyroid phase lasts 2–5 months. In this phase
changes may progress to form granulomas (granulo- the goiter gradually diminishes.
matous thyroiditis). In the phase of transient thyrotoxicosis serum T4
Pathophysiology. Destruction of follicular epithe- and T3 concentrations are slightly increased, serum
lium and loss of follicular integrity are the primary TSH concentration is decreased. The scintiscan re-
events in the pathophysiology of subacute thyroidi- veals that radioiodine accumulation in the affected
tis. Preformed hormones are released into circulat- area is low. In the hypothyroid phase serum thyroid
ing blood, often in quantities sufficient to produce hormone concentrations are decreased below normal
thyrotoxicosis (the thyrotoxic phase). Later in the and serum TSH concentration is appropriately ele-
disease, when stores of preformed thyroid hormones vated. In the hypothyroid phase radioiodine accumu-
are depleted, the patient may pass through a period lation may be temporarily increased. With recovery
of mild transient hypothyroidism (the hypothyroid the normal values for serum thyroid hormones and
phase). Ultimately, as biosynthesis of hormones re- TSH concentrations are restored.
sumes and their stores are repleted, the thyroid func- Occasionally, the locus of maximal involvement
tion usually becomes normal. migrates over the course of a few weeks to other
Clinical features. The characteristic feature of parts of the thyroid gland. This is usually mani-
subacute thyroiditis is the gradual or sudden appear- fested by the change of physical findings and by a
ance of pain in the region of the thyroid, which is relapse in other clinical symptoms and laboratory
slightly to moderately enlarged. One lobe generally findings as well. The disease usually subsides spon-
being more severely affected than the other. Less taneously within a few months, leaving no residual
commonly it may be unilateral. The goiter is painful deficiency of the thyroid function. Usually only very
spontaneously and on palpation. The pain is aggra- mild, functionally non-significant, residual fibrosis
vated by swallowing (dysphagia is present), yawning, has been left. The goiter usually completely dis-
and turning the head. The pain characteristically ra- appears. Rarely recidivation of subacute thyroiditis
diates to the ear, teeth of the lower jaw, or occiput. may occur, mainly after some viral diseases. In rare
A painless form of subacute thyroiditis may occur cases, the subacute thyroiditis may smoulder with re-
350 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

peated exacerbations over many months, permanent in presentation, course, and pathophysiology. Tran-
hypothyroidism being the result. sient thyrotoxicosis may occur some time within a
few months (usually 2–4) after delivery. The thyro-
5.4.4.3 Chronic thyroiditis with transient toxicosis phase is often followed by the phase of hy-
thyrotoxicosis pothyroidism which lasts several months. The phase
Chronic thyroiditis with transient thyrotoxicosis of self-limited hypothyroidism may be only compo-
(painless thyroiditis, silent thyroiditis) is a disease nent of the disease that is diagnosed because the thy-
in which a self-limited episode of thyrotoxicosis is as- rotoxic phase may be very brief. After the hypothy-
sociated with a histologic picture of chronic lympho- roid phase the patient usually returns to an euthyroid
cytic thyroiditis that differs from that of Hashimoto state. The postpartum thyroiditis syndrome may oc-
thyroiditis. It occurs in patients of any age, women cur in 4–8 % of pregnant women. Very likely, it has
are more frequently affected than men. an autoimmune basis. Most patients have a small
Etiology and pathogenesis of this disease are un- goiter and positive tests for antithyroid peroxidase
clear. Viral antibody titers show no characteristic antibodies (formerly called antimicrosomal antibod-
pattern. Lymphocytic infiltration and presence of ies), although titers are low. There is a strong associ-
plasma cells within the thyroid could suggest an au- ation with the HLA-DR3 and HLA-DR5 haplotypes.
toimmune basis. However, the absence of high titers The postpartum occurrence of this syndrome is prob-
of circulating antithyroid antibodies and the perma- ably due to a rebound of immune activity after its
nent resolution in most would argue against this. suppression during pregnancy.
The thyroid gland is enlarged in only about 50 %
of the patients. The thyroid enlargement is usually 5.4.4.4 Lymphocytic thyroiditis (Hashimoto
mild and unaccompanied by nodularity. Thyrotoxi- disease)
cosis is rarely severe, and elevation of serum T4 and
T3 concentrations is consonant with a degree of thy- Lymphocytic thyroiditis (Hashimoto thyroiditis,
rotoxicosis. Conventional essays reveal antithyroid struma lymphomatosa) is the most common type of
antibodies in only about one half of the patients. Un- inflammations of the thyroid gland. About 3–5 % of
like subacute thyroiditis, the erythrocyte sedimenta- population are affected, women more frequently than
tion rate is normal or near normal. men. It may occur at any age, most often between
It is presumed that thyrotoxicosis results from the ages of 30 and 50. It often develops also at pu-
leakage of preformed hormones from the thyroid berty participating in more than one half of goiters
gland (due to the destruction of follicular epithe- originated in this period. Hashimoto thyroiditis is an
lium and loss of follicular integrity), as in subacute autoimmune disease characterized by chronic course
thyroiditis. The thyrotoxic phase lasts usually two (chronic autoimmune thyroiditis), painless goiter,
manths. About one half of the patients return to and by gradual development of hypothyroidism. The
an euthyroid state and remain well. The remain- evidence of autoimmunity includes the lymphocytic
ing half patients pass through a short transient eu- infiltration of the thyroid tissue and the presence in
thyroid phase to hypothyroid phase. This phase of the serum of high titers of antibodies against several
self-limited hypothyroidism varies in duration from components of epithelial cells of follicles.
2 to 9 months. The tendency of the disorder to Etiology and pathogenesis are not exactly known.
pass through a hypothyroid phase is not surpris- It is assumed that autoimmunity in Hashimoto dis-
ing in view of the extensive depletion of glandular ease reflects genetically determined defect in the
hormone stores that must occur while hormones are function or deficiency of suppressor T cells (proba-
leaking from the gland and new hormone synthesis bly of autosomal dominant inheritance). This defect
is reduced. This phase gives way to a restoration allows the emergence and persistence of forbidden
of euthyroidism, but in about 5 % of the patients clones of helper T cells directed against the thyroid
permanent hypothyroidism develops years later. In antigens. The thyroid-sensitized helper T lympho-
some patients recurrence (sometimes multiple recur- cytes cooperate with B cells in the thyroid to produce
rences) of thyrotoxicosis may occur months or years a constellation of the specific antithyroid autoanti-
after restoration of an euthyroid state. bodies. In patients with Hashimoto thyroiditis, un-
The postpartum thyroiditis syndrome is similar like those with Graves-Basedow disease, the number
5.4. Pathophysiology of thyroid gland 351

of cytotoxic T lymphocytes, damaging epithelial cells tient swallows. Its surface is either smooth or scal-
of follicles, is increased. lopes, but well-defined nodules are unusual. There-
Lymphocytic thyroiditis, primary idiopathic hy- fore, compression of adjacent structures, such as tra-
pothyroidism, and Graves-Basedow disease often oc- chea, esophagus, and recurrent laryngeal nerves, oc-
cur familially. Therefore, it is generally agreed that curs rarely. Both lobes of the thyroid are enlarged,
the noted diseases are various variants of the same but one is often larger than the other. In occasional
autoimmune disease. Mechanisms responsible for the instances, however, the thyroid enlarges rapidly, and
development of individual clinical forms of the men- when accompanied by pain and tenderness the dis-
tioned triad of autoimmune thyroid disorders are not, order may mimic subacute thyroiditis.
however, known. The goiter is usually the only feature of Hashimoto
Hashimoto thyroiditis coexists in some frequency thyroiditis for a long time. It is manifested as an
with other diseases of an autoimmune nature, in- eufunctional goiter, and, therefore, the patient is
cluding type 1 diabetes mellitus, Addison disease, metabolically normal. However, clinical symptoms of
primary idiopathic hypoparathyroidism, pernicious hypothyroidism gradually appear and become more
anemia, rheumatoid arthritis, systemic lupus erythe- evident over several years. Slowly appearing symp-
matosus, chronic active hepatitis, myasthenia gravis, toms of hypothyroidism may be from the beginning
Sjögren syndrome, vitiligo, early graying of the hair, of the disease understood as growing old. In about
and others. These diseases, as well as Hashimoto 20 % of the patients, especially those with the fibrous
disease, also occur frequently in family members of variant, the symptoms of hypothyroidism may be ob-
the patients with Hashimoto diesease. A significant served already at the first detection of the Hashimoto
association between Hashimoto disease and the hu- thyroiditis in the patient.
man leukocyte antigens HLA-DR3, HLA-DR5, and Occasionaly, patients with Hashimoto disease
HLA-B8 also exists. present with hyperthyroidism in association with the
Histopathologic examination of the thyroid gland thyroid gland that is unusually firm and with high
reveals destruction of epithelial cells and fibrosis titers of circulating antithyroid antibodies, a combi-
which is more evident especially in the older lesions. nation which suggests, probably correctly, the con-
The most characteristic finding is an abundant dif- curence of Graves-Basedow disease and Hashimoto
fuse lymphocytic infiltration of the interstitial tissue. thyroiditis. In these patients, usually in midcourse
Interfollicular infiltration by plasma cells may be of- of Hashimoto thyroiditis, develops hyperthyroidism,
ten present. More of the remaining epithelial cells sometimes called ”Hashitoxicosis”. In other patients
may be larger and show oxyphilic changes in the cy- with Hashimoto disease, hyperthyroidism may super-
toplasm. They are called Askanazy cells and are con- vene presumably due to the emergence of clones of
sidered pathognomic for this disease. In some cases lymphocytes that produce stimulatory anti-TSH re-
epithelial hyperplasia may be prominent. ceptor antibodies. However, in some patients with
From the histopathologic point of view two vari- Hashimoto thyroiditis only transient thyrotoxicosis
ants of Hashimoto thyroiditis may be distinguished. without evidence of thyroid hyperfunction may de-
The more common is oxyphilic variant which is char- velop. Symptoms of transient thyrotoxicosis may
acterized by more evident exyphilic changes in the appear either during initial stage of the disease or
cytoplasm of epithelial cells, less fibrosis, and more as a consequence of rarely occurring exacerbation of
prominent infiltration with lymphocytes. The fi- chronic inflammatory process. In this phase of tran-
brous variant is characterized mainly by evident infil- sient thyrotoxicosis serum thyroid hormone concen-
tration with plasma cells and display of more fibrosis. trations increase as a result of more extensive de-
Hashimoto thyroiditis usually begins with discov- struction of the follicles, and not as a result of in-
ering of a small painless goiter, which enlarges grad- creased synthesis of the thyroid hormones. The evi-
ually over many years, especially if left untreated. dence of this is low radioiodine accumulation in scin-
It is often found during examination for some other tiscan.
complaint. Goiter is the outstanding clinical fea- Titers of antithyroid antibodies (antithyroglobulin
ture of Hashimoto disease. It is usually diffuse and and antimicrosomal) are high already from the onset
firm in consistency and moves freely when the pa- of the Hashimoto disease. Circulating autoantibody
352 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

titers tend to be higher in patients with the fibrous 5.4.4.6 Other types of thyroiditis
variant than in those with the oxyphilic variant.
They are very rare. These miscellaneous types of
The results of the tests of thyroid function depend thyroiditis include post-irradiation thyroiditis and
on the stage of the disease. At initial stage serum T4 trauma thyroiditis. They also include chronic non-
and T3 concentrations are normal, the patient is eu- pyogenic bacterial thyroiditis, which may originate
metabolic. As the disease progresses, thyroid failure, due to some specific infections (e.g., brucellosis, tu-
at first subclinical, may supervene owing to progres- berculosis, and syphilis). Occasionally thyroiditis
sive replacement of the thyroid parenchyma by lym- may occur also due to sarcoidosis, amyloidosis, and
phocytes or fibrosis. Although damage of the thyroid systemic mycosis.
gland is the obvious cause of the failing thyroid func-
tion, a contributing influence may be the presence of
TSH receptor-blocking antibodies. With the passage 5.4.5 Thyroid neoplasms
of time, thyroid function decreases gradually. Ability
Tumors of the thyroid gland are the most frequent
of the thyroid tissue to respond to TSH progressively
among the tumors of the endocrine system. They
diminishes. Therefore, the serum TSH concentration
are traditionally classified to benign and malignant
progressively rises and the serum T4 concentration
neoplasms. They may arise from epithelial cells (fol-
falls to subnormal values. The thyroid failure is ev-
licular cells or parafollicular cells), also from the
ident first in the rise in serum TSH concentration.
cells of connective tissue or from lymphoreticular
At this stage, the serum T3 concentration remains
cells. Therefore, epithelial, nonepithelial, or miscel-
normal for some time. However, with time, serum
laneous primary neoplasms of the thyroid gland may
T3 concentration may slightly increase, reflecting in
be distinguished. Secondary neoplasms (metastases
all likelihood maximal stimulation of the failing thy-
of extrathyroid tumors to the thyroid) of the thyroid
roid by the increased serum TSH concentration. The
gland may also occur.
foregoing sequence of symptoms (concerning serum
TSH, T4 and T3 concentrations) in the evolution of
complete thyroid failure has been termed diminished 5.4.5.1 Benign neoplasms
thyroid reserve or subclinical hypothyroidism. Ulti-
mately, the serum T3 concentration also declines to Benign neoplasms of the thyroid gland (benign goi-
subnormal values, and frank hypothyroidism super- ter) include predominantly follicular adenomas (the
venes. Autoimmune thyroiditis may account for as more highly differentiated adenomas) being hormon-
many as 90 % of cases of hypothyroidism. ally active (toxic adenomas) or hormonally inactive.
True adenomas are well encapsulated nodules of the
thyroid gland, which do not invade adjacent tissues,
and do not metastase.
5.4.4.5 Chronic fibrosing thyroiditis The patients often report that the nodule has
grown slowly over many years. Initially, if it is a hor-
Chronic fibrosing thyroiditis (Riedel thyroiditis) is monally active adenoma, its function is insufficient to
rare and is observed chiefly in middle-aged women. disturb hormonal equilibrium, though its capacity to
The etiology is unknown. From the histopathological accumulate radioiodine is evident in scintiscans as an
point of view it is characterized by extensive fibrosis area of increased density within the still-functioning
of the thyroid gland which gradually becomes unusu- extranodular tissue (warm nodule). With time, the
ally hard (a woody gland). Infiltrative growth of fi- nodule grows larger, its function increasing until it is
brous tissue into adjacent structures, including adja- sufficient to suppress TSH secretion. Consequently,
cent vessels, nerves, and muscles, is typical, too. Suc- the remainder of the gland undergoes relative atro-
cessive compression of the esophagus, trachea, and phy and loss of the function, and the scintiscan re-
recurrent laryngeal nerves gives rise to the symptoms veals intensive radioiodine accumulation only in the
of local mechanical syndrome. The goiter is mild region of the nodule (hot nodule). Frank thyrotox-
in size, usually asymmetrical, fixed, and stony hard. icosis usually supervenes. Relatively to its overall
The patient is usually euthyroid, hypothyroidism oc- rate of occurrence, hyperfunctioning adenoma is a
curs only occasionally. frequent cause of T3 toxicosis. The function of toxic
5.4. Pathophysiology of thyroid gland 353

adenoma is autonomous, independent of TSH stim- of nonepithelial malignant neoplasm of the thy-
ulation. roid gland. Miscellaneous malignant tumors include
About 95 % of adenomas are afunctional. Scin- mainly carcinosarcoma. The thyroid gland also may
tiscans reveal no accumulation of radioiodine (cold be the site of lymphoproliferative disease, namely
nodule). Epithelial cells of afunctional adenoma lost thyroid lymphoma. The relative risk of thyroid lym-
the iodide-trapping mechanism, and, therefore, they phoma is 67-fold higher in patients with Hashimoto
cannot produce hormones. thyroiditis than in the thyroid glands with colloid
Up to the present time it is not known whether nodules.
adenomas arise de novo or arise from hyperplastic
Primary thyroid carcinomas
perenchyma of the thyroid which is stimulated by
TSH for a long time. Toxic adenomas never undergo Primary thyroid carcinomas are the most common
malignant transformation. It has not been exactly endocrine malignancies, accounting for more than
known whether malignant transformation of afunc- 99 % of all thyroid malignancies. It occurs prevail-
tional adenomas is possible. ingly as a nodular goiter, most commonly as a soli-
From the histopathological view point structure of tary nodule. In the thyroid scintiscans malignant
adenomas is not uniform, but it is variable. There- nodules very often appear as a cold area, warm or
fore, thyroid adenomas are classified into follow- hot nodules are less common. About 80 % of thy-
ing histopathological types: embryonal adenoma, fe- roid carcinomas apear in the patients between the
tal adenoma, microfollicular adenoma, macrofollic- ages of 25 and 65. In children and young adults be-
ular adenoma (colloid adenoma), papillary cystade- fore the age of 40 mostly papillary carcinoma occurs,
noma, and Hürthle cell adenoma (it is composed of accounting for about two thirds of all thyroid car-
large acidophilic cells). In the thyroid gland various cinomas occurring in this period of life. Anaplastic
histopathological types of adenomas may be found carcinoma is very rare before the age of 40. In adults
in the same time, even in the same adenoma several after the age of 40, follicular carcinoma is more com-
of the above mentioned histopathological structures mon. At the same time the occurrence of anaplastic
may occur. carcinoma is also significantly increased. Medullary
carcinoma occurs mainly in elders.
Etiology and pathogenesis of the thyroid carcino-
5.4.5.2 Malignant neoplasms mas are not exactly known. It is assumed that sev-
Malignant neoplasms of the thyroid gland (malignant eral factors participate in their origin and develop-
goiter) account for about 1 % of all malignant tumors ment. The best known are:
of the population. Women are affected aproximately 1. Genetic factors. They have not been explored
twice more frequently than men. From the point precisely. However, the existence of familial
of view of histopathology primary malignant neo- type of medullary carcinoma has been consid-
plasms are divided into epithelial, nonepithelial, and ered proved (autosomal dominant inheritance).
miscellaneous. Rarely, metastases of extrathyroid
cancers to the thyroid may occasionally occur (sec- 2. Ionizing irradiation. It is the best known and
ondary malignant neoplasms). Breast cancer, bron- most significant external factor causing the ori-
chogenic carcinoma, renal cell carcinoma, malignant gin of malignant goiter. Its effect depends on
melanoma, and malignant lymphomas metastase to greatness of radiation dose applied to the area
the thyroid gland most frequently. of the thyroid gland or its vicinity, usually for
Epithelial malignant neoplasms of the thyroid diagnostic or therapeutic purposes, as well as
gland arise from follicular cells or parafollicular cells on the age in time of radiation. X-ray radiation
(C cells). Follicular carcinoma, papillary carcinoma is considered of a greater importance than ra-
and anaplastic carcinoma originate from the fol- diation by radioactive isotopes. Radiation dur-
licular cells. The parafollicular cells give rise to ing infancy or childhood is considered decisive.
medullary carcinoma. Carcinomas usually appear 6–8 years after radi-
Nonepithelial malignant neoplasms and miscella- ation of the neck area, but they may originate
neous malignant neoplasms of the thyroid gland oc- as late as 20 or even more years after the radia-
cur very rarely. Fibrosarcoma is the best known tion exposure. At present, it is assumed that
354 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

in most instances only microcarcinoma devel- Unlike other types of the thyroid carcinomas, fol-
ops. As this microcarcinoma stops growing, it is licular carcinoma may accumulate radioiodine, but
so-called ”sleeping carcinoma”. The microcarci- only to a small extent. Its metastases are some-
noma may start growing again and later metas- times hyperfunctional and may be sufficient to pro-
tase only when further stimulating and promo- duce clinical thyrotoxicosis, including T3 toxicosis.
tional factors are involved (e.g., long-lasting ex- However, its response to administration of suppres-
cessive stimulation of the thyroid gland by TSH sive doses of thyroid hormone (regression of the pri-
and suppression of the immune system are con- mary tumor and its metastases due to inhibition of
sidered). It is assumed that also some goitrogens TSH secretion by administrated thyroid hormone) is
and iodine deficiency may play a pathogenetic weaker than that of papillary carcinoma.
role in the origin of thyroid carcinoma.
B. Papillary carcinoma
Primary thyroid carcinomas are classified into two Papillary carcinoma accounts for about 60–75 %
varieties depending on whether the lesion arises in of all thyroid carcinomas. It may occur at any age
the thyroid follicular epithelium or from the parafol- but is seen more frequently in children and young
licular cells forming calcitonin. Three histopatho- adults. Women are affected 2–3 times more com-
logical types of carcinomas of follicular epithelium monly than men. Papillary carcinoma is the most
are distinguished: follicular, papillary and anaplas- common thyroid malignancy originating after X-ray
tic carcinomas. Parafollicular cells give rise to radiation exposure to the neck during childhood. In
medullary carcinoma. general, papillary carcinoma is the slowliest growing
one of all thyroid carcinomas. Clinically, it usually
A. Follicular carcinoma appears as an asymptomatic nodule, which varies in
size and is usually uncapsulated. It tends to spread
Follicular carcinomas tend to be slow growing and via the intraglandular lymphaties from its primary
account for 10–15 % of all thyroid cancers. In re- site to other parts of the thyroid and to the pericap-
gions with iodine deficiency they occur more often sular and regional lymph nodes, where it may remain
than papillary carcinomas. Follicular carcinoma oc- localized for years. Hematogenous spread to distant
curs in an older age group than papillary carcinoma, sites is uncommon. Its clinical course is relatively
most cases arising after the age of 40. Women are af- the most benign of all thyroid carcinomas. Papillary
fected two to three times more commonly than men. carcinoma has a tendency to become more malignant
The degree of malignancy varies but generally ex- with advancing age. Invasion of adjacent structures
ceeds that of papillary carcinoma. Follicular carci- and distant metastases may appear only as late man-
noma seldom spreads to the regional lymph nodes, ifestations. Papillary carcinoma may sometimes ded-
but undergoes early hematogenous spread to distant ifferentiate to the highly malignant anaplastic carci-
sites, particularly bone, lung, liver, or CNS. noma.
Follicular carcinoma histopathologically resem- Histopathological examination reveals that papil-
bles normal thyroid epithelium, is encapsulated, lary carcinoma is composed of columnar epithelium
and differs from benign follicular adenoma only that is thrown into folds, forming papillary projec-
by the presence of capsular and/or vascular inva- tions with connective tissue stalks. There may be
sion. Histopathological examination reveals the pres- gross or microscopic foci of carcinoma in other parts
ence of various size follicles containing subnormal of the thyroid gland, resulting from spread via the
amounts of colloid. The cells exhibit mitoses to a intraglandular lymphaties.
varying degree. Invasion of blood vessels and adja- Papillary carcinoma accumulates iodine less ef-
cent thyroid parenchyma is often observed. The de- ficiently than does follicular carcinoma. However,
gree of invasiveness is greatest in the older age group its response to administration of suppressive doses
of patients. The follicular carcinoma usually con- of thyroid hormone is better than that of follicular
sists of a single nodule. The regional lymph nodes carcinoma (regression of the primary tumor and its
are seldom enlarged. Pain and invasion of the adja- metastases is more evident).
cent structures manifest later than in papillary car-
cinoma.
5.4. Pathophysiology of thyroid gland 355

C. Anaplastic carcinoma carcinoma is firm, hard, and usually unencapsulated

Anaplastic carcinoma accounts for about 5–10 % and fixed nodule. It is sometimes bilateral, usually
of all thyroid carcinomas. It occurs after the age of localized to the upper two thirds of the gland, which
50, usually in the sixth to seventh decade of life. It are the anatomical location of the parafollicular cells.
is slightly more common in women. It is a highly Histopathological examination reveals that medul-
malignant tumor, rapidly invading adjacent struc- lary carcinoma is composed of the cells that vary
tures and metastasizing extensively throughout the widely in morphological features and arrangement.
body. Invasion of adjacent structures, such as skin, Round, polyhedral, and spindle-shaped cells form a
muscles, nerves, blood vessels, larynx, and esopha- variety of patterns. The cells may appear undifferen-
gus causes the origin of symptoms of local mechani- tiated and exhibit mitoses. Unlike the anaplastic car-
cal syndrome. Tumor mass is often fixed to adjacent cinoma, necrosis and polymorphonuclear infiltration
structures, therefore, moves poorly on swallowing. are absent. There is an abundant hyaline connec-
On histopathological examination, anaplastic car- tive tissue stroma that gives the staining reactions
cinoma is composed of atypical cells that exhibit nu- for amyloid (a distinctive amyloid stroma).
merous mitoses. Spindle-shaped cells and multinu- Medullary thyroid carcinoma occurs in both spo-
cleate giant cells are usually predominant. In some radic (80 %) and familial (20 %) forms. The famil-
cases, small cells are most prominent. Colloid ab- ial variety, usually appears at a yonger age, is more
sence is evident. Areas of necrosis and polymor- often bilateral, is less likely to have associated cer-
phonuclear infiltration are frequently present. Some- vical metastases when diagnosed, and has a better
times elements of papillary or follicular carcinoma prognosis. The familial form may occur as a part of
can be detected, suggesting that they may be the multiple endocrine neoplasia (MEN) types 2A or 2B,
precursors of anaplastic carcinoma, probably origi- or in a familial non-MEN setting (medullary thyroid
nating by their malignant dedifferentiation. Accord- carcinoma unassociated with other endocrine disor-
ing to histopathological finding spindle-shaped cell, ders). The peak incidence of the sporadic form is in
giant cell, and small cell types of anaplastic carci- the sixth and seventh decades of life, and patients
noma are distinguished. usually have cervical lymph node metastases at pre-
In general, anaplastic carcinoma does not accu- sentation.
mulate radioiodine. Therefore, it is refractory to ra- Differing from all the previously described thy-
dioiodine therapy, and it also does not response to roid carcinomas, medullary thyroid carcinomas are
administration of suppressive doses of thyroid hor- neuroendocrine neoplasms of parafollicular cell ori-
mone. gin. Neuroendocrine cells are widely dispersed in the
body and are capable of elaborating a large variety
D. Medullary carcinoma of amine and polypeptide bioactive products. There-
Medullary carcinoma makes up about 2 % of all fore, in addition to calcitonin, medullary thyroid car-
thyroid carcinomas. It arises from the parafollicu- cinoma may elaborate a variety of products. So,
lar cells producing calcitonin. It usually occurs af- a variety of symptoms, other than those related to
ter the age of 40 and is slightly more common in mass lesions, are present in patients with medullary
women. Medullary thyroid carcinoma is more ma- thyroid carcinoma. The carcinoid syndrome (flush-
lignant than follicular carcinoma, and by its malig- ing, diarrhea, and bronchospasm) and Cushing syn-
nity it may approach anaplastic carcinoma. Initially drome may occur, owing to secretion of serotonin
it invades the intraglandular lymphaties, spreading and ACTH, respectively. Prostaglandins, kinins, and
to other parts of the gland and to the pericapsular vasoactive intestinal peptide (VIP) may also be se-
and regional lymph nodes. In this phase it resem- creted and are variously responsible for the attacks
bles papillary carcinoma, but unlike the latter, later of watery diarrhea and circulation disorders.
it also spreads via the bloodstream to distant sites, Clinical manifestation of familial medullary carci-
particularly lung, bone, liver, and suprarenal gland. noma is antecedent by a premalignant hyperplasia of
In the time of origin of distant metastases medullary the C cells of the thyroid gland. This premalignant
carcinoma may resemble anaplastic carcinoma, but hyperplasia is the earliest demonstrable abnormality
unlike the latter it usually grows slowlier. Medullary (after the administration of provocative agents) in
356 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

the thyroid gland of individuals with familial form cal state resulting from undersecretion of parathy-
of medullary thyroid carcinoma. Infusions of pen- roid hormone (PTH) is denoted as hypoparathy-
tagastrin or calcium (and also having drunk alcohol) roidism. The pathophysiological state resulting
elicit secretion of calcitonin and successively increase from oversecretion of PTH is called hyperparathy-
calcitonin concentration in circulating blood. This is roidism. There is also a pathophysiological state
considered as an early biochemical signal of starting similar to hypoparathyroidism in which secretion of
medullary thyroid carcinoma. PTH is normal. The disorder is on the level of tar-
With time, premalignant hyperplasia of the C cells get tissues, which are insensitive to PTH. It is in
is followed by progression to nodular hyperplasia, fact pseudohypofunctional endocrine disorder (pseu-
microscopic medullary carcinoma, and finally frank doendocrinopathy) denoted as pseudohypoparathy-
medullary thyroid carcinoma. Basal plasma calci- roidism.
tonin concentration is elevated in about two thirds
of patients with clinically developed medullary car-
cinoma. In these patients, however, hypercalcemia is
5.5.1 Hypoparathyroidism
usually not present. It is a pathophysiological state when the parathyroid
In patients with the familial form of medullary thy- glands are not able to maintain normal calcium con-
roid carcinoma, there is often clinical or laboratory centration in circulating blood (normocalcemia) and
evidence of hyperparathyroidism and pheochromocy- thereby its homeostasis in organism. Hypoparathy-
toma (MEN 2A, Sipple syndrome). Hyperparathy- roidism is characterized by low plasma PTH concen-
roidism is most commonly due to parathyroid hyper- tration, hypocalcemia, hyperphosphatemia, and in-
plasia, rather than adenoma. Pheochromocytomas creased neuromuscular excitability.
are often bilateral. This variant of the MEN 2A syn- Etiology of hypoparathyroidism is heterogeneous.
drome is one in which medullary thyroid carcinoma, Organic and functional causes participate in its ori-
pheochromocytoma, and possibly parathyroid hyper- gin.
plasia are associated with ganglioneuromas. If there
are a marfanoid habitus, thickened corneal nerves, A. Organic causes. The most frequent or-
multiple mucosal neuromas, and typical facies simul- ganic causes are various iatrogenic influences, mainly
taneously present in the patient, this disease is de- postsurgical injuries or inadvertent removal of all
noted as the variant of the MEN 2B syndrome. Mu- parathyroid glands, respectively impairment of their
cosal neuromas may occur on the distal portion of vascular supply during thyroidectomy or during rad-
the tongue, on the buccal mucosa, on the lips (thick ical dissection in the neck for some form of malignant
bumpy lips), in subconjuctival areas (thickened and disease. Postoperative hypoparathyroidism origi-
friable eyelids-margin), and throughout the gastroin- nates when during surgical intervention more than
testinal tract (ganglioneuromatosis of the GIT). In 50 % of parenchyma of parathyroid glands is dam-
the patients with the variant of the MEN 2B syn- aged. It occurs as a complication in about 1 % of
drome tumors originate at younger age and metas- patients after the mentioned operations. The risk
tase more frequently than in those with the variant of the origin of permanent hypoparathyroidism ex-
of the MEN 2A syndrome. ists also in the patients after therapeutic subtotal
parathyroidectomy for parathyroid hyperplasia. Ac-
quired hypoparathyroidism is an extremely rare com-
plication of radioactive iodine therapy (postradia-
tion hyperparathyroidism). Its onset is generally
between 5 and 18 months after radiotherapy. Most
5.5 Pathophysiology of para- cases are associated with large doses of radioiodine
thyroid glands in the patients with Graves-Basedow disease rather
than in those with thyroid carcinoma. In the latter
hypoparathyroidism often originates after the ther-
apy by external irradiation.
Primary disorders of hormonal activity of the Spontaneous origin of hypoparathyroidism due to
parathyroid glands are rare. The pathophysiologi- organic lesion is rare. It is denoted as idiopathic
5.5. Pathophysiology of parathyroid glands 357

hypoparathyroidism. It may occur sporadically or moval of a parathyroid adenoma. It originates be-

familially. The familial form is usually manifested cause the remainder of the parathyroids is sup-
already in early childhood and the mode of its inher- pressed by preceding long-term hypercalcemia and
itance is uncertain. Sporadic variety usually begins its recovery is slow, usually occurs months after the
later. On histopathological examination lymphocyte surgery. Hypoparathyroidism of newborns (neona-
infiltration and atrophy of parathyroid parenchyma tal hypoparathyroidism) may originate by an analo-
with fatty replacement can be seen. In the sera of gous mechanism. It occurs in newborns of hypercal-
patients the presence of antibodies directed against cemic mothers or of those with mild secondary hy-
parathyroid tissue (anti-endothelial cell antibodies) perparathyroidism. These disorders in mother may
was found. These findings are the evidence of result in suppression of the parathyroid activity of
participation of autoimmunity in etiopathogenesis fetus. However, the parathyroid glands of newborns
of this variety of hypoparathyroidism (autoimmune recover their function quickly, generally within one
disease). This autoimmune form of hypoparathy- week.
roidism usually occurs as a part of the polyglandular- Functional hypoparathyroidism may be induced
autoimmune syndrome. Therefore, in patients with also by hypomagnesemia. The major effect of hypo-
this disease, or in their family members, Addison magnesemia is probably impaired PTH release (not
disease, Hashimoto thyroiditis, primary hypothy- its synthesis). Reduced responsivness to PTH may
roidism, primary hypogonadism, and type 1 dia- also contribute to hypocalcemia in patients with hy-
betes mellitus may also develop. Nonendocrine au- pomagnesemia. The possibility of secretion of bio-
toimmune diseases, such as alopecia areata, vitiligo logically inactive PTH in the origin of hypoparathy-
(with antibodies directed against melanocytes), per- roidism is admitted.
nicious anemia, and recurrent or chronic mucocuta-
Clinical picture of hypoparathyroidism depends on
neous candidiasis (resulting from a defect in cellular
the length of duration of the disease. At the onset of
immunity) may also occur in patients with idiopathic
hypoparathyroidism metabolic signs and symptoms
hypoparathyroidism and bolster the hypothesis on
of increased neuromuscular excitability are most ev-
autoimmune etiopathogenesis of this disease.
ident. Besides increased neuromuscular excitability
Any process that replaces or destroys sufficient for chronic hypoparathyroidism the most character-
amount of normal tissue of the parathyroid glands istic are psychic and neurological signs, heterotopic
may cause hypoparathyroidism. Iron storage dis- calcifications, trophic changes of skin and its ap-
ease (secondary to idiopathic hemochromatosis or pendages, and dental abnormalities.
hemosiderosis after repeated blood transfusion), Wil-
son disease (copper deposition in the parathyroids), The most evident metabolic manifestations of
metastases to the parathyroids (breast cancer is the hypoparathyroidism are hyperphosphatemia, hy-
most common primary tumor), or infiltration of the pophosphaturia, hypocalcemia, and hypocalciuria.
parathyroids in patients with sarcoidosis has been The cause of their origin is inhibition of urinary phos-
considered a rare organic cause of hypoparathy- phate excretion and decreased mobilization of cal-
roidism. cium from bones due to PTH deficiency.
A very rare form of hypoparathyroidism is due to Increase of neuromuscular excitability is related
congenital aplasia of the parathyroid glands which is to the decrease of serum total calcium concentration
manifested shortly after birth. There is a linkage be- and thereby also to the decrease of serum ionized
tween defective development of the thymus (thymic calcium concentration. Ionized calcium covers about
aplasia with resulting T cell abnormalities) and the one half of the total calcium in circulating blood,
parathyroid glands. This disorder is termed the Di- respectively in extracellular fluid. Therefore, the de-
George syndrome, and is associated with congenital crease of its concentration causes the change of pro-
cardiovascular malformations (mainly anomalies of portion of ions on outer and inner side of the cell
aortic arch) and other developmental defects. membrane, which leads to the decrease of thresh-
old of excitability, respectively to hyperexcitability
B. Functional causes. Functional hypoparathy- of nerve and muscle cells. Excitability of the whole
roidism is rarer than organic ones. It includes peripheral motor neuron, respectively neuromuscu-
transient hypoparathyroidism following surgical re- lar unit, is being increased. It is derived from the fol-
358 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

lowing simple relationship of Szent-György formula: tive symptoms, such as paresthesias (circumoral tin-
gling and numbness, ”needles and pins” feeling in
[Na+ ] + [K+ ] hands and feet), evident weakness, tensions even
Excitability = spasms of muscles when writing or walking.
[Ca ] + [Mg2+] + [H+ ]
2+

According to this formula neuromuscular ex- B. Manifest tetany. Spontaneous tetanic cramps
citability is indirect proportional to concentrations of originate due to rapid fall of calcemia below the level
calcium, magnesium, and hydrogen ions. If concen- of 1.75 mmol/L, and usually occur in attacks. This
trations of these ions in extracellular fluid decrease, degree of increased neuromuscular excitability is de-
neuromuscular excitability increases. The increase noted as manifest tetany. In the period between
of neuromuscular excitability is manifested by spon- single attacks the presence of latent tetany may be
taneous or poststimulative attacks of painful tonic proved. If the value of calcemia rapidly falls to the
contractions (convulsions) of certain groups of mus- level of 1.25 mmol/L, the tetanic attack is usually
cles which are termed tetany. The signs of increased fatal.
excitability of peripheral sensitive neuron (an origin Spontaneous tetany attack starts either without
of paresthesia, e.g., formication or numbness) and of evident cause or after emotional stress, physical
vegetative nerve (visceral tetany) may be simultane- work, or after other activity associated with hyper-
ously observed. ventilation (respiratory alkalosis due to overbreath-
Tetany is a clinical manifestation of increased neu- ing leads to depression of serum ionized calcium
romuscular excitability. Tetany due to hypoparathy- concentration). Before its origin prodromal symp-
roidism is termed parathyroprivic tetany which is toms may sometimes appear, e.g., paresthesias of
one of the types of hypocalcemic tetany. The clinical lips, tongue, and fingers and toes, feeling of tension
syndrome of tetany is manifested either by increased and stiffening of some groups of muscles, limitation
readiness to tetanic convulsions (latent tetany) or by of voluntary movements, muscle pain, or even slight
spontaneous origin of tetanic convulsions (manifest muscle twitches.
tetany). Spontaneous tetany attack may be manifested as
convulsions of only some groups of muscles or as
A. Latent tetany. In patients with increased generalized tonic cramps. Sometimes tonic-clonic
readiness to tetanic convulsions, tetanic attack may cramps may appear. The most frequent form of
be evoked by application of certain diagnostic meth- the tetany attack is a carpal spasm, which affects
ods. This subclinical degree of increased neuromus- both upper limbs. So-called obstetrical hand (main
cular excitability is termed latent tetany. It origi- d’accoucheur) due to the carpal spasm is character-
nates when calcemia is between 1.75 and 2.0 mmol/L ized by adduction and opposition of the thumb (its
(the normal range of calcemia is 2.25–2.75 mmol/L). relation to the other fingers when it is moved towards
The increased readiness to the origin of tetanic the palm), extension in interphalangeal joints, flex-
cramps may be objectively proved by gentle tapping ion in metacarpophalangeal joints, and flexion in the
over the facial nerve in front meatus acusticus exter- wrist. The cramp may affect arm muscles, too, re-
nus, which induces twitching of the muscles of the sulting in flexion in elbows. In the lower extremities
eye, nose, and mouth on the same side of the face tetany attack is manifested by the total extension of
(Chvostek sign). Alternatively, occluding the arte- the limbs with extreme plantar flexion of the foot
rial blood supply to the forearm and hand by in- and toes (a pedal spasm). The simultaneous affec-
flating a sphygmomanometer cuff (above blood pres- tion of upper and lower extremities is common. This
sure) about the arm for less than for 3 minutes in- form of spontaneous tetany attack is denoted as a
duces carpal spasm (Trousseau sign), which disap- carpopedal spasm.
pears as soon as the cuff is deflated. Due to irrita- Tonic cramps may affect also other muscle groups.
tion of peripheral nerve (median or ulnar nerve) by Tonic spasm of the upper lip causes pursy mouth
galvanic current of less intensity than 5 mA, tetanic (fish mouth). Tonic cramps of other mimic facial
convulsion of competent group of muscles originates muscles may also appear at the same time (facial gri-
(Erb sign). macing). Spasm of laryngeal muscles (laryngospasm)
Latent tetany may be also manifested by subjec- and spasm of respiratory muscles are most danger-
5.5. Pathophysiology of parathyroid glands 359

ous. They are manifested by inspiratory stridor, dys- various types may also occur. Papilledema, elevated
pnea, and cyanosis. In severe cases they may lead to cerebrospinal fluid pressure, and neurological signs
death by asphyxiation. mimicking a cerebral tumor may occur. Intracra-
Spasm of smooth muscles causes the origin of nial calcifications are visible on skull x-ray films in
symptoms of the visceral tetany. It is manifested by approximately 20 % of patients. They are most fre-
cardiospasm with dysphagia, pylorospasm, spastic quently present in the basal ganglia accompanied by
constipation, biliary colic, bronchospasm, dysuria, or a parkinsonian-like syndrome. Intracranial calcifica-
arteriolar spasm. Arteriolar spasm causes the ori- tions are rather common in cerebellum, too.
gin of Raynaud syndrome or migraine. Long-lasting In about 50 % of patients with chronic hy-
bronchospasm may cause death by asphyxiation. poparathyroidism calcification of the lens can lead
Generalized convulsions (tonic or tonic-clonic) to hypocalcemic cataract formation. Cataract may
may be the result of extremely severe cases of tetany also occur in children or young adults leading to se-
attack. The consciousness of the patient is not usu- vere disorders of vision. Correction of hypocalcemia
ally changed in the course of the attack. If the gener- by pharmacotherapy may stop its development, how-
alized convulsions are exceptionally associated with ever, it does not lead to regression of cataracts once
a loss of consciousness (especially in children) they formed. Development of calcified basal ganglia and
may remind of the epileptic seizure of grand mal cataract is probably a function of the duration of the
type. hypoparathyroid state and is more common in idio-
pathic hypoparathyroidism than in postsurgical hy-
Spontaneous tetany attack may last several sec-
poparathyroidism. The pathogenesis of heterotopic
onds, minutes, or even hours. Remissions between
calcifications in patients with permanent hypocal-
single attacks are of various duration. The attack
cemia is not menwhile known.
may withdraw spontaneously (in spastic muscles pH
In many patients with chronic hypoparathyroidism
decreases, and thereby concentration of ionized cal-
trophic changes of skin and its appendages origi-
cium increases), or it may withdraw after therapy.
nate. Skin is dry with eczematoid changes, hair
Possibility of repeating of tetany attack depends on
grows slowly and tends to fall out, and even alope-
removal of the cause of its origin, respectively on
cia may originate. Eyebrows, eyelashes, and other
proper treatment. If hypocalcemia continues, the
body hair are sparse. Uneven horizontal ridges on
signs of latent tetany are observed in the periods be-
the nails and white discoloration of the nails (leu-
tween the tetany attacks.
conychia) appear. The nails are thin, brittle, and
On the electrocardiogram persisting hypocalcemia fragile.
is manifested by prolongation of the Q-T interval Dental abnormalities occur frequently in the pa-
and by peaking T wave, or by its inversion. The Q- tients with chronic hypoparathyroidism. Depending
T interval returns to normal rapidly after correction on the age at the onset of the disease, one may find
of hypocalcemia, but T wave abnormality may be enamel hypoplasia, dental hypoplasia, defective root
slower to regress. On the electromyogram increased formation, and failure of adult teeth to erupt.
neuromuscular excitability induced by hypocalcemia
is manifested by the presence of groups of two, three,
or even more peaks (so-called duplets, triplets, or 5.5.2 Pseudohypoparathyroidism
multiplets). Pseudohypoparathyroidism (a syndrome of end-
Chronic hypoparathyroidism. Besides increased organ resistance to parathyroid hormone) is a rare
neuromuscular excitability, long-lasting nontreated hereditary disorder. Manifestations of hypoparathy-
hypoparathyroidism, likewise chronic hypocalcemia roidism are not due to PTH deficiency, but they
of any other origin, is manifested by further charac- are due to target organ unresponsiveness to PTH,
teristic clinical features. Mental changes and neuro- especially kidneys. There is no direct evidence of
logical signs are common. Anxiety, depression, emo- skeletal resistance to PTH in patients with pseudo-
tional lability, irritability, and frank psychosis may hypoparathyroidism. Serum PTH concentration is
be present in the patient. Sometimes a decrease of increased. Excessive secretion of PTH is the conse-
intellectual abilities may be observed, too. Severe quence of hyperplasia of the parathyroids, a response
headaches are quite common. Epileptic seizures of to the resistance to hormone action.
360 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

From the point of view of pathogenesis, resistance Individuals with pseudohypoparathyroidism types
to PTH might reflect defect at any multiple sites: Ia and Ib, the most common of the disorders, show a
deficient response in urinary cyclic AMP (lack of the
a) circulating antagonist of PTH action, which pre- normal brisk rise in urinary cAMP excretion) follow-
vents its binding to receptor of target organ; ing administration of exogenous PTH. This obser-
vation implies that hormone resistance in type I is
b) abnormal PTH receptor; due to a proximal defect in hormone action, presum-
ably in the receptor-adenylate cyclase complex. Pa-
c) abnormal adenylate cyclase component;
tients with pseudohypoparathyroidism type II have
d) abnormal cAMP-dependent protein kinase; a normal urinary cAMP response to exogenous PTH.
Therefore, the defect in the renal tubules appears to
e) defective protein substrate of the kinase. be distal to cAMP formation. It was suggested that
a defective cAMP-dependent protein kinase could
Defects at c, d, and e sites are on the level of be responsible, but there are no direct data on this
postreceptor mechanism. point.
Resistance of renal tubules to PTH results in hy- Clinical picture of pseudohypoparathyroidism de-
pophosphaturia, hyperphosphatemia, hypocalcemia, pends on the type of combination of the following
and hypocalciuria secondary to hypocalcemia. These four groups of symptoms:
metabolic changes are the same as those due to A. Symptoms due to resistance of renal tubules to
hypoparathyroidism. Along with reduced urinary PTH;
excretion of phosphate also insufficient hydroxyla-
tion of vitamin D in kidneys participates in the B. Somatic anomalies of type of Albright heredi-
origin of hypocalcemia. The cause of insufficient tary osteodystrophy;
renal hydroxylation of vitamin D is hyperphos-
C. Other skeletal changes;
phatemia, which is associated with inhibition of re-
nal 1-alfa-hydroxylase. This renal enzyme is nec- D. Presence of other endocrine anomalies.
essary to conversion of 25-hydroxycholecalciferol to
1,25-dihydroxycholecalciferol, which is the most ac- 1. Pseudohypoparathyroidism type Ia.
tive form of vitamin D. This tends to depress serum Essentially all subjects with this form of the dis-
calcium concentration futher by reducing intestinal order show the somatic features of Albright hered-
absorption of calcium secondary to low serum 1,25- itary osteodystrophy, such as short stature, round
dihydroxycholecalciferol level. face, short thick neck, obesity, and shortening of the
Hypocalcemia is clinically manifested by latent or metacarpals and metatarsals. The most character-
manifest tetany, which is persisting since the early istic is shortening of fourth and fifth metacarpals
childhood. Heterotopic calcifications (mainly in the (brachydactyly). The defects are usually bilateral.
basal ganglia, subcutaneous tissue, and lens) are Reduced intelligence and subcutaneous calcifications
rather common. In these patients intellectual im- are also present. Associated endocrine abnormalities
pairment is quite frequent. Some patients have ra- are common. Some, such as primary hypothyroidism
diographic evidence of excessive parathyroid action and primary hypogonadism, are usually clinically
on bones, i.e., osteitis fibrosa cystica. manifested. They probably originate due to primary
resistance of the thyroid gland and gonades to ade-
At present time four types of pseudohypoparathy- quate pituitary hormones, i.e., TSH and GTHs. It
roidism are known: is an inborn resistance to several hormones (multi-
hormonal resistance), which is due to defective G-
1. Pseudohypoparathyroidism type Ia
protein. Abnormalities of other hormones are more
2. Pseudohypoparathyroidism type Ib subtle and evident only upon provocative testing.
Pseudohypoparathyroidism type Ia is a familial dis-
3. Pseudohypoparathyroidism type II ease with an X-linked inheritance, but also the ex-
istence of either autosomal dominant or autosomal
4. Pseudopseudohypoparathyroidism recessive inheritance patterns have been identified.
5.5. Pathophysiology of parathyroid glands 361

2. Pseudohypoparathyroidism type Ib. tertiary hyperparathyroidism are distinguished. Hy-

Patients with this type of pseudohypoparathyroidism persecretion of PTH with primary hyperparathy-
have a normal phenotype without the Albright roidism does not depend on the needs of organism,
hereditary osteodystrophy syndrome. Hypocal- but production of PTH by the parathyroid glands
cemia, hyperphosphatemia, and high serum PTH is autonomous. The cause of its origin is within
level are present. Administration of exogenous PTH the parathyroid glands themselves. Oversecretion
detects the blunted urinary cAMP response. De- of PTH with secondary hyperparathyroidism is a
tailed endocrine testing has generally disclosed no compensatory response to the increased needs of
abnormality other than PTH resistance. PTH due to any condition in which there is a ten-
dency toward hypocalcemia and to calcium defi-
3. Pseudohypoparathyroidism type II. ciency in organism. During long-standing secondary
There are only few patients with this type of dis- hyperparathyroidism (most often in renal failure)
order. They manifest hypocalcemia, hyperphos- some part of hyperplastic parenchyma of parathyroid
phatemia, elevated serum PTH concentration, nor- glands may gradually escape the influence of home-
mal urinary cAMP level, but subnormal phospha- ostatic regulation by calcemia, and, therefore, secre-
turic response to PTH. These patients are normal in tion of PTH by this part of hyperplastic parenchyma
appearance, they do not have phenotypic abnormal- becomes autonomous. It may in time convert into
ities of Albright hereditary osteodystrophy. autonomous adenoma formation, usually refferred to
as tertiary hyperparathyroidism.
4. Pseudopseudohypoparathyroidism.
It is a hereditary disorder, which is uncomplete form 5.5.3.1 Primary hyperparathyroidism
of pseudohypoparathyroidism type Ia. These indi-
Primary hyperparathyroidism is a pathophysiolog-
viduals are usually first-degree relatives of patients
ical state manifesting permanent autonomous over-
with pseudohypoparathyroidism type Ia (pseudohy-
secretion of PTH by one or more parathyroid glands.
poparathyroidism type Ia is usually present in the
It is characterized by hypercalcemia and by its con-
mother of the patient). Patients with pseudopseu-
sequences, as well as by combination of symptoms
dohypoparathyroidism have the phenotypic features
resulting from renal and skeletal disorders. Mani-
of Albright hereditary osteodystrophy but without
festation of the mentioned symptoms and signs in
demonstrable metabolic abnormalities. These pa-
individual patients may be of various intensity.
tients have normal serum calcium concentration,
The most common cause of its origin is solitary
normal serum PTH concentration, and normal re-
adenoma of single parathyroid gland while the re-
sponse of urinary cAMP to exogenous PTH. For the
maining glands are normal. It occurs in about 80 %
present time it seems that the term pseudopseudo-
of cases. Parathyroid adenoma is most commonly
hypoparathyroidism should be reserved for patients
composed of the chief cells. Double or multiple ade-
meeting the following criteria:
nomas occur in about 3–5 % of patients. The sec-
(a) clear cut phenotypic features of Albright hered- ond most common cause of primary hyperparathy-
itary osteodystrophy; roidism is primary hyperplasia (chief cell hyperpla-
sia) of parenchyma of all parathyroid glands. It is
(b) first-degree relative with pseudohypoparathy- revealed in about 10–15 % of instances. Most, but
roidism type Ia; not all, of cases of primary hyperplasia are heredi-
tary and associated with other endocrine abnormal-
(c) relatively normal urinary cAMP response to ex- ities. Hereditary primary parathyroid hyperplasia is
ogenous PTH. a part of a multiglandular endocrinopathy. There
are several distinct MEN syndromes. The MEN 1
5.5.3 Hyperparathyroidism type consists of hyperparathyroidism and tumors of
the pituitary and pancreatic islet cells. Another
Hyperparathyroidism is a pathophysiological state distinct constellation of endocrinologic abnormali-
resulting from oversecretion of PTH. According to ties consists of hyperparathyroidism associated with
the mechanism of its origin primary, secondary, and pheochromocytoma and medullary carcinoma of thy-
362 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

roid (MEN 2A). Parathyroid carcinoma accounts for percalcemia is always present in patients with any
about 1–2 % of all cases of primary hyperparathy- combination of the above mentioned manifestations.
roidism though usually with severe hypercalcemia. Hypercalcemia and hypophosphatemia are the
In some patients with primary hyperparathyroidism laboratory hallmarks of primary hyperparathy-
anamnesis reveals irradiation of the neck area. The roidism. Hypercalcemia is almost always present,
increase of PTH concentration in circulating blood either sustained or intermittent hypercalcemia. Hy-
may be the result of its production in some tumors pophosphatemia does not have to be always present.
of bronchi, breast, kidneys, and thymus. This ec- The true hypophosphatemia is found in only about
topic PTH secretion is termed ectopic hyperparathy- half of cases. Therefore, it is a less reliable biochem-
roidism (paraneoplastic hyperparathyroidism). ical parameter for diagnosis than hypercalcemia.
In the past primary hyperparathyroidism was con- These both mentioned biochemical changes in cir-
sidered a very rare disease. According to the present cilating blood are the consequences of the direct
clinical experiences it is not such a rare disease as action of PTH on the skeleton and the kidneys.
considered. The prevalence of this disease is ap- Due to the increased activity of osteoclasts, calcium
proximately 1:1000. It is a prevalence approximately and phosphorus are in a higher extent released from
10-fold that ascertained in early studies of hyper- bones into extracellular fluid and circulating blood.
parathyroidism. The cause of this discrepancy is that Reabsorption of phosphate in renal tubules is de-
during medical examination of patients with other creased and that of calcium is slightly increased.
diseases the posible presence of hyperparathyroidism As a result of the mentioned changes in bones and
was not often considered, and, therefore, necessary renal tubules the increased serum concentration of
diagnostic tests were not realized (mainly hospital PTH is manifested not only by hypercalcemia and
screening of hypercalcemia). It is also due to the fact hypophosphatemia, but also by hyperphosphaturia.
that primary hyperparathyroidism is clinically mani- The total excretion of cAMP in the urine is also
fested by apparently noncharacteristic symptoms re- increased. Besides the increased release of calcium
sulting from disorders of distant organs. It is as- from bones, also the increased calcium absorption
sumed that 5 % of all cases of urolithiasis and 15– from intestine, which is secondary to the enhanced
20 % of bilateral recurrent cases of nephrolithiasis are rates of generation of 1,25-dihydroxycholecalciferol
caused by primary hyperparathyroidism. Therefore, by the kidneys in response to increased serum PTH
this disease is often revealed accidentally or as late as level, participates in the origin of hypercalcemia. In
the severe clinical symptoms suddenly appear. It is spite of slightly increased calcium reabsorption in
assumed that the number of diagnosed cases of pri- renal tubules by PTH, the content of calcium in
mary hyperparathyroidism has been still lower than glomerular filtrate due to hypercalcemia is increased
the real occurrence of this disease in population. to such extent, that it results in its increased excre-
tion into urine (hypercalciuria). However, urinary
In childhood primary heperparathyroidism is rare.
calcium is generally reduced relatively to serum cal-
The disease is most common in adults, with peak
cium level. Hypercalciuria and hyperphosphaturia
incidence between the fourth and sixth decades. It
evoke osmotic diuresis.
is more common in women (mainly after the age of
Primary hyperparathyroidism is clinically mani-
50) than in men (4:1).
fested either only by some of the following syn-
Primary hyperparathyroidism is the disease with dromes, or by their variable combination. They are
great variation in the clinical presentation. Patients the following clinical syndromes of primary hyper-
commonly remain asymptomatic for a long period, parathyroidism:
and only the finding of a mild elevation of serum
calcium may be present. Later, besides biochemi- 1. Simple hypercalcemic syndrome
cal changes in blood and urine, skeletal, renal, gas-
trointestinal, neuropsychical, neuromuscular mani- 2. Skeletal syndrome
festations, and other associated abnormalities in var-
ious combinations may be present. However, man- 3. Renal syndrome
ifestations of primary hyperparathyroidism involve
primarily the kidneys and the skeletal system. Hy- 4. Gastrointestinal syndrome
5.5. Pathophysiology of parathyroid glands 363

5. Other associated manifestations and abnormali- acute renal insufficiency, evident mental deteriora-
ties tion, altered consciousness, and coma. If the value
of hypercalcemia is above 4.0 mmol/L the patient is
in danger of so-called ”chemical death” due to asys-
1. Simple hypercalcemic syndrome (chemical hy- tole (the heart stops beating in systole).
percalcemic syndrome). It is the set of signs and
symptoms induced by hypercalcemia. The percent- 2. Skeletal syndrome. The severe bone abnormal-
age of this form of primary hyperparathyroidism has ities characteristic for primary hyperparathyroidism
been recently increasing. It is because of common ex- are also termed generalized osteitis fibrosa cystica, or
amination of several biochemical parameters, includ- sometimes denoted as von Recklinghansen bone dis-
ing also serum calcium concentration, in all clinical ease. It is the longest known syndrome of primary
patients, i.e., with any diagnosis. hyperparathyroidism. If the signs and symptoms of
If the serum calcium concentration is only slightly skeletal syndrome dominate the clinical picture, this
raised (value below 3.0 mmol/L), hypercalcemia is disease is usually denoted also as osseous form of
generally asymptomatic. If it is above 3.0 mmol/L, primary hyperparathyroidism. It originates in its
hypercalcemia evokes noncharacteristic symptoms later stage, when organ changes are already clinically
resulting from decreased neuromuscular excitability manifested. Data on the presence of skeletal syn-
and from osmotic diuresis. Decreased neuromuscu- drome in patients with primary hyperparathyroidism
lar excitability results in hypotonia of skeletal mus- rather differ. Some authors mention its 20 % occur-
cles and atonic dysfunction of gastro-intestinal tract. rence, others affirm that skeletal syndrome is present
It is manifested by generalized muscle weakness and even in 90 % of patients with this endocrinopathy.
hyporeflexia, increased tiredness, anorexia, nausea, Data accuracy on its occurrence probably depends
vomiting, meteorism, and constipation. Increased on experience and purposefulness of roentgenologist,
osmotic diuresis is manifested by polyuria (up to as well as on applying other diagnostic methods.
5 litres per day), dryness in mouth, feeling of in- The gist of skeletal syndrome origin is character-
tense thirst, and increased intake of fluid (polydip- ized partly by increased release of calcium and phos-
sia). The symptoms of hypercalcemic syndrome in- phorus from bones (bone demineralization) due to in-
clude also bradycardia, tendency to origin of arrhyth- creased bone osteoclastic resorption (particularly at
mias, shortening Q-T interval, apathy, lethargy, de- the subperiosteal surfaces), and partly by simultane-
pression, parosmias, and decrease of body weight. ous fibrous rebuilding of bone structure and the ori-
In the course of primary hyperparathyroidism gin of insufficiently calcificated osteoid tissue. Gen-
acute hyperparathyroidism (acute parathyrotoxico- eralized osteopenia is being developed gradually.
sis), which may result in hypercalcemic crisis, may On roentgenograms of long bones lamina corti-
originate. Acute hyperparathyroidism is manifested calis is thined and usually sharp cortical outline of
by sudden and expressive increase of calcium con- the bone is replaced by an irregular outline (subpe-
centration in serum and by simultaneous increase riosteal resorption). These subperiosteal resorptions
of intensity of hypercalcemic syndrome symptoms. (subperiosteal erosions, subperiosteal notching) are
Evident muscle weakness, general muscle flaccidi- patognomonic for hyperparathyroidism, and they are
ty even paralysis, expressive lethargy, depression, more frequent and expressive in patients with pri-
confusion, hallucinations, intense vomiting, evident mary than in those with secondary hyperparathy-
polyuria, great thirst, and severe dehydration ap- roidism. Bony trabeculae in the spongiosa are thick,
pear. Due to hypercalcemia between the levels 3.75– their countours are not sharp, and they form irreg-
4.0 mmol/L hypercalcemic crisis originates. It is a ular net. Acroosteolysis (resorption of bone epiphy-
life-threatening acute illness with 50 % mortality. It ses) may be also present. On radiographs it is mani-
is usually evoked by bone fracture, surgical inter- fested as disappearing of the phalangettes, proximal
vention, infectious disease, overdosage of vitamin D end of fibule and tibia, and lateral margins of clavi-
or calcium, over exposure to sun’s rays, dehydra- cles. Bone ends are nibbled-like, their countours are
tion evoked by diuretics, bleeding to hyperfunctional slightly indented.
parathyroid adenoma, or hypercalcemic pancreatitis. On roentgenograms of bones osteolytic foci are
Its clinical picture is characterized by the origin of evident. They are manifested as resorption cyst,
364 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

or cyst-like formations, and are denoted as ”brown during some activities, e.g., climbing stairs, getting
tumors” (pseudotumors). They are multiple and out of a chair, or getting into a bus or train.
are usually found as swellings on the epiphyseal-
diaphyseal border of long bones, mainly in the areas 3. Renal syndrome. It is the result of persisting
of knee, elbow, and arms. They may be also found hypercalciuria and hyperphosphaturia. If its signs
in the phalanges (especially of the hands), clavicles, and symptoms dominate the clinical picture, this
skull, patellae, and ribs. Relatively characteristic disease is usually denoted also as renal form of pri-
findings are presence of ”epulis” gigantocellularis of mary hyperparathyroidism. Renal syndrome is char-
the jaw and presence of the resorption of the lamina acterized mainly by the presence of nephrolithiasis,
dura of the teeth. Brown tumors are the areas in nephrocalcinosis, and by their complications.
which quantities of osteoclasts (they are multinucle- Nephrolithiasis is usually recurrent and occurs in
ated giant cells, probably originating by transforma- about 60–80 % of the patients with hyperparathy-
tion of tissue macrophages), osteoblasts and fibrob- roidism, and it is bilateral in about 20 % of them.
lasts are gathered, and in which signs of bleeding There is usually a larger number of renal stones
are often present. The brown color of this reactive and they are usually composed of either calcium ox-
lesion is the result of the hemorrhage, hemosiderin alate or calcium phosphate. Correlation has been
deposition, and vascularity. Frequently these lesions reported between 1,25-dihydroxycholecalciferol con-
undergo cystic degeneration. centrations in plasma and nephrolithiasis in patients
Histologically, the pathognomonic features are a with primary hyperparathyroidism. Renal colic is
reduction in the number of trabeculae, an increase one of the most common symptoms of hyperparathy-
of numbers of the giant multinucleated osteoclasts, roidism, sometimes it may be the first symptom of
proliferation of osteoblasts and fibroblasts, and a hyperparathyroidism. Repeated episodes of renal
replacement of the normal cellular and marrow el- colic or the formation of large calculi may lead to uri-
ements by fibrous tissue. Bone resorption as well nary tract infections (mainly pyelonephritis or inter-
as formation is, therefore, increased. The increased stitial nephritis), which usually appears recurrently.
bone formation is evidenced by increased osteoblast Nephrocalcinosis due to primary hyperparathy-
numbers and islands of newly formed bone tissue roidism is not so common as nephrolithiasis. It oc-
(unmineralized osteoid). Because osteoclast activ- curs in about 7 % of the patients. It originates by
ity exceeds osteoblast activity, the net result is bone deposition of calcium salts in parenchyma of the kid-
resorption. Histomorphometric analyses of biopsied neys (in distal tubules, renal papillae, and medullary
bone reveal an abnormality in bone turnover in most pyramids). Nephrocalcinosis may be evident on x-
patients, even in those who do not have a progressive ray films of the kidneys as multiple granular, lumpy,
loss of net bone mass. The progressive loss of bone or cloud-like small shadows.
mineral mass causes osteopenia.
4. Gastrointestinal syndrome. It is characterized
In more advanced stage of the disease pathologi- by symptoms of gastric or duodenal ulcer, acute or
cal fractures (spontaneous fractures) of bones may chronic pancreatitis, probably cholelithiasis as well.
originate as a result of the changes associated with Peptic ulcer occurs in about 15 % of patients with
skeletal syndrome. The most frequent pathological hyperparathyroidism. It is most frequently localized
fractures of neck of femur, some vertebrae, and some in the duodenum. It is 5 times more frequent in pa-
of pelvic bones may appear. Bone deformations are tients with hyperparathyroidism than in the rest of
quite common because bones become softer due to population. It is assumed that stimulation of gas-
production of insufficiently calcified osteoid tissue. trin secretion and an increase in gastric acid secre-
Most often they appear on lower limbs, chest, and tion participate in its origin. Symptoms of peptic ul-
pelvic bones. Due to kyphoscoliosis the stature of cer in patients with hyperparathyroidism are severer
the patient may shorten. than those in patients without hyperparathyroidism.
The mentioned skeletal changes are subjectively Peptic ulcer in patients with hyperparathyroidism is
manifested by gradating diffuse bone pain, mainly in more resistant to usual treatment and its recidiva-
spine, sacral area (sacralgia), hip joint, symphysis, tion is more frequent. Pancreatitis occurs in about
and lower extremities. The pain is more expressive 7–12 % of patients with hyperparathyroidism and its
5.5. Pathophysiology of parathyroid glands 365

recidivation is also more frequent. The cause of its and of compensatory hypersecretion of PTH, which
coincidence with hyperparathyroidism as well as its originates due to pathological state associated with
pathogenesis are unknown. long-lasting tendency to hypocalcemia. It is a reg-
ulatory response of the parathyroid glands to long-
5. Other associated manifestations and abnor- lasting negative balance of calcium in organism. Hy-
malities. Some of them are secondary to hypercal- perplasia of the chief cells is diffuse and occurs in all
cemia itself, but pathogenesis of many of them is parathyroid glands. The aim of secondary increased
unknown. They are usually not pathognomonic for serum PTH concentration is to prevent the origin of
hyperparathyroidism. hypocalcemia via the increased releasing of calcium
Psychical and neurological manifestations include from bones.
emotional lability, poor memory, slow mentation, ap- Etiology and pathogenesis. Long-lasting disorder
athy, somnolence, depression, paranoid features, and of calcium and phosphorous homeostasis in organ-
neuromuscular abnormalities. Intensity of the psy- ism, and thereby long-lasting tendency to the origin
chical disorder depends on the level of calcium in of hypocalcemia develops mainly due to the poor in-
circulating blood. Neurological symptoms are also testinal calcium absorption, phosphate retention in-
variable. The most evident of them are headache, duced by renal disorders, and increased urine excre-
somnipathies, parosmias, dysesthesias, and neural- tion of calcium.
gias. Muscular symptoms include easy fatigability,
The most frequent cause of secondary hyper-
muscle weakness, muscle hypotony, myalgias, and
parathyroidism is chronic renal failure. Secondary
postdenervational muscle atrophy which is due to
hyperparathyroidism is rarely evoked by some in-
neuropathy.
born tubulopathies (renal tubular acidosis and Fan-
The best known of cardiovascular symptoms are
coni syndrome). Though in the patients with tubu-
bradycardia, arrhythmias, shortening of the Q-T in-
lopathy considerable demineralization of bones origi-
terval on the electrocardiogram, arterial hyperten-
nates, hyperfunction of the parathyroid glands is of a
sion, and increase response of a heart to digitalis.
milder degree. Overproduction of PTH due to renal
Hematological symptoms include anemia and ele-
disorders is termed renal form of secondary hyper-
vated erythrocyte sedimentation rate.
parathyroidism.
Long-lasting hypercalcemia is associated with the
origin of subconjunctival and corneal calcifications. Pathogenesis of PTH oversecretion in patients
Corneal calcification is manifested as band keratopa- with chronic renal insufficiency is complex. Chronic
thy, which is recognized as opaque material in par- renal failure results in phosphate retention and hy-
allel lines within the limbus of the eyes. Arthralgias perphosphatemia. Phosphate retention is a conse-
and hypermobility of the joints also have been de- quence of the decreasing filtered load of phosphate as
scribed. Disorders of many organs resulting from glomerular filtration rate falls. This causes a recip-
long-standing hypercalcemia are also due to deposi- rocal fall in plasma calcium which, in turn, provokes
tion of calcium into various tissues. These deposits increased release of PTH. The result is normalization
of calcium are termed ectopic calcifications. They of plasma calcium concentration and increased phos-
may appear mainly in lungs, kidneys, wall of arter- phaturia, such that plasma phosphate also returns
ies (especially in the media), pancreas, myocardium, to normal. Thus, with each decrement in glomerular
gastric mucosa, subcutis of periarticular area, and filtration rate, a new steady state is reached with nor-
skin. Microscopic deposits of calcium within the skin mal plasma concentration of calcium and phosphate,
are presumably the cause of pruritus. Deposits of but only at the expense of secondary hyperparathy-
calcium in parenchyma of kidneys, cornea, and sub- roidism. The parathyroids compensate so well for the
conjunctival area are also considered as ectopic cal- alterations in calcium and phosphorous homeosta-
cifications. sis as renal function declines, that overt hyperphos-
phatemia develops only when glomerular filtration
rate falls to 25 ml/min. Hyperphosphatemia results
5.5.3.2 Secondary hyperparathyroidism
in decreased activity of renal 1-alfa-hydroxylase,
Secondary hyperparathyroidism is the state of com- and thereby in decreased production of 1,25-
pensatory hyperplasia of all four parathyroid glands dihydroxycholecalciferol (vitamin D3 ). Reduced for-
366 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

mation of 1,25-dihydroxycholecalciferol is also the in the patients with chronic renal failure. Unlike the
result of damaged and shrunken parenchyma of patients with primary hyperparathyroidism, in the
the kidneys. Low serum 1,25-dihyroxycholecalciferol patients with secondary hyperparathyroidism serum
concentration leads to a reduction of intestinal ab- calcium concentration is slightly decreased, some-
sorption of calcium. Concentration of PTH in cir- times even normal, and serum phosphate concen-
culating blood increases also due to decreased renal tration is increased. The symptoms of uremia are
clearance of PTH, which is caused by expressively also present. The skeletal abnormalities include os-
decreased glomerular filtration rate. It is assumed teitis fibrosa cystica (caused by the excessive ac-
that a further contributing factor to hypocalcemia is tion of PTH on bones), osteomalacia (caused by
relative skeletal resistance to PTH. impaired formation of 1,25-dihydroxycholecalciferol
Another, but less common cause of secondary hy- and by calcium deficiency), and generalized osteope-
perparathyroidism is vitamin D deficiency. Com- nia. These bone abnormalities in patients with sec-
pensatory PTH oversecretion is due to hypocal- ondary hyperparathyroidism induced by chronic re-
cemia, which originates as a result of insufficient nal failure are usually termed renal osteodystrophy.
intestinal calcium absorption. This reduced cal- Its expressive manifestations develop mainly in pa-
cium absorption is caused by undeproduction of tients undergoing chronic hemodialysis. In this sub-
its protein carrier in enterocytes. Decreased pro- jects generalized osteopenia may lead to a develop-
duction of this high-affinity calcium-binding protein ment of multiple pathological fractures. Any of the
of intestinal mucosal epithelia is induced by vita- classic lesions of primary hyperparathyroidism can
min D deficiency (its active hormonal form, i.e., also occur, although bone cysts are less common.
1,25-dihydroxycholecalciferol), By PTH oversecre- Clinically, osteodystrophy causes bone pain. In ad-
tion hypocalcemia is being normalized. By simulta- dition, proximal muscle weakness may be similar to
neous decreased reabsorption of phosphates in renal that in primary hyperparathyroidism.
tubules (due to increased serum PTH level) hyper- The clinical features of rickets develop with vita-
phosphaturia and hypophosphatemia develop. min D deficiency in infancy or childhood. Vitamin D
deficiency in the adults evokes the origin of the clin-
The third main cause of secondary hyperparathy- ical features of osteomalacia.
roidism is intestinal calcium malabsorption. Most
commonly it originates due to intestinal lipid malab-
sorption caused by pancreatic lipase and bile acid de-
ficiency, celiac sprue (gluten-induced enteropathy),
and tropical sprue. Nonabsorbed fatty acids together
with calcium form insoluble calcium soaps, and, 5.6 Pathophysiology of the
therefore, excessive intestinal calcium loss appears. adrenal glands
Decreased intestinal calcium absorption is also in-
duced by fat-soluble vitamin D deficiency which is
in patients with intestinal fat malabsorption caused
by its insufficient intestinal absorption. The suprarenal glands are composed of two de-
Clinical features. The clinical features of sec- velopmentally, morphologically, and functionally dif-
ondary hyperparathyroidism are analogous to those ferent parts, the cortex and the medulla. Cortical
of primary hyperparathyroidism, however, usually tissue is derived embryologically from the celomous
milder. Nephrolithiasis and nephrocalcinosis are mesoderm. Histologically it consists of three zones
less common in the patients with secondary hy- (zonae glomerulosa, fasciculata, and reticularis) and
perparathyroidism. Ectopic calcifications appear produces three kinds of functionally different cor-
mainly in subcutis, tissues of periarticular area, and ticosteroid hormones: glucocorticoids, mineralocor-
in the wall of arteries. Besides the symptoms re- ticoids, and androgens, and in small amounts also
sulting from PTH overproduction, also the symp- estrogen and progesterone. Medullary tissue is de-
toms of primary disease which gives rise to the dis- rived embryologically from neuroectoderm. Histolog-
order of calcium homeostasis may be observed. The ically it is rather homogenous and consists of chro-
symptoms of primary disease are the most evident maffin cells. The medulla produces catecholamines
5.6. Pathophysiology of the adrenal glands 367

(adrenaline, noradrenaline, and dopamine), the most by deficiency of all three types of corticosteroid hor-
important being adrenaline. The adrenal medulla mones due to gradually developing destruction of all
and the sympathetic nervous system make up an three zones of adrenal cortex. As the functional re-
anatomical and physiological unit that is often re- serve of adrenal cortex is large, deficiency of its hor-
ferred to as the sympathoadrenal system. mones clinically appears not until at least 90 % of the
functioning cortical cells have been destroyed. Ini-
tially secretion of adrenocortical hormones is enough
5.6.1 Pathophysiology of the adrenal for covering basal requirements of organism, how-
cortex ever, it is insufficient in the situations of increased
demands of body tissues. Therefore, it is clinically
There are two basic types of disorders of adrenal
revealed only during various situations associated
cortex, adrenocortical hypofunction and adrenocor-
with stress. In this stage of decreased adrenal re-
tical hyperfunction. According to the primary place
serve the disease is denoted as relative adrenocor-
of their origin the following types of disorders may
tical insufficiency (mild adrenocortical insufficiency
be distinguished: primary adrenocortical hypofunc-
that results only in inadequate cortisol increase in
tion or hyperfunction (the cause of these disorders is
response to stress). If the signs and symptoms of
within the adrenal cortex itself), secondary adreno-
adrenocortical hormone deficiency appear already at
cortical hypofunction or hyperfunction (the cause of
rest (severe adrenocortical insufficiency), it is de-
these disorders is in the adenohypophysis), and ter-
noted as absolute adrenocortical insufficiency. Ad-
tiary adrenocortical hypofunction or hyperfunction
dison disease may occur at any age, more often in
(the cause of these disorders is in the hypothalamus).
adults between 20 and 50 years of age, and usually
affects more frequently women than men (2–3:1).
5.6.1.1 Hypofunction of the adrenal cortex
Etiology and pathogenesis. Addison disease re-
Adrenocortical hypofunction includes all conditions sults from progressive bilateral adrenocortical de-
in which adrenal steroid hormone secretion falls be- struction, which must involve more than 90 % ot the
low the requirements of the body tissues. Isolated parenchyma of the glands before signs and symptoms
primary deficiency only of some kind of corticosteroid of adrenocortical insufficiency appear. Tuberculous
hormones is very rare. At present only primary hy- adrenalitis was once the most common cause of Ad-
poaldosteronism is known. Secondary hypoglucocor- dison disease. Now it accounts for about 20 % of
ticoidism resulting from isolated ACTH deficiency cases. The adrenal involvement is almost always a
or from its deficiency due to panhypopituitarism (a hematogenous dissemination from an active primary
deficiency of all adenohypophyseal hormones) is also disease elsewhere in the body, most often the lungs
known. Tertiary hypoglucocorticoidism is quite com- but sometimes the genitourinary tract. With tuber-
mon and originates as a result of inhibition of CRH culous adrenalitis the cortex and also the medulla
secretion, respectivelly as a result of suppression of are involved resulting in loss of all three types of cor-
hypothalamic-adenohypophyseal function by chronic ticoid hormones and catecholamines.
administration of pharmacological dosages of gluco-
Today, the most common cause of Addison disease
corticoids. Deficiency of all kinds of corticosteroid
is autoimmune adrenalitis which accounts for about
hormones (adrenocortical insufficiency) is more com-
75 % of cases. Autoimmune adrenalitis was previ-
mon, deficiency of glucocorticoids and mineralocorti-
ously known as idiopathic chronic primary adreno-
coids is decisive. According to clinical course chronic
cortical insufficiency. It is characterized by destruc-
and acute adrenocortical insufficiency may be distin-
tion of glandular cells of parenchyma (diffuse atro-
guished.
phy) of all three zones, by diffuse lymphocytic in-
filtration and fibrosis of the cortex. An autoim-
I. Chronic primary adrenocortical insufficien- mune process destroys exclusively the cortex, the
cy adrenal medulla is unaffected. Circulating antia-
Chronic primary adrenocortical insufficiency (Addi- drenal antibodies that react with all three zones of
son disease) is a rare disease occurring in about 0.03– the adrenal cortex are present in 60–70 % of patients
0.04 per mille of adult population. It is induced with autoimmune adrenalitis. Besides humoral im-
368 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

munity, cell-mediated immune processes may also anemia, chronic active hepatitis, alopecia, primary
be important in the development of adrenocortical hypothyroidism, and primary hypogonadism. This
insufficiency. Decreased suppressor T lymphocyte syndrome is rare and usually presents during child-
function has been described in patients with idio- hood. It is inherited in an autosomal recessive pat-
pathic adrenocortical insufficiency. There is a well- tern, in which females are affected slightly more than
defined increased incidence of certain histocompati- men, but there is no HLA association. Type II
bility antigens in patients with autoimmune adrenali- polyglandular autoimmune syndrome marked by co-
tis, particularly HLA-DR3, HLA-DR4 and HLA-B8, existence of adrenocortical insufficiency, chronic lym-
suggesting some genetic predisposition. phocytic thyroiditis, type 1 diabetes mellitus, and
The presence of antiadrenal antibodies seems to primary hypogonadism, sometimes accompanied by
precede the development of adrenocortical insuffi- nonendocrine autoimmune disorders, such as vitiligo,
ciency by several years. The first sign of adrenocorti- myasthenia gravis, immune thrombocytopenic pur-
cal insufficiency is an increase in plasma renin activ- pura, rheumatoid arthritis and Sjögren’s syndrome.
ity in association with a normal or low serum aldos- The type II is the more common polyglandular syn-
terone level, which suggests that the zone glomeru- drome than type I and usually expressed in adult-
losa is affected initially. After several months to hood. Women are affected three times more fre-
years, zone fasciculata dysfunction becomes evident, quently than men. About half of the type II cases
first by a decreased plasma cortisol response to are familial, but various modes of inheritance (auto-
ACTH, later by an increased basal plasma ACTH somal recessive, autosomal dominant, or polygenic)
level, and finally by a decreased plasma cortisol con- have been reported. Polyglandular autoimmune syn-
centration and overt symptoms. drome type III is not associated with adrenocortical
insufficiency.
In about half of patients with autoimmune
adrenalitis, the adrenal is the sole target of the au-
Rarely, other lesions can involve the adrenal
toimmune reaction (isolated autoimmune adrenocor-
glands and cause chronic primary adrenal insuffi-
tical insufficiency), but in the remainder, other en-
ciency, such as disseminated fungal infections (histo-
docrine glands are concomitantly affected. In the
plasmosis, blastomycosis, and coccidioidomycosis),
patients of the latter also antibodies against tissue
bilateral infiltration by metastatic cancer as well as
of other endocrine glands are usually present, and
by malignant melanomas and lymphomas, bilateral
also other types of antibodies related to involvement
amyloidosis, sarcoidosis, hemochromatosis, or bilat-
to some of nonendocrine organs or tissues may be
eral total adrenalectomy. This rare lesions of the
found. These disorders associated with autoimmune
adrenal glands cause only about 5 % of all cases of
adrenocortical insufficiency are referred as polyglan-
Addison disease.
dular autoimmune syndrome (autoimmune adreno-
cortical insufficiency associated with polyglandular
Addison disease is characterized by an insidious
autoimmune syndrome). The polyglandular autoim-
onset of slowly progressive nonspecific signs and
mune syndromes have been subdivided into three
symptoms. The most common of them are fatiga-
types, but only the type I and the type II are associ-
bility, tiredness, chronic weakness, lassitude, general
ated with autoimmune adrenocortical insufficiency.
malaise, anorexia, nausea, vomiting, weight loss, cu-
Autoimmune adrenocortical insufficiency may be taneous and mucosal hyperpigmentation, arterial hy-
familial or nonfamilial. It is less likely to be famil- potension, and occasionally hypoglycemia. All the
ial when it occurs alone, whereas about one half of mentioned nonspecific manifestations, besides hyper-
patients with adrenocortical insufficiency as a part pigmentations, are the direct consequence of glu-
of polyglandular autoimmune syndrome type I or II cocorticoid and mineralocorticoid deficiencies. In
have positive family histories. women the symptoms due to deficiency of adrenal
Polyglandular autoimmune syndrome type I repre- androgens also gradually appear. Therefore, the clin-
sents the combination of adrenocortical insufficiency, ical picture of frank Addison disease is formed by
primary hypoparathyroidism and chronic mucocuta- signs and symptoms resulting from deficiency of all
neous candidiasis. Other autoimmune diseases in three kinds of corticosteroid hormones, as well as by
these patients include nontropical sprue, pernicious those secondary to compensatory hypersecretion of
5.6. Pathophysiology of the adrenal glands 369

ACTH and other proopiomelanocortin-derived pep- ponatremia is due to both loss of sodium into the
tides (POMC peptides). urine and movement into the intracellular compart-
The generalized weakness, tirednes and fatigabil- ment. The hyperkalemia is due to a combination of
ity are in the early phase of gradual primary adreno- aldosterone deficiency, impaired glomerular filtration
cortical insufficiency transient and appear only af- rate, and acidosis. Extravascular sodium loss deplets
ter increased physical or psychical stress. They be- extracellular fluid volume, reduces circulating blood
come gradually more intensive and in more advanced volume, and accentuates hypotension. Initially only
stages of chronic adrenocortical insufficiency they be- postural hypotension may be evident, but later in
come permanent. The patient is continuously fa- most patients the blood pressure is low permanently
tigued, necessitating bed rest. Diffuse myalgias and and is usually associated with postural dizziness or
arthralgias are also common. syncope. The electrocardiogram may show nonspe-
cific changes of the T wave, QRS complex, and QT
Abnormalities of gastrointestinal functions are
interval. Hyperkalemic cardiac arrhythmias may
often the presenting complaint. Gastrointestinal
also occur.
symptoms vary from mild anorexia, occasional vom-
iting, weight loss, abdominal pain, and diarrhea that Mild to moderate eosinophilia, relative lymphocy-
may alternate with constipation, to fulminating nau- tosis, and anemia are common. The normocytic, nor-
sea, vomiting, diarrhea, and ill-defined abdominal mochromic anemia, which may initially be masked
pain, which may also be so severe as to be confused by hemoconcentration, is probably a direct effect
with an acute abdomen. The mechanism of these of glucocorticoid deficiency. Some patients have
gastrointestinal disorders is not exactly known. De- also neutropenia, which is presumably caused by in-
creased production of gastric acid and decreased ac- creased sequestration of neutrophils in the marginal
tivity of pepsin and other gastrointestinal enzymes pool. Splenomegaly and lymphoid tissue hyperpla-
are considered to participate. It is assumed that sia, particularly of the tonsils, may occur.
the deficiency of glucocorticoids and mineralocorti-
Hyperpigmentation of the skin and mucous mem-
coids are responsible for the origin of gastrointestinal
branes, which is evident in most patients with
symptoms. The wight loss (asthenia) is due mostly
chronic primary adrenocortical insufficiency, is one
to anorexia but partly to dehydration. Intensity of
of the characteristic physical findings. It is caused
gastrointestinal symptoms correlates with the sever-
by an increased content of melanin in the skin, which
ity of adrenocortical insufficiency.
is thought to be due to the melanocyte-stimulating
The loss of gluconeogenic effect of cortisol is man- activity of the increased circulating proopiome-
ifested by the origin of hypoglycemia which ap- lanocortin (POMC) peptide level (POMC peptide
pears mainly after prolonged fasting (usually in is precursor of ACTH, MSH and beta-lipotropin).
the morning) or, rarely, several hours after a high- ACTH, MSH and beta-lipotropin have probably a di-
carbohydrate meal. As the secretion of insulin is rect effect on epidermal melanocytes as well. The re-
normal, contraregulatory effect of cortisol is miss- sulting hyperpigmentation is generalized and it com-
ing in these situations. Hypoglycemia is infrequent monly appears as brown, tan, or bronze darkening
in adults, but in children with primary adrenocor- of the skin, particularly of sun-exposed areas, such
tical insufficiency is common. In adults it usually as the face, neck, and backs of the hands, and areas
appears after infection, fever, or alcohol ingestion. exposed to chronic mild trauma or pressure, such
Hypoglycemia is thought to be due to increased pe- as the elbows, knees, knuckles, spine, waist (belt),
ripheral glucose utilization associated with increased and shoulders (brassiere straps). Unlike the inso-
sensitivity to insulin and impairment of gluconeoge- lation, hyperpigmentation is also prominent in the
nesis, hepatic glucose production, and glycogen syn- palmar and finger creases, and in areas that are com-
thesis. Patients with chronic adrenal insufficiency monly hyperpigmented, such as the arealae and per-
may tolerate greater degree of hypoglycemia without ineum. Bluish black patchy buccal pigmentation oc-
developing symptoms. Therefore, the development curs on the inner surface of lips and the buccal mu-
of hypoglycemic coma is rare. cosa along the line of dental occlusion, the site of
Deficiency of mineralocorticoids is the cause of the repeated trauma. It may also occur on or under the
origin of hyponatremia and hyperkalemia. The hy- tongue, along the gingival border, and on the hard
370 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

palate. Scars acquired during untreated Addison dis- exhibit extreme sensitivity to some drugs, such as
ease are permanently pigmented. Scars acquired be- narcotics, anesthetics, and sedatives.
fore the onset of primary adrenocortical insufficiency Untreated Addison disease has usually slow and
remain unpigmented, and those acquired after treat- progressive clinical course and in its final stage acute
ment do not become pigmented. adrenal insufficiency (adrenal crisis) may develop.
The hair and nails may become darker, the nails However, if this disease is adequately treated, it has a
showing longitudinal bands of darkening. Darker favourable prognosis, especially if the physician man-
nails are due to hyperpigmentation of nail-bed. ages also therapy of intercurrent infections and other
Patchy, often bilaterally symmetrical areas of de- stress situations.
pigmented skin (vitiligo) occur on the trunk or ex-
tremities in 10 to 20 % of patients with autoimmune II. Secondary and tertiary adrenocortical in-
adrenocortical insufficiency. Their surroundings is sufficiency
hyperpigmented. Secondary adrenocortical insufficiency is due to
Psychiatric symptoms are present in most patients insufficient pituitary ACTH secretion and subse-
with severe or long-lasting Addison disease. Patients quent insufficient adrenal cortisol secretion. Tertiary
frequently have personality changes, usually exces- adrenocortical insufficiency results from deficient hy-
sive irritability, negativism, social withdrawal, hal- pothalamic secretion of CRH and subsequent pitu-
lucinations, and paranoid delusions. Sometimes ap- itary ACTH hyposecretion.
athy, depression, lack of initiative, and impairment
of memory that can progress to confusion, delirium, Chronic secondary adrenocortical insufficiency
and stupor, occur.
Chronic secondary adrenocortical insufficiency re-
Deficiency of androgens is clinically manifested lated to natural causes, like chronic primary adreno-
only in women, because the decisive source of an- cortical insufficiency, is also uncommon. ACTH de-
drogens in them are the adrenal glands. Decreased ficiency may rarely occur alone, but in common in-
axillary and pubic hair and loss of libido are typ- stances, it is only one part of panhypopituitarism.
ical. In about 25 % of women with Addison dis- Etiology and pathogenesis. Any process that
ease secondary amenorrhea may occur and it may involves the adenohypophysis and interferes with
be due to the effects of chronic illness, weight loss, the ability to secrete ACTH may cause secondary
or autoimmune-mediated primary hypogonadism. adrenocortical insufficiency. Large pituitary tumors
Basal concentrations of plasma cortisol and aldos- or craniopharyngiomas, lymphocytic hypophysitis,
terone are subnormal and fail to increase following head trauma, infectious diseases (such as tuberculo-
ACTH administration. ACTH and other POMC- sis or histoplasmosis), infiltrative diseases, pituitary
derived peptides, such as beta-lipotropin, are ele- metastases, large intracranial artery aneurysms, and
vated. The serum testosterone level is normal in pituitary infarction can destroy the pituitary tis-
men, because it is produced largely by the testes, sue. In these patients secondary adrenocortical in-
but is low in women, in whom it is derived almost sufficiency occurs in association with multiple pi-
entirely from peripheral conversion of adrenal andro- tuitary tropic hormone deficiencies (panhypopitu-
gens. The volume depletion resulting from aldos- itarism). ACTH deficiency may also be selective.
terone deficiency causes increased plasma renin con- However, this isolated ACTH deficiency is rare. The
centration and activity. Glucocorticoid deficiency re- defect probably is at the pituitary level because there
duces angiotensinogen level, but plasma concentra- is no ACTH-secretory response to CRH, as usu-
tion of angiotensin II is increased and, because of ally occurs in hypothalamic disorders. Selective cor-
a direct peripheral vasoconstriction effect, plays an ticotrope absence (their atrophy due to anticorti-
important role in maintaining blood pressure in Ad- cotrope antibodies) and disability of corticotropes to
dison disease. respond to CRH stimulation are considered.
The patients with Addison disease have dimin- In secondary adrenocortical insufficiency, cortisol
ished resistance to infections and other stress situ- production is inadequate because of deficient pitu-
ations. The course of intercurrent infection in them itary ACTH secretion. As a result of decreased corti-
is severer than in healthy subjects. Patients may sol negative feedback inhibition, hypothalamic CRH
5.6. Pathophysiology of the adrenal glands 371

synthesis and secretion and plasma CRH concentra- cause tertiary adrenocortical insufficiency. Such pro-
tions are increased. The clinical presentation is one cesses include tumors, infiltrative diseases (e.g., sar-
of pure glucocorticoid deficiency and, in women, loss coidosis), and cranial irradiation. In patients with
of adrenal androgen secretion. Because ACTH secre- primary pituitary deffect, the ACTH-secretory re-
tion is decreased, patients are not hyperpigmented. sponse to CRH is inappropriately low or absent,
Mineralocorticoid secretion usually remains normal whereas in those with primary hypothalamic defect,
because it is regulated by the renin-angiotensin sys- this response is usually exaggerated and prolonged.
tem. Suppression of hypothalamic-pituitary-adrenal
As in a patient with chronic primary adrenocor- function by chronic administration of pharmacolog-
tical insufficiency, the development of chronic sec- ical dosages of glucocorticoids is the most common
ondary adrenocortical insufficiency is usually grad- cause of tertiary adrenocortical insufficiency (iatro-
ual, going first through a stage of partial (relative) genic tertiary adrenocortical insufficiency). It de-
ACTH deficiency that results only in inadequate creases CRH synthesis and secretion from the hy-
ACTH and cortisol responses to stress. With pro- pothalamus and blocks its tropic and secretagogue
longed and more profound ACTH deficiency, the actions on the pituitary corticotropes. This results
adrenal fasciculata and reticularis atrophy and lose in decreased synthesis of ACTH by the anterior pitu-
their ability to respond acutely to ACTH. Depend- itary corticotropes, which decrease in size. Eventu-
ing on the extent of ACTH lack, the adrenals may ally, the number of corticotropes decreases. There-
be moderately to markedly reduced in size. However, fore, plasma ACTH concentration is low. In the ab-
the adrenal cortex can recover the ability to produce sence of ACTH stimulation, the adrenal zonae fas-
cortisol in response to continuous maximal ACTH ciculata and reticularis atrophy and can no longer
stimulation over a period of a few days to a week. secrete glucocorticoids and androgens. However, the
The clinical features of chronic secondary adreno- adrenals retain nearly normal mineralocorticoid se-
cortical insufficiency are similar to those of chronic cretion. If chronic administration of glucocorticoids
primary adrenocortical insufficiency with two major suddenly stops, acute adrenocortical insufficiency
exceptions. First, hyperpigmentation is not present may originate.
because plasma ACTH and other POMC peptides
concentrations are not increased. On the contrary, Tertiary adrenocortical insufficiency also occurs
plasma ACTH and related peptide levels are low, in those patients who are cured of Cushing’s syn-
which may be manifested by hypopigmentation or drome by removal of a pituitary or nonpituitary
depigmentation of skin. Therefore, the skin may ACTH-secreting or adrenal cortisol-secreting tumor,
have alabaster pale local colour. Second, dehydra- but who are left without an adequate cortisol ther-
tion and hyperkalemia are not present. apy. The chronic endogenous hypercortisolemia sup-
Weakness, fatigability, myalgias, arthralgias, and presses the hypothalamic-pituitary-adrenal axis in
psychiatric changes are as common as in chronic the same manner as exogenous glucocorticoids.
primary adrenocortical insufficiency, indicating that The clinical features and the laboratory findings
most of these symptoms are due to glucocorticoid of chronic tertiary adrenocortical insufficiency are
rather than mineralocorticoid deficiency. However, nearly similar to those of chronic secondary adreno-
gastrointestinal symptoms are less common, suggest- cortical insufficiency.
ing that electrolyte disturbances may be involved in
their etiology. Hypoglycemia occurs more frequently
III. Acute adrenocortical insufficiency
in chronic secondary adrenocortical insufficiency. In
Acute adrenocortical insufficiency (adrenal crisis,
these patients secondary adrenocortical insufficiency
Addisonian crisis) is a life-threatening acute illness,
often occurs in association with signs and symp-
which requires prompt adequate therapy. It is an
toms of hyposecretion or sometimes hypersecretion
uncommon clinical state that may appear as a result
of other anterior pituitary hormones.
of several processes, as folows:
Chronic tertiary adrenocortical insufficiency 1. In patients with chronic primary adrenocortical
Any process that involves the hypothalamus and insufficiency precipitated by any form of stress
interferes with CRH biosynthesis and secretion can that requires an immediate increase in corticos-
372 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

teroid hormone output from adrenals incapable Adrenal crisis may also occur as a result of sud-
of responding. den hemorrhagic destruction of both adrenal glands.
Extensive hemorrhages are usually present within
2. As a result of some massive destruction of pa-
the cortex and the medulla. These patients do not
renchyma of both adrenal glands by hemorrha-
have evidence of pre-existing chronic adrenocorti-
ge or acute ischemia in subjects without chronic
cal insufficiency. In children this is usually associ-
primary adrenocortical insufficiency.
ated with septicemia with Pseudomonas aeruginosa
3. In patients with chronic secondary adrenocor- or meningococcemia (Waterhouse-Friderichsen syn-
tical insufficiency precipitated by any form of drome). The basis for the adrenal hemorrhage in
major stress. patients with Waterhouse-Friderichsen syndrome is
uncertain but could be attributed to direct bacte-
4. From too rapid withdrawal of corticosteroid
rial seeding of small vessels in the adrenals, the de-
therapy in patients whose adrenals have been
velopment of disseminated intravascular coagulation
suppressed by long-term corticosteroid admin-
(DIC), endotoxin-induced vasculitis, or some form of
istration (patients with chronic tertiary adreno-
hypersensitive vasculitis. Because other small vessels
cortical insufficiency), or from failure to increase
in organism are affected as well, widespread purpura,
the level of administered steroids during stress
particularly of the skin, is also present. Occasionally
in a bilaterally adrenalectomized patient.
extensive bilateral adrenal hemorrhage in neonates
Acute adrenocortical insufficiency is most common results from prolonged and difficult delivery, with
in the patients with chronic primary adrenocortical considerable birth trauma and hypoxia. Newborns
insufficiency who have been subjected to infection, are particularly vulnerable because they are often
trauma, surgical intervention, or other stress. Its deficient in prothrombin for at least several days af-
clinical picture is developed in the course of several ter birth. In adults, anticoagulant therapy (espe-
hours or days. Intensive nausea, vomiting, diarrhea, cially in postsurgical patients who develop DIC), or
weakness, fatigue, and lethargy appear from the be- a coagulation disorder may result in massive bilat-
ginning. Later, nausea, vomiting, diarrhea, and ab- eral adrenal hemorrhage. Hemorrhage has been very
dominal pain may become intractable. Repeated in- rarely observed following adrenal vein thrombosis af-
tensive vomiting and diarrhea gradually lead to se- ter a back injury.
vere dehydration. Fever is often present, is usually Adrenal crisis is uncommon in patients with sec-
due to a precipitating infection, and may be exagger- ondary or tertiary adrenal insufficiency, because nor-
ated because of the hypocortisolemia. The abdom- mal renin-angiotensin-aldosterone physiology is usu-
inal pain and fever may lead to incorrect diagnosis ally maintained and hypovolemia is rare. Hypo-
of an acute surgical abdomen and potentially catas- glycemia is the more common presentation in these
trophic surgical exploration without corticosteroid patients, who often also have signs and symptoms
replacement. Hypoglycemia rarely may be the pre- of deficiency of other anterior pituitary hormones.
senting manifestation. By laboratory examination Because glucocorticoids have a role in maintaining
the presence of evident hyponatremia, hyperkalemia, peripheral vascular adrenergic tone, sudden loss of
hemoconcentration, metabolic acidosis, and hypera- ACTH secretion particularly in conjunction with
zotemia are found. Hyperazotemia is the result of other serious illness, can lead to hypotension and cir-
acute renal failure which is secondary to hypovolemic culatory shock.
shock. Lethargy deepens into somnolence and con-
fusion. Without appropriate therapy, hypovolemic
shock progresses to coma and death. IV. Isolated mineralocorticoid deficiency
It is assumed that the major pathophysiology pre- Isolated mineralocorticoid deficiency states are char-
cipitating adrenal crisis is mineralocorticoid, not glu- acterized by isolated aldosterone deficiency accom-
cocorticoid deficiency. However, glucocorticoid defi- panied by normal glucocorticoid and androgen pro-
ciency can contribute to the hypotension, perhaps duction. They include inherited enzymatic defects
resulting from decreased sensitivity to angiotensin II in aldosterone biosynthesis, acquired primary al-
and norepinephrine, and decreased synthesis of an- dosterone deficiency, and acquired secondary aldos-
giotensinogen. terone deficiency. Pseudohypoaldosteronism, a rare
5.6. Pathophysiology of the adrenal glands 373

salt-wasting syndrome caused by an abnormal min- mechanism apparently is insufficient in some indi-
eralocorticoid receptors, is also included among these viduals because of an impaired renin-angiotensin sys-
states. tem, as might exist in diabetes mellitus. Persistently
The feature common to all patients with hypoal- hypotensive, critically ill patients also have inappro-
dosteronism is the inability to increase secretion ap- priately low plasma aldosteron concentration relative
propriately during salt restriction. In severe cases, to the activity of the renin-angiotensin system. The
urine sodium wastage occurs on a normal salt in- defect is at level of the adrenal but is not associated
take, whereas in milder forms, excessive losses of with any particular disease state or therapy. The
urine sodium occur only during salt restriction. mechanism is unknown, however, a selective insensi-
tivity to angiotensin II is considered.
A. Congenital primary hypoaldosteronism
It is a rare inherited disorder transmitted as
C. Acquired secondary hypoaldosteronism
an autosomal recessive trait. The defect is in
the activity of one of the terminal enzymes in This disorder occurs in the patients with a de-
the aldosterone biosynthetic pathway, i.e., corticos- ficiency in renin production, and, therefore, is de-
terone 18-methyl oxidase (CMO) or corticosterone noted as hyporeninemic hypoaldosteronism. It is
18-methyl isomerase (CMI). These enzymes catalyze seen most commonly in adults with mild renal fail-
two terminal steps in aldosterone biosynthesis. Both ure and diabetes mellitus in association with hyper-
these enzymes are present only in zona glomeru- kalemia and metabolic acidosis out of proportion to
losa. Congenital defect of 18-methyl isomerase is the state of renal impairment. The pathogenesis is
more frequent. CMO refers to the enzymatic ac- uncertain. Possibilities include impairment of a jux-
tivity responsible for hydroxylation of corticosterone taglomerular apparatus (most likely) or a defect in
at C-18 (Fig. 5.1,374). Deficiency of this enzyme conversion of renin precursors to renin. Plasma renin
would be expected to produce low plasma levels activity and aldosterone concentrations are low.
of products derived from corticosterone, i.e., 18-
hydroxycorticosterone and aldosterone. CMI activ-
ity converts 18-hydroxycorticosterone to aldosterone D. Pseudohypoaldosteronism
(the C-18 methyl group of corticosterone to the C-18
aldehyde of aldosterone). Its deficiency should be as- It is a rare salt-wasting syndrome caused by
sociated with high plasma 18-hydroxycorticosterone tubular unresponsiveness to aldosterone (pseudoen-
level and low plasma aldosterone level. These pa- docrinopathy). Patients may have absent or greatly
tients have elevated plasma renin activity (hyper- reduced numbers of mineralocorticoid receptors. In
reninemic hypoaldosteronism). This disorder is clin- the patients with this disorder real aldosterone de-
ically manifested already in the early childhood. The ficiency does not originate. Plasma aldosterone
clinical picture reveals hyponatremia, hypochloremic concentration is even increased. Hypothalamic-
metabolic acidosis, dehydration, retardation of the pituitary-adrenal function is normal.
linear body growth, and failure to thrive of a child. Inherited and acquired forms of pseudohypoaldos-
Hyperkalemia is not usually part of this syndrome. teronism may be distinguished. Inherited form is a
Patients with this disorder have a high mortality rate rare salt-wasting syndrome of infancy with autoso-
(about 80 %). mal recessive transmission. It is present more fre-
quently in boys and is manifested already during the
B. Acquired primary hypoaldosteronism first year of life. Acquired form is due to obstructive
This disorder is characterized by aldosterone uropathy or may be present in a premature infant or
biosynthetic defect or a selective unresponsiveness follows renal transplantation.
to angiotensin II. Long-lasting heparin therapy sup- Clinical hallmarks of pseudohypoaldosteronism
presses aldosterone synthesis, leading to a compen- are those of aldosterone deficiency: hyponatremia,
satory rise in plasma renin activity (hyperrenine- hyperkalemia, and renal salt wasting. However,
mia), which in most subjects is sufficient to prevent plasma aldosterone level is elevated. Plasma renin
aldosterone deficiency. However, the compensatory activity is also increased (hyperreninemia).
374 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

CHOLESTEROL

❄
PREGNENOLONE ✲ 17αHYDROXYPREGNENOLONE ✲ DEHYDROEPIANDROSTERONE

❄ ❄ ❄
A❥
PROGESTERONE ✲ 17αHYDROXYPROGESTERONE ✲ ANDROSTENEDIONE ✲ ESTRONE

❥
21 ❥
21 ❥
11
❄ ❄ ❄
11–DEOXYCORTICOSTERONE 11–DEOXYCORTISOL 11–HYDROXYANDROSTENEDIONE
❥
11 ❥
11
❄ ❄
CORTICOSTERONE CORTISOL
✞ 
✝CMO ✆
❄
18–HYDROXYCORTICOSTERONE
✞ 
✝CMI ✆
❄
ALDOSTERONE

(Mineralocorticoid (Glucocorticoid (Androgen (Peripheral

Pathway) Pathway) Pathway) Tissues)

Figure 5.1: Steroid biosynthetic pathways in the adrenal cortex.

( 11 = 11β–Hydroxylase; 21 = 21–Hydroxylase; CMO = Corticosterone 18-methyl oxidase;
CMI = Corticosterone 18-methyl isomerase; A = Aromatase )

5.6.1.2 Hyperfunction of adrenal cortex mineralocorticoids is also known. Some carcinomas

of adrenal cortex may be manifested by oversecretion
Hyperfunction of adrenal cortex may be manifested of all kinds of corticosteroid hormones.
by oversecretion of any kind of corticosteroid hor-
mones: glucocorticoids (mainly cortisol), mineralo- The clinical picture of adrenal cortex hyperfunc-
corticoids (mainly aldosterone), adrenal androgens, tion may be rather variable and depends partly on
and rarely also estrogens. Selective (isolated) over- the kind of overproduced hormones, and partly on in-
production of one kind of the mentioned steroid hor- tensity of their hypersecretion. The clinical features
mones may originate. However, their combinated hy- are also influenced by the fact that effect of individ-
persecretion is more common. Overproduction of al- ual kinds of corticosteroid hormones partly coincide,
dosterone is typically isolated, while overproduction e.g., cortisol, the most important glucocorticoid in
of cortisol and androgens is being mixed quite often. men, has also weak mineralocorticoid effect and some
Combination of hyperproduction of androgens and of its metabolites have a slight androgenic effect.
5.6. Pathophysiology of the adrenal glands 375

I. Cushing’s syndrome (hypercortisolism) patients with Cushing’s syndrome. The cause of

In the past this term denoted only primary hyper- its origin may be in adenohypophysis or hypothala-
cortisolism. Nowadays this term denotes each patho- mus. The older term for adenohypophyseal disorder
logical state induced by the chronic increased plasma is Cushing’s disease (secondary hypercortisolism, pi-
cortisol concentration, regardless of a cause of its ori- tuitary Cushing’s syndrome). The hypothalamic
gin. If it is evoked by oversecretion of cortisol, it is disorder was denoted as Icenko-Cushing’s disease
termed endogenous Cushing’s syndrome. If it orig- (tertiary hypercortisolism, hypothalamic Cushing’s
inates as a result of long-term pharmacotherapy by syndrome). In the patients with adenohypophy-
synthetic glucocorticoids, rarely also by ACTH, it seal disorder the source of excessive ACTH pro-
is denoted as exogenous (iatrogenic) Cushing’s syn- duction is primary neoplasia of corticotrophs (usu-
drome. Endogenous Cushing’s syndrome is rare, oc- ally basophilic microadenomas or sometimes solitary
curring in about 1 per mille of adult population. It macroadenoma). In the patients with hypothalamic
is more common in women that in men (4:1), espe- disorder isolated CRH oversecretion occurs probably
cially between 25 and 45 years of age. However, it due to overstimulation of hypothalamus from higher
may occur at any age. Occurrence of neoplastic and centers of CNS or due to CRH-secreting gangliocy-
paraneoplastic forms is increasing after the age of 50. toma of the hypothalamus. Hypersecretion of CRH
Classification and pathogenesis. Basically Cush- causes corticotrope hyperplasia. The hyperplastic
ing’s syndrome is usually classified from two view- corticotropes secrete excessive amounts of ACTH. It
points. According to whether it is induced by over- is also supposed that this primary oversecretion of
production of cortisol or by administration of ex- CRH would lead to hyperstimulation of the pituitary,
cessive amounts of potent synthetic glucocorticoids resulting in adenoma formation. As the pituitary
endogenous and exogenous forms of Cushing’s syn- microadenoma grows, it may become independent of
drome are distinguished. According to the role of the regulating influence of CNS factors and/or circu-
ACTH in its pathogenesis ACTH-dependent Cush- lating cortisol levels.
ing’s syndrome and ACTH-independent Cushing’s In both cases of central form of Cushing’s syn-
syndrome are distinguished. drome, the result of permanently increased ACTH
ACTH-dependent Cushing’s syndrome is caused secretion is the origin of bilateral diffuse hyperplasia
by oversecretion of hypothalamic CRH, oversecre- of adrenal cortex (the zonae fasciculata and reticu-
tion of pituitary ACTH, ectopic production of CRH, laris) and successive overproduction of cortisol. In
ectopic production of ACTH, and rarely by admin- some patients production of adrenal androgens may
istration of excessive amounts of ACTH. ACTH- be also increased. Plasma ACTH and cortisol con-
independent Cushing’s syndrome is induced by pri- centrations are elevated. Other POMC-derived pep-
mary adrenocortical neoplasms, bilateral ACTH- tides parallel ACTH. The zona glomerulosa is nor-
independent macronodular adrenocortical hyper- mal. In about 20 % of patients with long-standing
plasia, bilateral ACTH-independent micronodular central Cushing’s syndrome bilateral macronodular
adrenocortical dysplasia, and by administration of adrenocortical hyperplasia may be present.
excessive amounts of synthetic glucocorticoids.
2. Paraneoplastic form of Cushing’s syndrome
A. Endogenous Cushing’s syndrome It is also denoted as ectopic form of Cushing’s
syndrome (ectopic ACTH syndrome). It accounts
All cases of endogenous Cushing’s syndrome are for about 10 % of the total number of the patients
due to increased production of cortisol by the adrenal with Cushing’s syndrome. It is induced by extrahy-
glands. According to the place of primary cause and pophyseal and extrahypothalamic hormonally active
according to the histological finding in the adrenal tumors which produce ACTH or CRH. The presence
cortex, following five forms of endogenous Cushing’s of tumor producing ACTH and CRH simultaneously
syndrome may be distinguished: is quite common. Isolated ectopic CRH production
is very rare.
1. Central form of Cushing’s syndrome The most frequent cause of paraneoplastic form of
It is the most common form of hypercortisolism Cushing’s syndrome are malignat tumors, e.g., small
accounting for about 70 % of the total number of cell lung carcinoma (accounts for about half of all
376 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

these malignant tumors), thymic carcinoma, pancre- ules in both adrenal glands. The nodules consist
atic carcinoma, malignant pheochromocytoma, thy- of large cells containing brown lipofuscin pigment.
roid medullary carcinoma, ovaric carcinoma, and The colour of these nodules is, therefore, brown or
prostatic carcinoma. Some carcinoids (bronchial and black (hence the synonym ”pigmented” micronodu-
gastrointestinal) may be less common cause of ec- lar adrenal disease). The ultrastructure of the cells
topic ACTH and CRH secretion. resembles that of fasciculata cells. The intervening
These malignant nonendocrine tumors secrete non-nodular cortex consists of small cells with clear
polypeptides that are biologically, chemically, cytoplasm characteristic of adrenal atrophy. The
and immunologically indistinguishable from either nodules function autonomously, the cortisol they se-
ACTH or CRH and that cause bilateral adrenal hy- crete suppresses ACTH secretion, and, therefore, the
perplasia. The ectopic production od ACTH is also remainder of the cortex atrophies.
accompanied by secretion of other POMC-derived Sporadic and familial forms of this disease are dis-
peptides, which is associated with intense skin pig- tinguished. About half of the patients with this dis-
mentation. order have no distinctive clinical presentation other
The development of bilateral diffuse adrenocorti- than being young, always less than age 30 (sporadic
cal hyperplasia is secondary to the permanent ectopic form of the disease). Median duration of the symp-
ACTH or CRH production. In spite of ectopicly con- toms before diagnosis is usually one year. The other
ditioned autonomous secretion of cortisol the loss of half of the patients have a familial form of the disease
regulation of its production by feedback mechanism that is a dominant trait and accompanied by pig-
is not usually total. mented lentigines and blue nevi on the face (includ-
Central and paraneoplastic forms of Cushing’s syn- ing the lips, conjuctiva, or sclera), neck, and trunk.
drome are denoted as Cushing’s syndrome due to bi- These patients may also have cutaneous, mammary,
lateral ACTH-dependent diffuse adrenocortical hy- and atrial myxomas, testicular tumors, and other tu-
perplasia. In the patients with long-standing persis- mors. Only 20 % of the patients have Cushing’s syn-
tence of these both forms of Cushing’s syndrome ade- drome, and none has all features of the syndrome.
nomatous changes of diffusely hyperplastic cortex of Plasma cortisol concentration is usually moderately
the adrenals may occur. Bilateral ACTH-dependent elevated. Plasma ACTH concentration is low or un-
micronodular or macronodular adrenocortical hyper- detectable.
plasia originates. Macronodularly changed adrenal This disease occurs very rarely. Together with bi-
cortex may manifest various degree of autonomy. lateral ACTH-independent macronodular adrenocor-
tical hyperplasia accounts less than 1 % of all cases of
3. Cushing’s syndrome due to bilateral Cushing’s syndrome, but macronodular hyperplasia
ACTH-independent macronodular adre- is rarer than micronodular dysplasia. Pathogenesis
nocortical hyperplasia of this disorder in unknown. But, it is assumed that
From the histopathological point of view it is char- circulating immunoglobulin (IgG) which stimulates
acterized by presence of the large nodules in the steroidogenesis and adrenal cell growth may be in-
adrenal cortex which is between these large nodules volved. However, it is unclear why the cells that form
hyperplastic. It occurs very uniquely. The patho- the nodules, but not the intervening cells, should be
genesis of this disorder is unknown. There is no evi- susceptible to stimulation by these autoantibodies.
dence that ACTH hypersecretion is involved. Plasma
ACTH concentration is very low even undetectable. 5. Peripheral form of Cushing’s syndrome
Participation of local growth factor in the pathogen- Peripheral (primary, adrenal) form of Cushing’s
esis of bilateral ACTH-idependent macronodular hy- syndrome originates due to primary adrenocortical
perplasia is considered. neoplasms with autonomous secretion of cortisol. It
accounts for about 15 % of the whole number of
4. Cushing’s syndrome due to bilateral patients with Cushing’s syndrome. Adrenocortical
ACTH-independent micronodular adre- cortisol-secreting tumors generally predominate in
nocortical dysplasia children and young adults. Adenomas are more com-
From the histopathological point of view it is mon than carcinomas (2:1). These tumors are usu-
characterized by the presence of numerous nod- ally unilateral and solitary, their bilateral and multi-
5.6. Pathophysiology of the adrenal glands 377

ple occurrence is less common. Pathogenesis of these sion occurs only if the patient is taking hydrocorti-
tumors is not known. sone or cortisone. The severity of iatrogenic Cush-
The adrenocortical adenomas and carcinomas pro- ing’s syndrome is related to the duration of the ther-
duce excessive cortisol. Its increased plasma con- apy and to the total corticosteroid dose.
centration inhibits hypothalamic-adenohypophyseal Iatrogenic Cushing’s syndrome caused by pro-
system by feedback mechanism (secretion of CRH longed administration of exogenous ACTH for ther-
and ACTH is inhibited, pituitary corticotropes are apeutic reason is rare. It is one of the variants of
atrophic). As pituitary ACTH secretion is sup- the ACTH-dependent Cushing’s syndrome. In spite
pressed, the remaining cortex of the adrenals is at- of inhibition of pituitary ACTH synthesis and se-
rophied (the zonae fasciculata and reticularis). cretion, bilateral adrenocortical hyperplasia and cor-
Plasma ACTH concentration is low or often un- tisol hypersecretion are present. The clinical signs
detectable. Plasma cortisol level is inappropriately and symptoms in these patients are similar to those
high. As ACTH and other POMC-derived peptides with endogenous ACTH hypersecretion (tertiary hy-
production is suppressed, signs of hyperpigmenta- percortisolism).
tion are absent. Adrenal adenomas usually produce The clinical picture of Cushing’s syndrome de-
only cortisol. Therefore, patients with adrenal ade- pends on both the degree and duration of hypercor-
noma usually have only gradual onset of hypercor- tisolism. Many of the signs and symptoms of this
tisolism. Hirsutism and other androgenic effects are syndrome logically follow the known action of glu-
absent. In contrast, patients with adrenocortical car- cocorticoids, but some probably reflect concominant
cinoma tend to have a more acute and progressive hypersecretion of androgens. The clinical picture
course, and hyperandrogenic effects may predomi- of Cushing’s syndrome is characterized mainly by
nate. Markedly elevated adrenal androgen secretion the symptoms resulting from the increased protein
often leads to virilization in the female. The adreno- catabolism, increased hepatic gluconeogenesis, and
cortical carcinoma may also produce estrogens. Be- increased fat deposition and redistribution. The dis-
sides that, the adrenocortical carcinomas usually se- ease develops slowly. For a long time it may produce
crete increased amounts of androstenedione which is oligosymptomatic clinical form (signs and symptoms
peripherally converted to the estrogens, estrone and are present in less number, sometimes also slight
estradiol. Feminizing estrogens usually present with Cushing’s habitus may be observed). Later symp-
gynecomastia in the male and dysfunctional uter- tomatology of fully developed Cushing’s syndrome
ine bleeding in the female. Approximately 30 % of originates.
adrenocortical carcinomas are hormonally nonfunc-
tional or produce biologically inactive steroid precur- Subjectively the patients usually complain of fati-
sors. gability, muscle weakness, back pain, facial changes,
increased susceptibility to infections, and poor
wound healing. Women also complain of menstrual
B. Exogenous Cushing’s syndrome
abnormalities.
Exogenous form of Cushing’s syndrome is usually The most evident somatic symptom is the change
caused by long-lasting administration of excessive of general appearance of the patient, which is condi-
amounts of potent syntetic glucocorticoids, rarely tioned partly by progressive obesity with a peculiar
by long-term ACTH administration. Therefore, it distribution of adipose tissue (its deposition in char-
is usually termed iatrogenic Cushing’s syndrome. acteristic sites), and partly by the decrease of muscu-
Iatrogenic (factitious) Cushing’s syndrome associ- lar mass (Cushing’s habitus). Obesity is character-
ated with chronic administration of synthetic glu- ized by typical centripetal (truncal, disproportional)
cocorticoids (such as dexamethasone or prednisone) fat redistribution manifested by rounded face, dor-
is ACTH-independent. Excessive amounts of exoge- socervical fat pad (buffalo hump), enlarged fat pads
nous glucocorticoids inhibit synthesis and secretion characteristically fill the supraclavicular fossae, and
of CRH, suppress pituitary ACTH synthesis and se- fat accumulation about trunk and abdomen. On the
cretion, resulting in bilateral adrenocortical atrophy. other hand gluteal area is inadequately slim in com-
Plasma ACTH and usually cortisol concentrations parison to prominent abdomen and enlarged chest.
are low. Hirsutism is absent and arterial hyperten- The extremities, mainly lower, are thin, spared,
378 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

or even wasted (spider-like figure). Slenderness of striae are most frequent on the lower flanks and
gluteal area and extremities is conditioned not only sides of lower abdomen but can be also found on the
by the decreased amount of adipose tissue in these breasts, hips, buttocks, shoulders, and upper thighs.
sites, but also by the loss of muscular mass, mainly They occur more frequently in younger patients. In-
of proximal muscles of the limbs. The loss of mus- creased proteocatabolic effect of cortisol causes also
cular mass is due to proteocatabolic effect of cortisol loss of perivascular supportive tissue probably re-
and also due to its antianabolic effect (amino-acids sulting in increased fragility of vessels. Therefore,
are to a higher extent used for gluconeogenesis, and, in a patient increased bruisability is present. Easy
therefore, they are not in a sufficient amount at a bruising can appear after minimal, unremembered
disposal for proteosynthesis). The muscular atrophy trauma, mainly on the forearms and shins. Exten-
of lower limbs, mainly the gluteus maximus and the sive ecchymoses at venipuncture are common.
quadriceps, in severe cases of the disease, is usually A very significant and frequent clinical symptom
manifested by muscle weakness even muscle wasting, of Cushing’s syndrome is osteoporosis. It originates
which is denoted as proximal myopathy. Most pa- rather quickly and affects diffusely the whole skele-
tients cannot rise from a squatting position without ton. It is clinically manifested by pain in bones
assistance, and those with severe disease may be un- (low-back pain is common), excessive kyphosis, and
able to climb stairs or get up from a deep chair (this pathologic fractures (most frequent are vertebral
state is similar to thyrotoxic myopathy). compression fractures, spontaneous rib fractures,
The origin of obesity in the patient with Cushing’s and, less commonly, long bone fractures). Osteo-
syndrome has been explained by the increased glu- porosis is the result of the effect of hypercortisolism
coneogenesis which displaces sources of energy to fat on metabolism of proteins and calcium (stimulation
tissue. Fat redistribution is probably the result of of proteocatabolism in bones, antianabolic effect, de-
the origin of different local sensitivity of fat tissue crease of intestinal calcium absorption, and decrease
to cortisol (causing lipolysis) and to insulin (causing of calcium reabsorption in renal tubules). Hypercal-
lipogenesis). Unlike adults, children with Cushing’s ciuria may result in nephrolithiasis (in about 15 % of
syndrome often develop generalized obesity. cases). In children Cushing’s syndrome is manifested
The result of the increased protein catabolism is by body growth impairment (linear growth is slowed
not only the loss of muscular mass, but also atrophy or arrested). Excessive diffuse osteoporosis is usually
of skin, osteoporosis, and involution of lymphatic tis- present, too.
sue. The skin is fine, thin, and fragile as a result Disturbed metabolism of glucose is one of the
of mobilisation of peripheral supportive tissue and main manifestations of Cushing’s syndrome. Due
weakening of collagen fibers in the dermis. Due to to increased hepatic gluconeogenesis and tissue in-
its increased transparency subcutaneous blood ves- sulin resistance, impaired glucose tolerance origi-
sels can be seen. Facial skin over the cheeks is, there- nates. Overt diabetes mellitus occurs in about 15 %
fore, plethoric, and together with rounded face is typ- of the patients (probably in individuals with a famil-
ical of the facial appearance of patients with Cush- ial predisposition to diabetes).
ing’s syndrome, and is termed a moon face (facies One of the most common symptoms of Cushing’s
cushingoides). Bizarre type of obesity in patients syndrome is moderate arterial hypertension. It oc-
with Cushing’s syndrome is, therefore, along with curs in about 80–90 % ot the patients. Several fac-
prominent abdomen, evidently thin extremities, and tors participate in the mechanism of its origin. The
buffalo hump, characterized also by moon face. most important of them is moderate mineralocorti-
In places with excessive fat accumulation the frag- coid effect of glucocorticoids resulting in hyperna-
ile skin is stretched, therefore, rupture of colla- tremia and hypervolemia (volume mechanism). The
gen fibers in the dermis originates producing cuta- change of natrium distribution between intracellular
neous striae. Unlike the striae of pregnant women and extracellular fluid owing to cortisol may have
(striae albi), they appear purphish or reddish (striae a supportive role. The result of this change is the
rubrae) because the thin, transparent skin reveals increase of natrium content in myocytes of vascu-
the color of venous blood in the dermis. The striae lar wall followed by their increased sensitivity to
rubrae are also more numerous and often wider. Such angiotensin II and norepinephrine (resistant mech-
5.6. Pathophysiology of the adrenal glands 379

anism). Glucocorticoids also induce hepatic produc- hypophyseal system which is probably conditioned
tion of angiotensinogen (renin substrate). Increased by chronic hypercortisolism.
circulating levels of angiotensinogen probably result In patients with Cushing’s syndrome susceptibility
in increased angiotensin II generation. to bacterial and fungal infections is increased. Migra-
Long-lasting evident hypernatremia results in the tory ability of leukocytes is decreased. Production of
origin of metabolic alkalosis. Increased natrium antibodies is also decreased. The most common in-
retention is associated with increased depletion of tercurrent infections are those of skin and urinary
potassium with successive hypokalemia which may tract.
aggravate muscular weakness. Red blood cell number is usually mildly increased
what contributes to plethoric skin. The leuko-
Profund emotional changes or psychiatric compli-
cyte number, mainly neutrophils, is also elevated.
cations are rather frequent symptoms of Cushing’s
Eosinopenia and lymphopenia are usually present as
syndrome of all etiologies (in about 70–75 % of pa-
well.
tients). Sometimes they may appear even at the be-
ginning of the disease. Insomnia is often an early Basic clinical picture of individual pathogenetic
symptom and is presumably caused by high plasma forms of Cushing’s syndrome is rather similar to
cortisol levels during sleep. Some patients appear eu- each other. Hyperpigmentation of Addison’s type
phoric or manic, particularly during the early course is the evidence of central or paraneoplastic Cush-
of the disease. Irritability, emotional lability, agi- ing’s syndrome. The clinical picture of those forms
tated depression, panic attacks, and mild paranoia of Cushing’s syndrome which are induced by tumors
are most common. Occasional patients may be sui- in hypothalamic-hypophyseal area, by malignant tu-
cidal. Hallucionations and delusions, or even frank mors with ectopic ACTH or CRH production, and
psychosis are rare. Psychiatric complications occur by adrenocortical carcinoma partly depends on the
in the patients with ACTH-dependent and ACTH- rate of tumor growth and on its degree of malignity.
independent Cushing’s syndrome. Therefore, it is In the clinical picture of Cushing’s syndrome due to
assumed that high plasma cortisol concentration at tumors in hypothalamic-hypophyseal area some lo-
least partially participates in their origin by its psy- cal symptoms secondary to compression of intracra-
chotropic effect. nial structures can be observed. In patient with
Cushing’s syndrome evoked by malignant neoplasm,
In women with Cushing’s syndrome mild hyper- mainly by a small cell carcinoma of lung producing
trichosis or even evident hirsutism often occur. In ACTH, centripetal obesity is usually missing, be-
both sexes manifestations of hypogonadism are also cause of cachexia and rapid dissemination of the tu-
present. Increased plasma cortisol concentration, mor. In patients with iatrogenic Cushing’s syndrome
causing the decrease of testosterone-binding glob- only signs from glucocorticoids excess are present
ulin synthesis in liver, is probably responsible for because of usual administration of synthetic gluco-
the origin of mild hypertrichosis. Because of de- corticoids having very weak mineralocorticoid effect
creased synthesis of testosterone-binding globulin the and no androgenic effect. Therefore, arterial hyper-
free fraction (the biologically active form) of testos- tension and hirsutism do not occur in their clinical
terone in circulating blood is increased. More ev- picture.
ident hirsutism, increased sebaceous gland activity,
acne, and thinning scalp hair are usually present in
those patients with Cushing’s syndrome which man- II. Hyperaldosteronism
ifest simultaneous hypersecretion of adrenal andro- Hyperaldosteronism is a chronic pathological state
gens. In women they cause masculinization and vir- induced by overproduction of aldosterone by the cells
ilization. Fast developing virilization is usually the of zona glomerulosa. Hypersecretion of aldosterone
result of adrenocortical carcinoma. Hypogonadism may be autonomous (primary hyperaldosteronism),
in women is manifested by oligomenorrhea even sec- or it is a response to other basic disease (secondary
ondary amenorrhea, decreased libido, and infertility. hyperaldosteronism) associated with formation of
Hypogonadism in men is manifested by decreased peripheral edema. Primary hyperaldosteronism sig-
libido and impotence. It is assumed that hypogo- nifies that the stimulus for the excessive aldosterone
nadism is evoked by the disorder of hypothalamic- production resides within the adrenal gland; in sec-
380 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

ondary hyperaldosteronism, the stimulus is extraa- lateral adrenal hyperplasia is occasional. It is de-
drenal. noted as primary adrenal hyperplasia because subto-
tal adrenalectomy (75 %) apparently results in per-
A. Primary hyperaldosteronism manent cure. Its pathogenesis is unknown.
Primary hyperaldosteronism (Conn’s syndrome, Adrenal carcinoma is also a rare cause of primary
primary aldosteronism) is a clinical syndrome char- hyperaldosteronism. Unilateral adrenocortical hy-
acterized by high plasma aldosterone concentration perplasia is even a rarer cause. Its pathogenesis is
associated with suppressed plasma renin activity. unknown, too. A solitary cause of primary hyper-
Plasma cortisol and adrenal androgen levels are nor- aldosteronism may be an ectopic secretion of aldos-
mal. Low plasma renin activity is the evidence of terone, mainly by ovarian carcinomas.
autonomous aldosterone hypersecretion, e.i., chronic
The data on occurrence of primary hyperaldostero-
excess aldosterone secretion is independent of the
nism rather vary. The most frequent information
renin-angiotensin system. Low plasma renin activity
is that primary hyperaldosteronism is the cause of
is the main criterion to distinguish between primary
about 0.5–2 % of all arterial hypertensions. Primary
and secondary hyperaldosteronism.
hyperaldosteronism may appear at any age, however,
The most common cause of primary hyperaldos-
the peak incidence occurs between ages 30 and 50. It
teronism is solitary unilateral adenoma composed
tends to occur in women more often than men (2:1).
of glomerulosa cells. Aldosterone-producing adrenal
adenoma is present in about 65 % of all cases. It The clinical picture of primary hyperaldosteronism
is more often found on the left. In about 30 % of is characterized mainly by arterial hypertension, hy-
cases primary hyperaldosteronism is caused by bi- pokalemia, mild metabolic alkalosis, and suppressed
lateral idiopathic hyperplasia of zona glomerulosa. plasma renin activity. However, adrenocortical ade-
The pathogenesis of zona glomerulosa hyperplasia is noma tends to produce severer hyperaldosterone-
unknown. mia, with consequent severer hypertension, more
Besides bilateral idiopathic hyperplasia there are profound hypokalemia, and more complete renin sup-
also two rare types of bilateral adrenal hyperplasia. pression.
The first type is dexamethasone-suppressible hyper- The clinical symptomatology of primary hyperal-
aldosteronism (dexamethasone inhibits secretion of dosteronism of all etiologies results from the disor-
ACTH). Aldosterone level falls also after glucocor- ders of electrolyte metabolism due to chronic hy-
ticoid administration and remains suppressed dur- peraldosteronemia. As a consequence of persisting
ing the course of administration, indicating the de- hyperaldosteronemia renal distal tubular sodium re-
pendence of aldosterone secretion on ACTH stim- absorption and renal distal tubular potassium de-
ulation. Therefore, it is also called glucocorticoid- pletion are increased. The continual hypersecretion
suppressible hyperaldosteronism. It is supposed that of aldosterone increases the renal distal tubular ex-
its origin is the result of the failure of normal dif- change of intraluminal sodium for secreted potas-
ferentiation of transitional zone cells to zona fasci- sium and hydrogen ions, with progressive depletion
culata cells (the transitional zone is found between of body potassium and development of hypokalemia.
zona fasciculata and zona glomerulosa during em- The electrochemical gradient generated by excessive
bryonal development). This mutation leads to the sodium retention also causes hydrogen ion loss in the
origin of hybrid cells which do not lose the activ- distal tubules. As hypokalemia increases, so does re-
ity of terminal enzymes in the aldosterone biosyn- nal ammoniagenesis, contributing to the metabolic
thetic pathway, i.e., 11β-hydroxylase, corticosterone alkalosis. The increased tubular sodium reabsorp-
18-methyl oxidase, and corticosterone 18-methyl iso- tion is associated with the increased water reten-
merase Fig. 5.1, 374). The postulated defect results tion, so serum sodium concentration remains nor-
in ACTH-response cells that retain the ability to syn- mal, or tendency to hypernatremia is present. Total
thesize aldosterone and 18-hydroxycorticosterone. body sodium content, and thereby also total extra-
The first type of bilateral adrenal hyperplasia is cellular fluid volume are increased. Therefore, mild
more common than the second type. It occurs fa- hypervolemia originates. Unlike the secondary hy-
milially, mainly in young subjects, and has autoso- peraldosteronism, the patients with primary hyper-
mal dominant inheritance. The second type of bi- aldosteronism do not have edema. It is caused by so-
5.6. Pathophysiology of the adrenal glands 381

called escape phenomenon of the renal tubules from hypokalemia is the origin of hypokalemic nephropa-
the sodium-retaining action of aldosterone. In the thy (tubulopathy). It is manifested by diminishing
patients with primary hyperaldosteronism this phe- of renal concentrating capacity (hyposthenuria even
nomenon originates due to long-lasting effect of ex- isosthenuria), diminishing of acidification ability of
cessive amount of aldosterone on the renal tubules. the renal tubules (urine pH is alkaline), polyuria,
Escape phenomenon is possibly mediated by a com- polydipsia, and nycturia. The polyuria results from
pensatory increase in atrial natriuretic factor (ANF) impairment of concentrating ability and is often as-
secretion, but renal hemodynamic changes may also sociated with polydipsia. Those are the signs of pe-
play a role in the escape. Inhibition of sodium reten- ripheral (symptomatic) diabetes insipidus, which is
tion prevents futher expansion of extracellular fluid resistant to ADH therapy, because the renal tubules
volume, and thereby also futher increase of circu- have lost sensitivity to ADH.
lating blood volume. There is no evidence of es- Laboratory examination reveals metabolic alkalo-
cape from the potassium-lossing effect of aldosterone, sis, increased plasma aldosterone concentration, low
therefore, depletion of potassium continues despite plasma renin activity, low plasma angiotensin II con-
hypokalemia. centration, and glucose tolerance impairment.
Low plasma renin activity is the result of in-
Arterial hypertension is the main objective symp-
hibition of the juxtaglomerular apparatus by hy-
tom of primary hyperaldosteronism. It is usually not
pernatremia, hypervolemia, and arterial hyper-
of marked severity, but most patients have an ev-
tension. Metabolic alkalosis (hypokalemic and
ident systolic hypertension. Characteristic feature
hypochloremic) originates secondary to increased hy-
of the hypertension is its stationary (fixed) course.
drogen ion loss into the urine and hydrogen ion mi-
The presence of escape phenomenon and mainly
gration into potassium-depleted cells. The alkalosis
the increase of diastolic pressure indicates that it is
is perpetuated by potassium deficiency, which partly
not only volume expansion (hypervolemia) that par-
increases the capacity of the proximal tubules to re-
ticipates in its pathogenesis. Increased peripheral
absorb filtered bicarbonate and partly increases renal
vascular resistance seems to be simultaneously in-
ammoniagenesis. Metabolic alkalosis may be associ-
volved. Increased vascular sensibility to vasoactive
ated with fall of plasma ionized calcium concentra-
substances is secondary to the increase of intracel-
tion what is manifested by paresthesias and signs of
lular vascular smooth muscle cell sodium content.
tetany. Glucose intolerance originates probably only
Approximately half of the patients with arterial hy-
in genetic predisposed individuals. Evoking factor,
pertension have severe headaches (mainly frontal).
causing the disorder of insulin secretion, is potassium
Later, consequences of hypertension may appear, es-
depletion from the B cells of islets of Langerhans due
pecially left ventricle hypertrophy and atherosclero-
to long-lasting hyperkaliuresis.
sis. However, fatal complications of hypertension
and atherosclerosis are rare, and occur only in the B. Secondary hyperaldosteronism
untreated patients.
The term secondary hyperaldosteronism denotes
Hypokalemia (usually less than 3.5 mmol/L) is al- the state of a chronic aldosterone hypersecretion
most regular finding. In some patients it may be se- evoked by primary extraadrenal causes. Primary dis-
vere, less than 3 mmol/L. The origin of hypokalemia ease begins outside zona glomerulosa and aldosterone
is the result of permanently increased potassium loss overproduction is only one of the symptoms of this
in the distal renal tubules (hyperkaliuresis). Evi- primary disease. Therefore, it is also termed symp-
dent hypokalemia may evoke striking muscular weak- tomatic hyperaldosteronism. Aldosterone overpro-
ness and fatigue, sometimes even flaccid paralysis. duction is a response to activation of the renin-
Tonus of smooth muscles is also decreased and is es- angiotensin system included to pathogenetic pro-
pecially manifested by constipation and by disorders cess only secondary as a compensatory mechanism
of urinary bladder discharge. Tendency to cardiac (secondary hyperreninemia). An overproduction of
arrhythmias may also appear. Electrocardiographic renin is secondary to a decrease in renal blood flow
signs of hypokalemia, such as flattening or inversion and/or a decrease in renal perfusion pressure. These
of the T wave and prominent U wave, are usually changes of renal hemodynamics are caused by pri-
present. Common consequence of evident chronic mary disease. The aim of this compensatory hyper-
382 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

secretion of aldosterone is to restore the changed re- with all the mentioned states activation of the renin-
nal hemodynamics to normal by increased natrium angiotensin-aldosterone system is common compen-
retention and by successive expansion of circulatig satory response to the decrease of effective circulat-
blood volume. ing blood volume. This decrease is evoked by transu-
Increased plasma renin activity and angiotensin II dation of intravascular fluid into extravascular space,
concentration differ secondary hyperaldosteronism by reduced cardiac output, or by a large loss of fluid
from primary hyperaldosteronism. Plasma concen- or blood. Reduced renal perfusion is the major stim-
trations of both these components of the renin- ulus to the increased renin secretion, angiotensin II
angiotensin-aldosterone system are low in the pa- production and aldosterone secretion, and thus to
tients with primary hyperaldosteronism. Secondary sodium and water retention. In patients with cirrho-
hyperaldosteronism usually occurs on the basis of the sis of the liver, decreased degradation of aldosterone
disease states associated with formation of peripheral also participates in the increase of its plasma concen-
edema, in association with the accelerated phase of tration.
hypertension, or in association with malignant hy-
pertension. However, unlike primary hyperaldostero- 2. Hereditary renal tubular acidosis and Bart-
nism, in secondary hyperaldosteronism the sodium- ter syndrome. They are pathological states
retaining effect of aldosterone persists because the with secondary hyperreninemia but without edemas
mechanism of escape is not activated. Its activation and arterial hypertension. They are salt-wasting
is prevented by the fact that the cause of the decrease nephropathies.
in effective circulating blood volume persists, and, Hereditary renal tubular acidosis of both, proxi-
therefore, the fluid retained by the kidneys does not mal or distal tubules, is associated with urinary de-
remain in circulation, but transudation of intravas- pletion of sodium and potassium and with succes-
cular fluid into extravascular sites continues. Home- sive activation of the renin-angiotensin-aldosterone
ostasis occurs as late as the edema is stabilized. In system. In the clinical picture besides hyperrenine-
the time of stabilized edema the activity of the renin- mia, hyperaldosteronemia and hypokalemia, hyper-
angiotensin-aldosterone system becomes normal. In chloremic metabolic acidosis is present. Hyper-
patients with secondary hyperaldosteronism neither chloremic acidosis makes renal tubular acidosis dif-
hypokalemia is usually so evident nor arterial hyper- ferent from Bartter syndrome.
tension is necessarily always present as it is in the Bartter syndrome is a rare hereditary disease of
patients with primary hyperaldosteronism. the kidneys. Inheritance is autosomal recessive, and
Besides secondary hyperaldosteronism caused by manifestations commonly begin in childhood. It
the mentioned secondary hyperreninemia, rare form is characterized by renal potassium wasting, sec-
of secondary hyperaldosteronism which is the result ondary hyperreninemia, hyperaldosteronemia, hy-
of a primary overproduction of renin (primary hyper- pokalemia, and metabolic alkalosis without hyper-
reninemia, primary hyperreninism) also exists. This tension or edema. In the patients also hypona-
rare form of secondary hyperaldosteronism, caused tremia, hypochloremia, and hyporesponsiveness of
by primary hyperreninism, occurs with or without blood pressure to infused angiotensin II may be
arterial hypertension. found. Hyperplasia of the granular cells of the juxta-
From the point of view of etiopathogenesis follow- glomerular apparatus of the kidneys is observed. Hy-
ing causes of secondary hyperaldosteronism are dis- perplasia of renal medullary interstitial cells, which
tinguished: produce prostaglandins E and F, has been also de-
scribed. The disease is usually manifested by evident
1. Diseases associated with hypovolemia and/or muscular weakness or periodic paralysis, occasional
with arterial hypotension. These diseases include cramps, frequent vomiting, urinary frequency and
mainly those associated with the origin of edemas, polyuria, and by developmental impairment. The
such as congestive heart failure, cirrhosis of the liver patients are, therefore, of short stature.
(respectively portal hypertension with ascites), and A number of primary defects have been proposed
nephrotic syndrome. This group of diseases may to account for Bartter’s syndrome, but the cause is
also include the states associated with dehydration unknown. The main defect seems to be reduced
and large loss of blood (hemorrhage). In patients NaCl reabsorption by the thick ascending limb of
5.6. Pathophysiology of the adrenal glands 383

Henle’s loop. Volume depletion stimulates the renin- teronism is manifested by hypokalemia. Paraneo-
angiotensin-aldosterone system. The combination of plastic autonomous production of renin may rarely
high plasma aldosterone levels and increased deliv- occur in bronchogenic carcinoma or ovarian tumor
ery of NaCl and water to the distal part of nephron (ectopic renin secretion).
causes kaliuresis and hypokalemia. The hyperal-
dosteronism presumably is not the cause of the hy- III. Adrenal androgen excess
pokalemia because bilateral adrenalectomy does not Adrenal androgen excess (adrenal hyperandro-
correct the kaliuresis. Magnesuria and hypomagne- genism) is the cause of the origin of adrenal
semia occur, perhaps because the thick ascending virilization, which is the common term for
limb of Henle’s loop is a main site for magnesium all virilizing syndromes induced by hypersecre-
reabsorption. Hypomagnesemia enhances kaliuresis. tion of adrenal androgens (adrenogenital syn-
Hy- dromes). The principal adrenal androgens are dehy-
pokalemia futher increases aldosterone production droepiandrosterone (DHEA), androstenedione, and
by stimulating release of prostaglandins E2 and I2 , 11-hydroxyandrostenedione. However, adrenal an-
which promote increased secretion of renin. Both an- drogens are biologically weak androgens. Therefore,
giotensin II and aldosterone increase renal kallikrein, they are not a direct cause of virilizing changes. But,
which increases plasma bradykinin. Elevated level of they are converted to the potent androgen testos-
bradykinin could participate in the origin of arteri- terone and dihydrotestosterone in extraglandular tis-
olae hyporesponsiveness to angiotensin II, stimulate sues. Only elevated levels of these biologically more
production of prostaglandin E2 and stimulate natri- active androgens are the main cause of the origin of
uresis. The normal blood pressure probably reflects virilization and other androgenic effects. In general,
an interaction between the vasodepressor actions of the degree of virilization reflects both the duration
prostaglandin E2 and bradykinin and vasoconstric- and the degree of excess androgen secretion. With
tive effect of elevated level of angiotensin II. Exces- regard to the heterosexual character of the hormonal
sive production of prostaglandin E2 resulting from disorder, virilization in girls and in women means
hypokalemia is probably a secondary consequence. partly predominance of male sexual characteristics
In some cases blockade of prostaglandin E2 produc- (hirsutism, male habitus, deepening of voice, and cli-
tion with indomethacin lowers renin level and re- toral enlargement), and partly absence or withdrawal
stores vascular response to angiotensin II infusion of female sexual characteristics (oligomenorrhea even
but does not reduce potassium wasting. amenorrhea, breast atrophy, and loss of female body
contours) denoted as defeminization. The term hir-
3. Diseases associated with a local decrease in
sutism is limited to females and means hair growth
renal blood flow. Secondary hyperreninism and
in a male pattern of distribution. Hair grows in those
thereby also secondary hyperaldosteronism originate
areas which are typical for males, such as the face,
as a result of renal ischemia occurring in the patients
upper pubic triangle, chest, areolae, back, buttock,
with a narrowing of one or both of the major renal ar-
thighs, ears, nose, and back of the hands and feet.
teries (renal artery stenosis) either by an atheroscle-
According to the period of ontogenesis in which
rotic plaque or by fibromuscular hyperplasia. Over-
adrenal androgen overproduction originates, prena-
production of renin from both kidneys also occurs
tal and postnatal forms of adrenal virilization are
in association with severe arteriolar nephrosclerosis
distinguished. Adrenal androgen hypersecretion may
(malignant hypertension) or secondary to profound
be either selective or may be associated with the
renal vasoconstriction (accelerated phase of hyper-
secretion of smaller or greater amounts of other
tensive disease).
adrenocortical hormones. In patients with congen-
4. Primary hyperreninism (Robertson syndrome). ital form it may be associated with decreased pro-
It is a rare disease induced by autonomous renin- duction of glucocorticoids and simultaneosly with in-
secreting renal or extrarenal neoplasm. Plasma con- creased or decreased secretion of mineralocorticoids.
centration of renin is high. Renin-secreting tumor, In patients with acquired form of adrenal androgen
made up of juxtaglomerular cells or hemangioperi- hypersecretion, adrenal virilization may be associ-
cytes, occurs most commonly in young patients with ated with excessive production of glucocorticoids and
severe arterial hypertension. Secondary hyperaldos- some characteristics of Cushing’s syndrome.
384 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

A. Prenatal form of adrenal virilization which is present. The three following distinctive syn-
dromes may be segregated:
Prenatal form of adrenal virilization (congenital • Simple virilization (simple virilizing adrenogen-
adrenal hyperplasia, congenital adrenogenital syn- italism)
dromes) is a disease owing to inherited enzymatic
defects (inherited enzymopathy) in cortisol biosyn- • Virilization with sodium depletion (salt-wasting
thetic pathway. Any of the enzymes participating adrenogenitalism)
in cortisol synthesis can be affected (a defect in en-
zyme quantity or activity) and, therefore, cortisol • Virilization with sodium retention (salt-retai-
production is permanently insufficient. Since corti- ning adrenogenitalism)
sol is the principal adrenal steroid regulating ACTH
The first two clinical syndromes are due to 21-
synthesis, and since the ACTH stimulates both corti-
hydroxylase deficiency occurring in about 95 % of
sol and andrenal androgen production, an enzymatic
all patients with prenatal form of adrenal viriliza-
interference with cortisol synthesis may result in the
tion. The third clinical variant is evoked by 11β -
enhanced synthesis of adrenal androgens. Namely,
hydroxylase deficiency and occurs in about 5 % of all
due to low plasma cortisol concentration, pituitary
patients with prenatal form of adrenal virilization.
ACTH secretion is increased by feedback mecha-
nism. ACTH overproduction results in adrenal cor-
tex hyperplasia and excessive secretion of precur-
21-hydroxylase deficiency
sor steroids that are synthetized before the defec- It is a rare disorder. Incidence of its classic form
tive enzyme step. Some of these cortical precur- (prenatal form) in our country is approximately 1
sor steroids belong to precursors of adrenal andro- to 6 000 to 8 000 live births. The deficiency of 21-
gens (pregnenolone and 17α-hydroxyprogesterone). hydroxylase is transmitted as a single-gene autoso-
Production of precursor steroids and thereby also mal recessive trait linked to the major histocompati-
adrenal androgens is, therefore, permanently in- bility complex locus on the short arm of chromosome
creased, which is clinically manifested by the origin 6. It occurs more frequently in persons with HLA-
of virilization. A3, DR7, B14, B35, BW47, B51, and B60 alleles.
21-hydroxylase deficiency has two following clinical
According to the place of enzymatic defects in cor-
variants:
tisol biosynthetic patway, synthesis of mineralocorti-
coids may be normal, insufficient, or excessive. Syn- 1. Simple virilization
thesis of steroid hormones located behind the defec- In the clinical picture of simple virilizing form
tive enzyme step, especially synthesis of cortisol, is of 21-hydroxylase deficiency (simple virilizing
in spite of permanently increased ACTH secretion congenital adrenal hyperplasia) only symptoms
still insufficient. The degree of glucocorticoid def- of virilization (without salt-wasting symptoms)
ficiency and simultaneous adrenal androgen excess are present. It accounts for only about 35 %
depend on the degree of the enzyme deficiency. Due of cases of 21-hydroxylase deficiency. The de-
to the severe degree of enzymopathy (a total lack of fect of this enzyme is present in zona fascicu-
a particular enzyme involved in the biosynthesis of lata and zona reticularis. Conversion of 17α-
cortisol) hypocorticolism and virilization originate, hydroxyprogesterone to 11-deoxycortisol and
already prenataly or in the early childhood (classic thus also synthesis of cortisol stagnate (Fig. 5.1,
forms). In patients with partial adrenal enzyme de- 374). Accumulation of cortisol precursors,
ficiency, symptoms of cortisol deficiency need not be that are synthetized before the defective en-
present at all. Only the symptoms of virilization can zyme step, is present. Accumulated precursor
be clinically manifested, however, only after adoles- steroids, mainly 17α-hydroxyprogesterone and
cence (nonclassic forms, delayed virilizing steroid en- 17α-hydroxypregnenolone are in increased ex-
zymopathies). tent converted to adrenal androgens. In ex-
Prenatal form of adrenal virilization is clinically traglandular tissues adrenal androgens are con-
manifested in three variants depending on the en- verted to the potent testosterone which is the
zyme of adrenal steroidogenesis the deficiency of main cause of virilization.
5.6. Pathophysiology of the adrenal glands 385

2. Virilization with sodium depletion hirsutism, virilization, and male habitus are typical
It accounts for about 65 % of cases of 21- for affected adolescent girls.
hydroxylase deficiency. In the clinical picture, The excessive androgens result in accelerated lin-
besides the symptoms of virilization, the symp- ear growth already in childhood (usually before the
toms resulting from the increased sodium loss age of 10), with bone age exceeding chronologic age.
from organism also occur (salt-wasting con- Since epiphyseal closure is hastened by excessive an-
genital adrenal hyperplasia). The defect of drogens, growth of the long bones stops (usually be-
21-hydroxylase is present not only in zona fore the age of 13), but truncal development con-
fasciculata and zona reticularis, but also in tinues, giving the characteristic appearance of an af-
zona glomerulosa. The consequences of 21- fected subject, whose stature is short and dispropor-
hydroxylase defect in fascicular and reticular tional (well-developed trunk and short extremities).
zones are the same as those of previous variant, High plasma concentrations of progesterone and an-
i.e., virilization originates. However, the defect drogens inhibit hypothalamic-hypophyseal system.
of 21-hydroxylase in zona glomerulosa causes Secretion of GTHs is, therefore, reduced resulting
the block of progesterone conversion to 11- in atrophy of ovaries and disorder of maturation of
deoxycorticosterone (Fig. 5.1, 374). Production ovarian follicles (hypogonadotropic hypogonadism).
of 11-deoxycorticosterone and thus also produc- Uterus remains infantile, menarche does not appear,
tion of succeeding mineralocorticoids, i.e., cor- primary amenorrhea and infertility originate (sexual
ticosterone, 18-hydroxycorticosterone, and al- infantilism).
dosterone, stagnate. In spite of compensatory
increased plasma renin activity, the deficiency At birth there may be enlarged genitalia in the
of mineralocorticoids causes the salt depletion male infant with 21-hydroxylase deficiency. In the
(salt-lossing form of congenital adrenal hyper- postnatal period, congenital adrenal hyperplasia is
plasia). associated with isosexual precocity in the male (pre-
cocious masculinization). High plasma androgen
Virilization. It is present in the clinical picture of concentration in untreated boys accelerates growth
the both variants of classic form of 21-hydroxylase of penis in childhood and causes also premature pu-
deficiency, i.e., in the patients with simple viriliza- bic and axillary hair (already at age 3 to 7). Their
tion and in those having virilization with sodium de- voice starts to break and facial hair appears approx-
pletion. Virilization is usually apparent at birth in imately at the age of 10. The clinical picture of
the female and within the first 2 to 3 years of life in precocious pseudopuberty originates (pseudopuber-
the male. tas praecox). This state is also denoted as macro-
Female fetus with 21-hydroxylase deficiency may genitosomia praecox. Due to inhibition of GTH se-
be virilized in utero, if adrenal androgen production cretion, testes are atrophic and spermiogenesis is ab-
is evidently increased already during intrauterine de- sent. Linear body growth disorder of the boys is the
velopment. Congenital adrenal hyperplasia due to same as that of the girls. The excess of androgens
classic 21-hydroxylase deficiency is the most com- accelerate both linear growth and epiphyseal closure,
mon cause of ambiguous external genitalia in the so despite the early accelerated growth velocity, bone
newborns. Hypertrophy of the clitoris, partial or age advances rapidly and ultimate adult height is
complete labial fusion, and formation of a urogen- diminished. Therefore, affected adult men are of a
ital sinus result from androgen effect on the devel- short stature with disproportionally short limbs.
opment of the external genitalia. Genital ambiguity Sodium depletion. Unlike virilization occurring in
may be so profund that inappropriate sex assignment the both classic variants of 21-hydroxylase deficiency,
may be made at birth. In untreated girls the change sodium depletion occurs only in the patients with
of external genitalia may gradually resemble male the second variant (salt-wasting congenital adrenal
external genitalia (female pseudohermaphroditism). hyperplasia). If the severer degree of aldosterone de-
Complete fusal majus labia resemble scrotum, minus ficiency is present, the symptoms of sodium depletion
labia remain infantile, and enlarged clitoris resembles appear already during the first 2-3 weeks of postna-
a penis. Pubic and axillary hair appears already in tal life. In a short time life threatening disturbance
childhood. Coarse voice, infantile mammary glands, of water and electrolitic metabolism may develop.
386 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

The increased natriuresis causes the origin of hy- than 21-hydroxylase deficiency. Its precise incidence
ponatremia, volume depletion, arterial hypotension, is not known, because it is usually diagnosed only
metabolic acidosis, and hyperkalemia. This distur- in individuals with the severest defect of this en-
bance of water and electrolitic metabolism become zyme. According to some authors, incidence of 11β-
severer due to vomiting and diarrhea occurring al- hydroxylase deficiency is 1 in 100 000 live births, and
ready at the onset of the disease. Later, the affected it accounts for about 5 % of all cases with prenatal
child develops severer dehydration, finally resulting form of adrenal virilization. This disease is inherited
in hypovolemic shock. If the aldosterone deficiency as an autosomal recessive disorder without evidence
is milder, only anorexia, retardation in normal in- of linkage to the HLA locus. The classic form of 11β-
creasing of body weight, and overall failure to thrive hydroxylase deficiency (presented already at birth
of a child are present. or in childhood) is more frequently diagnosed than
The clinical picture of the both classic variants its nonclassic form (with the later-onset and milder
of 21-hydroxylase deficiency is supplemented by the symptomatology). The defect of 11β-hydroxylase is
symptoms of hypocortisolism and hyperpigmenta- present in zona fasciculata and zona glomerulosa.
tion. Hyperpigmentation is the result of increased
In the zona fasciculata 11β-hydroxylase catalyses
secretion of ACTH and other POMC-derived pep-
the terminal step of cortisol biosynthesis, i.e., hy-
tides.
droxylation of 11-deoxycortisol (Fig. 5.1, 374). Due
Some individuals with inherited 21-hydroxylase to 11β-hydroxylase deficiency conversion of 11-de-
deficiency do not manifest the symptoms of viriliza- oxycortisol to cortisol stagnates. Therefore, plasma
tion at birth or during childhood, but only at the cortisol concentration is low. Because of low cor-
time of puberty, or at the onset of adolescence or tisolemia hypothalamic-adenohypophyseal system is
even in adulthood. This form of 21-hydroxylase defi- chronicly stimulated to increased ACTH secretion.
ciency with late-onset adrenal hyperplasia is denoted The result of permanently increased plasma ACTH
as delayed virilizing adrenal enzymopathy (nonclas- level is excessive synthesis of cortisol precursor
sic form of 21-hydroxylase deficiency). It is proba- steroids. 11-deoxycortisol, 17α-hydroxyprogestero-
bly a special group of homozygous carriers of com- ne, and 17α-hydroxypregnenolone accumulate prox-
bination of genic mutations with different degree of imally to the 11β-hydroxylation step. These accu-
expressivity. It seems that the nonclassic disease is mulated precursor steroids, especially 17α-hydroxy-
much more common than the classic one. The first progesterone and 17α-hydroxypregnenolone, are be-
symptom in adolescent girls may be premature pub- ing shunted into the androgen biosynthetic pathway.
arche or persisting acne. In affected women men- The increased substrate flow through the androgen
strual abnormalities and hirsutism of various inten- biosythetic pathway results in an excess adrenal an-
sity may appear. However, virilization, if present, drogen secretion. Therefore, in an affected subject
is minimal. In adolescent boys and adult men with virilization originates (usually already in female fe-
delayed virilizing adrenal enzymopathy gynecomas- tus). Unlike 21-hydroxylase deficiency conversion of
tia, hypotrophy of testes, azoospermia, and infertil- androstenedione to 11-hydroxyandrostenedione is in-
ity may originate. In either, female and male indi- hibited, because 11β-hydroxylase catalyzes this con-
viduals with nonclassic form of 21-hydroxylase defi- version as well (Fig. 5.1, 374).
ciency, sodium depletion does not originates, plasma
ACTH concentration is not increased, symptoms of In the zona glomerulosa the conversion of 11-
hypocortisolism are not present, and hyperpigmen- deoxycorticosterone to corticosterone, and thereby
tation does not occur. also synthesis of aldosterone stagnate due to 11β-
hydroxylase deficiency (Fig. 5.1, 374). However, this
11β -hydroxylase deficiency disorder results in the accumulation and excess secre-
tion of 11-deoxycorticosterone, a weak mineralocor-
Inborn 11β-hydroxylase deficiency is the cause of ticoid. The increased plasma 11-deoxycorticosterone
the origin of the third variant of prenatal form of concentration gives rise to the increased retention
adrenal virilization, i.e., virilization with sodium re- of sodium and water resulting in arterial hyper-
tention (the hypertensive form of congenital adrenal tension despite low plasma renin activity and low
hyperplasia). 11β-hydroxylase deficiency is rarer plasma aldosterone concentration. Therefore, 11β-
5.6. Pathophysiology of the adrenal glands 387

hydroxylase deficiency is also denoted as the hyper- The clinical features of postnatal adrenogenital
tensive form of congenital adrenal hyperplasia. syndrome depend on the sex and age of a patient.
In the clinical picture of the classic form of 11β- Sudden onset of progressive hirsutism and viriliza-
hydroxylase deficiency virilization dominates. De- tion suggests adrenal carcinomas. In the patients
pending on the sex and age, the virilization is mani- with virilizing adrenal adenomas symptoms of viril-
fested equally as it does due to 21-hydroxylase de- ization develop gradually.
ficiency. Simultaneously the symptoms resulting In the girls, virilizing adrenocortical tumors evoke
from the increased plasma 11-deoxycorticosterone manifestations analogous to those originating due
are present. Due to the increased retention of sodium to congenital form of adrenal virilization. Female
and the increased depletion of potassium, hyperv- pseudohermaphroditism, having milder manifesta-
olemia, arterial hypertension, metabolic alkalosis, tions than that of congenital form, originates.
and hypokalemia originate. In the clinical picture In the boys, the clinical picture of precocious pseu-
of the disease the symptoms of hypercortisolism and dopuberty originates. Its manifestations resemble
hyperpigmentation may be also observed. those observed in boys with congenital adrenogen-
In some individuals with inherited 11β-hydroxy- ital syndrome.
lase deficiency the symptoms of virilization may ap- In the adult women, with regard to heterosexual
pear as late as at puberty or even later. This form of hormonal disorder, menstrual irregularities, infertil-
11β-hydroxylase deficiency belongs to the group of ity, hirsutism, breast atrophy, and coarse voice orig-
delayed virilizing adrenal enzymopathies (the non- inate. In the affected women defeminization gradu-
classic form of 11β-hydroxylase deficiency, late-onset ally develops and male habitus originates.
form of the disorder). In the clinical picture of the In the adult men, with regard to isosexual hor-
nonclassic form of 11β-hydroxylase deficiency only monal disorder, hirsutism need not be striking.
the symptoms of overproduction of adrenal andro- Adrenal androgen excess may be unnoticed for a long
gens are present. In both sexes they are analogous time. The disorder is often diagnosed only when at-
to the nonclassic form of 21-hydroxylase deficiency, rophy of testes, azoospermia, and infertility appear.
i.e., they are milder than those of classic form and These symptoms are the consequence of inhibited
virilization is minimal. Plasma ACTH concentration GTH secretion due to increased plasma adrenal an-
is not increased, and, therefore, increased production drogen concentrations. Though testicular androgen
of 11-deoxycorticosterone, sodium retention and ar- secretion is reduced, sexual potence of affected men
terial hypertension do not develop. has not been usually changed because of the effect of
adrenal androgens.
B. Postnatal form of adrenal virilization
Postnatal form of adrenal virilization (postnatal 5.6.2 Pathophysiology of adrenal
adrenogenital syndrome) is caused by an androgen- medulla
secreting adrenocortical tumors. These neoplasms The most common and most significant disease of
may appear in childhood or adulthood. They may the adrenal medulla is pheochromocytoma being the
be in the form of virilizing adrenal adenomas or car- cause of its hyperfunction. While this hyperfunc-
cinomas. Virilizing adrenal adenomas are rare and tional state of the adrenal medulla is exactly de-
are most common in adults. Virilizing adrenal carci- fined, its hypofunctional states are not precisely de-
nomas are the most common adrenal tumors causing fined and their existence is even considered spec-
virilization and appear more frequently in childhood. ulative. Idiopathic orthostatic hypotension, occur-
Adrenal adenomas usually cause a pure viril- ring in middle-aged and elders is sometimes consid-
izing syndrome (an androgen-secreting adenomas). ered a manifestation of hypofunction of the adrenal
Adrenal adenomas which may simultaneously pro- medulla.
duce also cortisol are very rare.
Adrenal carcinomas usually cause a mixed viriliz-
5.6.2.1 Pheochromocytoma
ing syndrome because they secrete not only adrenal
androgens, but also intermediate products of other Pheochromocytoma is a catecholamine-producing
adrenocortical steroid hormones. tumor derived from chromaffin cells. It arises
388 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

most commonly from adrenomedullary chromaf- More than 90 % of pheochromocytomas appear to

fin cells (intraadrenal pheochromocytoma). If a be benign (adenomas), less than 10 % are malig-
catecholamine-producing tumor arises from extraa- nant (carcinomas). Because benign and malignant
drenal chromaffin cells (usually from the sympathetic pheochromocytomas may have an identical histologic
chain in the abdomen), it is denoted as extraadrenal appearance, the only criterion of malignancy is local
pheochromocytoma or paraganglioma. Chromaffin invasion of surrounding tissues and mainly origin of
cells of pheochromocytoma synthesize, store, and distant metastases. The metastases occur more fre-
secrete excess catecholamines (norepinephrine and quently to the related retroperitoneal lymph nodes,
epinephrine). They may be released into circulating liver, lungs, and bones. Paraganglioma is more often
blood continually or intermittently (in paroxysmal malignant than intraadrenal pheochromocytoma.
attacks) causing the origin of severe hemodynamic In about 80 % of the patients with pheochromo-
disorders and also evoke series of metabolic changes. cytoma solitary and unilateral intra-adrenal tumor
In the patients with pheochromocytoma the most accurs. It is more common on the right side. About
evident and severest hemodynamic disorder is the 10 % of cases are bilateral in the adrenals, and about
origin of arterial hypertension (secondary hyper- 10 % are extra-adrenal. Extra-adrenal pheochromo-
tension). It is induced by excess stimulation of cytomas (paragangliomas) are most often located
α-adrenergic receptors of vessels by intermittently within the abdomen, mainly in the area of the or-
or permanently increased plasma noradrenaline con- gan Zuckerkandl (caudal to the origin of the infe-
centrations. Pheochromocytoma occurs in approx- rior mesenteric artery, respectively close to the aor-
imately 0.1–0.2 % of the hypertensive population. tic bifurcation). Extra-adrenal pheochromocytomas
Some authors assume that its real incidence is higher are more rarely located in the thorax (mainly in the
(0.5–0.6 %). Pheochromocytoma may occur at all posterior mediastinum), in the neck, or within the
ages but is most common in young to midadult life. urinary bladder.
In adults pheochromocytoma is more common
Similar clinical manifestations may occur in
than in children. Children account for about 10–
patients with other tumors of sympathetic and
12 % of the total number of cases, boys are affected
adrenomedullary origin, such as ganglioneuroma,
more often than girls. In adults pheochromocytoma
neuroblastoma, and ganglioneuroblastoma. These
most often occurs between 40 and 50 years of age,
tumors, like pheochromocytomas, are derived from
with a slight female preponderance. It is rare after
the neural crest and are located in the adrenal
age 60.
medulla or sympathetic ganglia. Therefore, like
pheochromocytomas, they are often associated with Approximately 90–95 % of pheochromocytomas
excessive production of catecholamines and their are considered as acquired disease with unknown
metabolites. Ganglioneuroma is a benign tumor pathogenesis, they occur sporadically. In about 5–
consisting of mature cells derived from the sympa- 10 % of cases, pheochromocytoma is inherited as an
thetic ganglia. Neuroblastoma is the most imma- autosomal dominant trait either alone or in combina-
ture and malignant of these tumors and is consid- tion with familial multiple endocrine neoplasia (as a
ered derivative of primitive sympathetic cells or neu- part of the MEN 2A and the MEN 2B). Most tumors
roblasts which are intermediate grade in the process in the familial syndromes are bilateral (70 %), but in
of differentiation of primitive sympathetic cells into the nonfamilial setting only 10–15 % are bilateral. In
mature cells of sympathetic ganglion. Ganglioneu- the patients with the MEN syndromes, the adrenal
roblastoma is partially differentiated neuroblastoma medullary involvement may take the form of diffuse
containing also certain amount of mature ganglion or nodular hyperplasia accompanied by one or more
cells. Its malignity is not so severe as that of neu- neoplasms.
roblastoma, therefore, its prognosis is better than The clinical manifestations of pheochromocytoma
that for neuroblastoma. Neuroblastomas almost ex- are the result of intensified physiological and phar-
clusively occur in individuals younger than 18 years macological effects of noradrenaline (norepinephrine)
of age, 85 to 90 % are found in children younger than and adrenaline (epinephrine), the synthesis of which
five years of age. Ganglioneuroma also occurs mainly in its chromaffin cells is increased and autonomous.
in childhood. Unlike the normal adrenal medulla, adrenaline of
5.6. Pathophysiology of the adrenal glands 389

which is major product, pheochromocytoma usu- is normal or sometimes slightly decreased. The other
ally secretes noradrenaline most predominantly. 50 % of all patients with pheochromocytoma have
Most extraadrenal pheochromocytomas secrete no- sustained arterial hypertension without the parox-
radrenaline exclusively, Rarely, pheochromocytomas ysms or crises.
produce adrenaline alone, particularly in association
The paroxysmal release of catecholamines from
with the MEN. Prevailingly increased adrenaline se-
pheochromocytoma and thereby successive paroxys-
cretion may be the evidence of intraadrenal localiza-
mal blood pressure elevation may be evoked by phys-
tion of pheochromocytoma, because only in adrenal
ical (mechanical, termal, or cooling), chemical, or
medulla phenylethanolamine N-methyltransferase,
pharmacological influences. It may be initiated by
which catalyzes the N-methylation of norepinephrine
vigorous palpation of the abdomen or by any activ-
to epinephrine, is present. Malignant pheochro-
ity that displaces the abdominal contents, respec-
mocytomas usually produce increased amounts of
tively increases intraabdominal pressure (e.g., cough-
dopamine.
ing, sneezing, lifting, straining, bending or strenu-
The clinical symptomatology of pheochromocy-
ous excertion of any kind, defecation, micturition,
toma is rather variable depending on the total
coitus, delivery, or change of body position). The
amounts of released noradrenaline and adrenaline,
paroxysm may be also precipitated by trauma, sur-
as well as on the mutual ratio of their concentrations
gical intervention, high or low temperature of the
in circulating blood. The clinical symptomatology of
patient’s surroundings, intake of hot or cold drink
some pheochromocytomas is also influenced by possi-
or meal, intake of alcohol or coffee, and smoking).
ble production of other substances, e.g., enkephalins.
Severe and occasionally even fatal paroxysm or cri-
In the clinical picture of pheochromocytoma com-
sis have been induced by some sedatives, opiates,
bination of arterial hypertension and metabolic
histamine, and glucagon. These agents appear to
changes (symptoms of metabolic syndrome) is most
release catecholamines directly from the pheochro-
common. However, the dominant clinical feature in
mocytoma. In some patients a particular stimulus
patients with pheochromocytoma is arterial hyper-
may reproduce an attack in a characteristic man-
tension. According to the way of catecholamine re-
ner. In other cases the paroxysmal release of cat-
lease from pheochromocytomas (intermittent or con-
echolamines from pheochromocytoma may originate
tinual) three types of the arterial hypertension are
without clearly evident cause (spontaneously), even
distinguished:
during sleep. Mental stress or psychological tension
1. Paroxysmal arterial hypertension does not usualy provoke the paroxysm or crisis.
The paroxysm or crisis is the classic manifestation
2. Sustained arterial hypertension with paroxys-
of pheochromocytoma. It is the consequence of cate-
mal attacks
cholamine release from the tumor and the subsequent
3. Sustained arterial hypertension stimulation of adrenergic receptors. The paroxysmal
attack of blood pressure elevation usually has a sud-
In the both first types of the disease blood pressure den onset. It may last from a few minutes to several
is significantly elevated only during the paroxysmal hours. Most paroxysms subside within 40 minutes.
attaks. The paroxysmal increase of blood pressure is Rarely, more prolonged episodes occur. The parox-
pathognomonic for pheochromocytoma. It occurs in ysm is associated with several symptoms, most evi-
about 50 % of all patients with pheochromocytoma. dent of which are: headache, palpitations, excessive
Approximately in about half of these patients with sweating, and apprehension, often with a sense of
the paroxysmal attacks it occurs as paroxysmal arte- impending doom. Headache may be severe, throb-
rial hypertension and in the other half as sustained bing or steady. It is localized in frontal or occipital
arterial hypertension with the distinct paroxysmal areas. Palpitations are usually the result of tachycar-
attacks. In some patients the blood pressure during dia or cardiac tachyarrhythmia, they may, however,
the paroxysm may be so elevated that a hyperten- occur without these changes of cardiac rhythm. In
sive crisis occurs. In the periods between the parox- some patients other accompanying symptoms may
ysms or crisis catecholamines are not being released occur during the attack. Chest pain and nervous-
from pheochromocytoma, therefore, blood pressure ness or anxiety may accompany the attack. Pal-
390 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

lor or flushing of the face is also frequent, with a result of increased diuresis which is secondary to
flushed, warm feeling afterward. Hands and feet of both the attack of arterial hypertension and glyco-
some patients are cold and sometimes also cyanotic suria.
(acral cyanosis). Mydriasis accompanied by blurred Sustained arterial hypertension (without paroxys-
and vague vision is rather common. Tachypnea and mal attacks) occurs in about 50 % of all patients with
sometimes dyspnea are also present. Gastrointesti- pheochromocytoma. Permanently increased systolic
nal symptoms, mainly epigastric pain, nausea, and and diastolic blood pressure is the result of continual
vomiting are rarer. The decrease of intestinal motil- releasing of catecholamines from pheochromocytoma
ity due to catecholamines may result in constipa- and successive sustained increase of their concentra-
tion. Fine tremor of fingers and eye-lids is some- tion in circulating blood. If blood pressure labil-
times present. Feeling of fatigue, weakness or ex- ity is present, it may sometimes resemble essential
haustion may also appear. Occasional paresthesias hypertension. However, severe headaches, increased
and tetanic convulsions resulting from hyperventila- sweating, frequent palpitations, or also presence of
tive respiratory alkalosis are described. After the symptoms of metabolic syndrome are the evidence
paroxysm the patient feels rather exhausted. After of pheochromocytoma occurrence. It differs from es-
finishing the attack, profuse sweating and increased sential hypertension also by its usual unsatisfactory
diuresis persist even for several hours. response to conventional antihypertensive treatment.
During the severe paroxysm the systolic arterial Prognosis of sustained arterial hypertension is
pressure may be 250–300 mmHg. In these patients determined by the development of complications
angina pectoris or even acute myocardial infarction associated with high blood pressure, mainly by
may occur in the absence of coronary artery disease. atherosclerosis and hemodynamic overload of the left
Catecholamine-induced increase in myocardial oxy- ventricle. In a large number of patients so called
gen consumption and, perhaps, coronary spasm may catecholamine cardiomyopathy, being the result of
play a role in these ischemic events. During a very a direct effect of catecholamines to myocardium, is
severe attack, mainly in the patients with sustained developing. Histologically, numerous focal areas of
arterial hypertension with paroxysmal attacks, blood myocytolysis, and occasionally myofiber necrosis and
pressure may reach critical values associated with interstitial fibrosis, sometimes with mononuclear in-
possible origin of a fatal complication (fatal hyper- flammatory infiltrates, are present. In patients with
tonic crisis). Due to such extreme increase of blood sustained hypertension the development of malig-
pressure there is a danger of cerebral hemorrhage, nant hypertension is relatively fast. However, the
congestive heart failure, or ventricular fibrillation. prognosis of patients affected by sustained arterial
Duration, frequency, and intensity of the parox- hypertension with paroxysmal attacks is worst.
ysms are variable. At the onset of the disease, the Metabolic syndrome is the result of an increased
attacks of arterial hypertension are usually shorter, metabolic rate (glucose and lipid mobilisation), ther-
milder and the intervals between them are usually mogenetic effect (mainly due to increased oxidation
quite long (several months or even several years). In of free fatty acids associated with the increased oxy-
some patients, as the disease progresses, the parox- gen consumption and heat production), and anti-
ysms tend to increase in frequency, severity, and insulin effect of catecholamines. The increased heat
duration. Later, the attaks may occur every day, production is manifested by profuse sweating, heat
or even several times a day. Untreated paroxysmal intolerance, and slightly elevated basal body tem-
type of hypertension may persist lifelong or may be perature even occasionally fever. Hypermetabolism
changed to sustained arterial hypertension without may be manifested by weight loss, mainly in pa-
paroxysmal attacks. tients with continual releasing of catecholamines
Laboratory examination during the attack of hy- from pheochromocytoma. Suppression of insulin se-
pertension reveals hyperglycemia, glycosuria, in- cretion (mediated by stimulation of α2 –adrenergic
creased plasma concentrations of free fatty acids and receptors) and increase of hepatic glucose output
lactic acid, and the increase of BMR. Sometimes the (mediated by stimulation of β–adrenergic receptors)
elevated hematocrit, secondary to diminished plasma are the cause of impaired carbohydrate tolerance and
volume, is present. Plasma volume depletion is the elevated plasma glucose concentrations. Glucose in-
5.7. Endocrine disorders of the ovaries 391

tolerance and hyperglycemia may occur during the 3. The basic cause of endocrine disorder, i.e., in-
paroxysms, later after fasting are also present. born or acquired endocrine disorder.
In untreated patients with sustained arterial hy-
pertension orthostatic hypotension is often present.
4. Number of hormones of which secretion is im-
It is manifested by a significant postural fall in blood
paired, i.e., disorder of only some or all ovarian
pressure (more than 30 mmHg in comparison with
steroid hormones.
current values of the patient) accompanied by dizzi-
nesses. In some patients with orthostatic hypoten-
sion collapse may sometimes originate. Hypotension
may last several minutes. During trauma or surgi- 5.7.1 Ovarian endocrine hypo-
cal intervention in untreated patients with pheochro- function
mocytoma unexplained hypotension or circulatory
shock may develop. Hyposecretion of ovarian hormones is denoted as
In the patients with untreated pheochromocytoma female hypogonadism (hypogonadismus femininus).
several factors probably participate in the origin of Its etiopathogenesis is rather variable. The cause
orthostatic hypotension. It may be partly a con- of ovarian hormone deficiency may be within the
sequence of hypovolemia (as a result of increased ovaries themselves (primary female hypogonadism),
diuresis which is secondary to arterial hyperten- in the adenohypophysis (secondary female hypogo-
sion and glycosuria), and partly a consequence of nadism), or in the hypothalamus (tertiary female hy-
blunted postural reflexes due to a prolonged excess pogonadism). The clinical picture of ovarian hypo-
of catecholamines. According to some authors ortho- function depends on the age of a patient in the time
static hypotension occurs mainly in the patients with of its origin. If the ovarian endocrine hypofunction
oversecretion of adrenaline and enkephalins from originates prior to puberty in girls its consequences
pheochromocytoma. begin usually to appear at the time of expected on-
set of puberty. Insufficient sexual maturation (sexual
infantilism) develops. If the ovarian endocrine hypo-
function originates in adult female it is manifested
by menstrual abnormalities and infertility.
5.7 Endocrine disorders of the
ovaries 5.7.1.1 Primary ovarian hypofunction

Primary (peripheral) ovarian hypofunction is a com-

plete disorder of ovarian hormone secretion, i.e., the
Endocrine disorders of the ovaries are the third production of all ovarian steroid hormones is insuffi-
most common endocrinopathy, more frequent are cient. Primary ovarian hypofunction can result from
only the thyroid gland disorders and the disorders multiple causes, but principally it may be inborn or
of the endocrine portion of the pancreas. Their clas- acquired. The menopause is a special form of pri-
sification has not been yet sufficiently transparent mary ovarian hypofunction (physiological cessation
and uniform. At present pathogenetic classification of ovarian function). However, cessation of ovar-
has been considered most convenient. It is based on ian function can occur at any age, even in utero. If
the following four criteria: it occurs before puberty, the presentation is as pri-
1. The type of intensity of hormonal secretion, i.e., mary amenorrhea; after pubertal development and
hyposecretion or hypersecretion of ovarian hor- menarche the presentation is as secondary amenor-
mones, respectively secretion of hormones atyp- rhea. Due to decreased plasma ovarian hormone con-
ical for ovaries. centrations hypothalamic-adenohypophyseal area is
stimulated to increased secretion of gonadotropins
2. The place of origin of an endocrine disorder, i.e., by feedback mechanism. The pituitary gonadotropin
primary, secondary, or tertiary disorder of hor- concentrations in circulating blood are, therefore, in-
monal secretion. creased (hypergonadotropic female hypogonadism).
392 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

A. Inborn primary ovarian hypofunction resides in the response of the chondrocyte to the so-
It may originate due to ovarian agenesis, gonadal matomedins.
dysgenesis with abnormal karyotype (most common The most common congenital somatic anomalies
Turner syndrome), gonadal dysgenesis with normal of Turner syndrome include: short and broad neck
karyotype (pure gonadal dysgenesis), or ovarian 17α- (even bilateral neck webbing) with a low posterior
hydroxylase deficiency (adrenal cortex is usually si- hairline; redundant skin folds on the back of the
multaneously affected by this hereditary enzymopa- neck (pterygium colli); micrognathia (shortened up-
thy as well). Inborn primary ovarian hypofunction per jaw); prominent, low-set, rotated or deformed
occurs in about 30 % of female patients with a disor- ears or both; a fish-like mouth; a narrow, high arched
der of sexual maturation. palate (Gothic palate); ptosis; a square shield-like
Turner syndrome chest with widely spaced nipples; and increased num-
ber of pigmented nevi. Additional anomalies which
It is the best known form of inborn primary ovar- are less common include: cubitus valgus, short fourth
ian hypofunction and most common among gonoso- metacarpals, strabismus, congenital heart disease
mal anomalies causing the disorder of sexual mat- and renal abnormalities, lymphedema of the dorsum
uration of adolescent girls. Its incidence in female of the hands and feet, puffiness of the dorsum of the
population is about 0.03 %. fingers, and hypoplastic nails. Sometimes also fur-
From the cytogenetic point of view it is a simple ther skeletal anomalies may be present.
monosomy X manifested by the 45,X karyotype of
all cells of the patient (symbolic sign is 45,X0). Mo- The genital ducts and external genitalia are fe-
saic monosomy X is also known. In the patients with male in character (female phenotype) but immature.
mosaicism the cells with the normal 46,XX karyotype The external and internal genitalia remain infantile,
occur along with the cells with the 45,X0 karyotype there is no breast development, uterus and tubes are
(the 45,X0/46,XX karyotype). Other mosaic pat- hypoplastic, and menstruation is absent (primary
terns, e.g., 45,X0/47,XXX or 45,X0/46,XX/47,XXX, amenorrhea). The secondary sexual characteristics
are rarer. Genotype and phenotype of the affected have not been developed. In an affected subject
individual is female. Due to gonosomal anomaly only the clinical picture of sexual infantilism originates.
bilateral streak rudimentary gonads (dysgenetic go- Psychosexual feeling of an affected subject is female.
nads) are present instead of the ovaries. Neither oo- The mental status of these patients is usually nor-
genesis nor biosynthesis of steroid hormones are re- mal, but a few may exhibit some signs of mental
alized in these fibrous gonadal streaks. Therefore, it retardation.
is characterized primarily by hypogonadism in phe- The clinical picture of mosaic variants of mono-
notypic female. somy X is variable. The 45,X0/46,XX mosaicism
The clinical picture of simple monosomy X (typi- is the most common. Some patients with the
cal Turner syndrome, the classic form of the 45,X0 45,X0/46,XX karyotype may have the some clini-
gonadal dysgenesis) is characterized by short stature, cal features as those with the 45,X0 karyotype, how-
multiple congenital anomalies, and disorder of sexual ever, the patients without an evident clinical symp-
maturation. tomatology may be also found. A gonadal differ-
In adult affected women, the average height rarely entiation may vary from that of a gonadal streak
exceeds 150 cm, the legs are usually shorter com- to that of an ovary. More women with this form
pared with the trunk (disproportional stature). The of mosaicism usually exhibit fewer of the associated
growth retardation and disorder of skeletal matura- somatic anomalies, are not invariably short stature,
tion appear in about 8th year of age. They are sup- and may menstruate and even be fertile. In some in-
posed to be the secondary changes conditioned by dividuals with the 45,X0/46,XX karyotype its clin-
deficiency of estrogens, probably secondary to the ical manifestation may appear as late as after pu-
lack of the estrogen-induced rise in plasma growth berty as postpubertal female hypogonadism. Vari-
hormone concentration and consequently insufficient ous degrees of Turner’s stigmatization, and gonadal
production of IGF I at puberty. As yet, the exact dysgenesis and dyshormogenesis are most common.
cause of the progressive growth failure has not been These introduced differences in intensity of the clin-
defined. It is also considered that the abnormality ical features in individuals with the presence of the
5.7. Endocrine disorders of the ovaries 393

45,X0/46,XX mosaicism probably depend on mutual disproportional linear growth (eunuchoidal habitus).
quantitative ratio of the cells of both lines, e.g., the At present, postpubertal primary ovarian hypog-
cells with the 45,XO karyotype and those with the onadism is included among disorders of the men-
46,XX karyotype in the gonads and in peripheral tis- strual cycle and infertility, which besides periph-
sues. eral comprise also central (hypothalamic and pitu-
itary) ovarian hypofunction originating during re-
B. Acquired primary ovarian hypofunction productive years of women. Principally premature
menopause originates (women cease menstruating
Etiology of acquired primary ovarian hypofunction prior to age 40). In affected women secondary amen-
is usually miscellaneous. The foundation of its origin orrhea and infertility occur. Internal genitalia and
may be an impairment of the gonads already in utero, mammary gland atrophy, and sparse pubic hair may
e.g., due to a viral disease of the mother. Another appear. In most affected women changes similar to
cause of acquired primary female hypogonadism may those typical for the period of the female climac-
be autoimmune oophoritis, which participates in the teric, mainly osteoporosis, symptoms of vegetative
origin of about 20 % of acquired primary ovarian hy- vasomotor lability, and psychological changes, may
pofunction. Antiovarian autoantibodies are present occur.
in circulating blood, the ovaries are infiltrated by
the lymphocytes. The result of autoimmune inflam-
5.7.1.2 Central ovarian hypofunction
matory process is the origin of hypoplastic ovaries
and insufficient secretion of ovarian hormones. Ovar- In women with central ovarian hypofunction plasma
ian failure due to ovarian antibodies is often associ- gonadotropin concentrations are low, therefore, it is
ated with other autoimmune endocrinopathies and also denoted as hypogonadotropic female hypogo-
also with autoimmune diseases of other organ sys- nadism. It may be associated with only insufficient
tems. Acquired primary ovarian hypofunction may secretion of progesterone (a partial disorder of ovar-
be induced also by other factors, such as gonadal ian hormone production) or with insufficient secre-
damage by radiation therapy or cytotoxic chemother- tion of all ovarian steroid hormones (a complete dis-
apy, polycystic ovarian disease, and rarely by mumps order of ovarian hormone production).
oophoritis. The cause of peripheral ovarian hypo- Partial central ovarian hypofunction is character-
function may be also bilateral ovariectomy. ized by insufficient production of progesterone. Its
The clinical picture of acquired primary ovarian cause may be hyperprolactinemia or insufficient se-
hypofunction depends on the age at which the ovar- cretion of gonadotropins in the time of ovulation or
ian hormone deficiency develops (before or after pu- during luteal phase of menstrual cycle. It may be
berty). manifested as luteal phase dysfunction, respectively
At present, prepubertal primary ovarian hypo- as estrogen breakthrough bleeding which is one of
function ranks among a common term the disorder the forms of anovulatory bleeding (anovulatory cy-
of sexual maturation (delayed puberty and sexual cles). Estrogen breakthrough bleeding occurs when
infantilism), which originates in girls before puberty continuous estrogen stimulation of the endometrium
not only in the consequence of peripheral, but also is not interrupted by cyclic progesterone secretion
of central (pituitary or hypothalamic) ovarian hy- and withdrawal.
pofunction and as a consequence of inborn primary Etiology of complete central ovarian hypofunction
ovarian hypofunction as well. The disorder of sexual has been partialy mentioned in the chapter on patho-
maturation is clinically manifested in the time of ex- physiology of hypothalamic-adenohypophyseal sys-
pected puberty, when its signs begin to appear. All tem. In the following text, therefore, general survey
signs of the onset of puberty (thelarche, pubarche, of central ovarian hypofunction will be presented.
adrenarche, and menarche) are usually absent. Pu- Female hypogonadotropic hypogonadism may be
berty does not appear spontaneously, external and induced either by organic or functional disorders of
internal genitalia remain infantile. In affected fe- the CNS-hypothalamic-pituitary axis. Organic le-
male primary amenorrhea and infertility originate. sions of the hypothalamic-adenohypophyseal area in-
Secondary sexual characteristics are immature. Epi- clude, e.g., tumors (craniopharyngioma, germinoma,
physeal plates remain open for a long-time leading to astrocytoma, glioma, hamartoma, and metastatic
394 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

tumors), granulomas, aneurysms, cysts, inflamma- 5.7.2 Ovarian endocrine hyper-

tory process, and head trauma. Hypogonadotropic function
hypogonadism may be associated with some in-
born syndromes, as such Laurence-Moon-Biedl- Hypersecretion of ovarian hormones is denoted as fe-
Bardet syndrome and Kallmann syndrome. Hypogo- male hypergonadism (hypergonadismus femininus).
nadotropic hypogonadism may be also a part of pan- The cause of its origin may reside in the ovaries (pri-
hypopituitarism. Combinated deficiency of growth mary female hypergonadism), in the adenohypoph-
hormone and gonadotropins (combinated hypopitu- ysis (secondary female hypergonadism), or in the hy-
itarism) is rare. More commonly, female hypogo- pothalamus (tertiary female hypergonadism). The
nadotropic hypogonadism arises from functional dis- clinical picture of ovarian hyperfunction depends on
orders of the hypothalamus or higher nerve cen- the age of a patient at the time of its origin. Primary
tres. They include psychoemotional stress (psy- (peripheral) ovarian hypergonadism occurs mainly
chogenic amenorrhea), weight loss associated with after puberty, central (secondary and tertiary) hy-
dieting or malnutrition, rigorous excercises (such as pergonadism occurs prevailingly before puberty.
long-distance running or other athletic disciplines,
ballet, dance, or swimming), and anorexia nervosa. 5.7.2.1 Primary ovarian hyperfunction
Delayed puberty may be also evoked by idiopathic
The cause of the origin of peripheral ovarian hyper-
hypogonadotropic hypogonadism or it may occur as
function may be the ovarian hormonally active be-
constitutional delay in growth and puberty.
nign or malignant tumors. According to the kind of
Central ovarian hypofunction may be caused produced hormones they are divided into feminizing
also by other endocrine and nonendocrine diseases and virilizing tumors. The concentrations of circulat-
primarily not afecting reproductive system of a ing gonadotropins are decreased by feedback mecha-
woman. Other endocrine diseases include mainly nism (hypogonadotropic female hypergonadism).
severer hypothyroidism or hyperthyroidism, insuffi-
ciently compensated diabetes mellitus, Cushing syn- A. Feminizing ovarian tumors
drome, Addison disease, hyperprolactinemia, con-
Excess estrogens may be produced by hormonally
genital adrenal hyperplasia, and all virilizing syn-
active granulosa cell neoplasms, theca cell neoplasms,
dromes. Nonendocrine diseases include obesity, con-
primary ovarian carcinoma, and rarely by cystade-
genital heart diseases, severer anemia, pulmonary
nofibroma. The cells of these estrogen-secreting
tuberculosis, collagenosis, and chronic renal failure.
ovarian tumors produce estrogens autonomously.
Prognosis of ovarian hypofunction in the patients
Granulosa cell tumors are the most frequent hor-
with these endocrine or nonendocrine diseases de-
monally active ovarian neoplasms. They account for
pends on the development and on the treatment of
about 1–3 % of all ovarian neoplasms. About 55 % of
the primary disease.
granulosa cell tumors originate during reproductive
The clinical features of central ovarian hypofunc- years of women, 40 % in post-menopausal women,
tion depend on the age at the time of its origin. If and 5 % before puberty. They are composed of cells
it originates before puberty, it evokes the disorder resembling granulosa cells of Graafian follicle. These
of sexual maturation manifested by delayed puberty tumors belong to malignant tumors, but their ma-
or sexual infantilism. Central ovarian hypofunc- lignity and hormonal activity are variable. The tu-
tion originated after puberty is manifested by men- mors originated before puberty are malignant only
strual irregularities even by secondary amenorrhea very rarely. Granulosa cell ovarian tumors are usu-
and infertility. The signs and symptoms of female ally unilateral. Besides estrogens they may produce
hypogonadotropic hypogonadism are usually asso- also gestagens, and occasionally androgens. Some-
ciated with other clinical features (e.g., symptoms times these tumors may contain a mixture of granu-
of deficiency of other adenohypophyseal hormones, losa and theca cells.
symptoms resulting from compression of structures Theca cell tumors occur more rarely than granu-
of hypothalamic-pituitary area, symptoms of other losa cell tumors. In 70 % of cases they may be discov-
endocrine or nonendocrine primary diseases, and the ered in the post-menopausal period. During repro-
like) depending on the cause of its origin. ductive years of women they occur mainly after the
5.7. Endocrine disorders of the ovaries 395

age of 30. In younger females they are seen rarely. Arrhenoblastoma (androblastoma) recapitulates,
They do not occur before puberty. They are prevail- to a certain extent, the cells of the testis (Sertoli-
ingly benign. Histologically, they are composed of Leydig cells) at various stages of development.
the cells resembling those of theca interna of ovarian They are the most common virilizing ovarian tu-
follicle. They are usually unilateral. Along with es- mors. They are malignant in about 20 % of cases.
trogens they may produce also progestogens and oc- They usually originate during reproductive years of
casionally androgens. Sometimes, theca cell tumor women, mainly between the ages 20 and 40.
may coexist with granulosa cell tumor. Hilar cell tumors are almost always benign. They
The clinical features of feminizing tumors are con- usually occur in the perimenopausal period. These
ditioned by hypersecretion of estrogens and depend tumors originate rarely and are unilateral.
on the age of a female in the time of their origin. The clinical picture of virilizing ovarian tumors
In childhood they result in the origin of preco- is conditioned by overproduction of androgens. It
cious sexual maturation of prepubertal girls (iso- is usually the same as the clinical picture in the pa-
sexual precocious pseudopuperty, pseudopubertas tients with virilizing neoplasms of adrenal cortex. At
praecox isosexualis) with irregular uterine bleed- the onset of the disease hirsutism originates. It grad-
ing and hypoplastic endometrioma. The increased ually progresses to striking virilization and masculin-
plasma estradiol level inhibits secretion of pituitary ization. Plasma testosterone and sometimes also an-
gonadotropins by feedback mechanism. In the con- drostenedione concentrations are increased. In the
sequence of low plasma GTH concentrations the patients with virilizing ovarian tumors, unlike those
ovaries remain immature, ovulation is not present, with virilizing neoplasms of adrenal cortex, plasma
female is infertile. Breast development appears pre- adrenal androgen concentrations are normal.
cociously (precocious thelarche), the vaginal mucosa
thickenning originates, vaginal cytology examination 5.7.2.2 Central ovarian hyperfunction
reveals various degrees of estrogenism, labia minora
Central ovarian hyperfunction is conditioned by
are enlarged. The rate of skeletal maturation, height
the increased secretion of adenohypophyseal go-
velocity, and somatic development increase, but epi-
nadotropins and by the successive increase of their
physeal fusion is premature. These changes lead to
concentrations in circulating blood. It is, therefore,
the paradox of tall stature in childhood but short
also denoted as hypergonadotropic female hyperg-
adult height. The stature of the adult affected man
onadism. It may be associated with hypersecretion
is short and disproportional (the legs are short in
of all ovarian hormones (complete central ovarian
relation to the trunk).
hyperfunction) or with only some ovarian hormones
If feminizing tumor originates in reproductive
(partial central ovarian hyperfunction). The com-
years of a woman, various manifestations of hyper-
plete ovarian hyperfunction originates only before
estrogenism appear. Abnormal uterine bleeding, in-
puberty, the partial ovarian hyperfunction may orig-
terrupted by amenorrhea of various duration, is most
inate before or after puberty.
frequent. A feminizing tumor originated in the post-
menopausal period is associated with enlargement of A. Complete central ovarian hyperfunction
mammary glands, endometrial hyperplasia, and ab-
normal uterine bleeding. On laboratory examination It may be induced by functional (more com-
an increased plasma estradiol concentration is found. mon) or organic disorders of the hypothalamic-
Plasma FSH and LH levels are low. hypophyseal area. In affected girls it is clinically
manifested by the origin of true precocious pu-
berty (pubertas praecox vera). Etiology and clini-
B. Virilizing ovarian tumors cal features of precocious secretion of hypothalamic
They are also denoted as masculinizing ovarian tu- gonadotropin-releasing hormone (LHRH), as well as
mors. They produce androgens, mainly testosterone. etiology of primary induced precocious secretion of
They form a heterogenous group of neoplasms, the pituitary gonadotropins have been described in the
classification of which has not been standardized yet. chapter on the pathophysiology of hypothalamic-
The best known of them are arrhenoblastoma and hi- adenohypophyseal system. The causes of true pre-
lar cell tumors. cocious puberty in girls are almost the same as those
396 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

in boys. However, while in boys the organic cause of 3. Stein-Leventhal syndrome

the origin of true precocious puberty is discovered in About 1.5–3.5 % of female population are affected
about 60 % of cases, in girls the organic lesion can by this syndrome. It is probably a familial, geneticly
be proved only in 15–20 % of the patients. In both conditioned disease. Type of heredity is not exactly
sexes the rest of the cases accounts for idiopathic true known, but X-linked type inheritance is supposed.
precocious puberty. From morphological point of view it is character-
ized by evidently enlarged ovaries (usually twice nor-
B. Partial central ovarian hyperfunction
mal size), with whitish colour and nacrous lustre of
It has three forms: follicular cyst, luteal cyst, and their smooth surface. Albuginea tunica is thickened,
Stein-Leventhal syndrome. subcortical multiple follicles in various stages of atre-
1. Follicular cyst. sia are present. In women with Stein-Leventhal syn-
It originates from a cystic formation of atretic fol- drome, the classic term polycystic ovaries is, there-
licles which arise due to involution of the original fore, misleading, because the ovaries are studded
primordial, primary, secondary or Graafian follicle. with atretic follicles, not with cysts. The ovarian
The cystic formation contains pure liquid and is a stroma and theca cells are hyperplastic. Corpora al-
normal part of atretic follicles. Probably due to ex- bicans are rare or absent.
cess stimulation by gonadotropins a cystic formation From endocrinological point of view the syndrome
of one or more atretic follicles may be evidently en- is characterized by twofold even threefold increase of
larged. One or several follicular cysts being able to LH/FSH ratio in plasma. The increase of this ratio is
produce estrogens. In a short time follicular cysts conditioned mainly by the evident increase of plasma
usually regress spontaneously by resorption, disrup- LH level. Plasma FSH concentration may be normal
tion, or by hemorrhage into the cyst. However, some or decreased.
of them may persist and cause a permanent overpro- Pathogenesis of Stein-Leventhal syndrome is not
duction of estrogens (persisting estrogen-secreting exactly known. The increase in both the pulse am-
follicular cyst). In girls it is manifested by prema- plitude and the frequency of LH pulses, which is the
ture thelarche, true precocious puberty, or by tran- fundamental pathogenetic mechanism, is conditioned
sient or incomplete sexual precocity. In adult women by an abnormality of the LHRH pulse generator lo-
it is manifested by abnormally severe and long men- cated in the hypothalamus. The most plausible ex-
strual bleeding (menorrhagia) or by bleeding from planation is that the increased secretion of LH oc-
the uterus in other than normal menstrual periods curs secondary to disturbances in steroid feedback in
(metrorrhagia, acyclic vaginal bleeding). the hypothalamic-pituitary unit. On biochemical ex-
2. Luteal cyst amination several days lasting irregular waves of in-
It originates spontaneously or may be iatrogenic due creased plasma LH concentrations have been found.
to long-lasting administration of clomiphene (antie- However, in an affected woman typical ovulatory
strogen). Spontaneous luteal cyst is considered as peak of plasma LH concentration is missing. Per-
the corpus luteum persisting after unnoticed early manently increased plasma LH level stimulates syn-
miscarriage. Iatrogenic luteal cysts are usually mul- thesis of androgens in the cells of the theca interna
tiple and cause enlargement of the ovary. Luteal cyst and in the interstitial cells of the ovary (both kinds of
may also originate due to stimulative effect of human these cells have LH receptors and enzymes catalyz-
chorionic gonadotrophin (hCG) produced by ovarian ing the biosynthesis of androgens). Plasma androgen
choriocarcinoma. Luteal cyst autonomously and per- (mainly testosterone and androstenedione) concen-
manently produces estrogens and progestogens usu- trations are, therefore, permanently increased. But,
ally in larger amounts than they are produced by plasma adrenal androgen concentrations are normal.
the corpus luteum during luteal phase of the nor- In about 15–20 % of affected women plasma pro-
mal menstrual cycle. In the prepubertal girl it is lactin level is also moderately increased. Hyperpro-
manifested by sexual precocity. In adult woman it lactinemia is probably the result of dopamine defi-
is manifested by a sudden origin of amenorrhea, hy- ciency in hypothalamus, which is the most impor-
peremic cervix uteri, hyperemic vagina, and enlarged tant prolactin-inhibiting factor (PIF). Dopamine de-
and sensitive breasts. ficiency may be the evidence of the existence of more
5.8. Endocrine disorders of the testes 397

extensive dysfunction of hypothalamus in women 5.7.3 Secretion of hormones atypical

with Stein-Leventhal syndrome. for the ovaries
Because the plasma androgens are a substrate for The ovaries may produce human chorionic go-
peripheral aromatization (mainly in the cells of fat nadotrophin (hCG), thyroid hormone, or serotonin.
tissue) their permanently elevated concentration in Thyroxine is secreted by some specialized ovarian
circulating blood usually results in an increased for- teratomas. High level of hCG is caused by ovar-
mation of extraglandular estrogens. The increased ian choriocarcinomas, occasionally dysgerminomas,
plasma estrogen concentration, conditioned by the and rare immature malignant teratomas. Serotonin
mentioned mechanism, is considered as the cause of may secrete primary or metastatic intestinal ovarian
inhibition of FSH secretion by a negative feedback, carcinoids.
and the cause of stimulation of LH secretion by a Ovarian choriocarcinomas. They are very malig-
positive feedback, giving the characteristic LH/FSH nant tumors. Most of them exist in combination with
ratio in plasma. In women with Stein-Leventhal syn- other germ cell tumors, pure ovarian choriocarcino-
drome (with or without obesity) insulin resistance mas are extremely rare. Ovarian choriocarcinoma
has been discovered. The increased plasma insulin usually originates in girls before puberty. As hCG
concentration is supposed to stimulate androgen se- itself (also LH itself), without simultaneous presence
cretion in ovarian stroma. Insulin may probably act of FSH, does not stimulate ovarian estrogen produc-
on the ovary via IGF receptors. tion. Therefore, the increased plasma level of hCG
does not induce precocious sexual maturation of af-
Stein-Leventhal syndrome begins clinically mani- fected girls. Precocious pseudopuberty cannot origi-
fest usually in the period of adolescence or in young nate unless estrogens have been simultaneously pro-
women (in 2nd or 3rd decennium). Varying degrees duced by ovarian choriocarcinoma.
of hirsutism appear. In adolescent girls it may cause Specialized ovarian teratomas. The most com-
late onset of menarche, but uterine bleeding is dys- mon of them are struma ovarii and carcinoid. They
functional and is unpredictable in onset, duration, are unilateral. Teratomas that contain mature thy-
and amount. Oligomenorrhea (prolonged menstrual roid tissue (struma ovarii) may secrete thyroxine, al-
cycle over 35 days), hypomenorrhea (weak menstrual though rarely in sufficient quantities to cause thy-
bleeding), and amenorrhea ensue after a variable rotoxicosis. This type of teratomas is usually be-
time. About 5–10 % of affected women present with nign. Primary ovarian and metastatic intestinal car-
primary amenorrhea. Due to hormonal inbalance cinoids may secrete serotonin (5-hydroxytryptamine)
ovarian follicles mature insufficiently, and, therefore, in quantities sufficient to produce the carcinoid syn-
multiple atretic follicles are found. These women drome. The primary ovarian carcinoid presum-
have persistent anovulation and are infertile. About ably rises from intestinal epithelium in a teratoma.
40 % of affected women are obese. Metastatic ovarian carcinoid is virtually always bilat-
eral. A combination of struma ovarii and carcinoid
Stein-Leventhal syndrome is considered a special in the same ovary is very rare.
type of polycystic ovarian syndrome. The term poly-
cystic ovarian syndrome includes those endocrine
states which lead to the origin of multiple ovarian
cysts associated with similar functional abnormal-
ities to those occuring in the patients with Stein-
Leventhal syndrome. Such diseases include: clas-
5.8 Endocrine disorders of the
sic and nonclassic virilizing adrenal enzymopathies, testes
virilizing tumors of adrenal cortex, Cushing syn-
drome, hyperthyroidism, hypothyroidism, and acan-
thosis nigricans. Heterogenity of polycystic ovarian
syndrome points up the fact that polycystic ovaries Classification of endocrine disorders of the testes,
may also occur in about 20 % of healthy and fertile similarly as classification of endocrine disorders of
women. the ovaries, has not been yet sufficiently transparent
398 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

and uniform. At present pathogenetic classification testes syndrome”), bilateral cryptorchidism, testicu-
has been considered most convenient. It is based on lar biosynthetic defect (enzymopathy), and agenesis
the following three criteria: of Leydig cells.
The most common form of inborn primary male
1. The type of intensity of hormonal secretion, hypogonadism is Klinefelter syndrome. Other forms
i.e., hyposecretion or hypersecretion of testicu- of gonosomal anomalies are rare.
lar steroid hormones.
Klinefelter syndrome
2. The place of origin of an endocrine disorder, i.e., Klinefelter syndrome (syndrome of seminiferous
primary, secondary, or tertiary disorder of hor- tubular dysgenesis) is the most common form of pri-
monal secretion. mary male hypogonadism. Its incidence is approx-
3. The basic cause of endocrine disorder, i.e., in- imately 0.1–0.2 % of male population. It originates
born or acquired endocrine disorder. due to gonosomal anomaly. From the cytogenetic
point of view it is a simple trisomy XXY mani-
fested by the 47,XXY karyotype of all cells of the pa-
5.8.1 Hyposecretion of testicular hor- tient (the classic form of Klinefelter syndrome). The
mones mosaic form of Klinefelter syndrome has been also
found. There are several variants of the mosaic form.
Deficiency of testicular androgens is also denoted as
The most common of them being the one with the
male hypogonadism (hypogonadismus masculinus).
47,XXY/46,XY karyotype. Other mosaic patterns,
It is almost always accompanied also by insufficient
e.g., 47,XXY/48,XXXY or 47,XXY/48,XXYY, are
spermatogenesis, however, in most adult men with
rarer. The classic form accounts for about 80–90 %
insufficient spermatogenesis regulated by FSH, the
and the mosaic form for about 10–20 % of all cases
deficiency of testicular androgens regulated by LH is
of Klinefelter syndrome.
not present. Hyposecretion of testicular androgens
Pathogenesis. The classic form of the 47,XXY
occurs more often than their hypersecretion.
trisomy results from nondisjunction of the chromo-
Pathogenesis of hyposecretion of testicular hor-
somes during either the first or second meiotic divi-
mones is variable. Principally, the male hypogo-
sions in the course of gametogenesis in one of the par-
nadism may be divided into peripheral and central
ents. About 40 % of the responsible meiotic nondis-
hypogonadism. Hypogonadism conditioned by the
junctions occur in the father during spermatogene-
disorder on the level of peripheral tissues (resistance
sis, and 60 % occur in the mother during oogenesis.
of target tissues to androgens or the disorder of their
The result of meiotic nondisjunction of XX chromo-
degradation by cells of peripheral tissues) is a sepa-
somes during oogenesis is the origin of one ovum with
rate form of hypogonadism.
XX chromosomes (its karyotype is 24,XX) and the
other ovum has no X chromosome (its karyotype is
5.8.1.1 Primary male hypogonadism 22,O). After fertilization of an ovum with the 24,XX
The cause of its origin is within the testes them- karyotype by a sperm with the 23,Y karyotype, the
selves, therefore, it is also denoted as peripheral or zygote with the 47,XXY karyotype originates. The
testicular hypogonadism. It may be inborn (con- result of meiotic nondisjunction of XY chromosomes
genital) or acquired. Primary male hypogonadism during spermatogenesis is the origin of one sperm
is characterized by the increased concentration of with the 24,XY karyotype and the other sperm with
gonadotropins (mainly LH) and decreased plasma the 22,O karyotype. After fertilization of a 23,X
testosterone level. It is, therefore, also denoted as ovum by a 24,XY sperm the 47,XXY zygote origi-
hypergonadotropic male hypogonadism. nates. The 47,XXY zygote may also originate after
fertilization of a 24,XX ovum by a 23,Y sperm. There
is no phenotypic difference between those who re-
A. Inborn primary male hypogonadism
ceive the extra X chromosome from their father and
Its most common cause are gonosomal anomalies. those who receive it from their mother. The cause of
Occasionally it may originate due to testicular age- meiotic nondisjunction of XX chromosomes during
nesis, gonadal dysgenesis, anorchia (the ”vanishing oogenesis may be advanced maternal age. The influ-
5.8. Endocrine disorders of the testes 399

ence of age on paternal nondisjunction of XY chro- in the liver. The increased plasma concentration of
mosomes is not assumed. Some authors consider also TeBG is the cause of even greater decrease of free
the existence of genetic predisposition to the origin testosterone in circulating blood.
of meiotic nondisjunctions. The participation of ir-
radiation or viral infection as predisposing factors of The clinical picture of Klinefelter syndrome is
meiotic nondisjunctions has not been found for the characterized mainly by signs and symptoms result-
present. ing from seminiferous tubular dysgenesis and hyper-
The mosaic form of Klinefelter syndrome results gonadotropic hypogonadism. Though it is congen-
from chromosomal mitotic nondisjunctions after fer- ital gonosomal anomaly, the boys usually develop
tilization of the zygote (mainly during the first cell normally before puberty. However, most prepuber-
divisions) and can arise either in a 46,XY zygote or tal patients have a distinctive body habitus with an
a 47,XXY zygote. The latter situation, i.e., dou- increase in length between the soles and the pubic
ble nondisjunction (meiotic and mitotic), may be the bone, which creates the appearance of an elongated
usual of the mosaic form and thus explain why the body. The disorder begins clinically manifested al-
mosaic form is less common than the classic form of ready in the time of expected puberty. Classic man-
Klinefelter syndrome. ifestation of this disease is the origin of sexual infan-
tilism. However, such severe degree of the disorder is
Chromosomal aberration is usually manifested at not frequent. The intensity of the disorder of sexual
the time of expected puberty, when plasma FSH con- development in the patients is usually variable. In
centration is physiologically increased. However, its some affected boys only delayed puberty may orig-
effect on primary dysgenetically changed germinal inate. It is also possible that the onset of puberty
epithelium of seminiferous tubules of the testes does is not delayed, but impaired Leydig cell reserve and
not lead to their enlargement, but cause their pro- low testosterone levels may lead to slow progression
gressive fibrotization and hyalinization. With the or arrest of pubertal development. In other patients
onset of puberty, progressive histological changes puberty may be normal, spermatogenesis is, how-
also originate in Leydig cells, but their number is ever, missing.
normal or more often increased (pseudoadenomatous
changes of the Leydig cells). The ability of impaired The classic form is characterized by small, firm
Leydig cells to synthetize testosterone is, therefore, testes, impaired spermatogenesis, a male phenotype,
gradually reduced. Plasma testosterone concentra- insufficient androgenization, and later by a variable
tion gradually decreases resulting in the origin of degree of feminization. The reduced spermatogene-
primary male hypogonadism. Plasma LH level is sis is related to the degree of morphologic changes
gradually increasing by feedback mechanism (hyper- in the testes. Most of affected men are infertile.
gonadotropic male hypogonadism). The small atrophic testes are often associated with
The increased plasma LH concentration initially a small penis, and the lack of such secondary male
stimulates production of estradiol in Leydig cells. characteristics as deep voice, beard, and male distri-
Later, due to progressive impairment of testes, ev- bution of pubic hair. Gynecomastia occurs in about
ident decrease not only of testicular testosterone 90 % of patients, and is probably secondary to an
secretion, but also of testicular estradiol secretion increased ratio of serum estradiol to testosterone.
develops. Extraglandular production of estrogens, The eunuchoid body habitus with abnormally long
however, continues. They are formed by aromatiza- legs is also characteristic. Most individuals have a
tion of adrenal androgens in extraglandular tissues. male psychosexual orientation and function sexually
Though plasma estrogen level is low, with regard to as men. Potency may be initially normal, but due to
very low plasma testosterone concentration it is rela- progressive decrease of plasma testosterone concen-
tively high. Due to the increased ratio of circulating tration it may decrease. The mean IQ is somewhat
estrogen to androgen various degrees of feminization lower than normal, but mental retardation is uncom-
of the patients, including gynecomastia, have been mon. Plasma gonadotropin concentrations, particu-
developed. Besides that, relative predominance of larly FSH, are consistently elevated, whereas testos-
plasma estradiol over plasma testosterone increases terone levels are variably reduced. Mean plasma
production of testosterone-binding globulin (TeBG) estradiol levels are relatively elevated. The ratio of
400 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

circulating estrogen to testosterone determines the curs in childhood and adulthood. The best known
degree of feminization in individual cases. of them is mumps orchitis. Other viral agents may
The mosaic form is present in about 10–15 % of act in a similar fashion, including echovirus, lym-
the patients with Klinefelter syndrome. The most phocytic choriomeningitis virus, and group B ar-
common of mosaic patterns is the one with the boviruses. Primary hypogonadism may originate
47,XXY/46,XY karyotype. The presence of a normal also secondary to extensive impairment of testes in
XY cell line in these patients can modify the clinical patients with autoimmune orchitis, and also with
expression of the 47,XXY cell line. Thus, in general, gonorrheal or syphilitic orchitis. The testes can also
these patients manifest a lesser degree of testicular be damaged after long-lasting therapy by antineo-
pathology, testosterone deficiency, and gynecomas- plastic and chemotherapeutic drugs, after radiother-
tia. The testes may be normal in size. The decreased apy, or after trauma. The cause of its origin may
libido and potency may not appear until the fourth be also castration of the patients with malignant tu-
or fifth decade. Secondary sexual characteristics are mors of the testes. Certain signs of peripheral hy-
less impaired than those of patients with the clas- pogonadism may originate due to chronic alcohol in-
sic form. In many patients with the mosaic form gestion. Large doses of ethanol damage not only ger-
seminiferous tubules exhibit spermatogenesis being minal epithelium, but also Leydig cells.
usually insufficient (oligospermia), however, some of The clinical picture of acquired primary male hy-
them may be even fertile. pogonadism depends on the age at which the tes-
Many other variants of Klinefelter syndrome have ticular hormone deficiency develops (before or after
been described, including those with uniform cell puberty). The consequences of extensive impairment
lines (such as 48,XXYY, 48,XXXY, 49,XXXYY, and of the testes in childhood begin manifested clinically
49,XXXXY) and various mosaic patterns. All these as late as in the time of expected onset of puberty.
forms are rare. With an increase in the number of 1. Prepubertal testicular hypogonadism. It is
X chromosome, the severity and frequency of vari- manifested by the disorder of spontaneous on-
ous somatic anomalies also increase. The presence set of puberty or it may result in the origin of
of three or more X chromosomes in genotype is usu- sexual infantilism. A degree of the disorder de-
ally associated with a severer degree of mental re- pends on the extent of Leydig cell damage, and
tardation of the patients. The presence of two or thereby on the degree of testicular androgen de-
more Y chromosomes in genotype is usually associ- ficiency. It is manifested by hypogenitalism and
ated with antisocial, deliquent behavior. In general, by the disorders in the development of secondary
the greater the degree of chromosomal abnormality sexual characteristics which may be sometimes
(and in mosaic forms the more cell lines that are ab- completely absent. In an affected subject break-
normal), the severer are the clinical manifestations. ing the voice does not occur, libido is absent,
female fat distribution and sometimes also gy-
necomastia originate.
B. Acquired primary male hypogonadism
2. Postpubertal testicular hypogonadism. It need
It is a rare disorder, because the organic fac- not evidently influence a masculine look of the
tors damaging the testes most frequently affect only patient. Pubic hair may be thinned. Moustache
seminiferous tubules (germinal epithelium). Rarely, and beard growth is slowed. Sometimes also
only due to severe form of damage also Leydig cells partial regression of genitalia, though impercep-
are affected leading to hyposecretion of testosterone tible at the first sight, may occur. In some pa-
and thus to peripheral male hypogonadism. Due tients libido and potence may be decreased, in
to lowered plasma testosterone level hypothalamic- others may be preserved (due to psychic condi-
pituitary system is stimulated to an increased secre- tional nature of sexuality). Possible change of
tion of GTHs by positive feedback mechanism. Their behavior may be manifested by the loss of ag-
plasma concentration is, therefore, increased (hyper- gressiveness. Anemia, osteoporosis, and muscle
gonadotropic male hypogonadism). weakeness may originate. Obesity also develops.
One of the most common causes of acquired pe- The change of fat distribution may be associated
ripheral male hypogonadism is viral orchitis. It oc- with the loss of typical masculine figure.
5.8. Endocrine disorders of the testes 401

5.8.1.2 Central male hypogonadism 8. severe chronic systemic disease (renal failure
and cirrhosis of the liver) altering the overall
In the patients with central male hypogonadism health state of a patient;
plasma concentrations of gonadotropins are low, and,
therefore, it is also denoted as hypogonadotropic 9. long-term starvation.
male hypogonadism. The causes and consequences
of the origin of adenohypophyseal and hypothalamic The clinical picture of central male hypogonadism
male hypogonadism have been partially mentioned is essentially the same as that of in the patients with
in the chapter on pathophysiology of hypothalamic- primary hypogonadism. It depends on the age of a
adenohypophyseal system. patient at the time of the origin of testicular andro-
gen deficiency. It is quite often only a part of more
Central male hypogonadism originates due to: complex clinical picture determined by the cause of
its origin. In boys either true delayed puberty or
1. organic lesion in hypothalamic-pituitary area sexual infantilism originate. In adult men hypogo-
(tumors, aneurysms, hemorrhages, inflamma- nadism is manifested by a decrease even loss of libido
tory processes, surgical interventions, irradia- and potence, regression of secondary sexual charater-
tion, head trauma, and others); istics, and muscle weakness.
2. various inborn syndromes (Laurence-Moon-
Biedl-Bardet syndrome, Kallmann syndrome, 5.8.2 Hypersecretion of testicular
Babinski-Fröehlich syndrome); hormones
3. hyperprolactinemia (hypothalamic or adenohy- Hypersecretion of testicular androgens is denoted as
pophyseal); male hypergonadism (hypergonadismus masculinus).
The cause of its origin may be within the testes
4. fertile eunuch syndrome being a special form of themselves (primary male hypergonadism) or is lo-
central prepubertal male hypogonadism. This calized in the hypothalamic-pituitary area (central
syndrome is conditioned by a selective resis- male hypergonadism). Male hypergonadism occurs
tance of gonadotrope cells of adenohypophysis much more rarely than male hypogonadism. The
to LHRH. FSH secretion is normal, LH secre- clinical picture of hypersecretion of testicular andro-
tion is, however, missing. LH deficiency is the gens depends on the age at which the hypersecretion
cause of disorder of Leydig cell development and appears. The clinical features are similar to those
subsequent testosterone deficiency. Due to nor- originated in male individuals with oversecretion of
mal concentration of FSH in circulating blood adrenal androgens.
seminiferous tubules and testes are of normal
size after puberty and spermatogenesis is usu- 5.8.2.1 Primary male hypergonadism
ally preserved, therefore, the term fertile eunuch
Peripheral male hypergonadism originates due to
is used. However, as a consequence of testos-
hormonally active testicular tumors autonomously
terone deficiency, spermatogenesis is often insuf-
producing testosterone and sometimes also estradiol.
ficient. The clinical picture is characterized by
It occurs very rarely. Excess testosterone is secreted
the contrast between the well developed testes
mainly by Leydig cell tumors and rarely by Ser-
and decreased length of penis and by the pres-
toli cell tumors (androblastomas). Leydig cell tu-
ence of eunuchoid habitus;
mors may elaborate androgens, or sometimes an-
5. combinated disorder of pituitary hormone pro- drogens and estrogens (estradiol). They are usually
duction, mainly deficiency of gonadotropins unilateral. Sertoli cell tumors may elaborate estra-
with deficiency of growth hormone; diol (more commonly) or androgens, but only infre-
quently in sufficient quantity to cause masculiniza-
6. constitutional delay in growth and puberty; tion or feminization. They are frequently bilateral.
Both kinds of these testicular tumors may arise at
7. prepubertal or postpubertal panhypopituita- any age, although the majority of the reported causes
rism; of Leydig cell tumors have been noted between 20–40
402 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

years of age and those of Sertoli cell tumors have been ical picture of isosexual precocious pseudopuberty
found in childhood. Leydig cell tumors and Sertoli (incomplete isosexual precocity) originates. It is
cell tumors account for about 2 % of all testicular tu- manifested by precocious development of genitalia
mors. Approximately 10 % of these both kinds of tes- and secondary sexual characteristics. Spermato-
ticular tumors are malignant, the great majority of genesis is absent, indicating that androgen forma-
them are benign. In some patients the mixed tumors tion is not the result of premature activation of the
containing cells of germinal (germ cells) and stromal hypothalamic-pituitary system. If hypersecretion of
(Leydig and Sertoli cells) origin may occur. Most testosterone originates in adulthood, it need not be
distinctive of them is the gonadoblastoma which pre- evidently clinically manifested.
vailingly synthesize androgens. When the cells of a testicular tumor produce also
Enhanced formation of testosterone and estradiol estradiol, in the clinical picture the symptoms of fem-
by Leydig cells may be also present in patients with inization are simultaneously also present. Enhanced
germ cell tumors secreting endocrinologically active formation of estradiol by testicular tumors is more
hCG. The hCG acts to increase testosterone and common in adult men than in boys. Feminization is
estradiol production in unaffected areas of the testes. manifested by the origin of gynecomastia, thinning
This secretion of testosterone and estradiol is inde- of pubic hair, decrease even loss of potence, and di-
pendent of the hypothalamic LHRH. The testicular minishing of prostate.
germ cell tumors include seminoma, embryonal car-
cinoma, choriocarcinoma, and benign or malignant 5.8.2.2 Central male hypergonadism
teratomas. They account approximately for 95 %
In the patients with central male hypergonadism
of all testicular neoplasms. Germ cell tumors of all
plasma concentrations of gonadotropins (mainly LH
types can also originate in extragonadal sites, most
concentration) are primarily increased. Therefore, it
commonly in the brain or in the mediastinum. These
is also denoted as hypergonadotropic male hyperg-
extragonadal germ cell tumors presumed to arise ei-
onadism. The causes and consequences of its origin
ther from aberrant migration of germ cells early in
have been partially mentioned in the chapter on the
embryogenesis or, alternatively, from some common
pathophysiology of hypothalamic-adenohypophyseal
precursor stem cell line that normally gives rise to
system.
germ cells and to cells of the thymus and the pineal.
A primary germ cell tumor localized in the pineal or The cause of central male hypergonadism may be
in the suprasellar regions is denoted as germinoma. various organic (mainly CNS tumors) or functional
disorders of the hypothalamic-pituitary area. The
Increased plasma testosterone and estradiol con- functional disorders are usually of unknown etiology
centrations cause suppression of the production (idiopathic form of central male hypogonadism). The
of endogenous adenohypophyseal gonadotropins by best known organic causes of central male hyper-
feedback mechanism. Plasma gonadotropin levels gonadism include hypothalamic hamartoma, pineal
are, therefore, low (hypogonadotropic male hypogo- tumors, other tumors of the pineal region, and go-
nadism). When production of testosterone and estra- nadotrope adenomas of hypophysis. Gonadotrope
diol by testicular tumor is autonomous, testosterone adenomas most often occur in the middle age, mainly
secretion by uninvolved portions of the testes is de- between the ages 35 and 45. Less common causes of
pressed (due to low plasma LH level), and azoosper- central male hypergonadism include hydrocephalus,
mia and decreased size of the contralateral testis are intracranial aneurysms, encephalitis, sarcoid or tu-
common (due to low plasma FSH level). The clinical berculous granulomas of the hypothalamus, arach-
picture of hormonally active testicular tumors de- noid cysts, or brain abscess.
pends on the age of patients at which the neoplasms The above mentioned organic or functional dis-
originate. It also depends on the fact whether the orders of the hypothalamic-hypophyseal area most
testicular tumor secretes only testosterone or testos- commonly cause increased secretion of LHRH and
terone and estradiol as well. Similar clinical fea- subsequently increased secretion of gonadotropins.
tures can result from endocrinologically active hCG- Primary increase of production of GTHs (without
secreting testicular and extratesticular tumors. preceding increase of LHRH) is rare.
If excess testosterone occurs in childhood, a clin- The clinical picture of central male hypergonadism
5.8. Endocrine disorders of the testes 403

depends on the age at which the cause of increased pothalamic hamartomas are not associated with true
secretion of LHRH or GTHs originates. If the cen- precocious puberty.
trally conditined hyperfunction of the testes occurs Hamartomas of the tuber cinereum are most fre-
prepubertaly in boys, isosexual true precocious pu- quently associated with true precocious puberty.
berty originates. Its occurrence in boys is, however, They are congenital tumors composed of heterotopic
rarer than in girls. In affected boys spermatogene- mass of neurosecretory mature neurons, fiber bun-
sis is present and possible fertility may also occur. If dles, and glial cells. These neurosecretory cells are
the oversecretion of gonadotropins originates in adult similar to the LHRH-containing neurons in the me-
men (rare occurrence) its clinical consequence may dial basal hypothalamus. LHRH neurosecretory cells
be low plasma testosterone concentration and the of the tumor are unrestrained by the intrinsic CNS
origin of impotence. It is apparently paradoxical ori- mechanism that inhibits the normal LHRH pulse
gin of testicular hypogonadism in the affected adult generator and act as an ectopic LHRH pulse genera-
men with increased plasma concentration of GTHs. tor independently on the LHRH neurosecretory neu-
The pathogenesis of this testicular hypogonadism in rons in the medial basal hypothalamus to produce in-
adult men with overproduction of gonadotropic hor- termittent secretory bursts of LHRH. It seems, that
mones is not exactly known. It is supposed that long- many causes previously thought to be idiopathic true
lasting increased concentration of gonadotropins in precocious puberty are due to hamartomas of the tu-
circulating blood leads to down-regulation of recep- ber cinereum (sometimes miniature). Hamartomas
tor number, i.e., to reduction of LH receptors on the grow slowly, if in fact they do enlarge.
Leydig cell membrane. The relationship between the origin of true pre-
In the clinical picture of central male hyperg- cocious puberty and the presence of tumors of the
onadism, which is caused by expansive growth of pineal gland has been known for a longer time. A
cerebral tumors, some local symptoms induced by tumor of the pineal parenchymal cells is termed
compression of intracranial structures may be also pinealoma. According to its degree of differentiation
present. it can be a pineocytoma or pineoblastoma. Other
In about 40 % of boys with true precocious puberty tumors localized in the pineal region include mainly
the cause of origin of precocious LHRH production astrocytoma, glioma, glioblastoma, germinoma, and
is not known (idiopathic true precocious puberty). ependymoma. True precocious puberty in boys with
Tumors and other organic cerebral causes of true a pineal tumor or with other tumor of the pineal re-
precocious puberty probably activate precocious re- gion is probably due to the effect of this tumor on
leasing of LHRH by their effect on hypothalamus, function of the adjacent hypothalamus. In the hy-
However, hypothalamic hamartomas associated with pothalamus precocious production of LHRH occurs.
true precocious puberty may secrete LHRH them- The hypothesis, that pineal tumors and tumors of
selves, because they are composed of disordered but the pineal region influence the function of the hy-
mature neural elements. LHRH secretion by these pothalamus, is supported also by frequent simulta-
ectopicly placed LHRH peptidergic neurons is prob- neous occurrence of insipidus diabetes, polyphagia,
ably not subject to the normal restraining influences obesity, somnolence, or behavioral disturbance. It
of the anterior hypothalamus, and early pubertal de- is likely, therefore, that tumors of the pineal gland
velopment is likely the consequence of unrestrained and tumors of the pineal region cause true precocious
LHRH secretion. Precocious puberty is believed to puberty by mechanism similar to that of other types
occur when the cells of the hamartoma make connec- of cerebral tumors or other types of brain organic
tions with the median eminence and thus serve as an lesions.
”accessory hypothalamus”. About 10 % of hy-
404 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

tissues, usually in the presence of a relative or abso-

lute excess of glucagon. Absolute insulin deficiency
5.9 Pathophysiology of the or its insufficient effect in peripheral tissues causes
a disorder of glucose metabolism. When the insulin
endocrine pancreas deficiency is extreme this hormonal abnormality is
responsible for the tendency to develop ketoacido-
sis. The impaired glucose utilization is subsequently
associated with the origin of disorder of fat and pro-
The endocrine pancreas consists of about 1 million tein metabolism, as well as with the disorder of wa-
microscopic cellular units (the islets of Langerhans) ter and electrolyte metabolism. Therefore, a com-
accounting for about 1–2 % of the total weigh of the plex metabolic disorder originates. In the period of
pancreas. In the human adult the islets consist of overt diabetes mellitus this complex metabolic dis-
three major and three minor cell types. The three turbance is manifested by hyperglycemia, glycosuria,
main types are B, A, and D cells making up about increased protein catabolism, and ketoacidosis. Due
95 % of the islet cell population. The B cells account to nontreated evident insulin deficiency ketoacidosis
for about 70 % of the islet cell population and pro- may result in diabetic coma. Diabetes mellitus is
duce insulin. The A cells account for about 20 % of hence considered not only as endocrine disorder, but
the islet cell population and secrete glucagon. The also as metabolic disorder. In patients with long-
D cells secrete somatostatin and make up about 5 % lasting diabetes mellitus late complications develop,
of the islet cell population. In immunohistochemi- the most frequent and severest being degenerative
cal studies that employ specific antibodies to indi- changes of blood vessels and nerve system.
vidual hormones, the existence of the three rare cell
types has been proved. The three minor cell types
5.9.1.1 Etiology and classification of dia-
are PP cells, D1 cells, and G cells. The PP cells
betes mellitus
produce a unique pancreatic polypeptide (PP). The
D1 cells elaborate vasoactive intestinal polypeptide The World Health Organization (WHO) defines di-
(VIP). The G cells synthesize pancreatic gastrin. Ac- abetes mellitus as a state of chronic hyperglycemia
cording to their effect, pancreatic polypeptide, va- caused by simultaneous affect of genetic and envi-
soactive intestinal polypeptide, pancreatic gastrin, ronmental factors including nutrition. This defini-
and somatostatin belong to the group of gastroin- tion indicates that diabetes mellitus has a multifac-
testinal hormones. torial genesis. Genetic, immunological, viral, toxico-
The endocrine diseases of the pancreas include dia- chemical, and nutritional factors participate in the
betes mellitus and tumors of the endocrine pancreas. origin of diabetes mellitus. Besides that diabetes
The best known tumors of the islet cells include mellitus is associated with other primary diseases or
insulinoma, glucagonoma, gastrinoma, somatostati- syndromes.
noma, and VIPoma. Tumors of the endocrine pan- During the 70s and 80s a lot of new information
creas may be also a part of the multiple endocrine on etiology and pathogenesis of diabetes mellitus was
neoplasia, type 1 (MEN 1), denoted as Wermer syn- obtained. Therefore, in 1985 WHO accepted the fol-
drome. lowing new classification of diabetes mellitus:

A. Clinical groups
5.9.1 Diabetes mellitus
Diabetes mellitus is the most common endocrine dis- 1. INSULIN-DEPENDENT DIABETES MELLI-
order. However, it is not an individual nosological TUS (type 1 diabetes)
unit. This term denotes a diabetic syndrome com-
prising an etiologically and clinically heterogenous 2. NON-INSULIN-DEPENDENT DIABETES
group of pathological states, the common and per- MELLITUS (type 2 diabetes)
manent symptom of which is hyperglycemia origi-
(a) Non-obese
nating secondary to long-lasting absolute or relative
insulin deficiency or to its insufficient effect in target (b) Obese
5.9. Pathophysiology of the endocrine pancreas 405

3. MALNUTRITION-RELATED DIABETES type 2 diabetes. But a clinical practice that has

MELLITUS been criticized, since some patients with apparent
non-insulin-dependent diabetes may in fact be des-
(a) Fibrocalculous pancreatic diabetes tined to become fully insulin-dependent and prone
(b) Protein-deficient pancreatic diabetes to ketoacidosis. Therefore, some authors apply the
term insulin-dependent diabetes mellitus to all forms
4. OTHER TYPES OF DIABETES MELLITUS
of diabetes in which exogenous insulin is required
associated with certain conditions or syndromes
to prevent diabetic ketoacidosis, regardless of eti-
(a) Pancreatic disease ology. They apply the term type 1 only to dia-
betes resulting from autoimmune destruction of B
(b) Disease of hormonal etiology
cells regardless to whether the destruction is suf-
(c) Drug-induced or chemical-induced condi- ficiently complete to result in ketoacidosis. They
tions use the term type 2 to denote all forms of diabetes
(d) Abnormalities of insulin or its receptors mellitus which did not arise from autoimmune de-
(e) Certain genetic syndromes struction of B cells. Thus in this formulation the
terms type 1 and type 2 distinguish between autoim-
(f) Other conditions or syndromes mune and nonautoimmune forms of diabetes (these
5. IMPAIRED GLUCOSE TOLERANCE terms refer to pathogenetic mechanism), whereas the
terms insulin-dependent and non-insulin-dependent
(a) Non-obese indicate only the absence or presence of B cell func-
(b) Obese tion, respectively describe pathophysiologic states
(c) Associated with certain conditions or syn- (ketoacidosis-prone or ketoacidosis-resistant). Using
dromes such a classification, for example, if a patient with
autoimmune diabetes were to pass through a tran-
6. GESTATIONAL DIABETES MELLITUS sient non-insulin-dependent period during which B
cell destruction is incomplete, he or she would be
classified as having type 1 NIDDM until such time
B. Statistically dangerous groups
as insulin dependence appeared, whereupon the clas-
1. POTENTIAL ABNORMALITY OF GLUCO- sification would change to type 1 IDDM. The type 1
SE TOLERANCE NIDDM is an intermediate state of autoimmune de-
struction in which sufficient insulin remains to pre-
2. PREVIOUS ABNORMALITY OF GLUCOSE vent ketoacidosis but not to maintain normal con-
TOLERANCE centration of blood glucose (normoglycemia). The
stage of type 1 NIDDM likely occurs when the au-
The first two main clinical forms, i.e., insulin- toimmune process begins at an older age and pro-
dependent diabetes mellitus (IDDM) and non- gresses at a slower rate. It is infrequently seen when
insulin-dependent diabetes mellitus (NIDDM) are IDDM appears in childhood or early adolescence.
most common (some authors consider them as two
variants of primary diabetes mellitus). Insulin de- 5.9.1.2 Clinical groups of diabetes mellitus
pendence in this classification is not equivalent to
insulin therapy. Rather, it means whether endoge- According to WHO classification there are six fol-
nous insulin secretion is sufficient to prevent diabetic lowing clinical groups of diabetes mellitus:
ketoacidosis. Other types of diabetes mellitus and
1. Insulin-dependent diabetes mellitus
gestational diabetes mellitus are rare. Malnutrition-
related diabetes mellitus (MRDM) does not occur in Insulin-dependent diabetes mellitus (type 1 dia-
our country. betes) is characterized by rather sudden onset of clin-
In WHO classification the term insulin-dependent ical symptoms, almost full or completely full defi-
diabetes mellitus and type 1 diabetes are used syn- ciency of endogenous insulin, rapid development of
onymously, and the term non-insulin-dependent di- diabetic ketoacidosis, and after the origin of ketoaci-
abetes mellitus has been considered equivalent to dosis by vital dependence on therapeutical adminis-
406 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

tration of exogenous insulin. A severe, absolute lack autoimmune endocrinopathies with IDDM is 30–50
of insulin is caused by a severe or complete reduction times more frequent than their individual occurrence
in the B cell mass due to autoimmunity. This form in rest of population). The carriers of this antigene
of diabetes may originate at any age, prevailingly, are more commonly females, at onset of IDDM they
however, in childhood or adolescence (between the are mostly of an older age, the degree of diabetic dis-
ages of 1 and 20), most frequently about 10 years order is milder with less ketonuria at diagnosis, and
of age. It accounts for about 10–15 % of all patients diabetic disorder has a greater tendency for partial
with diabetes mellitus. remissions. During the remissions exogenous insulin
Etiology and pathogenesis. Genetic and environ- is not necessarily to be administered. The remissions
mental factors share participation in the origin of are probably evoked by transient regenerations of B
insulin-dependent diabetes mellitus. cells (a partial recovery of their function).
Genetic factors. The type 1 IDDM is thought to In the patients with HLA-DR4 antigene islet cell
arise as a consequence of an autoimmune destruc- autoantibodies are not present in circulating blood,
tion of B cells in a genetically predisposed individ- titer of insulin autoantibodies is increased, and these
uals. Genetic predisposition to IDDM is associated patients have little, if any, association with other au-
with the presence of certain antigens of HLA sys- toimmune diseases. Subjects with this HLA antigene
tem. Approximately 95 % of patients with this type exhibit a male predominance, tendency to younger
of diabetes carry the HLA-DR3 or HLA-DR4 or onset, and the degree of diabetic disorder is severer
both antigens. In about 60 % of the patients both than that in the patients with HLA-DR3 antigene.
these HLA antigens can be found. If one of them is Environmental factors. The genetic contribution
present, the risk of the origin of the type 1 IDDM is necessary but ordinarily insufficient to cause the
is 5 times increased, however, the occurrence of both type 1 IDDM; usually an environmental factor is re-
mentioned HLA antigens increases the risk of the ori- quired as the trigger for its initiation. The most sig-
gin of IDDM 40–50 times compared to the population nificant environmental factors inducing the clinical
without these HLA antigens. manifestation of genetic predisposition are consid-
Immunogenetic heterogenity of type 1 IDDM ered viral infections evoked mainly by mumps virus,
seems to exist. Some authors even assume that there rubella virus, cytomegalovirus, coxackieviruses B4
are two diabetogenic genes responsible for genetic and B5, retroviruses with type C particles, retrovirus
predisposition to type 1 IDDM. The first diabeto- with type A particles, reoviruses, and encephalomy-
genic gene is made up of association of HLA-DR3, ocarditis virus. Presentation of the type 1 IDDM
B8, Cw7, and A1 antigens. The second diabeto- is more common in the spring and autumn than in
genic gene is made up of association of HLA-DR4, the summer (its seasonal incidence), and it has been
B15, Cw3, and A2 antigens. Recently the signifi- suggested that this might be related to the greater
cance of HLA-DQ allele participation has been stud- prevalence of viral infections at these times. The
ied and strong associations are being reported with influence of chemical substances (betacytotoxins),
HLA-DQ allele. Today it is thought that HLA-DQb mainly nitrosamines, is considered. Nitrosamines oc-
chain gene primarily determine susceptibility and re- cur widely in small amounts in both natural and
sistance to autoimmune destruction of B cells. This processed foodstuffs. They are found in variable
finding may explain the observation that combina- amounts in fresh vegetables and in substantial quan-
tions of HLA-DR and HLA-DQ alleles confer higher tities in foods high in nitrates and nitrites, e.g.,
risk than either alone. The participation of other some smoked or cured meats and fish. They are
genes not belonging to HLA area are also supposed. also formed in vivo from precursors in foods such
However, the information on them is controversial, as nitrates and nitrites, especially in the stomach at
and the mode of their inheritance is unknown. low pH, and even from certain medicaments. Some
In the patients with HLA-DR3 antigene circu- other, by now unknown environmental factors, may
lating islet cell autoantibody titer is evidently in- be a possible etiological agents triggering a clinical
creased, insulin antibodies are absent, other au- manifestation of type 1 IDDM as well.
toimmune endocrinopathies and nonendocrine au- Autoimmunity. A role of autoimmunity in the
toimmune diseases also often occur (association of pathogenesis of type 1 IDDM is supported by sev-
5.9. Pathophysiology of the endocrine pancreas 407

eral morphological, clinical and experimental obser- with all islet cell types. However, only the B cells
vations. Due to direct effect of triggering environ- are destroyed (selective destruction of the insulin-
mental agent originates an inflammatory response in secreting cells). The other cell types are normal.
the pancreatic islets (their early infiltration by ac- In the subjects with genetic predisposition to type
tivated T lymphocytes and macrophages) called in- 1 IDDM they appear alredy several months or even
sulitis. The mechanism, by which participation of several years before the clinical manifestation of di-
genetic predisposition and environmental factors ini- abetes. These antibodies are detected in circulat-
tiates an impairment of B cells and subsequent defi- ing blood of 70–90 % of newly diagnosed patients
cient insulin secretion, is not exactly known. How- with the type 1 diabetes. They are still present in
ever, from the etiopathogenetic point of view type about 20–30 % of the patients 1 year after onset of
1 IDDM is considered as an autoimmune disease in the IDDM and persist in 10–15 % of the patients 2–3
the origin of which mechanisms of humoral and cell- years after the diagnosis of the IDDM.
mediated immunity participate. In the patients with persistence of islet cell cy-
toplasmic antibodies in circulating blood simulta-
A. Humoral immunity. The following two types of neously with the type 1 IDDM also other autoim-
islet cell autoantibodies have been found in circulat- mune diseases occur, such as Hashimoto thyroiditis,
ing blood of the patients: islet cell cytoplasmic an- Graves-Basedow disease, Addison disease, pernicious
tibodies and islet cell surface antibodies. The both anemia, myasthenia gravis, vitiligo, rheumatoid ar-
kinds of these antibodies belong to IgG. Islet cell tritis, and collagen diseases. Islet cell cytoplasmic
cytoplasmic and surface antibodies may be present antibodies persist in their circulation even 10 years
simultaneously in the same patient, but either can after onset of the IDDM. In plasma of these patients
occur alone. or in circulation of some members of their families
The precise mechanism by which the environmen- cell cytoplasmic antibodies against the cells of other
tal factors trigger production of islet cell antibodies endocrine glands or other tissues simultaneously oc-
in individuals with genetic predisposition to IDDM cur. These patients exhibit a female predominance
is not known. It is supposed that the exogenous and frequent association with HLA-DR3 and HLA-
agent might act in one of several ways. It has been B8 antigens. In subjects with HLA-DR3 and HLA-
suggested that an environmental factor might form B8 antigens the IDDM is clinically manifested at
a neoantigen in association with normal membrane older age (about 30 years of age and later) than in
structures. It is also possible that islet cell antibod- individuals with HLA-DR4 and HLA-B15 antigens.
ies are secondary to the direct destruction of B cells Islet cell surface antibodies are reported to be
by an environmental trigger, and are formed in re- present in about 90 % of new-onset IDDM patients.
sponse to liberated cellular constituents as a part of They persist in about 38 % of patients five years af-
the polyclonal immune activation. This alteration ter the clinical manifestation of diabetes. The islet
or transformation of islet B cells leads to conver- cell surface antibodies have a cytotoxic effect. They
sion of B cells from ”self” to ”nonself”, which are predominantly (selectively) lyse B cells in the pres-
no longer recognized as ”self” but are acceptated by ence of complement. Thus if any of the islet cell
the immune system as a foreign cells or ”nonself”. antibodies are responsible for B cell destruction, it
The autoimmune system is, therefore, activated. Be- is more likely that surface rather than cytoplasmic
cause the B cells of Langerhans islets are now con- antibodies play the critical role.
sidered ”nonself” cytotoxic islet cell antibodies are
produced by B lymphocytes and act in concert with B. Cell-mediated immunity. The increased num-
cell-mediated immune mechanisms. It is supposed ber of cytotoxic T lymphocytes (natural killer cells
that islet cell antibodies evoke autoimmune inflam- – NK cells) and the decreased number or defective
matory lesion of islet B cells, the evidence of which function of suppressor T lymphocytes are the evi-
is early infiltration of islets by T lymphocytes and dence of participation of cell-mediated immunity in
macrophages (autoimmune insulitis). The end result the pathogenesis of type 1 IDDM. Decline in num-
is the destruction of the islet B cells and later the ber or decrease of suppressor T lymphocyte activ-
appearance of diabetes. ity probably activates helper T lymphocytes which
Islet cell cytoplasmic antibodies generally react play an important role in pathogenesis of IDDM.
408 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

They produce interleukin-2 (IL-2) which activates the blood indicates that some B cells have survived.
cytotoxic T lymphocytes, the number of which is The classic clinical manifestations of type 1 diabetes
increased in about 50–60 % of the patients in the appear when more than 90 % of the B cells have been
time of diagnosis of the diabetes. It is supposed that destroyed. C-peptide is still present, but its concen-
in response to viral or other exogenous stimuli IL-2 trations are exremely low. When the total destruc-
and also interferon-γ (IFN-γ) are secreted by lym- tion of all B cells of islets originates, C-peptide level
phocytes and macrophages which infiltrate the pan- will become unmeasurable (type 1 IDDM). Hence,
creatic islets (insulitis). Under the influence of these plasma C-peptide concentrations may provide a use-
cytokines, macrophages and NK cells are activated ful index of the degree of functional reserve of B cells.
to produce IL-1 and tumor necrosis factor-α (TNF- The pathogenetic process is slow and several months
α). IL-1 has a selective cytotoxic effect on B cells even several years may elapse from the time anti-
of Langerhans islets leading to destruction of the B islet immunity can be detected until type 1 IDDM
cells. This action of IL-1 is strongly potentiated by becomes clinically manifest.
TNF-α. It has been postulated that cytotoxic effect
of IL-1 on the B cells is mediated by oxygen-derived 2. Non-insulin-dependent diabetes mellitus
free radicals. The B cells are exquisitely sensitive to
free radicals and have the lowest free radical scav- Non-insulin-dependent diabetes mellitus (type 2
enger potential of any cell in the body. Therefore, diabetes) is characterized by relative deficiency of
when production of free radicals exceeds the capac- endogenous insulin and by absence of tendency to
ity of the antioxidant defences, impairment of cell the origin of ketoacidosis. The patients are not de-
membrane and membrane of intracellular organels, pendent on administration of exogenous insulin. Al-
and also disorganization of intracellular enzymes will though in the patients with this type of diabetes
originate. there is no danger of the origin of ketoacidosis under
circumstances of usual life style, it may be evoked by
In summary, on the basis of the mentioned data various stress situations (e.g., intercurrent infection,
the following hypothesis for the pathogenesis of the trauma, surgical intervention, and the like). Under
type 1 IDDM may be postulated. It is a progressive these circumstances administration of exogenous in-
autoimmune disease which is clinically manifested sulin is almost always inevitable.
when the destruction of more than 90 % of B cells of Non-insulin-dependent diabetes mellitus is the
Langerhans islets originates. Macrophages, B lym- most common type of diabetic syndrome. It ac-
phocytes, helper T lymphocytes, suppressor T lym- counts for about 80–85 % of all patients with diabetes
phocytes, and cytotoxic T lymphocytes participate mellitus. It may originate at any age, but it mostly
in its origin. It is now recognized that type 1 diabetes develops not before 30 years of age. Its incidence
usually proceeds through the following sequence: ge- increases markedly with age. The clinical symptoms
netically susceptible people begin their lives without of this type of diabetes usually develop slowly. The
any detectable abnormality (prediabetes). A trig- affected subjects may be asymptomatic for several
gering factor causing minimal destruction of islet B years. This disease is often discovered casually.
cells is followed by autoimmunity. This is reflected Etiology and pathogenesis. The precise etiology of
in positive tests for islet cell antibodies. Although the type 2 diabetes is unknown. Both genetic factors
B cell mass decreases, the functional reserve of B and environmental factors are supposed to partici-
cells is more than enough to mantain normal plasma pate in the origin of NIDDM. By contrast, however,
glucose level. Continual injury results in sufficient with IDDM it is clear that B cell destruction is min-
loss of B cell mass to cause diminution in glucose imal, that autoimmunity does not play a role, and
stimulated insulin secretion (impaired glucose toler- that insulin action is defective.
ance). As the destruction of B cells continues, fasting Genetic factors. They are of greater importance
glucose levels will rise above normal. Later, a mild than in IDDM. Genetic basis of the origin of NIDDM
persistent hyperglycemia appears (type 1 NIDDM). is, however, different to that of IDDM. There is no
In this phase of diabetes, C-peptide in circulating association with HLA antigens in the patients with
blood of the patients is present, but its concentra- NIDDM. From genetic studies it has been known for
tions are decreased. The presence of C-peptide in many years that NIDDM is a familial disease. The
5.9. Pathophysiology of the endocrine pancreas 409

genetic contribution is illustrated by the fact that 70–90 % of patients with type 2 diabetes. A role
even 85 % of the patients’ parents with NIDDM have for amylin deposition in the islets of subjects with
also had diabetes, while only 11 % of the patients’ NIDDM is not precisely established. Amylin may
parents with IDDM have had diabetes (IDDM is not accumulate, either because of a primary defect of B
a familial disease). The identical twin of a patient cell function or because of abnormal B cell function
with NIDDM has an almost 100 % chance of devel- secondary to prolonged hyperglycemia (which is sec-
oping the diabetes, whereas the identical twin of a ondary to the insulin resistance). It is possible that
patient with IDDM has only a 30–50 % chance of progressive accumulation of amylin disrupts islet ar-
developing the diabetes. chitecture and leads to impaired B cell function and
Despite the strong influence of genetic factors their so it might contribute to the late failure of insulin
precise nature in etiology of NIDDM remains elusive. production in patients with long-standing NIDDM.
Mutations in insulin gene, insulin receptor gene, or Whether extracellular deposits of amylin contribute
glucose transporter genes (genes for glucose trans- also to early disturbance in insulin secretion is con-
port protein units – GLUTs – which transport glu- troversial. In animals, amylin has been reported to
cose across the cell membrane) are considered. It has induce also insulin resistance. Hyperamylinemia may
not been known yet, whether inheritance of NIDDM impair insulin action mainly in skeletal muscle cells.
is monogenic or polygenic. Polygenic inheritance is
usually preferred. B. Insulin resistance is the other prime charac-
It is generally accepted that the pathogenic basis teristic of NIDDM. Patients with overt NIDDM un-
for NIDDM is made up by the defect in B cell func- doubtedly have marked insulin resistance in target
tion (dysfunction of B cells) and insulin resistance tissues. Insulin insensitivity may be a primary def-
in peripheral tissues. For the present, however, it is fect (genetically conditioned) or is secondary to hy-
not exactly known, whether the genetic defect pri- perglycemia. Most authorities believed that insulin
marily affects B cell function or peripheral insulin resistance in patients with type 2 NIDDM is primary,
resistance, or whether one defect causes the other, with hyperinsulinemia being secondary, i.e., insulin
or at least precedes the other. secretion increases to compensate for the resistance
state. However, it is possible that hypersecretion
A. The defect in the function of B cells is a quali- of insulin (and probably also amylin) causes insulin
tative and not quantitative defect. Normal subjects resistance, i.e., a primary islet cell defect causes in-
have a biphasic insulin response to intravenous glu- sulin hypersecretion, and insulin hypersecretion, in
cose. In the patients with NIDDM the most char- turn, leads to insulin resistance. The insulin resis-
acteristic defect is loss of the first phase insulin re- tance can have many distinct mechanisms including
sponse to an intravenous glucose challenge. The sec- a reduced number of seemingly normal receptors, re-
ond phase release of insulin is not as severely altered, ceptors which function abnormally (due to abnormal
although it cannot be considered truly normal. In- insulin binding to the alpha subunit of the insulin re-
sulin secretion in response to oral glucose is delayed ceptor, or due to defective tyrosin kinase activity in
and exaggerated. This impaired insulin secretion is the beta subunit of the insulin receptor), and postre-
due in part to a reduction of GLUT-2 glucose trans- ceptor defects associated with normal insulin bind-
porter that facilitates glucose entry into the B cells ing. More important postreceptor defects include
(it facilitates rapid equilibration of glucose between impaired postreceptor signaling or reduced synthe-
extracellular and intracellular compartments). sis and/or translocation (from the Golgi apparatus
Current interest is also focused on the role of to the plasma membrane) of the glucose transporter
amyloidogenic peptide of islets in etiopathogenesis molecules of GLUT-4 in muscle and fat cells. Pri-
of type 2 diabetes. This material is 37-amino acid mary or secondary insulin resistance may cause a
peptide termed amylin. Amylin is normally copack- secondary defect in the B cells via their exhaustion
aged with insulin in secretory granules of B cells and or direct damage due to long-lasting hyperglycemia.
is cosecreted to insulin secretagogues. However, in At the present time, it is not possible to assign
patients with NIDDM, amylin tends to accumulate primacy to either process, i.e., B cell dysfunction or
autside the B cells, in close contact with their cell peripheral insulin resistance. One must state that
membranes. Isled amylin deposits are seen in about both a defect in the function of B cells and peripheral
410 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

insulin resistance are present in patient with overt netically predisposed subjects a sedentary life style
type 2 NIDDM and that both are probably required associated with physical inactivity may participate in
for the appearance of clinical diabetes. the clinical manifestation of type 2 NIDDM by the
Environmental factors. Although environmental origin of insulin insensitivity in cells of skeletal mus-
factors are extremely important in the genesis of cles. Some studies suggest that an excercise training
type 2 NIDDM, it is likely that they can only lead in subjects with an initially high insulin secretion
to diabetes in genetically predisposed individuals. leads to improvement in peripheral insulin sensitiv-
The following environmental factors (risk factors) are ity, decrease of insulin secretion, and improvement of
those which are currently suspected of being precip- glucose tolerance.
itants of NIDDM: obesity, physical inactivity, and
psychosocial stress. C. Psychosocial stress. A role of psychoso-
cial stress in the development of NIDDM in genet-
A. Obesity. It is the most frequent and most ically predisposed individuals is not exactly known
studied of all the risk factors for NIDDM. While in at present. It has been suggested that a long impli-
the whole population prevalence of diabetes mellitus cated psychoemotional stress may participate in the
has been somewhere between 3–6 %, in the popula- clinical manifestation of type 2 NIDDM by means
tion having obesity the prevalence of diabetes has of increased secretion of hormones which are insulin
been estimated at 20 %. With regard to importance antagonists (mainly glucocorticoids).
of obesity in pathogenesis, type 2 NIDDM is di-
Relationship of NIDDM with some chronic dis-
vided into non-obese and obese variants. The lat-
eases. Recently increased attention is paid to the
ter form is more common and accounts for approxi-
relationship of NIDDM with some diseases, mainly
mately 80 % of all cases of type 2 NIDDM. The risk
with primary arterial hypertension and primary hy-
of clinical manifestation of NIDDM shows a close
percholesterolemia. Rather frequent coexistence of
relationship to the degree and duration of obesity.
these diseases with NIDDM may indicate common
In most obese persons insulin secretion is excessive
genetic influence, cooperation of common environ-
(from the begining mainly postprandial hyperinsu-
mental factors, a causal sequence among these condi-
linemia is present). In spite of it, however, it is in-
tions themselves, or to existence of random chronol-
sufficient for increased demands of insulin evoked by
ogy in realization of the mentioned endogenous and
peripheral insulin resistance. In theory hyperinsu-
exogenous factors (overeating, physical inactivity,
linemia could induce secondary insulin resistance by
and psychosocial stress). Insulin resistance and hy-
down-regulation of insulin receptors. This results in
perinsulinemia are often associated with obesity, ar-
hyperglycemia. It is possible that in some individ-
terial hypertension, hypertriacylglycerolemia, and
uals prolonged hyperglycemia could lead to the in-
hyperuricemia. The complex of these disorders has
crease of insulin resistance and to the impairment of
been termed ”syndrome X” or the Modan-Reaven
B cell function. It gradually leads to B cell exhaus-
syndrome.
tion and their irreversible damage. This hypothesis
is supported by the finding that after the reduction of To summarize, the type 2 NIDDM appears to be a
excess body wight the clinical and laboratory symp- disease of complex etiology. It is probably caused by
toms of diabetes are reduced. Insulin resistance in the interaction of several different genetic and envi-
patients with type 2 NIDDM may be the result of ronmental factors. Although specific genetic mark-
two separate factors. Because insulin insensitivity ers for the disease have yet to be defined, there is
occurs in obesity without hyperglycemia, increased clear evidence for genetic predisposition. The most
adiposity undoubtedly plays an important role in plausible environmental precipitants appear to be
the insulin resistance of obese patients with NIDDM. the inter-related triad consisting of obesity, low lev-
However, nonobese relatives of persons with NIDDM els of habitual physical excercise, and psychosocial
may have hyperinsulinemia and diminished insulin stress. On the basis of present knowledge the fol-
sensitivity, proving that obesity is not the sole cause lowing hypothesis for the pathogenesis of the type 2
of insulin resistance. NIDDM may be postulated: By the influence of the
risk factors in a subject with genetic predisposition
B. Physical inactivity. It is possible that in ge- to B cell dysfunction and/or genetically determined
5.9. Pathophysiology of the endocrine pancreas 411

predisposition to insulin resistance at first impaired toxic, or other form of damage of pancreas. It
glucose tolerance originates. Later, mild persistent may occur in patients with chronic pancreatitis,
hyperglycemia appears. Long-lasting moderate hy- cystic fibrosis, hemochromatosis, carcinoma of
perglycemia intensifies the impairment of islet B cells the pancreas, and pancreatectomy.
and simultaneously leads to the origin of secondary
insulin resistance in target tissues. The result is overt (b) Diabetes mellitus associated with other en-
type 2 NIDDM. docrine disease. It is mostly induced by over-
production of insulin antagonists (growth hor-
3. Malnutrition-related diabetes mellitus mone, cortisol, or glucagon). It appears most
often in the patients with Cushing syndrome,
Malnutrition-related diabetes mellitus (MRDM) acromegaly, or gigantism. Glucagonoma, so-
occurs only in tropical equatorial countries of Africa, matostatinoma, thyrotoxicosis, or pheochromo-
Asia, and South America. Therefore, it is also cytoma may be a rare cause of its origin. Di-
termed tropical diabetes. It is characterized by an abetes is usually mild and without tendency to
onset before the age of 30, a history of severe malnu- ketoacidosis.
trition and severe malnutrition on presentation, and
by fluctuating insulin dependence and insulin resis- (c) Diabetes mellitus induced by administration of
tance. However, ketoacidosis does not develop when some hormones, drugs, and chemicals. The ori-
insulin is withdrawn. There are two variants of this gin of diabetes depends on the amount of ad-
disorder: ministrated substance, on the duration of its
administration, and on sensitivity of the sub-
(a) Fibrocalculous pancreatic diabetes. It is associ-
ject to administrated substance. The disor-
ated with exocrine pancreatic deficiency, pan-
der of glucose metabolism is mostly transient
creatic fibrosis which often leads to calcifica-
and after a withdrawal of the administrated
tion, and the presence of stones in the pancreatic
substance it becomes normal. If diabetes per-
duct. Its etiology is not exactly known.
sists, it is probably a manifestation of predi-
(b) Protein-deficient pancreatic diabetes. This abetes and the administrated substance was
form appears to be caused directly by malnutri- only a factor provoked its clinical manifesta-
tion. Unlike fibrocalculous pancreatic diabetes, tion. The most common diabetogenic drugs in-
there is no impairment of exocrine pancreatic clude: hormones (ACTH, synthetic glucocorti-
function, and no evidence of pancreatic fibrosis coids, and growth hormone), thiazide diuretics,
or calcification. β-adrenoceptor blocking drugs, drugs blocking
ovulation, and tricyclic antidepressants. The
In both forms of tropical diabetes, insulin secretion most common diabetogenic chemicals are al-
is preserved, although impaired. This is the likely loxan and streptozotocin having cytotoxic effect
explanation for the resistance to ketoacidosis. Alter- on islet B cells.
natively, malnourished individuals may have so little
stored fat that free fatty acids cannot be released in (d) Diabetes mellitus due to an abnormal insulin
sufficient quantities to fuel the process of ketogenesis. or insulin-receptor abnormalities. Abnormal in-
sulin (e.g., insulin Chicago) originates due to
mutation in the insulin gene. The usual clini-
4. Other types of diabetes mellitus cal picture is mild hyperglycemia with hyperin-
sulinemia and decreased binding of the mutant
In the previous classification these forms of dia-
insulin to target tissues (prereceptor insulin re-
betes were termed secondary diabetes mellitus. At
sistance). The response to normal insulin is in-
present this classificatory category includes diabetes
tact.
mellitus associated with other basic diseases, syn-
dromes, or certain conditions. It is divided into fol- At present two abnormalities of insulin receptors
lowing six subgroups: are known:
(a) Diabetes mellitus associated with pancreatic 1. A defect due to mutation in the insulin
disease. It is caused by traumatic, infectious, receptor itself which is manifested by de-
412 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

creased affinity of receptor to insulin or by more frequently in the patients with cirrhosis com-
decreased number of insulin receptors (in pared to those with normal liver. Similarly, in dia-
the patients with congenital lipodystrophy betics cirrhosis of the liver is 2–3 times more frequent
or with acanthosis nigricans). than in the persons without diabetes. In the patients
2. An existence of antibodies against insulin with cirrhosis hyperinsulinemia, hyperglucagonemia,
receptors (e.g., in women with androgen and peripheral insulin resistance are often proved.
excess, particularly in those with polycys- Increased insulin and glucagon concentrations in cir-
tic ovary disease) which are the cause of culating blood of the patients with cirrhosis can be
insulin resistance. explained by their decreased degradation in the cir-
rhotic liver.
(e) Diabetes mellitus associated with some genetic
syndromes. This form of diabetes originates 5. Impaired glucose tolerance
mainly as a result of combination of some ge- Impaired glucose tolerance (IGT) is an intermedi-
netic syndromes with various factors, as e.g., ate category between normal glucose tolerance and
nutrition disorders, physical inactivity, obesity, diabetes mellitus. The persons with IGT are not
immunological disorders, and the like. They are considered to be diabetics, but probability of the ori-
the following genetic syndromes: gin of diabetes is higher in them than in the rest
of population. This category is extremely heteroge-
• inborn metabolic disorders (glycogenosis
nous. Some subjects with IGT are obese or non-
type I, hyperlipoproteinemia, and acute in-
obese, some have liver disease, some are on medi-
termittent porhpyria);
cation that impairs glucose tolerance, and in others
• syndromes with insulin resistance (heredi- IGT is associated with other certain conditions or
tary ataxia-teleangiectasia, myotonic dys- syndromes. About 20 % of the patients with IGT
trophy, and lipoatrophic syndrome); may progress to overt diabetes mellitus, about 50 %
• hereditary neuromuscular disorders (mus- of them may spontaneously fall back to normal glu-
cular dystrophy and Friedreich’s ataxia); cose homeostasis, and in about 30 % of the patients
IGT persists during the whole life. Individuals with
• syndromes associated with obesity (Pra- IGT have a substantially increased risk of atheroscle-
der-Willi syndrome and achondroplasia); rotic disease, but are not at risk of developing the
• cytogenetic disorders (Down syndrome, specific microvascular late complications of diabetes.
Klinefelter syndrome, and Turner syn- The development of atherosclerosis is fast mainly in
drome). those subjects whose IGT is associated with obesity
and hyperlipoproteinemia.
(f) Diabetes mellitus associated with other condi-
tions or syndromes. This category is poorly de- 6. Gestational diabetes mellitus
fined and is meant to include any condition as-
sociated with diabetes which does not belong The term gestational diabetes mellitus (GDM) de-
to any of previous five subgroups. Such con- notes diabetes or impaired glucose tolerance that de-
dition may by potassium depletion which origi- velop in the course of pregnancy. Women with dia-
nates due to primary hyperaldosteronism or dur- betes who became pregnant are not included in this
ing a long-time treatment by diuretics. Potas- group. This type of diabetes is typically asymp-
sium deficit in islet B cells causes the disorder tomatic and is demonstrated biochemically on the
of the first phase of insulin secretion. basis of random testing or an oral glucose toler-
ance test. Multiple investigations have shown that
Other pathological state associated with diabetes fetal malformations during pregnancy are not in-
is cirrhosis of the liver. However, the relationship duced only by existence of diabetes, but also by
between cirrhosis and diabetes mellitus has not been presence of impaired glucose tolerance in a pregnant
unambiguously explained yet. It has not been proved women. Fetal macrosomia, neonatal hyperglycemia,
whether corrhosis causes diabetes or whether dia- and an increased perinatal mortality rate are fre-
betes is prior to cirrhosis. Diabetes occurs 3 times quent. However, by increased health care and ap-
5.9. Pathophysiology of the endocrine pancreas 413

propriate therapy of pregnant women with diabetes, symptoms are, however, different. In the patients
the origin of the mentioned consequences may be pre- with type 1 IDDM the onset of these symptoms of-
vented. Approximately half the mothers who develop ten occurs over a short period, mostly in the course
gestational diabetes revert to normal after delivery. of several few days or weeks. Diabetic ketoacidosis
But gestational diabetes may reappear with subse- also originates in a short period, and without admin-
quent pregnancies and there is a higher incidence of istration of exogenous insulin it gradually leads to ke-
NIDDM later in the life (even 5–10 years after de- toacidotic coma. This does not mean that the patho-
livery). It has been found that the higher degree of logical process leading to overt type 1 IDDM is brief
impaired glucose tolerance during pregnancy is as- or that the symptoms always appear suddenly. As
sociated not only with higher risk of the origin of discussed previously, destruction of the B cells usu-
NIDDM, but also with the shortening of the period ally requires more than a year. In the patients with
during which NIDDM develops after delivery. In type 2 NIDDM these characteristic symptoms de-
dependence on an actual state of glucose tolerance velop slowly, usually in the course of several months
(glucose metabolism disorder) and on etiology of its or years. They are milder, weight loss is often absent.
impairment, gestational diabetes has to be reclassi- The typical patient is overweight. Most patients are
fied after delivery in some of the types of diabetes or asymptomatic, hyperglycemia may be detected on
in impaired glucose tolerance. If the glucose toler- a routine examination. In some cases the presence
ance test after delivery normalises, gestational dia- of type 2 NIDDM in women may be indicated by
betes mellitus is reclassified in previous abnormality the origin of Candida vulvovaginitis with a pruritus
of glucose tolerance. vulve. In men the presence of NIDDM may be in-
dicated by the origin of Candida balanitis. Neither
5.9.1.3 Epidemiology of diabetes mellitus tendency to ketoacidosis is present. In the decom-
pensated metabolic state they are susceptible to the
Diabetes mellitus is a relevant medical and social syndrome of hyperosmolar nonketotic coma. Occa-
problem in the most countries of the world. In sionally the presenting symptom of type 2 NIDDM
well-developed countries its occurrence has approxi- may be one of the late diabetic complications that
mately 10 times multiplied during the last fifty years. leads the physician to test for hyperglycemia or per-
In Slovakia its prevalence in 1965 was 0.33 % and at form a glucose tolerance test. Only rarely the onset
present it is about 3.7 %. In the group of population of symptoms of type 2 NIDDM is as acute as in type 1
over 65 years of age prevalence of diabetes is even IDDM. When this occurs it is usually the result of
16 %. In the first years of life diabetes mellitus is the stress of an acute intercurrent illness. In the indi-
rare. However, children are affected between 10–15 viduals with the Modan-Reaven syndrome diabetes
years of age most frequently. In our country in the mellitus is often diagnosed on medical examination
first decade of life in two children per 100,000 in- initiated by the origin of symptoms of arterial hyper-
habitants diabetes mellitus is supposed to be newly tension or ischemic heart disease.
diagnosed anually. In each of the following decades
diabetes mellitus is doubled. To the age of 40 dia- The insulin lack reduces glucose utilization and in-
betes occurs in both sexes equally, later it is a little creases glucagon secretion. Therefore, the metabolic
more frequent in women. Probability of the origin derangements of diabetes are due not only to rela-
of diabetes mellitus is doubled in those individuals tive or absolute deficiency of insulin but also to rel-
whose body weight is 20 % higher than normal. ative or absolute excess of glucagon. A fall in the
insulin/glucagon ratio causes increased production
5.9.1.4 Pathophysiology and clinical features of glucose by the liver while the absolute decrease in
of diabetes mellitus plasma insulin concentration reduces glucose utiliza-
tion in peripheral tissues. Insulin deficiency block
Characteristic symptoms of clinically manifested di- glucose utilization by insulin-requiring tissues, acti-
abetes mellitus are polyuria, polydipsia, decrease in vates lipolysis in adipose tissue, enhances proteolysis
body activity, and wieght loss. They occur in most in skeletal muscles, causes hyperglucagonemia, and
of patients with both basic types of diabetes melli- intensifies glucagon effects on the liver. Glucagon,
tus. Rate and intensity of the development of the when unoposed by a normal insulin response, is pri-
414 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

marily responsible for the hepatic components of dia- may occur. Affected patient suffers from dryness
betic decompensation, i.e., increased glycogenolysis, in mouth and intense thirst causing excess drinking
gluconeogenesis, and ketogenesis. In other words, (polydipsia).
insulin deficiency is the cause of augmented delivery Rather early symptoms of diabetes mellitus are
to the liver of the substrates for glucose and ketone decreasing of physical activity, intensifying of over-
production (mainly amino acids and free fatty acids, all weakness and fatigue. Simultaneous weight
respectively) and glucagon is the switch that acti- loss appears (despite polyphagia which is sometimes
vates the hepatic production machinery for glucose present) in the consequence of:
and ketones. Therefore, a further decrease in the in-
sulin/glucagon ratio leads to more serious syndromes a) Decrease of muscle tissue mass (due to enhanced
of diabetic decompensation, i.e., diabetic ketoacido- catabolism of proteins);
sis and hyperosmolar nonketotic coma.
b) Decrease of fat tissue mass (due to activation of
The first and direct consequence of absolute or rel-
lipolysis in adipocytes);
ative insulin deficiency is the disorder of glucose me-
tabolism, the most evident biochemical manifesta-
c) Increased loss of water and electrolytes.
tion of which is hyperglycemia. The rising of glu-
cose concentration in circulating blood and in extra- At the onset of diabetes increased appetite,
cellular fluid is due to sharply diminished or abol- even polyphagia are less common. With grading
ished glucose utilization by insulin-requiring tissues metabolic derangements of diabetes appetite grad-
(mainly by muscle, fat, and liver cells). Lipogene- ually decreases.
sis (conversion of glucose to fatty acids) decreases in Because insulin deficiency blocks glucose utiliza-
adipose tissue. Glycogenolysis (glycogen breakdown)
tion by insulin-requiring tissues, free fatty acids
and gluconeogenesis (synthesis of glucose from non- and in less extent amino acids are utilized as a
carbohydrate sources, mainly from amino acids) in- source of energy. Free fatty acids (FFA) become the
crease in the liver. Glucose is, therefore, to a higher main energetic source, because the increased protein
extent released from the liver into circulating blood. catabolism cannot be sufficient to cover energetic de-
Thus, insulin deficiency does not lead only to under-
mands of body tissues. Activation of lipolysis in adi-
utilization of glucose in peripheral tissues but also to pose tissue and successively enhanced FFA release
hepatic glucose overproduction. The result of both from adipocytes results in hyperlipidemia. Plasma
a reduction of transmembrane glucose flow into the FFA, triacylglycerols, and rarely cholesterol concen-
cells of insulin-requiring tissues and hepatic glucose trations are increased. Plasma HDL concentration is
overproduction is the origin of a state which is char- usually decreased. The increased lipolysis is marked
acterized by excess of extracellular glucose and by by an accompanying rise in glycerol release into cir-
deficiency of intracellular glucose. culating blood which is then used in the liver as a
When the level of circulatig glucose exceeds the gluconeogenic substrate.
renal threshold (about 10 mmol/L) a capacity of glu- Increased oxidation of FFA within the liver is as-
cose reabsorption of the least efficient nephrons is ex- sociated with increased production of ketone bodies
ceeded. Non-reabsorbed glocose from these nephrons (β-hydroxybutyric acid, acetoacetic acid, and ace-
is excreted by urine, glycosuria ensues. If the ca- tone). Glucagon is the hormone that accelerates such
pacity of glucose reabsorption of all nephrons is ex- FFA oxidation. The rate at which ketone bodies
ceeded, the whole quantity of filtered glucose exceed- are formed may gradually exceed the rate at which
ing maximum tubule glucose transport (350 mg/min) accetoacete and β-hydroxybutyrate are oxidised in
is lost by urine. As glucose is an osmoticly active sub- extrahepatic tissues, mainly in skeletal muscles, my-
stance, the excessive glycosuria induces an osmotic ocardium, and other tissues. Thus increasing ketoge-
diuresis and thus polyuria (usually also nocturia). nesis leads to hyperketonemia. As the renal thresh-
In more advanced cases the volumes of urine may old for ketone bodies is low, their urinary excretion
reach 5–10 litres per day. Due to evident polyuria originates rather soon leading to ketonuria. Acetone
a profound loss of water and electrolytes may origi- is used for gluconeogenesis although most is excreted
nate and so the danger of extracellular dehydration in the urine or by the lung. Some ketones may be
5.9. Pathophysiology of the endocrine pancreas 415

esterified to triacylglycerols leading to hypertriacyl- phagocytosis, and bactericidal activity of leucocytes.

glycerolemia. Triacylglycerols are to a high extent Extracellular dehydration and increased glucose
stored in the hepatocytes (steatosis originates). concentration in extracellular fluid (the both caus-
ing hyperosmolarity of extracellular fluid), as well
Acetoacetic acid and β-hydroxybutiric acid are
as increased protein breakdown and metabolic aci-
weak (but fully disociated at physiological pH) and
dosis lead to the origin of intracellular dehydration,
nonvolabile organic acids which cannot be freely ex-
increased intracellular depletion of potassium and to
creted by the kidneys, and, therefore, are buffered
the increased urinary potassium loss. Finally it leads
by plasma bicarbonate. Gradually, plasma bicar-
to a severe total body deficit of potassium. Extracel-
bonate concentration decreases, plasma hydrogen ion
lular dehydration, which is gradually increased not
concentration increases, and systemic metabolic ke-
only by polyuria but also by vomiting and hyper-
toacidosis results. From the beginning ketoacidosis
ventilation, in insufficiently treated or in nontreated
is compensated, later, even maximum utilization of
patients may result in hypovolemia, arterial hypoten-
compensatory mechanisms cannot prevent the evi-
sion, and later even in hypovolemic shock.
dent decrease of pH in blood and extracellular fluid
(decompensated metabolic acidosis). Due to the de-
crease of pH in extracellular fluid the respiratory cen- 5.9.1.5 Acute metabolic complications of di-
tre is intensively stimulated which gives rise to mildly abetes mellitus
accelerated and evidently deep respirations termed
The patients with diabetes mellitus, mainly those
Kussmaul respiration. This form of respiration par- with inadequate therapy, are susceptible to two ma-
tially compensates the metabolic acidosis by blow- jor acute metabolic complications: hyperglycemic
ing off carbon dioxide (i.e., by respiratory alkalosis). diabetic coma with ketoacidosis and hyperosmolar
Evident metabolic decompensation (ketoacidosis) is
nonketotic diabetic coma. The former is a com-
often associated with vomiting which further exacer-
plication of IDDM, while the latter usually oc-
bates the water and salt depletion. curs in the setting of NIDDM. Lactacidotic coma
Insulin deficiency also grossly affects protein meta- and hypoglycemic coma are less common acute
bolism, what is manifested by increased proteolysis, metabolic complications of diabetes. All these four
hyperaminoacidemia, and increased urinary nitrogen acute metabolic complications of diabetes are a life-
loss. In more advanced degree of insulin deficiency threating clinical states requiring prompt hospital-
protein synthesis is also decreased. The overall in- ization and adequate intensive therapy.
crease in proteolysis is probably quantitatively more
important than a decrease in protein synthesis in de- A. Hyperglycemic diabetic coma with keto-
termining the effects of insulin deficiency. The result acidosis
of increased protein catabolism and decreased pro- It is the severest degree of complex metabolic dis-
teosynthesis is the origin of evidently negative nitro- order induced by absolute or almost absolute insulin
gen balance and reduction in body proteins (body deficiency. It originates in insufficiently treated sub-
protein depletion) what is manifested mainly by re- jects with type 1 IDDM, or rarely in individuals with
duction of skeletal muscle mass. This disorder of type 2 NIDDM due to stress load (e.g., intercurrent
protein metabolism contributes to slow healing of infection or other illness, trauma, surgery, psychoe-
wounds. Protein depletion in diabetics decreases also motional stress). The increased need of insulin dur-
resistance of organism to infection. The increased ing stress load is conditioned by the increased se-
glucose concentration in extracellular fluid is a con- cretion of stress hormones which are insulin antago-
venient environment for microorganisms, what may nists (cortisol, growth hormone, and adrenalin which
also contribute to the increased suspectibility of di- is in stress the operative stimulus for glucagon re-
abetics to bacterial or fungal infections. Glycation lease). Also hypovolemia, which is the consequence
of circulating immunoglobulins and glycation of pro- of increased diuresis, directly increases the secretion
teins of leucocyte membrane also participate in de- of glucagon, catecholamines, and other hormones of
creased resistance of diabetics to bacterial infections. stress and, via decreasing renal blood flow, reduces
Glycation of the leucocyte membrane proteins prob- glucagon degradation by the kidneys. The result is
ably results in inhibition of chemotaxis, diapedesis, marked hyperglucagonemia and hyperglycemia. Hy-
416 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

perosmolality thus becomes a factor and water moves This type of diabetic coma may originate mostly
out of cells (intracellular dehydration). in elderly patients with type 2 NIDDM in whom an
Hyperglycemic diabetic ketotic coma is very rele- intercurrent illness increases glucose production sec-
vant, life-threatening clinical state, evoked mainly by ondary to stress hormones and impairs the capacity
hyperosmolality, dehydration and ketoacidosis. Hy- to ingest fluids (the patients are unable to drink suf-
perosmolality of extracellular fluid is caused by high ficient water to keep up with increased urinary fluid
concentration of glucose in circulatoing blood and in losses evoked by increased osmotic diuresis). The
extracellular fluid (16–41 mmol/L) and by extracel- mortality rate in hyperosmolar nonketotic diabetic
lular dehydration. In the consequence of hyperos- coma is high (over 50 %).
molality and toxic effect of ketoacidosis on CNS, de-
creased consciousness gradually develops in the dia- C. Lactacidotic coma
betic patient (somnolence, disorientation, sopor, stu-
It is a very rare acute metabolic complication in
por, and confusion), and later frank coma occurs.
diabetics. It may originate in the diabetics suffer-
Skin and mucous membranes of the patient are dry,
ing from evident tissue hypoxia associated with in-
skin turgor is decreased, eyballs may be soft (intraoc-
sufficient removing of lactic acid by the liver and
ular pressure is usually decreased) and sunken into
kidneys (mainly in diabetics with cardial and res-
the sockets, and breathing is typical acidotic (Kuss-
piratory hypoxia and in diabetics-alcoholics). Blood
maul respiration). A high plasma acetone level im-
lactic acid concentration is higher than 6–8 mmol/L
parts a fruity odor to the breath. Rigidity of the ab-
(the norm is 1.6 mmol/L). Glycemia need not be
dominal wall is a common finding due to increased
much increased. Neither ketonemia and ketonuria
tonus of abdominal muscles which is secondary to
are present. In some cases, however, concentrations
the loss of water and electrolytes from the organism
of ketone bodies in blood and urine are slightly in-
(pseudoperitonitis diabetica). Body temperature is
creased. Blood bicarbonate concentration and pH
normal or lowered in uncomplicated ketoacidosis by
are low.
infection, extremities are cold. Pulse is soft and ac-
celerated (thready pulse), arterial blood pressure is
decreased. Polyuria is replaced by oliguria even by D. Hypoglycemic coma
anuria what leads to prerenal azotemia. With greater It can occur in diabetics treated by insulin, for
degrees of volume depletion a frank oligemic shock example, when insulin doses are excessive or poorly
may occur. Without early adequate intensive terapy timed, when meal is missed or food intake is delayed
diabetic coma may, therefore, lead to death. after administration of insulin, when endogenous glu-
cose production is impaired (as after alcohol inges-
B. Hyperosmolar nonketotic diabetic coma tion), or when glucose utilization is increased (as
It is the characteristic acute metabolic complica- during excercise). Symptoms of hypoglycemic coma
tion of type 2 NIDDM, analogous to ketotic diabetic originate when blood glucose concentration falls to
coma in type 1 IDDM. It is also termed a syndrome about 2.5 mmol/L. Breathing of a patient is normal,
of glucose hyperosmolarity or a syndrome of extreme dehydration is not present. Urine does not contain
hyperglycemia and dehydration. The clinical picture ketones or glucose.
of hyperosmolar nonketotic diabetic coma develops
slowlier (during several days even weeks) than ke- 5.9.1.6 Late complications of diabetes melli-
totic diabetic coma. It is characterized by extreme tus
hyperglycemia (usually above 56 mmol/L), hyperos-
molality of extracellular fluid, and volume depletion. Better diagnostic possibilities, insulin treatment, and
Prerenal hyperazotemia and extremely high glyco- increased care of diabetics have prolonged their lives.
suria have been found out. As the concentration of At the same time, however, this resulted in more fre-
ketones in circulating blood is not increased, Kuss- quent occurrence of late (mainly degenerative) com-
maul respiration, a fruity odor of the breath, and plications of diabetes mellitus. Some of them origi-
ketonuria are absent. Central nervous system dys- nate only in diabetics, and therefore, are considered
function is presumably the consequence of intracel- as specific late complications of diabetes mellitus.
lular dehydration. They include diabetic microangiopathy and diabetic
5.9. Pathophysiology of the endocrine pancreas 417

neuropathy. Others are nonspecific late complica- chemically attaches to the amino group of proteins
tions of diabetes mellitus. Nonspecific complications without the aid of enzymes. Lysine and valine amino
can be also present in the rest of the population (in groups are the primary sites of glucose addition. The
nondiabetic persons with other diseases), but less level of glycation of protein is determined by the level
frequently than in diabetics. They include mainly of hyperglycemia and by the duration of protein con-
atherosclerosis and its sequalae (myocardial infarc- tact with a given level of hyperglycemia. Glusose
tion, cerebral stroke, and gangrene of low limbs), forms chemically reversible glycosylation products
various infections, and cataract. with protein (named Schiff bases or aldimines) that
In some patients several chronic complications may rearrange to form more stable Amadori-type
occur simultaneously, in others one late complica- early glycosylation products (ketoamines), which are
tion is prevailing in the clinical picture of diabetes. also chemically reversible. The early glycosylation
Though, the long-term complications accur in both products with protein undergo a slow series of chem-
main types of diabetes mellitus, some of them are ical rearrangements to form irreversible advanced
more common in one type, and others in the other glycosylation end-products (AGE), which accumu-
type. Chronic renal failure resulting from diabetic late over the life-time.
microangiopathy is the most frequent cause of death
AGE formation occurs on proteins, lipids, and
in type 1 IDDM. The consequences of macroangiopa-
nucleic acids. On proteins, such as collagen, they
thy occur equally in the both basic types of diabetes
cause cross-links between polypeptides of the colla-
mellitus. Diabetic neuropathy is much more frequent
gen molecule and also trap nonglycosylated plasma
in the patients with diabetes type 1. Due to late com-
or interstitial proteins. Glycated collagen is more
plications the health of diabetics becomes essentially
insoluble and resistant to digestion (degradation
impaired. Chronic complications cause their more
by collagenase) than native collagen because of in-
frequent and longer working incapacity, the change
creased intramolecular cross-linking, which decreases
of working place, or precocious invalidism of diabet-
its degradation. In large vessels, trapping LDL,
ics. Therefore, late complications give rise not only
for example, retards its efflux from the vessel wall
to health problems, but also to social and economic
and enhance the deposition of cholesterol in the in-
ones.
tima, thus accelerating atherogenesis in diabetics. In
Patogenetic mechanisms. Most ot the available
small vessels (especially in capillaries) plasma pro-
experimental and clinical evidences suggest that the
teins such as albumin bind to the glycosylated base-
chronic complications of diabetes mellitus are a con-
ment membrane, accounting in part for the increased
sequence ot the metabolic derangements, mainly hy-
basement membrane thickening characteristic of di-
perglycemia. Because due to insulin deficiency in
abetic microangiopathy. AGE cross-linked proteins
diabetics, glucose is not metabolized by normal way,
are resistant to proteolytic digestion. Thus, cross-
metabolic processes in which insulin is not necessary
linking decreases protein removal while enhancing
for glucose metabolism are activated. Glycosylated
protein deposition. AGE-induced cross-linking in
proteins, sorbitol, and fructose are produced. These
collagen type IV in basement membrane may also
products of aberrant glucose metabolism play an im-
impair the interaction of collagen with other ma-
portant role in pathogenesis of specific late compli-
trix components (proteoglycans, laminin) resulting
cations of diabetes mellitus.
in structural and functional defects of the basement
Currently following two mechanisms linking hy-
membranes.
perglycemia to the complications of long-standing
diabetes mellitus are considered important: nonen- AGEs are found in increased amounts not only
zymatic glycosylation (glycation) and activation of in connective tissues, but have been also demon-
the polyol pathway. strated in cardiac myosin from diabetic subjects.
AGEs also bind to receptors on many cell types, such
(a) Nonenzymatic glycosylation. When a pro- as endothelium, monocytes, macrophages, lympho-
tein is exposed to a high glucose concentration, cytes, and mesangial cells. Binding induces a variety
nonenzymatic incorporation of glucose can occur, re- of biologic activities, including: monocyte emigra-
sulting in unregulated glycosylation. Nonenzymatic tion, release of cytokines and growth factors from
glycosylation refers to the process by which glucose macrophages, increased endothelial permeability, in-
418 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

creased procoagulant activity, enhanced proliferation to fructose by the enzyme sorbitol dehydrogenase
of fibroblasts and smooth muscle cells, and enhanced with NAD+ as coenzyme. The accumulated sorbitol
synthesis of extracellular matrix by fibroblasts and and fructosa lead to increased intracellular osmolar-
smooth muscle cells. All these effects can potentially ity and influx of water (osmotic cellular swelling)
contribute to chronic diabetic complications. and, eventually, to osmotic cell injury. Intracellular
Proteins in plasma that turn over slowly, such as sorbitol accumulation is associated with a decrease in
albumin, LDL, HDL, immunoglobulin G, antitrom- myo-inositol content, resulting in decreased phospho-
bin III, red blood cell membrane, hemoglobin, and inositide metabolism, and a subsequent fall of protein
von Willebrand factor become also significantly gly- kinase C and Na+ /K+ –ATPase activity. This mech-
cosylated in diabetics. It has been found that also anism may be responsible for damage to Schwann
lens and myelin proteins are glycated. Glycosylated cells and to pericytes of retinal capillaries. In the
proteins react in the presence of metal ions to pro- lens, osmotically imbibed water causes swelling and
duce superoxide. The action of oxygen-derived free opacity.
radicals is potentially enhanced by the reduced lev- Nonenzymatic glycation of proteins and the polyol
els of antioxidants found in diabetics. Increased ac- pathway may not be unrelated mechanisms. It is
tivity of the polyol pathway (see below) depletes known that fructose generated in the polyol sequence
NADPH, making scavenging of free radicals less ef- can nonenzymatically bind to protein (called fructa-
ficient. Cytosolic superoxide dismutase has been tion). It is thus possible that an active polyol path-
found decreased in diabetes mellitus. way contributes significantly to nonenzymatic glyca-
In comparison to original nonglycosylated pro- tion (fructation) of proteins. The rate of glycation
teins, glycated proteins have different physicochem- with fructose is seven or eight times faster than with
ical properties what is manifested by the change of glucose.
their function. Long-term persistence of metabolic
derangement (mainly hyperglycemia) of diabetics, Pathophysiology and clinical features of indi-
therefore, to a high degree participates in the origin vidual forms of specific and nonspecific late compli-
of late complications of diabetes mellitus. Relation- cations of diabetes mellitus:
ship between the severity of late complications and
cumulative hyperglycemia (metabolic imbalance of A. Diabetic angiopathy
diabetes) is significant from the point of view clinical Diabetic angiopathy is the severest and most com-
practice (long-term attendance of correction of the mon late complication of diabetes mellitus. At
metabolic and hormonal abnormalities of diabetes). present it determines the prognosis in diabetics. This
It points out the possibility of utilization of long- long-term complication considerably increases inva-
lasting normoglycemic compensation in diabetics for lidity and mortality of diabetics. About 75 % of dia-
delay of the onset and for the relief of consequences betics die of the consequences of cardio-vascular dis-
of late complications of diabetes mellitus. However, orders. Diabetic angiopathy is traditionally divided
there is no evidence that meticulous control of dia- into two forms, which are pathogeneticly and clin-
betics (correction of the metabolic and hormonal ab- ically different: diabetic microangiopathy and dia-
normalities) reverses clinically established microan- betic macroangiopathy. Diabetic microangiopathy is
giopathic complications. a specific and macroangiopathy is a nonspecific late
complication of diabetes mellitus.
(b) Activation of the polyol patway. It is a sec-
ond general mechanism possibly underlying late com- 1. Diabetic microangiopathy
plications of diabetes mellitus. In some tissues (e.g., Diabetic microangiopathy is a generalized disease
nerve, retina, lens, kidney, and endothelial cells, per- of small vessels causing various disorders of microcir-
icytes and mesangial cells) that do not require insulin culation. Although it is a generalized disease, patho-
for glucose transport, hyperglycemia leads to an in- logical changes preferentially affect retinal vessels
crease in intracellular glucose content. The excess and renal glomeruli. However, they also participate
glucose is metabolized to sorbitol, a polyol, under in the disorder of microcirculation in myocardium,
the influence of the enzyme aldose reductase with brain, and peripheral tissues, but less significantly.
NADPH as cofactor. Sorbitol can then be oxidized Diabetic microangiopathy invalides a great number
5.9. Pathophysiology of the endocrine pancreas 419

of diabetics already in their productive age. In dia- the amount of glycosylated hemoglobin (HbA1c ), the
betics, incidence of renal failure is 17 times and in- decrease of deformability and increase of adhesivity
cidence of blindness is 25 times more frequent, in of the red cells, and the increase of platelet aggrega-
comparison with nondiabetic population. Severity tion.
of microangiopathy and mortality depend mainly on Glycosylated hemoglobin originates by nonenzy-
the age at which diabetes originates, on the period matic addition of glucose to hemoglobin over the life
of its duration, and on the level of management for span of the red blood cell. Glucose is attached to
the metabolic control of diabetes. α-amino group of the terminal valine of the β-chains
Morphological changes affect arterioles, capillar- of globine. Glycosylation of hemoglobin block the
ies, and venules. They are characterized by diffuse reaction of 2,3-diphosphoglycerate with positively
thickening of basement membrane, which is caused charged residues on the β-chains, causing a slight
by a large accumulation of PAS-positive material. increase in oxygen affinity. Impaired release of oxy-
Chemically, this substance resembles advanced gly- gen from hemoglobin results from the combined ef-
cosylation end-products which are the result of glyco- fect of increased hemoglobin A1c and reduced 2,3-
sylation of structural proteins. However, thickening diphosphoglycerate level. In the patients with evi-
of basement membranes is also conditioned by the dently increased blood level of HbA1c the tissue hy-
increased binding of glycated plasma proteins (par- poxia can, therefore, originate in spite of normal pO2
ticularly albumins) to its components, and also by in arterial blood, what is most evidently manifested
the decrease of catabolism of AGE cross-linked pro- in tissues with increased demands for oxygen supply,
teins of basement membrane. e.g., mainly in retina.
In chemical constitution of basement membrane of With regard to a relatively long life span of the
capillaries also other abnormalities have been found, red blood cells the amount of glycated hemoglobin
e.g., the decrease in content of sialic acid and hep- is the indicator of the level of metabolic compen-
aran sulphate (the main proteoglycan). They are sation of diabetes minimally during the last 4–6
negatively charged molecules influencing filtration of weeks before the examination. Glycated hemoglobin
negatively charged molecules of plasma, e.g., albu- constitues up to about 5 % of total hemoglobin in
mins. As a result of the mentioned changes, perme- normal adults. The diabetics with a very good
ability (porosity) of basement membrane is increas- metabolic compensation exhibit the value of glycated
ing. The change of electrical properties of basement hemoglobin of about 8 %, those with satisfactory
membrane may be conditioned also by glycosylation metabolic compensation exhibit its value less than
of its own proteins, especially by the origin of gly- 12 %. The higher values are the evidence of insuffi-
cated collagen type IV. It has been found that syn- cient metabolic compensation of diabetes.
thesis and amount of collagen type IV are increased It has been reported that glycosylation of the red
that results in the decrease of elasticity and distensi- cell membrane decreases elasticity and fexibility of
bility of capillaries. The content of collagen-related erythrocytes, and their increased adhesivity has been
components (e.g., glycine, hydroxyproline, and hy- also observed in poorly controlled diabetes. Normal
droxylysine) is increased. All the mentioned changes red blood cells pass easily through capillaries with lu-
in chemical constitution and morphologic features of minal diameters smaller than their own because they
the basement membrane are the cause of the origin of are deformable. The loss of erythrocyte deformabil-
the increased permeability and decreased reactibil- ity deteriorates their pass through capillaries and can
ity of the terminal vascular bed. cause sludging of blood and contribute to retinal and
The disorders of microcirculation in patients with renal ischemia in diabetics. Overglycosylation of von
diabetic microangiopathy are caused not only by Willebrand factor could contribute to the increased
morphological, but also by functional changes. The platelet aggregation what makes conditions for the
functional changes concern partly the decreased re- origin of multiple microthrombi in microcirculation.
actibility and the increased permeability of the ter- The decreased activity of fibrinolytic system in di-
minal vascular bed (already mentioned), and partly abetics also contributes to their origin, probably as
some blood components. The best known functional a consequence of the decreased release of plasmino-
changes of blood components include the increase of gen activator from endothelial cells. These changes
420 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

also contribute to tissue ischemia in diabetics with renal hypoxia, presumably the consequence of
insufficient metabolic control. interactions among increased levels of glycosy-
The accumulation of sorbitol in endothelial cells of lated hemoglobin, decreased levels of red blood
capillaries, in pericytes, and mesangial cells causes cell 2,3-diphosphoglycerate, increased blood vis-
their osmotic swelling. The successive obliteration cosity, and diminished red blood cell deformabil-
of small blood vessels lumen contributes to the tis- ity (the hemodynamic hypothesis). Hyperperfu-
sue hypoxia. The small blood vessel closure is most sion leads to shear stress and tangential pres-
characteristic in the retina. Later, injury even de- sure on the microvascular wall. This results,
struction of these cells can originate what leads to with the interaction of advanced glycosylation
the formation of capillary microaneurysms and to of proteins, in changes of basement membrane
the increase of permeability of capillaries. It is man- and in the increased production of extravascu-
ifested by their increased readiness to produce exu- lar matrix proteins (by the microvascular en-
dates and later also hemorrhages into adjacent inter- dothelium) that contribute to the expansion of
stitium. In the retina after vascular occlusion for- mesangium. Glomerular filtration rate is in-
mation of new blood vessels (neovascularization) ap- creased (supernormal function), the kidneys are
pears. Retinal neovascularization is the result of the usually enlarged. Low microalbuminuria, which
effect of angiogenetic factor (a local capillary growth is detectable only by special techniques, may ap-
factor) produced by hypoxic retina. The new ves- pear, however, only during long standing insuf-
sels and microaneurysms are fragile, and, therefore, ficient metabolic compensation of diabetes. It is
hemorrhages are more frequent and extensive. These termed transient microalbuminuria. Blood pres-
changes and contraction of fibrous proliferations are sure is not increased.
the principal mechanisms leading to a higher prob-
ability of retinal detachment and subsequent visual • The second stage is characterized by thicken-
loss (blindness). ing of glomerular basement membrane and by
The best known manifestations of diabetic mi- expansion of the mesangium (a diffuse increase
croangiopathy are diabetic nephropathy and diabetic in the mesangial matrix between the glomerular
retinopathy. The microvascular kindney disease is capillaries). Microalbuminuria (30–300 mg/day)
characterized by thickening of the capillary base- is reversibly increasing only during insufficient
ment membrane and increased deposition of extra- metabolic compensation or due to increased
cellular matrix components, while formation of mi- physical activity (usually after a provocative ex-
croaneurysms, obliteration and loss of microvessels ercise test). Glomerular filtration rate is normal.
with subsequent neovascularisation are predominat Blood pressure is also normal, but in elderly it
in the retina of diabetics. may be slightly increased.
• The third stage is denoted as incipient diabetic
a) Diabetic nephropathy nephropathy. Microalbuminuria is permanently
Diabetic nephropathy (nodular Kimmelstiel-Wil- increased (later the high microalbuminuria is
son glomerulosclerosis) is one of the severe chronic present). Glomerular filtration rate is normal,
complications of diabetes mellitus. In about 30 % later, however, it may be slightly decreased. Ar-
of the patients with type 1 IDDM it is clinically terial blood pressure is gradually increasing, and
manifested after 15–20 years of the duration of di- during increased physical activity blood pres-
abetes. Its incidence in the patients with type 2 sure is increased inadequately to the degree of
NIDDM is evidently lower than in those with type 1. the physical load.
The following five stages of development of diabetic
nephropathy are distinguished: • The fourth stage is denoted as manifest dia-
betic nephropathy. At the onset of this stage
• The first stage is characterized by hyperfunction intermittent nonselective proteinuria is present.
and hypertrophy of glomeruli which are proba- Later, the persistent nonselective proteinuria
bly the result of chronic renal hyperperfusion (macroproteinuria) originates (proteinuric pe-
(increased flow and pressure). One important riod). Proteinuria is greater than 550 mg/day.
factor in the induction of hyperperfusion may be Arterial hypertension is present. Progression of
5.9. Pathophysiology of the endocrine pancreas 421

diabetic nephropathy is accelerated by arterial common. Therefore, this stage is also denoted
hypertension. A progressive loss of glomeruli as diabetic maculopathy. Maculopathy can lead
appears. Since the reduction in the num- to serious disturbances or even to loss of vision.
ber of functioning nephrones is increasing, the
• Proliferative diabetic retinopathy is character-
glomerular filtration rate is gradually decreas-
ized by new vessel formation, proliferation of
ing and serum creatinine concentration increases
connective tissue and scarring, vitreal hemor-
(the beginning of an azotemic period).
rhage, and retinal detachment. New vessels may
• The fifth stage is denoted as a terminal renal be found anywhere in the retina, but often occur
failure. It is characterized by a massive re- on or near the optic disc. They lie on the reti-
duction in the number of functioning glomeruli nal surface or extend to the vitreous. This leads
(nephrones) what is clinically manifested by the to fibrosis and scarring. A bleed into vitreous
symptoms of uremia (uremic period). The kid- causes partial or complete loss of vision in the
neys are reduced in size. Long-standing arterial affected eye. Fibrous proliferation gives rise to
hypertension together with hypervolemia may traction bands that contract with the course of
lead to heart failure. The duration of interval time, producing retinal detachment, which usu-
from the onset of persistent proteinuria to the ally also leads to blindness.
origin of overt renal failure varies in individual Diabetic retinopathy need not be developing in
diabetics. Its average length is about 10 years. the both eyes simultaneously. Several factors influ-
ence its origin and course. The frequency of diabetic
b) Diabetic retinopathy retinopathy appears to vary with the age of onset as
well as the duration of the diabetes. The younger
It is characterized by progressive pathological the individual at the onset of diabetes is, the later
changes of retinal vessels leading to the damage of retinopathy originates. In older patients it develops
retina what is manifested by gradual impairment of earlier. The occurrence of retinopathy increases with
vision which may result in blindness. Three following the duration of diabetes. If diabetes persists more
forms of diabetic retinopathy are distinguished: non- than 15 years every patient has at least incipient
proliferative (background; simple), preproliferative, structural abnormalities in the retina. An adequate
and proliferative diabetic retinopathy. They proba- metabolic compensation of diabetes delays the ori-
bly represent different stages of the same pathophys- gin of retinopathy, but it cannot absolutely prevent
iological process. its origin. If the diffuse retinal ischemia or the in-
• Nonproliferative diabetic retinopathy is charac- cipient proliferative retinopathy originates neither a
terized by dilatation, constriction, and tortu- perfect metabolic compensation is sufficient to pre-
osity of vessels; hard exudates (they are rich vent further progression of proliferative retinopathy.
in lipids and proteins which leakage from hy- Blindness is reported to occur within 5 years after
perpermeable capillaries); arteriovenous shunts; the onset of proliferative retinopathy. The course of
microaneurysms; and by causal small inner reti- diabetic retinopathy is unfavourably influenced by
nal hemorrhages. Macular edema is not present. high arterial blood pressure and smoking.

• Preproliferative diabetic retinopathy is char- 2. Diabetic macroangiopathy

acterized by occurrence of the increased num- Diabetes mellitus is a risk factor for the develop-
ber of hard exudate spots, capillary microa- ment of atherosclerosis, particularly in women. Dia-
neurysms, and dot-shaped inner retinal hem- betic macroangiopathy is the disease of middle and
orrhages. It is also characterized by cotton- large arteries, mainly coronary, cerebral and lower
wool spots (they are patches of retinal edema) extremity arteries, and aorta. It is the severest
which represent microinfarctions, and by dot- nonspecific complication of diabetes mellitus. Dia-
blot, linear, or flame-shaped preretinal hemor- betic atherogenesis neither morphologically nor by
rhages. Hard exudates are arranged in horse- its distribution differs from atherosclerosis in non-
shoe or circular fashion around the central and diabetics. However, atherosclerosis in diabetics oc-
lateral part of the macula. Macular edema is curs more extensively and earlier than in the general
422 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

population, it is twice more frequent, its course is ac- a) Ischemic heart disease
celerated and it is more common in women than in It is one of the most common causes of death of
men. Diabetic atherosclerotic lesions faster undergo diabetics. Myocardial infarction is 3–5 times as
to changes leading to complicated atherosclerotic le- common in diabetics than in non-diabetic sub-
sions, that is, ulceration, calcification, hemorrhage, jects. Myocardial infarction in diabetics is char-
and superimposed tromboses. Therefore, its prog- acterized by certain peculiarities. Silent my-
nosis is worse and mortality rate is evidently higher ocardial infarction is thought to occur with in-
than in persons without diabetes. creased frequency in diabetics, what is proba-
The enhancing susceptibility of diabetics to bly due to the presence of diabetic neuropathy.
atherosclerosis is due to several factors. The signifi- Myocardial infarction is often associated with
cant place is occupied by hyperlipidemia, especially congestive heart failure which is usually severer
increased concentration of LDLs (mainly oxidized than in nondiabetics with myocardial infarction.
and glycosylated) in poorly metabolic controlled dia- Sometimes congestive heart failure occurs also
betic patients. Plasma HDL level (HDLs protect the in the diabetics with the absence of coronary
arterial wall against the development of atherosclero- atherosclerosis. The common complication of
sis) is reduced, therefore, a high LDL/HDL ratio also myocardial infarction in diabetics is the origin
favours atherogenesis. The increased glycosylation of of cardiogenic shock. Mortality rate of the di-
the LDL apoprotein reduces its cellular recognition. abetics with myocardial infarction is 3 times
Glycated LDL is not recognised by the normal LDL higher than in nondiabetics, extremely high is
receptor, and its plasma half-life is increased. Up- in women. Unfavourable prognosis of myocar-
take and degradation of LDLs are reduced, therefore, dial infarction in diabetics suggests that in di-
their plasma concentration is high. The magnitude abetic patients along with coronary atheroscle-
of reduction in glycosylated LDL uptake and degra- rosis also the other pathological changes partici-
dation is related to the degree of their glycosylation. pate in pathogenesis of myocardial damage. Mi-
Both processes of LDL modification, i.e., oxidation croangiopathy has a significant role. Interstitial
and glycosylation, contribute to the acceleration of and perivascular fibrosis has been also observed,
atherosclerosis in diabetic patients. HDL in diabet- associated with PAS-positive deposits (glycated
ics is also glycated. Glycated HDL unlike glycated proteins), what negatively influences diastolic
LDL, has an accelerated catabolism what contributes properties of myocardium, i.e., decreases dias-
to the reduced plasma HDL concentration. It is also tolic compliance (distensibility) what restricts
possible that glycosylation of HDL may be respon- diastolic filling of ventricles. Changes in cardiac
sible for the ineffective removal of cholesterol from myosin and an intracellular Ca2+ overload have
cholesterol-overloaded cells. Both these effects con- been observed in diabetes mellitus. With regard
cerning of HDL enhance atherogenesis. to the fact, that myocardial disease in diabet-
ics is characterized by certain histological, bio-
Other factors of potential importance for accel- chemical, functional, pathogenetic, and clinical
erated atherosclerosis in diabetes mellitus are: al- peculiarities, it is denoted as diabetic cardiomy-
teration of macrovascular endothelial function, re- opathy by some authors. However, increasingly
duced synthesis and release of prostacyclin, in- diabetic cardiomyopathy is being accepted as a
creased platelet adhesiveness and aggregation, en- clinical reality, although the pathogenesis of this
hanced tromboxane A2 synthesis and release, and putative entity is varied and multifactorial.
decreased fibrinolytic activity. Most patients with
type 2 NIDDM tend to be obese and hypertensive, b) Cerebral stroke
so that other contributing influences are present. Cerebrovascular accidents in diabetics are also
A clinical consequence of diabetic macroangiopa- characterized by some peculiarities. The strokes
thy is the origin of ischemic heart disease, cere- are prevailingly due to ischemic cerebral infarc-
bral stroke, or diabetic foot syndrome. However, tion. In spite of the fact that diabetes mellitus
atherosclerosis in diabetics may also induce aneurys- is frequently associated with arterial hyperten-
mal dilatation, seen most often in the aorta, with the sion, the strokes due to brain hemorrhage in di-
grave potential of rupture. abetics are rather rare. Not only atherosclero-
5.9. Pathophysiology of the endocrine pancreas 423

sis of larger intracranial and extracranial arter- tant role in its pathogenesis. Successive abnormal
ies, but also pathological changes of small cere- blood flow distribution which is associated with in-
bral vessels (microangiopathy) and multiple mi- creased blood pressure in veins is probably the cause
crotrombi participate in the pathogenesis of se- of the origin of osteolysis in the metatarsophalangeal
vere ischemic focal changes in the brain of dia- region.
betics. Mortality rate in diabetics with cerebral
stroke is three times higher than in nondiabetic B. Diabetic neuropathy
subjects. Diabetic neuropathy is a very frequent specific late
complication of diabetes mellitus. It occurs espe-
c) Diabetic foot syndrome
cially in the patients with type 1 IDDM affecting sen-
The diabetic foot syndrome is the consequence
sory, motor, and autonomic nerves. The prevalence
of coexisting vascular insufficiency and diabetic of diabetic neuropathy parallels the duration and
neuropathy. The vascular insufficiency involves
severity of hyperglycemia and it ultimately affects
large vessels of the lower limbs (atherosclerosis),
approximately 50 % of patients with long-lasting di-
and small vessels (diabetic microangiopathy).
abetes mellitus. It is rare before the 5th year of
There is also an extensive arteriovenous shunt-
diabetes. There are three recognized forms of dia-
ing at the precapillary level. The neuropathy is betic neuropathy: symmetrical peripheral polyneu-
predominantly sensory and is characterized by
ropathy, mononeuropathy, and autonomic neuropa-
a diminution or even absence of pain. Diabetic
thy.
dermopathy (mainly severe trophic changes lo-
Pathogenesis. Diabetic neuropathy is now gen-
cated on feet or over the anterior tibial surface)
erally considered to be a secondary consequence of
and diabetic sensory neuropathy cause that also insulin deficiency and/or hyperglycemia. Its patho-
minimal, casual, and often unknown wounds are physiological and clinical expressions are thought to
dangerous for a diabetic. They result in the ori-
be influenced by various additional independent ge-
gin of the skin lesions, even in the development
netic and environmental factors. There are following
of diabetic ulcers, the infection of which is com-
three major hypotheses trying to explain the patho-
mon (often with multiple microorganisms). The
genesis of diabetic neuropathy: vascular hypothesis,
ulcer may be initiated by illfitting shoes or by metabolic hypothesis, and axonal hypothesis. These
other forms of trivial trauma. If the capacity
major hypotheses, however, are clearly not indepen-
to sweat is lost because of diabetic autonomic
dent of one another but are linked at one or more
neuropathy, the resulting dryness of the skin
levels.
may lead to spontaneous cracking, supperficial
The vascular hypothesis postulates diabetic mi-
inflammations or to the development of ulcers croangiopathy of the vasa nervorum as the prime
as well. The final consequence of these changes
cause. This seems likely in isolated mononeuropa-
may be the origin of the gangrene, which is 15
thy, but microvascular disease is also considered as a
times more common in diabetics than in non-
contributor to other forms of diabetic neuropathy.
diabetics. Moist gangrene is typical for dia-
The metabolic hypothesis is the best known and
betics while dry gangrene for nondiabetics with
best-explored of all three mentioned hypotheses. The
atherosclerosis of lower limb arteries. Amputa- metabolic abnormalities are generally acknowledged
tion of a foot for gangrene is 50 times more com-
as a primary cause of diabetic symmetrical periph-
mon in diabetics than in nondiabetic subjects.
eral polyneuropathy and diabetic autonomic neu-
The clinical picture of diabetic foot syndrome in- ropathy. Hyperglycemia leads to increased glucose
cludes also night muscle spasms, severe night burn- concentration in Schwann cells. Due to activation of
ing pain, and diabetic osteopathy. Bone deminer- the polyol pathway formation of sorbitol and fructose
alization and later even deformation of small joints in Schwann cells increases. Sorbitol, which diffuses
of the metatarsophalangeal region originate (Char- poorly across cell membrane, accumulates intracellu-
cot joints). These changes are denoted as neu- larly. Osmotic swelling of Schwann cells, secondary
ropathic osteoarthropathy. Autonomic neuropathy to intracellular sorbitol and fructose accumulation,
(functional sympathectomy) causing extensive open- has been considered as a cause of both functional and
ing of arteriovenous shunts plays probably an impor- structural alterations in diabetic nerve. Metabolic
424 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

abnormalities in diabetic nerve, however, involve also cells. In the early stages axons are preserved, im-
decrease of myo-inositol content and decrease (Na+ , plying prospects of recovery, but at a latter stage
K+ )–ATPaze activity which are also initiated by hy- irreversible axonal degeneration develops.
perglycemia. Hyperglycemia lowers the myo-inositol The following three varieties of diabetic neuropa-
content of Schwann cells and axons, probably by in- thy may occur:
creasing the sorbitol-fructose content of the nerve via
the polyol pathway. The decreased myo-inositol con- 1. Diabetic symmetrical peripheral polyneuropa-
centration in Schwann cells and axons may lead to thy
the diminution of phosphoinositide metabolism, pro- It is the most commonly recognized form of dia-
tein kinase C activity, and (Na+ , K+ )–ATPaze acti- betic neuropathy prevailingly affecting the both
vity. These metabolic disorders lead to abnormal en- lower limbs simultaneously. Its most common
ergy metabolism, subsequently to nerve dysfunction manifestation is symmetrical sensory loss in the
and finally to structural damage (the axonal demyeli- distal lower extremities (distal symmetrical sen-
nation or degeneration). The role of glycosylated sory neuropathy). Motor deficits and upper ex-
myelin in the pathogenesis of diabetic neuropathy is tremity involvement are less common, although
not exactly known. Some authors suppose that gly- deep tendon reflexes, especially the Achilles ten-
cated protein of myelin could be a signal for activa- don reflex, may often be diminished or absent.
tion of macrophages. Activated tissue macrophages At the beginning it is manifested by paresthe-
remove and degrade glycated myelin and by these sias (mainly tingling) and dysesthesias persist-
processes may support segmental demyelination. ing several months or even years. Later, hyper-
esthesias (burning), pain (it may be deep-seated
The axonal hypothesis supposes early functional
and severe) or lancinating originate which are
changes, such as slow axonal transport, followed
worse at night. Lancinating may become ex-
by structural degeneration. Impaired anterograde
tremely severe, and suicides are known to have
transport would produce defects in the most dis-
occured because of it. This severe pain, however,
tal portions of axons, and altered retrograde trans-
is not permanent and will subside spontaneously
port might likely impair neurotrophic function. The
within months to years as the involved neurons
mechanisms responsible for transport defects and
became destroyed.
the exact contribution of altered axonal transport to
the pathogenesis of diabetic neuropathy are not well Sensory findings appear first in the most dis-
understood. However, recent studies indicate that tal portions of the extremities, progress prox-
some component of nerve (Na+ , K+ )–ATPaze is in- imally in a ”stocking-glove” distribution. The
deed carried by both antegrade and retrograde trans- signs, symptoms, and neurological deficits of dis-
port, rising the possibility that alterations in axonal tal symmetric polyneuropathy vary depending
transport, some of which are related to altered sor- on the classes of nerve fibers that are involved.
bitol and myo-inositol metabolism, may contribute A loss of large sensory and motor fibers dimin-
to the derangement of (Na+ , K+ )–ATPaze in dia- ishes light touch and proprioception (vibratory
betic nerve. perception) and produces weakness of intrinsic
muscles of the hands and feet, while a loss of
Diabetic neuropathy can be classified into two dis- small fibers diminishes pain and temperature
tinct stages: subclinical neuropathy and overt or perception, resulting in repeated injury due to
clinical neuropathy. The latter consists of the pres- an ill-fitting shoe, a hot water bottle, or embed-
ence of symptoms and/or neurological deficits con- ded foreign bodies leading to ulceration, espe-
sistent with one or more of the clinical syndromes cially foot ulceration.
of diabetic neuropathy, while the former consists of
demonstrable evidence of peripheral nerve dysfunc- 2. Mononeuropathy
tion (e.g., slowed nerve conduction velocity or ele- Diabetic mononeuropathy is a relatively uncom-
vated sensory perception thresholds, and etc.) in the mon late complication. Motor disorders (pare-
absence of clinical signs and/or symptoms of overt di- sis) usually affects only single peripheral nerve,
abetic neuropathy. The earliest histological change is e.g., ulnar, median, proneus, femoral, or sci-
segmental demyelination, due to damage of Schwann atic nerve (diabetic motor neuropathy; diabetic
5.9. Pathophysiology of the endocrine pancreas 425

asymmetrical neuropathy). Several peripheral anorexia, nausea, and vomiting. Diabetic en-
nerves may be rarely affected at the same time teropathy encompasses the clinical symptom of
(mononeuropathy multiplex). diabetic constipation, which is usually intermit-
tent and alternate with diabetic diarrhea, and
Cranial nerve lesions (isolated or multiple) are
fecal incontinence. Diarrhea often occurs at
more common in diabetics. Especially the third,
night accompanied by urgency and incontinence.
fourth, sixth, or seventh cranial nerves are af-
Fecal incontinence reflects impaired sensation
fected (cranial diabetic mononeuropathy).
of rectal distension and sphincter dysfunction.
Affection of the nerve roots (radiculopathy) is Dysfunction of gallbladder and biliary tract may
rare. In older patients with diabetes mellitus also appear.
after 15–20 years of its duration diabetic amy-
Genitourinary autonomic neuropathy is mani-
otrophy may originate. This syndrome is char-
fested by diabetic cystopathy, neuropathic erec-
acterized by weakness, painful wasting, and at- tile impotence, and retrograde ejaculation. All
rophy of muscles of the limbs, usually asymmet-
these changes result from loss of coordination of
rical. The disorder is considered to be a severe
the autonomic innervation of the genitourinary
manifestation of microangiopathy of peripheral
tract. Autonomic neuropathy of the bladder be-
nerves. Diabetic amyotrophy is usually associ-
gins with the selective involvement of autonomic
ated with periods of poor glycemic control. sensory afferents resulting in diminished sensa-
tion of bladder fullness and a resultant reduction
3. Autonomic neuropathy
in urinary frequency. With progressive efferent
Diabetic autonomic neuropathy affects the sym-
involvement, urination is incomplete, leading to
pathetic and parasympathetic nervous systems
poor stream, dribling and overflow incontinence,
and may be presented in a variety of ways.
predisposing to urinary infection. Impotence ul-
Cardiovascular autonomic neuropathy usu- timately occurs in up to 75 % of men with pro-
ally initially involves cardiac parasympathetic longed diabetes mellitus. It may be due to either
nerves, producing asymptomatic absence of the diabetic neuropathy and vascular disease. The
normal sleep bradycardia, presence of tachy- syndrome is particularly disturbing because the
cardia at rest, or diminished variation of the libido is intact.
pulse rate with respiration (reduced sinus ar-
rhythmia). More advanced sympathetic cardiac Diabetic autonomic sudomotor dysfunction pro-
denervation (resembling a transplanted heart) duces an asymptomatic distal anhidrosis (of the
is manifested by diminishing exercise tolerance, lower extremities). This diminished thermoregula-
Q–T interval prolongation, and hypersensitizing tory reserve is usually associated with compensatory
the heart to circulating catecholamines, predis- central hyperhidrosis (of the upper half of the body).
posing to tachyarrhythmias and sudden death.
Cardiovascular reflexes, such as the Valsalva
manoeuvre, are impaired. Cardiovascular auto- C. Other complications of diabetes mellitus
nomic neuropathy is also responsible for the high
Infections in persons with diabetes mellitus,
frequency of painless myocardial infarctions in
mainly if poorly controlled, occur more frequently
patients with long-lasting diabetes. Barorecep-
than in normal subjects, and they tend to be
tor insufficiency, reduction in catecholamine se-
severer. In diabetics infections of urinary tract,
cretion (loss of sympathetic tone to peripheral
mainly chronic interstitial nephritis, are rather com-
arterioles), and inability to increase the pulse
mon. Chronic interstitial nephritis is 5 times more
rate combine to cause orthostatic hypotension.
frequent in diabetics than in nondiabetics and is
Gastrointestinal autonomic neuropathy can be most commonly presented as a chronic pyelonephri-
manifested by esophageal dysmotility associated tis with casual exacerbations of acute pyelonephri-
with difficulty in swallowing (dysphagia) and re- tis. Pyelonephritis in the patients with long-lasting
flux, decreased vagally-mediated gastric acid se- poorly controlled diabetes can lead to acute necro-
cretion, and delayed gastric emptying, produce tizing papillitis if not treated promptly.
426 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

Bacterial infections of the skin, mainly impetigo potent cells of embryonal neuroectoderm and become
or furunculosis (pyoderma), are frequent. Mucocu- a part of the diffuse neuroendocrine system. On the
taneous candidiasis, mainly epidermophytosis, Can- other hand, 20–40 % of islet cell tumors are nonfunc-
dida vulvovaginitis associated with vulvar pruritus, tioning; that is they do not release hormones into
and Candida balanitis, are typical for diabetes melli- the circulation despite the presence of functioning
tus. Mucocutaneous candidiasis and cutaneous pru- endocrine cells on histological examination.
ritus in some cases may be the first symptoms of till The best known tumors of the cells of the pancre-
then unknown diabetes mellitus. atic islets include: insulinoma, glucagonoma, gastri-
Rather frequent nonspecific complication of dia- noma, and somatostatinoma. Pancreatic endocrine
betes mellitus is parodontosis which may originate tumors can also be a part of the syndrome multi-
already at a younger age period. It is sometimes the ple endocrine neoplasia type 1 (MEN type 1). Islet
first symptom of diabetes. Bacterial stomatitis or cell carcinomas are rare and can secrete hormones
fungal infection of the mouth may also occur. Ma- in addition to insulin, including ACTH, MSH, hCG,
lignant external otitis, usually due to Pseudomonas glucagon, somatostatin pancreatic polypeptide, gas-
aeruginosa, tend to occur in older diabetics. Staphy- trin, VIP, and serotonin.
lococcal, pneumococcal, or Gram-negative pneumo-
nia is also rather frequent in diabetics. The origin 5.9.2.1 Insulinoma
of tuberculosis in diabetics is evidently frequent. In-
tercurrent infections in diabetics tend to have severer Insulinomas are the B cell tumors. Tey are the sec-
course. ond most common functioning islet cell tumors. The
Senile cataracts develop some 10–15 years earlier hallmark of insulinoma is the development of symp-
in diabetic patients than in the remainder of the pop- tomatic hypoglycemia from unregulated insulin hy-
ulation. Juvenile cataracts, so-called ”snowflake” persecretion leading to the origin of endogenous hy-
cataracts are much less common and occur more of- perinsulinism.
ten in type 1 IDDM. These are diffuse, rapidly pro- Insulinomas arise most frequently in the fifth to
gressive cataracts associated with very poorly con- seventh decades, although cases have been reported
trolled diabetes. Sorbitol accumulation, as well as at all ages. It is very rare in children to 10th year of
aggregation and precipitation of crystalline glycated life. About 90 % of the patients is older than 30
proteins of the lens, participate in the pathogenesis years. The majority of infants and children, and
of cataracts. some adults do not have discrete tumor. Hyperin-
sulinemia in these cases has been attributed to the
B cell hyperplasia termed nesidioblastosis.
5.9.2 Tumors of the endocrine pan- Single, benign insulinoma is present in 80–85 % of
creas patients with excessive secretion of insulin. About
10 % of cases are multiple adenomas or microadeno-
Pancreatic endocrine tumors may be benign or ma- mas. An additional 5–10 % of insulinomas are malig-
lignant. They may occur as a solitary adenoma or nant, with spread to the local lymph nodes and the
as multiple adenomas. They are usually composed liver. The metastases may be the cause of recidiva-
of one type of Langerhans islet cells, sometimes, tion of hypoglycemia even after the surgical removal
however, heterogenous population (several different of primary pancreatic insulinoma. Insulinoma may
types) of endocrine cells may occur in endocrine tu- be situated in any part of pancreas, most often in
mors of the pancreas (mixed pancreatic endocrine the body or tail of the gland. About 0.5–1 % of in-
tumors). The predominant type of cell and the pre- sulinomas occur ectopicly; ectopic insulinomas have
dominant hormone produced define the clinical syn- been found in the areas of pancreatic heterotopia, in-
drome of the multiple hormone-secreting pancreatic cluding the wall of the duodenum, the porta hepatis,
tumor. Rarely one type of tumor cells can pro- superior mesenteric artery, and the vicinity of the
duce several kinds of hormones simultaneously (a pancreas. Insulinomas may be also associated with
pluripotent capacity allows these cells to produce any MEN type 1, and such tumors are more likely to be
polypeptide). It is the evidence that the cells of the multifocal.
pancreatic islets are derived from functionally multi- Insulin secretion from insulinoma is usually peri-
5.9. Pathophysiology of the endocrine pancreas 427

odical, rarely continual. According to the way of in- 5.9.2.2 Glucagonoma

sulin secretion from insulinoma and according to the
Glucagonoma is the A cell tumor of the islets
origin of subsequent hyperinsulinemia either parox-
of Langerhans causing overproduction of glucagon.
ysmal or permanet hypoglycemia originates. Sudden
It occurs rarely. The two thirds of glucagono-
fall of glycemia appears mainly due to prolonged fast-
mas are malignant and have metastasized to the
ing (usually in the late morning or afternoon) or after
liver, regional lymph nodes, and bones. They are
increased physical activity.
more frequent in women, especially after menopause.
The most consistent insulin secretory abnormality
Glucagonomas are characteristically single, large,
in patients with an insulinoma is a failure of the nor-
and slow-growing. Glucagonomas have been also re-
mal decrease in insulin secretion as the plasma glu-
ported in association with MEN type 1.
cose level declines in the postabsorptive state. This
Pathophysiology and clinical features. The
failure results in hyperinsulinism. Hyperinsulinism
glycogenolytic and gluconeogenic actions of glucagon
in the portal and peripheral circulations results in
result in mild hyperglycemia. The levels of hyper-
low rates of glucose production with high rates of
glycemia and plasma glucagon are poorly correlated,
glucose utilization that are not high in the absolute
possibly because of down-regulation of glucagon re-
but are inappropriately high relative to the plasma
ceptors but more likely because of the ability of in-
glucose concentration. Thus the plasma glucose con-
tact the B cells to counteract the hyperglycemic ef-
centration declines progressively in the postabsorp-
fect of glucagon by releasing insulin.
tive state. Hypoglycemia induces dysfunction of the
The clinical picture of glucagonoma is character-
CNS and the secondary release of catecholamines.
ized by impaired glucose tolerance or by diabetes
Symptoms of hypoglycemia in patients with insuli-
mellitus. The diabetes is usually mild or asymp-
noma fall into two main categories:
tomatic. Ketoacidosis has not been reported.
• Symptoms induced by inadequate supply of the The disorder of glycoregulation is associated with
CNS by glucose termed neuroglycopenic symp- a characteristic skin rash, necrolytic migratory ery-
toms, or neuroglycopenia; thema, which is frequently the major manifesta-
• Symptoms induced by activation of sympathoa- tion of the glucagonoma. Erythematous lesions are
drenal system, mainly by an excessive secretion raised (with a moving edge), scaly, sometimes bul-
of adrenaline. lous, sometimes psoriatic, and ultimately encrusted.
They are located primarily on the face, abdomen,
a) Symptoms of acute neuroglycopenia are the re- buttocks, perineum, and thighs. After resolution,
sult of a sudden decline of ATP in cells of the the regions of the acute eruption usually remain in-
CNS. These manifestations range from subtle durated and hyperpigmented. The rash disappears
impairment of mentation to coma (if glycemia promptly when the plasma glucagon level (hyper-
falls under 2.5 mmol/L) and death. Between glucagonemia) returns to normal after the complete
these extremes a variety of other expressions can tumor resection.
occur, including visual symptoms (diplopia or Glucagon excess causes increased hepatic conver-
blurred vision), weakness, lethargy, somnolence, sion of amino acid nitrogen to urea nitrogen, re-
confusion, behavioral changes, impaired perfor- sulting in decreased blood amino acid concentration
mance of routine tasks, vertigo, paresthesias, (hypoaminoacidemia). Enhanced protein catabolism
incoordination, slurred speech, hunger, hemi- is associated with weight loss. In patients with
paresis, and clonic convulsions. Convulsions are glucagonoma other manifestations are also present.
more frequent in children than in adults. Rarely, They include: glossitis, stomatitis, angular cheilitis,
chronic hypoglycemia results in demention or diarrhea, venous thrombosis, anemia, depressions,
psychosis. dystrophic nails, hair thinning, hypocholesterolemia,
b) Symptoms of activation of sympathoadrenal hypoproteinemia, and hyperinsulinemia.
system (rapid adrenaline release) include sweat-
ing, paleness, anxiety, behavioral irritability,
tremulousness, restlessness, tachycardia, cardiac
arrhythmias, palpitations, and headache.
428 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoš )

5.9.2.3 Gastrinoma diarrhea and steatorrhea. Diarrhea occurs in about

40 % of patients and may precede peptic ulcer symp-
Pancreatic gastrinoma (Zollinger-Ellison syndrome) toms. The major cause of diarrhea is the large
is a tumor arising from the G cells of pancreatic islet amount of hydrochloric acid entering the duodenum.
and generating high serum gastrin levels (hypergas- The excessive acid has been shown to reduce also
trinemia), leading to hypersecretion of gastric acid the pH of the content of the jejunum. Steatorrhea,
and consequent peptic ulcer. Therefore, it is also which is less common than diarrhea, results from in-
denoted as ulcerogenic tumor of pancreas. Gastrino- activation of pancreatic lipase by large concentra-
mas are the most common of the hormone-secreting tions of hydrochloric acid in the proximal small in-
tumors of the pancreatic islets. They are usually testine and from decrease in luminal bile acids. The
small and multiple. The tumors are most common decrease in intraluminal bile acid concentration is
in the head of the pancreas. Gastrinomas, like most caused by precipitation of the major bile acids at low
other islet cell tumors, are generally slow-growing. pH. This leads to impaired micelle formation, which,
Approximately 60 % of gastrinomas are malignant in turn, reduces intestinal absorption of fatty acids
with metastases in the lymph nodes and the liver, and monoglycerides.
and less frequently in bones. Between one-fourth and
one-half of gastrinomas occur in association with the
MEN 1, an autosomal dominant disorder with a high 5.9.2.4 Somatostatinoma
degree of penetrance and great variability in expres- Pancreatic somatostatinoma is the D cell tumor
sivity. Gastrinomas in non-MEN 1 patients are con- of the islets of Langerhans. It is a somatostatin-
sidered to be usually sporadic. Multiple gastrinomas secreting tumor, therefore, plasma somatostatin con-
are usually present in patients with MEN 1 and are centrations are high. Somatostatinoma is usually a
usually smaller than sporadic gastrinomas. single and a large tumor. It is often malignant tumor
Approximately 80 % of gastrin-secreting tumors which metastasizes to the liver. Somatostatinomas
arise in pancreatic islets, including nearly all those have been reported in association with MEN 1 only
associated with MEN type 1. Another 10–15 % arise rarely.
from G cells in the duodenum (duodenal gastri- The classic triad of somatostatinoma comprises di-
noma), and the remainder are located in other sites, abetes mellitus, steatorrhea, and cholelithiasis. The
such as the hilum of the spleen and rarely in the diabetes is usually mild. In some patients with so-
stomach. The Zollinger-Ellison syndrome may occur matostatinoma only impaired glucose tolerance may
most commonly between the ages 30 and 60. be present. Other features include indigestion (dys-
In patients with gastrinoma, gastric acid hyper- pepsia), hypochlorhydria, diarrhea, and weight loss.
secretion is caused by excessive production of gas- All these symptoms derive from the widespred in-
trin by tumor cells. Due to high rate of gastric hibitory actions of somatostatin, including inhibition
acid secretion peptic ulceration of the gastrointesti- of insulin and glucagon release, pancreatic enzyme
nal tract develops in 90–95 % of patients with gas- and bicarbonate secretion, gallbladder motility, and
trinoma. The anatomic site of the peptic ulcer in gastrointestinal function, respectively.
patients with gastrinoma is similar, but not identi-
cal, to that of patients with common type of peptic
5.9.2.5 Multiple endocrine neoplasia, type 1
ulcer. About 75 % of gastrinoma patients have ul-
cers in the first portion of the duodenum or in the The multiple endocrine neoplasia (MEN) syndromes
stomach. These ulcers are usually single but may be are classified into two broad categories, MEN type 1
multiple. When multiple ulcers occur, they are fre- (MEN 1) and MEN type 2 (MEN 2). The MEN 2
quently located in the remainder of the duodenum syndrome has been subcategorized into two variants
or even the jejunum. Especially early in the course called MEN 2A and MEN 2B (formerly MEN 3).
of the disease, symptoms are usually similar to those Hormonally active tumors arise from the cells of the
of patients with typical peptic ulcer. In gastrinoma APUD system (the diffuse neuroendocrine system).
patients, however, ulcer symptoms may be more ful- The APUD cell type is thought to derive embryolog-
minant, progressive, and persistent. ically from neuroectoderm. Pancreatic endocrine tu-
Clinical features other than peptic ulcer include mors can be a part of MEN 1 syndrome only.
5.9. Pathophysiology of the endocrine pancreas 429

Multiple endocrine neoplasia type 1 (Wermer syn- veral different peptides and biogenic amines.
drome) is the association of neoplastic transforma- The syndromes of pancreatic islet cell hormone
tion of parathyroid, pancreatic islet, and pituitary excess, associated with MEN 1, include:
cells. Hyperplasia is the initiating lesion, followed
later by adenomatous or carcinomatous changes. • Zollinger-Ellison syndrome caused by ex-
The syndrome is inherited as an autosomal domi- cessive production of gastrin (hypergas-
nant trait. The MEN 1 locus has been mapped to trinemia) by pancreatic gastrinoma.
a specific region on chromosome 11, but the gene it- • Fasting hypoglycemia with inappropriately
self has not been identified. The MEN 1 syndrome elevated serum insulin and C peptide con-
generally evolves over a 30- to 40-year period. Its centrations caused by insulinoma. The tu-
pancreatic neoplasm includes: pancreatic polypep- mor may be benign or malignant. The clin-
tide producing tumor (in 75–85 % of cases), gastri- ical features do not differ from those asso-
noma (60 %), insulinoma (25–35 %), glucagonoma ciated with sporadic insulinoma.
(5–10 %), VIPoma (3–5 %), and somatostatinoma • The glucagonoma syndrome consisting of
(from 1 to 5 percent of cases). The growth of the hyperglycemia, a characteristic skin rash
parathyroid, pancreatic islet, and pituitary tumors termed necrolytic migratory erythema, and
is usually slow and not of the same rate. other symptoms typical for glucagonoma.
Pathophysiology and clinical features. The clinical
picture of the MEN 1 syndrome is usually various • The watery diarrhea syndrome (Verner-
and depends on the types of hormones overproduced Morrison syndrome) consisting of watery
by individual tumors of the parathyroid glands, the diarrhea, hypokalemia, hypochlorhydria,
pancreatic islets, and the anterior pituitary. and systemic acidosis. Patients with this
syndrome have elevated plasma VIP levels.
a) Hyperparathyroidism is the most common ma- Excessive production of VIP is caused by
nifestation of the MEN 1 syndrome. It is present VIPoma. The major clinical manifestation
in 90–95 % of cases. The general clinical fea- of VIPoma is a large-volume secretory di-
tures of hyperparathyroidism in MEN 1 are not arrhea, which is termed pancreatic cholera
different from those associated with other forms because the diarrhea results from the mas-
of hyperparathyroidism. Parathyroid hyperpla- sive intestinal secretion of fluid.
sia is the most common cause of hyperparathy- • Overproduction of pancreatic polypeptide.
roidism in MEN 1, although single and multiple Its plasma concentration is frequently el-
adenomas have been described. Hyperplasia of evated in MEN 1 patients, but does not
one or more parathyroid glands is common in appear to cause clinical manifestations.
younger patients; adenomas are generally found Whether the elevated pancreatic polypep-
in older patients or those with long-standing dis- tide level is always related to a pancreatic
ease. islet cell tumor is not clear.
b) Neoplasia of the pancreatic islet cells is the sec- c) Pituitary tumors occur in more than half of
ond most common manifestation of MEN 1 syn- patients with MEN 1. The most common
drome, and these abnormalities tend to occur manifestation is the galactorrhea-amenorrhea
parallel with parathyroid abnormalities. The syndrome caused by prolactinoma. Tumors
islet cell tumors produce various hormonal man- that produce growth hormone are the second
ifestations and can undergo malignant transfor- most common pituitary tumors in patients with
mation and metastasis. Although a pancreatic MEN 1 (25 % of pituitary adenomas). There-
islet cell tumor is frequently identified by the fore, acromegaly is a frequent syndrome in pa-
clinical syndrome caused by a single hormone tients with MEN 1. Cushing syndrome due to
product, most of these tumors demonstrate hy- an ACTH-producing pituitary tumor also can
perplasia of multiple cell types and produce se- occur in patients with MEN 1 syndrome.
Chapter 6

Pathophysiology of the nervous

system

At a certain level of development there will be such

a situation, where the response to a certain stimulus
6.1 The basic anatomical and happens to be complicated variable and there will
be selection of the specific answer. The organism
physiological aspects reacts to the same stimulus variably depending on
the variability of the situation.
There will be the formation of memory and this
forms actualities. Further specialization of the sys-
The nervous system forms a collection of special- tem that has the ability to respond to outside stimuli
ized forms and specialized structures, the aim of by a specific reaction, learning depending on the fact
which is to provide communication and feedback in- that experience and memory leads into the formation
formation of the organism with the outside world. of the nervous system.
The integration of all functions of the organism into a The nervous system is composed by many types
united reacting entirely called (the organic union) is of cells:
equally important. The endocrine system has a role
in the actualization of this duty. The dependence of • Cells specialized for the reception of stimuli from
the organism on the environment is given by its de- the outside or inside enviroments (receptors,
pendence on the outside energy sources, that change sensors).
continuously. The organism has to be adapted to
• Cells specialized for processing the received in-
those changes all the time.
formation, providing the contact and handling
Any change in the environment can be considered information in the network along with other
as an action (stimulus) and the following change parts of the nervous architecture (interneu-
in the response of the organism is the reaction or rones).
answer. The quality and characteristics of the re-
sponse are given by the characteristics of the or- • Nerve cells – the neurons themselves, that gives
ganism (given genetically) and by the outside con- the orders and reach the effect organ via their
ditions (characteristics of the stimulus). Feed back peripheral nerve endings (for example endocrine
relation will be formed between the stimulus and the glands) or those reaching tissues (muscle) – ef-
response. fector neurons.
The stimulus is the specific change in the outside
• Cells having only supporting or helping function
or inside environment, that affect the nervous system
in the nervous system (glial and satellite cells)
in a way that result in the generation of an impulse.
Impulse is the change of the electrical processes that Upon the realization of the nervous function usu-
excite tissues, and that can spread via nerves or con- ally many nervous cells (the neurons) are intercon-
ductive membranes. nected in a form of a chain. The beginning of the

430
6.1. The basic anatomical and physiological aspects 431

chain is usually formed by a sensor (a receptor) that act morphological distinction of those two types of
is able to register a certain type of stimuli. The stim- synapses can not be performed.
ulus induces excitation on the membrane of the re- In some parts of the nervous system another way
ceptor cell, and this will spread in the network of of transmission might take place. This transmission
neurons. consist of some transmitters released from the neu-
The nerve cells (the neurons) that are connected rons to the blood capillaries and those are transferred
in this network will overtake the excitation in an un- via blood stream to the place of their action. Due to
changed form or modificated form the will handle it the resemblance of these cells to the endocrine sys-
to the other neurons till it reaches the effector. The tem they are hence called the neuroendocrine cells.
excitation is represented by the change in the rest- The transformation of the outside stimuli into a
ing electrical potential of the neurons that spreads neuronal stimulation forms what is known as the
from the site of its generation to its vicinity or can code of the nervous system. The outside stimulus
be directed to a certain direction (for e.g. the site (mechanical, chemical, electromagnetic) is changed
of contact with other neurons – synapses – are per- in the receptor to electrical activity, and a slow gen-
meable only in one direction). The transmission of erator potential will be formed. If the generator po-
impulse to another neuron in the network takes place tential reaches the threshold value it will evoke action
via synapses by the transmission of the potential ex- potential in the nervous tissue. The size of the stimu-
citation (the electrical transmission of excitation) or lus will be coded to frequent impulses. Such a coded
via some specific substance – neurotransmitter (hu- information is during impulse conduction quite sta-
moral transmission). bile.
The level of organization of the nervous system in
The transmitter has a different chemical structure human is of variable degrees, that means that the
and is typical for certain part of the nervous archi-
nervous system forms a setting of relatively auto-
tecture. The transmitter or its precursors are syn-
nomic but on the other hand regulatory centers and
thesized in the neuron body where they are passing functional and integration areas. We can differenti-
to the peripheral branches of the cell, to the axon ate 3 such levels:
along to the synapses. The speed of transmission is
10–100 mm per 24 hours. The transmitter is usually • medulla oblongata,
stored in specific cell organelles (vesicules covered
by membrane), by this way it is protected from the • the subcortical area,
enzymes degradation. Contractile proteins such as
• the cortical area.
stenin and neurin do present in the presynaptic part
of the synapses. These might be stimulated by mem- If we compare the development of the nervous sys-
brane stimulation and Ca2+ ions influx and by their tem according to the development of that kind and
contraction they bring the vesicle with the contained species, then it is quite natural to notice the shift
transmitter near the synapse. After the vesicle unites of the nervous system functions from the medulla
with the presynaptic membrane the transmitter is oblongata to the brain in the human – we are talk-
released to the synaptic cleft. The transmitter then ing about cranialization of the nervous functions. In
reacts with the subsynaptic membrane receptor and the brain this shift is done from the lower subcorti-
activates them. cal areas to the cortex and hence the thalamocortical
For e.g.: Ach. opens the Ca2+ channels directly, functioning complex – and this is known as the corti-
adrenaline on the other hand promotes its effect via calisation of functions. In man we may see the great-
the cAMP. As the result of the released mediator est centralization and itegration of function and the
together with Ca2+ ions the subsynaptic membrane relative autonomy of the lower areas is decreasing.
finally becomes highly permeable for the hydrated An important parameter, that can be consider as
ions of Na+ (depolarization – excitation), or its per- the functional principle of the nervous system organi-
meability increases for even the less hydrated ions zation is the combination of the stabile (unchanged)
K+ and Cl− (hyperpolarisation – inhibition). Ac- reflex mechanisms with the great variability (plastic-
cording to the characteristics of the change we may ity). Plasticity is the landmark of the organic adap-
have an excitatory or inhibitory synapses. The ex- tation due to the effect of the external environment.
432 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

It ďs basis is the ability to create temporary junc- respiration, circulation, and cardiac and vascular ac-
tions, the process of learning and memory. Generally, tivity are situated there. At the same time there is
the plasticity of the higher centers is higher than the presence of the connecting fibers of many tracts that
plasticity of the lower centers. carry information from the peripheries to the higher
The nervous system is morphologically devided centers. The cerebellum is the regulatory center of
into central nervous system (CNS), that constitutes muscle tonus, muscular movement coordination and
of the brain, medulla oblongata and the peripheral body balance.
nervous system, to which other parts of the nervous The midbrain (mesencephalon) is the smallest,
system belongs. but functionally very complicated part of CNS. The
The autonomic nervous system is further more subcortical optic, auditory, and motor centers as well
subdivided into sympathetic and parasympathetic, as the center of body balance of others do present in
that regulates the vascular system, the glands and the mid brain. Many tracts pases via the midbrain
the smooth muscles. as well and these transfer information from the pe-
The human brain is the most difficult and compli- ripheries to the cerebral cortex and vice versa.
cated organ in its intrinsic structure. It is situated
Medulla oblongata is the lowest part of the CNS.
in the cranial cavity and is devided into three major
It forms the first center into which information are
divisions:
carried from the peripheries (cold, pain, heat, pres-
• forebrain (prosencephalon), sure and so on). These information are transferred
from the medulla to higher centers or directly to the
• hindbrain (rhombencephalon) corresponding medullary motor centers that regulate
the skeletal muscles and provide some involuntary
• midbrain (mesencephalon). reflexes (for e.g. the defense reflex). In the medulla
there are also centers of the autonomic sympathetic
The forebrain is devided into telencephalon and
and parasympathetic nervous system.
diencephalon. The forebrain is the conduction sta-
tion of the tracts that joint the cerebral cortex to At this point we have to add that, the localization
the lower compartments of the CNS and at the same of functions (neuronal center for a specific function)
time the center of the emotions. In this location has to be understood in relation with other parts
there is also the center of the autonomic system reg- of the nervous system. For example in the medulla
ulation and the regulation center of the endocrine oblongata the localization of functions is relatively
glands. The The surface of the cerebrum is charac- constant and topographically exact. We might dis-
terized by many convolutions (gyri and sulci) – the tinguish exactly the inervation of some muscle groups
cerebral cortex, in which the nerve cell bodies can by one medullary segment. In the cerebral cortex al-
lie and thereby maxisizes their function, is the most though we might localize the entry of some sensory
developed part of the central nervous system. It con- tracts (optic, hearing and so on) and the projection
sists of about 15 milliards neurons, that are intercon- of, for example long direct motor tracts (pyramidal
nected with each other by means of their dendrites. tracts), other functions and mainly those complex
Certain areas of the cerebral cortex have the charac- ones that require a wider sensory – motor interac-
ter of so called projection centers, where some tracts tion can be only vaguely localized. If for e.g. we
end (from e.g. the sensory information from the pe- are talking about the respiratory center specifically,
ripheries). As the result of the analysis of the en- it is not possible to be so specific in localizing some
tering information there will be formation of orders complex function such as consciousness, language, or
for the lower parts of the central nervous system (for sleep anatomically. This conclusion is important for
some effectors). The cerebral cortex performs even the topical diagnosis during which we might suggest
the higher integration and analytic activity, that is the localization of injury on the basis of functional
the basis of the higher nervous function (the second disturbances.
signal system). The basic functional performance of the nervous
The hindbrain is formed of the myelencephalon centers are similarly as in the synaptic function the
(medulla oblongata) and the metencephalon ( pons time and space summation and occlusion. The re-
and cerebellum). Life important (vital) centers for sult of activation of a certain center can be larger in
6.1. The basic anatomical and physiological aspects 433

case of summation as in case of simple addition of The basic functional unit of the nervous system is
its response. Similarly we might have to deal with reflex. Its structural basic unit is the reflex arc, that
an opposite case – occlusion. The final response is is formed of a receptor, an afferent sensitive path-
modulated by neurons that are outside the main di- way, the center (in the medulla or the brain),the ef-
rection of the afferent information and stay below ferent motor pathway, and the effector (muscle or
the threshold level, that come to be realized upon gland). This structure enables the receive of in-
stimulation (or depression) due to the effect of sen- formation (receptor, free nerve terminal), the con-
sibilized neurons (of the main direction). The basic duction of information to the center, the conduc-
process of the CNS are stimulation and depression. tion of the efferent information to the effector (mo-
Stimulation can be characterized as change of con- tor neuron) and the reaction of the effector. The
duction and excitation in the synapses. On the con- simple reflexes are mediated via a direct reflex arc,
trary during depression the transmission of impulses i.e. The sensitive neuron is connected directly to the
in the synapses becomes slower or even blocked. In motor neuron – known also as the monosynaptic re-
the vicinity of the stimulation there will be depres- flex (proprioceptive). If there is one or more neurons
sion and contrary in the vicinity of depression there placed between the sensitive and the motor neuron,
will be stimulation – we are talking about spatial in- the reflex arc become indirect or multisynaptic. The
duction. If the result is stimulation we talk about direct reflex arc mediate reflexes, in which the recep-
a positive induction, and if the result is depression tor and the effector belong to one organ (e.g. contrac-
we are dealing with a negative induction. Similar tion of muscle by hitting the corresponding muscle
to this is the realization of time induction which is tendon). An indirect reflex arc mediates exterocep-
understood as the occurrence of an opposite reac- tive reflexes, where the receptor lies in a different or-
tion after the primary reaction cases. The rules of gan than the effector organ (for the corneal reflex we
induction are markedly applied in higher nervous ac- need the connection between the sensitive nucleus of
tivity. In the CNS the afferent fibers branch and do the trigeminal nerve (that inervates the cornea) with
not enter only one center. By this way the afferent the motor nucleus of the facial nerve (that inervates
stimulus might reach a certain center via variable the circular muscle of the eye). Even more complex
pathways and gradually might lead to its repetitive reflex arces are those known by the defense reflexes
stimulation. If the mentioned tract composes of an such as (cough, tear secretion, etc.) and others. Re-
inhibitory interneuron, the repeated effect might be flexes, that take place during normal conditions in
inhibition. This phenomena is marked as the fol- the same way all the times are known as the uncon-
lowing exhaustion and its basis is the circulation of ditional reflexes (inborn). On those basic reflexes we
stimuli in the neuronal circles (reverberation). Re- may build the system of the conditional reflexes (ac-
verbericing is most probably the reason of what is quired). A specific group is composed of instincts,
known as kindling and is considered as a general ba- that are considered as the most important uncondi-
sis of some physiological functions (for e.g. learning, tional reflexes.
memory) and even some pathological states such as Analogically we might evaluate the function of the
(for e.g. epilepsy). CNS as well. There are 3 main functions dominant,
basic and complementary to each other:
The peripheral nervous system contains all the
other connections between the CNS and the organ- 1. The transfer of information from the periph-
ism. The main duty of the peripheral nerves is to eries.
conduct the information from the peripheries (body
2. The central processing of information.
surface, receptors, body organs and tissues, etc.) to
the CNS and vice versa. According to the direction 3. The conduction of information from the center
of the conduction of information may be devided the to the effector organs.
nerve fibers to afferent and efferent fibers.The sys-
tem of the peripheral nerves is composed of 12 cra- Information reaches the CNS via many channels
nial nerves and 31 pair of the spinal nerves together – specific pathways conduct information from a cer-
with the system of the peripheral nerve ganglia and tain sensory system to specific nuclei. Yet in the
plexuses. brain stem some collaterals emerge from the retic-
434 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

ular formation to the reticular (nonspecific) projec- • The efferent vegetative tract (glandular and vis-
tion system of the thalamus. By this way informa- creromotor) forms bundles of tiny fibers, that
tion from multiple sensory systems are collected in joins the vegetative nuclei at different levels.
the reticular formation and they form the nonspe- Their topography is not exactly known.
cific afferent pathway system. Its importance lies
in the parallel transfer of information to the higher The interconnection of the nerve centers forms
compartments of the CNS, by which it can promote circles of nerve tracts, that are the basis of the coor-
adequate reactions to the information brought up by dination of afferent and efferent systems at different
special pathways. The nonspecific systems have a levels of CNS. Some other parts also belongs here
higher number of synapses, a longer latency, but they such as the reciprocal connections of the cerebral
effect the extend and the depth of the information. cortex and thalamus, the circles of the limbic system
There are some places in the subcortical and cortical and the feedback fibers of the extrapyramidal tracts
level where information are collected from different and others. The ascending and descending tracts are
modalities and these are known as the association known as the vertical junctions (to be differentiated
centers (nuclei). The information that reaches the from horizontal junctions).
CNS, is evaluated and it can serve for the regulation Anatomical and physiological notes about the
of some functions, to evoke others, or possibly to stop structure and function of the nerve system is im-
them, or to keep them active . Nervous centers are portant from the pathophysiological point of view of
interconnected even on the same level – horizontal the disease cases that may take place in the nervous
junction. These are: system, and consequently can be of influence.
The basic protective system of the CNS consti-
1. Local junctions, that provide connection be- tutes of the cranium (scull) and the vertebral col-
tween the nuclear neurons. For e.g. between dif- umn, where we might find the central part of the
ferent layers of the cerebral cortex. brain and the spinal cord. The rigidity of the skelet
2. The homolateral associations, that promote the is yet a disadvantage during an increase in the intra
transfer of information among different nuclei at cranial pressure because the cranium is composed of
the same level of the CNS. only a potential space to compensate the increasing
pressure and hence there will be a gradual compres-
3. The collateral commisures, that mainly join the sion of the brain tissues with some serious regulatory
homolateral brain centers (but in the cerebral disturbances . The brain lies in the cerebral cavity
cortex it joins the heterolateral centers as well). and it is covered by many covers (meninges) in a way
Interruption of the commisures of the brain is that it actually swims in the cerebrospinal fluid. The
known as split brain. There will be loss of coor- cerebrospinal fluid circulates freely in the subarach-
dination of functions of both hemispheres, and noid space covers the whole brain surface and its ven-
the result is a negative effect on intellect func- tricles surface. And hence it is quite clear that this
tions. place forms a good culture media via which different
– and mainly – infections diseases that might affect
The efferent systems are adapted to transform the the whole surface of the brain and spinal cord (for
instructions (the descending efferent pathways): e.g. meningitis) might find a way in . On the other
• Somatomotor efferent neurons form two main hand errors and disturbances in the cerebrospinal
systems: fluid circulation causes an increase in the intracra-
nial pressure and hydrocephalus.
1. Pyramidal and extrapyramidal tracts The most important thing is an intact nondis-
where the extrapyramidal is more neuronal turbed function and structure of the meningies. The
and it provides the coordination of multi- course dura mater (meaning literally ”hard mother”)
ple centers in different parts of the of the is composed of two layers, which the venous sinuses
CNS. formed between them. The outermost layer forms
2. Peripheral motor neuron, that is common the periosteum tightly attached to the bone (en-
for both tracts and together with the mus- dosteal layer, it actually serves as the periost). The
cle fibers it forms a motor unit. inner dura (meningeal layer) is firm, and in some ar-
6.2. Neuronal injury 435

eas it enters into the cranial cavity and forms the falx a different embryonic origin. These are most of
cerebri, tentorium cerebelli and those being a rigid all tissues of neuroectodermal origin, i.e. the CNS
structures might be the cause of cerebral injury in tissue itself that constitutes of neurons, and neu-
case of its displacement during (accidents, intracra- roglia (ependymal cells, astroglia, oligodendroglia,
nial hypertension, herniation). What is known as microglia). These tissues are characterized by a
the extradural lesions are commonly localized be- highly specialized functions, they are hence vulnera-
tween dura matter and the bone – dura mater is ble, sensitive, to many injuries and degenerative pro-
sloughed or separated from the bone. Subdural le- cesses.
sions are also common. They might spread very eas- Another group of tissues is mesodermal in ori-
ily to the peripheries, because the arachnoid mem- gin. Many kinds of tissues belong to this group
brane and dura mater are attached to each other for e.g. blood vessels, brain coverings (meninges)
quite freely (only slightly attached). The arachnoid and macrophages. The macrophages reach the brain
membrane is a very smooth cover from which tiny tissue during the embryonal development and they
trabeculae arise via the subarachnoid space to the change to microglia. These tissues have some similar
pia mater. The subarachnoidal space is composed of characteristics to any other tissue anywhere in the
blood vessels and cerebrospinal fluid. Diseases that organism and they are affected by for e.g. inflamma-
affect this space, do spread very quickly to the pe- tory diseases.
ripheries, above the whole brain and spinal cord sur-
face. Pia mater prevents the penetration of infection
to the brain tissues. Pia mater is closely attached
to the cerebral surface and the surface of the spinal
cord and it copies its curves and invaginations and
it invaginates along with the cerebral blood vessels 6.2 Neuronal injury
to the brain tissue. All the mentioned covers – dura
mater, arachnoidea and pia mater play the role of a
true barrier (the blood-brain barrier), that separates
cerebrospinal fluid and blood from the brain tissue.
Neurons are very sensitive to many external and
It is important to remember that although the cere-
internal unfavorable effects. We are mainly talk-
brospinal fluid has a very similar composition like
ing about anoxia, hypoglycemia, viral infections,
the extra cellular fluid of the brain, the changes of
metabolic disorders, vitamin deficiency (for e.g. vi-
the cerebrospinal fluid cause only a minor indirect
tamine B) and so on. The resulting effects of these
effect on the brain tissues in different CNS diseases.
factors on the nervous system mainly depends on the
The blood-brain barrier at the level of pia mater is
degree of injury of the throphic function of the neu-
formed of astrocyte dendrites. This barrier is made
ron and the maintenance of its integrity. The decisive
of three layers:
factor is the site of injury, type of the nerve cell, but
1. On the brain surface other factors also have a great value (for e.g. the de-
gree of cellular differentiation, the relation to glial
2. Along the penetrating vessels to the depth of the
cells etc.). During some physical or chemical effects
brain tissue. The space remaining between the
there might be either reversible short lasting injury
vascular wall and pia mater is called Virchowďs
or an irreversible neuronal injury. Neuronal injury
space and it is analogous with the subarachnoid
might be of many degrees:
space.
1. Functional injury caused for e.g. by pressure
3. At the level of capillaries pia mater does not ex- (hypoxia, that is reversible with the following
ist any more. And here the astrocyte dendrites normalization.
together with the capillary endothelium and the
basal membrane form the true specialized selec- 2. Death of an axon without interruption to the
tive blood-brain (hematoencephalic) barrier. endoneural tubes.
Pia mater actually separates two CNS compart- 3. Axonal death with interruption of the endoneu-
ments – the external and the internal, that have ral tubes.
436 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

4. Interruption of the nerve fibers. some signs of regeneration were noticed in the den-
tale gyrus of the hipocampus.
5. Interruption of the nerve cords. The ability of the nervous system to become ac-
The regeneration of peripheral nerves is possible, commodated to the variable effects – even the patho-
as long as the interruption is not very long lasting logical – for e.g. the compensation of many dysfunc-
and as long as the endoneural sheath remains intact. tion is related to the previously mentioned CNS plas-
Upon its interruption we might need a surgical repair ticity. Many mechanisms take place in this process:
to enable the regeneration of the nerve fibers to grow
1. Redundancy (the ability of other centers to com-
within the repaired endoneural sheath.Regeneration
pensate the function of the injured neuron).
is a long lasting process (according to nerve length) it
might last few months. Upon an interruption of mo- 2. Alternation (the ability of other centers to take
tor fiber and its muscular ending, the skeletal muscle over the function of the injured area).
will atrophy and its sensitivity towards a certain neu-
rotransmitter will increase. We are talking about a 3. Vicariing functions (other physiological mecha-
denervation hypersensitivity that is explained by the nisms that make up for the disturbed physiolog-
activation of a larger number of receptors compared ical function – for e.g. the loss of vision is par-
with the number of activated receptors before den- tially compensated by a more adequate touching
ervation (acetylcholine), or the disturbance of the sensation or hearing sensation.
back trapping (uptake) of the transmitter to the pre
4. Dischiasis (the functional depression of a certain
synaptic area (noradrenalin).
center as a result of its lower or on the con-
When we talked about the primary degeneration
trary extraordinary higher stimulation by the
of neurons, we have to mention, that neurons might
injured part, the function is then normalized,
also be injured secondary:
if the stimulation activity is normalized).
1. The retrograde degeneration – upon axonal in-
In relation to the mentioned facts we might draw
jury there will be first of atrophy of the distal
the attention to the fact that during certain life peri-
part of the axon and later on there will be de-
ods the compensatory abilities of the nervous system
generation of the neuron itself.
are markedly variable. As a rule, in the early postna-
2. The transsynaptic degeneration process, is that tal period and in the early childhood the plasticity
process where the injured neuron is connected is the highest and it decreases with age. Some fac-
to a neuronal network via the help of synapses tors are very important such as the nutritional fac-
and hence it can spread to the other connected tors, the composition of diet, but even the qualitative
neurons and lead to their degeneration. factors such as the effect of environment, the social
contact and the factors that enable the communica-
What concerns the nerve cell bodies themselves – tion of the member with his environment (for e.g. an
neurons – there basically might be what is known appropriate function of the sensory organs). These
as fast necrosis that is associated with acute func- have very effective effects on the formation of the
tional disturbances of the neuron, or slow atrophy, highest function of the nervous system in the areas
that is associated with gradual loss of neuronal func- of the highest neuronal function.
tion. A specific type of this slow (cumulative) atro- On the other hand it is necessary to point out to
phy and reduction of neurons is represented by the the fact that the largest group of psychiatric patients
effect of age on the CNS (mainly during senile age). do not suffer any morphological changes of the CNS,
The symptom of these might be for e.g. dementia, brain cells, neurons, that might spot the light (and
disturbance of memory, disturbance of some other explain) the cause of the illness. Attention in this
functions of the higher nervous function (senile de- case is drawn to the subcellular level, eventually to
mentia). If this process of slow atrophy is activated the brain biochemistry.
during early age, we are talking about presenile de-
mentia.In these case we have to realize that there is
no way for the atrophied neurons to regenerate. Neu-
rogenesis in man was not yet proven, even though
6.4. The basic etiopathogenetic factors in the nervous system disturbances 437

6.4 The basic etiopathogene-

6.3 Neuroglia
tic factors in the nervous
system disturbances
Glia reacts very prominently towards many CNS
diseases. The neuroglial cells have supportive and
nutritional functions. The etiopathogenic factors, that cause nervous
system diseases, are classified depending on many
1. Astrocytes, having many fiber branches, serve conditions. One of the basic classifications is a clas-
as supportive cells. The nutritional function of sification into two groups: (1) intrinsic and (2) ex-
astrocytes is enabled by the fact that part of its trinsic ones. Although this is a general and very
branches is situated on the endothelial cells that wide division, it is not possible to enclose all the dis-
form the wall of the capillaries (known as vas- eases within the mentioned groups because both the
cular ped). From this site they acquire the nu- groups are interchanged and interconnected with
tritional substances and transport them to the each other.
nerve cells. Upon neuronal injury the astrocytes Diseases of the nervous system from the etiopatho-
together with the microglial cells fagocytose the genetical point of view are devided into three groups:
detris and the products of digestion and form
the so called glial scar. They are less vulnerable 1. diseases with mainly intrinsic causes,
than the neurons. They share in the formation 2. diseases with mainly extrinsic causes,
of scar in a way that they produce and increase
the fibrin formation, later on the cells with at- 3. diseases with mixed or possibly unknown etiol-
rophy and there will be the formation of a thick ogy.
fibrinous network. This process is called glio-
sis. Gliosis accompanies many diseases and it
6.4.1 Diseases with mainly intrinsic
is analogous with scar formation. The collagen
scar forms in CNS only upon the injury to meso- causes
dermal structures such as for e.g. the vascular An important subgroup of this group are the genet-
tissue. ically conditioned diseases. Changes of the chromo-
somal number are very often associated with devel-
2. Oligodendrocytes are small cells with short opmental disorders of the nervous system, for e.g. tri-
branches. They perform mainly nutritional somy of the 21st chromosome – Down syndrome).
functions in relation to neurons. It is mainly Down syndrome is characterized by a prominently
seen during neuronal injury. Upon neuronal in- slow mental development, with the typical mongoloid
jury the number of oligodendrocytes increases, expression of the face (sometimes marked as mon-
and cells become enlarged. The whole process golism) and brachiocephaly.
is known as satellitosis. Another cause might be changes of the chromoso-
mal structures, and hence their abnormality (2) for
The microglial cells are part of the mononuclear e.g. changes in sequence of the DNA on the short arm
phagocytic system. Their reaction is best seen upon of chromosome the 4th are the cause of Huntington
tissue necrosis, around the infarct. The activated chorea, that is manifested by choreatic movements
large foamy cells phagocytose lipids, haemosiderin, with the consequent loss of intellect. As a differ-
and others. They are very different from the small entiation from the Parkinson disease the amount of
inactive microglial cells. According to the shape and dopamine in the basal ganglia is higher.
type of phagocytosed material those cells are vari- The 3rd group of the genetically conditioned dis-
ably marked as: lipophages, foamy cells or so the eases is composed of many diseases in which the in-
called gitter cells. jury of disturbance of function is not localized.
438 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

To this group we may count the metabolic distur- Leucodystrophy (Krabbe disease) – is the distur-
bances, the neuromuscular diseases and some neu- bance of ceramid metabolism. The brain white mat-
ropathies: ter degenerates very quickly, myelin is lost and is sub-
stituted by globoid cells. The disease starts in the
1. group of the congenital disturbances of the 3–6 month by an increased muscular stimulation. Af-
aminoacid metabolism: ter blindness and some serious neuronal disturbances
and loss of function the disease ends by exitus within
• phenylketonurea – an increased phenylalanin
two years. An experimental model of this disease in
level in the blood due to the absence of pheny-
dogs is known by now. This disease is identical in its
lalanin hydroxylase, The low phenylalanin con-
cause and course.
tent in a child nutrition can prevent oligophrenia
Sphingomyelin lipidosis (Niemann-Pick disease) –
in the first years of life.
is an autosomal recessive disease, in which lysosomal
sphingomyelinase enzyme is absent. This enzyme
• maple sirup disease – a higher blood leucin con-
function is to degrade sphingomyelin. Sphingomyelin
centration as well as isoleucin and valin is caused
then cumulates in the foam cells of the reticuloen-
by the deficient decarboxylation, a disease ends
dothelial system. During the acute neuropathic form
up lethaly in the first years of life with sighs of
of the disease we might notice loss of motor and in-
de cerebration rigidity,
tellectual function in the children. Treatment is yet
unknown.
• mental retardation is accompanied with another
aminoacid metabolism disturbance – cystation-
inurea, citrulinurea, hyperprolinemia, hydrox- 3. Disturbances of sacharide metabolism
yprolinemia, hyperglycinemia etc. These disturbances are known under the name
glycogenosis. The diseases during which an increases
2. Lipid metabolism disturbances amount of a normal or atypical glycogen is stored in
the cells belong to this group. The cause is either
Generalized gangliosidosis – gangliosides are cu- a high synthesis or a disturbance of its break down.
mulated due to the absence of specific galactosidase. There are many types of glycogenosis:
The disease is typically manifested by the psychomo- Gierke disease – glucose 6-phosphatase deficiency,
tor disturbances, hepatosplenomegaly due to foamy Pompe disease – a generalized glycogenosis, that
cells and skeletal deformity. The disease can have is also manifested with neuromuscular form with hy-
two forms and both are fatal. poreflexia, language abnormalities as well as some
Tay-Sachs amaurotic familiar idiocity – due to disturbance of swallowing and muscular hypotonia.
the accumulation of gangliosides in the neurons, this Cori disease – is a limiting dextrinosis and it is a
ganglioside side can not be metabolised. The dis- relatively rare disease.
ease is manifested by psychomotor retardation and McArdle disease being a deficiency of the muscle
disturbance of vision. phosphorylation, during ischemia the muscle activity
The disease have a progressive course with blind- is lower, and no lactate is formed during work. The
ness and idiocity and ends by death 3–4 years later. symptoms of this disease are prominent tiredness,
Glycosphingo-lipidosis (Fabry syndrome). There and painful muscular spasms.
is an X-chromosomal hereditary disease, during Galactosemia – is an aotosomal recessive disease
which ceramid is cumulated. Skin dark red lesions with nutritional disturbances and mental retarda-
are very characteristic. During the attacks there is tion. By controlling the diet we might prevent the
severe neuralgia. occurrence of nervous system injury.
Gaucher disease – cerebrocyte tezaurism with In gargoylism there is a metabolic disorder of mu-
many form types. There is the acute neuropathic copolysacharides, during which heparansulphate and
form during the first months of life, when a progres- dermatansulphate accumulate in the central nervous
sive loss of neurons takes place, disturbance of motor system with the consequent disturbance of its func-
function, and idiocity. In the chronic form of the dis- tion. The name of this disease comes from the gotic
ease there are neurological signs. statues and is named as water spout which patients
6.4. The basic etiopathogenetic factors in the nervous system disturbances 439

looked very much like. In all these disorders it is very coma, mercury – narrowing the vision field, ataxia,
important to prevent hypoglycemia. tremor, psychological changes, and extrapyramidal
Other disease – and mainly those that belong symptoms, thallium – affects vision till blindness,
to the group of degenerative diseases, that we de- spasms, delirium, and death, manganese – signs of
scribe elsewhere in this chapter we suggest the hered- the Parkinson disease, arsenic – polyneuritis, en-
itary factor to play the most important role (for cephalitis, and neuritis of the optic n.).
e.g. Wilson disease – hepatolenticular degeneration Disturbances of the nervous system is also caused
with damage of the basal ganglia, Friedreich ataxia by inappropriate use (and mainly overdosing) of
– that affect the cerebellum and medulla oblongata), some pharmaceutics. Upon a long use of barbitu-
some rare disease are the familiar spastic paraple- rates, psychopharmaceutics, antihistaminics ataxia
gia, hereditary cerebellar ataxia with spasticity and might occur, as well as lethargy desorientation, and
other diseases. memory changes.
Antibiotics and chemotherapeutics mainly affect
the sensory functions (for e.g. streptomycine has the
6.4.2 Diseases mainly die to extrinsic
affinity to the vestibulocochlear system). Some stim-
causative agents ulants might evoke convulsive states.
The most common cause is the mechanical damage An important cause of nervous system damage at
of the nervous system at different levels. Upon an the time being is the drug dependence. The most
accident there might be cut, tear, or compression of common drug dependence is to alcohol. Chronic in-
the nervous tissue. According to the mechanism of toxication is characterized by spasms, polyneuritis,
injury trauma is commonly combined with hemor- cerebellar degeneration, personality decomposition,
rhage, and edema that always worsen the result of and Korsakoffďs psychosis, that apart of the men-
trauma. A special group consist of so called birth tioned is manifested by desorientation, confabulation
trauma, that are usually associated with hypoxia. and memory loss. Due to the effect of alcohol there
Hypoxia belongs to the basic etiopathogenetical fac- might be degeneration of the other parts of the CNS
tors of nervous system injury. The sensitivity of the and even myelin degeneration.
nervous tissue to hypoxia is variable. The most sensi- CNS infection can be devided according to the
tive to hypoxia are the phylogenetically younger and causative agent into many groups (pyogenic menin-
the functionally higher specialized neurons (cerebral gitis, nonpyogenic meningitis – serous meningitis,
cortex, centers with high metabolism, interneurones, parasitic diseases, viral diseases). Pyogenic menin-
where ischemia produces disconnection signs). Even gitis is most commonly caused by meningococci and
nutritional disturbances can predispose to CNS dam- staphylococci. The nonpyogenic meningitis are usu-
age. If there is a deficiency of the energetic substrates ally viral in origin but also due to mycosis or tu-
and mainly during development (marasmus) or pro- berculosis and syphilitic infection. Thank to the an-
tein deficiency (kwashirkor), there will occur a long tibiotic therapy the prognosis of the mentioned dis-
term affection of the CNS, and mainly some defects eases today is much better than previously. Vaccina-
of the intellectual functions. tion could eradicate acute viral polymyelitis (Heine-
For the normal CNS development in man it is nec- Medine disease). Meanwhile there is a special group
essary to provide an adequate sensory stimulation, of diseases known as the infection with slow viruses
adequate social and emotional suggestions. Dur- (meaning infection with slow course). From the hu-
ing the child development this sensory stimulation man diseases it is mainly the subacute sclerosing en-
is equally necessary as the adequate nutrition. The cephalitis, Creutzfeld-Jackob disease and kuru – a
deficiency of stimuli in the sensory and emotional diseas of Melanesian population. In the last years
area leads to the retardation of the intellectual de- the acquired immune defficiency syndrom (AIDS) is
velopment, personality abnormalities and emotional spreading, and upon brain affection with this dis-
disturbances. ease there will be encephalopathy with the gradual
Many toxic substances have unfavorable effect on desintegration of the intelectual functions and per-
the CNS. These are mainly some metal (lead – sonality and a progressing atrophy and brain tissue
encephalopaties with spasms and hemiplegia with degeneration that ends lethally. The CNS due to its
440 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

high afinity to the virus (nearly 80 % compared with fection, but demyelinisation might be a secondary
the leucocytes) is threatened with direct viral inva- change resulting from the destruction of the nervous
sion, but also an indirect invasion upon the failure of system. Some unclear etiology is for e.g. that of
selfdefence immunological mechanisms against other senile demencia, degenerative changes of the cere-
infactions. bellum, or progressive subcortical encephalopathy.
Compared to the previous diseases Parkinson syn-
drome (paralysis agitans) has got a well known etiol-
6.4.3 Diseases with mixed or un- ogy and mainly what concerns the neurotransmission
known etiology and dopaminergic mechanism in the nigra strata.
Neuroinfections as well as poisoning, arterosclerosis
The diseases that belong to this group are those dis- and other factors might be triggering factors yet the
eases of medical interrest not marely because of the direct mechanism of the substancia nigra destruction
therapeutico – preventive point of view but also due remain unclear.
to their scientific research value. Upon the manifes-
tation of nervous system disease the main cause never
is an individual isolated cause of that disease. There
is always a multifactorial conditioned state. In many
diseases the decisive factors remain unknown. Dis-
eases that belong to this group can be futher subde- 6.5 Some syndroms occuring
vided into three subgroups: CNS tumors, neuroim-
munological diseases and neurodegenerative diseases upon the injury of the ner-
of the CNS. vous system
Tumors of the CNS develop either directly in the
nerve tissues (primary tumors), or they originate
from other tissues (secondary, metastatic tumors).
Even in case of tumors we suppose the presence To the extrinsic causes of nervous system injury
of an inborn predispositions, that are activated due we might commonly add trauma, accidents, the ef-
to the effect of the outside enviroment and mainly fect of mechanical power. Because of the fact that
the blastogenic effects. The question of the chemical all the medullary nerves are mixed (they contain the
or viral origin of these tumors remain still unsolved. afferent sensitive, and efferent motor fibers), upon
During childhood as well as during adultdood the their injury ther will be a resulted so called periph-
most common tumors are gliomas (about 88 % of eral nerve syndrom, that commences disturbance of
the affected children and 50 % of adults). In chil- sensation as well as motor disturbances. Upon the
dren there is commonly craniopharyngeoma (4 %) destruction of the anterior horn (that contains motor
and teratoma (3 %). In older people there is often fibers) there will be plegia and upon the destruction
meningeomas (20 %), metastases (10–20 %) and tu- of the posterior horn (that contains only the sensi-
mors of the neural sheeths (10 %). tive nerve fibers) the result will be loss of sensation
The neuroimmunological diseases of the CNS form (hyposthesia or anaesthesia, yet if the lesion conserns
till now a nonhomogenous group of diseases, that the afferent fibers in the affected horns, there might
have a common manifestation and immunological ba- be hyperesthesia).
sis. Multiple sclerosis most probably belongs to this Upon the lesion of spinal cord or brain the condi-
group of diseases (with a high content of gamma- tion is more complicated by bleeding (haemorhage),
globulins in the cerebrospinal fluid), and myesthenia an increased pressure in the closed cranial system or
gravis that is a defect in nerve impulse transmission the closed spinal canal, edema and other lesions (de-
at the neuromuscular junction. Antibodies against generative changes) of the nerve tissue. The neuro-
the brain tissue were described even in Alzheimer logical finding is characterized according to the level
disease (a disturbed cholinergic neurotransmission). and the localisation of the CNS injury: we devide
The degenerative diseases of the CNS might have them into spinal syndroms (for e.g. the transversal
many etiopathogenic causes. There causes might be separation of the spinal cord syndrom – with motil-
vascular changes, nutritional disturbances, neuroin- ity and sensation loss acording to the level of lesion,
6.5. Some syndroms occuring upon the injury of the nervous system 441

the period of spinal shock with the gradual develop- tical center for motor and vegetative automatisms.
ment of the spinal automatism), the partial separa- It envolves the mechanism of sleep, attention, and
tion of the spinal cord syndrom also known as the emotions.
Brown – Sequard syndrom is muscular plegia at the Hypothalamus is an important leading and coor-
affected side with the loss of all kinds of sensation dination vegetative center. It is closery connected
except temperature, cold, and pain that are loss on to the neuroendocrine diencephalo-hypophysal func-
the same side of the lesion due to the decussation of tion, blood pressure, thermoregulation mechanisms
tracts. are quite complex and hence their topographic diag-
Upon the longitudional spinal cord injury (bul- nosis might be very difficult.
bar syndroms) and pons (pontine syndroms) the nu- Between the thalamus and corpus striatum there
clei of the cranial nerves together with the pyramidal is a strip of white mater, that is known as the inter-
tract above its decusation are often affected (crossed nal capsule. Most of the ascending and descending
hemiparesis). It is manifested for e.g. by unilat- tracts pass through it and they join the cerebral cor-
eral paralysis of the facial nerve, and a contralateral tex with the spinal cord, the cerebellum, and the
paralysis of the body. Upon the injury of impor- reticular formation. The intermal capsule is com-
tant regulatory centers (and mainly the respiratory monly affected with cerebral haemorhage. In case of
center) sudden death might occur (usually due to a unilateral lesion there will be a prominent hemi-
respiratory center paralysis). This might occur up paresis or hemiplegia (paralysis of half of the body)
medullary compression and fracture of the atlas – on the contralateral side of the lesion. The paraly-
the second cervical vertebrae. sis is so called central type of paralysis. Sometimes
Upon midbrain injury it is important to remind there are associated parasthesia, dysesthesia or even
you that the midbrain is the outlet of the oculomo- pain on the affected side (the ipsilateral side).
tor and trochlear nerves. There are also the pyra- Lesion of the diencephalon is rarely localized in a
midal tract and the sensory tracts here. That is small area. The cause is usually haemorhage. We can
why upon the lesions of midbrain we most of all deal differentiate the hypotonic-hyperkinetic neostriatal
with the oculomotor reflex mechanisms (accomoda- syndrom (1) (inflamatory disease during childhood
tion, anisocoriosis, loss of light reflex, pathological and the so called minor chorea – that is manifested
nystagmus) and hemiparesis and hemianaesthesia of with a prominant decrease of the muscle tonus and
the contralateral side of the body. More extensive motor hypermetria), and hypertonic-hypokinetic pa-
lesion might result in decerebration rigidity. leostriatal syndrom (2) – the incidence together with
Cerebellar syndroms are manifested by cerebellar the extrapyramidal system disturbance occurs with
disfunction – i.e. loss of the coordination of auto- some encephalitis, and is manifested by disturbances
matic movements. Dysfunction of paleocerebellum of sleep (somnolence), rigidity (that is characterized
(vermis) are manifested by static dysfunction and by the fact that the patient stays in the given po-
automatic synkinesis – the coordination between the sition). The tremor is resting tremor, and the hy-
muscles of true an the lower limbs during walking pomimia is typical.
and standing (the patient stands and walks on wide Parkinson disease is an individual degenerative
base, then it looks as if under the effect of alco- disease of the paleostriatum (see the degenerative
hol). Cerebellar disfunctions are manifested mainly diseases). Another one is athetosis (3), that mainly
by disturbance of limb movement and disturbance occurs as a result of the prenatal injury of the motor
of language. The movenments become hypermetric centers in the diencephalon. There will be a com-
and dysmetric, the patients finger either misses the bined lesion of the paleostriatum and neostriatum,
point or hits it strongly.There is no tremor at rest, that is manifested by rigidity combined with hyper-
yet it appears upon movement (so called intentional kinesis which is known as the athetotic type (a slow
tremor). The landmark is the scanded language and spasmatic tortuous involuntary movements that ap-
a shaky handwriting. pear upon every intention to perform an active move-
The thalamus is considered as a kind of conduct- ment). Typical are the spasmatic expressions of the
ing station of the sensory tracts that are directed to- face. The hypothalamic syndrom (4) also belongs to
ward the cerebral cortex. It is an important subcor- this group. It is manifested by a prominant distur-
442 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

bance of the vegetative function. Many times we deal

with an extensive inflamatory, vascular, or tumor in-
jury, and that is why the symptoms are combined 6.6 Head injuries
with other signs.
Syndroms that occur due to prosencephalon (fore-
brain) injury are usually manifested as cortical in-
jury, that is very sensitive area,and that also con- Head injuries differ according to the mechanism
tain the finest differentiated functions. Injury to by which the head injury occured and its exten-
the occipital area (1) is manifested at the beginning sion. There are two main mechanisms that can be
as disturbance of vision (cortical blindeness). Upon characterised as follows: closed-head trauma (blunt
parietal lobe injury (2) there will be some localized trauma, e.g. box) and open-head trauma (penetrat-
sensory disturbance but also some gnostic changes ing trauma). In both categories neural tissues are
i.e. inability to recognize objects upon touching and damaged by compression that pushes the tissues to-
holding (apraxia – inability to recognize the shape of gether, tension that pulls or exerts traction on the
the subject upon touching it). During frontal lobe le- tissues, shearing that slides tissues onto other tis-
sion (3) there will be some motor changes as well as sues, or a combination of forces. With open-head
behavioural and intelectual disturbance. Localized trauma, tissues are directly damaged.
lesions of the pyramidal area are manifested by a Direct strike or blow. That is usually causing in-
precisely localized paralysis. More extensive damage jury to the soft tissue of the head, skull fructure with
might be manifested by hemiparesis. An epileptic the consequent contusion and brain tissue laceration
locus in this area can result in the so called Jackson in the area of injury. Soft tissue injury is not dan-
epilepsy. Disturbances of hearing and speech occur gerous despite the often occuring haemorhage. Skull
in case of temporal lobe lesion (4). When the white fructure that is associated with the invagination of
mater is affected by the lesion as well (tructs from bone fructures into the brain with haemorhage and
the thalamus to the occipital lobe), there will also brain tissue injury is very serious condition. This
be visual disturbances. Disturbances of speech (5) condition requires a non postponed (immediate) neu-
belong to this group of injuries as well. The speech rosurgical approach.
is a complex mechanism during which the integra- Injury caused by accelaration, deceleration and
tion mechanism of the whole extent of cortex takes rotation. Due to the fact that the head is relatively
place. The function of speech is devided into sensory freely mobile and the brain is also relatively loosely
component (hearing distinguishing the spoken word, situated in the cranial cavily, during some sudden
vision – distinguishing the written word) and into movements and acording to the action-reaction low,
a motor or expressive component that is concerned acceleration-deceleration low, or possibly the rora-
with thought arrangement into words and sentences tional movement of the brain there might be some
and the preparation and realization of the motor plan damage occuring by the bony cover and respectively
during articulation or writing. In cases of the poste- by the hard covering layers, that separate the an-
rior temporal lobe lesion (Wernick area) there will terior and the posterior part of the brain (gyri are
be sensory aphasia – being the inability to under- damaged, whereas the sulci are relatively protected).
stand the written or the spoken word. Whereas in le- The clinival manifestation of this condition is con-
sions of the Brocaďs area of the frontal lobe there will cussion, that is manifested by a transitional loss of
be motor aphasia, that means the inability to express consciousness that result due to the disfunction of
with a speaking language. In cases of dysarthria the the temporal neurones. The injury is not permanent
patient is able to create words and sentences, but and there will usually be a complete renewal of all
cannot realize them due to the bad coordination of the functions. In all types of head injury we have to
the articular muscles. These centers are located in know the mechanism of the injury and the possible
the left hemisphere (the dominant hemisphere) in the brain destruction. For e.g. the so known a contra-
right handed people. coup injury that occurs when the contusion of the
brain tissue, is on the opposite site od the original
strike (a coup injury – on the site of impact, where
the skull hits the brain).
6.6. Head injuries 443

6.6.1 Brain tissue injury primary injury. The difference can be in the number
of cells, that are damaged or reversibly damaged.
The brain is totally protected against the mechanical
effects of the external enviroment because it is situ- The faith of the reversibly damaged cells is deter-
ated in the cranial cavity and covered by the brain mined by the nutritional supply, and mainly oxygen
meningi and the connective collgen stripes on which supply. The oxygen supply is the limiting factor of
the brain lies and the cerebrospinal fluid by which regeneration, that starts at the moment of injury oc-
it is enclosed. Despite all these facts the traumatic curence even with those injuries that lead to an acute
injuries of the brain and spine are quite common disturbance or even stop the oxygen supply to the
(e.g. box). cells (for e.g. vasospasm), the changes occur gradu-
Generally those injuries are devided into open and ally with increasing intensity with time. In tissues
closed brain injuries. The closed brain injury can there is a certain oxygen reserve that is bound to the
be furtherly subclassified into many types such as haemoglobin, and namely soluble Hb in the tissue
commotio cerebri, contusio cerebri, and compressio fluid. The following changes are those of the slowing
cerebri. The injuries is most commonly caused by a or stop ATP synthesis, the Ca2+ transport distur-
pressure wave. Even an extensive shift of the brain bances into the mitochondria and Na+ out from the
in the cranial cavity (acceleration) can lead to brain mitochondria. This condition is accompanied with
tissue destruction as well as loss of function. the drop of the ATP, and an increase of the AMP
In case of open injuries there will be a communi- + PO3− 4 on the cytoplasm. Ischemia is characterised
cation between the extracranial and the intracranial by the continuously increasing lactate concentration.
space, the site of the injury will bleed (haematoma, The reversibility after cellular injury is associated
ischemia, and edema, and the consequent – infam- with the fact whether the oxygen supply is renewed
mation). so that there will be renewal of the ATP produc-
When thinking about the mechanogenesis of brain tion. If this doesnďt hapen, there will be worsening
injury we have to think about the traumatic destruc- of the cytoplasmic pH as a a consequence of the men-
tion of the cervicocranial junction. Injury of the cer- tioned changes and this will have its negative effect
vical spine is usually primary and it even determines on glycolysis and homeostasis of the internal cellular
the clinical symptomatology. The consequent brain enviroment. The permeability of the cellular mem-
damage (commotion or contusion) can be associated branes will change, and the passive movement of the
with the primary injury of the cervical spine – as ac- ions and water across these membranes is increased.
tion and reaction there will be a sudden and promi- Mitochondria are the most commonly affected struc-
nant hyperflexion with a consequent hyperextension tures (the loss of Ca2+ , the condensation of matrix,
(or on the contrary according to the direction of the and the drop or ceasing of ATP production, Na+ and
pressure wave effect). It is expected that in some water cummulation in the mitochondria, the drop of
sport injuries this mechanism is of a marked impor- pH, and a partial protein denaturation), endoplas-
tance. matic reticulum (a higher permeability, dilatation
When dealing with the characteristic changes on and the block of proteosynthesis) and the cytoplas-
the cellular level in case of brain injuries we have mic membrane (an increasing permeability). These
to keep in mind that the brain cells can not dev- changes are still reversible. The persistence of those
ide, and hence their number is constant, and can not conditions for a certain critical time that differs from
be renewed by substitution with new functional neu- tissue to another, can cause reversible changes or ir-
rones. Brain injury can also be characterized as an reversible ones. The irreversibility is manifested by
interferance with the nervous system integrity, inter- the inability to keep the homeostatic mechanisms,
ferance with tissue organisation, and their subcellu- the loss of free energy production, and the dom-
lar share as a result of aplication of external power. inance of the catabolic events, that are no longer
The outcomes of the injury are determined by the connected to the structure, and further affection of
type of injury, its localisation and extension. What the ion transport between the intra and extracellu-
is important for the patient are the associated com- lar spaces, till their complete similarly in concentra-
plications such as (associated injuries, infections, in- tion on both sides of the membrane. The irreversible
flammations, edema and etc.) that accompany the changes continue to damage the cellular structures
444 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

and consequently cause its (necrosis). As an exam- hit on the head (a vertical force on the head) the
ple to demonstrate some of the described changes we main parts that are affected are the cortical areas of
will talk about the cerebral commotion. the cerebellum and the corpus callosum (a strike on
the tentorium and falx cerebri), on the brain base
6.6.1.1 Closed-head trauma the affected parts are the basal parts of the frontal
and temporal lobes, and even the cranial nerves and
Concussion is an acute, most commonly traumatic vesseles. Upon an anterio-posterior blow there will
globally conditioned, yet short lasting and full re- be a horizontal shift of the intracranial masses, that
versible disturbance of the cerebral functions. leads to frontal lobes contusion and haemorhage can
The basic symptom is loss of consciousness, that occur due to the injury of the connecting vesseles. In
can last for few seconds to hours. In the clinical the posterio-anterior direction the frontal lobes, the
classification of the cerebral commotion we evaluate temporal lobes, and the brain sterm are the endan-
the time of lost consciousness and the length of the gered areas. The impact of the liquor wave damages
posttraumatic amnesia (a postconcussive syndrome). the base of the 3rd ventricle. During these impacts
The changes of consciousness are in direct relation the opposite sides of the brain might be injured due
or proportional with brain structure injuries. The to oscillation (contre coup mechanism). Upon the
patientďs condition yet, is influenced by other ac- rotational shifts of brain apart from the blasts on
companied symptoms of the trauma, such as shock, the bony cover there might be tissue injury due to
tiredness, pain and others. torsion. Some tiny tears will appear on the borders
Concussion is not marely a functional or a patho- between the grey and white mater with a multiple
anatomical unit. One of the first trials to explain vascular damage and the possibility of intracerebral
the functional changes during the cerebral commo- haemorhage. The notes about the structural basis
tion is the Monakow’s asynapse theory, that explains of consciousness is incomplete up to date, and that
the transitional changes due to reversible biochem- is why even the explanation of loss of consciousness
ical changes at the level of the synaptic junctions upon the cerebral contusion is not unified. We have
(their dysjunction). Despite the fact that many the- to keep in mind, that the complete pathomechanism
ories about the synaptic junctional blocks caused by is yet unknown. We know that different brain struc-
an increased release of acetylcholine are overcommed, tures have different sensitivity. Upon the cerebral
this theory is becoming important once again. It contusion the mechanical tension affects the brain
seems that the midbrain and its neurotransmitters in the centripetal direction. With the increasing in-
play an important role in the pathogenesis of cerebral tensity of injury the damage will include only the su-
commotion. The disturbance of noradrenaline and perficial brain structures (a mild degree) affects even
acetylcholine in the reticular formation of this area the deeper structures of the brain (a moderate and a
causes some disorders of the postural activity and severe damage). It is very likely that the most com-
can be the cause of multiple neurovegetative signs mon cases of cerebral commotions (the typical) with
that accompany cerebral commotion or are its re- loss of consciousness are upon involving the ascend-
sult. It seems that some authors often talk about the ing reticular activation system the reticular forma-
physico-chemical changes in the brain cells that can tion (ARAS) of the brain stem. In cases of severe dis-
be either directly associated with the effect of the turbances even the diencephalo-mezencephalic area
pressure wave, that moves very fast via the brain is affected by the damage. On the contrary there
tissue, or even with the accompanied neurovegeta- are some known cases of the so called concussion on
tive changes. It’s mainly dealing with vasospasms, feet, that is characterized by only a mild alteration
that result in a transient ischemia of many parts of of consciousness, with no memory disorders or loss
the brain. The mechanism of these changes causes of motor control. Here we expect that the trauma
the reversible type of neuron changes as mentioned didn’t involve the ARAS.
above.
The mechanical pressure wave that passes via the In cases of cerebral commotion we are dealing with
cerebral tissues affects all its structures with either a functional disorder, without a clear pathologico-
major or minor outcomes. That is why the actual anatomical or histoloical changes. The injury of
mechanism of the injury is quite complex. Upon a the membrane functions is reversible. Upon recur-
6.6. Head injuries 445

rent cerebral commotions (for e.g. boxers) there will consciousness is associated with a retrograde amnesia
be some qualitative changes in the pyramidal cells (the patient doesnďt remember the situation shortly
(chromatolysis, prolongation up to axonal tearing). before the injury) or sometimes an anterograde am-
Those mentioned changes are irreversible and their nesia (where the patient doesnďt remember situa-
compensation is possible only thank to the plasticity tions shortly after or during the gain of conscious-
of the nervous system as whole. ness). The accompaning signs of the cerebral com-
The extent and the localisation of the injury upon motion are some vegetative changes such as – nauzea,
the cerebral commotion is found out with the help of vomiting, dizziness, giddiness, and headache. In
the electroencephalography recording (EEG) and of worse conditions there will be the so called hypotha-
the cerebral evoked potentials (EVP). Changes such lamic signs: disorders of miction (oliguria, polyuria)
as reduction and slowing of the bioelectrical activity salivation, sweating, disorders of blood glucose reg-
in the cortical and subcortical structures, that were ulation (abnormal oral glucose tolerance test, sleep
found with the help of implanted electrodes exper- disturbances, leucocytosis and others). An impor-
imentally, prove the presence of a relationship be- tant sign is the blood pressure change, the ortho-
tween the pressure wave and the membrane struc- static hypotension and orthostatic tachycardia. In
tures of the brain. In the pathogenesis of cerebral the period of reconvalescence there might usually be
commotion the changes of the vascular system and some sleep changes, inability to concentrate, head-
hence the oxygen supply of blood to the brain during che, and dizziness the so called postcommotion syn-
the trauma play an important role. The angiography drom). The cerebral commotion can be the cause
showed that within the first minutes after the injury of the manifestation of a latent brain disease, it can
there is a prominant decline of blood flow via the worsen the already present disease, it might accel-
brain and oedema occurs (the increase of brain vol- erate the process of aging, the process of cerebral
ume by about 3 %). The generation of brain oedema atherosclerosis, worsen Parkinson disease, worsen
is related to the higher permeability of the cerebral some psychological disease or even expose some la-
vasculature and hence the disturbed blood flow reg- tent brain tumor etc.
ulation as a consequence of the injury of the brain
worsens during the initial minutes. These changes 6.6.1.2 The following complication
usually return to normal spontaneously in the next
Apart from the direct outcomes of head injury there
stages.
might commonly be some complications that occur
Many authors pay an attention even to the neu- after few hours or days:
roendocrine changes (dysregulation) upon the cere-
bral commotion. An overcommed traumatic in- 1. haemorhage
jury together with cerebral commotion represent
2. brain edema
a stress for the organism. Due to the affection
of hypothalamo-hypophysal system by the injurious 3. leak of the cerebrospinal fluid
mechanism (pressure wave, changes of vascularisa-
tion, liquor wave) there will be a disturbance of the 4. infection
adrenocortical balance, the concentration of biologi-
cally active substanes in the blood, the Na+ propor- 1. Bleeding (haemorhage)
tion (hypernatriemia) and K+ ions (hypokaliemia)
due to the renal tubular changes, because the kidney (a) Extradural haematoma. This type classically
is actually an excretory organ of the neurohumoral occurs as a complication of the linear skull frac-
(hypothalamo-hypophyso-adrenal) system. tures, when a meningeal artery is injured. In
The clinical picture of the cerebral commotion is the typical case and as a result of haemorhage
manifested with loss of consciousness (a mild degree the dura mater is unsloughed from the bone and
till 15 min, a moderate degree till 60 min, and a se- it compresses the brain tissue, so there will be a
vere degree of more than 60 min lost consciousness). haematoma. According to the seriosity of bleed-
In case of the severe states we shoud keep in mind ing will be the clinical manifestation. The lucid
the possibility of cerebral tissue contusion. Loss of phase can last for few hours, gradually there will
446 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

be signs of intracranial hypertension and differ- it is not uncommon to find only a benign head injury
ent neurological symptoms that bring the pa- (for e.g. getting into or out of a car).
tient to the neurologist.

(b) Subdural haematoma. Can ocur in any location,

is extensive because dura mater and the arach-
noidea are not tightly adherent. It occurs most
commonly due to the rupture of small bridging 6.7 Brain edema
veins.

(c) Intracerebral haemorhage usually occurs to-

gether with the cortical contusion – most com-
Edema (a swelling) of the brain can be charac-
monly in the temporal or the frontal region due
terized as an increasing fluid content in the brain
to the effect of the injurious mechanism. Yet the
tissue. Brain edema results in an increased extra-
haemorhage during the trauma might be deep in
cellular (more in the white mater) or an intracellu-
the tissues. The cause is vascular injury that is
lar (more in the grey mater) volume, increases the
usually not very extensive.
intracranial pressure, worsens the course of the pri-
mary disease. It occurs in many brain diseases. This
2. Brain edema (is described elsewhere 3.7) process might be localized or generalized according
to the causative agent. An example of the localized
3. Leak of the cerebrospinal fluid (CSF) and edema can be brain infarction, local brain ischemia,
blood from the nose and ear can be a complication haematoma or tumor. An example of a generalized
of cranial base fructure. It can be prolonged and it brain oedema can be that caused by intoxication,
creates an entery for infection. metabolic disorders, hypoglycemia, generalized hy-
poxia and a severe head injury or malignant hyper-
4. Infection. Might complicate fructure healing and tension. Brain edema can occur in association with
it can affect other structures e.g. meninges. the disequilibration syndrom that occur with dial-
ysis, diabetic ketoacidosis, hypoosmolarity, in dif-
6.6.1.3 Late complications ferent forms of obstructive hydrocephalus and upon
hepatic dysfunction.
1. Scar formation and epilepsy. During the process
The outcome of brain edema, either the localized
of scarring by the resorption of necrotic tissue degra-
or the generalized type, is, worsening of brain perfu-
dation products, there will be formation of pigment
sion, a disturbance of cerebral haemodynamics, and
scars. These can potentiate the occurance of epilep-
metabolism disturbances with the consequent loss
tic firing, mainly when the meniges adhere to the
of consciousness. The pathomechanism is given by
brain tissue.
the characteristics of the initial insult. In the initial
2. Chronic subdural haematoma. Occurs mainly stages the most common mechanism applied is the
in the elderly patients and alcoholic patients. A thick so called cytotoxic component, that leads to cellu-
layer of fluid and a partially coagulated blood grad- lar membrane injury, disturbance of ion balance of
ually cummulates between the thickened dura mater the membrane (Na+ ,K+ ) and the shift of water from
and the arachnoidea. Signs of brain atrophy and the plasma to the interstitium. The major compo-
compression appear in the adherent area. The path- nents of this phase is hence the shift of water into
omechanism is not clearly understood. We assume the interstitium based on the ionic imbalance that
that, there will be damage of the small connecting results from cellular membrane injury. In the later
bridging veins, which together with the lower blood stages there will be the so known vasogenic compo-
coagulability can be the causative factor of this type nent, that is manifested by capillary wall damage,
of bleeding. The clinical manifestation usually in- and the shift of plasma proteins to the interstitium
cludes a marked beginning with the progression of with the consequent oncotic water binding (shift of
neurological symptomatology. The history doesnďt water to the interstitium). The edematous fluid has
include any serious head injury in most of the cases, the tendency to spread in the white mater. From the
6.7. Brain edema 447

pathogenetic point od view we can differentiate two tissue hypoxia there will be an irreversible damage
types of brain edema: and necrosis where lysosomes are released from the
cells. Lysosomes initiate an autodigesting process,
1. The cytotoxic (metabolic) edema during which the blood brain-barrier is prominantly
further destroyed and its permeability is increased.
2. The vasogennic edema
Diffuse edema of the gray and the white mater ap-
A unique position is that of the interstitial edema, pears in status epilepticus, uremia and eclampsia.
where some authors even describe brain edema as a Interstitial edema is most commonly seen in case
result of ischemic causes – ischemic edema – as an of obstructive hydrocephalus. Edema is caused by a
indipendent unit. transependymal shift of the cerebrospinal fluid from
In case of the cytotoxic (metabolic) edema the the ventricles to the extracellular spaces of the brain
toxic factors cause a direct disturbance of the active tissue. By this way the volume of fluid is increased
transport of brain cells (neurones, glia, endothelial mainly around the ventricles. The hydrostatic pres-
cells). The cells loose K+ where as Na+ enters the sure in the white mater rises and there will be de-
cells and the cells enlarge. This is how the volume struction of the myelin sheeths. The involvement of
of the brain cell is increased on the account of the white mater mainly is typical for edema that occurs
extracellular space. The cytotoxic edema is usually with inflamations or allergic situations.
localized in the gray mater and can be combined Brain edema is potentiated by the so called stress
with the vasogenic edema. post-burden reaction. There will be the activation
The vasogenic edema is the most important type of hypothalamo-hypophyso-adrenal system with the
clinically. It is caused by osmotic disturbances, consequent release of catecholamines. There will be
changes in the membrane permeability, disturbance peripheral vasocontriction and dilatation of the cere-
of the Na pump, the toxic effect of free O- radi- bral arterial system. This will become more promi-
cals (oxygen) that cause the Ca2+ influx to the cells nant by cerebral hypercapnia. The resulting perfu-
to be increased. There might be a co-association of sion disturbance, will worsen the ischemia even more
prostaglandins with leucotriens. The generation of and there will be ganglion cell membrane injury with
the so called permeability disturbance of the blood the disturbance of the active and passive transport.
brain barrier as a consequence of a certain pathegenic The neurones undergo Alzheimers degeneration and
effect of (trauma, inflammation, tumor or vascular they necrotize. By this the brain edema reaches its
injury). The blood-brain barrier dysfunction can peak.
lead to the diffusion of plasma proteins extravasally The progressive progression of the brain oedema
to the extracellular spaces. Water follows the shift has apart of the primary outcomes even secondary
of plasma proteins, which increase the content of wa- outcomes due to increasing the intracranial pressure.
ter in the brain parenchyma. The vasogenic edema In more advanced stages these two mechanisms com-
appears in the area of injury and it spreads to the plete each other and prominently worsen the patien-
peripheries, where it affects the white mater promi- tďs general condition.
nantly, whereas the gray mater is relatively resis-
tant. The first to be affected are the basal ganglia. A precisely localized brain edema is very rarely
Edema is worsened by the coaffection of the result- seen. The most common form is the combined one.
ing ischemia (tissue compression, worsening of the The primary ischemic origin of the brain edema can
perfusion). occur in blood diseases (anaemia, haemoglobinopa-
thy, etc.), in cardiovascular disorders (shock, MI,
Some authors consider some other type of brain arhythmia, bleeding, vasospasms, decapitated hyper-
edema: tension, hypotensive states, etc.), in breathing disor-
Ischemic edema is most commonly associated with ders, in cases of high cerebrovascular resistance, in
brain infarction. Brain ischemia is accompanied by cases of intracranial expansive processes, intracranial
vasogenic or even cytotoxic component. Ischemia hypertension, and spasm states (epilepsy, eclamp-
of the brain tissues will gradually result in an in- sia). On the other hand when the brain edema is
tracellular edema of the subcellular organeles (mi- rather due to toxicity it is usually a case of malignant
tochondria). In case of a continuous ischemia and brain tumors, upon contusions and brain malacia, in
448 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

cases of haematoma, and in case of using neurotoxic

poisons. Brain edema might also ocur in cases of hy-
poproteinaemia, or in ionic spectrum disturbances. 6.8 Intracranial hypertension
Brain edema very commonly occur as a consequence
of a neurosurgical performance.
According to the course of the disease the brain Intracranial hypertension or a high intracranial
oedema might be either acute or chronic, localized pressure syndrom. The intracranial tension is de-
or generalized. The localized brain edema is char- termined by the reciprocal relation between the in-
acterized by localized symptoms, headache, vertigo, tracranial space volume and the volume of the tissues
vomiting, papillary edema, and slight disturbance of (brain, blood, and the cerebrospinal fluid). That are
consciousness. A generalized brain edema is associ- situated within it. The intracranial pressure in the
ated with loss of consciousness, signs of brain stem normal conditions ranges between 5–5 mm Hg (0.7–
compression with threatening of vital functions, and 1.2 kPa or 60–180 mm H2 O). During the physiolog-
there might be decerebration rigidity. The char- ical conditions the intracranial volume can change
acteristic sign that accompanies this condition is only during childhood (until a complete adhesion of
bradycardia and an increased blood pressure in the the intracranial sutures). The ratio of the brain
systemic circulation. Tachycardia and a decreased tissue to the liqour and blood might change only
blood pressure is usually a sign of deterioration. slightly. Despite of this fact there are some com-
The diagnosis of brain edema has to be based on pensatory possibilities, and mainly those of regula-
a proper evaluation of all signs of intracranial hyper- tion of liquor formation and resorbtion and even a
tension. It is incorrect to talk about brain edema, partial shift of liquor extracranially. Later on it is
as soon as the brain volume increases. It might be a possible to achieve a partial reduction of the blood
case of increased blood volume (bleeding) or liquor volume upon increasing the blood pressure.
volume (obstruction), that doesnďt have to be linked The intracranial pressure increases due to two gen-
to the brain edema. It is of a great value to monitor eral causes:
the intracranial liquor pressure, X-ray of the scull,
• an expanding process and
angiography and mainly CT.
The treatment has to be systematic in treating the • flow obstruction of the cerebrospinal fluid (hy-
cause, early, and complex. It has to provide an ade- drocephalus)
quate exchange of gases, stabilize the circulation and
An intracranial expanding process arrises either
remove the cause of brain edema. The symptomatic
from the brain tissue itself or from its covers
tratment leads to:
(meninges). The most important examples are:
1. Intracerebral bleeding and haematomas (trau-
1. The decrease of the metabolism and energy re-
matic or spontaneous), brain infarcts and tu-
quirement of the brain tissue,
mors (primary or secondary – metastasis).
2. Usually a traumatic bleeding to the area of brain
2. Stabilization of the metabolic balance by the meninges (extradural, subdural, and subarach-
balanced fluids, electrolites and proteins, noidal).
A very rare condition is the appearance of
3. Increase in the stability of haematoencephalic meningeoma and hydrocephalus that will be
(blood-brain barrier), thorowly discussed elsewhere.
In children with still opened cranial sutures the
intracranial hypertension (ICH) is associated with
4. Removal of the pathological overload of fluids
cranial expansion of the fontaneles and their pulsa-
from the brain tissues by changing the osmotic
tions. Upon percussion of the head there will be
gradient (osmotherapy). what is known by cracked-pot sound. In older peo-
ple the intracranial cavity can not be changed in size
6.8. Intracranial hypertension 449

and that is why upon exhaustion of all the com- 4. The vasomotor paralysis. In this stage there
pensatory mechanisms together with the intracra- will be a viscious circle: due to the higher in-
nial pressure raise there will be the appearance of tracranial pressure there will be a low brain tis-
papillary n. edema on the eye background, and due sue perfusion, that leads to hypoxia of brain
to the pressure on the vital centers in the medula tissues (and the pCO2 will increase). These
oblongata there might be some resulting respiratory changes already lead to a progressive neuronal
disturbanes as well as disturbances of the heart rate injury and a vasomotor paralysis, that worsen
and action and blood pressure with multiple vegeta- the hypoxia even more. Hypoxia and hence the
tive signs. accumulation of CO2 in the low perfused tissues
In more advanced cases of intracranial pressure disturbes vasoconstriction and leads to a promi-
there will be formation of intracranial pressure cones nant vasodilatation, that increases the intracra-
– the compression of the brain into foramen mag- nial pressure. Upon the increasing intracranial
num (Arnold-Chiaris syndrom) and hence below the pressure in this stage even brain edema might
tentorium cerebelli. Due to the brain tissue shift a occur. By this the pathological ring is closed.
disturbance of function and structure of the CNS will
occur. Brain edema is a serious complication of the The intracranial hypertension is manifested with
intracranal hypertension. many subjective and objective symptoms and signs.
In general the seriosity of the case depends on he We are mainly talking about headache (e.g. the areas
site of lesion, time length of the expansion and the known as the ventilation areas in the IVth ventri-
character of the causative agent. According to this cle obstruction due to a localized carcinoma, that
we distinguish 4 stages of intracranial hypertension: will worsen upon laying down, upon holding the
breath, and other conditions leading to an increase of
1. The stage of total compensation. Where the the intracranial pressure. The patients complain of
expansive process causes an increase of the in- nauzea, vomiting, respiratory disturbances, vertigo,
tracranial pressure, that leads to an increase in blurred vision (papillary edema). The alterations of
the resorbtion of the CSF and its lower pro- the brain are manifested with disturbances of the
duction. This is how the volume of CSF is de- higher neurological activity (bad memory, concen-
creased, so that the space that is formed can be tration and etc.).
filled with the expansive process. In this case From the objective signs the higher liquor pressure
the expansion doesnďt compress the brain tis- is in the first place in the early stages the blood pres-
sue yet, and so the symptoms of compression sure raises (in the late stages it decreases ), the heart
are minimal. rate and action is decreased (bradycardia), papillary
edema might even lead to optic nerve atrophy and
2. The stage of partial compensation. In this stage
the compensation reduces the intracranial vol- blindness. In case of brain tissue lesion some lo-
ume of the circulating blood with no change of calized neurological signs might appear. We ought
the tissue perfusion. This is possible by vaso- to mention that upon a sudden diagnostic lumbar
constriction, that increases the blood pressure. punction the so called medullary conning might oc-
cur with its fatal drowbacks due to the injury to the
The systemic arterial blood increases, remind-
ing you that this shoud provide the proper brain vital centers of the medulla oblongata and the base
perfusion. of the brain. Apart of these so called primary re-
sults of the intracranial hypertension, there might
3. The stage of decompensation. In this stage also be some secondary complications. These might
there are no possibilities to further compensate be vascular injuries (1), intracranial nerve injuries
the brain tissue expansion without an injury (2), a cerebrospinal fluid flow obstruction (3) and
to the brain tissue. There will be a shift of bony changes of the cranium (4).
the brain tissue in the cranial cavity, hernia-
tion and distorsion, that accompany many CNS 1. Papillary edema of the optic nerve is a sign of
functional abnormalities. The systemic arterial intracranial hypertension that occurs due to the
pressure will raise yet the heart rate is slower compression of the central retinal vein. Vascu-
(Cushingďs effect). lar compression and expansion can lead to their
450 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

rupture, haemorhage and infarction that might whereas the resorbtion is relatively unchanged. Yet
mask the original disease. the overproduction of the CSF is not the cause of
hydrocephaly. We have to look for the cause of the
2. The oculomotor nerve (the IIIrd) and the ab- overproduction of the CSF.
ducent nerve (the VIth) are the anatomically
most vulnerable nerves, and this is shown by 2. CSF flow obstruction (the most common
the paralysis of the eye bulbs. The abducent cause), that disturbes the circulation of the CSF in
nerve is vulnerable due to its long course in the the intracerebral or the extracerebral space. Ac-
subarachnoidal space. It is commoly injured on cording to the level of obstruction we devide hy-
the contralateral side (the paradoxical sign) of drocephalus into the non communicating – closed
the causative lesion. (obstruction above the level of the IVth ventri-
cle e.g. aqueductus Sylvii, foramina Megendie and
3. An expansion that leads to intracranial hyper-
Luschke – the CSF doesnďt reach the subarachnoidal
tension might compress the midbrain, that can
space) or the communicating (the CSF circulation is
lead to the narrowing or even the obstruction of
obstructed in the subarachnoidal space.).
the aqueductus Sylvii. The cerebrospinal fluid
circulation will be disturbed and the CSF will 3. Disturbance of the CSF absorbtion (a rare ab-
cumulate in the lateral ventricles and the IIIrd normality). The absorbtion usually takes place in
ventricle. An increased pressure leads to tissue the venous sinuses of the arachnoid. This abnormal-
damage in the area of the ventricular systems. ity can result from an inflamatory process, bleeding,
The distension of the ventricular system worsen or the obliteration of the areas of resorbtion. The
the intracranial hypertension. obstruction might be temporary upon taking some
positions, or upon some head movements – this is
4. A longlasting increase of the intracranial blood
known as a ventil hydrocephaly. It can develop with
pressure leads to the errosion of the brain
some tumor types, that grow from the stalk into the
bony cover, which could be seen on the X ray.
ventricular system of the brain.
In children with intracranial hypertension the
skull is deformed in shape, and especially if
the fontanels are still open. Widening of the The causes of hydrocephaly are devided into two
bony sutures of the skull, the pulsation of the groups:
fontanels and the prolonged time of fontanel os-
1. congenital (developmental) abnormality,
sification are other mechanisms, that can par-
tially compensate for the process that leads to 2. acquired hydrocephaly
intracranial hypertension.
The congenital or the developmental abnormalities
that might cause hydrocephalus can be devided into
many groups:

1. Arnold-Chiary malformation, in which due to

6.9 Hydrocephaly the increased intracranial pressure the cerebel-
lum and medulla oblongata are pushed into the
foramen magnum, upon which there will be CSF
In hydrocephaly the volume of the cerebrospinal flow obstruction. The intracranial pressure in-
fluid (CSF) is increased and the ventricles are di- creases and this might injure the respiratory
lated. In most of the cases the intracranial pressure centers in the medulla oblongata.
is increased as well. Generally 3 possible mechanisms
2. Congential stenosis or atresia of aqueductus
are accepted to be the cause of the development of
Sylvii, that is manifested by an excessive dilita-
hydrocephaly:
tion of the IIIrd ventricle and the lateral ventri-
1. An excessive production of CSF. Where the cles with a following increased intracranial pres-
choroid plexus produces more CSF, than normal sure.
6.10. Demyelination disease 451

3. Atresia of foramen Magendie and Luschke that the neurons and axons remain intact. The affection
leads to the dilitation of the IVth ventricle, the of their function is secondary. It is usually not con-
IIIrd ventricle, and the lateral ventricles. nected to specific neuronal pathways or tracts. There
are two types of demyelination disease:
Acquired hydrocephalus can be caused by many
factors. The usual causes are brain tumors (pri- 1. The myelin-classical type – where the myelin is
mary or secondary), haemorhage or meningitis, upon normal until adulthood, and its degradation oc-
which the resorption capacity of the arachnoidea is curs later on.
decreased.
A unique type of hydrocephaly is the so called 2. Dysmyelin type – the myelin is structurally ab-
secondary hydrocephaly, that in contrast with the normal from the early childhood.
former mentioned types, is not manifested with high The pathomechanism is yet unknown. We assume
intracranial pressure. This condition follows an over- that there is an autoimmune process, viral infection,
commed brain infarction or a generalized brain atro- or the presence of both processes.
phy, where the ventricular system dilatation comes The secondary type might follow a previous injury
secondary and this space is then filled with the CSF. to the neuron itself, or its axon. This type usually
As an outcome of hydrocephally in the newborn affects certain nerve tracts and hence it is possible to
and in children with still opened fontanels there will localize the precise anatomical position of the injury.
be an expansion of the brainy part of the skull, and This type of degeneration is typical for more disease
a prominent network of cerebral vessels will appear, groups. As a typical example we may take the de-
the childďs eyes will look very much like a sun set, generation of the neuronal tract as a consequence of
and the percussion of the head will reveal a sound a regional infarction.
that is similar to the sound of a cracked ceramic pot. Demyelination loci create neuritic plaques. The
The brain is dilated, the CT or sonography reveals a size of these plaques is variable. Histochemically it
massively dilated ventricular system in the cut sec- is a lipid degeneration of the myelin sheaths. The
tions, the brain tissue and according to the severity remainder of the degenerated myelin sheaths is re-
of hydrocephaly forms a thicker or a thinner layer moved by macrophages, that together with lympho-
on the margins. The brain groves become flattened, cytes are geathered around the locus. The older loci
and the gray mater might often form only a layer are gray and sclerotic (hard). There is no cavitation
of few mm. Some mental disorders will appear, as what so ever. The consequences of the pathoanatom-
well as disturbances of vision, fine motor movements, ical changes are very similar in both cases (demyeli-
and other functions. In the adults or in children with nation, the removal of the lipid particles by the
closed cranial sutures upon hydrocephaly there will phagocytic cells, gliosis).
be a raise in the intracranial pressure and the domi- Not only the covers of the neurons but even the
nant signs and symptoms arise from this syndrom. axons themselves are inju red by demyelination. De-
myelination causes block of the neuronal conduction
of stimuli.
Depending on the recent notes about the patho-
genesis some of this disease group are classified un-
6.10 Demyelination disease der the so known neuroimmunological diseases. A
relatively common disease such as multiple sclerosis
belongs to this group.

The group of demyelination diseases includes dis-

6.10.1 Multiple sclerosis
eases, in which there will be a local or a diffused de-
myelination of the central or the peripheral nervous Multiple sclerosis (MS) is a chronic, primarily de-
system. Demyelination occurs most commonly in myelination disease that involves the central nervous
the white mater, and only rarely in the gray mater system, and only very rarely the peripheral nervous
of the CNS. The loss of myelin sheath can be pri- system. It usually affects the young adults, more
mary or secondary. Upon myelin sheath destruction women than men (ratio 2:1). The beginning of the
452 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

disease is between the 20–40 year of age. As a rule course of the disease, and it increases with the dis-
this disease leads fast to a permanent invalidity. The ease exacerbation. It is manifested with a high IgG
course of the disease can be in bouts, after which the titer in the liquor, but not in the serum. The num-
patient’s condition always deteriorates, or the disease ber of T-supressor cells in the peripheral blood and
develops slowly, but continuously. It is interesting to in the initial stages of MS or its exacerbation promi-
notice the occurance of MS in some geographical ar- nantly decreases.
eas – almost always to the north of the 40 parallel There is another theory that claims that the slow
(the European, and south American zone). Accord- viruses release basic proteins form the neuronal
ing to the geographical position there are some dif- membranes and hence the myelin sheath cells that
ferences in the characteristics of the disease course. are potent antigenes. The lymphocytes in the affeted
Multiple sclerosis in our country affects about 1/1000 areas initiate the formation of antibodies against
citizen (nearly 10 % of all neurological patients). The those basic proteins and they transfer this informa-
patients close relatives have the risk of the disease 15 tion about this antigen type to the lymphatic tissues.
times higher than normal population. Here this information is transferred to other genera-
The etiopathogenesis of multiple sclerosis is not tions of lymphocytes. Upon a repeated lymphocyte
clearly understood. There are many theories that diffusion into the injured locus in the CNS an im-
attempt to explain the pathomechanism of the oc- mune reaction will occur with the consequent myelin
curence and the development of MS, based on the sheath injury (demyelination, plaques, neurological
immuno-genetico-viral etiology. We expect an in- symptomatology).
teraction between the genetic predisposition and the Together with the previous theory in the past they
risk factors of the external and internal environment. also mentioned some metabolic abnormalities of the
Some histocompatibility markers (HLA-A3, B7, Dr2, oligodendroglia, that have got a direct effect on the
Bf, DW2) were more often found in patients suffer- myelin sheath metabolism. Probably they tried to
ing from MS. According to this theory there was an find the relationship between small vessel thrombo-
introduction of a haplotype MS gene marker that sis in the cerebral field and the demyelination pro-
has got a low penetration, and it modificates the re- cess, or the disturbance of some heavy metal or lipid
sponce of immune system to the external enviroment metabolism in the CNS.
antigenes in a wrong direction.
There are some famous experimental work, where
The pathophysiological mechanisms in the devel- the transport of lymphocytes from animals with ex-
opment of MS are: perimental alergic encephalitis to other animals led
to the transport of this disease to these animals. It
1. The interaction between the immune system
was proved experimentally that there is an immuno-
and the CNS
logical reaction activated by basic proteins of the
2. Demyelination of the CNS nerve fibers – and the myelin sheath.
formation of neuritic plaques. The cell mediated immunity leads to the destruc-
tion of the normal myelin and oligodendroglia. This
3. Affecting the CNS function.
mechanism will then act as a triggering factor for the
How does the interaction occur is yet unknown. occurence of demyelination in the already injured
Chronic viral infection probably the so called slow myelin. In this relation the question of vascular in-
viruses – results in a mild inflamatory reaction in the jury (the vascular component of the disease) remains
small vesseles of the central nervous system (vasculi- unsolved. Some studies show that the myelin of pa-
tis). The injury to the vascular wall causes an inter- tients with MS has got a different composition and
mittent local disturbance of the blood brain barrier. mainly in the content of non saturated fatty acids
There is a chance for the B-lymphocytes to be in (less). It is not clear wheather it is a congential pre-
contact with the CNS tissues. As a responce to an disposition or an acquired defect.
antigen the stimulated B-lymphocytes form plasma Upon evaluating the present information we might
cells. That start to produce immunoglobulins G- say that most of the facts point to the neuroimmuno-
antibodies against the provoking antigenic structure. autoagressive mechanism for the occurance and de-
The production of IgG continues during the whole velopment of the MS.
6.10. Demyelination disease 453

From the clinical course: MS most commonly oc- will be a perivascular cellular infiltration (lympho-
curs in attacks, among which there are some long cytes, plasma cells, macrophages) and demyelina-
or short-lasting remissions, with a basic yet never tion. We might notice cellular infiltration even in
complete dissapearance of clinical signs and symp- the meninges.
toms. The flare up of the disease is usually associ-
ated with common cold, another infectious disease,
physical or psychological tension (stress, gravidity, 6.10.3 The acute haemorhagic leuko-
lactation, etc.). Patients with M.S. can not tolerate encephalopathy
an increased body temperature. The flare up of the
In this condition it is common to notice some tiny
disease might raise the plasma calcium level.
petechial hemorhage in the affected vessels mainly
The manifestation of the disease depend on the in the white mater. This condition is not always
type of CNS affection: the consequence of viral infection. The recent patho-
physiology of this process is pointing to the indirect
1. The cerebrospinal form (the most common, af- injury of myelin sheath by the viral infection, in other
fects the wole body). words there is an autoimmune reaction, where the
antigen is a part of the myelin and the virus (via
2. The spinal form (rare, mixed symptomatology). yet unknown mechanism) acts as a trigger for this
reaction. A very good model for this type of dis-
3. Cerebello-brain stem form (relatively rare). eases is the so called experimental alergic encephali-
tis (EAE) in animals. This relatively rare form of
4. Diencephalic form (rare, endocrinal disorders). encephalitis has got a great value for understanding
the pathophysiology of the demyelination diseases,
5. Polyneuritic form (rare, demyelination of the because it forms the transformation from viral infec-
peripheral nerves). tions to chronic demyelination diseases.

MS can be generally devided into 3 forms accord-

ing to the course of the disease: (1) an acute compli- 6.10.4 Experimental alergic encepha-
cated disease, that leads fast to death, (2) a chronic lomyelitis
disease without remissions and (3) a chronic disease
EAE belongs to the group of demyelination diseases
with some gradual small changes. A benign process
(depending on the pathomorphological substrate),
of MS is more common in patients with late man-
and hence to the group of neuroimmunological dis-
ifested disease, on the contrary the young patients
eases (depending on the pathophysiological mecha-
usually suffer a malignant course of the disease with
nism). It is a disease that is used in the experimental
prominant immobility.
modeling of the demyelination diseases in animals.
EAE can be brought up (produced) in experimen-
6.10.2 Acute disseminated encephalo- tal animals by injecting a homologous or heterolo-
myelitis gous nerve tissue. First who produced this condition
was Rivers in the 1933 in monkies post their 44 or
Acute encephalitis, in which the dominant and char- more times innoculation with rabbit brain extract.
acteristic sign is demyelination, it is a very rare In the year 1947 Kabat et al. prepared a mycobac-
complication of some viral infections and post vacci- teria (Freundďs) adjuvans, that in combination with
nation complications (e.g. chicken pox, rabies etc.). the nerve tissue antigen might provide surely and in
The clinical manifestations of the disease are fever, quite a very short time (only upon one or few in-
headache, vomiting, disturbances of consciousness jections) EAE. It is important to mention that the
that might end with coma. There might be some correlation between the effect of the adjuvans and
neurological signs of focal brain lesion. The patho- the human medicine is yet unknown. It was shown
logical changes include the whole brain (mainly in shortly after that, the extract from the whole brain
the deep structures of the white mater and pons) contains so many high molecullar weight substances,
and the medulla and their progression is fast. There that we canďt expect the reaction to occur with the
454 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

same substance all the time. Many of these anti- 5. The release of chemotactic factors, that attack
genically active substances do not have encephalitis other non sensitized leukocytes (a great sec-
generating effect. Finally it was found out that the ondary inflamatory reaction).
determinant protein is localized in the myelin.
Injection of the prepared antigen will provoke an EAE can hence occur when antibodies against the
imunne reaction, the consequence of which are histo- administred antigen also react with the same (simi-
logical changes in the brain of the experimental an- lar) CNS tissue antigenes.
imals. The clinical picture is apathy, paresis, paral- The possibility to transfer the EAE from an animal
ysis, loss of weight, incontinence, spasms and death. with an induced EAE to another healthy animal via
The immunological etiopathogenesis of the EAE is a passive transfer of the sensibilized lymphocytes has
supported by evidences since the 60 yrs: got a great value in the research of the demyelination
diseases.
1. The experimental animals will have signs of sen- EAE serves as a model to discover the etiopatho-
sibilisation after administrating the nervous tis- genesis of demyelination diseases. By this way it
sue extract. would be necessary to produce EAE that comes in
attacks, similar to the MS for example. Following
2. The disease will appear after 10 days of the day the formerly explainged method this is not possi-
of antigen administration. ble yet. EAE also helped in the classification of
encephalomyelitis into primary (infectious) and sec-
3. Upon reimmunisation the latent period is short- ondary (neuroimmunological).
ened

4. The reaction is very specific. The disease pro- 6.10.5 Dysmyelination diseases
cess occurs only after the administration of the
antigen that is present in the white mater of the In this group of leukodystrophies, the molecular
brain and medullary myelin. structure of the myelin is disturbed or namely dif-
ferent from the normal. Most of the cases has some
The immunological reaction is the delayed hyper- genetic basis, that manifest from the childhood and
sensitivity type. This reaction is manifested by the is very progressive. The abnormal or the disturbed
cytotoxic effect of lymphocytes on the antigen con- enzyme structure leads to the accumulation of dif-
taining cells. ferent metabolities in the macrophages, glia, or neu-
We conclude from the mentioned facts that EAE is rons. An example of this might be metachromic
an autoimmune disease, in which the hypersensitiv- leukodystrophy with the accumulation of sulfatids,
ity is experimentally induced by an encephalitogenic or Karbbes disease with the deposition of cerebro-
component of the nervous tissue (myelin). sides in the so called globoid cells (polynuclear histi-
ocytes).
The pathogenesis of EAE can hence be the sum of We often use the term diffuse cerebral sclerosis in
the following: those cases where the abscence of myelin is accom-
panied with a prominant gliosis.
1. Lymph node cells sensitization after the tran-
sition of antigen-adjuvans complex via the
lyphatic system form the infected site.

2. Circulation (possibly recirculation) of the im-

muno competent lymphatic cells via blood and 6.11 Degenerative diseases of
lymph.
the CNS
3. The entrance of the specifically sensitized cells
into the nerve tissue via the cerebral circulation.

4. The formation of contact with the target tissue A large group of diseases belong here. The com-
(oligodendroglia, and myelin). mon sign is the gradual degeneration of neurones and
6.11. Degenerative diseases of the CNS 455

axons of certain nuclei and nerve tracts. Those dis- there will be loss of equilibrium in the extrapyrami-
eases affect all parts of the NS from the cortex to the dal system due to the dopamine deficit. Dopamine
peripheral neurones. This group of diseases belongs belongs to a large group of mediators. Nowadays
to the genetically conditioned diseases. the original Daleďs principle do not apply any more:
one neuron one transmitter. It was proved that more
than one neurotransmiter might present in one cell.
6.11.1 Parkinson disease (paralysis Usually one transmiter has got multiple receptors
agitans) and hence the final result might be variable. This
situation might occur in substancia nigra in the neos-
Parkinson disease (PD) is a chronic degenerative dis- triate (extrapyramidal tract), where the glycinergic
ease of the CNS, that is characterized by the pro- neurons for example are inhibited by the dopamin-
gressing hypokinetic rigidity syndrom. In occurs in ergic tracts, and at the same time the dopaminer-
older ages over 50 yrs as an idiopathic disease and it gic tracts are under the inhibition of the gamma
is associated with some age related changes. aminobuteric acid system (GABA) of the corpus
As a secondary disease it is often associated with striatum. In the corpus striatum itself the glyciner-
a previous inflammatory (postencephalitic form) in- gic inhibitory circle on the contrary to the previous
jurious (repeated cerebral commotin) or toxic (neu- example, lies between the GABA-ergic and DOPA-
rotropic drugs, CO poisoning, Hg), damage to the ergic neurons. The disturbances of these bonds that
CNS. In case of toxic damage to the CNS it is thought are in equilibrium leads to an inadequate processing
that there is a disturbed balance of the brain neu- of information and hence to the disturbance of not
rotransmitters. The cause of which might even be only motor but also some cognitive functions.
the disturbed vascular supply of the brain (arteri-
The function of extrapyramidal motor regulation
opathy). The pathologicoanatomical substrate of the
lies in multiple junctions, control and feed back inhi-
PD is degeneration and atrophy of the extrapyrami-
bition to direct the movement. The feed back circle
dal nuclei, and mainly the cells of substantia nigra
might form even between the cortex, the basal gan-
and basal ganglii. There will be degeneration of the
glia (corpus striatum) and thalamus. Between the
nigral neurons , that lead to corpus pallidum, where
corpus striatum and thalamus the main neurotrans-
they produce dopamine. This is how the dopamine
mitters are acetylcholine and GABA (activation).
production in the basal gaglia is reduced and its in-
Substantia nigra plays an essential role here due to
hibiting effect on the transmission of neuronal im-
the formation of DOPA (inhibition), that helps to
pulses in the extrapyramidal tract that regulates the
modulate, and balance the programmed motor ac-
intentional and fine motor movements is eliminated.
tion. In cases of PD the destruction of the inhibitory
The extrapyramidal system joins the highest mo-
part of the pathway results in the overwhelming
tor centers (the cortex) to the effector motor cells
of cholinergic activity (tremor, rigidity, non coordi-
(the anterior horn cells) of the spinal cord. What
nated or even abnormal muscle movements), possibly
is left of the basal ganglia in the midbrain is the
akinesia.
pons cerebri and a joining complex between the basal
ganglia and other parts of the cerebrum, cerebellum The disease is clinically manifested with a mus-
and spinal cord. Its function lies in the facilitation cular tonus disturbances, the patient has a mask
and inhibition of the neuronal activity of the anterior face, sometimes with some grimases, the typical hand
horn cells so that it integrates the sensory impulses tremor and the typical finger movements known as
in a way that makes the tendon reflexes continuous pin rolling. The abnormal postural tonus is mani-
and coordinated. The most important neurotrans- fested with changing the center of body weigh (bend-
mitter in this system is dopamine (but also cate- ing) with a stiff, tong, dragging behind the lower
cholamines and 5-hydroxytryptamine), acetylcholin limbs when walking. Some neuroendocrine signs and
and gammaaminobuteric acid (GABA). dementia migh complete the picture of the disease.
In the healthy adults the dopaminergic and cholin- The treatment arises form the need to supply the
ergic extrapyramidal systems are in a state of equi- organism with L-DOPA as a precursor of dopamine,
librium. Due to the neuronal degeneration in the that is produced in the targed structures by the pro-
substantia nigra, where dopamine is formed, in PD, cess of decarboxylation. The problem is that this de-
456 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

carboxylation might occur in the peripheral tissues minium has been established and results from the
as well so it might exhaust the original substrate de- degenerating neurons releasing detectable amounts
termined for the CNS. That is why we give drugs of aluminium. Researchers have not yet been able
that inhibit the peripheral decarboxylase enzyme, as to isolate a virus that causes Alzheimer disease, but
an adjuvant therapy so less dopamine will be formed submicroscopic proteineous infectious particles ”pri-
in the peripheries and more L-DOPA might reach the ons” have been isolated. These prions have already
CNS. been linked to at least one other from of degenera-
PD therapy was one of the first areas of the CNS tive brain disease. Antibrain antibodies may account
pathology where neurotransplantation was applied. for Alzheimer disease, and an autoimmune etiology is
It is not true that the nervous system tissue do not also being investigated. Regarding a genetic etiology,
produce an immune reaction. The non prominant Alzheimer disease may be due to an autosomal dom-
immune reactions of the CNS in the normal situ- inant gene. An extra copy of a gene on chromosome
ations are due to the very low permeability of the 21 may be responsible for the production of protein
blood-brain barrier. Upon its destruction there will amyloid in cells from both patients with Alzheimer
be a whole series of diseases that have immunolog- disease and Down syndrome. Familial risk appears
ical basis. Despite this fact many transplantations to be greatest in families affected by the classic early
were provided for patients with PD. The transplant onset of Alzheimer disease. The risk when a sibling
should consist of tissue that is rich with dopamin- develop Alzheimer disease after age 70 does not differ
ergic neurons form the adrenal cortex. The results from that of the general population.
show that this therapy is not long lasting. Although Microscopically, the protein in the neurons be-
there will be some improvement post transplanta- comes distorted and twisted forming a tangle called
tion yet it is only temporary. We might decrease the a neurofibrillary tangle. There is an accumulation of
doses of drugs, yet the patients have to continue the these bundles of paired helical abnormal protein fi-
treatment with L-DOPA. bres (filaments) within the neurons. Groups of nerve
cells, especially terminal axons, degenerate and coa-
6.11.2 Alzheimer disease lesce around a fibrous core. These areas of degener-
ation appear like plaques under microscopy and are,
Alzheimer disease is a very commonly occuring neu- therefore, called senile plaques. These plaques dis-
rologic disorder. Formerly believed to occur mostly rupt nerve impulse transmission. Senile plaques and
in persons under 65 yrs of age, Alzheimer disease has neurofibrillary tangles are more concentrated in the
now been demonstrated to be one of the most com- cerebral cortex and hippocampus. The greater the
mon causes of severe cognitive dysfunction in older number of senile plaques and neurofibrillary tangles,
persons. Alzheimer disease is found in 2 % to 3 % the more dysfunction is present.
of the general population and in 5 % to 6 % of per-
sons 65 yrs of age or older. Presenile dementia of the 6.11.2.1 Clinical manifestation
Alzheimer type is a rare disorder in which persons,
typically in their 50s, develop a rapidly progressing Initial clinical manifestation are insidious and of-
deterioration in cognitive function. Senile dementia ten attributed to forgetfulness, emotional upset, or
of the Alzheimer type is the common disorder devel- other illness. The individual becomes progressively
oping in persons after the age of 65. more forgetful over time, particularly when related
Pathogenesis. The exact cause of Alzheimer dis- to recent events. Memory loss increases as the dis-
ease is unknown. Several possible causes are cur- order advances and the person become disoriented
rently under investigation. Alzheimer disease has re- and confused. The ability to concentrate declines.
cently been linked to chemical changes – a loss of the Abstraction, problem-solving, and judgment gradu-
enzyme choline acetyltransferase resulting in a selec- ally deteriorate. There is a failure in mathematical
tive deficit in acetylcholine in acetylcholine-releasing calculation ability, language, and visuo-spatial ori-
neurons. Alzheimer disease has also been recently entation. Dyspraxia may appear. The mental sta-
linked to the uninhibited activity of ribonuclease, an tus changes induce behavioral changes including ir-
enzyme that breaks down RNA in neurons. The link ritability, agitation, and restlessness. Mood changes
between the pathology of Alzheimer disease and alu- also result from the deterioration in cognition. The
6.12. Epilepsy (J. Holzerová) 457

person may becomes anxious, depressed, hostile, To understand epilepsy as a nozological unit one
emotionally labile, and prone to mood swings. Motor basic requirement is not fulfilled being one etiological
changes may occur if the posterior frontal lobes are factor. From the etiological point of view we may
involved. The individual exhibits rigidity (parato- devide epilepsy into primary and secondary.
nia) with flexion posturing, propulsion, and retropul-
sion. 1. Primary epilepsy, the cause of which was not
possible to determine yet using the recent di-
agnostic methods. It is a functional disorder
6.11.2.2 Evaluation and treatment
of the CNS, that usually has an electrophysio-
The diagnosis of Alzheimer disease is made by ruling logical correlation in the EEG recording. The
out other causes of a dementing process. A blood-cell neuroradiological examinations are negative. It
membrane aberation is currently being investigaed as forms about 75 % of cases. Using the modern di-
a biologic marker of Alzheimer disease. The history, agnostic methods the number of cases with pri-
including the mental status examination, and the mary epilepsy are decreasing and many cases are
course of the illness are used to diagnose Alzheimer diagnosed as secondary epilepsy.
disease. The course of the disorder is highly variable,
usually developing over 5 yrs or more. 2. Secondary epilepsy, or symptomatic, which
The treatment of Alzheimer disease is directed at cause is known, occurs in about 25 % of cases.
decreasing the need for the impaired cognitive func-
From the topographical point of view, nowadays
tion by a compensation technique, such a memory
we devide epilepsy into:
aids, maintaining those cognitive functions that are
not impaired, and maintaining or improving the gen- • focal epilepsy with a defined epileptic focus,
eral state of hygiene, nutrition, and health. Environ- most commonly in the cerebral cortex, and
mental management, counseling, education, pharma-
cotherapy, and health promotion measures are the • non focal epilepsy, centrencephalic, in which the
foundation upon which a comprehensive treatment epileptic discharge arises from the so called cen-
program is built. trencephalic area of the brain and then it is gen-
eralized.

6.12.1 The etiopathogenesis of the e-

pileptic attack
6.12 Epilepsy
The pathophysiological basis of the epileptic attack
is the epileptic discharge. There will be production
of pathological rhythmic excitation in a certain pop-
The term epilepsy includes a group of disorders of ulation of neurons. It is synchronized and it spreads
the CNS, that are characterized by repeated parox- in the nervous system form the area of its generation
ysmal changes of the nervous function caused by an either to a bordered area (partial attacks) or to the
abnormal electrical activity in the brain. Epilepsy whole CNS (generalized attacks). The basis of the
is usually manifested by changes of consciousness of epileptic discharge is a change of the neuronal meta-
a paroxysmal character, that are usually associated bolism, that is associated with a high energy expen-
by motor, vegetative, biochemical, and electrophysi- diture. As an evidence of this is the increased level
ological changes. of the adenosindiphosphate (ADP) and a decreased
According to the recent studies about 1 % of the level of ATP, a lower level of glucose, glycogen and
population suffers from reccurent epileptic attacks creatinphosphate, and the drop of pH in the blood
and it is assumed that about 10 % of people survives and the brain.
some form of an attack at least once in a lifetime. Three pathogenetic factors may share the mani-
Inheritance is thought to be an important factor in festation of the epileptic attack: the epileptic focus,
the formation or predisposition to the attacks, not in the readiness (predisposition) for epileptic attacks,
the occurance of the attack itself. and the epileptic stimulus.
458 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

6.12.2 The epileptic focus subdural haemotomes). The occurance of

epileptic focus is directly caused by the mechan-
The inactive centre of the epileptic focus is sur-
ical effect.
rounded by a transient zone, that consists of a patho-
logically changed neurons. Their bodies lack some • Post operative conditions (that follow brain
synaptic contacts. The astrocytes will degenerate surgery). The epileptic attacks are similar to
and fibrocytes will form instead, these are unable to those cases that follow meningocerebral scars.
fulfil the normal metabolic function. The dendritic
branching is reduced and synapses degenerate. The • Cerebrovascular
ratio between the excitatory and inhibitory synapses diseases. These are posthaemorhagic or postis-
is disturbed, where the inhibitory synapses are more chemic attacks, and rarely follow a congenital
vulnerable. The extracellular space will expand and arterio-venous malformations, and aneurisms of
such an affected tissue is a source of hyperactivity. intracerebral vessels.
What is characteristic for the autonomic activity of
• Chronic intoxications (organophosphates, alco-
the epileptic neuron is the persistant dendritic de-
hol, lead, etc.). These are caused by the changes
polarisation, that forms a potential gradient, that is
directed towards the depolarised site. This keeps the of the brain metabolism. The ethanol-toxic en-
neurons in a state of a continuous parital depolarisa- cephalopathy is the most common etiological
tion. Their excitability threshold is lowered. When cause of epilepsy that occurs after the age of
30yrs.
the current exceeds this treshold, there will be a high
frequency discharge, that will be manifested by the • Biochemical lesions. Based on experimental ob-
typical electrophysiological changes. The epiletic fo- servations we expect that the epiletic firing is
cus is mainly manifested in cases of focal epilepsy. caused by biochemical lesions of the neurons,
The etiology of epiletic discharge is multifactorial. that affect the depolarisation and polarisation
It is believed that the occurence of the epileptic dis- phase of action potential:
charge depends on exogenous factors (organic brain
damage) as well as on endogenous factors (biochem- • Disturbances of the eletrolyte metabolism
ical lesion of the tissue). We think that a disturbance of the Na+ and K+
metabolism is the basic change in the epilep-
Organic brain damage tic focus. Samples of human epileptogenic tis-
• Perinatal brain injury. Might be mechanical in- sues could show Na+ − K+ -pump dysfunction,
jury due to head injury, or due to changes of the i.e. an inability to renew the intracellular conce-
brain circulation of a local or general character, tration of the K+ and remove the Na+ from the
diffuse hypoxia upon changes of the placental or neurons. This means that during the epileptic
pulmonary ciculation. The most sensitive area activity there might be a higher release of K+
for the perinatal noxi is the hippocampus. from the cell and an increase of the Na+ level
intracellularly, this will initiate another depolar-
• Traumatic brain injury (commotion, contusion, isation of elements, the degeneration of action
intracranial haemorhage). Repeated micro- potential, and irradiation of the stimulus. The
trauma might be also manifested. Epileptic at- anticonvulsive drugs of the hydantoin type act
tacks can occur directly following trauma, or by stimulating the Na+ pump.
with some latency due to the effect of glial scar.
• Disturbanes of the oxidative metabolism
• Neuroinfection (encephalitis and meningitis).
Epileptic attacks in the acute stage can result The occurence of the epileptic attacks is caused
from brain damage by bacterial toxins, and the by hypoglycemia. In the interparoxysmal pe-
attacks that appear after the disease might be a riod it was proven that the activity of oxydase
result of some traction changes enzymes (cytochrom oxidase) was lower as well
as the enzymes for glucose metabolism (hexok-
• Expansive intracranial processes (benign and inase), and this might lead to a disturbance of
malignant tumors, brain abscesses, chronic and oxygen and glucose metabolism. These causes
6.12. Epilepsy (J. Holzerová) 459

might be genetically determined or might result • A high membrane permeability for excitatory
from the glial scars. Most of the antiepileptic substances
drugs stimulate the transport of glucose into the
In some epileptic foci we could prove a higher
tissues.
permeability of the blood brain barrier. The
• Disturbances of the amino acid metabolism dysfunction of this barrier leads to the accumu-
During glucose metabolism there is the forma- lation of folic acid in the area. Folic acid acts
tion of free aminoacids and mainly glutamic as an effective inhibittor for the back resorbtion
acid, glutamin and GABA (gammaaminobuteric of the glutamic acid, and the accumulation of
acid). Glutamic acid is an excitatory transmit- glutamic acid might lead into an epileptic tonic-
ter while GABA, glycin, and taurin act as in- clonic attack.
hibitory transmitter that transmits inhibitory
impulses. It was proven that there was a de- • Disturbances of the metabolism of biogenic
crease of the free aminoacids in all the epileptic amines
foci. The decarboxylation of the glutamic acid Monoamines are moderators of the stimulation
– excitatory factor will result in GABA forma- threshold in the epileptic loci and other struc-
tion that acts as a mediator in the inhibitory tures as well. In some types of epileptic loca-
brain synapses. In some epileptic foci there was tions we could find less noradrenalin endings
a disturbance or dysfunction of the decarboxy- than normal. An increased level of brain nora-
lase enzymes that might lead to the presence drenalin have a protective effect against spasms,
of insufficient amount of GABA and the forma- and its insufficiency increases the epileptic activ-
tion of a pathological membrane activity. The ity.
decarboxylase dysfunction might also lead to the
inhibition of the inhibitory effect of taurin, that Ischemia of the nerve cells as well as a higher water
is used successfully in the treatment of epilepsy. content and some other metabolic changes stimulate
the epileptic firing. All the mentioned metabolic dis-
• Pyridoxin deficiency
turbances are interconnected in a pathogenic chains,
Pyridoxin participates in the oxidative metabo- where it sometimes becomes very difficult to deter-
lism and in the metabolism of aminoacids and mine which one of them is the primary one.
mainly on the glutamic acid decarboxylation to
form the inhibitory neurotransmitter GABA.
6.12.2.1 Attack predisposition
• Intracellular excess of amoniak
For the development of epileptic attack it is impor-
This might be a case of overproduction, or a
tant whether the non injured neurons have the lia-
case of disturbed amoniak detoxication, or pos-
bility to be connected into a synchronized activity
sibly the combination of both mechanisms. The
and wether there are appropriate conditions for its
convulsive effect of amoniak is indirect, and its
effect is promoted by the gammaguanidinbuteric spread in the CNS. The attack predisposition is the
acid. liability of a certain population of brain neurones
for a synchronized automatic rhythmic activity, that
• Acetylcholine excess on the synaptic area might be caused by a permanent slight depolarisa-
Migh be the result of its overproduction, its over tion of the neuronal membrane, the insufficiency of
release or the inhibition of cholinesterase. the repolarisation mechanisms, and the inadequate
function of the feed back mechanisms. As a result of
• Abnormalities of the neuronal membrane the attack predisposition some abnormal potentials
The membrane composition is determined ge- from the epileptic focus will induce a synchronized
netically. We know those abnormalities that are activity in the surrounding healthy tissue (hypersyn-
due to changes of the phospholipids, changes of chronization phenomena). The predisposition for the
Ca+ binding to the membrane, all together with attack is mainly obtained in the nonfocal (centren-
a higher permeability and a higher Ca2+ entry cephalic) epilepsy. It is partially and constitutionally
to the cells. heriditary conditioned. It is influenced by multiple
460 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

factors e.g. level of consciousness, water and ion me-

tabolism, age, and endocrine factors. The predispo-
sition for epilepsy is the greatest in the first years of
life due to the brain tissue being immature and after
a transient decrease it raises again during the mat-
urance that is related to the endocrine variations.
During adulthood it is stable. It is influenced by
exogenous factors and different diseases. The pre-
disposition for the attack is affected by the attacks
themselves, because repeated epileptic attacks facil-
itate the generation of new attacks. This fact was
proven experimentally by a long lasting stimulation,
causes a permanent increase in the excitability after
a period of time in an originally healthy neuronal
population. This effect finally showed up as sponta-
neous impulses. This phenomena is called kindling.
The mentioned mechanism applies in the formation
of secondary mirror image foci, that maintain their
independance of stimuli generation even after the re-
moval of the primary epileptic focus. The spread of
the epileptic stimuli is related to the so called brain
modulating systems. These systems are capable of
influencing some special and relatively vast neuronal Figure 6.1: The etiopathogenic components of the
population and tunning them into a certain type or a epileptic proces: 1. cortical, focal, 2. thalamocortical,
certain level of activity. Electrophysiologically they 3. diencephalotemporal (according to Vasku et al.:
appear as a synchronized activity of wide brain areas 1984)
and that is why they are called the synchronization
systems. They have anatomical basis as well as some clinically it is manifested as forms of abscence
functional abilities to enhance or inhibit the spread of seizures or a generalized attack of the grand mal
epileptic impulses. In conclusion we see that to facili- type.
tate or irradiate the stimulation three etiopathogenic
factors might take place (Fig. 6.1). 3. Diencephalotemporal component, that is in-
fluenced by the hyperactivity in the second
1. Cortical focal component, that is a condition main synchronization diencephalotemporal cir-
for the existance and the activity of the epilep- cuit. The cause is usually traumatic, hypoxic,
tic focus in the neocortex. This etiologic factor or inflamatory that occured in the early child-
is mostly secondary in origin (trauma, vascu- hood. The EEG reveals some local abnormali-
lar disturbances, tumors). The EEG shows a ties in the shape of theta waves, localized tem-
cortical electrographic focus and clinically it is porally. This condition is clinically manifested
manifested with attacks of symmetrical spasms as psychomotor seizures.
with cortical aura.
6.12.2.2 Epileptogenic stimulus
2. The centrencephalic or thalamocortical compo-
nent that’s based on the hyperactivity of the The occurance of epileptic seizure needs apart from
modulating thalamocortical circle. The activ- the focus and a certain level of attack predisposition
ity is on its maximum during the puberty. It the presence of a third factor that is the epileptogen-
might be as well influenced by a genetic predis- nic stimulus. Such a stimulus might be represented
position or a metabiloc disturbance. The EEG by a sudden change in the endogenous or exogenous
shows bilateral changes that are symmetrical in environment (electric shock, and a visual or audi-
the shape of spike and wave complexes, and tory stimuli). The epileptogenic stimulus in man is
6.12. Epilepsy (J. Holzerová) 461

rarely the determining component of epileptogenesis. epileptic seizure and this process is called recruiment.
This is more frequently seen in animals (audiogenic The intact zone of neurons that surrounds the
epilepsy in rodents and photogenic epilepsy in mon- epileptic focus will form an anextremely inhibited
keys). Practically in man the most common reaction zone that surrounds the focal hyperactivity. This
we meet is reaction to light that is either discontinu- zone of neurons represents an obsticle that prevents
ous, with a rhythmically changing intensity, possibly the spread of the hyperactivity to the nearby areas,
an interchanging black and white plains (disco, water and only if this zone is dispensed the hyperactivity
surface, the sun between the tree lieves, TV, etc.). A might continue to spread. This theory is supported
very rare form is the reflex epilepsy where the seizure by the fact that if the focus lies in the cortex these
always occurs following the same stimulus. obsticle zones are always the cortico-thalamic junc-
tions, and the generalization of the attacks can occur
6.12.2.3 The neurophysical and the electro- only when it passes through thalamus.
physical substrate of epilepsy We assume that the generalization of the patholog-
ical hyperactivity from its primary focus demands a
The epileptic focus is a site in the CNS that is charac-
certain predisposition of the surrounding neurons to
terized by a hyperactivity or hypersynchronization.
conduct this hyperactivity. Their excitation should
It represents a neuronal network, that is prominantly
be very similar to the spikes generation threshold
excitable and the synchronized generation of spikes
(this means that the post synaptic potential must be
(action potentials) of single neurones is one of its
relatively similar to the critical potential), so that
characteristics. The cause of these characteristics
further excitation that spreads from the epileptic lo-
are changes in the architecture of the neuronal net-
cus can result in the generation of high frequency
work (the deficiency of the inhibitory neurones) and
spikes.
changes in the function of the focal neurones. The
functional injury of the neurones is proven by the re- This neuronal network state of function in the
sults of the scientific researches according to which vicinity of epileptic focus i.e. their attack predis-
the increased neuronal metabolism in the focus is not position, can be achieved with a certain type of af-
marely the result of hyperreactivity but partially itďs ferentation. It is well known that, some stimuli can
cause. From the electrophysiological point of view cause an epileptic seizure (e.g. some epileptic foci are
the changed physiological state of the focal neurons unblocked by a blinking light). The end result of this
will cause their characteristic repeated rhythmical situation is the spread of the hyperactivity to the cor-
hypersynchronized depolarisation. tex and the occurence of epileptic seizure. The syn-
The expressive synchronized activation is shown chronized activity of the epileptic focus usually lasts
on the EEG recording as typical high amplitude for 50 till 100 ms. If they last few seconds or minutes
spikes and hence spike and wave complexes. Between and spread to all the cortical areas, there will be a
the attacks the electrical activity of the focus neurons generation of a partial or a generalized attack. Af-
is characterized by a prominant depolarisation of the ter a certain time of this hyperactivity on a constant
non stimulated neuron membrane (the so called de- level there will be (and due to the feed back mech-
polarisation shift), that accompanies the generation anism ) a lateralized inhibitory junction that leads
of spikes. into neuronal inhibition and the attack (seizure) is
After the depolarisation shift, hyperpolarisation ended. Another theory explains the ending of the
will occur and the production of action potential will seizure that it happens because of the exhaustion
stop. It seems that apart from the inhibition zone in of the energy supply and reserves of the neurons and
the vicinity of the focus there is also inhibition in their resulting inability to generate action potentials.
the focus itself, despite the fact that this inhibition Another important neurophysiological aspect of
is charecterized by a certain latency. If the popula- epilepsy is the synaptic conduction that becomes
tion of neurons transforms into the state of seizure, modified by a repeated synaptic activation (the post
the inhibition will be lost and replaced with depo- tetanic potentiation phenomena). The more often
larisation. The shooting of spikes by the neurons the synapse is activated the more conductive it be-
will hence last for long. The neurons in the vicinity comes. Upon activating the synapses by a patho-
are activated and by this they become a part of the logical activation there will be some fixation of this
462 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

activity. The vicinity of the epileptic focus will then • Jacksonian epilepsy is manifested with focal
become easily depolarized and tends to become one (partial) attacks with a simplex symptomatol-
of the epileptic functional parts. This mechanism ex- ogy. A cortical spread of the discharge might
plains the occurence of the so called a mirror image occur, yet it remains sectorally limited. If the
loci in the contralateral hemispheres in those areas discharge comes to affect the precentral gyrus,
where synaptic junctions with the primary focus are it will then manifest clinically as a typical Jack-
located. sonian motor epilepsy. The spasms begin in a
Theoretically we might think that personality small localized area of the body (face, upper,
changes of some complicated cases of epilepsy can or lower limb) and it gradually spreads to the
be apart of other causes, a result of the mentioned homolateral half of the body. When the at-
pathological changes of the synaptic conduction in tack finishes, there might be a temporary pare-
the cerebral cortex. sis in the affected areas, so calld Todd paralysis.
The localization of the discharge in the postcen-
tral gyrus is manifested as a Jacksonian sensory
6.12.3 Classification of the epileptic epilepsy with the typical spread of unpleasent
seizures dysesthesis. The person remains conscious.

The symptomatology of the epileptic manifestation

is quite variable. The evaluation of the epilepsy
development and the appropriate causative ther- • Psychomotor attack. One of the focal (par-
apy largely depends on the accurate classification tial) attacks with a complex symptomatology.
of the attacks. The recent clinical practice basi- The epileptic focus is localized in the temporal
cally depends on the Gastout Classification, that lobe, in gyrus hippocampus or amygdala. The
was accepted in 1969 by The international associ- discharge spreads to the centrecephalic struc-
ation against epilepsy. It depends on the pathophys- tures and to other parts of the brain, includ-
iological theories of the occurence and development ing the limbic system, that is the main mor-
of epilepsy with some insight into the clinical, elec- phological substrate for the demonstrated af-
trophysiological and developmental aspects. ferentation and the vegetative function of the
organs. It is closely related to the phylogenet-
ically younger structures of the cortex, as well
6.12.3.1 Focal epilepsy as the brain stem. This explains that the mo-
tor and sensory symptoms of the attack are ac-
Focal (parcial) epilepsy is usually secondary in ori- companied by vegetative, affective, and instic-
gin. Its causes might be variable: perinatal trauma, tive manifestation. The psychomotor attack has
head injury, neuroinfection, brain tumors, circula- got the widest symptomatology of all forms of
tory disturbances of the brain, etc. The discharge epilepsy. It usually begins with a gastric aura,
most commonly occurs in the cerebral cortex, most that is described as a hardly defined feeling in
often in the temporal lobe and it is related phy- the epigastrium. The attack itself is manifested
logenic older structures (amygdala, hippocampus). with different mechanical automatism – moving
The EEG record shows an evident focal discharge the mouth, licking, smacking, swallowing, un-
that is composed of either rhythmic or nonrhythmic dressing, opening the buttons running around,
sharp waves and some localized discharges of spikes walking around etc. that are accompanied with
and slow waves in the vicinity of the epileptic fo- psychological manifestation (illusion of the seen
cus. There might be a focal simplex seizure (with- before, the feeling of depersonalisation, dreamy
out loss of consciousness), a complex seizure (with states, attacks of depression, etc.). The EEG
loss of consciousess), or a group of seizures with a occasionally shows some tonic spikes. The po-
focal character in the beginning that later on trans- tentials range between 4–7 Hz in frequency, it is
forms to the generalized form (secondary generalized the so called theta activity. The psychomotor
seizures). Every focal attack can transform to a gen- attack is associated with cloudy consciousness
eralized one. and amnesia.
6.12. Epilepsy (J. Holzerová) 463

6.12.3.2 The non-focal epilepsy • Petit mal. Small seizures, petit mal, occurs
mainly in children. The classical petit mal is
In cases of the non focal (centrencephalic) epilepsy manifested in three forms which are absency pe-
the discharge originate in the central brain structures tit mal, myoclonic petit mal and akinetic petit
(in the centrencephalic area), from where it general- mal.
izes. These are primary generalized seizures, and
they differ from those secondary generalized attacks Absency petit mal is characterized by a sudden
in that they are generalized from the very beginning short lasting disturbance of consciousness, that is
of the attack. The sudden involvement of both hemi- manifested with a discontinuation of the previous ac-
spheres is shown as loss of consciousness and symet- tivity. The child suddenly stares infront of him and
rical mechanical manifestations. Compared with the does not react. There might be some attacks of blink-
focal epilepsy the non focal epilepsy is mostly caused ing sometimes with deviation of eye bulbs or possi-
by an increased attack predisposition. bly some grimase with the mouth. After regaining
the consciousness the child returns to his previous
activity. The EEG recording shows bilateral syn-
• Grand mal. Lay people imagine a grand epilep- chronized and symmetrical discharges in the form of
tic attack under the term epilepsy, the so called spikes and waves of a high amplitude and a frequency
grand mal epilepsy. It seems very dramatic. It of 3 Hz. There is complete amnesia after the attack.
starts with a sudden deep loss of consciousness The number of such attacks might be very high per
and the patient falls on the floor, this could day.
be accompanied by an abnormal scream due Myoclonic petic mal (impulsive petit mal) occurs
to tonic spasm of the respiratory muscles that in puberty. It is manifested by a short lasting and
pushes the air out of the lung. In the tonic phase relatively strong grimases mainly of the upper limbs,
there will be a generalized spasm of the striated and neck. They occur unilaterally and symmetrically
skeletal muscles. The limbs will transform from either individually or in clusters. The EEG record-
a short lasting initial flexion into extension, the ing shows complexes of multiple spikes and one slow
head will be in opisthotonic position. The ini- wave. There is no loss of consciousness.
tial palor will be replaced with cyanosis due to Akinetic petit mal (Lennox syndrom) affects
a short stop of breath. The pupils are mydriatic mainly children in the preschool age. It is mani-
with a negative photoreaction. After about 30 fested with a sudden flexory myoclonic contraction,
seconds the attack starts its clonic phase, that and loss of postural tonus, so the patient falls down.
is characterised by symmetrical rhythmic mus- The loss of consciousness is only temporary.
cular spasms of the whole body. After about 2 Infantile spasms (propulsive petit mal) occur in
minutes the spasms start to relief and become the early childhood before 6 months of age. These are
slower till they fade away. Due to the spasm clinically manifested as a sudden spasms (a sudden
of the muscles of the larynx the patient breaths flexion of the head, neck, or the limbs), or as salaam
with difficulty and a frothy sputum flows out spasms (a slow flexion of the head with crossing the
of his mouth, it could be bloody if the patient upper limbs on the chest) that reminds the oriental
bites his tongue. The patient might urinate. greeting. The EEG recording shows some irregular
The EEG recording shows generalized rhyth- synchronized discharges in the form of spikes as well
mical bilateral synchronized and symmetrical as, sharp and slow waves.
sharp waves of high amplitude, and frequency
of 100 Hz. In the post paroxysmal phase the 6.12.3.3 Status epilepticus
patient is extremely tired, in deep coma, swet-
ting and breaths with difficulty and stridor. The Is a serious complication of epilepsy. The epilep-
patient does not respond to spoken words nor tic seizures are repeated continuously one after an-
to painful stimuli. After the patients gain their other, during which the patient remains unconscious
consciousness they are usually confused , disori- and does not regain consciousness between the at-
ented and often aggressive. They have complete tacks. Attacks of the grand mal type the patient life
amnesia about the attack. is threatened. Death might occur due to heart at-
464 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

tack or brain edema. Status epilepticus rarely occur them develop an epileptic attack even without phar-
in other types of epilepsy (Jacksonian status epilep- macological interaction upon auditory stimulus. The
ticus, status psychomotorius, and status petit mal). reason of this audioepileptogenic disposition in rats
is yet unknown. It is interresting that upon extripa-
tion of the auditory and motor areas from the cere-
6.12.4 Experimental epilepsy bral cortex, or even a complete decorticalisation can
Experimental epilepsy on animals is characterized as not prevent the occurens of audiogennic attack.
a motor reaction that is disproportional to the given The manifestations of audiogenic epileptic attack
situation. In psychological conditions the nervous in experimental animals are very much similar to the
stimuli that occur upon the stimulation of the nerve attack in human. Adversive syndrom of head and
endings spread in a precisely defined tracts to sub- eye bulbs deviation to one side, with a simultaneous
cortical and cortical areas in the CNS. In the place occurence of tonic and clonic spasms might occur in
of the analyzor there will be stimulation that is bor- the grand mal type. Akinesis accompanies the petit
dered by inhibition. After processing the stimuly are mal form. This similarity of signs enables us to use
conducted to afferent pathways and the result will be animal models not marely for demonstration but also
an organic cousative reaction – so called reflex. Any for the study of epileptic attacks.
error in the interfunctioning processes of stimulation
and inhibition in the brain leads to a non coordinated
simultaneous spread of stimuli via many pathways in
different directions, as a result of this, there will be
an epileptic seizure. 6.13 Disturbances of the oxy-
An epileptic attack in animals could be evoked by: gen supply to the brain
• electric current (electroshock)
An adequate supply of oxygenated blood to all
• pharmacological and metabolic substances
parts of the nervous system is a condition for its
(e.g. setting metabolic alcalosis in rabbits)
normal function. The most sensitive parts of the ner-
• focal brain damage (freezing of brain tissue in vous system to oxygen defficiency are the most spe-
dogs, electrocoagulation of brain tissues in mon- cialized ones – especially the cerebral cortex. The
keys) blood supply of the brain comes via the common
carotid artery and the internal carotid artery as well
• audiogenic and photogenic stimuli (audiogenic as the vertebral artery. Both supplied areas are inter-
epilepsy in rodents and photogenic epilepsy in connected via the posterior cerebral artery that will
monkeys). complete the circle of Willis. This is how the distur-
bances of blood supply can be compensated by one
The model of audiogenic epilepsy in rats demon- of these vessels. Those compensatory mechanisms
strates an epileptic seizure and the possibility of are favourable mainly in the pathological conditions,
pharmacological alternation of the resulting func- they are more efficient in young age.
tional state of the nervous system. The cerebral circulation depends on many factors:
It is well known that the organism responds to the perfusion pressure of the brain, blood viscosity,
unexpected or intensive sound by motor reaction. the characteristics of the cerebral blood field.
This is a phylogenic old unconditional orientation The perfusion pressure is determined by the differ-
reaction, that predisposes the organism for flight or ence between the mean arterial and the intracranial
fight. A rat that lives in dark environment most of pressure that represents the venous pressure and the
the time has a very developed auditory organs (the interstitial pressure of the brain tissue. Upon a de-
rat hears in the region between 22 Hz – 100 KHz). It crease of the arterial pressure, and hence an increase
is extermely sensitive to tones of high frequency and in the venous pressure (disturbed outflow, stasis) or
intensity. About 90 % of the infantile rats react to upon an intracranial hypertension the blood supply
light by a marked motor restlessness, and some of is worsening.
6.13. Disturbances of the oxygen supply to the brain (M. Bernadič) 465

Similar to the mentioned the increased blood vis- Cerebral ischemia may resulted from sudden drop
cosity that is manifested as a higher requirement for of the blood pressure in systemic hypertention – we
the cardiac function and a worse tissue perfusion, in- are talking about a transient ischemic attack, that
cluding the brain. When the blood viscosity is high can lead to a transient loss of cerebral function that
(e.g. when the content of proteins is high, in cases lasts for about 24 hours. In more coplicated cases
of dehydration and blood concentration). The flow there might be vascular occlusion due to thrombo-
of blood is slower and the possibility of vascular ob- cyte aggregation on the injured endothelial lining of
straction (e.g. thrombosis). the aterosclerotically changed vessels. A change in
The cerebral vascular field maintains a consider- the thromboxan prostacyclin ratio plays an impor-
able ability for autoregulation of the blood flow. The tant role. More than 80 % of the vascular attacks
basis of the autoregulation are changes of the pCO2 , are abstructive in type and only 20 % are vascular
H+ , and K+ inside cells of the vascular smooth mus- ruptures with haemorhage.
cle. An increase of pCO2 and a decrease of pO2 lead In cases of a gradual decrease of pO2 (e.g. upon
to vasodilitation of the cerebral vascular field and climbing up high attitudes, pulmonary edema, cere-
hence the blood flow can be doubled. On the con- bral aterosclerosis) in the early stages there will be
trary a decrease of pCO2 and an increase of pO2 lead some psychological tiredness, disturbances of mem-
to vasoconstriction and here the flow is decreased. ory, lengthening the reaction time, and later loss of
This autoregulatory ability is related to the state of consciousness and spasms.
the vascular smooth muscle and that is why it is dis- A continuous supply of oxygen and glucose to the
turbed in cases of arteriosclerotic changes and that brain,and to neurons is necessary because brain tis-
is manifested by disturbances of the cerebral blood sue can not form reserves of these substrates.
flow.
Cerebral hypoxia can be caused not only by low 6.13.2 Localized ischemia
pO2 due to low cerebral perfusion (anoxia and is-
chemia) but also due to other extracerebral ex- In localized ischemia, that might be caused by
travasal or extracardial causes. One of those causes thrombosis or emboli of the cerebral vassels or their
are lower pO2 in the inspired air. Anoxia caused by branches, vascular compression, brain edema, tumor
ischemia is moreover accompanied with disturbances pressure or haematoma there will be some localized
of nutritional supply of the brain (mainly glucose) necrosis (malacia) in the region supplied by the af-
and metabolite conscription. fected blood vessels. Reminding you that cerebral
One of the most serious causes of brain damage vessels are terminal and that is why an alternative
is the hypoxic (anoxic) syndrom and localized is- supply via collaterals can not be provided.
chemia. When the oxygen supply to the brain is inadequate
we have to realize its relationship with other systems.
In the first place the determining factor is the cere-
6.13.1 Hypoxic syndrom
bral blood flow and the oxygen content of the blood.
In cases of hypoxic syndrom the CNS function is dis- The cerebral perfusion is determined by the cerebral
turbed in relation to whether it is acute disturbance perfusion pressure and the characteristics of the cere-
of the blood supply, or a gradual slow decrease of bral vascular system. The oxygen content of the
cerebral tissue perfusion. Acute hypoxia occur ei- blood depends on the Hb concentration and hence
ther due to external causes (e.g. disturbed oxygen the blood ability to carry oxygen as well as the par-
apparatus), or due to internal causes (e.g. ventricu- tial O2 pressure. Cerebral hypoxia can result from
lar fibrillation, heart failure, shock). A sudden cere- conditions that cause hypotension (cardiac arrest,
bral hypoxia is manifested as loss of consciousness shock, heart failure etc.), increased intracranial pres-
(syncopy). If the oxygen supply or vascular supply sure (edema, expansive pressures), vasoconstriction
lasts for more than 5 min (according to the situation (aterosclerosis, emboli, malignant hypertension), as
the time length might be shortened or lengthened well as factors that affect the oxygen circulation in
for few min) there will be irreversible changes of the the organism (anemia, acute or chronic haemorhage,
neurons (necrosis), its functional disturbance occur pulmonary diseases , chest diseases, that lead to the
much earlier. failure of ventilation).
466 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

According to the type of cerebral oxygen supply emboli from the sloughed atheromatous plaques
disorder there will be some localized changes that in the region of the internal carotid artery.
usually occure upon short lasting and mild decrease
of pO2 , or generalized (diffuse) injury, that might 2. Arterial stenosis. Commonly occurs in cases of
be the result of a total disorder of oxygen supply atheromatosis, because atheroma causes a tur-
to the brain. In this relation, it worths mentioning bulant blood flow in the area of narrowing and
that similar neuronal injuries can also occur in acute there will be some disturbance of the vascu-
hypoglicemia, and barbiturate or CO intoxication. lar anastomosis among the neighbouring areas
and blood vessels. Despite of all that its not
necessary that an atheromatous narrowing it-
6.13.3 Hyperoxic syndrom self should always result in infarction. The in-
One of the disturbances of O2 supply to the brain in farction usually occurs when a central cardiovas-
which brain damage occur due to an increased pO2 in cular insufficiecy contributes to the narrowing.
the brain. It follows inhalation of pure O2 under high The cerebral infarction usually occurs upon low-
pressure (e.g. upon treating CO poisoning). There ering the blood pressure during sleep, or when
might be syncopy, nausea, blurred vision, epileptic the blood pressure decreases in cases of shock
attack. The mechanism is unknown. We suppose or myocardial infarction. One of the less com-
that a high pO2 results in vasoconstriction and low- mon causes of the brain infarction is dissecting
ering of glucose supply and hence a slower metabolite aneurism, arteritis and very rarely it could be
wash out that leads to the injury of nerve cells. caused by vascular spasm.

Hypertensive patients have a higher risk to de-

velop cerebral infarction, that is indirectly caused
by speeding up the development of arteriosclerotic
changes and formation of atheromas. In these cases
6.14 Cerebral infarction there will be formation of large and small cerebral
infarctions, as well as dementia that is conditioned
by arteriopathy. In cases of malignant hyperten-
sion there might occur the so called hypertensive en-
The basic cause of brain (cerebral) infraction is cephalopathy. The pathomechanism of its occurence
failure of oxygen supply to the brain (as well as is a very fast raise of the blood pressure that conse-
failure of glucose supply). The infarction is in the quently leads to disturbed cerebral circulatory au-
area supplied by a terminal vessel. The most com- toregulation. There will be a focal dilitation of the
mon cause is a local disturbance of the blood flow small vessels, an injured endothelial lining and a dis-
via vessels (occlusion), yet it is very common that turbance of the integrity of vascular wall that leads
a central cardiovascular failure contributes to these to protein leak into the interstitial space (together
disturbances of perfusion.The result will be necrosis with the erythrocytes),that might end up with brain
of all tissues supplied by the terminal vessel. edema. This condition is clinically manifested with
The pathophysiology of the occurence of infarction some neurological signs, spasms, supor till coma.
can be summarized as follows: Papillary edema of the optic nerve is always a sign
risk factors – disturbance of perfusion – infarction of an increased intracranial pressure.
(ischemia, necrosis). The clinical picture differs according to the af-
As we already mentioned, there is commonly a lo- fected site. The injury might affect any area of the
cal arterial occlusion or stenosis. brain yet some areas and localities are more com-
monly involved. The most vulnerable area is the
1. Arterial occlusion is usually caused by thrombo- area of the so called end arterioles in those areas
sis on the atheromatous plaque or embolization that lack collaterals. The cerebral cortex is relatively
(mostly cardiac – atrial fibrilation – endocarditis protected by a rich network of vascular collaterals.
– intramural thrombus that follows myocardial The injury is common to occur in the area of the
infarction). Small infarcts can result from small medial cerebral artery and mainly the end arterioles
6.15. Intracranial haemorhage 467

that supply the area of basal ganglia and capsula in- and mainly its bifurcation to supply the basal gan-
terna. The cerebral tissue changes that occur due to glia and the internal capsule, the haemorhage might
age are multiple such as microemboli that result in also occur in pons and cerebellum. The course is
microinfarction with the following reduction of cere- usually sudden (acute), from complete health, the
bral function. This type of cerebral atrophy is a very patient develops headache, diziness and hyperten-
common cause of senile dementia in our population. sion commonly accompanies these conditions, the
The greatest loss of function occur directly follow- haemorhage will procede very fast. There will be
ing the occurence of infarction. During this period an intracranial hypertension CNS functional disabil-
the situation is worsened by brain edema and dis- ity, unconsciousness and death might occur. If the
turbance of the cerebral vascular supply (ischemia, haemorhage is localized, the manifestations will be
hypoxia, hypoglycaemia, etc.) A large infarction is less dramatic. There might be variable degrees of
associated with loss of consciousness. Whithin few dysfunction (paralysis according to the locality of the
days, when the infarct is organized, macrophages will haemorhage). Intracerebral haemorhage always runs
appear in the area, there will be the formation of the typical course and usually spills into the ventric-
new capillaries, the edema ceases, and the area of ular space or the subarachnoid space.
functional dissability dicreases. The compensation In cases of untreated hypertension, the pressure
of the lost functions is one of the characteristics of in the brain capillaries might increase resulting in
the brain tissue. However, this compensation might altered vascular wall permeability. This is how pro-
require few weeks and commonly maximal rehabilita- teins, erythrocytes and other intravascular compo-
tion. A complete clinical renewal of the lost functions nents reach the brain tissues and brain edema might
is possible in cases of small infact only. occur. We are talking about microhaemorhages into
the brain tissue. The common end result of this
process is the gradual necrosis of brain tissue and
the formation of the hypertensive encephalopathic
symptomatology.
6.15 Intracranial haemorhage The risk of intracranial haemorhage is higher in
patients suffering from hypertension by about 7-
folds. The pathomechanism arises from the fact
that in hypertensive patients the blood pressure is
A spontaneous intracranial haemorhage (IH) is markedly raised in small arterioles with the result-
very rare to occur. Usually there is a local vascu- ing degeneration of the vascular wall. This might di-
lar abnormality, that is manifested incases of hyper- rectly lead to wall rupture and hence the formation
tension. A number of IH cases occur in cerebral of aneurism and its following rupture. The promi-
tumors, systemic diathesis and arterio-venous mal- nant pulsation of these arterioles leads to the com-
formations. pression of the surrounding tissues (excavation), and
a small perivascular space will be formed (lacunes).
Basically, the intracranial haemorhages are dev- The vascular wall loses its back up that also leads to
ided into two groups: its weakening.
1. Intra cerebral haemorhage
6.15.2 Subarachnoid haemorhage
2. Subarachnoid haemorhage.
Subarachnoid haemorhage is the most common man-
ifestation of sacular aneurisms that are situated in
6.15.1 Intracerebral haemorhage
the area of circle of Willis. The basic cause is a con-
Intracerebral haemorhage occurs in middle aged pa- genital malformation of the elastic constituent of the
tients suffering from hypertension. They often have vascular wall. The aneurism is rare to be manifested
microaneurisms on the small of the cerebral arter- during birth. The size of the aneurism can vary from
ies. A direct cause of haemorhage is rupture of 1–2 mm till 1–2 cm. However not all aneurisms cause
one of these aneurisms. The haemorhage commonly haemorhage. The incidence increases with age. The
occurs in the region of medial cerebral artery – aneurism can rupture directly into the brain tissue
468 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

and there will be intracerebral haemorhage. When of memory, new memory and disturbance of the int-
bleeding into the subarachnoid space the intracra- electual functions. This gradual disorientation wors-
nial pressure increases and the perfusion worsens. ens progressively and relatively fast and hence the
Some regulatory machanisms are activated and these stage of complete dementia can develop within few
will provide the adequate amount of oxygen supply years. The wide variability of manifestations of the
to the brain. In the area of haemorhage vascular clinical picture points to the fact, that these changes
spasm might occur and this might lead into a sec- are not marely related to age. There is probably
ondary brain infarction. In this case the infarction some multifactorial process. We suppose that a com-
is a complication of the original disease. Examina- mon incidence is related to a high incidence of car-
tion of the cerebrospinal fluid reveals blood and pink diovascular diseases. Even in those diseases many
supernatant that remains after centrifugation due to heriditary factors as well as factors of the external
erythrocyte haemolysis. After 24 hr. xanthochro- environment could be more accurately specified.
mia appears (yelow discoloration of the CSF due to
degeneration products of the blood).

6.17 Infections
6.16 Aging changes and brain
tissue atrophy CNS infections are in comparison with infections of
other localities very rare diseases. The course of CNS
infection can be asymptomatic with some minimal
pathological changes (e.g. viral infections), yet the
We know that brain tissue atrophy begins in the course of the infection might be very difficult and
3rd decade and the morphological changes of the may lead to a permanent dysfunction and death.
brain tissue are associated with aging. The brain Generally we devide the infectious diseases of the
volume decreases by 2–3 % for every 10 or 20 years CNS according to their localization into two groups,
and by about 100 g wt from the 30th year of age. those which can cross the barrier formed by pia
Its necessary to mention that these results were col- mater, such as diseases of the meninges (meningi-
lected from many studies and still they donďt con- tis, empyema and abscess), and those diseases affect-
tain a wide scale of variability in relation to individ- ing the brain tissue (encephalitis and abscess). The
ual characteristics, life style, geographical and other etiopathological agents are usually bacteria, viruses
conditions. and mixed infections.
Macroscopically the brain of older people is smaller
(the normal weight is about 1380 g in men and 1204 g
in women), the arachnoid mater is thicker with a 6.17.1 Bacterial infections
higher number of granulations, the subarachnoid 1. Infections that usually spread via blood. Very
space is thickened, the gyri are narrow and on the common infections to occur this way are infec-
contrary the sulci are wide (normally itďs the oppo- tions in the area of subarachnoid space (menin-
site). The most important microscopic aspect is the gitis) that can be pyogenic (e.g. meningococci,
reduction of neocortical neurones, as well as the re- pneumococci and haemophilus), and granulo-
duction of the number of Purkinje cells layers of the matous (e.g. tbc, treponema pallidum). If the
cerebellum and the motor cells of the spinal cord. In bacteria sett directly in the brain tissue a brain
cases of senile dementia (as well as in cases of senile abscess will form, that could be of two types
Alzheimer dementia) these signs are very marcable. (pyogenic – mixed infection, staphylococcal in-
Yet if the dementia occurs in any age, itďs always fection, or granulomatous – tuberculotic).
accompanied with degenerative or atrophic changes
of the brain. 2. Infections that cross the blood brain barrier due
Dementia is clinically manifested with disturbance to the distruction of the protective tissues (dis-
6.17. Infections 469

truction of the skin or the bony cover, fructures, bacterial endocarditis. The brain pathology in this
infections). In this case we usually have a pyo- case is only a part of the general systemic infection.
gennic infection. According to the existence of
distruction and the entrance of infectious agents 6.17.2 Viral infections
to the wound there might be the following re-
sults: The viral infections of the CNS are rather rare if com-
pared with the general viral infection. Viruses with
(a) extradural abscess higher affinity to the CNS, are called neurotrophic
viruses. Generally they couse three types of infec-
(b) subdural abscess (empyema)
tion:
(c) meningitis.
• acute (cellular injury accurs before the end of
the viremic phase of the infection. It is the com-
The spread of infection to the cranial cavity can be
monest type of infections)
a very grave complication in cases of untreated pyo-
genic infection of the middle ear (otitis media), or the • persisting (viruses that apart from the CNS
cavity system involvement of the mastoid bone. The cause tissue injury, and their behaviour in the
infection spreads to the bone, and penetrates into CNS is atypical, the active affection of the CNS
the dural spaces (meningitis, infectious thrombosis appears later – months or years)
of the lateral sinus) and hence to the whole brain tis-
sue with consequent abscess formation. In cases of • slow (viruses of this group are not yet classified,
purulent meningitis, the whole subarachnoid space is and after a long period – years – they cause a
filled with purulent exudate, that is concentrated in fatal disease).
the brain base and fills the gyri. This inflammation The last group mentioned contains the so called
in its early stages does not injure the brain tissue it- latent viral infections (e.g. herpes zoster), to which
self, and an early effective treatment usually leads to we relate the accurence of demyelination diseases.
complete healing (primam intentionem). When un- Viral infections have a great role in the oncogenesis
treated or upon a non effective treatment some seri- of the CNS.
ous complications might appear, that might be some The site of entry of the viruses to the organism
cranial nerve injury, hydrocephalus, and brain tissue is usually the gastrointestinal tract (enteroviruses),
injury. The inflammation is diagnosed by examining the nazopharyngeal mucous (meningococci), and an
the cerebrospinal fluid. interrupted skin cover. Viral multiplication usually
Pyogenic brain abscess is the result of direct accurs outside the CNS tissues (e.g. in the lymphatic
spread of the infectious agents into the brain tis- tissue). The viruses reach the CNS via a haematoge-
sue (haematogenous spread, bronchiactesis, and a di- nous spread (viremia). Yet in case of rabies the virus
rect etry). The abscess that results from a wound, reaches the CNS via the peripheral nerves, and the
has usually got less marked clinical symptomatol- site of entry is a wound (usually where the sick an-
ogy. The original wound might heal together with imal bites the person). Factors that potentiate the
the local inflammation far before the abscess is man- accurence of the disease in the CNS are yet unknown.
ifested. The abscess is usually covered with a pyo-
genic membrane. Further development might be to-
wards healing (scar formation) with the possible re- Some clinical notice about the viral infections of
sulting functional changes and dysfunction (includ- the CNS:
ing epilepsy), or towards a gradual development of 1. The infection is usually mild, affects the
the disease stage, that is manifested with the devel- meninges (aseptic meningitis), the recovery is
oping local edema around the abscess that might in- complete, with no residuals.
crease the intracranial pressure and the abscess rup-
ture into the ventricular system of the brain or the 2. When the course of the disease is severe there
subarachnoid space that leads to the development of will be an associated injury of the nervous tissue
meningitis. Other complications of the staphylococ- of variable degrees (encephalitis, meningoen-
cal infection might be microabscesses of the brain, or cephalitis). Examination of the CSF reveals
470 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

mononuclear cellular infiltration (lymphocytes, The destruction is usually unilateral, and it is sur-
plasma cells, mononuclears), protein, glucose. rounded by aseptic meningitis. Some serious compli-
The brain tissue shows a perivascular infiltra- cations might occur in this phase due to the paralysis
tion and some acutely destroyed neurons due of respiratory muscles, upon the involvement of the
to inflammation (neuronal lysis, inflammatory bulbar motor centers.
changes). In certain cases we might observe Paralysis occur in the reversible stage of the dis-
some neuronal inclusions that might be either ease and if the course is mild there might be a com-
nuclear or cytoplasmic. Together with the men- plete recovery. The neuronal destruction and degen-
tioned changes there might be changes of myelin, eration will continue together with gliosis and atro-
glia, and small haemorhages. The viruses cause phy.
injury either directly or indirectly. The virus – The irreversible stage is the result of some mor-
antibody complexes, cause the vascular inflam- phological changes, destruction of the anterior horn
matory reaction. motor neurons (scar, thinning of the anterior roots),
The clinical manifestations in aseptic meningi- that is manifested as muscular affection (neuropathic
tis are as follows: the disease is mild, mild fever, muscular atrophy) and some deformities of limbs (the
headache and stiff neck, the healing is always com- pull of nonaffected muscles is not opposed by the pull
plete. of the affected muscles).
In case of meningoencephalitis the signs of CNS
irritation appear and the neuronal injury manifests
6.17.2.2 The group of herpes viruses
itself as some mental dysfunction, disturbances of
consciousness, spasms and coma. There might be Herpes zoster – is an infection of the aduts, that
some signs of local tissue destruction (neurological affects one or more unilateral dermatomes (in the
symptomatology). If the course is mild, a complete course of a certain nerve). There will be a forma-
recovery might result yet in some severe cases there tion of painful vesicles. This is actually a recurrent
might be some residual paralysis, or other sings of a varicella infection. The virus is in its latent form
permanent injury of the cerebral tissue. In some rare from the childhood. The virus is usually located
conditions there might be paralysis of the respiratory in the posterior root ganglia. It might be activated
center and death might occur. by trauma, radiotherapy, immunological defect etc.
After the infection flares up (ganglionitis) the virus
6.17.2.1 Enteroviruses slides via the sensory nerve fibers to the skin, and the
mucous membrane of the mouth or conjectiva where
Entroviruses are small RNA viruses (picornaviruses,
it starts its replication. The virus can be isolated
coxackie viruses, and echoviruses). Infection occur
from the vesicular content. It should be mentioned
after ingesting food that is contaminated with feces
that there might be some mild secondary degenera-
of infected individuals. The virus is replicated in
tive changes in the spinal cord. In some cases and
the GIT. It is rare for this virus to cross the blood-
after the end of the acute stage there will be paras-
brain barrier and cause CNS infection. Polioviruses
thesia that lasts for variable period or anaesthesia
(sometimes even the coxackie and echoviruses) cause
in the region of injury. When the 5th cranial nerve
the classical paralytic diseases – poliomyelitis. The
(trigeminal n.) is affected there might be some seri-
pathophysiological development of this disease can
ous visual disturbance.
be devided into three stages:
Herpes simplex – even this virus can cause a mild
1. The acute phase (up to 2 weeks) aseptic meningitis in some cases. Only in rare cases
it might cause an acute necrotizing encephalitis, and
2. The reversible phase (few weeks or months) here it mostly affects the temporal lobes. It usually
3. The irreversible phase. appears in cases where the immunity is defficient, yet
in many cases the ocurence of infection could not be
In the acute stage the viremia is manifested with explained. Due to the fact that 100 % of population
fever. The virus has a high affinity towards the mo- is infected by this virus we relate it to a very common
tor neurons in the anterior horn of the spinal cord. vascular disease – atherosclerosis.
6.17. Infections 471

6.17.2.3 Rabies inflammation present. We have to mention that the

disease is transmitted by an agent that is resistant
The rabies virus has got a very strong neurotropic
against the common physico – chemical factors that
attraction. The disease generally affects mammals.
usually destroy viruses.
The carriers of the disease are different types of wild
This disease is very similar to Creutzfeld-Jackob
carnivorous (wolf, fox, dog, etc). Most of the rabies
disease in men. Some cases of this disease were reg-
cases in man are those following a dogs bite. The
istered in middle Slovakia, too. The slow viruses
virus enters the body at the site of bite from the
were discovered by the american virologist and pedi-
dogďs saliva via the interrupted skin (wound). In
atrition of Slovak origin Charleton Daniel Gajdusek
the portal of entry there will be local viral replica-
(born in 1923). He received a Nobel price for his
tion and the incubation period will start. The incu-
discovery in the year 1976.
bation period varies from 1–2 months till up to 12
months. The viruses travel along the sensory nerves
to the ganglia and spinal roots, and from here they 6.17.3 Infections with yeast and fungi
progress to the CNS. Only when the nerve roots are
1. Primary CNS fungal infections are very rare in
affected and hence the CNS is affected the disease
human being. Some localized infections appear
manifestations will appear. Viral encephalitis affects after a longlasting and intensive exposure to
the cerebral gray mater. A diagnostic sign of the
a massive infection. In cryptococcal infections
disease is the presence of the viral inclusions (negri
(cryptococcus neoformans) the infection shows
bodies), that are located in the pyramidal cells of
neurotropism and causes meningitis.
the hippocampus and the Purkinje cells of the cere-
bellum. Encephalitis is clinicaly manifested as an 2. Opportunistic infections increase in their fre-
extreme excitation of the sensory system. There will quency of occurance due to the common use of
be the classical hydrophobia (fear from water) due to immunosupressive treatment. Many fungi in-
spasms of the deglutition muscles and disturbance of cluding Candida and Aspergillus nocardia can
swallowing reflexes. Death occurs due to the spasm cause a serious brain damage due to abscess for-
or paralysis of the respiratory muscles. mation.

6.17.2.4 Lethargic encephalitis (post ence- 6.17.4 Protozoal infections

phalitic Parkinsonism)
6.17.4.1 Cerebral malaria
Lethargic encephalitis occured in the form of epi-
demy in the year 1920. Despite we still do not know Brain complication can appear following a heavy
the real cause, we suppose it was a viral encephali- acute form of malaria (falciparum), that affects non-
tis. The unique fact about this disease was that the immune individuals. This disease progresses very
inflammation affected substantia nigra of the basal fast to a lethal end. Here there will be a massive
ganglia and there were some permanent results – the affection of the erythrocytes by the parasites, that
development of Parkinson disease. will cause haemolysis, anemia and a heavy brain hy-
poxia. This brain hypoxia might also develop as a
6.17.2.5 Infections with slow viruses result of the thickening of the endothelial lyning of
the brain capillaries with the consequent low cere-
An example for this type of infection is kuru (sub- bral perfusion. During autopsy the brain tissue is
acute spongioform encephalitis). This infection oc- edematous with petechie (haemorhage). Histologi-
curs in the eastern parts of New Guinea and it is cally we might see capillary congestion, plasmodium
related to canibalism. The disease is manifested as malari and pigmentation (free or phagocytosed in the
a progressive cerebral ataxia and it is always fatal. macrophages).
What is important in the pathological finding is the
presence of neuronal degeneration and the abscence
6.17.4.2 Toxoplasmosis
of astrogliai proliferation, that will result in the for-
mation of small cystic areas in the gray mater of the Even though infections with Toxoplasma gondii is
brain (spongiosis). It is very interresting that is no relativly common, the affection of brain tissue is
472 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

quite rare. It occurs in two occasions, always as

a part of a systemic infection (in cases of congeni-
tal toxoplasmosis and opportunistic infections of the 6.18 Nutritional, toxic, and
adults).
The primary infection in the gravid women ap-
metabolic dysfunctions of
pears as a mild fever, and enlargement of the lym- the brain (encephalopa-
phatic nodes, as well as some other clinical manifes-
tation. T. gondii can affect the intrauterine devel-
thies)
oping foetus. According to the stage of foetal devel-
opment the disease might cause discourage, heavy
brain destruction as well as the destruction of other In the end cosequence most of these diseases are
tissues with the consequent foetal death, or foetal caused by abnormal neuronal metabolism, so it is dif-
brain destruction and chorioretinitis, that are com- ficult to make an accurate classification. Despite that
patible with life, but with a permanent physical af- we might devide those diseases into three groups:
fection of the child.
The opportunistic infection of the adults is not 1. Diseases caused by nutritional disturbances.
always manifested after the contact with the infec-
tious agent. Toxoplasma gondii for example survives 2. Diseses caused by the effect of extrinsic (exoge-
inside the cyst till the flare up of the disease. This re- nous) toxic substances.
activation can occur in cases of disturbed immunity,
immunosupressive treatment, Hodgkin disease, etc. 3. Metabolic injury of the nervous system that is
Systemic infections here always lead to a localized secondary to other diseases.
meningoencephalitis.
6.18.1 Diseases caused by nutritional
6.17.4.3 Amoebiasis disturbances
Amoeba only rarely cause CNS diseases. Practically Vitamins of the B group are well known coenzymes
we know only two types of diseases: of many intracellural oxidative events. Their def-
ficiency, that might result from a primary malnutri-
1. Brain abscess – often complicates the course of
tion (usually related to alcoholism), is the main cause
collitis or hepatitis caused by Entamoeba histo-
of degnerative changes of the brain tissue, spinal
litica.
cord, and peripheral nerves.
2. Meningoencephalitis caused by free living amoe- Wernicke encephalopathy belongs to this group.
bas, that are not usual pathogenes for man It is clinically manifested by disturbances of atten-
(Naegleria and Hartmannella). They reach the tion, ataxia, and visual disturbances, without an im-
CNS from the water, where they could be in mediate and effective treatment it will progress fast
high concentrations, e.g. when swimming, div- and cause death in coma. Alcoholism and mainly its
ing, these microorganisms enter the body via chronic form is a serious problem of many countries
the nasal cavity and the cribriform lamina. The – similar to the case in Slovakia. Chronic alcoholism
intracanial infection is usually fatal. is related to the disturbance of normal nutrition that
by itself leads to vitamin B defficiency, and mainly
thiamin. The nutritional disturbances are accentu-
6.17.5 Metazoal infections
ated by alcoholic vomiting. The pyruvate level in the
The important agent of this group is cysticercosis. blood raises. Lesions such as glial proliferation and
Larvae of Taenia solium, that can reach CNS, form neuronal absence appear in some typical localities –
cysts and made some complications (intracranial hy- along the 3rd ventricular wall, along the aqueducts
pertension, edema) or even epilepsy. and on the base of 4 ventricle. We might find some
small haemorhages.
The prevention of further progression is done by
thiamin intake. Yet if the treatment is inadequate
6.18. Nutritional, toxic, and metabolic dysfunctions of the brain (encephalopathies) 473

or late, it is not possible to prevent the permanent function (hepatic enzyme defect of many
brain injury. types). The nervous system injury is not
always primary, and this is a non specific
6.18.2 Diseases caused by exogenous disease of the nervous system.
toxic substances (b) hepatolenticular degeneration (Willson
disease) in this relativly rare disease there
The nervous system is very sensitive to a number will be accumulation of Cu, that has got
of different substances, poisons, heavy metals, and some serious toxic effects. This is an au-
pharmaceutics that are commonly used in medicine tosmal recessive disease, in which there is
(e.g. hypnotics, and narcotics). a primary lysosomal defect in the hepatic
In many acute situations the metabolism of neu- cells. Most patients have low levels of
rones is prominantly blocked and can lead to cellu- ceruloplasmin. The proper relationship be-
lar death. The most common is cerebral hypoxia, tween the deficit of ceruloplasmin and the
and hence metabolic disturbances of the brain cells primary deficit of the liver enzymes is yet
caused by the injury of other organs, which function unknown. We suppose that there might be
is necessery for the provision of adequate function of some abnormalities of the feedback inhibi-
the brain tissue. So from this point of view it seems tion with the ceruloplasmin deficit that will
that it is very hard to determine the primary cause cause a deficiency in Cu absorbtion (low
of many types of brain tissue injury. Cu: ceruloplasmin ratio).
The end results of the primary effect are mainly
biochemical changes and only minimal or no mor-
phological changes. During autopsy we might find
6.18.3 Secondary conditioned meta-
non specific edematous and hypoxic changes. Spe- bolic injury to the nervous sys-
cific changes are usually not present. In some cases tem
there will be changes in the peripheral nerves – neu- First of all we have to mention that, the CNS me-
ropathies. In alcoholism it is hard to document the
tabolism can be affected by a disease in any other
direct toxic neuronal destruction, but it is probable
system of the organism.
that the brain is suffering from a nutritional deffi-
Acute hypoxia and hypoglycaemia cause distur-
ciency due to liver dysfunction. bances in the basal metabolism of the neurones and
This group includes the metabolic diseases, that a serious disturbance might continue even after the
are discussed elsewhere. A group of congental
removal of the main cause. In many other diseases,
metabolic abnormalities (dysfunction and distur-
the neuronal injury is commonly reversible, apart
bance of lysosmal enzymes:
from cases that were long lasting. In the last cases
1. Demyelination diseases (leukodystrophy) in there will be a permanent affection of the nervous
which there is an abnormal metabolism of the system in the chronic stage of the original disease.
central nervous system cells, that form an ab- The mechanism in these cases is usually not well un-
normal myelin. derstood or defined – it is usually indirect and it
contains:
2. Diseases that deposit substances in the neu-
rones, this group is manifested in the first 1. Disturbances of water and electrolyte balance
decade of life. Due to the defficit or desturbed (mainly Na+ and K+ ) as well as changes in the
lysosomal enzymes there will be accumulation pH, that have a prominant effect on the neuronal
of metabolites or metabolic products in the neu- enviroment.
rones. The diagnosis depends on the histochem-
2. The effect of abnormal (toxic) metabolites,
ical determination of the accumulated product.
e.g. ketones, organic acids (including amino
3. Metabolic diseases that affects the nervous sys- acids), directly disturb the neuronal metabo-
tem together with other organs: lism.
(a) aminoacidopathies – a wide scale of ab- 3. The changes mentioned above as point 1. and 2.
normalities, that mostly affect the hepatic have a negative effect on the chemical transmis-
474 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

sion of stimuli in the synaptic junction of the on the membranes. Those ionic changes will disturb
nervous system. the transmembrane action potentials in the active
cells, and the transport of nutrients across the mem-
The mentioned disturbances might occur in those brane is surpressed. When the level of ethanol in
cases for example: blood is high (0.2 %) the function of airobic oxydase
1. Cases of diabetes mellitus, where the most se- is supressed mainly in the Liver and myocardium,
rious disturbances are usually worsened by the the ATP turnover is lowered, Creb’s cycle becomes
effect of other disturbances, these are hypov- slower, and this will lead to disturbances of glucose,
olemia (due to dehydration), hyperosmolarity lipid, and protein metabolism.
(due to hyperglycemia), Na+ , and K+ depletion, The largest portion of alcohol is absorbed in the je-
ketoacidosis, and lactoacidosis. junum, yet it also passes via the oral mucosa, esoph-
agus, stomach, and the large intestine. When the
2. In cases of hepatic failure – and mainly due to stomach is empty the absorption is much faster. 2–
disturbances of NH3 and amino acid metabolism 10 % alcohol is excerceted in an unchanged form from
(see hepatic failure) . the lungs, the kidneys, and by sweat glands. Alcohol
is metabolised into acetaldehyd via three pathways,
3. In cases of renal failure (uremia) – there will be
and this takes place in the liver:
a whole complex of disturbances that lead to wa-
ter balance disturbances, electrolite balance dis- 1. Cytosol alcohol dehydrogenase is a non specific
turbance and disturbances of metabolite excre- enzyme that contains Zn. It needs a coenzyme
tion (see renal failure). Moreover renal failure NAD, that is reduced into NADH+. Any change
is usually accompanied by malignant hyperten- in the hepatic membrane polarization, and this
sion, that leads to some neurological dysfunc- will depress gluconeogenesis.
tions.
2. The microsomal ethanol oxygenase system
6.18.4 Ethanol (MEOS) is usually activated when a high level
of alcohol is reached in the blood. The reac-
6.18.4.1 The mechnism of action of ethanol tion requires NADPH that will produce NADP.
metabolites In alcoholic people the activity of MEOS is in-
creased by induction.
Ethanol molecule is weakly ionized, and can easily
pass via the biological membranes. Ethanol can very 3. Catalase needs H2 O2 for the reaction to occur,
quickly reach a state of balance between blood and and this is a limiting factor for its activity. It
organs. The effect of alcohol depend on the quantity only slightly participates in the metabolism of
used. The level of ethanol in the blood is expressed ethanol.
in centiles (promile). Ethanol in higher doses de-
presses the CNS functions, where as in low doses it The product of all reactions is acetyldehyde, that
causes agitation. It is action is similar to other seda- is a substrate for the enzyme aldehyde dehydroge-
tives, e.g. benzodiazepins, barbiturates, yet it dif- nase. It is a ubiquitary non spesific enzyme. It
fer from the others by that the psychopharmaceutics could be inhibited by disulfiram. An inborn defi-
bind a special membrane receptors, whereas ethanol ciency of the mitochondrial fraction occur in some
acts on all membranes. It increases the fluidity of Chinese and Japanese. This is why manifestation of
the phospholipid fraction of the membrane, where acetaldehyde intoxication occur in them upon taking
transmethylation takes place. In cases of chronic al- a very small amount of alcohol. (And even their hab-
coholism the amount of cholestrol in the membrane bits are formed accordingly, they consume wine in
wall increases and this will equilize the higher fluidity very small amount from a 0.03 l glasses). The prod-
caused by ethanol. This mechanism is most probably uct of the reaction is acetate, that is metabolized in
responsible for the developing tolerance to ethanol. the Crebďs cycle into CO2 and H2 O.
The effect of ethanol on the membrane structure will The behavioral changes upon alcohol abuse are
change the membrane permeability for Na and K, caused by acetaldehyde, and the organic changes
and this will decrease the stabilization effect of ions upon the parenchymal organs.
6.19. Tumors of the nervous system 475

6.18.4.2 Changes of behavior, tolerance, de- Chronic abuse of alcohol causes peripheral neu-
pendance ropathy in 5 upto 15 % alcoholics. The cause is prob-
ably thiamin deficiency and acetaldehyde. Patients
The most important problem of ethanol intake is the complain of parasthesia and burning feeling in all
problem to ditermine the maximal daily dose that limbs, especially the peripheral parts.
could not cause dependance nor organic or personal- A serious complication of alcoholism is Korsakof-
ity changes. According to Ontario Research Fonda- fďs syndrom. It develops in people with an inborn
tion an alcoholic is a person who uses what is equiva- defect of transketolase. Patients with Korsakoffďs
lent to 150 ml absolute alcohol daily (2.5 dl destilate, syndrom show a retrograde and anterograde (disabil-
or 7.5 dl wine or 5 bottles of bear). ity to learn) amnezia, comfabulation (and hence fill
According to specialists ”the safe” daily dose the defect in the past events, and they believe their
ranges between 60 up to 100 g absolute alcohol, re- own stories), are emotionally labile. Their intelec-
minding that a long term use of such a small amount tual ability is not always affected. Some alcoholics
also causes organic changes. We should not for- are suffering from cerebellar degeneration. The ner-
get that there is an interindividual variability that vous cells in the cerebellum die due to the toxic effect
is very important in the tolerance to alcohol. Af- of ethanol and acetaldehyde. Vitamin deficiency is
ter 1–2 weeks of regular alcohol use the tolerance another co-factor.
increases by 30 %. Ethanol has a caloric value of Not only cerebellar neurones are affected by
7.1 kcal (30 kj)/g. This enables the coverage of the ethanol and acetaldehyde. The decreasing brain vol-
daily caloric need with alcohol drinks. Yet their bio- ume is manifested by an increasing volume of the
logical value is minimal, because they do not contain brain ventricles, and the development of alcoholic
minerals, proteins, nor vitamins. Ethanol lowers vi- dementia. The old doctors used to say that alco-
tamin absorbtion (mainly vitamin B) in the small hol is the greatest pretender, and in chronic alcohol
intestine and hence cause its deficiency. Thiamin de- abusers we might register all forms of psychological
ficiency is responsible for Korsakoffďs syndrom. diseases e.g. dementia, depression, all forms of psy-
In cases of chronic ethanol abuse (probably due choses, states of hallucination, and paranoid cases.
to membrane disturbances) the ionic distribution is
changed. The level of K+ , Mg+2 , Ca2+ , Zn+2 and
P in the serum is lower. And the level of Na+ in
the serum is increased because the Na+ will flow
out of cells. The acid base balance might be dis-
turbed as well in term of acidosis. The intake of a 6.19 Tumors of the nervous
higher amount of ethanol might cause a transiet hy- system
poglycemia within 6–36 hours. Due to the ethanol
effect on gluconeogenesis. The hypoglycemia effect
of alcohol is potentiated by poor nutrition. This is
why alcoholic patients might develop disturbed glu- Brain tumors can grow directly from the brain tis-
cose tolerance after few days of abstinance. sue, mostly from the microglial cells, from the cra-
nial nerves, or from the brain coverings (meningi).
6.18.4.3 The effect of ethanol on central ner- Tumors that arise from the brain tissue usually infil-
vous system trate the surroundings, and there are no defined bor-
ders between the tumor and the healthy surround-
Upon a single use of a high dose there will be some ing tissue. Tumors that grow from cranial nerves
changes in the behavior that depends on the ethanol are called neurinomes and those arising from the
concentration in the blood and organs. A very low meningi are called meningeomes. They cause pres-
concentration promotes sleep and shortens the REM sure on the brain tissue, increase the intracranial
sleep before midnight, and after midnight the dreams pressure and in some localizations they might block
are multiple and nightmares might appear. In some the cerebrospinal fluid circulation, and it will accu-
individuals ethanol might cause fragmetation of sleep mulate in the brain ventricles. This is how the in-
the so called frequent waking up. tracranial pressure is raised and brain edema might
476 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

develop, some signs and symptoms due to local dys-

function of some brain centers or pathways might
appear. Apart from this there will be some general 6.20 Injury of the spine
signs (headache, vomiting, blurred vision). When
the frontal lobe is involved by a tumor process there
will be some psychological changes, if the parietal
lobe is affected there will be epileptic seizures to- The primary pathological process plays role in the
gether with the psychological changes. Attacks of anatomical and functional outcomes of the spinal in-
spasm and paralysis on the contralateral side oc- jury. There is no space to compensate the pressure
cur when there is a tumor in the temporal lobe. or volume changes and this has got a very serious
When the occipital lobe is affected, some visual dis- outcomes. An example of this might be fructure or
turbances will appear (scotomes in the visual field.) dislocation of spinal vertebra, a tumor (usually sec-
Expansive processes in the posterior cranial cavity ondary) that expands into the the spinal canal, disc
is manifested with cerebellar and cranial nerves dys- prolapse, or meningeal tumor that causes compres-
function. Some characteristic signs and symptoms sion of the nervous tissue.
accompany hypophysial tumors, craniopharyngeo- The spinal cord is very similar to the brain tissue,
mas, and vestibular nerve neurinomes that could be the anterior and posterior roots as well as the ves-
diagnosed by the charecteristic bony changes. Apart seles are freely situated in the watery enviroment of
from the histological classification of tumors into be- the cerebrospinal fluid. Upon compression there will
nign and malignant we have to think about some be some injury to the nervous and neuronal path-
malignant tumors due to their position when deal- ways and the extension of this injury depends on the
ing with brain tumors. seriousness and time length of the compression. The
Tumors of the spinal cord can arise directly from injury might be in the mild cases only focal, yet in the
the spinal tissue. They either grow inside the spinal complicated cases there might be a transverse lesion
cord (intra medullary tumors) or they grow from of the spinal cord – a complete discontinuation of the
the spinal nerves or spinal cord coverings (extra spinal cord. The vascular compression leads to tissue
medullary tumors), or they might arise from the infarction, and there might be an extensive injury to
vertebral column (extra dural tumors). The extra the nervous tracts and pathways with the consequent
medullary and extradural tumors compress the spine loss of function. This is commonly a complication of
from outside. Metastatic tumors (most commonly in mechanical injury. Upon compression there will be
ca lung, ca prostate, renal carcinoma, tumors of the some traction of tissue and coverings that can cause
thyroid gland, and the ca brest) usually grow from a secondary injury to the spinal roots for example.
the outside into the spinal coverings (extradurally) . This might result in radicutilis and spondylosis. At
Tumors of the spine are manifested by backache that the level of the lesion connections between the sen-
commonly radiate along the spinal nerves and their sory and the motor fibers will be discontinued, those
enervation sites. Spinal compression will reveal some connections form the spinal reflex arch. According
motor disturbance of the limbs (paraparesis paraple- to the extent of injury there might even be a com-
gia, quadriparesis, or quadriplegia), disturbances of plete discontinuation of the longitudinal spinal tracts
sensation and disturbances of sphincter function. Be- and hence disturbance in the regulatory effect of the
nign tumors of the spine appear on x-ray due to their brain on the regions below the lesion. There will
pressure changes, while the malignant tumors show be mascular paralysis and a loos of sensation below
distructive changes. the lesion. Spinal reflexes below the lesion are not
affected.

6.20.1 Ascending and descending de-

generation
Long axons that are disconnected with their bod-
ies will undergo progressive degeneration. Upon a
6.21. Diseases of the motor neuron 477

transversal lesion of the spine all the long tracts de- axons and their coverings and hence results in dis-
generate upwards (sensory tracts) and dawnwards turbances of transmission.
(motor tracts). The most common example of a In both cases i.e. upper motor neuron and lower
descending degeneration is the condition following motor neuron lesion (UMNL and LMNL) the clinical
brain infarction in the area of internal capsule. The picture will reveal paralysis, yet there are some im-
degeneration spreads from the lesion along the cor- portant changes that differ in their quality and spec-
ticospinal axons till their terminals in the anterior trum of the present reflexes in both the mentioned
horns of the spine. After a period of time we might cases. When the lesion is in the upper motor neuron
register this degeneration in the form of demyeli- (central paralysis) the lower motor neurons will es-
nation along the whole corticospinal tract. Those cape the control of the higher centers so the muscle
changes actually involve the whole pyramidal system. tonus will increase, the tendon and other spinal re-
After a long time there will be gliosis and scarring of flexes are increased, and the extensory (Barbinsky)
the tissue. reflex will appear. This is why we call this type of
paralysis the spastic type. Following a lower motor
6.20.2 Injury of the motorpathways neuron lesion there is actually an error in the con-
nection to the effector, so the reflexes are absent, and
The division of motor neurons and pathways into the there will be muscular atrophy. This type is known
upper motor neuron (UMN) and the lower motor as the hypotonic paralysis.
neuron (LMN) based on anatomical and functional
characteristics has got a great clinical and diagnostic
value.
The upper motor neuron is formed of the corti-
cal motor neurones (the precentral gyrus), the motor
pathways in the brain that (pass through the internal
6.21 Diseases of the motor
capsule), motor pathways in the brain stem (where neuron
decussation of tracts on to the contralateral side take
place) to meet the cranial nerves of the contralateral
side. This crossing takes place in the pyramidal de-
cussation, where the anterior corticospinal tract (non Are usually of unknown etiology. They appear
crossed) is separated from the pyramidal tract (being more frequently in adult patients and mainly in men.
the crossed part of the motor pathway). The basic lesion is a progressive degeneration of the
The lower motor neuron is composed of the carnial cortical and the spinal motor neuron, that will be
nerve nuclei (the motor nuclei) and their axons in the manifested by their dysfunction. The variability of
carnial nerve fibers, as well as the anterior horn cells symptoms depends on the ratio of affected upper mo-
with their axons in the spinal nerves. It is important tor neuron to the affection of the lower motor neuron,
to realize that during the long course of the motor and on the site of the clinicial lesion. The evaluation
neuron from the cerebral cortex till the anterior horn of this ratio is possible in the initial stages of the dis-
of the spine represent the upper motor neuron and ease when the changes are bound to a certain local-
this could be injured by multiple disease processes. ization, but later on there will be a diffused affection
The lower motor neuron can be injured in the spine, of tissue and here the differentation becomes much
as well as in the peripheral nerves. harder.
The most common cause of injury to the UMN is A progressive muscular atrophy is the main sign
hemorhage in the area of internal capsule, different of neuronal atrophy (mostly due to lower motor neu-
levels of this pathway could be involved in cases of ron injury) due to the degeneration of neurons in
multiple sclerosis or in case of other diseases that the anterior horn. This degeneration worsens within
cause demyelination of the motor from the cortex many years, and the cells will become necrotic. Signs
till the spinal cord and its segments. and symptoms of the initial stages appear within (1–
A typical example for LMN injury is poliomyelitis 4) years and are manifested as the affection of fine
that affects the motor neurons in the anterior horn of movement of the fingers, their fasciculation, later on
the spine, or a peripheral neuropathy that destroys the muscles of the hand will be affected, and at last
478 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

the muscles of the arm and sholder will be involved. Neuropathies – this term is prefered more than
The spread of dysfunction is towards the spine. Only neurities, because most of those diseases are not in-
in the progressive stages there will be paralysis of the flammatory in type. We might devide them into
lower limb muscles as well as the upper limbs – here parenchymal and interstitial.
it is a lesion of both upper and lower motor neurons
In parenchymal neuropathies the axon and the
(the period around 5–6 years from the beginning of
myelin sheeth are the primary affected parts (the
illnes).
myelin sheeth is composed of Schwann cells). Most
In cases of amyotrophic lateral sclerosis the main
of those diseases are consequences of toxic and nerve
affected neuron was the upper motor neuron. The
fibers – polyneuropathies. According to the etiology
so called lateral sclerosis means the degeneration of
we can devide those diseases into:
the pyramidal tracts and the cortical motor cells are
involved as well. The lesion will be manifested with 1. toxic (diphtheria, arsen, some drugs)
motor disturbances of the limbs and from the early
stages, disturbances of muscles of the face and neck. 2. current (e.g. beri-beri due to vit B deficiency)
The corticospinal tract will gradually degenerate and
3. metabolic (diabetes mellitus, porphyria, meta-
gliosis will appear. Only in rare cases there is a pure
chromic leukodystrophy in some malignancies,
injury of the upper motor neuron. When the disease
uremia).
progresses there will be a consequent lesion of the
lower motor neuron. Degeneration can be of two types: first of all af-
fects the axon with the consequent demyelination
(similar to the Wallerian degeneration upon neu-
6.21.1 Progressive bulbar paralysis
rotmesis) or there will be a primary degeneration of
and pseudobulbar paralysis the Schwann cells with the consequent axonal degen-
Lower motor neuron lesion with fasciculation and at- eration. The diseases might of course affect only one
rophy and upper motor neuron lesion without muscu- nerve, or one group of nerve fibers. In interstitial
lar atrophy. In these diseases and as shown from the neuropathies the blood vesseles and connective tis-
headline the condition is worsened by the progressing sue are the primary part affected (epineurium, per-
degeneration of the motor neurons. A critical con- ineurium and endoneurium). In this type of diseases
dition occurs when the bulbar nuclei are involved, only certain types of nerves or nerve groups can be
and as a result of this the organism is unable to re- affected according to the type of the disease. The
move the secretions from the respiratory tract, and most common is neuropathy. Nerve fibers can be
there will be an aspiration bronchopneumonia and injured during their compression. The most com-
sometimes there will be an acute asphyxia. mon cause of injury is ischemia. The carpal tunnel
syndrom is an example, where the median n. is com-
presed between the carpal bones and ligaments. The
cranial nerves are vulnerable to injury in cases of in-
creased intracranial pressure, and this might end up
with their degeneration. The degenerative ischemic
changes of the nerve fibers can occur due to arteritis.
6.22 Peripheral nerves No neuronal changes occur in the area of vasculitis,
yet those changes present in the area supplied by this
vessel (below the vasculitis). In the area of neuronal
degeneration, the inflammatory changes are not al-
Peripheral nerves can be classified into different ways present.
groups according to some criteria – e.g. into myeli-
nated and non myelinated fibers, according to nerve
thickness, into sensory and motor etc. In most dis-
eases all those groups are affected, but we know some
diseases that are selective for certain types of nerve
fibers.
6.23. Neuromuscular diseases 479

well. There is a shortening and smoothening of the

postsynaptic membrane and widening of the synoptic
6.23 Neuromuscular diseases grove. Commonly there is arborization of the nerve
endings, that leave the failing synaptic junctions, and
search for a new contact along the muscle fibers.
The pathomechanism of the disease is connected
This is a large group of diseases, that are mani- to the motor end plate – the transmission of nervous
fested with disturbances of skeletal muscle functions. stimuli into the skeletal muscle. The transmission of
The cause of which lies in the injury to a part of neu- nervous stimuli is disturbed due to the abnormalities
romuscular unit. The region of the primary lesion is of ACH in the neuromuscular junction. The release
the determinant factor for the clinical symptomatol- of ACH from the vesicules of the presynoptic neu-
ogy, and this is why we devide these diseases into 4 ronal endings depends on the depolarisation of the
groups: presynoptic membrane by the effect of action poten-
1. myopathies (muscular dystrophy) tial, due to which Ca2+ influx activates the presy-
naptic vesicules. Those vesicules will difuse into the
2. neural atrophies (primary affection of the pe- synaptic space and ACH will be released into this
ripheral nerves, secondary muscular atrophy) space. After the depolarisation ends, the Ca2+ is re-
leased fast into the terminal ending, or it might be
3. atrophy of the ganglionic cells (affection of the absorbed by the mitochondria. The destiny of the
neuromuscular cells) released ACH is either:
4. diseases of the neuromuscular plate (muscular 1. Acetylcholin esterase (ACHE) is present in the
dysfunction). grove and hydrolyses ACH into acetate and
Most of the diseases of this group have genetic and cholin, and those products return back to the
heriditary basis. Some role might be related to the nerve ending.
effected external environment and metabolic abnor- 2. Acelylcholin will pass via the junctional space
malities. and reaches the ACH-receptors on the postsyn-
optic membrane.
6.23.1 Myasthenia gravis
The interaction of ACH and the receptor leads to a
Myasthenia gravis (MG) is a disease that affects higher permeability via the postsynaptic membrane
the neuromuscular junction. It is manifested by a for Na+ , K+ , Ca2+ , and Mg2+ along their electro-
chronic tiredness. When repeating the movement chemical gradient. These changes are proportional to
the limb becomes weak and tired as paralysed. This the amount of released ACH, and the number of ACH
disease might spread to the surrounding segments – R interaction. For an adequate number of interac-
(iradiation of the tiredness). MG mostly affects the tions there will be depolarisation of the post synoptic
facial muscles to form what is called myasthenic fa- membrane, transmission of impulses, and muscular
cies as well as affecting the language. The patient contraction. The whole event normally lasts for 10–
loses the ability to talk after few words. But after 20 ms. For the proper function of the neuromuscular
a short rest he is able to talk again. Generally pa- junction we need to renew the passage which means
tients having MG are more vital after rest and sleep the removal of ACH from the synaptic area. This is
e.g. in the morning if compared to the evining (they performed by ACHE, that is present in an amount
are tired). The gradual fade of activity, that returns of 5 – folds its needed quantity. This means that
back after a short rest is known as the myasthenic abnormalities of ACH removal and hence abnormal-
reaction. The disease might occur in any age, yet it ities in preparing the neuromuscular junction for the
usually appears after 20 years of age and it is more transmission of stimuli will happen when the level of
common in women than men. ACHE drops to 20 % of its normal amount.
In our books of neurology they only mention the The mechanism, that disturbs those smoothly go-
disturbance of the presynaptic area, despite that it ing on procedures on the neuromuscular junction is
is clear that the postsynapotic lesion is present as related to many physiological, pharmacological and
480 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

viral interactions. Recently the pathomechanism of ies showed that, the postsynaptic membrane is the
MG is related to immunological mechanism. target of the autoimmune reaction in cases of the
Because MG is known from the year 1672 when experimental autoimmune MG in animals and the
the disease was described by T. Willis (the doctor of functional as well as the morphological changes are
Charles the 2nd in England), we have a quantity of markedly similar to the human MG The result of
clinical observations, that reflect the development of both cases is a lower number of functioning acetyl-
openion about the pathogenesis of this disease. The cholin receptors, which is most probably the most im-
first theory, the deficiency of the living energy was portant factor of the disturbed neuromuscular trans-
replaced with openions about the microbial origin of mission.
the disease. After the year 1900 MG was related to The role of thymus in the pathogenesis of MG is
diseases of thymus. Thymectomy that is used up to yet not much understood. The hypothesis, claiming,
date really improves the patientďs situation. In 1932 that thymopoetin, that has got a role in the trans-
Loewi described ACH as a transmitter in the neuro- formation of lymphoid cells into T-lymphocytes, at
muscular junction and two years later a symptomatic the same time has an inhibitory effect on the neuro-
treatment with physostigmin was used. From the muscular junction was left nowadays. A new concept
60s long acting blockers of ACHE were used. It was about the initiation of autoimmune aggressive pro-
shown that serum of patients with MG had a depres- cess in MG came upon the exploration of the thymic
sive effect on the transmission of impulses in the neu- myoid cells. These cells compose acetylcholin recep-
romuscular apparatus of the frogs. A positive thera- tors on their surface and we assume that exactly here
peutic effect of the corticosteroids confirmed the im- the reaction between ACH-receptor proteins with T-
munological pathogenesis of MG that was pointed lymphocytes can occur for the first time (e.g. during
to by the clinical experience with thymectomy. The a viral infection) and this could initiate the forma-
proven immunological alteration of the post synaptic tion of antibodies. This hypothesis says that thy-
part of the neuromuscular junction and the common mus is the primary site of autoimmunization, where
association of MG with other autoagresive diseases the T-lymphocytes after sensitization by the ectopic
but mainly the experimentally evoked autoimmune acetylcholin receptors, the myoid cells act as induc-
MG, lead to the present opinion about the patho- tors for the production of pathological IgG in the B-
genesis of this discase. lymphocytes. The T-lymphocytes at the same time
From the neuromuscular junction functional point act as helpers to maintain the pathological process.
of view in cases of MG many authors wrongly If we want to understand the pathogenesis of the
thought that there was an altered function of the disease completely, we have to know which patho-
presynaptic part and hence the synaps contained physiological moment is the most important in the
low amount of ACH. Some precise calculations could course of the disease: whether it is the autoaggressive
prove that the production of ACH on the neuromus- immunity pathway itself, or it is an immunity defect
cular junction in patients with MG is similar to nor- that released those autoimmune processes from the
mal individuals. Some marked changes were found in controlling effects.
the sensitivity of postsynaptic membrane and hence
the acetylcholin receptors for the acetylcholin. In
patients with MG this decrease was up to 80 % com- 6.24 Autonomous (vegetative)
pared with the normal value. The lower postsynaptic
sensitivity can be caused by many factors:
nervous system
Most pathologic conditions do not represent a simple
• lower number of the ACH – receptors
change of some organ function. They mostly evoke
• an abnormal acetylcholin-receptor binding a secondary alteration of activity in the autonomous
nervous system. A non-causal therapy of diseases of-
• disturbed function of the ion channels, that pro-
ten represents an intervention into the autonomous
vide the occurance and the continuation of the
nervous system. Thus, from the pharmacological
stimulation on the muscle.
point of view it is often not the pathologically al-
The last possibility was not proven yet. On tered organ that is influenced but the autonomous
the other side many clinical and experimental stud- nerves that control its activity.
6.24. Autonomous (vegetative) nervous system (A. Král’) 481

The autonomous nervous system is the component tivity, the vegetative afferentation (interoreceptors)
of the nervous system supervising the vegetative (au- and the directing signals from CNS.
tonomous) functions of the organism by controlling The resulting activity is further transformed into
the activity of smooth muscle cells, myocardial cells, efferent signals, led by several efferent pathways. We
endocrine and exocrine glands as well as parenchy- mean the sympathetic, parasympathetic, dopaminer-
matous organ cells. It contributes to the organisms gic nervous fibers and a supposed fourth type of out-
homeostasis. Its typical traits are not to be influ- put (see below). These pathways are defined qual-
enced by free will and not to be directly connected itatively (the effect of sympathetic NS is different
to consciousness. - ”opposite” - to that of parasympathetic NS) as
The autonomous nervous system is a subsystem of well as anatomically, and by their transmitters. In
the nervous system, controlling the very basic activi- the case of sympathetic NS the transfer from the
ties of the body and assuring that the state variables nervous fibers to the effector is assured by cate-
of the organism are maintained in that part of the cholamine, whereas in the parasympathetic NS this
phase space that defines life. It is autonomous in the happens by means of acetylcholine. While dopamine
sense that it is able to perform its activities in an acts as neurotransmitter in the dopaminergic path-
independent way. If the central nervous system is af- way, in the fourth pathway the transmitter role is be-
fected (as a consequence of traumatism, CVA, tumor ing attributed to nitric oxide (NO). The description
or other factors), concomitantly the motor functions of these two latter pathways is still rather imprecise.
in the corresponding part of body can be completely The sense of such multichannel output consists in
lost (plegia). In this case any output of the so called a reciprocal combination of several individual infor-
somatic nervous system is blocked, but the vegeta- mation channels enabling to widen the spectrum of
tive functions remain conserved. We can take the the organisms reactions (i.e. an increased informa-
physiological condition of sleep as another example. tion capacity of the ANS output). As a consequence
During the sleep, the motor functions are to an on of sympathetic activation a given organ can e.g. be-
rest important degree due to insufficient activity of have in different ways corresponding to different pos-
reticular formation. The latter is responsible for such sible activities of the parasympathetic fibers. It is
a level of excitation of the cortex that an additional important to keep this in mind and on the other hand
input from other regions of the central nervous sys- to realize that e.g. a block of the sympathetic activ-
tem (CNS) will induce activity (spike generation) in ity can theoretically be compensated by a diminution
the corresponding cortical area. In the case of sleep, of the parasympathetic tonus or by a complex mod-
as well, the homeostasis in conserved. Eventually, ification of the activity of the resting 3 autonomous
the most striking example is that of an animal de- output channels. Obviously, the corresponding func-
cerebrated above the hypothalamus. Such an animal tions have to be regulated (and not simply controlled,
shows no signs of disturbances in autonomous func- with absent feedback).
tions.
Considering all these facts we can imagine the au- 6.24.1 The architecture of the ANS
tonomous nervous system as an independent entity. The anatomy of the dopaminergic and fourth (above
We might divide the nervous system into two sub- mentioned) vegetative output channels are not pre-
systems: the somatic nervous system and the au- cisely defined yet. We shall therefore concentrate on
tonomous nervous system. We can conclude that the sympathetic and parasympathetic NS in this sec-
the autonomous nervous system (ANS) can indepen- tion.
dently control the life-inevitable functions of the or- Principally, the efferent channels are composed of
ganism (obviously, in relation to the higher centers 3 neurons. The first of them (called preganglionic)
of the CNS). connects the ANS centers located in the CNS to the
The ANS is under regulatory influence of higher peripheral ganglia. The axon of the preganglionic
centers in the CNS. These centers can modulate the neuron is myelinated. In the ganglion area this pre-
reacting capacity of the autonomous nervous system ganglionic neuron is connected to a postganglionic
on the vegetative afferentation. The resulting activ- neuron. The axon of the latter is no longer myeli-
ity of the ANS is so a consequence of its intrinsic ac- nated. There are more postganglionic then pregan-
482 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

glionic neurons and this gives a divergent character itself has not been well concretized in all cases. It
to this neural network. Sometimes a third, s.c. in- has however been possible to define several concrete
tramural neuron is described, located directly in the centers of the ANS, like the respiratory centers, vaso-
wall of the innervated organ. The latter population motor centers, cardioacceleratory or inhibitory cen-
of neurons is being currently designed as intramural ters, the center of cough reflex, the vomitus center
autonomous system. or the regulatory center of the body temperature.
The afferent information of the ANS follows sev-
6.24.1.1 Sympathetic NS eral pathways. Most of them originate in the visceral
receptors and in chemoreceptors. The axons of affer-
The efferent sympathetic output channel originates
ent neurons can be found for example in the vagus,
in the spinal intermediolateral nucleus. Following the
glossopharyngeal nerve, in the splanchnic nerves, but
way of white rami (rr. communicantes albi) it reaches
also in somatic nerves. The afferent compartment
the ganglia of the sympathetic chain (truncus sympa-
is not negligible, e.g. for vagus it represents to four
ticus, paravertebral ganglia), located along the sides
fifths of all its fibers. A part of the afferent axons
of the spine. These form, as a result of their inter-
synapse with the preganglionic fibers of the ANS. At
connections by means of longitudinal interconnecting
the recent level of knowledge the afferent part of the
fibers, a united system. Within this chain pregan-
ANS can not be divided in a similar way as its ef-
glionic fibers synapse with sympathetic neurons in
ferent (output) part. This is interesting in that it
ganglia at the same, higher, or lower levels. After
underlines the reality of a conception of integrated
integrative processes involving dopaminergic neuro-
ANS structures, a sort of centers analyzing the affer-
transmission they send postganglionic axons either
ent information (feedback signal) and, at the same
back to the spinal nerves as gray rami (gray because
time, controlling the activity of efferent pathways. It
unmyelinated), or to prevertebral plexuses or gan-
is also interesting to mention here that the visceral
glia in the abdominal cavity. A part of the mentioned
afferentation does not only condition the vegetative
nervous fibers pass through these ganglia without be-
nervous system, but also the somatic efferent system
ing interrupted. These fibers form synapses in gan-
and vice versa. We can give several spinal reflexes
glia placed around vessels (ganglia plexorum auto-
as an example: there are pathological processes in
nomicum) or in prevertebral ganglia. The last neu-
the splanchnic regions that are accompanied by a
ron of the sympathetic pathway ends on the effector.
redness of the dermatomes innervated by the same
spinal segments.
6.24.1.2 Parasympathetic NS
In this case the visceral afferentation probably ex-
The preganglionic parasympathetic fibers run in the erts a direct influence on the activity of the sym-
cranial nerves and in the sacral spinal roots. Their pathetic efferent fibers in the given segment lead-
interconnections take place in the plexi located in ing to dilatation of blood vessels of the correspond-
the proximity of these roots or directly in the organ ing dermatome (viscerocutaneous reflexes). In the
plexi. Cranial nerves containing parasympathetic s.c. viscerosomatic reflexes the activity spreads from
neurons are the following: the oculomotor nerve, the ANS to the somatic nervous system – e.g. an
facial nerve, glossopharyngeal nerve and the vagus. augmented tonus of the abdominal muscles can
Other parasympathetic neurons are included in the be observed in the corresponding area of the ab-
nerve fibers of the sacral plexus. The mentioned domen following increase of autonomous afferent ac-
nerves take their origins either in the corresponding tivity. Clinical practice offers us still more examples,
nuclei of the cranial nerves, in the Edinger-Westphali e.g. the cutanovisceral reflexes, where the warming
nucleus, or in the spinal areas representing a contin- up of certain areas of the skin leads to a diminution in
uation of the intermedial nucleus. the motility of the intestines. Surgeons describe the
The central regulatory structures of the ANS: sev- postoperative ileus, an event sometimes complicating
eral structures of the CNS have a close relationship to postoperative care following an operation in abdomi-
the ANS. First of all, this is the case of the hypotha- nal cavity. Here visceral afferentation from intestine,
lamus and medulla oblongata. Whether or to what as a consequence of mechanical manipulation, acti-
extent these represent the central part of the ANS vates its own sympathetic efferentation (intestinoin-
6.24. Autonomous (vegetative) nervous system (A. Král’) 483

testinal reflexes). The intestinal ANS is correspon- fusing from the circulation, if this is possible with
sible for this reflex. Identical causal mechanisms are regard to local conditions. In a similar way pharma-
implied in the Ogilvie’s syndrome, which is an acute ceuticals diffusing from the circulation can stimulate
intestinal pseudoobstruction. Except for a surgical a receptor (or, in an opposite case, block the effect
abdominal intervention it can be induced by sepsis, of its stimulation).
myocardial infarction, respiratory insufficiency, all of Catecholamines are synthesized from the amino-
them sharing a hyperactivity of the sympathetic NS acid tyrosine. This is first hydroxylated to dihy-
leading to the a dilation of intestinal wall. However, droxyphenylalanine (dopa), then decarboxylated to
the precise pathomechanism of these phenomena has dopamine and finally hydroxylated on the beta po-
not been elucidated yet. All these reflexes become sition of its lateral chain with norepinephrine as
more apparent after a transversal spinal lesion above a result. The regulated link in this chain (the
the corresponding spinal segments. Then a mechan- rate-limiting step of this process) is the hydrox-
ical stimulation of the skin can lead to a profuse ylation of tyrosine. Norepinephrine (the reaction
sweating and to an excessive vascular reactivity of product) induces a modification in the activity as
the skin. This is explained as a consequence of the well as the mass quantity of the enzyme tyrosine-
interruption of the continually active descendent in- hydroxylase, which is responsible for the mentioned
hibitory pathways. step. The described metabolic process is followed by
methylation of norepinephrine to epinephrine by the
phenylethanolamine-N-methyltransferase in adrenal
6.24.2 The sympathetic nervous sys-
medulla.
tem and the adrenal medulla.
Interestingly it has been observed that the en-
The dopaminergic system. zyme phenylethanolamine-N-methyltransferase is in-
As we have already mentioned, among the character- ducible by glucocorticoids. When we look at the
istics of the efferent pathways of the ANS the func- anatomy of the organ we see that the blood supply
tion and the type of transmitter play an important entering adrenal medulla is already enriched by glu-
role. If we simplify we can say that the sympathetic cocorticoids, originating in the adrenal cortex. Thus
NS is most often activated in situations requiring mo- this further enhances the adrenomedullar synthesiz-
bilization of the organism, like in danger. The role of ing capacity.
this activation is then to provide the necessary oxy- The degradation of catecholamines is per-
gen and nutrients supply to the organs responsible formed by the catechol-O-methyltransferase (O-
for the safeguard of life and to switch the function- methylation) that takes place in the liver and
ing of the latter over to a more economic alternative. the kidney. It permits a removal of the ac-
It activates the cardiovascular and respiratory sys- tive catecholamines from the blood circulation.
tem and assures a sufficient perfusion of the heart A second catecholamine-degrading enzyme is the
and brain. monoaminooxidase (MAO), which is located in the
In the human body three catecholamines occur nerve endings (and synaptic clefts), playing a role
naturally: epinephrine (adrenaline), norepinephrine in the inactivation of catecholamines in the nervous
and dopamine. They function as neurotransmitters system. The products of the catecholamine degra-
in the CNS as well as in the ANS. For the sym- dation are the metanephrines and the vanilmandelic
pathetic NS epinephrine and norepinephrine are the acid (there are two forms of MAO, a central form,
most important. acting in the CNS, and a peripheral form). In the
Principally one can say that norepinephrine is dopaminergic system, the degradation product is the
rather locally acting, while epinephrine, a product of homovanilic acid. Catecholamines are being stored
adrenal medulla, exerts its effect after passing into in vesicles and are released by exocytosis. Both in the
the blood circulation, i.e. globally. adrenal medulla and in the sympathetic nerve end-
The catecholaminergic receptors, localized on the ings, there are important stores of catecholamines,
postsynaptic membranes of the effectors, can be interpreted as a reserve for situations requiring a
stimulated either by a catecholamine eliminated from massive stimulation of sympathetic NS.
the innervating nerve ending or by catecholamine dif- This localization of catecholamines inside vesicles
484 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

has a key meaning also from another point of view ble of activation 1000 times a second. After every
– the free monoaminooxidase, present in the cyto- single activation, however, a state of peace must be
plasm, would otherwise lead to a rapid degradation restituted. The biochemical processes taking place
of the synthesized catecholamines. In this way the at the synapse must fit well with the elimination
catecholamine compartment represented by the vesi- speed and with short duration of the transmitter ef-
cles is a compartment protected from intracellular fect at the postsynaptic membrane. These synaptic
degradation. processes must be extremely short-lasting (at a speed
The adrenal medulla occupies a highly specific of 1000 Hz less than 1 ms), allowing the next spike to
place in the ANS. It can be characterized as a trans- be transferred to the postsynaptic neuron. This is
formed sympathetic ganglion composed of modified made possible so that the quantity of the eliminated
postsynaptic neurons. The adrenal medulla pro- transmitter is small (about 10−13 mol/impulse), by
duces a mixture containing approximately 80 % of removal of the transmitter by reuptake, by its degra-
epinephrine and 20 % of norepinephrine. Once this dation by MAO that finds itself in the synaptic cleft
mixture is released into the blood circulation, it and by internalization of the occupied receptors at
can potentiate the effect of a sympathetic activation the postsynaptic membrane.
on the corresponding effectors, but in fact, its role Let us now give a description of the complex event
is providing the function of a metabolic hormone. called the activation of sympathetic NS. The sym-
Adrenaline mobilizes oxidable substances (glucose pathetic pathway can be activated either by a lo-
and fatty acids) from their stores. This could be cal reflex (e.g. intestino-intestinal reflex) or by an
interpreted as the providing for fuel to the organism activation of the central control structures (e.g. va-
that, due to a longer lasting sympathetic activation, somotorical center). Under basic conditions, every
works at a higher speed. nerve fiber is characterized by a basal (spontaneous)
activity, where the spikes run along the axons with
The neuro-sympathetic communication: An im- a rather low frequency. If the nerve fiber is acti-
portant process taking place on the peripheral end- vated, this frequency becomes higher. This situation
ing of the sympathetic NS is the s.c. reuptake of is designed as an increase of tonus. An inhibition of
catecholamines from the extracellular space into the the corresponding neuron on the contrary, leads to a
presynpatic neuron by means of a special transport diminution of this frequency.
system. This mechanism becomes evident in several
physiological processes. On one hand, it protects the
stores of catecholamines (to some extent, however, 6.24.2.1 The receptor theory. Sympathoad-
the catecholamines transported in this way are de- renal and dopaminergic receptors.
graded by the cytoplasmatic fraction of the MAO), Every organ reacts on stimulation of the correspond-
on the other hand, it is one of the classical mech- ing part of the ANS in a different way. This is very
anisms enabling an activation of the postsynaptic important, according to different roles different or-
membrane at high-frequency. gans play in the maintaining of the functional equi-
In order to clarify these events we must go back librium of the organism. In a life-saving situation,
to the fundamentals of neurophysiology. The neu- some organs are necessary to be stimulated while
ral system recognizes basically 2 distinct codes: the others, less important in such situation, can be in-
anatomical code and the frequency code. The fre- hibited due to an energy-economizing requirement.
quency code is based on the capacity of neurons to In such situations it is very important that the organ
carry several action potentials (spikes) in a rapid se- reactions may be greatly diversified. Here, two mech-
quence. We know that this ability is not equal for anisms are involved. First, every organ has its inner-
all neural cells. Generally, the value of 1000 Hz is vating autonomous fibers differently active. This is a
taken as the upper limit for the spike frequency. That consequence of an integration of different influences
means that the spikes run on the neural axon with on the ANS at different levels of control (e.g. spinal
a speed of 1 to 1000 per second. The neural path- vegetative reflexes). The degree of activation of sin-
ways can this effectively use only if the chemical pro- gle sympathetic fibers depends also on the character
cesses on the synapses run at least at the mentioned of the stimuli responsible for this activity. Besides
speed. This means that the synapse must be capa- this, it is important that the organ’s reaction to the
6.24. Autonomous (vegetative) nervous system (A. Král’) 485

release of adrenaline from adrenal medulla is a spe- is such excessive (like in the case of shock) that the
cific one, characteristic for the given organ. For this, ability to keep the regulated variables in a stable area
the organs are equipped with a specific spectrum of is lost so that a desired progression of the patholog-
receptors. This enables a more complex organ reac- ical process appears.
tion to a rather general (uniform) answer of the ANS The receptor has a binding component to which
(especially of the adrenal medulla) to stimulation, so different substances can bind. If the latter respond
that eventually, the vegetative reaction in a given to certain criteria, they induce such a modification of
situation can be more general (and more economic). the 3-dimensional structure of the receptor that an
The diversity is also achieved on the periphery as intracellular receptor-dependent cascade is triggered.
different structures and organs express different re- We call the so behaving substances the agonists of
ceptors for the same mediators. Hypothetically we the receptor function. Contrary to them, the antag-
must consider an additional factor: the answer of an onists of the receptor function are substances able to
organ to its vegetative stimulation should rely on the block the mentioned effect. Two basic origins can be
particular state of this organ or on the concrete sta- recognized for the agonists: the synaptic button of
tus of the whole organism at a given moment. The the innervating fiber and the circulation. The ago-
receptor molecules are proteins. As such, their struc- nists appearing in the circulation can be of endoge-
ture, similarly to the structure of all other proteins nous origin (e.g. epinephrine synthesized in adrenal
of the organism, is encoded in the DNA of the cell medulla) or of an exogenous origin (e.g. drugs).
nucleus under the form of genes. The moment and
the extent of the activation of these genes is a strictly
6.24.2.1.1 Adrenergic receptors We have al-
controlled process. It means that the number of re-
ready mentioned that the effect of the efferent path-
ceptors expressed on the cell membrane is not con-
ways on the effector is chemically mediated. The ef-
stant and undergoes a regulation. Like this a cell
fector is equipped by the same receptors to which the
(an organ) disposes of a modification possibility of
neurotransmitter liberated from the synaptic button
its answer to vegetative influences according to local
of the innervating nerve fiber is bound. In order to
factors.
react to the control signals from the sympathetic NS
Let us close this subject by saying that the diver- the tissues must be equipped by receptors suscep-
sity of the organism reactions to a particular state of tible to react to the corresponding transmitter. In
the organism functional equilibrium can be achieved the case of sympathetic NS these are the adrenergic
in several ways. First, by the existence of a multi- receptors. Those can be found first of all in the car-
channel output from the ANS, second, by the fact diovascular system, but also in the splanchnic area,
that the organs are innervated by vegetative fibers in the respiratory system, urogenitary tract, etc. We
the activity of which is not necessarily uniform, third, recognize several types of adrenergic receptors. Their
due to the fact that the effectors of ANS present a differences mean in fact a differentiated influence on
diversity of receptors associated with different types different functions, mediated through different mech-
of responses, more or less specific to the given organ. anisms at the cellular level. The corresponding bio-
In this way, with exceptional economy and a very chemical structures of the receptors are also different,
short reaction time (almost immediately) the ANS so that there is a possibility of a selective activation
reaction is started, leading to an adaptation of the or blocking of these different receptors. We divide
organism to changed conditions, with respect to its adrenergic receptors in alpha and beta receptors.
stability. Alpha adrenergic receptors: In general we can
The reactions of the ANS change inside a large say that the activation of the alpha receptor induces
spectrum, from very discrete, sometimes at a limit vasoconstriction, relaxation of the intestine and my-
of recognition (change in body position, food in- driasis. Epinephrine and norepinephrine bind to al-
take, change of vigilance, mental activity, physical pha receptors and their effect is approximately the
exercise) to whole-body extensive reactions (like the same. Alpha receptors are divided in alpha1 and
”fight and flight” reaction after Cannon, triggered alpha2 receptors.
by a life danger). This system is highly effective and The alpha1 receptor was originally considered a
fails only if so intervention to the organism’s integrity receptor of the postsynaptic membranes. The main
486 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

effect mediated through these receptors are vasocon- gic and dopaminergic receptors. The biochemistry
striction and mydriasis. of these receptors teaches us that the binding of the
The alpha2 receptor was, according to the original corresponding transmitter to the receptor leads to
conception, a receptor of the presynaptic membrane a modification of the receptor structure, initiating
of the sympathetic nerve ending. As in the case of further biochemical processes inside the cell. The re-
the alpha1 receptor so for the alpha2 receptor sev- ceptor molecule is associated with a regulatory pro-
eral new functions have been discovered. The alpha2 tein called G protein (G, because as soon as it is
mediated effects include the inhibition of the nore- activated, the GTP binds to it) that will decide the
pinephrine secretion from the adrenergic nerve end- further character of the response. Alpha2 and D-
ings, the inhibition of the acetylcholine release from 2 receptors are associated with the Gi protein, the
the cholinergic nerves, the inhibition of lipolysis in activation of which leads to a decrease of cAMP
the fat tissue, the inhibition of the insulin secretion, level. The information passed further by this second
the stimulation of the platelet aggregation and vaso- messenger then mediates the effect on the cAMP-
constriction of some vessels. dependent proteinkinases. It is relevant to mention
Beta receptors: Through the activation of the that not all responses to an alpha2 receptor stimula-
beta receptors the heart frequency acceleration as tion can be exclusively explained by this mechanism
well as an augmented myocardium contractility are and that, actually, a modification in the permeability
achieved and at the same time vasodilation and lipol- of some ion channels is being considered.
ysis are favored. We recognize 2 subtypes of recep-
tors: The alpha1 receptor is associated with a Gp -
Beta1 receptor is equally sensitive to both protein (not precisely identified yet) that activates
epinephrine and norepinephrine, it exerts influence the phospholipase C. This enzyme induces a de-
on the heart action and is responsible for lipolysis composition of the phospholipids that find them-
in fat tissue (recently the lipolytic effect has been selves bound to the cellular membrane, mainly
ascribed to beta3 receptors). of the phosphatidylinositol-4,5-biphosphate, having
Beta2 are more sensitive to epinephrine. They the consequence of the formation of inositol-1,4,5-
trigger vasodilation and bronchodilation regulate triphosphate and 1,2-diacylglycerol. Both these
hepatic glycogenolysis and gluconeogenesis, skeletal products act as second messengers. The inositol-
muscle glycogenolysis and other metabolic processes. 1,4,5-triphosphate liberates calcium from its intracel-
lular stores and, acting on the calcium/calmoduline
dependent proteinkinases, mediates the transmitter’s
6.24.2.1.2 Dopaminergic receptors Dopami-
effect on the cell. This pathway is further potentiated
nergic receptors can be found in a large variety of
by the entry of calcium into the cell, due to a longer-
tissues, mainly in the CNS and the peripheral NS,
lasting stimulation by an agonist of alpha1 receptor
but also elsewhere. Their classification is very com-
(the mechanism of this elevated uptake of calcium
plex. For the sake of simplicity let us divide the
is not yet well known). The 1,2-diacylglycerol stays
dopaminergic receptors into two types (the effect of
in the cell membrane and activates the proteinki-
dopamine on both of them is equal):
nase C, which acts on substrates other than the cal-
D-1 receptor induces vasodilation in the following
cium/calmoduline dependent proteinkinase. The ef-
vessel beds: cerebral, coronary, renal and mesenteric.
fects mediated by proteinkinase C (which phosphory-
D-2 receptor inhibits the conductivity in sympa- lates proteins) have still not been clearly elucidated.
thetic ganglia, inhibits the release of norepinephrine
from the sympathetic nerve endings, inhibits the se- The beta1 , beta2 and D-1 receptors are associated
cretion of prolactin from the pineal gland and induces with the s.c. Gs protein. The latter enhances the
vomiting. activity of the adenylatecyclase with a consecutive
rise in cAMP. Due to this, the cAMP-dependent pro-
6.24.2.1.3 The structure of adrenergic and teinkinases are activated. These on their turn induce
dopaminergic receptors In the following text we the phosphorylation of proteins, responsible for the
shall try to elucidate the intracellular mechanisms final cellular effect attributed to the activated recep-
implied in the mediation of the effects of adrener- tor.
6.24. Autonomous (vegetative) nervous system (A. Král’) 487

6.24.2.1.4 Influencing the sensitivity to the the preganglionic sympathetic neuron originates.
adrenergic effects It has been discovered that the The activity of the mentioned centers depends on
sensitivity to the adrenergic effects is rather variable numerous factors. Among the most important are
than constant. We shall mention two kinds of pro- activities arising from the cortex, limbic system and
cesses taking place at the receptor level: the homol- hypothalamus. We can further enumerate afferenta-
ogous and heterologous regulations. tions communicating with sympathetic NS directly
Homologous influences. It is a well-known fact at the brainstem level, and, equally, the qualitative
that a long-lasting exposition of receptors to their variations of the extracellular fluid composition. The
agonists induces a decrease in their number (it is an role of the higher centers is to coordinate the effects
opposite process to the long-term potentiation in the of the sympathetic system with mental functions,
CNS during engram formation, where the efficiency emotional reactions and with homeostasis.
of synaptic transmission is increased). The mecha- At this place it is important to attract the atten-
nism of such s.c. down-regulation is not well under- tion to the difference between the neural and hu-
stood for the ANS. It is possible that the internal- moral component of the sympathetic NS. The neural
ization of the occupied receptors plays a role in it, it component reflects itself in the rapidity of reaction,
could be so in the case of beta receptors. Besides this while the humoral component has a prolonged and
it is supposed that the receptors associated with the slightly different effect. Different stimuli activate the
adenylatecyclase (beta and alpha2 ) might alternate sympathetic NS at different points and to a different
between two states: one with high affinity to its ag- extent. Upright posture activates the neural compo-
onist and a second, with low affinity to this agonist. nent, while hypoglycemia first acts on the humoral
One of the existing theories on this subject is that component.
a long-lasting exposition of a receptor to its agonist
leads to a changed ratio between the two components 6.24.2.3 Modification of the transmitter re-
in favor of the low-affinity state of the receptor. The lease on the presynaptic membrane
kinase, phosphorylating the beta receptor, is proba-
bly involved in this phenomenon. Even if the exact The effect of a sympathetic stimulus on a given organ
mechanisms of these events are still but hypothetical, is determined by the extent of activation of the corre-
it is doubtless that the s.c. tachyphylaxy (diminished sponding efferent pathway. The mediation of the ef-
responsiveness of a tissue following its long-lasting fect is realized by a neurotransmitter. The greater its
stimulation) indeed appears in the ANS. quantity released into the synaptic cleft, the more re-
Heterologous influences. There are more het- ceptors of the postsynaptic membrane are activated
erologous factors that influence the sensitivity of a and the more intense signal is achieved inside the
synapse. A drop of the ambient temperature aug- cell.
ments the affinity of the alpha receptor to its agonist. Not only the activity of the efferent pathway, but
Thyroidal hormones augment the number of beta re- also other mechanisms affect the quantity of the
ceptors and make the cellular response to beta recep- transmitter released. There is an important number
tor stimulation more effective. Estrogens and pro- of these factors. We speak about presynaptic mod-
gesterone modify the sensitivity of the myometrium ulation. Among the less specific these are e.g. fall
to catecholamines (by means of the alpha receptor). in body temperature or acidosis, both reducing the
Glucocorticoids prevent from the tachyphylactic ef- quantity of the released norepinephrine. Other fac-
fect on the adrenergic receptor level. tors are more specific and their effects pass in the
most cases through a receptor on the synaptic mem-
6.24.2.2 Central regulation of the sympa- brane. Such a receptor probably triggers a cascade
of events in the presynaptic area, that have not been
thoadrenergic system
sufficiently precised yet. The consequence of these
We can trace the output from the sympathetic NS events is a modification of the transmitter quantity
starting with the reticular formation in the pons and that will be released in response to the passage of the
medulla oblongata. There is also a part originating spike through the presynaptic button. The release of
in the hypothalamus. Descendent fibers then end in a transmitter can be either subjected to facilitation
the intermediolateral nucleus of the medulla, where or to inhibition. The catecholamines themselves have
488 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

an inhibitory effect on the release of norepinephrine 6.24.3 Parasympathetic NS

(by the alpha2 receptor). Such negative feedback as-
sures a very small amount of the transmitter to be Parasympathetic NS represents the 2nd output chan-
released, which contributes to a shortening of the nel of the ANS. Its effect (being contrary to the sym-
synaptic passage time. Acetylcholine (muscarinic re- pathetic effect, roughly speaking), is evident e.g. dur-
ceptor), dopamine (D-2 receptor), histamine (H-2 re- ing sleep, in a resting state or during digestion. Of
ceptor), serotonin, enkephalines and prostaglandins course, here, for didactic reasons, we are presenting
act also in an inhibitory way, while catecholamines examples with a high degree of simplification. It is
(beta2 receptor !), acetylcholine (nicotinic receptor !) important to know that in reality, also the parasym-
and angiotensin II have facilitating effects at this pathetic NS is participating in the enumerated situ-
level. Even if we knew the effects of the enumer- ations.
ated substances, the modulation of this pathway as We have already mentioned the anatomical partic-
a whole still needs further clarification. ularities of the sympathetic NS. Acetylcholine acts
as a transmitter in its postganglionic neuron (it also
The ambivalent effects of catecholamines and
plays the role of neurotransmitter in all vegetative
acetylcholine (inhibitory as well as facilitating) re-
ganglia and in the postganglionic sympathetic neu-
quire a more detailed analysis.
rons innervating the sweat glands).
Presynaptic adrenergic receptors: As for the am- Acetylcholine is synthesized from choline actively
bivalent effect of catecholamines no explanations are extracted from the extracellular space by the neu-
available, however, two hypotheses are being evoked. ron and from CoA (a product of the neuron itself).
The first one suggests that the effect on beta recep- The mentioned synthesis is catalyzed by the enzyme
tors dominates within a range of lower concentra- cholinacetyltransferase. The reaction product acetyl-
tions of the ligand, while higher concentrations are choline is then stored in the synaptic vesicles until it
required to trigger an alpha receptor effect. At a is liberated due to passage of an action potential.
lower firing rate less transmitter is released and by Acetylcholine binds to more receptor types that
means of a positive feedback on the beta receptor, can be divided into two groups. They have been
this quantity is augmented. If, on the contrary, large discovered during a series of pharmacological exper-
amount of transmitter is released (due to an intense iments where nicotine and muscarine were admin-
stimulation of the sympathetic NS, i.e. to a high dis- istered in experimental animal models leading to
charge rate), the alpha effect will predominate, lead- the finding of distinct reactions due to each stim-
ing to a decrease of this quantity by a negative feed- uli. Later the corresponding subgroups of parasym-
back. pathetic receptors were successfully identified.
The second hypothesis suggests that the beta re- The first, referred as nicotinic receptors, include
ceptors are more sensitive to epinephrine than to receptors that can be activated by nicotine. For most
norepinephrine and that, therefore, the circulating of them, they are located in the adrenals, in the au-
epinephrine increases the effect of the neural sym- tonomic ganglia, as receptors of the neuromuscular
pathetic component. The alpha receptor then only junction and in the CNS. The second type, mus-
functions as the above mentioned negative feedback carinic receptors, can be activated by muscarine and
on the transmitter release. they are mainly located on the membranes of the ef-
Presynaptic cholinergic receptors: Despite the fector cells of the parasympathetic NS and in the
fact that two types of presynaptic cholinergic re- CNS.
ceptors exist and, as a result of this, two different The muscarinic receptors can be further divided
effects of acetylcholine on the presynaptic ending, into two subtypes: the M1 receptor (found mainly
it is presumed that the muscarinic receptor plays in the CNS and probably also in the parasympathetic
the preponderant role. Its effect is the inhibition of ganglia) and the M2 receptor (a non neural receptor)
the catecholamine release from the presynaptic area, detectable on the effectors like the smooth muscle,
achieved at lower concentrations of acetylcholine. cardiomyocyte or the glandular epithelium.
This is considered to be an important component of The M1 receptor, like the alpha1 receptor, is as-
the functionally often reciprocal reactions between sociated with a Gp protein, so that the subsequent
sympathetic and parasympathetic NS. intracellular cascade is the same as was described for
6.24. Autonomous (vegetative) nervous system (A. Král’) 489

the alpha1 receptor. The M2 receptor is associated parasympathetic message to the GIT leads to an in-
with a Gi protein and the mechanism of the cellular crease in the smooth muscle tonus, increase in peri-
effect includes the same biochemical steps as in the staltic motility and the relaxation of sphincter mus-
case of the alpha2 and D2 receptors. cles. Additionally, the parasympathetic NS stimu-
The acetylcholine is inactivated in the synaptic lates the exocrine secretion of gastrin, secretin, in-
cleft by acetylcholineesterase. This enzyme is not sulin and the production of gastric mucine.
identical with the serum acetylcholinesterase, the lat- As for the urogenital system acetylcholine here
ter having any influence on the mentioned physiolog- leads to an increase in the urethral peristaltics, a con-
ical reactions. traction of the detrusor muscle of the urinary blad-
der (there are two sphincters at this level, an internal
6.24.3.1 Parasympathetic NS at the organ one, containing smooth muscles and a second, exter-
level nal, composed of striated muscle. The parasympa-
thetic NS only influences the internal sphincter.) In
The parasympathetic fibers innervate the cardiovas- this way, it plays an important role in the coordina-
cular system, the GIT and the urogenitary system, tion of the urinary function. Also the genital organs
including the kidneys, liver, thyroid gland, pancreas are largely influenced by the parasympathetic inner-
and other organs and tissues. This explains why it vation. Together with a massive sympathetic activa-
might intervene in a lot of metabolic events. Such tion during the orgasm also the parasympathetic NS
interventions have, however, not been concretized in is involved.
detail yet. In the upper respiratory tract, acetylcholine leads
The parasympathetic NS reaches the cardiovascu- to an increase in the tracheobronchial secretion and
lar system by means of vagus. It leads to a decreased it triggers bronchoconstriction.
automaticity in the sinoatrial node and by this to a
decrease in heart rate (negative chronotropic effect).
Additionally, it slows down the conduction (negative
6.24.4 Non-adrenergic and non-choli-
dromotropic effect). Not only it slows down the con- nergic autonomic nerves
ductivity, but it also shortens the refractory phase of Besides the sympathetic and parasympathetic NS
the myocyte, an association of effects predisposing to there are also efferent fibers using neither nore-
arrhytmias. The right vagus primarily affects of the pinephrine nor acetylcholine. If we try to block
function of sinoatrial node while the left vagus acts pharmacologically the conduction at the mentioned
primarily on the atrioventricular node. These facts synapses of these fibers with norepinephrine and
may be exploited in clinical practice. acetylcholine antagonists, they still remain active,
Acetylcholine decreases the conductivity and pro- indicating their special role in the ANS. These
longs the refractory phase in the atrioventricular nerve fibers are included into a system called non-
node. The negative inotropic effect is attributed to adrenergic non-cholinergic. We recognize 2 possible
the presynaptic inhibition of the sympathetic fibers candidates for the neurotransmitter role in this sys-
by acetylcholine, as well as to the decrease of the ra- tem: dopamine and NO.
pidity of excitatory conduction. This leads to a gen-
tle desynchronisation of myocardial contraction, di-
6.24.4.1 The peripheral dopaminergic sys-
minishing its efficiency. The ventricular myocardium
tem
is but very little influenced, as its parasympathetic
innervation is not extensive. It seems rather improb- The role of dopamine is usually an inhibitory one in
able that the parasympathetic NS could have a direct the CNS. Additionally, it seems that dopamine also
effect on blood vessels. It is supposed, actually, that plays a role of a transmitter in the sympathetic gan-
its only effect consists in presynaptic inhibition of glia. Finally, there is evidence that except for this
the sympathetic fibers. classical roles, dopamine serves a transmitter func-
The GIT is the organ system, in which the ef- tion on the periphery. Actually, we suspect the ex-
fect of parasympathetic NS is the most evident. The istence of a peripheral dopaminergic system as there
parasympathetic innervation reaches this organ sys- are effects induced by dopamine that can not be ex-
tem through vagus nerves and the sacral plexus. The plained by the mechanism of activation of the re-
490 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

ceptors of any other type (adrenergic, cholinergic, 6.24.4.3 The intestinal ANS
histaminic, etc.). The mentioned system probably
The intestinal ANS has a particular position inside
participates in the relaxation of the lower esophageal
the ANS. It is autonomous in the true sense of the
sphincter, it slows down the gastric evacuation, leads
word. It is well known that the intestine will con-
to a dilation of the renal and mesenteric arteries, de-
tinue working after a total liquidation of its inner-
creases the secretion of aldosterone, directly stimu-
vating fibers. In addition to a conserved motoric-
lates the sodium excretion in the renal tubules and
ity, some secretory functions will remain conserved
inhibits the elimination of norepinephrine on the pe-
as well. This is possible because of its proper ”ner-
ripheral sympathetic nerve endings. How precisely
vous system” inside the intestinal wall. This ner-
these effects are brought on has not been thoroughly
vous system is composed of the s.c. myenteric and
explained yet. We do not think dopamine could act
submucose plexus that are sometimes designed by a
as a classical hormone through its presence in blood.
popular common term ”intestinal brain”. This web
Most often it is evoked that the dopaminergic sys-
of neurons includes a subgroup of sensory neurons
tem could be primarily located in the kidneys, as
excited by a tension or contraction of the intestinal
it has been demonstrated that the urine contains
wall, interneurons and efferent neurons, innervating
more dopamine than can be explained by its clear-
the smooth muscles of the intestinal wall.
ance from the blood circulation.

6.24.5 Involvement of the ANS in

6.24.4.2 NO and the ANS the pathophysiology of disease
It has been shown that the endothelium derived re- states
laxing factor of vessels (the last link-molecule in The very complex structure of the ANS is in constant
the regulatory cascade of vasodilation) was identi- interaction with other regulatory systems. Such in-
cal with nitric oxide. A large spectrum of functions teractions can be revealed at the level of spinal au-
of this chemically very simple substance (until then tonomous neurons, but also at higher levels, under-
only considered as an air pollution factor) have been standing structures such as medulla oblongata or hy-
discovered since. pothalamus. The open character of the ANS makes
The NO-synthetase, a constitutive enzyme (con- it difficult to determine its role in the pathophysiol-
stantly present) in a number of neurons, produces ogy. There is also the problem that changes in the
the NO from the aminoacid L-arginine. It is not ANS activities accompany practically every disease
only to be found in the CNS, where it is thought that leads to a dysbalance of homeostasis. It is there-
to contribute to the existence of memory (long-term fore not easy to decide, whether in concrete cases the
potentiation of synaptic efficacies) mainly in the hip- ANS plays a primitive or just a secondary role. We
pocampus and the cortex, but it also can be found in shall thus mention only a small number of diseases
the peripheral nerve endings of the ANS. The partici- concerning the ANS. We shall namely give examples
pation of this, still imprecisely characterized system of such diseases (chosen from the vast group of dis-
inside the ANS, can be documented on the case of ease states with a participation of the ANS), where
hypertophic pylorostenosis and achalasia. This sys- the vegetative nerves play a key role.
tem also intervenes in intestinal relaxation. Cardiac insufficiency: Sympathetic NS partici-
A recently acquired knowledge about NO is that pates to a high degree in the picture of cardiac insuf-
it can induce vasodilation in corpora cavernosa (re- ficiency. In the initial phase the venoconstriction and
laxation of the smooth muscle of the vessel wall), so the positive inotropic, dromotropic and chronotropic
that it is an agent participating on erection (its fail- effects of catecholamines have a key meaning for the
ure plays a role in pathogenesis of impotence). More, safeguard of basic tissue perfusion. This regulatory
NO probably has a transmitter function in retina and mechanism has, however, also a negative side - an
adrenal medulla. The relation between the NO sys- elevated tonus of sympathetic NS increases the oxy-
tem and the dopaminergic system is not clear, how- gen consumption by the myocardium, impairing the
ever an important physiologic role of the NO in the state of this organ. In the particular case when car-
ANS seems rather probable. diac insufficiency occurs as a complication of myocar-
6.24. Autonomous (vegetative) nervous system (A. Král’) 491

dial infarction, it is of extreme importance that the is concerned, the organism possesses several mecha-
sympathetic NS is activated. Shock and trauma are nism. First, by peripheral vasoconstriction heat loss
other examples of situations with an elevated sym- will be limited, second, the heat production will in-
pathetic activity. The main sympathetic effect con- crease through a physical effort, by tremor or due to
sists of a mobilization of the energetic sources and the caloric effect of an elevated production of thy-
of favorization of the circulation in these situations. roxin. The main heat producent in the organism is
Physical effort also leads to an activation of the sym- the Na/K pump.
pathetic NS. Due to it, a better perfusion of the skele- Another important factor participating in the reg-
ton muscles is achieved, together with an increased ulation of the sympathetic activity is food intake.
output volume of the heart, an adequate circulation Fasting inhibits and excessive food intake stimulates
and liberation of energetic substances. This situation the sympathetic NS. During fasting the activity of
is at the same time an example of anticipatory reg- the sympathetic NS is inhibited, consequently the
ulation. Physical training will lead to a diminished basal metabolism is diminished and bradycardia and
activation not only during the resting state but also hypotension appear. Like this organism chooses a
during effort, thereby increasing the compensatory lower turnover, regulating its energy consumption
ability of cardiovascular system. towards a more economic way. The influence on the
If the concentration of blood glucose falls under ANS is in this case probably exerted from the center
the physiological limit, the CNS neurons sensitive to of hunger in the hypothalamus.
glucose will be activated, the information will pass Hypoxia also activates the sympathetic NS, prob-
to the ANS, which in turn stimulates the adrenals ably by activating first the corresponding CNS struc-
to secrete adrenaline. As a consequence, glucose tures.
will be mobilized from liver and fatty acids from The ANS is, to an important degree, involved in
fat tissue, the insulin secretion will decrease (hin- the development of angina pectoris. We have already
dering the blood glucose to leave circulation) and mentioned that the sympathetic NS increases the
the insulin-regulated consumption of glucose in the consumption of oxygen by the myocardium through
skeleton muscle will be inhibited. If we examine the the positive inotropic, chronotropic and dromotropic
symptoms at the beginning of a hypoglycemic com- effects resulting from its excitation. Let us have a
plication in a diabetic patient (palpitations, agita- look at the symptoms of angina pectoris from this
tion, tremor and others) we realize that they can be point of view. We known that constant angina pec-
attributed to adrenaline. In a long-lasting diabetes, toris manifests itself in some charge situations. If
however, the answer of the sympathetic NS becomes the blood supply of the myocardium becomes pro-
less important and the mentioned symptoms less ex- gressively insufficient, it first manifests only in stress
pressed. situations requiring an optimal perfusion of the my-
Cold: The skin and the CNS thermoreceptors can ocardium. In such situations the sympathetic NS will
react to a decrease in body temperature by sympa- be excited and, as a consequence, in agreement with
thetic activation. The training to cold probably in- what we have previously mentioned, the productivity
creases the quantity of heat generated as an answer of the heart will be increased.
to the sympathetic activation. The regulating center It is interesting to note that chest discomfort more
of the body temperature finds itself in the posterior easily appears in a cold environment or as an direct
part of the hypothalamus while a warm receptor is answer to cold, like, e.g., during a walk against cold
being localized in the anterior part of hypothalamus. wind and during angina decubitus, even when the
The latter registers the temperature of the body core skin enters into contact with cold bed cloth. The
- core temperature. The skin cold receptors register cold as such (as we have mentioned above) stimulates
the temperature on the periphery and send the in- sympathetic NS. In addition, as an answer to cold,
formation on it to the thermoregulation center (body thyroxin is secreted, further potentiating the effect of
shell temperature). The skin warm receptors seem sympathetic NS. All this increases the myocardium
to be of no importance for thermoregulation. The requirements of oxygen.
organism can get rid of the heat by peripheral va- Hyperthyroidism comprises symptoms that are
sodilation and by sweating. As far as heat generation without any doubt mediated by the sympathetic NS.
492 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

The accentuation of the sympathetic effects is here tum contain precisely described areas, correspond-
probably achieved through the beta receptors. On ing to precise cortical areas. This underlines the
one hand, as an answer to thyroxin, the number of importance of striatum in the architecture of CNS.
receptors is increased, on the other hand the asso- A projection from striatum to the pale globe (stri-
ciation of the receptor with adenylatecyclase is fa- atopallidal tract) entertains, by means of fascicullus
vorized. Both of these effects lead to an accentuated thalamicus, a close relationship to the ventrolateral
reaction to an adrenergic stimulus in the correspond- thalamus. Ventrolateral thalamus provides fibers to
ing tissue. As in hyperthyroidism the plasmatic lev- the area 4 of the cerebral cortex. The activity of this
els of catecholamines rest unchanged (i.e. the activity neural network is modified by 3 circuits:
of the ANS is not directly influenced by thyroxin) we
1. striatum – pale globe – thalamus – striatum
consider the mentioned effects of thyroxin as causal
in the relation to the signs of sympathetic hyperac- 2. pale globe – subthalamic nucleus – pale globe
tivity in hyperthyroidism.
3. striatum – substantia nigra – striatum
The ANS activity is also affected in Parkinsons
It is namely this third accessory circuit that plays
disease. The pathophysiology of this disease has not
a decisive role in the pathophysiology of Parkinsons
been thoroughly explained yet. In order to approach
disease. Tremor and rigidity are the main symptoms
this problem we must first touch, at least for a very
in parkinsonism. The rigidity of parkinsonian type
basic reference, the neurophysiology of basal ganglia.
is a consequence of malfunction in the control mech-
It is important to know that the human motor sys-
anisms of muscle tonus (the gamma system plays the
tem can be devided into pyramidal and extrapyra-
important role here). Experiments on animals show
midal. However, this division is very artificial. In
that a lesion of the substantia nigra evokes rigidity.
reality the two parts are very tightly interconnected
There are still obscure points in our understanding of
on several levels and work as a functional unit.
the pathomechanisms of rigidity in Parkinson’s dis-
The planning of movements takes place in the ease as well as of the clinical manifestations of the
basal ganglia. The neurophysiological cascade of vol- disease as such. A deficient nigrostriatal pathway
untary movements starts with the s.c. readiness po- seems indeed its most decisive element and the ther-
tential, a diffuse activity on the cortex of both hemi- apy of the disease is oriented to a correction of such
spheres, which later concentrates on the associative deficit. (The locus coeruleus changes in parkinson-
cortex of the corresponding hemisphere (areas 5, 6 ism are of unclear consequence on the pathomech-
and 7 after Brodmann). The activity then spreads to anism of the disease.) The substantia nigra is, ad-
the cerebellum and to basal ganglia. These pathways ditionally to the system described, associated by its
then converge in the ventrolateral nuclei of thalamus efferent fibers with superior colliculus and reticular
and continue from there by means of the thalamo- formation (nigrotectal fibers). Tremor is explained
cortical fibers into the primary motor cortex (pre- by a lesion of those structures near the black sub-
central gyrus). There the pyramidal pathway is acti- stance, where its afferent fibers from the cerebellum
vated. The collaterals of this pathway reach the cere- and the red nucleus pass.
bellum, where fine adjustments of movements take If we consider that we have a lesion of substantia
place. (Except the pyramidal tract there are tracts nigra and that the nigrostriatal tract is composed of
originating in red nucleus - cerebellum, superior col- dopaminergic neurons, in fact we have a deficit in the
liculus, vestibular nuclei and reticular formation.) dopaminergic system. A dysbalance appears with a
This description clearly reveals the key role of basal prevalent activity of the cholinergic neurons. The
ganglia in movement preparation. As for every basal situation of parkinsonism is, of course, much more
ganglion, however, their individual functions remain complicated, deficiencies of other transmitters like
unclear. The neural signal at this level is processed the noradrenaline, serotonin and GABA are implied.
in 4 pathways. The main striatum circuit represents It has been impossible to restitute the exact cascade
one of them. The excitation of the corresponding of events until know. The mentioned prevalence of
cortical region (area 5,6,7) passes through the cor- the cholinergic system leads to a manifestation of
ticostriate tract to reach the striatum (caudate nu- parasympathetic hypertonicity. Sometimes the sali-
cleus and putamen). Both components of the stria- vation is increased, sometimes it is unchanged, but
6.24. Autonomous (vegetative) nervous system (A. Král’) 493

the deglutination is impaired, other GIT troubles oc- tension the baroreceptor fails to respond to steping
cur, the blood pressure is instable with a tendency over the upper threshold of blood pressure. Hyper-
to hypotonia. tension does not improve easily, as the regulation as
There is recent knowledge that the disease could such is affected, namely its feedback (the afferenta-
be associated with a disturbance in the serotonin- tion of the sympathetic NS). The baroreceptor is a
melatonin system (biorhythms). Other sources sensor monitoring changes in blood pressure, not its
claim that the primitive damage might concern the absolute value. If (e.g. as a result of repeated stress
glutamate-producing neurons (what seems to be as- situations) the pressure repeatedly rises as a physio-
sociated with a disturbed NO production) and the logical response to a nonphysiological stimulus, and
deficiency of the dopaminergic neurons is just sec- if this situation does not rapidly improve (in animals
ondary. stress is usually followed by physical activity, while
The ANS is equally involved in the pathogenesis in man a stress stimulus is usually not followed by
of bronchial asthma, migraine, other cases of cefalea, physical activity, so that the elevated blood pressure
etc. The ANS represents a sort of neuralgic point persists much longer), the baroreceptors stop react-
in the pathogenesis of terminal states as they de- ing to the elevated blood pressure (they adapt to it).
cide about their reversibility. If, in these states, the Like this, a nonphysiological value of blood pressure
ANS is disturbed, the homeostasis regulation fails will be interpreted as a physiological one at the level
and death appears. of baroreceptor. Thus, a tendency to react to physio-
logical values as to values in the hypotensive range
6.24.5.1 Pathophysiology of the ANS will appear. The hypertension becomes fixed. Of
course, there can be other reasons for a longer last-
Diseases in which the ANS is primitively concerned ing elevation of blood pressure, like increased sodium
can be inborn (consequences of factors having ap- intake, etc. (see chapter on hypertension), but the
peared intrauterinary or intra partum), induced by pathophysiological mechanisms that appear further
an invasive intervention into the ANS (inflamma- are thought to be common for those situations.
tions, injuries, etc.) or may even be functional in
If we see the problem from this point of view, the
character (alteration in the interconnection patterns
therapy of hypertension by vasodilators and diuretics
of the ANS centers, e.g. based on pathological af-
can seem delicate, as both medicaments show a ten-
ferentation). The cause and the character of the
dency to further activate the sympathetic NS. We
problem is often not clear. This can be explained
must take into account, however, that if their hy-
by the open character of the ANS and by a large
potensive effects are maintained for a longer time,
convergence and divergence inside the system (ANS
they will have the tendency to reset the barorecep-
is influenced by a multitude of other systems and in
tors back to lower blood pressure values. This also
turn it influences the activity of several other sys-
gives the sense of such therapy. Then we also under-
tems).
stand that the therapy with antiadrenergic agents
A classical example of a disease associated with
will be justified.
primitive alterations inside the ANS is essential hy-
pertension. The organs participating in the regu- Dysautonomia (autonomic neuropathy) is a dis-
lation of blood pressure are the vessels themselves, ease englobing the classical neuropathies, with re-
the heart, the kidney, the adrenal gland, all of them gard to autonomic nerves. It is characterized by
underlying a regulation by the ANS. We shall not structural modifications occurring on the pregan-
explain the details of this regulation here, as it is glionic as well as on postganglionic neurons. It
described in the chapter dealing with hypertension. appears usually as a part of a picture of an over-
An involvement of the sympathetic NS in the de- all polyneuropathy (e.g. in diabetes mellitus, al-
velopment of an elevated blood pressure is evident. coholism, to name two most mentioned), or, sel-
However, the evaluation of the degree of its involve- dom, as symptoms of an isolated autonomous neu-
ment is very complicated, especially because there ropathy. Among the symptoms we can find ortho-
is a number of factors impaired in hypertension and static hypotension (will be explained in detail be-
the temporal consequence in the pathophysiology is low), syncopes, anhidrosis, hypothermia, vesical ato-
difficult to assess. It seems that in essential hyper- nia, dry mouth, impotence, etc. Rarely hyperfunc-
494 Chapter 6. Pathophysiology of the nervous system ( M. Bernadič et al.)

tional symptoms are seen: hypertension, diarrhea, and of body temperature regulation.
hyperhidrosis, sometimes tachycardia. In the Babinski-Froment syndrome reflex trophic-
Orthostatic hypotension is most frequently ity disturbances appear, most often following in-
mentioned as a nosological entity. Principally, we juries. It is supposed that if there is a predisposition
must be aware of the fact that here again (similarly to excessive vegetative reactions then even a small,
to hypertension) the autonomous system must be af- traumatic or other pathologic process can make such
fected. Otherwise it would be able to compensate the troubles apparent. A modified somesthesia seems to
disorder to a large degree in activating the sympa- be an important element of the disease. Sometimes
thetic NS. Behind a significant postural hypotension osteoporotic changes are found (Sudeck’s atrophy)
either a deficient intravascular volume can be found accompanied by modified tonus and other symptoms.
(that can no longer be compensated by the ANS) or It is interesting that this disease state does not touch
disturbed circulatory reflexes. Its picture illustrates any typical area of innervation of a nerve or nerve
diseases of the neural system as tabes dorsalis, sy- root. A similar syndrome is the algodystrophic syn-
ringomyelia or diabetes mellitus. But also receptor drome, with pain being the main symptom.
blockers, given for a therapeutical purpose, can lead The sympathetic ganglia of the neck can be in-
to orthostatic hypotension. volved in pathological processes touching the neck
In the case of idiopathic orthostatic hypotension area. Here the Claude-Bernard-Horner syndrome
(Shy-Drager syndrome) the pre- and postganglionic (ptosis, miosis and enophthalmus) is associated with
sympathetic neurons are affected. The term ”idio- a disturbed sympathetic innervation of the eye. If
pathic” is for its unknown cause. The described neu- a disturbance in trophicity of a delimited skin area
ropathologic changes are located in the brainstem, appears (corresponding to the innervated area of the
basal ganglia and intermediolateral column of the lesioned ganglion) associated with a cervicobrachial
thoracic spinal cord. Abnormalities are also found or cervicocranial syndrome, it will be designed as
in the peripheral autonomic ganglia. The changes quadrant syndrome.
include cell loss and an accompanying gliosis, which Causalgias represent another interesting problem.
are widespread and symmetric, affecting the caudate They are perceived as intense pain, accompanied
nucleus, substantia nigra, locus coeruleus, olivary by trophicity and vasomotor disturbance. They are
nuclei, dorsal vagal nuclei and sometimes the cere- most often induced by a partial lesion of the periph-
bellum. The s.c. Lewy bodies typical of Parkinsons eral mixed nerve. The manifestation of such lesion
disease are present in some cases. The disease can is a consequence of interruption of some nerve fibers.
manifest all symptoms of dysautonomia. The hy- In addition, a short circuit of electric activity arises
potension does not improve sufficiently after nore- between the vegetative, sensitive and motor fibers
pinephrine. on one side and nociceptive fibers on the other. This
We very often hear about the disease state of gives rise to an intensive pain whenever an irritation
the ANS designed as neurovegetative dystonia. Its of the (e.g.) sensitive nerve in the given area takes
etiology is unknown, according to some authors it place. It is a problem very difficult to treat.
could be a congenital condition, marked by func- Another serious problem are vasoneuroses. They
tional modifications in the integrative parts of the exist in two distinct forms: vasoconstrictive and va-
ANS leading to a dysbalance of efferent autonomous sodilatative ones. Raynaud disease, for example, is
pathways. The whole system is destabilized and this a vasoconstrictive alternative. The etiology of this
becomes apparent when reactions to deviations of disease is not clear. The existing dysbalance in ANS
regulated variables are required (reaction to the per- manifests itself by paroxysmal vasoconstrictions in
turbations in the controlled variables) – they are not the limbs. It is characterized by episodic digital is-
adequate. Such dysregulation can even impair the chemia clinically manifested by the sequential devel-
symptomatology in question. In psychiatry, for an opment of digital blanching, cyanosis and rubor of
equivalent dysbalance the term neurasthenia is ap- the fingers or toes following cold exposure and subse-
plied. The instability of the ANS activity can man- quent rewarming. Emotional stress may also precipi-
ifest itself as heart rate lability, blood pressure in- tate this phenomenon. The therapy of this condition
stability, GIT disturbances, troubles of the sweating is very difficult. Among the vasodilative forms
6.24. Autonomous (vegetative) nervous system (A. Král’) 495

we can name erythromelalgia. Its pathogenesis is hemorrhage into the 3rd ventricle. If the poste-
supposed similar to that of causalgias. rior parts of the hypothalamus are touched, poikilo-
In the category of rare ANS diseases we can men- thermia is diagnosed (in hypothermia other possible
tion, e.g. facial progressive hemiatrophy (Romberg). diagnoses like renal insufficiency and hypothyreosis
This disease is the consequence of a traumatic or should be eliminated).
degenerative lesion of the facial nerve. Its associa- Lesions of the anterior part of hypothalamus can
tion with encephalitis, sclerosis multiplex, tabes dor- lead to insomnia (there are several other structures
salis and certain tumors has been described. It can with such importance in the CNS, e.g. nuclei raphe
also appear as a sign of a neck sympathetic lesion. in reticular formation). If lesions are localized in
The disease gives rise to facial neuralgias and trophic the posterior part of this structure, the water (and
changes. It often improves spontaneously and is be- also food) intake can be modified. Rarely a primitive
ing considered as benign. polydipsia without the context of diabetes insipidus
can be diagnosed.
Progressive facial hemihypertrophy (Freidrich) is
Rare cases of diencephalic epilepsy with par-
a disease characterized by facial hemihypertrophy.
oxysmal states of sympathetic and parasympathetic
Contrary to Romberg disease it is not associated with
hyperactivity have been described (while parasym-
pain. Here a hypertrophy of one half of the face
pathetic hyperactivity can be achieved by stimula-
appears (usually the right one). Its etiopathogenesis
tion of anterior parts of hypothalamus, sympathetic
remains largely unknown, a primitive participation of
hyperactivity can be induced by stimulation of its
the ANS is supposed. Its progression usually stops
posterior part). A classical example of an internal
spontaneously.
disease associated with sympathetic hyperactivity is
Diencephalopathy is a term that was frequently pheochromocytoma. It is a (most often) benign tu-
used in the past, but has been abandoned recently. mor of adrenals or sympathetic ganglia, secreting
It was used to design ANS changes induced by patho- catecholamines. It manifests itself by sympathetic
logical processes in the diencephalon. Today, the hyperactivity and by the presence of an elevated level
term diencephalic syndrome is still used for some of of vanilmandelic acid in the urine.
them. Here, the etiologies are multiple, from tumors Computer models indicate that a part of A-V
through vascular lesions and injuries to encephalitis. blocks could be the expression of a modified ratio
Symptomatology appears only if the lesion is bilat- of the sympathetic and parasympathetic tonus. The
eral. There are several centers implied in the food role of the ANS is equally being considered in the
intake regulation in the hypothalamus. Food intake sudden cardiac death syndrome.
(its initiation and its interruption) can be influenced
by opioid peptides and by neuropeptide Y. Lesions of
6.24.5.2 Determination of ANS activity
the corresponding regions can lead to troubles of food
intake. The hypothalamic type of obesity can be as- The activity of the ANS can be evaluated by a test
sociated with lesion of the ventromedial nuclei of the called the sympathetic skin response. It consists of
hypothalamus. In the case of diencephalic syndrome measuring the resistance changes on the skin follow-
due to some tumors loss of weight with no limitation ing ANS stimulation by e.g. electrical stimuli, noise
of food income can be found. or profound inspirium. In these cases we are in fact
In the hypothalamus, as we have already men- monitoring the activity of the sympathetic fibers that
tioned, there is also the regulatory center for body mediate sweating.
temperature. Paroxysmal alterations of body tem- Another possibility is to analyze the R-R interval
perature in the sense of hyperthermia as well as hy- variability on the ECG and to perform it in resting
pothermia can be observed, for example, during a conditions as well as during profound respiration.
Chapter 7

Pathophysiology of the
gastrointestinal tract

perficial cellular layer of the gastroinstestinal tract

turns over in its entirety every 24 to 72 hours. Owing
to this fact, the entire tract is protected against var-
7.1 Introduction ious impairments. On the other hand, the capability
of proliferation can be disadvantageous regarding the
impact of carcinogens on DNA, and from the aspect
of the origin of neoplasms which are very frequent in
The essential role of the gastrointestinal tract is
GIT.
to prepare and process components of food in order
to obtain products which may be easily resorbed. Impairments within GIT can be brought about
The second function of GIT resides in elimination of by alteration in absorption and secretory functions
waste products. of the mucosal surface. Impairmets of mucosa can
The entire GIT is a continuous long tube of uneven result in bleeding, excessive fluid loss, invasion of
width and shape with organs which participate in the pathogens, as well as deterioration of absorption of
processes of digestion. The luminal surface of the di- nutrients. The disturbance of these processes may be
gestive tract is lined with mucosa which contains an of local character afflicting only certain areas of GIT.
enourmous amount of cells with an outstanding capa- Absorption and excretory functions of GIT depend
bility of transmembraneous absorption and secretion. also on the muscular layer, the coordinated action of
The absorption is the basic acitivity of the digestive which propels the chyme via the tract. The intestinal
tract. The mucosa of the entire tract represents an motility depends on the nervous and humoral regu-
ideal barrier against all potentially pathogenic sub- lations. Impairments in intestinal motility are very
stances emerging inside its lumen. This function frequent. Approximately 15 % of adults suffer from
can be procured solely by an intact luminal surface, impaired motility of the large intestine. Abdomi-
namely by means of its protective cells. Intraepithe- nal pain and nausea may arise resulting from motil-
lial lymphocytes suppress the response of organism ity impairment, or from its combination with other
to the presence of a large amount of potentially anti- discrete disturbances. Essentially they can arise di-
genic substances within the lumen. They inhibit the rectly due to motility impairment, or indirectly ow-
activation of inflammatory processes. Inversely, lam- ing to the presence of inflammatory mediators, such
ina propria and submucosa contain a large amount as metabolites of arachidonic acid which have an im-
of leukocytes which are prepared to interfere in case pact on the activity of smooth muscles. However,
of mucosal surface impairment. Consequently, the the development of the defect per se depends on the
entire digestive tract is predisposed to inflammatory particular section of GIT that is involved.
processes. GIT impairments can appear in consequence of
The mucosal surface has an outstanding potency various changes in organism. They can develop from
to regenerate the epithelial cells. Assumedly, the su- renal, endocrine and other diseases of more remote

496
7.2. Oesophagus 497

organs and systems, as well as due to administration pends of the velocity of secretion. Slow production
of a number of substances. intensifies reabsorption of sodium, chlorides and bi-
Digestion begins in the oral cavity during mastica- carbonates in the draining ducts of salivary glands.
tion of food and continues in the stomach where the
chyme is triturated with hydrochloric acid, mucus,
enzymes and other components of gastric juice. Par-
tially processed chyme is propelled from the stomach
into the small intestine where hepatic and pancreatic 7.2 Oesophagus
secretions are admixed. Their function is to split the
nutrients and thus to enable absorption of proteins,
carbohydrates and fat. Useful substances resulting
from digestion are absorbed through the wall of the
small intestine into the blood and lymphatic vessels; 7.2.1 Deglutition
thereafter they are transported to the liver where
they are stored or processed further. Chyme compo- The oesophageal anatomical structure is relatively
nents which are either not useful or not utilised enter simple. Basically, it is a tube which connects
the colon. Water and some of the substances are ab- oropharynx with the stomach. Deglutition is a pro-
sorbed in the colon being thereafter eliminated by cess which forces the food bolus to proceed in aboral
urine. The remnant substances constitute the basis direction to the stomach. This action takes place
of stool. owing to the contraction of circular and longitudinal
muscles of the oesophagus. The upper third of the
All processes carried out in GIT, apart from mas-
oesophagus is equipped with striated musculature
tication of food and defecation, are controlled by
innervated by motor nerves. The lower two thirds
the autonomous nervous system and hormones. The
of the oesophagus are constituted of smooth mus-
autonomous nervous system, its sympathetic and
cles which are innervated by preganglionic cholin-
parasympathetic parts, are controlled by higher cen-
ergic fibers of the vagus nerve. The oesophagus is
tres in the brain as well as affected by local factors.
an ideally enclosed tube. Upper oesophageal sphinc-
The oral cavity basically serves for the pre- ter inhibits penetration of air into the oesophagus
preparation and mixing of food with saliva. The oral during inspiration. The lower oesophageal sphincter
cavity contains many nervous endings which trigger inhibits regurgitation of the stomach contents. This
the process of digestion as soon as the food enters the function of the lower sphincter is of great importance
oral cavity. The lingual surface contains thousands because the intraabdominal pressure is higher than
of chemoreceptors and taste buds which are able to the intrathoracic or atmospheric pressures.
distinguish taste components of food: salty, bitter, The act of deglutition is a complex action which
sweet, and sour. The entire process has its meaning is regulated by the deglutition centre localised in the
in initiating the secretion of gastric juice. reticular formation. Basically, the deglutition takes
The oral cavity is moistened by saliva originat- place in two phases: oropharyngeal phase which
ing from three pairs of salivary glands, namely sub- is governed by voluntary control, and oesophageal
mandibular, sublingual and parotid. The principal phase. The task of the oropharyngeal phase of deg-
constituents of saliva are water, mucus, sodium, bi- lutition is to propel a part of food into the upper oe-
carbonates, chlorides and potassium. Salivary alpha- sophagus. A sufficiently high pressure must be devel-
amylase, the further significant component of saliva oped in order to overcome the resistance of the upper
(previously referred to as ptyalin) initiates the di- oesophageal sphincter. The basic fact in this phase is
gestion of carbohydrates already in the oral cavity. that the deglutition is simultaneously accompanied
Further digestion of carbohydrates continues later in by stoppage of respiration, and the epiglottis inhibits
the stomach. the penetration of food into the trachea.
Salivation is controlled by the parasympathetic The oesophageal phase of deglutition begins as
and sympathetic nervous systems. Application of soon as the food bolus enters the oesophagus. Peri-
atropine inhibits salivation and evokes the feeling of staltic movements of the oesophagus transport the
dryness in the mouth. The composition of saliva de- bolus as far as to the lower oesophageal sphincter.
498 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

The latter reflexively becomes relaxed as the food Odynophagia is a pain which appears in coinci-
bolus occurs in its proximity. After the transition of dence with deglutition. It usually is associated with
the bolus, the tension of the distal sphincter is re- oesophageal obstruction, mucosal impairment, infec-
newed. The oesophageal phase of deglutition takes tion or reflux oesophagitis.
5–10 seconds. Under physiological conditions, the Abrupt retrosternal pain is most frequently a
bolus’s motion velocity is 2–6 cm/sec. symptom of ischaemia of the heart muscle (angina
Each food bolus when forced into the oesophagus pectoris), but it can represent a consequence of ab-
stimulates the receptors sensitive to distension. Con- normal motoric oesophageal function, or diffuse oe-
sequently, the impulses of the deglutition centre in- sophageal spasm.
crease, thus initiating the peristaltic movements of
the oesophagus. The distal sphincter constitutes a 7.3.2 Gastro–oesophageal reflux
barrier between the oesophagus and stomach. The
tension of the distal oesophageal sphincter is affected The gastro-oesophageal reflux represents a reverse
by nervous and hormonal pathways. Progesteron, flow of the gastric or duodenal contents into the oe-
secretin and glucagon affect the distal oesophageal sophagus. It appears owing to a wide spectrum of
sphincter in sense of its relaxation. On the contrary, impairments. The oesophagus is normally protected
gastrin increases the tension of the lower sphincter. against the prolonged effect of gastric acid, pepsin,
During deglutition, the sphincter’s relaxation is pro- bile acids and pancreatic enzymes. The protection is
cured by the vagus nerve. carried out by three mechanisms:
1. the antireflux barrier is formed by tonic contrac-
tion of the lower oesophageal sphincter
2. fast backward shifting of the regurgitated mate-
rial
7.3 Diseases of the oesophagus
3. neutralisation of the acidic material in the oe-
sophagus by swallowed saliva
The patients with gastro-oesophageal reflux usu-
ally develop one of the following detectable impair-
7.3.1 Dysphagia ments:
Impairments of oesophageal functions are manifes- a) decreased tension or sluggishness of the lower
tant by swallowed food being held up in its passage oesophageal sphincter,
within the oesophagus. The patient is often able to
assess the site where the bolus has stuck. Dyspha- b) impaired coordination of relaxation of the lower
gia can be caused by impaired oesophageal motility, oesophageal sphincter
oesophageal stricture, benign or malign processes. If
c) decreased neutralisation and oesophageal peri-
dysphagia appears after meal, it is mostly due to the
stalsis
impairment of motility. The patient is unrestful, per-
forms the so-called Valsalva maneuver, or repeatedly The gastro-oesophageal reflux can cause the devel-
swallows until the bolus is forced further. opment of oesophageal peptic ulcer or stricture.
Pyrosis is a frequent oesophageal symptom which
is percieved as a burning retrosternal discomfort. 7.3.3 Motor impairments of the oeso-
This sensation is caused by the reflux of the gastric
phagus
contents into the oesophagus. It can be suppressed
by antacids. More frequently it appears after occu- Impairments of oesophageal motility can appear in
pying a recumbent position. Sometimes the burning consequence of changes in the smooth musculature
retrosternal sensation is associated with a sensation (sclerodermia), or in the nervous system (achala-
of bitter or acid tastes. The reflux of the gastric sia). Systemic sclerodermia develops owing to at-
contents into the oesophagus during sleep, can cause rophic changes in the smooth oesophageal muscula-
aspiration pneumonia. ture. Muscular contractions of the lower two thirds
7.4. Stomach and duodenum (I. Hulı́n, I. Ďuriš) 499

of the oesophagus are therefore weakened and this An empty stomach contains approximately 50 ml
condition is accompanied by incompetence of the of fluid. The tension of its walls is low. At the be-
lower oesophageal sphincter. Achalasia is a condi- ginning, the intake of food causes relaxation of the
tion caused by ganglionic cellular degeneration of the gastric fundus. This relaxation is perfectly coordi-
Auerbach’s plexus. Consequently, this degeneration nated. This so-called receptive relaxation is posi-
decreases the tension and deteriorates the relaxation tively affected by gastrin and cholecystokinin. Peri-
of the lower oesophageal sphincter. The peristalsis staltic movements proceed from the fundus to the
is frequently absent as well. The particular cause of antrum. Usually, three peristaltic waves are observed
the diffuse oesophageal spasms is not known. Appli- per minute. Gastrin and the vagus nerve enhance the
cation of immunosuppressive substances can bring contractions. Cholecystokinin hinders gastric motil-
about oesophageal infection by herpes virus or by ity and consequent evacuation of the stomach. The
Candida albicans. Radiation oesophagitis appears velocity of peristaltic waves is assessed by muscular
in coincidence with the therapy of mediastinal and cells which act as pacemakers.
pulmonary malign processes. It is more pronounced The mixing of food and evacuation of the stom-
in combination with chemotherapy. ach takes several hours. When the bolus gets to the
antrum, the contraction becomes stronger. If the py-
lorus does not open, the chyme returns to the gastric
corpus. This activity is referred to as retropulsion
and enhances proper mixing of food. Each peristaltic
movement results in shifting a small bulk of prepared
7.4 Stomach and duodenum chyme via the pylorus into the duodenum. The py-
lorus, in its narrowest portion is 1.5 cm in length.
This portion contains a permanent aperture, only
2 mm in diameter.
Owing to the gastro-oesophageal and pyloric
sphincters, the stomach can retain the received food Evacuation of the stomach is a complex process
for the period which is necessary for the small intes- which depends on the conditions within the stomach
tine to become prepared to digestion. During this and duodenum, including the chemical conditions.
stage of gastric storage, the food is mixed with gas- The first products of fat digestion together with bile
tric juice. Thereafter it is released into the duode- and pancreatic juices stimulate the secretion of chole-
num in small bulks. cystokinin. The duodenum contains osmoreceptors
The structure of gastric mucosa is highly special- which are sensitive to the changes in osmotic pressure
ized. The blood supply is performed via branches of in the duodenal contents. Both hyperosmotic and
the arteria coeliaca. The largest arteries are localised hypoosmotic gastric chymes delay the gastric evacu-
along the major and minor curvatures. The stomach ation in order to maintain the isoosmotic conditions
possesses a rich collateral circulation. Assumedly, within the duodenum. Secretions of the duodenal
this fact aids to the origin of ischaemic changes in mucosa, pancreas and liver neutralise the acid gas-
the gastric wall. The venous blood is drained away tric contents within the duodenum. Evacuation of
from its right half into the vena gastroepiploica dex- the stomach is subordinated to these conditions.
tra (vena mesenterica superior) and the blood from The ingestion of food stimulates the secretion of
the left half of the stomach is drained into the vena gastric juice. The gastric mucosa produces various
gastroepiploica sinistra and venae gastricae breves substances. Parietal cells of the gastric mucosa pro-
(vena lienalis). The sympathetic and parasympa- duce hydrochloric acid and the intrinsic factor. The
thetic innervation systems are subordinated to lo- chief or central cells form pepsinogen. The compo-
cal effects and are controlled by brain centres. The sition of gastric juice depends on the velocity of its
muscular layer of the gastric mucosa (muscularis mu- production. Slow production results in low concen-
cosae) contains ”plexus submucosus Meissneri” and trations of hydrogen and chlorine ions, and the con-
the muscular layer of the stomach (tunica muscu- centration of sodium ions is high. Fast production
laris) contains a ”plexus myentericus Auerbachi”. brings about reverse conditions. Potassium is always
The subserous tissue contains a ”plexus subserosus”. released into the gastric juice in an amount exceeding
500 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

its concentration in the plasma. In general, the gas- teric plexus. The release of acetylcholine stimulates
tric secretion in the morning is low and increases in parietal and chief cells to produce HCl and pepsino-
the afternoon. It also decreases due to disagreeable gen. The G-cells in the antrum release gastrin into
odour or taste, anger, fright and pain. These sensa- the blood. The transport of gastrin into the gas-
tions and emotions are applied via the sympathetic tric glands thus stimulating the secretion of gastric
impulses and by inhibition of the parasympathetic acid. The secretion of gastric acid precedes the ar-
impulses. Inversely, aggressivity and hostility induce rival of food into the stomach. Insulin represents
an increase in secretion thus participating in the ori- another strong stimulus of gastric secretion. Owing
gin of pathological changes in the stomach. to insulin, the secretion of gastric acid is mediated
The main task of the gastric acid is to dissolve food via the vagus nerve from a special hypothalamic sen-
fiber, to extinguish bacteria brought into the gas- sor. This sensor reacts to a decreased level of glu-
trointestinal tract together with food and to convert cose caused by insulin. The recovery of the glucose
pesinogen to pepsin. The production of hydrochlo- level to the standard suppresses the gastric secretion
ric acid by parietal cells is principally based on the caused by insulin.
transport of hydrogen and chlorine ions into the lu- The gastric phase of stomach secretion begins as
men of gastric glands. High secretion of acid causes soon as the food arrives into the stomach. The ar-
that the bicarbonates originating within the produc- rival of food represents the strongest stimuli for se-
tion of hydrogen ion, return into the venous blood. cretion. Basically, they are the distension of the
This process can become manifestant as late as by stomach and the presence of digested proteins which
alkaline reaction of urine. activate the process. The distension of the stomach
activates the mechanoreceptors, and the stimulation
Gastric secretion is stimulated by acetylcholine,
of secretion is performed by the vagus nerve. The
gastrin and histamine. The vagus nerve releases
activation is mediated by acetylcholine. Therefore it
acetylcholine and stimulates the secretion of gastrin.
can be blocked by atropine. Protein chains which
Histamine is stored in enteroendocrine cells of the
get into contact with the pyloric mucosa stimulate
gastric mucosa. The gastric mucosa contains also
the release of gastrin from G-cells in the antrum. An
histamine receptors (H2 ). Antagonists of H2 recep-
increase in gastric pH up to 3.0 causes an inhibition
tors can significantly decrease the secretion of gastric
of the gastrin release.
acid in patients with gastric ulcer. Acetylcholine and
The release of gastrin is inhibited also by somato-
gastrin stimulate the chief cells to release pepsino-
statin which is produced in the antral gastric mucosa
gen during meal. The conversion of pepsinogen takes
by endocrine cells (D cells). Somatostatin reduces
place as soon as pH drops below 5.0. The optimal pH
gastric acid secretion by inhibiting gastrin release,
value for conversion is 2.0. When the gastric content
and at the same time it directly inhibitits the secre-
reaches the alkaline environment of the duodenum,
tion of the neighbouring parietal cells.
the effects of pepsin are inactivated.
The intestinal phase of gastric secretion is induced
The gastric mucosa is protected from autodiges- when the chyme reaches the duodenum. The gastric
tion by mucus. The adhesion of mucus to gastric secretion in this phase is stimulated by absorption
epithelial cells is very tight. The mucous barrier is of amino acids in the small intestine. A reverse sit-
impermeable for gastric acid. Prostaglandins partic- uation, i.e. a sufficient amount of acid chyme in the
ipate in the formation of the barrier by stimulating duodenum inhibits the gastric secretion and gastric
the production of mucus and bicarbonate, and by in- motility. The acid reaction of chyme in the duode-
hibiting the secretion of gastric acid. An impairment num stimulates the release of these intestinal pep-
of the barrier (by e.g. aspirin, ethanol, regurgitated tides which via the blood inhibits the secretion of
bile, or ischaemia) can lead to inflammation and ul- gastric acid thus restricting the intestinal phase of
cer development. gastric secretion.
The secretion of gastric acid is liable to a large
variety of effects. The cephalic phase is based on
sensory stimuli – smell, sight, and taste of food, the
process of mastication and deglutition. The cephalic
phase is mediated by vagal activation via the myen-
7.5. Diseases of the stomach and duodenum 501

7.5.1.2 Non–erosive (atrophic) gastritis

7.5 Diseases of the stomach Non-erosive gastritis is usually divided into type A
which is localised in the fundus, and type B which
and duodenum is localised in the antrum. Inflammatory infiltra-
tion can be minimal. Observations of cellular dys-
plasia and metaplasia of the gastric mucosa are fre-
quent. The development of hyposecretion is a com-
mon consequence of atrophic changes in the mucosa.
7.5.1 Gastritis The cause of non-erosive gastritis is not precisely
known. Helicobacter pylori infection is now recog-
Gastritis is inflammation of the gastric mucosa. It is nized as major cause of chronic gastritis beginning by
manifestant by histopathologic changes. Its clinical acute neutrophilic gastritis lasting 7–10 days, associ-
manifestation can be present as well. Gastritis can ated sometimes with clinical symptomatology. After
bring about an undesirable development of morpho- penetrating the viscous mucus most microbes pene-
logical changes resulting in metaplasia, dysplasia and trate regions of the tight junctions between adjanced
carcinoma. Regarding the causes and pathogenesis, mucosal epithelial cells. Epithelium responds with
we can distinguish three groups of gastritis: cellular exfoliation and regenerative changes. If the
• erosive (haemorrhagic) gastritis, Helicobacter pylori is not eradicated comes to dis-
balance between gastrin overproduction and multi-
• non-erosive gastritis plication of histamin producing cells, what can lead
to pathological circulus vitiosus and at the end to at-
• unusual or specific forms of gastritis rophy. In non-erosive gastritis the mucosal atrophy,
achlorhydria and vitamin B12 malabsorption dom-
Regarding the clinical aspect, the symptomatol-
inate. Antiintrinsic factor antibodies are present.
ogy varies greatly. Therefore, various dyspeptic and
The intrinsic factor depletion usually accompanies
postprandial difficulties are due to the absence of
such finding. After some time, pernicious anaemia
morphological findings incorrectly diagnosed as gas-
can develop.
tritis.

7.5.1.1 Erosive (haemorrhagic) gastritis 7.5.1.3 Specific forms of gastritis

Erosive (haemorrhagic) gastritis develops in a large In the past, gastritis occured mostly in consequence
number of patients who use aspirin, or other non- of tuberculosis and syphilis. Currently, gastritis
steroidal anti-inflammatory drugs (NSAID). There- dominates in coincidence with AIDS. This group in-
fore, this type of gastritis is usually referred to as cludes also gastritis due to infectious diseases of prox-
NSAID gastritis. At the mucosa there are petechiae, imate and remote organs. Oesophageal candidosis
erosions and mucosal ulcerations. Superficial gastric can develop on the background of gastritis.
lesions can cause chronic blood losses and the devel-
opment of hypochromic anaemia. 7.5.2 Peptic ulcer
Similar changes in the gastric mucosa may develop
in patients exposed to severe stress. Therefore they Peptic ulcer refers to ulcerations in the upper part
are observed in patients hospitalized in intensive care of the gastrointestinal tract. This chronic disease is
units, in coincidence with acute diseases and surgi- manifestant by characteristic signs. Ulcerations oc-
cal interventions, hypothermia, and trauma. Even cur especially in the proximal part of the duodenum
burns can cause gastric ulcer, referred to as Curling’s and in the stomach. The pathogenesis is based on
ulcer. Trauma, CNS disturbances, or surgical inter- the effect and relationship of two common factors,
vention can cause ulcerations which are referred to namely hydrochloric acid and pepsin. Ulcers devel-
as Cushing’s ulcers. Excessive alcohol abuse causes oped in coincidence with Zollinger-Ellison syndrome
haemorrhages which are revealed by endoscopic ex- are considered to constitute their independent form.
amination and referred to as haemorrhagic gastritis. It is caused by excessive production of gastrin by
502 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

gastrin-secreting islet cell tumours (gastrinoma) lo- drochloric acid increases. Receptors of parietal cells
cated most commonly in the head of pancreas. Gas- stimulated by gastrin, affect the activity of other re-
trinomas also have been located less commonly in ceptors and simultaneously activate the intracellular
other sites (duodenum, antrum). messenger, in this case the calcium ions. The latter
A decisive responsibility for the development of activate the protone pump which produces hydrogen
the peptic ulcer, as presented above, resides on the ions. The mucosal glands of the stomach contain
gastric acid and pepsin. They can be referred to mast cells. The cytoplasmic granules of mast cells
as being aggressive factors. Against them, stands contain large amount of histamine. Mast cells are
the mucus layer constituting a protective mechanism localised in between every two or three parietal cells.
against auto-digestion. Histamine is considerated as the last link in the chain
of cholinergic or gastrin stimulations. The parietal
Aggressive factors (hydrochloric acid and pepsin).
cells contain histamine receptors, referred to as H2
Parietal cells secrete hydrogen ions in concentration
receptors. These receptors can be inhibited only par-
which is three times as high as the concentration of
tially by the classic antihistamines which inhibit H1
hydrogen ions present in the blood. Each secreted
receptors. H2 receptor antagonists (cimetidine, ran-
hydrogen ion combines with a chlorine ion. The final
itidine, famotidine and nizatidine) inhibit the basal
step in the secretion of hydrogen ions is performed by
secretion and secretion which appears in response to
means of the proton pump which includes the specific
food intake, gastrin, histamine, hypoglycaemia, or
K+ , H+ -ATPase occuring on the membranes of mi-
stimulation of the vagus nerve. This implies that
crovilli. This K+ , H+ -ATPase exchanges hydrogen
histamine has a significant role in the secretion of hy-
for potassium across the microvillus membrane. The
drochloric acid. The protone pump in parietal cells
parietal cells produce a pure solution of HCl which
is activated by means of cAMP.
mixes with the secretion of non-parietal cells.
A decrease in gastric pH below 1.5 entirely blocks
The HCl secretion is regulated by chemical, ner- out the production of gastrin. Somatostatin which
vous and humoral factors. The membrane of parietal inhibits also the release of gastrin, is produced by D
cells harbours specific receptors (H2 receptors) re- cells in the mucosal glands in the pyloric antrum. Its
sponding to histamin released from the neigbouring local effect can also be applied as D-cells are localised
mast cells. Then there are receptors sensitive to mus- in the proximity of G-cells. Pepsin has a significant
carine effects of acetylcholine which is released by the position in the pathogenesis of the ulcerative disease
vagus nerve’s endings. Parietal cells contain recep- of the stomach and duodenum. It is produced from
tors which respond to endogenous circulating gastrin. pepsinogen which is secreted by the chief cells in the
Gastrin is the strongest stimulator of gastric acid se- gastric body and fundus (pepsinogen 1) and pyloric
cretion. It occurs in form of secretory granules in glands (pepsinogen 2). The production of pepsinogen
G cells which are spread individually or in small clus- is followed by its conversion to an active proteolytic
ters among epithelial cells in the medium and more enzyme – pepsin. The conversion is carried out un-
profound parts of glands in the pyloric antrum. Gas- der the influence of hydrochloric acid. Pepsin has
trin is contained by tissues and body fluids in several its optimum of effect at pH ranging from 1.5 to 2.0.
forms. Its basic form in the glands of antral mucosa When pH increases to 4.0 the activity of pepsin is
is represented by heptadecapeptide which is consti- gradually brought down and at the value of 7.0 it is
tuted of 17 amino acid remnants (G 17). Big gastrin entirely inhibited.
is constituted of 34 amino acid remnants (G 34). The
half-life of G 17 is shorter than that of G 34. Gastrin
occurs also in the duodenal mucosa, especially in its 7.5.2.1 Mechanisms protecting the mucosa
proximal part. The effects of both gastrin and va- from autodigestion
gus nerve on the production of hydrochloric acid are The protection within the stomach is carried out
tightly associated. by mucus. Mucus is produced continuously by gas-
Stimulation of the vagus nerve supports the re- tric mucous cells of the gastric mucosal epithelium
lease of gastrin into circulation and simultaneously and gastric glands. The production of mucus is in-
increases the response of parietal cells to the cir- creased in response to mechanical stimuli, chemical
culating gastrin. Consequently, the secretion of hy- irritation and cholinergic stimulation. Mucus consti-
7.5. Diseases of the stomach and duodenum 503

tutes an insoluble layer lining the surface of mucosa accordance between the participating factors.
in width of 0.6 mm. In addition to the mucus layer, In the protection of gastric mucosa, a significant
a soluble phase of mucus is present also in gastric role is played by endogenous prostaglandins which
juice. Mucus is basically constituted of glycoprotein. are present herein in a large amount. Foremostly
It is a heterogenous substance containing glycosy- the E series of prostaglandins can inhibit the mu-
lated polymers joined by disulphidic bridges. Gas- cosal impairment in several modes. They especially
tric mucus contains also fatty acids. This condition stimulate the secretion of mucus and bicarbonate in
contributes to its viscosity and ability to slow the gastric and duodenal mucosae. Prostaglandins par-
diffusion of hydrogen ions. Mucus maintains the pH ticipate in optimalisation of gastric mucosal blood
gradient between the epithelial surface and gastric flow. They also maintain the integrity of gastric mu-
lumen. Preservation of the intact quality of mucus cosal barrier and enhance regeneration of impaired
requires the mucus to maintain its neutral values of mucosa.
pH. In addition to its proteolytic activity, mucus pro-
cures a one-way flow of hydrogen ions and inhibits 7.5.2.2 Duodenal ulcer
the backward diffusion of pepsin. Mucus yields bac-
teriostatic properties. It is indeed interesting that Duodenal ulcer is a chronic and recurrent disease.
the gastric mucus also contains antigenic determi- The duodenal ulcer is strictly demarcated, most fre-
nants. quently oval lesion. Its diameter does not exceed
1 cm, rarely reduces below 3 mm. In cases of such
Under normal circumstances, the mucus layer ide- a reduction it is not radiologically detectable. It
ally adheres to the mucosal surface. It constitutes can be confirmed but by endoscopic examination or
a one-way barrier against the backward diffusion of post mortem. Duodenal ulcers extend into submu-
hydrogen ions into the cells through the mucus. This cosa and muscularis propria. The defects are usually
fact can represent a very important factor which surrounded by granulation tissue and to a certain ex-
principally protects the mucosa from impairment in- tent by fibrosis. The base of the ulcer contains blood
ducible by pepsin. The mucous barrier can be easily or exudate with erythrocytes and cellular inflamma-
disturbed by e.g. bile acids, ethanol, and weak or- tory infiltration. More than 95 % of cases develop an
ganic acids. The mucous barrier can be disturbed ulcer localised approximately 3 cm from the junction
by a number of drugs, especially nonsteroidal anti- of the pyloric and duodenal mucosae. The prevalence
inflammatory drugs and salicylates (aspirin). An of duodenal ulcers is not precisely known. It occurs
impairment of mucus does not have to be compre- in 6–15 % of the population. The past years yield
hended in the morphological sense. It is manifes- a moderate decrease in the occurrence of duodenal
tant in the fact that mucus, albeit morphologically ulcers especially in men. Approximately 10 % of the
present, ceases to represent a barrier for the penetra- population have or have overcome duodenal ulcers.
tion of hydrogen ions. The impairment can involve Duodenal ulcers occur 3 times more often than gas-
a break down of the disulphide bonds. Bile acids tric ulcers.
can alter the currently existing electric charge of the The production of hydrochloric acid in the stom-
mucus. The impairment of the mucous barrier in ach is an inevitable condition for the development
the above mentioned sense can represent the cause of duodenal ulcers. A part of patients yield an in-
of cellular impairment by acids and pepsin. Conse- creased secretion of hydrochloric acid, but a part of
quently, histamine can be continuously released from them have normal secretion. Patients with duodenal
mast cells thus leading to permanent secretion of hy- ulcers have 1.9 billion parietal cells with the maxi-
drochloric acid. This impairment can be succeeded mal capacity of 42 mmol of HCl per hour. Persons
by impairment of small vessels with mucosal haemor- without duodenal ulcers have approximately 1 billion
rhages and erosions. The principal condition, under parietal cells with the maximal secretion of 22 mmol
which the protective properties of mucus come into of HCl per hour. Some patients have an increased
effect, is represented by normal blood flow via the secretion of pepsin and an increased level of pepsino-
gastric mucosa. Each reduction in the blood flow gen I in the serum. Ulcers develop where there is an
is associated with a backward diffusion of hydrogen unfavourable balance between the acid-pepsin secre-
ions. Then the stage of impairment depends on the tion and the protective properties of mucus. After
504 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

an intake of fully valuable food the patients with ing gastric. They are classified as duodenal ulcers
duodenal ulcers yield normal concentrations of gas- as their clinical symptomatology is equal to those
trin in the serum. However, after an intake of food localised in the duodenum.
high in protein, the serum levels in comparison with
healthy people increase. After adminstration of gas- 7.5.2.3 Gastric ulcer
trin the patients with gastric ulcers yield a higher
secretion of hydrochloric acid when compared with Gastric ulcers most frequently occur in the sixth
healthy people. Furthermore, intragastric acid does decade of life. They are more frequent in males. Ul-
not inhibit sufficiently the release of gastrin. Evac- cus ventriculi is a variously profound defect capable
uation of the stomach is enhanced, resulting in an of penetration. Histologically it resembles the duo-
increased supply of acid into the duodenum. denal ulcer. The difference resides in the fact that
Duodenal ulcers occur more frequently in patients the surrounding tissue is more markedly afflicted by
with a positive family history concerning this dis- local gastritis, often with intestinal metaplasia. A
ease. Duodenal ulcers occur prevalently in persons prevalent proportion of ulcers is localised in sites
with the blood group 0. An increased incidence is with more intensive acid production, most frequently
observed in the presence of HLA–B5 antigen. An in- in the site of the interface between the gastric body
creased level of pepsinogen I in the serum is present and so-called physiological antrum. Benign ulcers
in 50 % of patients. are rarely localised in the subcardial area.
Cigarette smoking relatively closely correlates The production of acid in patients with gastric
with the occurrence of duodenal ulcers. Smoking ulcers is either normal, or decreased, the latter be-
does not increase the gastric secretion, but deterio- ing more frequent. Some patients yield achlorhydria.
rates microcirculation. It inhibits, however, the pan- 10–20 % of patients with gastric ulcers also have duo-
creatic bicarbonate secretion and accelerates emp- denal ulcers. It is mostly probable that the develop-
tying of stomach content into the duodenum. The ment of gastric ulcers is prevalently based on the
occurrence of duodenal ulcers in smokers is higher principle of mucous barrier impairment. In compar-
than that in patients with chronic renal failure, al- ison with duodenal ulcers, the patients with gastric
coholic cirrhosis, hyperparathyreosis and a chronic ulcers yield a significantly increased serum gastrin
levels. This is valid in patients with gastric acid hy-
obstructive disease of the lungs.
posecretion. In these patients, the evacuation of the
80 to 100 % of patients with duodenal ulcers yield stomach is delayed. It is assumed that regurgita-
the presence of Helicobacter pylori. It is not known tion of the duodenal contents together with bile takes
as to whether it plays the etiologic role. However, place. This event can impair the mucous barrier with
it has a negative impact on the velocity of healing resultant back-diffusion of secreted hydrogen ions.
processes.
Epigastric pain is the most common symptom, al-
Anxiety and psychological stress can cause an ex- though not so typical as in coincidence with duo-
acerbation of ulcer activity. However, it is not clear denal ulcers. Gastric ulcers tend to heal, however,
as to whether these factors play the primary part in they often reoccur in the same location. A number
the pathogenesis of ulcers. of gastric ulcers is asymptomatic. Haemorrhage is a
Epigastric pain is the main symptom of duodenal frequent complication. Obstruction and perforation
ulcer. It usually appears in 90 minutes to 3 hours are less frequent. Obstruction occurs when the ulcer
after a meal. The pain wakes the patients at night. is localised in the pyloric canal.
It withdraws after a meal and antacids. The ulcers
have a tendency to penetrate. If an ulcer penetrates 7.5.2.4 Zollinger–Ellison syndrome (gastri-
the pancreas, it causes pancreatitis. It can perfo- noma)
rate the gastric wall and penetrate the peritoneal
cavity. A massive gastrointestinal haemorrhage can This disease is characterized by ulcerations in the
develop. Some duodenal ulcers are not manifestant upper part of GIT and gastrin-producing pancreatic
clinically. They are detected accidentally in coin- tumor. Pancreatic tumors can vary in size from 2 to
cidence with endoscopic examinations. Ulcers lo- 20 cm. More than 1 tumour can occur. They are lo-
calised in the pyloric canal are not considered as be- calised in the pancreatic head, which however, is not
7.5. Diseases of the stomach and duodenum 505

a rule. It can be also localised in the duodenal wall 7.5.4 Helicobacter pylori and diseases
and in other sites. These tumors usually grow slowly. of GIT
Patients yield an increase in plasma concentration of
G34. Circulating gastrin has a trophic effect on the Great attention is currently world-widely viewed to
parietal cells and therefore their fast reproduction the problem of participation of this microorganism
is observed. 90 % of patients with gastrinoma de- in some diseases of the gastrointestinal tract.
velop an ulcer in GIT. The clinical symptomatology Helicobacter pylori (HP) is a small, mi-
resembles that of duodenal ulcer, but instead of con- croaerophilic gram-negative bacillus. Epidemiologic
stipation, diarrhoea is present. studies have indicated that 60 % of the popula-
tion above 50 years of age in modern countries,
are HP seropositive. Less advanced countries yield
a seropositivity already in childhood in more than
50 % of the population. In adults, the prevalence
of seropositivity is 100 %. The source is not known.
7.5.3 Stress ulcers and erosions The importance of interpersonal transmission is sug-
gested by evidence of its occurrence in families and
custodial institutions. High seropositivity among
This condition involves an impairment of GIT which
gastroenterologists and the occurrence of microepi-
is distinct from chronic peptic ulcers. Acute ulcera-
demies (assumedly due to the use of contaminated
tive lesions develop in patients with intensive stress,
nasogastric tubes) suggest that the iatrogenic pro-
with shock, massive burns, sepsis and severe trauma
cess of infection is possible. Helicobacter pylori is
(erosions and superficial ulcus occur in about 90 %
responsible for some forms of acute and chronic gas-
of patients with massive burns). Impairments are
tritis and its role in the development of peptic ulcer
multiple, ulcers are localised in the duodenum and
is being investigated.
gastric antral area. The clinical picture is dominated
This microorganism has an exclusive affinity to
by gastrointestinal bleeding; erosions usually appear
the cells of gastric mucosa. It especially harbours
within 24 hours after trauma.
areas of the pyloric antrum. Colonisation of HP in
It is assumed that the cause of stress ulcers or ero- the duodenum is restricted to areas of gastric meta-
sions resides in mucosal ischaemia with subsequent plasia. It can occur in the distal part of oesophagus
impairment induced by gastric acid. The mecha- in patients with abnormal cylindric glandular epithe-
nism of stress reaction (e.g. due to an unapt situ- lium in this area (Barret’s oesophagus). HP was also
ation) is partially clarified. Peptide hormones and found in individual cases of heterotopic gastric mu-
neuropeptides secreted by gastrointestinal cells en- cosa in the Meckel’s diverticulum and in the rectum.
ter the circulation and subsequently enter the brain It always resides the mucous layer above the apical
via the brain-blood barrier. Similarly, from the brain surface of epithelial cells, but it occurs also in areas
they pass into the cells of the so-called gastointesti- with close connection between the adjacent epithelial
nal brain (APUD system). This pathway leads the cells. It does not penetrate into the mucosa.
transmission of impulses by means of complex neu- Helicobacter pylori releases several factors which
rohumoral mechanisms. These processes can result induce inflammation, impair the epithelial cells and
in motor-secretion impairments. Increased secretion retard reparation of impairment localised in the tis-
of gastric juice induced by stress, or an impairment sue weakened by gastric acid and pepsin. Heli-
of perfusion of the gastric mucosa can lead to the de- cobacter pylori releases adhesins, proteases, phos-
velopment of ulcerations. Pain and hypersecretion of pholipases, chemotaxins and cytotoxins. Adhesins
hydrochloric acid lead to a backward suppression of enable the HP to adhere to the surface of gastric
secretion. In very simple terms, the humoral reaction epithelium. Factors that are chemotactic for neu-
triggered by stress, in addition to other substances, trophils and monocytes, as well as for PAF, mediate
releases endorphins which moderate the pain. In- the inflammatory response. Activated macrophages
versely, at rest, a greater amount of cholecystokinin release cytokines which participate in inflammation
(CCK) which represents a ”hormone of easefulness” by means of TNF-α, IL-1 and oxygen radicals. Pro-
is secreted with all secretion-motoric consequences. teases and phospholipases degrade the glycoprotein-
506 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

lipid complex of the superficial gel. The thickness back. The pancreatic head is in the duodenal flex-
and viscosity of gel is hereby reduced despite its in- ure and its tail touches the spleen. Pressure on the
creased production. HP is a strong, possibly exclu- spleenic vein (vena lienalis) can cause varicous di-
sive source of gastric urease. The latter catalyses latation of gastric veins. An impaired drainage of the
the hydrolysis of urea, thus producing alkaline mi- lymph from the stomach can be caused by e.g. reac-
croenvironment which protects the mucosa from the tive inflammation of the pancreas. The pancreas has
effect of gastric acid. an outstanding position among glands in organism
Helicobacter pylori is an extremely world-wide as it comprises both endocrine and exocrine glands.
spread infection. However, it brings about gastri- The exocrine pancreas consists of acini which pro-
tis or ulcerative disease only in a small group of in- duce enzymes and alkaline fluid. Acinal cells are ar-
fected persons. On the basis of its limited incidence ranged spherically around small outlets. Pancreatic
it is possible to state that the disease develops when juice is drained via the major pancreatic duct which
supported by the presence of certain decisive factors. enters the duodenum together with the common bile
Unconfirmed, but still appealing are the hypotheses duct (ampulla Vateri). Anatomical conditions in this
explaining the liability to succumb the disease on the area vary. In some individuals the pancreatic juice is
basis of more aggressive HP strains, higher bacterial drained by the Santorini’s duct which is independent
density, or exaggerated response of organism. A cer- from the major pancreatic duct, and enters the duo-
tain critical density of HP is assumedly inevitable to denum via the minor duodenal papilla. The secretory
enable the neutralisation of its surrounding by ure- pressure in the efferent ducts reaches approximately
ase and generation of sufficiently strong chemotactic 200 mm H2 O. The lumen of ducts is lined with one-
signals supporting the active inflammation. The im- layer epithelium which is permeable neither for bile
pacts of acid, pepsin and other impairment-inducing and trypsin, nor for E. coli suspension. At rest, the
factors are of secondary importance. pancreas secretes approximately 2 ml of juice, after
Helicobacter pylori is alleged to be responsible for stimulation its amount reaches 5 ml. The insular ap-
a majority of chronic active gastritis. Histologically paratus is localised predominantly in the pancreatic
it is moderate superficial gastritis. The superficial tail. It is separated from the exocrine parenchyma
area of lamina propria comprises neutrophils and by connective tissue. Endocrine pancreatic agents
mononuclear leukocytes. Children develop lymphoid get into circulation via portal veins.
hyperplasia. The most common sign resides in a The arterial blood is brought into pancreas via
moderate reduction of mucus. branches of the truncus coeliacus and from the ar-
There is a link between the peptic ulcer and HP. teria mesenterica superior. The venous blood is
The presence of HP in the antrum was found in 90 % drained from the pancreatic head into the portal
of patients with duodenal, and 70 % of patients with veins and from the pancreatic tail into the spleenic
gastric ulcer. HP is considered to be an important vein.
factor in the pathogenesis of peptic ulcer. However,
Postganglionic fibers stimulate the enzymatic and
it still remains to be clarified as to whether HP rep-
hormonal secretions. The sympathetic postgan-
resents the causal factor of the development of peptic
glionic fibers from the coeliac ganglion and superior
ulcer, or a merely auxilliary and modificating factor.
mesenteric plexus innervate the blood vessels and
stimulate vasoconstriction. In general, the sympa-
thetic nervous system inhibits the pancreatic secre-
tion and the parasympathetic nervous system stim-
ulates it.
7.6 Exocrine pancreas Pancreatic juice is isoosmotic. It contains potas-
sium, sodium, the most important anions include bi-
carbonates and chlorides which participate in a re-
verse ratio (an increase in bicarbonates causes a de-
The pancreas is localised retroperitoneally behind crease in chlorides and vice versa). The potassium
the stomach. The pain coinciding with pancreatitis and zinc levels in the pancreatic juice is twice as high
therefore spreads from the epigastric area into the as those in the serum, the contents of proteins cor-
7.6. Exocrine pancreas (M. Bernadič) 507

relates with the contents of enzymes. A markedly stimulated by cholecystokinin and acetylcholine.
alkaline pancreatic juice neutralises the acid duode- Cholecystokinin is released in the duodenum. Its re-
nal contents of the stomach. The alkaline environ- lease is stimulated by amino acids and fatty acids
ment is optimal for the impact of digestive enzymes. which are present in the gastric chyme. The acti-
The secretory cells in acini transport H+ into blood vation of pancreatic enzymes in the duodenum and
and bicarbonates into the acinal lumen. Bicarbon- small intestine hinders the release of cholecystokinin.
ates are transeferred into acini by active transport. In this way, a feedback involving several pancreatic
Potassium and chlorides are excreted by diffusion. enzymes is applied. Acetylcholine is released from
Water transgresses into acini iso-osmotically. Slow the pancreatic branches of the vagus nerve. An in-
production of pancreatic juice brings about an ex- creased release of acetylcholine takes place during
change of bicarbonates to chlorides. In consequence the cephalic phase of digestion. The pH of gas-
of fast production there is not enough time for this tric chyme (pH 3.5–4.5) stimulates S-cells (secretin-
exchange and therefore the juice is more alkaline. producing cells) to release secretin. Secretin is ab-
This is brought about during the intake of food. sorbed in the intestine and transported to the pan-
Pancreatic enzymes (trypsin, chymotrypsin and creas by blood. Secretin within the pancreas stim-
carboxypeptidase are able to hydrolyse proteins, sac- ulates the duct and acinar cells to secrete alkaline
charides, and fat. These enzymes are secreted in fluid. The effects of secretin include also an inhibi-
acini and transported into the duodenum in an inac- tion of gastrin which results in a decrease of gastric
tive form (trypsinogen, chymotrypsinogen, and pro- secretion and motility.
carboxipeptidase). Pancreas must be protected from
the impact of the organism’s own enzymes. There- 7.6.1 Classification of pathological
fore the pancreas produces an inhibitor of trypsin states of the pancreas
which hinders the activation of proteolytic enzymes,
providing they are present in the pancreas, or in 1. Impairment of the exocrine function of pancreas
its draining ducts. As soon as the pancreatic juice 2. Inflammatory diseases of pancreas
reaches the duodenum, the proenzymes are acti-
vated by enterokinase which is produced by duode- • acute pancreatitis
nal mucosa: enterokinase activates the conversion • recurrent acute pancreatitis
of trypsinogen to trypsin. Trypsin in turn stim-
ulates the conversion of chymotrypsinogen to chy- • chronic pancreatitis
motrypsin and the transformation of procarboxipep- • recurrent chronic pancreatitis
tidase to carboxipeptidase. Each of these enzymes
splits specific peptide bonds and reduces polypep- 3. Tumours of pancreas
tides to smaller peptides. The central role in activa- • tumours of draining ducts
tion of enzymatic precursors is performed by trypsin
which activates not only the precursors of other pro- • tumours originating from acinous cells
teases, but yet it is able to activate itself (autocatal- • tumours of pancreatic islets
ysis). Trypsin splits also its own inhibitory complex
in the small intestine and in this way it activates it- 4. Traumatic impairment of pancreas
self. This inhibitory system procures the protection • blunt non-penetrating injuries
of ducts from autodigestion.
• penetrating injuries
The pancreatic alpha-amylase is secreted in an ac-
tive form. The optimal pH for alpha-amylase is ap- 5. Diseases of genetic origin
proximately 6.9. The pancreatic lipase hydrolyses
triglycerides to free fatty acids and monoglycerides. • cystic fibrosis
The pancreatic juice includes also cholesterol-ester- • hereditary pancreatitis
hydrolase and phospholipases A and B. These en-
zymes have its optimum pH ranging from 7 to 9.
Enzymatic secretion of acini is maintained and
508 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

disease in men equals with that in women. The dis-

ease occurs especially in the fifth decade of life. The
7.7 Impairment of the exo- occurrence of pancreatitis coincides with further fac-
tors, such as alcoholism, cholelithiasis, obstruction of
crine function of pancreas biliary ducts, peptic ulcer, hyperlipidaemia and the
impact of some drugs (Tab. 7.1).

Pancreatic juice is a clear colourless alkaline fluid. Table 7.1: Etiologic factors of acute pancreatitis
It is discharged into the duodenum in volume of
1–1.5 l per day. The secretion of pancreatic juice disease of gallbladder and bile ducts
is relatively frequently decreased (the evaluation is
performed after stimulation by certain substances, alcoholism
e.g. by dietary burden). A severe damage of pan-
creas is associated with so-called pancreatic achylia, obstruction of draining ducts
i.e. minimal secretion. Various stages of pancre- and Vater’s papilla
atic insufficiency can be caused by acute or chronic
pancreatitis, kwashiorkor, fatty degeneration of pan- duodenal diseases
creas, toxic impairment (e.g. alcoholism), or tumours (ulcer, diverticulum, obstruction)
(most frequently carcinoma). The pancreas reacts injuries, surgeries
very sensitively to an impairment of the protein me-
tabolism. A decreased supply of proteins leads to infections (viral, bacterial and parasitic)
an impairment of the endogenous stimulation of pan-
creas. This condition can be manifestant by atrophy endocrine metabolic impairments (diabetes
of acinous cells and fibrosis of pancreas (e.g. long- mellitus, hyperlipaemia, hypercalcaemia)
term fasting). The changes in the amount of pan-
creatic juice are often associated with a decreased toxic substances (alcohol, drugs –
contents of pancreatic enzymes. This can be evoked thiazides, glucocorticoids, etc.)
either by a decreased secretion of their proenzymes,
immunologic factors
their insufficient intraluminal activation, or inactiva-
tion of enzymes which have been already activated. hereditary factors
E.g. in patients with coeliac sprue, the secretions of
lipase and trypsinogen are decreased. Trypsin defi- idiopathic pancreatitis
ciency is automatically associated with the deficiency
of chymotrypsin and other enzymes which are acti-
vated from proenzymes by trypsin. An increased in-
traluminal inactivation of enzymes (especially those
of amylase and lipase) takes place in cases of gastri- 7.7.1.1 Acute pancreatitis (acute haemor-
noma. In such cases a small amount of acid gastric rhagic pancreatitis)
juice gets into the duodenum and its pH drops to Acute pancreatitis is an inflammatory impairment
1–1.5 for a long period. This state externally mani- of pancreas associated with oedema, various stages
fests itself as a malabsorption syndrome with weight of autodigestion, necrosis and haemorrhage in its
loss (further symptoms include macrocytic anaemia, parts. The cause of this impairment is ascribed to
metabolic osteoporosis, hypoalbuminaemia). the intrapancreatic activation of proteases. It is not
exactly known as to why intrapancreatic activation
7.7.1 Pancreatitis of proteases takes place. The course of acute pan-
creatitis allows us to construct the development of
Acute pancreatitis constitutes approximately 1–2 % its etiopathogenesis from its origin to the fatal end.
of patients hospitalised in surgical wards with the Its etiopathogenesis can be depicted as a cascade of
diagnosis of acute abdomen. The incidence of the causes and consequences:
7.7. Impairment of the exocrine function of pancreas (M. Bernadič) 509

• at the beginning, the cell impairment of the area as far as into the back. It varies from moderate
ducts and acini is either evident (biliary re- discomfort to a severe debilitating pain badly toler-
flux, choleliths, ethanol, trauma) or hidden (in- ated by the patient. The pain is evoked by oedema,
creased pressure in the system of pancreatic distension of pancreatic ducts and acini, chemical ir-
ducts), ritation and peritonitis, or by obstruction of biliary
• which brings about the release of digestive pan- pathways.
creatic enzymes, Manifestation of pancreatitis includes nausea and
vomiting with intestinal hypermotility, or even par-
• hydrolases trigger the activation of proteolytic, alytic ileus in consequence of peritoneal irritation.
lipolytic and other pancreatic enzymes by an im- Peritoneal exudation appears in the abdominal cav-
pairment of acinar cells, ity (ascites). Obstructive jaundice develops either
• the activation of these enzymes causes an im- owing to the pressure caused by the oedematous en-
pairment of blood vessels and lymphatic path- largement of the pancreatic head, or owing to an
ways, overgrowth of pancreatic tumor. The release of en-
zymes into circulation is severely complicated by hy-
• the impairment of capillaries and lymphatic
povolaemia, hypotensia, or even circulatory shock to-
ducts ends up by their obstruction or overall de-
gether with heart failure in consequence of vascular
struction,
bed dilatation. The impact of pancreatic proteolytic
• consequently, an impairment or even autodiges- enzymes in circulation leads to defibrination and dis-
tion of the acinar cells release and activate en- seminated intravascular coagulation. A part of pa-
zymes and cellular proteins, tients (10 %) develops tachypnoe and secondary hy-
• the pancreatic kallikrein system is activated, poxaemia in consequence of pulmonary oedema and
the appearance of atelectases (destruction of pul-
• further progression brings about an overall va- monary surfactant).
sodilatation, increased capillary permeability, The decrease in perfusion presssure leads to an
shock with acute renal failure, impairment of renal functions. The necrotic tisssue
• the subsequent change resides in the occurrence takes up calcium more intensively, possibly leading
of ARDS (adult respiratory distress syndrome), to the development of tetany (however, a decreased
response to parathormone is present as well). The
• and finally the chain of events leads to irre- overall state is complicated also by transient hyper-
versible shock. glycaemia which is associated with the release of
glucagon from the impaired alpha cells of pancreatic
The entire process is often associated with the re- islets. Frequent impairments include those of CNS,
flux of bile into the efferent pancreatic ducts. This the condition of which is referred to as pancreatic
situation enables also the activation of pancreatic en- encephalopathy.
zymes. The biliary reflux most frequently takes place The basic therapeutic rule is to discontinue au-
due to obstruction of pancreatic pathways in the todigestion and avoid the systemic impairments de-
area of its junction with the bile duct, i.e. in papilla veloping in consequence of the release of enzymes
of Vater. Activated enzymes (trypsin, elastase, li- into circulation. Surgical intervention may reside in
pases) impair the cells of pancreas. Oedema appears, resection of necrotic part of pancreas and removal of
impairment of vessels results in haemorrhage, and ascitic fluid.
necrosis intervenes (local effect). Enzymes enter the
circulation, impair vascular walls and other organs 7.7.1.2 Chronic pancreatitis
(lungs, kidneys) by their toxic effect. This systemic
effect developing in coincidence with acute pancreati- Chronic pancreatitis is characterized by progressive
tis causes high morbidity and mortality. The mortal- destruction of glandular parenchyma with gradual
ity rate in severe haemorrhagic necrotic pancreatitis extinguishment of acinar cells, fibrosis and tissue at-
currently reaches even 70 %. rophy. The clinical picture includes impairments of
The most important phenomenon of the pancre- the pancreatic exocrine function; impairment of en-
atitis is pain. The pain projects from the epigastric docrine function occurs later. The main criterion of
510 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

morphological classification is the stage of impair- from perspiration and saliva examinations by detect-
ment of the pancreatic ducts. ing abnormal concentrations of NaCl. The therapy
Pathophysiological mechanisms of chronic pancre- is antiinfectious (antibiotics), supportive and substi-
atitis are similar to those present in acute pancreati- tutional.
tis. Furthermore, it is held that chronic pancreatitis
can appear in consequence of autoimmune diseases.
It is possible to prove antibodies against pancreatic
cells in patients with chronic pancreatitis (these an-
tibodies are present also in patients with pancreatic
cancer). 7.8 Small intestine

7.7.2 Cystic fibrosis of the pancreas

(mucoviscidosis) The small intestine is a tube reaching 3.5 m in
length. It comprises 3 segments: duodenum, jejunum
Cystic fibrosis is an autosomal recessive hereditary and ileum. The duodenum is a part which extends
systemic disease characterized by a severe impair- from the pylorus to the ligament of Treitz. The je-
ment of metabolism. The disease is manifestant junum has a wider lumen and anatomically it is not
already in childhood (the incidence in live birth is too distinct from ileum. The ileum terminates in the
1 : 2000) as a dysfunction of exocrine glands produc- ileocoecal valve or sphincter, the function of which is
ing mucus in the bronchi, pancreas, liver and intes- to control the transition of chyme into the large in-
tine. The secretions in gastrointestinal, bronchial, testine and to prevent its reflux from the colon into
salivary, lacrimal and sweat glands are extremely the small intestine.
viscous. The viscosity of secretions causes obstruc- The vascular supply of the duodenum arises from
tion of glandular ducts.The pancreatic ducts dilate, the gastroduodenal artery. Both jejunum and ileum
cysts are formed and fibrosis develops. Acinar tis- are supplied by the branches of the superior mesen-
sue becomes atrophic, but islets of Langerhans re- teric artery. The superior mesenteric vein joins the
main intact. The lungs develop obstructive bron- spleenic vein and their blood drains into the por-
chitis. Bronchiectasis and pulmonary fibrosis su- tal circulation. The lymphatic drainage leads to the
pervene. The disease becomes manifestant also in thoracic duct. The secretion, motility, pain and in-
the liver, namely by accumulation of bile and fibro- testinal reflexes are regulated by parasympathetic
sis. The clinical picture varies. Primary manifes- nerves. The sympathetic activity inhibits the motil-
tation includes pulmonary infections which occur in ity and induces vasoconstriction. Motor innervation
consequence of bronchiectasis and bronchial obstruc- is procured by the myenteric and submucous plexi.
tion by mucous plugs. Obstruction of the pancreatic The mucous plicae present in the small intestine slow
ducts leads to the diffuse form of interstitial chronic down the passage of food and enlarge the surface
pancreatitis. As many as 85 % of children with cystic of resorption. They are more pronounced in the je-
fibrosis suffer from manifestant malabsorption which junum and the upper part of ileum. The absorption
is determined by impairment of the pancreatic ex- of substances per se is performed by intestinal villi
ocrine function (even pancreatic achylia). The in- which cover the mucosa. Each villus represents a
testinal mucosa is coated by a thick layer of mucus functional unit. It produces enzymes necessary for
which inhibits normal resorption of nutrients. The digestion. The villi comprise absorbent cylindrical
sera of patients yield an increased level of alpha- cells and mucus-producing cells. Despite the fact
glucosidase (its level correlates with the severeness that the tightness of mutual adhesion of the cylindri-
of the disease). Abnormal intestinal secretion of vis- cal cells increases toward the intestinal lumen, water
cous mucus in newborns can lead to the formation of and electrolytes are absorbed through the intercellu-
so-called meconium ileus. Steatorrhea represents the lar space. The surface of each cylindrical cell is cov-
consequence of insufficiency of lipases in pancreatic ered by thin projections – microvilli. In this way, the
juice, a majority of patients yields bile acid losses overall mucosal surface is enlarged seven-fold, thus
by stool. The diagnosis becomes obvious already enabling the absorption of substances to take place
7.8. Small intestine (I. Hulı́n, I. Ďuriš) 511

on a larger surface. Lamina propria below the ep- the capillaries in the intestinal villi and afterwards
ithelial cells contains macrophages, lymphocytes and the liver via the portal circulation. The components
plasma cells producing immunoglobulins. Each villus of lipids get into the lymphatic circulation, or by the
is supplied by a central artery which branches into blood into the liver. Intestinal movements procure
two capillaries. Each villus comprises also a central the contact of chyme with the large mucosal surface.
lymphatic canal which is important for absorption Various constituents of the gastrointestinal contents
and transport of fat molecules. are absorbed in various intestinal areas.
Among the villi, Lieberkühn’s crypts are located.
They extend as far as into the submucosa. The
crypts comprise non-differentiated secretory cells. 7.8.1.1 Absorption of water and electrolytes
These cells represent precursors of cylindric epithe-
lial cells. Non-differentiated cells leave the crypt’s Cellular epithelial membranes are constituted by
base and move toward the peak of the villi. During lipid layers. Therefore these cells behave in a
this process they mature regarding their morphology hydrophobic manner. The transition of water in
and function. When they reach the peak of the villi, both directions (from lumen into capillaries and
they fulfil their function for several days and there- vice versa), as well as the transition of a particular
after they exfoliate into the intestinal lumen where amount of electrolytes is performed through inter-
they are destructed and digested. The exfoliated ep- cellular space, hence not through the membranes of
ithelial cells are a significant source of endogenous epithelial cells. Water diffuses passively depending
proteins. In 4–7 days the population of all epithelial on the hydrostatic pressure and osmotic gradient. In
cells regenerates. Many factors – e.g. fasting, vita- addition to other substances, the greatest share in
min B12 deficiency, cytostatic drugs and radiation – the exertion of osmotic pressure is carried out by
suppress the substitution of these cells and thereby sodium. Sodium transgresses not only the intercel-
decrease the height of the villi. A decreased cellular lular space, it is also actively transported through
overturn results in atrophy, decreased absorption, di- cellular membranes in order to be exchanged for hy-
arrhea and impairment in nutrition. A reverse effect drogen ions. The sodium pump is localised on cel-
is induced by food intake and also by intestinal re- lular basolateral membranes. Sodium and glucose
section. are transported by common transport mechanisms,
while sodium absorption increases the transport of
glucose. Chlorides actively enter the cells in order
7.8.1 Digestion and absorption in the to substitute bicarbonates and thus to maintain the
small intestine electroneutrality. Potassium transgresses passively
through intercellular space depending on the elec-
The process of digestion is initiated in the stom- trochemical gradient.
ach by the breakdown of proteins and destruction
of fibrous components of food by hydrochloric acid
and pepsin. During the passage via the duodenum, 7.8.1.2 Saccharides
the chyme is exposed to the impact of further secre-
tions and only some food components are resorbed Saccharides are absorbed in the duodenum and in the
herein. The digestion continues in the proximal part upper part of jejunum. The salivary and pancreatic
of the small intestine where the chyme is exposed to amylases split polysaccharides into oligosaccharides
the effect of pancreatic enzymes, intestinal enzymes which are hydrolysed as far as on the intestinal sur-
and bile salts. Saccharides are split into monosac- face. The intestine is able to absorb solely monosac-
charides and disaccharides. Proteins are degraded charides (galactose, glucose, fructose). Absorption of
to amino acids and peptides. Fat is emulsified and sugar is carried out on the principle of diffusion. Glu-
degraded to fatty acids and monoglycerides. These cose and galactose are actively transported through
compounds together with water, vitamins, and elec- the membrane by means of the sodium carrier and
trolytes are absorbed through the intestinal mucosa therefore they are absorbed more rapidly than fruc-
by active transport, diffusion or enhanced diffusion. tose. Insulin is not necessary for the absorption of
The constituents of saccharides and proteins reach saccharides in the intestines.
512 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

7.8.1.3 Proteins Mechanical activities of the stomach and small in-

testine disperse the triglycerides into small droplets.
Adults should accept 44–56 g of protein by food. Emulsification assisted by fatty acids, monoglyc-
Out of this protein intake, under physiological con- erides, lecithin, cholesterol, proteins and bile acids
ditions, 5–10 % is discharged by stool. Digestion produces small particles; a reverse aggregation of
of protein is initiated in the stomach by the im- droplets to larger drops is impossible. Emulsified fats
pact of pepsin, but the essence of digestion is car- are in this way prepared for lipolysis by pancreatic li-
ried out in the small intestine. Pancreatic enzymes, pase. The lipase splits triglycerides into diglycerides,
namely trypsin and chymotrypsin hydrolyse large monoglycerides, free fatty acids and glycerol. The
protein molecules, and carboxypeptidases split off impact of lipase comes to the effect merely in the
amino acids. The hydrolysis of proteins is performed presence of the pancreatic ezyme – colipase which
also on the surface of epithelial cells. The superficial enables lipase to penetrate the molecules of triglyc-
enzymes of epithelial cells hydrolyse large oligopep- erides. The products of hydrolysis of lipids must be
tides into smaller peptides which transgress cellular soluble in water in order to be effectively absorbed
membranes. Amino acids are actively transported in the intestinal lumen. This can be achieved by for-
through the basal membrane. According to the type mation of molecules which are soluble in water and
of transport, amino acids can be divided into three referred to as micelles. Micelles are composed of bile
groups: salts, products of fat hydrolysis, fat-soluble vitamins
and cholesterol. Fat constitutes the nucleus of mi-
1. methionine, glycine, phenylalanine, tryptopha-
celles and polar bile salts form the coating layer with
ne
the hydrophobic part directed towards the molecular
centre and the hydrophilic part directed outwards.
2. arginine, ornithine, lysine, cystine
Owing to this fact the micelles get into intermediate
3. proline and hydroxyproline contact with the intestinal epithelium, whereas the
bile salts remain in the lumen and are moved as far as
Each of the above presented groups of proteins into the ileum. Inside the ileum, they are absorbed,
enter the circulation by specific transport mecha- and returned to the liver.
nisms. Protein absorption is directly associated with When individual components of fat get inside
active sodium transport. Only a small proportion the epithelial cells, they repeatedly resynthesize to
of proteins enters the cells by means of pinocytosis. triglycerides and phospholipids. The triglycerides
Proteins are absorbed, similar to saccharides, in the are coated by phospholipids, lipoproteins and choles-
proximal part of the small intestine. terol. They constitute particles which are referred to
as chylomicrons. Chylomicrons are shifted to the ba-
solateral membrane of cylindric epithelial cells where
7.8.1.4 Fat they are eliminated into the intercellular space. From
People accept 90–100 g of fat in average per day. Fats here they get into lymphatics or blood circulation.
are a significant source of calories, as well as primary
components of cellular membranes and organelles. 7.8.1.5 Minerals and vitamins
The main compounds of fats in food are triglycerides.
Cholesterol, phospholipids and fat-soluble vitamins The optimal intake of calcium ranges from 1000 to
are important regarding the nutrition. Digestion and 1500 mg per day. The amount of 500–600 mg of
absorption of fat is carried out in four phases: calcium basically re-circulates, as it originates from
the exfoliated enterocytes. High concentration of
1. emulsification and lipolysis calcium in the lumen brings about its absorption
by passive diffusion. However, if the concentra-
2. formation of micelles tion of calcium in the intestinal lumen is low, it
is transported actively through cellular membranes
3. fat absorption by means of a protein carrier. The participation
of the carrier requires the presence of the active
4. resynthesis of triglycerides and phospholipids form of vitamin D (1,25–dihydroxyvitamin D). The
7.8. Small intestine (I. Hulı́n, I. Ďuriš) 513

calcium-protein complex enters the epithelial cell Water-soluble vitamins are absorbed by the
where calcium binds with proteins or other sub- sodium-dependent active transport. Vitamin B12
stances. Thereafter, by means of diffusion or active is released from food by means of peptic digestion.
transport via the basolateral membrane, enters the Each change in the gastric mucosa which results in
interstitial fluid. Calcium is absorbed in the small an insufficiency of the intrinsic factor leads to insuf-
intestine, dominantly in the ileum. It is absorbed ficient absorption of the B12 vitamin. Vitamin B12
faster in children, in pregnancy and lactation. The deficiency impairs the maturation of erythrocytes.
overall turnover of calcium is greater in these groups
of the population. Bile acids indirectly increase the 7.8.2 Motility of the small intestine
absorption of calcium by increasing the absorption
of vitamin D and free fatty acids. Movements of the small intestine are a significant
Elderly people daily accept 300–350 mg of magne- component of natural digestion and absorption of
sium. Magnesium is absorbed by active transport or substances. The presence of chyme entering the
passive diffusion in the jejunum and ileum. Absorp- small intestine from the stomach stimulates the in-
tion of phosphates is carried out in a similar manner. testinal movements which procure the mixing of
Their level in body is regulated to a substantial ex- chyme with enzymes, and currently the contact with
tent by intestinal absorption and secretion. the large intestinal surface. Intestinal motility is
composed of two types of intestinal movements.
A daily intake of iron is 15–30 mg. A general
Firstly, the intestinal motility is carried out by rhyth-
principle is held that absorption of iron is carried
mic contractions of the circular musculature. They
out merely in an amount which is necessary. Iron
appear in various parts of the small intestine and
insufficiency enhances its absorption. The primary
with various velocity. The upper part of the small in-
sources of iron in animal proteins are represented by
testine yields 12 contractions per minute. The lower
haemoglobin and myoglobin. This iron is quickly
part yields 8 contractions. The sites of their ori-
absorbed by epithelial cells of the duodenum and je-
gin comprehensively alternate. This contraction as-
junum. The absorption of anorganic iron from fruit,
sists in the mixing of chyme and procures the contact
eggs, and vegetables is also relatively fast.
with the surface of villi. The contraction of intestinal
Iron absorption is assisted by the presence of vi- smooth musculature is triggered by stimuli originat-
tamin C. Adversely, calciumphosphate and phospho- ing in the myenteric plexus. The contractions can be
proteins (milk, antacids) and tea bind iron in bowel intensified by the impact of the vagus nerve.
and in this way they reduce its absorption. In addition to the above presented segmental
Iron in cytosole is primarily bound with protein movements, the small-intestinal motility is also car-
– ferritin, as well as non-protein low-molecular com- ried out by longitudinal muscular fibers. Their con-
ponents of cytosole. Iron transport through the ba- traction brings about a peristaltic movement in a
solateral membrane is determined by the amount of short section of 10 cm. The velocity of the contrac-
iron present in circulation. tion proceeding in this section reaches 1–2 cm per
At a sufficiently high concentration in the plasma second. Peristaltic movements procure the move-
the absorbed iron remains in the epithelial cells. Iron ment of chyme in aboral direction. Their significance
gets back into the intestinal lumen together with ep- does not reside solely in the movement of chyme.
ithelial cells after their exfoliation. Adversely, during Owing to the peristaltic movements, the position and
bleeding, in pregnancy, or during growth, iron is ac- altitude of the villi alter optimising thus their con-
tively transported from epithelial cells into plasma. tact with chyme. Very important changes involving
In coincidence with sudden iron losses caused by the absorption of substances are brought about by
bleeding, the intestinal absorption of iron increases the fact that the increased pressure procures evacu-
appropriately in 3 days. This period is necessary for ation of the plicae and movement in the lymphatic
the precursor cells in Lieberkühn’s crypts to become vessels.
functionally formed, and to migrate to the surface of The optimal intestinal motility is procured by neu-
the villi. This process is stimulated by the iron defi- roreflexive mechanisms. The ileogastric reflex in-
ciency. The transfer of iron into the plasma is carried hibits the gastric motility in coincidence with in-
out by transferrin (the component of globulins). testinal distension. Hence, the transition of subse-
514 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

quent bulks of chyme from the stomach into the dis- the bowel thus determines its typical shape. The
tended small intestine is inhibited. The intestinoin- circular musculature is separated into sections which
testinal reflex procures the hindrance of intestinal are referred to as haustra. Muscular contractions
motility in cases when some part of the intestine is reduce and enlarge the haustra.
extremely distended. The gastroileal reflex arises in The large-intestinal mucosa contains cylindric
coincidence with increased gastric motility and secre- cells which absorb water and electrolytes. Mucus-
tion. It causes an increase in the motility of ileum. producing cells create a protective layer on the mu-
In this way, a more rapid evacuation of the ileum cosal surface.
is procured, in order to continue the acceptance of
The motor and secretory acitivities of the large
more chyme. The gastroileal reflex is probably reg-
intestine are regulated from the myenteric plexus
ulated by neurotensin. During long-term fasting, or
which is to a great extent independent from other
sleep, a slow contraction proceeds from the stomach
systems. The parasympathetic innervation of the co-
to the terminal ileum. In this way this reflex procures
ecum, ascendent colon and the first part of the trans-
the evacuation of gastric and intestinal contents into
verse colon originates from the vagus nerve which
the large intestine. The gastrocolic reflex (urgency
in this area of the large intestine stimulates rhyth-
to defecate after meal) is pronounced especially in
mic contractions. The distal colon is parasympa-
childhood.
thetically innervated from the pelvic nerves. The
The ileocoecal junction is procured by a valve internal anal sphincter is innervated by the sym-
(sphincter) which is enclosed at rest. Its opening pathetic nervous system (the sympathetic system
is stimulated by peristaltic waves. After the transi- enhances contractions) and parasympathetic system
tion of a small part of chyme it encloses again. This
(the parasympathetic system supports relaxation).
mechanism inhibits both regurgitation of chyme and It is permanently in state of contraction. It relaxes
extreme distension of the large intestine. only for a short time in coincidence with the disten-
sion of the rectum and at defecation. The external
sphincter is innervated by sacral branches of spinal
nerves. The sympathetic innervation originates in
the coeliac and superior mesenteric ganglia. Destruc-
7.9 The large intestine tion of the lower part of medulla spinalis paralyses
the external sphincter whereas the internal sphinc-
ter does not respond. The sympathetic activity in
the area of the large intestine modulates intestinal
The large intestine is approximately 1.5 m in reflexes, somatic sensations and pain.
length. It is constituted by the coecum, appendix, Basic movements of the large intestine are repre-
colon (ascendent, transverse, descendent, sigmoid), sented by segmental contractions which always in-
rectum and the anal canal. The coecum accepts volve an entire haustrum. Peristaltic movements in-
the chyme from the ileum. The vermiform ap- volve several haustra. They procure the transition
pendix might have its significance in elimination of of the faecal mass aborally to the rectum. The gas-
unusual components of food present in the bowel. trocolic reflex enhances peristaltic movements of the
The sphincter in the distal part of the sigmoid colon large intestine after the stomach filling, which stim-
controlling the transport of chyme into the rectum ulates defecation. It is probable that gastrin partic-
is in comparison with the ileocoecal sphincter less ipates in this reflex.
demarcated. It is an intestinal part which fulfils the Fluid is absorbed in the large intestine by diffu-
task of a sphincter of a longer section. The anal canal sion or by active transport. Under the influence of
encloses the internal sphincter constituted by smooth aldosteron, the diffusion of sodium into the cells and
musculature and the external sphincter which is con- its active transport through the basolateral mem-
stituted by striated muscles. brane into the interstitial fluid increase. Together
The longitudinal musculature of the large intestine with sodium, also chlorides – as complementary an-
constitutes three stripes referred to as colic taeniae ions – are absorbed. They enter the cells on the basis
(taeniae coli). The fact that they are shorter than of exchange for bicarbonates. The active transport
7.10. Malabsorption 515

of sodium currently increases the gradient for the dif- sequence of defective digestion. The accepted food
fusion of potassium from cells into the lumen. The must be initially processed down to basic compo-
substances being absorbed in the large intestine in- nents. These acitivites enable further steps to be
clude also the chains of fatty acids which are pro- carried out with subsequent resorption. The pro-
duced during fermentation. Neither saccharides, nor cess takes place within the lumen, on the mucosal
amino acids are absorbed in the large intestine. surface (contact digestion). A significant role in
Under physiological circumstances, the gastric the process of digestion is carried out by the pan-
contents, owing to the presence of HCl, is almost creas. It produces lipase, colipase and proteases,
sterile. The bacterial reproduction in the duode- especially trypsin. Therefore malabsorption is the
num is inhibited by bile and antibodies. Duode- cardinal symptom of chronic pancreatitis. In order
num contains only a minimal amount of aerobic, and to procure the optimal digestion of fat, the chyme
no anaerobic microbes. Anaerobic microbes harbour must contain a sufficient amount of bile acids which
the more remote part of the ileum – the ileocoecal are necessary for normal lipolysis and formation of
area. The intestinal flora mostly includes Escherichia micelles. A decreased production of bile salts can
coli, Clostridium Welchi and streptococci. Bacte- develop in consequence of its decreased synthesis in
ria significantly participate in the metabolism of bile the liver, however more often it is caused by cholesta-
acids, namely in the reabsorption of bile components, sis in coincidence with hepatic cirrhosis. A further
elimination of toxic metabolites from bile and the cause resides in an increased deconjugation of bile
breakdown of fibrous material. The intestinal bac- acids caused by bacterial overgrowth.
terial flora participates in the metabolism of oestro- Bile acids deficiency may be caused also by dis-
gens, androgens, lipids, various nitrogen substances eases of the ileum or ileal bypass by leading to insuf-
and drugs. ficient recirculation of bile acids. The liver in these
cases is not able to synthesize bile acids de novo in
a sufficient amount. This condition results in mal-
absorption of fat and deficiency of fat-soluble vita-
mins. These global disturbances can be simultane-
ously present in specific defects of digestion. Thus,
7.10 Malabsorption e.g. lactase deficiency on the surface of enterocytes
deteriorates the absorption of saccharides. This con-
dition can result in intolerance to milk and clinical
symptoms as flatulence, intestinal distension and di-
The main function of the gastrointestinal tract is
arrhea. It occurs more frequently in black people.
to digest and absorb the nutrients serving as the
It can occur as a consequence of a diffuse defect of
source of energy. In addition to the latter, an or-
mucosa in coincidence with other diseases.
ganism needs small amounts of other significant sub-
stances for the optimal procurement of specific func-
tions. 7.10.2 Inadequate absorption (malab-
In a precise pathophysiological sense, the term
malabsorption refers to a defective absorption of nu-
sorption)
trients by the intestinal mucosa, whereas an impaired The inadequate absorption can appear in normal in-
hydrolysis of nutrients is referred to as maldigestion. tact digestion. Most frequently it is caused by a
However, as the processes of digestion and absorption reduced surface for absorption of substances. It de-
are very closely associated, all aspects of impaired di- velops after intestinal resection due to mesenterial
gestion and absorption are in clinical practice com- infarction, bypass due to morbid obesity, or due to
monly referred to as malabsorption syndrome. Crohn’s disease.
In other cases, the surface necessary for absorp-
7.10.1 Inadequate digestion tion may be sufficiently large, but insufficiently in-
(maldigestion) volving the processes of absorption per se. These
impairments are caused by the defects in mucosal
The malabsorption syndrome often develops in con- cells (inborn or acquired). Examples of this condi-
516 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

tion can include the selective defect in absorption absorption. There are several tests which allow to
of particular amino acids in cystinuria, or the de- detect particular types of malabsorption.
fect in absorption of fat in coincidence with alpha- Confirmation of fat in stool can be performed by
lipoproteinaemia induced by an intracellular defect quantitative tests. A more precise assessment can
of the synthesis of apolipoproteins. A selective de- be achieved by a quantitative test which sets the
fect in absorption of calcium can occur due to insuffi- amount of fat in stool within a period of three days.
cient synthesis of 1,25 dihydroxycholecalciferol in the The patient receives 80–100 g of fat daily. Under
kidneys. physiological conditions the amount of fat in stool
However, the cause of malabsorption more fre- does not exceed 6 g per 24 hours (the usual average
quently resides in impairments of intestinal mucosa value is below 2.5 g per 24 hours). The content of
and submucosa. Sometimes the cause remains un- fat above 6 g per 24 hours (steatorrhea) indicates to
known, or obscure. Such state might involve immu- malabsorption, although it does not suggest any hint
nity or allergic impairments (gluten enteropathy – of its cause. Examination of the pancreatic exocrine
coeliac disease). Malabsorption occurs also in co- function can reveal the possible cause of steatorrhea.
incidence with infections. In Whipple’s disease, the Absorption of sugars can be judged by the xylose
submucosa contains activated macrophages. The pa- test. Patients are administered 125 g of D-xylose.
tients can develop fever, arthralgia, lymphadenopa- This sugar is straightly absorbed in the proximal part
thy and neurologic symptoms. It is a rare disease. of the small intestine. After administration of 125 g
Giardia lamblia can just as well cause malabsorp- of D-xylose, under normal conditions, an amount
tion. The symptoms include flatulence, nausea and of 4,5 g is eliminated by urine in five hours. The
diarrhoea. Deconjugation of bile acids due to bac- eliminated amount decreases with age. Abnormal
terial overgrowth can represent a further cause of results of the xylose test occur most frequently in
malabsorption. Sometimes the cause of malabsorp- malabsorption, a decrease, however, may be possi-
tion resides in a diffuse infiltration of mucosa in sys- bly caused by impaired renal function and bacterial
temic diseases. The wall of the small intestine may overgrowth in the intestine.
become undesirably attenuated due to irradiation. X-ray examinations of the stomach in patients
The cause of malabsorption in these cases resides in with malabsorption display almost normal findings.
altered functions of mucosa, abnormal motility and Some unspecific changes as attenuation of mucosa
bacterial overgrowth. and intestinal distension can be present. Strictures,
After resorption of fatty acids, triglycerides are fistulae, blind intestinal loops and diverticula are
resynthesized in enterocytes. Triglycerides enter the detected. Neither the peroral biopsy of small in-
lymphatic system as chylomicrons. Therefore, the testine provides precise specific findings confirming
defects of the lymphatic system result in appearance malabsorption. The changes displayed in X-ray pic-
of malabsorption. tures are not specific to malabsorption. However,
the symptoms of the coeliac disease always include
The origin of malabsorption is often enhanced by
atrophy of the intestinal mucosa.
a simultaneous impact of several factors. They in-
Valuable results can be provided by the investi-
clude defective digestion together with an impaired
gation of the absorption of vitamin B12 (Schilling’s
intestinal motility and absorption. Such a picture
test). After its binding with the intrinsic factor, vi-
can be induced by administration of drugs and toxic
tamin B12 is selectively absorbed in the distal ileum
substances (antacids, neomycine, tetracycline, alco-
(detail information is analysed in the chapter on
hol). Some patients develop a severe absorption
megaloblastic anaemia). Abnormalities in vitamin
impairment resulting from hyperabsorption. E.g.,
B12 resorption can imply from several facts:
haemochromatosis is an inborn disease involving hy-
perabsorption of iron, and D hypervitaminosis in- a) impairment of distal ileum (Crohn’s disease)
volves excessive absorption of calcium.
b) intrinsic factor insufficiency
Malabsorption may concern defective absorption
of a single substance. This condition occurs in per- c) impaired exocrine function of pancreas (pancre-
nicious anaemia. atic trypsin is necessary for the release of cobal-
It is very difficult to confirm the presence of mal- amine from the bond with R-protein in gastric
7.11. Diarrhea 517

juice in order to be able to bind with the intrin- Therefore, e.g. the presence of weakly absorbable and
sic factor) osmotically active solutes in intestinal lumen deters
absorption of water, or even causes secretion of wa-
d) increased consumption of cobalamin in coinci- ter.
dence with bacterial overgrowth The mechanisms responsible for absorption of so-
lutes vary in individual parts of the intestine. In
Malabsorption can occur in many systemic dis-
general however, salts and other substances are ab-
eases. Patients with hyperthyroidism often display
sorbed by specific mechanisms. Several substances
moderate steatorrhea. Its main cause assumedly re-
are absorbed in dependence on the sodium transport.
sides in a high intake of fat in consequence of hy-
The latter involves both the entrance of substances
perphagia and faster motility of the digestive tract.
into, and their elimination from enterocytes. The
Furthermore, steatorrhea can be enhanced by gas-
sodium transport involves a large amount of com-
tric, biliary and pancreatic secretions and by changes
ponents including protons, chlorides, glucose, amino
in the jejunal morphology.
acids, bile acids and other substances. Secretion of
Malabsorption is less frequently associated with
bicarbonates is associated with the sodium-hydrogen
hypothyreosis. Malabsorption in hypothyreosis is
exchange. The chyme in the ileum is moderately al-
ascribed to pancreatic impairment. Patients with
kaline. Jejunal and ileal contents attain significant
diabetes mellitus can develop malabsorption in co-
values of ions as follow: Na+ – 1140 mmol, K+ –
incidence with the bacterial overgrowth which ap-
6,0 mmol, Cl− – 100 mmol, HCO− 3 – 30 mmol.
pears in consequence of delayed passage caused by
The absorption of solutes in the large intestine
autonomous neuropathy. Systemic sclerosis may be
takes place in a partially different manner. It is lim-
accompanied by bacterial overgrowth together with
ited by the presence of electrolytes. Absorption is
consequent malabsorption. Malabsorption in sys-
carried out through specific sodium channels where
temic vasculitis can be determined by partial atrophy
the electric potential is developed in the membranes.
of the villi, in rheumatoid arthritis by amyloidosis.
The membrane potential is the basis of chlorides ab-
sorption and potassium secretion. The large intes-
tine contents yields high concentration of potassium.
Organic acids produced by colonic bacteria and bi-
carbonates release organic anions and CO2 from non-
7.11 Diarrhea absorbable saccharides and fat. The fluid in the large
intestine contains: Na+ – 40 mmol, K+ – 90 mmol,
Cl− – 15 mmol, HCO− 3 – 30 mmol and organic anions
– 85 mmol.
Diarrhea is a state of abnormally liquid faeces. In addition to the above mentioned processes,
The amount of stool exceeds 200 g per day. An in- the small and large intestines simultaneously secrete
creased number of bowel evacuations can occur, ac- electrolytes and water. The secretion in small in-
companied with a sensation of defecatory urgency testine is associated with the entrance of chlorine
and perianal discomfort. Faecal incontinence can be anions. Sodium and water are thereafter passively
present. transported in accordance with the electric and os-
The intestine receives 8 to 10 l of fluid daily. Out motic gradients.
of this amount, 1500 to 2000 ml are included in food. Diarrhea can occur in consequence of several
The remnant is constituted by the secretions of sali- changes:
vary, gastric, pancreatic, biliary nad intestinal secre-
tory glands. Out of this amount, the small intestine 1. decreased absorption of solutes and water
absorbs approximately 1 l. The large intestine ab-
2. increased secretion of electrolytes
sorbs 90 % of fluid. A volume of 100 to 150 ml of
fluid per day is eliminated by stool. 3. the presence of hardly absorbable and osmoti-
Absorption of water depends on absorption of so- cally active solutes in the intestinal lumen
lutes. Basically, the water within intestines is moved
passively in the direction of the osmotic gradient. 4. abnormal intestinal motility
518 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

5. intestinal inflammation with exudation and pro- after abstaining from their intake. The value of stool
duction of mucus, haemorrhage and the pres- pH in malabsorption of saccharides is significantly
ence of pus. shifted to the acid side.
Basically, the diarrhea may be divided into three
groups: secretory diarrhea, osmotic diarrhea and di- 7.11.3 Diarrhea due to abnormal in-
arrhea due to abnormal intestinal motility. testinal motility

7.11.1 Secretory diarrhea Abnormal motility can enhance bacterial overgrowth

within the intestine. Increased motility shortens the
The secretory diarrhea is caused by abnormalities in contact period of chyme with mucosa. Therefore in
both secretion and absorption of electrolytes. The consequence of this change, the volume of chyme
central role in these impairments is played by an in- in the large intestine increases which causes faster
crease in cAMP which has two basic effects: evacuation. The consequent abbreviation of contact
of chyme with mucosa results in a decrease in wa-
1. inhibits neutral NaCl absorption
ter absorption. Diarrhea due to abnormal intestinal
2. stimulates the secretion of chlorides without im- motility is usually present in coincidence with irri-
pairing other transport mechanisms. table bowel syndrome, after gastrectomy, vagotomy,
diabetic neuropathy, sclerodermia and thyreotoxico-
The impact of the cyclic AMP is evident e.g. in sis.
cholera. In cases of cholera, the intestinal mucosa In general, patient’s information on subjective
binds the toxin which stimulates adenylate cyclase sensations concerning defecation and stool are of im-
to produce the cyclic AMP. Since other transport portant diagnostic value. Voluminous stools give ev-
mechanisms are intact, rehydration can be achieved idence of an impairment either in the small intestine,
by oral application of the solution of glucose with or in the proximal part of the large intestine. A small
sodium. Hypersecretion can be associated also with volume of stools and frequent defecatory urge give
an increased intracellular calcium or cyclic GMP. Im- evidence rather of an impairment in the descendent
pairments of the small intestine which cause atrophy colon, or rectum. Presence of blood in stool indicates
of microvilli are associated with an increased secre- to mucosal inflammation and other pathological con-
tion of electrolytes. Non-absorbable bile acids and ditions. Foamy stool gives evidence of malabsorption
fatty acids can stimulate the secretion of ions in the of carbohydrates. Fatty stool, its offensive odour, or
mucosa of the large intestine. The secretory diar- the presence of visible admixture of fat (steatorhea)
rhea has the character of a copious profuse diarrhea signifies malabsorption of fat. It is very important to
which lasts for two days. The diarrhea fluid contains keep in mind that antibiotics and a number of drugs
prevailingly water and electrolytes. can induce diarrhea on the basis of various mecha-
nisms. In addition to antibiotics, antacids, antihy-
7.11.2 Osmotic diarrhea pertensives, thyroxine, digitalis, propranolol, quini-
dine, colchicine, lactulose, ethanol and laxatives can
Osmotic diarrhea is caused by an accumulation of
be involved.
weakly absorbable solutes in the intestinal lumen. It
Acute diarrhea is caused by infection, drugs or de-
can appear:
velops after consuming particular substances in food.
1. after an intake of weakly absorbable solutes, Intestinal ischaemia is not associated with acute di-
such as lactulose, Mg+ , SO− −
4 , or PO3 ,
arrhea.
Faeces in acute diarrhea contain pus and leuko-
2. due to malabsorption, cytes. In order to assess precisely the cause, it is nec-
3. in specific impairments of absorption of such essary to distinguish which of the pathological states
substances as lactose. is involved. Inflammation, malabsorption, struc-
tural changes or abnormal intestinal motility must
Osmotic diarrhea caused by the presence of weakly be taken into consideration. Each case of diarrhea
absorbable solutes is typical by the fact that it ceases must be judged regarding the possible presence of
7.12. Constipation (H. Sapáková) 519

an overall disease. It is necessary not to exclude the acute or chronic; according to the origin, obstipation
patient’s sexual orientation from diagnostical consid- can be organic or functional.
erations. Homosexuals yield a high incidence of in- Symptomatic (secondary) obstipation represents
testinal infections. merely a symptom that accompanies other primary
Chronic diarrhea can occur in several forms. Se- pathological states, most frequently being the dis-
cretory chronic diarrhea is usually induced by drugs, eases of the digestive tract or other organs. It can
hormones, bile or fatty acids. Osmotic chronic diar- occur in acute or chronic forms.
rhea is usually induced by drugs, laxatives, or mal- The acute form, i.e. cessation of natural and habit-
absorption. Inflammatory intestinal diseases (ulcer- ual defecatory manners can be due to strangulation,
ative colitis, Crohn’s disease), ischaemic colitis, par- obturation and paralytic ileus. A retention of gases
asitic invasions, motility impairments, sclerodermia and stool, meteorism, colicky pain, intestinal hyper-
and diabetic neuropathy can also bring about chronic peristalsis above the site of obstruction, emesis and
diarrhea. shock can arise.
The chronic form occurs in coincidence with in-
complete stenosis of the large intestine in conse-
quence of slow tumour growth or of adhesions. It
occurs in cases of lead toxicosis, morphinism, hyper-
acidity, cholelithiasis, hypothyreosis etc.
7.12 Constipation The independent (primary) obstipation represents
rather a clinical entity than a symptom. It is referred
to as habitual obstipation, which according to its
pathogenesis can be divided into simple obstipation
Constipation is a prolonged period of the pas- which is caused by an inhibition of the defecatory
sage of intestinal contents through the large intes- reflex, and spastic obstipation which involves a neu-
tine, dense intestinal contents, less frequent defeca- romuscular disturbance of the large intestine and is
tion with a small amount of stool and an impairment one of the forms of the irritable bowel syndrome.
of the defecatory reflex. Regarding the wide range of According to the prior classification, the types
normal habits of bowel evacuation, it is difficult to of obstipation were divided into spastic and atonic
define obstipation accurately. Obstipation is defined forms. Later, the classification took into considera-
as a reduction in frequency of defecation down to less tion the aspect of the site of obstipation. Yet, an-
than 3 times per week. other classification takes into consideration anatomi-
The amount of stool depends on many factors, cal and physiological aspects. According to the latter
such as the amount and quality of food, velocity of three following forms are distinguished:
its intestinal passage, resorption, bacterial flora, in-
testinal excretion etc. . Neither frequency, nor the 1. obstipation caused by impaired motility of the
amount of stool represent signs indicating to obsti- large intestine (spastic form),
pation. However, many patients yield normal fre- 2. obstipation caused by impaired mechanisms of
quency, but they must develop excessive strain in or- defecation (dyschezia),
der to achieve bowel evacuation. Their stool is hard
and they have a sensation of fullness in the hypogas- 3. obstipation in consequence of decreased motility
trium and as well as that of incomplete evacuation. (atonic form).
Therefore, when stating the definition of constipa-
tion, it is necessary to take into consideration both Spastic form
objective and subjective criteria. Spastic obstipation usually represents merely a
Constipation can be divided according to several symptom arising in coincidence with various impair-
aspects. The most important is the classification of ments of the large intestine. Most frequently it oc-
obstipations that is based on causality. Such classi- curs as a symptom within the irritable bowel syn-
fication justifies the distinguishment of symptomatic drome.
(secondary) and independent (primary) obstipation. Spastic obstipation is characterized by a com-
On the basis of its duration, obstipation can be either bination of several types of motility impairments,
520 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

initially by hypertonic-hypokinetic and dyskinetic inactivity or immobilisation. Supportive factors can

forms of obstipations. Hypertonia (spasmus) is most include: deficiency in food fiber, overall weakness,
frequently localised in the descendent and sigmoid stress and anxiety. When judging the acute consti-
colons, while the coecum and the ascendent, or trans- pation, obturation should always be regarded as a
verse colons are dilated (hypotonia), hence the in- possible cause of this state. In addition to neoplastic
testinal contents is forced through the contracted processes in the large intestine, strictures induced by
portions of intestine with excessive effort and in small ischaemia, diverticulosis, or inflammatory intestinal
bulks. In consequence of a prolonged stasis in the diseases, foreign bodies and anal strictures may be
spastic area, the stool becomes dense and commin- involved. Spasms of the anal sphincter caused by
uted due to resorption of water. Such consistency of painful haemorrhoids or fissures can also suppress
stool does not represent an adequate stimulus able the need of bowel evacuation.
to evoke defecation. If no obstacle is present, the obstruction can be
simulated by the impairment of motility of the large
Dyschezia (pelvirectal obstipation, torpor recti, intestine. Disruption of the parasympathetic inner-
proctogenous obstipation). vation of the large intestine in coincidence with in-
Stool accumulates in the rectal ampulla without juries, or other diseases of the lumbosacral spine
evoking defecation. The cause assumedly resides in or sacral nerves can induce constipation with hypo-
an increase in the threshold of irritability neccessary motility, colon dilation, decreased tonus and sensitiv-
for the arousal of the defecatory reflex and abnormal ity of the rectum resulting in defecatory disorders.
capability of adaptable relaxation of the rectum. Patients with sclerosis multiplex may develop con-
stipation (in coincidence with neurogenous dysfunc-
Atonic form tions of other organs). Constipation can be associ-
ated also with CNS disturbances caused by parkin-
X-ray pictures in this form of obstipation display a
sonism or cerebro-vascular episodes. The Chagas’s
dilated atonic large intestine, enlarged in its volume.
disease – parasitic trypanosoma infection which oc-
It does not involve any congenital inferiority of the
curs in South America, evokes constipation by dam-
colonic musculature. Hypotonia is caused by several
aging the ganglionic cells of the myenteric plexus.
further factors, e.g. food poor in dietary roughage
(incapable of representing a sufficient signal for the Hirschsprung’s disease – aganglionosis is charac-
accomplishment of peristalsis) and fat, insufficient terized by an absence of myenteric neurons in the
intake of fluids, deficiency in B-complex vitamins and distal segment of the colon closely proximal to the
some mineral deficiencies. The above described pic- anal sphincter. The diagnosis of Hirschprung’s dis-
ture is referred to as diffuse hypokinetic obstipation. ease in a majority of patients is assessed up to the
A transversoptotic form is characterised by slug- age of 6 months, in special cases the symptoms are so
gishness of the transverse colon which is consequently moderate that the disease remains undiagnosed until
suspended within the abdomen as a garland. It adulthood.
occurs more frequently in women. The cause as- The drugs inducing constipation include especially
sumedly resides in slackened abdominal walls. those with anticholinergic effect, antidepressants,
antipyretics, codein and other narcotic drugs. Fur-
ther noteworthy substances include aluminium or
7.12.1 Etiology and pathogenesis calcium containing antacids, sucralfate, iron contain-
From the pathophysiological point of view, constipa- ing drugs, and calcium antagonists.
tion represents a general consequence of impaired In patients with some endocrinopathies, such as
transition of the intestinal contents through the hypothyreosis or diabetes mellitus, the constipation
large intestine or impaired anorectal function caused is usually moderate and affectable. Patients with
by primary impairment of motility, in association myxoedema rarely develop megacolon that would en-
with some drugs or a large number of systemic dis- danger their lives. Constipation can be an accompa-
eases afflicting the gastrointestinal tract. Constipa- nying disturbance in pregnancy, assumedly in con-
tion may exarcerbate during chronic disease leading sequence of the changes in levels of progesteron and
to either physical or psychical deteriorations, and to estrogen which decrease the passage of stool through
7.12. Constipation (H. Sapáková) 521

intestines. Vascular collagenoses can be accompa- Young and middle-aged persons most frequently
nied by constipation. Constipation can be an espe- develop constipation in coincidence with the irrita-
cially pronounced symptom in progressive systemic ble bowel syndrome. In contrast to the syndromes
sclerosis. In this disease, the delay in intestinal pas- of idiopathic obstipation, the irritable bowel syn-
sage is induced by fibrosis of the smooth colonic mus- drome is typical by concomitant abdominal pain, es-
culature. In a majority of patients, the cause of pecially that in the hypogastrium with hard pellet-
constipation is not obvious. An important role in like stool, sensation of incomplete evacuation and ex-
the pathogenesis of idiopathic constipation in child- treme effort at defecation. Patients can complain
hood is ascribed to psychological and physiological of meteorismus, inflated abdomen, heartburn, nau-
factors. Afflicted children suffer from retardation in sea, difficulties at deglutition, back pain and urogen-
stool passage. It is assumed that voluntary suppres- ital symptoms. The pathophysiological mechanism
sion of the call to stool, or abnormal anorectal func- of the symptoms is not precisely clear.
tion are involved. Young and middle-aged women A precise description of symptoms and their du-
can suffer from severe constipation with scarce defe- ration are data of great importance in case history.
cation, extreme strain at defecation with low effect Constipation lasting from birth or early childhood
of laxatives and rigidity of this condition even af- is assumedly of congenital origin, whereas its later
ter diet rich in fiber. 70 % of these cases display development suggests an acquired character of the
slow passage of stool via the large intestine (iner- disease. Diagnostic considerations should always in-
tia coli). This state can be proved by administra- clude the possibility of obstruction being caused by
tion of x-ray contrast markers which visualize the neoplastic processes.
slow passage through the proximal colon. However, Especially valuable is the information on the
in 30 % of patients, the passage through the large precedent use of laxatives and modes of their applica-
intestine is normal and abnormalities are proved in tion. It is very important to evaluate sensitively and
the anorectal sensoric and motoric functions. This carefully the signs of anxiety and the use of mood
state is referred to as outlet obstruction or anismus affecting substances.
and arises assumedly in consequence of insufficient
intestinal relaxation or inappropriate contraction of 7.12.2 Irritable bowel syndrome
both puborectal muscle and external anal sphincter.
It is held that this dysfunction of rectal sfincter is Irritable bowel syndrome (IBS) foremostly involves
an acquired or learned habit rather than an organic disturbances of motoric and secretory functions of
or neurogenous disease. Chronic strain at defecation the large intestine. The assumed pathogenetic mech-
per se can lead to descending perineum and stretch- anism of this impairment proceeds as follows: in-
ing of the pudendal nerve thus impairing the anal creased irritability of the neuromuscular intestinal
sphincter muscle which in turn leads to faecal incon- apparatus impairs the normal peristaltic rhythm, the
tinence, or disability to retain stool. Rectocele is a condition of which results in constipation alternating
rectal hernia (bulge) which can affect defecation as with diarrhea.
it fills up with stool especially during the attempts IBS is typical by painful dyspepsia. Basically, it
to defecate. coincides with an uncertain colicky pain varying in
localisation and developing on the basis of dyskine-
Chronic idiopathic pseudo-obstruction is a scarce
sia. A particular intestinal portion is afflicted by
impairment in which the episodes of intestinal ob-
spasm which hinders the propulsion of the intestinal
struction are not accompanied by visible evidence of
contents. In the attempt to overcome the obstacle,
the mechanical blockade. This impairment can have
the section above the spasm develops an increased
a familial occurrence in consequence of neuropathy
activity which distends the intestinal wall. Owing to
and myopathy of the intestines, and sometimes also
the wall distension, the patients undergo the sensa-
of the urinary bladder.
tion of pain.
Idiopathic megacolon or megarectum is a dilated It is frequent in this condition that mucus appears
large intestine or rectum, possibly due to constipa- in stool. An especially typical symptom arising in
tion and extreme effort at defecation. This condition coincidence with an atack of mucous colic is that the
is ascribed to neurogenous dysfunction. patient defecates pure mucus. The stool has often
522 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

the shape of a cast of the intestinal lumen. The cause subsequent ulceration and perforation. Currently we
of this state is not clear. Hypersecretion of mucus distinguish:
occurs in vegetatively stigmatized individuals. Some
consider it to be an impact of allergy. 1. Megacolon congenitum (Hirschsprung’s disease)
The factors leading to the onset of irritable bowel is caused by the absence of ganglia in the rectal
Meissner’s and Auerbach’s plexuses. The agan-
syndrome are classified as local or overall. The over-
glionic segment is most frequently in the area
all factors include an increased vegetative irritability
of the junction of sigmoid colon with rectum.
and instability. The corticovisceral theory explains
This aganglionic segment is narrowed down, the
its commencement as being a consequence of func-
tional disturbances, cortex-subcortex relations with peristaltic movements cease before it, while the
segment lying proximally to it (in the oral direc-
an origin of parasympathotonia resulting in spasms,
tion) is dilated and its wall is hypertrophic. This
hypermotility and hypersecretion.
condition can even lead to a subileous state, re-
Out of the locally effective factors, the influence
sorption impairment, vomiting and weight loss.
of food must be taken into consideration, as well as
that of laxatives, or other drugs, and the reflexive 2. Idiopathic megacolon is difficult to be distin-
impact of the surrounding tissues. guished from the congenital form. It is a dis-
ease assumedly acquired in consequence of inap-
propriate defecatory habits and the main role is
7.12.3 Congenital and acquired mega- played by psychogenous factors. The rectum is
colon overfilled with stool, and its distension extends
as far as to the anal sphincter.
The congenital megacolon occurs in childhood. It
is characterized by an enormously distended large 3. Symptomatic megacolon develops in conse-
intestine, and constipation. Children have a large, quence of acquired organic disorders, e.g. nar-
tympanic abdomen. Stool is absent for days, even rowment of the rectum due to its strictures en-
weeks. Evacuation of bowels is seldom, but the tailed by injury, infection, etc. . It also can in-
weight of stool may attain the amount of 10 kg. tervene in consequence of dilatation developed
due to ulcerative colitis.
The disease was described for the first time by
Hirschsprung. He believed that the disease involved
a congenital intestinal anomaly, e.g. abnormal pli-
cae which enclose the intestine in a valvular man-
ner. Later it was believed that the predominance of
the sympathetic innervation decreases the intestinal
motility with the development of the above described 7.13 Intestinal obstruction
clinical picture.
The current conception apprehends that this con-
dition involves a state which is analogic to achalasia
of the cardia. It was found out that the afflicted in-
7.13.1 Terminology, classification,
testinal segment (most frequently the sigmoid colon
and rectum) is narrower in comparison with the rest clinical impact
of the intestine due to congenital absence of the in- Intestinal obstruction refers to a situation when the
tramural neural plexuses. The intestine above the af- intestinal contents cannot be forced further in aboral
flicted portion is dilated and its wall is hypertrophic. direction. Transit of intestinal content depends not
Such defect of the autonomic innervation is man- only on an intact state of intestinal lumen, but also
ifestant by an inability to arise peristalsis within on peristalsis. Intestinal obstruction can be therefore
this portion, thus causing functional obstruction. It caused by two principally distinct mechanisms:
seems that this disease is incompatible with life. If it
is not treated by replacement of the rectum and the • mechanical obstruction (occlusion, obturation)
lower part of the sigmoid colon, ileus develops with of the intestinal lumen, or
7.13. Intestinal obstruction (M. Turčáni) 523

• paralysis of the intestinal musculature (intesti- forms is of great value. Regarding the quantitative
nal pseudoobstruction). The clinical symptoma- aspect, mechanical obstruction represents a severe
tology of this state yields symptoms of a severe problem as it is the cause of approximately 20 % of
obturation, however, it is impossible to detect all urgent cases where surgical intervention is neces-
the mechanical obstacle disabling the propulsion sary. 95 % of cases yield an affliction of the small
of the intestinal contents. intestine, most frequently in consequence of abdom-
inal adhesions. Abdominal adhesions can develop
Both mechanisms (mechanical obstacle and inhi- spontaneously, or in consequence of intraperitoneal
bition of intestinal motility) can take place indepen- inflammation. The majority of adhesions causing
dently, subsequently, as well as simultaneously. They intestinal obstruction is however caused by preced-
can cause a partial or complete obstruction which ing operations. Approximately 5 % of abdominal op-
in turn can be of temporal or permanent character, erations are complicated by intestinal obstruction,
acute or chronic. A simple mechanical obstruction in a number of cases as late as some years after
(single obstacle in single site) is rarely complicated surgery. Post-operative scars detectable by inspec-
by strangulation, i.e. impairment of mesenteric ves- tion are therefore a significant diagnostic indicator.
sels and nerves. However strangulation is a common Most frequent causes of the small intestine obstruc-
complication if the bowel is occluded at least in two tion include internal and external hernias, and tu-
sites (obstruction of an enclosed loop) as e.g. in incar- mours. Mechanical obstruction of the large intestine
cerated hernia or volvulus. The obstructed intestinal occurs more frequently in the elderly population, and
loop can be evacuated neither in aboral direction, nor is caused by tumours, inflammatory processes and
by progressive dilatation of the bowel proximal to the volvulus.
obstacle. The enclosed intestinal loop develops high
intraluminal pressure, which in turn decreases the in- Historical aspects
flow of arterial blood and hinders the venous outflow. First documentation describing the clinical symp-
In cases of pseudoobstruction, strangulation can de- toms associated with intestinal obstruction are dated
velop secondary to the compression of mesenterium far back to the past. They can be found, e.g. in the
by the distended bowel. If the obturation lasts for a studies of Hippocrates. The success rate of therapy,
period which is sufficiently long to enable an impair- either surgical (Praxagoras, 350 B.C., enterocuta-
ment of mucosa by autodigestion, a severe state is neous fistula) or conservative (reposition of incarcer-
developing which is even now incurable – the ileus. ated hernias, analgetic therapy by opium, mercury
This clinical syndrome is characterized by intestinal or lead p.o. aimed at reopening of the enclosed intes-
inactivity, autodigestion of the intestinal mucosa and tine, gastric irrigation, etc.) was until the 20th cen-
breakdown of the internal environment. tury minimal. Had ileus developed in consequence
Regarding its causes, ileus can be classified as be- of intestinal obstruction, the mortality rate reached
ing post-obstructional when caused by a mechani- 100 %. An improvement took place after 1912, when
cal obstruction, and pseudo-obstructional when de- Hartwell and Hoguet noticed that infusion of the
veloped in consequence of the cessation of intestinal physiological solution prolonged the survival of dogs
peristalsis. Keeping its pathogenesis in mind, ileus is with intestinal obstruction. Infusion is even nowa-
an irreversible, incurable clinical syndrome. Hence, days a part of the therapy of intestinal obstruction.
great attention must be paid to early diagnosis and The second chief therapeutic principle – suction by
treatment of all states which enable its development. nasogastric or intestinal tubes – was gradually intro-
Mechanical intestinal obstruction frequently induces duced into clinical practice in the 1920’s (McIver,
an acute abdominal pain and requires urgent exami- 1926). Antibiotics began to represent a standard
nation which is often immediately followed by surgi- part of therapy algorithms of intestinal obturation
cal intervention. in the 1940’ and 1950’s. Infusion therapy, intestinal
The identification of the cause of intestinal ob- suction, antibiotics and somatostatin together with
struction is not always simple. Owing to the fact improved surgical and anaesthetic techniques have
that individual pathomechanisms of intestinal ob- substantially reduced the mortality rate, especially
struction require principally distinct therapies, early that of the simple mechanical obstruction. Other
distinguishment of the mechanical and paralytic causes of intestinal obstruction, such as strangula-
524 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

tive intestinal obstruction or generalised shock have tion, digestion, absorption and immunity functions.
even now a very bad prognosis and remain a serious In addition, intestinal obstruction generally leads to
clinical problem. hypoxia of the intestinal mucosa which represents
the primary mechanism in the pathogenesis of ileus.
7.13.2 Etiology Hypoxia decreases the resistance of intestinal mu-
cosa and thereby enables autodigestion, which is the
The causes of mechanical intestinal obstruction secondary mechanism leading to ileus.
can be localised in the intestinal lumen (poly- The correct function of intestinal mucosa is de-
poid tumours, intususception, bezoars, meconium, termined by a continuous supply of oxygen, either
bile stones, etc.), intramural (congenital anoma- by blood, or by aerophagia (alimentary respiration).
lies – e.g. atresia, stenosis, Meckel’s diverticulum, Bearing this in mind, hypoxia of intestinal mucosa
tumours, post-inflammatory structures – e.g. in can be formally caused by intestinal hypoperfusion,
Crohn’s disease, radiation enteritis, chronic intesti- hypoxaemia and hypoventilation of the intestinal lu-
nal ischaemia, lesions induced by KCl enteral tablets, men.
posttraumatic states – e.g. duodenal haematoma), Luminal hypoventilation represents a common
or in the intestinal surroundings (congenital, but es- pathogenetic mechanism of mechanical intestinal ob-
pecially post-operative adhesions, incarcerated ex-
struction and pseudoobstruction. Hypoventilation is
ternal hernias, internal hernias, volvulus, compres- caused by every mechanical obstacle disabling the
sion of intestine by abscess, tumour, etc.). Acute transport of intestinal contents and by all changes
pseudoobstruction can accompany the conditions af- leading to the cessation of peristalsis.
ter laparotomy and orthopedic operations, diseases
Intestinal motility depends on the functional state
of abdominal organs (intestinal ischaemia, pancre-
atitis, pyelonephritis, peritonitis, intraperitoneal ab- of intestinal musculature, its supply by oxygen and
scess), thoracic organs (pneumonia, acute myocar- its nervous and humoral regulation. The etiology of
dial infarction), and overall diseases (sepsis, shock, intestinal pseudoobstruction is therefore of heteroge-
polytrauma, decreased level of plasma potassium). nous character. All impairments of the contractile
apparatus of the intestinal smooth musculature and
Chronic pseudoobstruction is caused by primary
(familial visceral myopathies), or secondary (col- excitation-contraction coupling, local impairments of
lagenoses, muscular dystrophies, amyloidoses, radi- intestinal circulation, all situations associated with
ation impairment) diseases of the smooth intesti- activation of the sympathetic system and centralisa-
nal muscles, diseases of the myenteric plexus (fa- tion of circulation, as well as all hypoxaemic states
milial visceral neuropathy, paraneoplastic degener- can halt the peristalsis, thus causing intestinal pseu-
ation, Chagas’ disease, intestinal agangliosis, neu- doobstruction.
ronal intestinal dysplasia, myotonic dystrophy), di- Negative impacts of hypoperfusion and hypox-
verticulosis of the small intestine, coeliac sprue, je- aemia on the intestinal supply by oxygen are of two
junoileal bypass, some neurologic diseases (Parkin- kinds. They either cause a deficit in blood-delivered
son’s disease, tumours in the brain stem), endocrine oxygen within the intestinal mucosa, or decrease the
and metabolic disorders (myxoedema, feochromocy- intestinal motility thus leading to luminal hypoven-
toma, hypoparathyreoidism, acute intermittent por- tilation. A great variability in the clinical course of
phyria), and drugs (opiates, phenothiazines, cloni- mechanical intestinal obstruction and especially that
dine, tricyclic antidepressive drugs, vincristine). of pseudoobstruction can be ascribed to the possi-
bility of mutual compensation of oxygen supply by
intraluminal air and blood, as well as to varying ag-
7.13.3 Pathogenesis gressivity of the intestinal contents depending on the
Initial pathogenesis and clinical manifestation of in- amount and composition of digestive juices.
testinal obstruction vary as they are determined by The pathogenesis of intestinal obstruction is char-
mechanism, localisation, and the stage of obstruc- acterised by several positive feedbacks which cause
tion, actual state of the gastrointestinal system and its progression, and since the moment of ileus devel-
organism per se. Each intestinal obstruction impairs opment, also the irreversibility of this clinical syn-
in a specific manner the intestinal transport, secre- drome.
7.13. Intestinal obstruction (M. Turčáni) 525

Vitality of intestinal mucosa and primarily its ab- tion, aerophagia is an inappropriate mechanism, as it
sorptive function react very sensitively to the deoxy- does not procure the exchange of gases. In addition,
genation of the intestinal contents, especially in cases aerophagia gradually leads to intestinal distention.
which include reduction in the delivery of oxygen Later, when the oxygen contained in the swallowed
by blood. Organism strives to get rid of the deoxy- air is depleted, hypoxia becomes more profound as
genated intestinal contents (vomitus, diarrhoea) and the epithelial cells occur in anoxic environment of
to compensate the physiological level of oxygen in the pure nitrogen. The distention per se enables the de-
intestinal lumen by aerophagia. Failing to perform velopment of further positive feedbacks. The intesti-
this, absorption ceases as the first of physiological nal distention limitates the movement abilities of the
functions, later the mucosa afflicted by autodigestion diaphragm which has a negative impact on the ex-
develops inflammation with a pronounced exudation, change of gases by the lungs, thus contributing to
and finally the mucosa succumbs to necrosis. These hypoxaemia. In addition to the latter, the increased
processes impair the immunity functions of the in- contents of gases inside the intestine brings about
testinal wall, the state of which enables the develop- intestinal angularities which not only enclose the in-
ment of migrating peritonitis. Reduced absorption, testinal lumen, but also comprime the mesenterium,
increased secretion and exudation lead to the accu- thus deteriorating the intestinal perfusion, and in-
mulation of fluid in the intestinal lumen. Together creasing the congestion of the intestinal wall.
with vomiting and reduced oral intake of food, the
oedema of the intestinal wall and splanchnic vasodi- Acid gastric juice, IgA antibodies and nor-
latation can evoke extreme hypovolaemia, or even mal peristalsis maintain low bacterial contents (0–
hypovolaemic shock. These mechanisms can deduct 103 bacteria/mm3 ) in the proximal part of the gas-
as much as 6 l of fluid from the circulation system, trointestinal tract. The bacterial count increases in
especially in cases of proximal or complete obstruc- the aboral direction, and in the terminal ileum it
tion. During the acute compensatory response to attains 109–1012 bacteria/mm3 . The effects of in-
hypovolaemia, a part of which resides in centralisa- testinal antibacterial mechanisms substantially de-
tion of circulation, the bowel is hypoperfused thus crease during the intestinal obstruction. Bacteria
making mucosal hypoxia more profound. (primary enteric aerobic bacteria) proliferate out of
control until their count reaches that in the large
In addition to hypoperfusion of intestinal muscu-
intestine. These bacteria can enter the mesenteric
lature, hypovolaemia causes also the hypoperfusion
lymph and portal circuit and assumedly participate
of respiratory muscles. Hypoperfused respiratory
in the severe, deadly course of intestinal obstruc-
muscles reduce the ventilation of the lungs, and con-
tion. A significant role in the pathogenesis of in-
tributes in this way to the development of pneumo-
testinal obstruction is taken by bacterial endotox-
nia. Pneumonia intensifies the hypoxaemic condi-
ins. They directly incur damage to intestinal mu-
tion and thereby profounds the hypoxic impairment
cosa, but can also transgress the walls of the ob-
of intestinal motility and that of mucosa. In addition
structed bowel. Endotoxins stimulate the elimina-
to the intestinal obstruction, hypovolaemia and hy-
tion of vasoactive intestinal peptide, other intestinal
poxaemia are also important components of shock.
peptides and various prostaglandins (PGI2, PGF2)
Both these clinical syndromes therefore often mutu-
which mutually cause abnormal hypersecretion in the
ally combine. Shock can occur as either cause or
obstructed bowel.
consequence of intestinal obstruction. The possibil-
ity of autodigestion and the tendency to limitate in-
The intestinal myoelectrical and motor activities
testinal perfusion within the course of the general
in pseudoobstruction are impaired primarily. The
adaptation reaction cause that the bowel becomes
impairment brought about by the mechanical intesti-
liable to irreversible damage during the circulatory
nal obstruction is of secondary character. The phases
shock, and can influence negatively the prognosis of
of hyperperistalsis and antiperistalsis are followed by
all hypovolaemic and hypoxaemic states.
a reduction in the electrical activity of myocytes and
Hypoxia of intestinal mucosa stimulates aeropha- the migrating myoelectric complex is substituted by
gia which delivers air into bowel. However, un- conglomerates of action potentials and contractions
der the condition of prolonged intestinal obstruc- which are not able to bring about luminal transport.
526 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

7.13.4 Pathophysiological principles Alterations within the internal environment

of ileus prevention evoked by dehydration or circulatory shock quickly
succumb to changes; therefore it is necessary to mon-
Intestinal obstruction is curable until ileus develops. itor continuously the serum electrolytes, acid-base
Several positive feedbacks which progressively inten- balance and haemogram. Azotaemia and a pro-
sify both intestinal and overall impairments, disable nounced increase in haematocrit give evidence of a
the successful therapy of ileus. The therapy, or pre- severe decrease in intravascular volume. Metabolic
vention of intestinal obstruction include therefore the acidosis and leukocytosis are frequently present in co-
measures disabling ileus to develop. Preventive an- incidence with intestinal strangulation and advanced
tiileous algorithms are based on the pathogenesis of ileus. No biochemical parameters can be however
ileus and are aimed at the procurement of luminal used for unambiquous assessment of the diagnosis of
ventilation, removal of digestive juices from the in- intestinal strangulation.
testinal lumen, and the procurement of sufficient in-
testinal perfusion by oxygenated blood. In a ma- OVERVIEW OF THE ILEUS PREVENTION
jority of cases, the mechanical intestinal obstruction
A. Procurement of luminal ventilation
requires surgical therapy (assessment of the local-
isation and cause of obstruction, resection of the 1. Gastrointestinal aspiration
necrotic intestine). The significance of the preven- 2. Intraluminal insufflation of oxygen
tive measures resides in the fact that an entirely re-
suscitated patient is able to tolerate better the state B. Removal of digestive juices
of anaesthesia and surgical intervention per se.
1. Gastrointestinal aspiration
In some cases, especially if partial obstruction of
the small intestine is involved, the intestinal trans- 2. Fasting prior to operation
port can be renewed solely by means of conserva- 3. Parenteral nutrition
tive therapy. Intestinal pseudoobstruction often re- 4. Fasting after operation until the reappear-
quires a long-term conservative therapy lasting even ance of intestinal motility
for several weeks, and its supplementation by par-
enteral nutrition. An exclusively conservative ther- C. Procurement of intestinal perfusion by oxy-
apy of intestinal obstruction, however, increases the genated blood
risk of the development of intestinal strangulation. 1. Infusion therapy – maintenace of the vol-
Therefore it should be applied solely in cases when ume and capacity of blood to transport
the risk of intestinal strangulation is low. Inversely, oxygen. Correction of the deficit in fluids
if the assumed cause of complete obstruction resides and electrolytes
in intususception, volvulus or incarcerated hernia, it
2. Optimalisation of the cardiopulmonal and
will be necessary to operate immediately, with no
renal systems
regard to the clinical state.
Non-standard, although frequent is the use of var- 3. Anaesthesia without hypoxaemia
ious antimicrobic interventions. Administration of 4. Spinal anaesthesia
wide-spectrum antibiotics can restrict the growth of
intestinal bacteria. An analogue of somatostatin –
octreotide is administered with the aim to restrict
the secretion of intestinal mediators of inflammatory
reaction induced by bacteria, or endotoxins.
A primary significance of prevention is ascribed to 7.14 Inflammation and other
those techniques of abdominal operations which re- intestinal diseases
duce the risk of the development of adhesions. A pro-
nounced protective effect resides in the preservation
of the omentum, inhibition of both contamination
and the drying out of the peritoneum, and avoidance Inflammatory bowel diseases represent two clini-
of extensive peritoneal ligatures. cally distinct diseases, namely ulcerative colitis and
7.14. Inflammation and other intestinal diseases (I. Hulı́n, I. Ďuriš) 527

Crohn’s disease. They are severe chronic diseases of The intestinal distension brings about attenuation of
unknown etiology. Both these diseases will be anal- its wall. In this manner the picture of toxic mega-
ysed mutually in order to emphasise their distinc- colon develops. In such cases danger implies from
tions. intestinal perforation.
The cause of inflammatory bowel diseases is not If ulcerative colitis lasts for a long period, hyper-
known. Etiological considerations can involve sev- plasia muscularis mucosae develops. It is a result
eral factors. The incidence of ulcerative colitis yields of long lasting inflammation and processes of repa-
familial occurrence in 20 % of cases, and the famil- ration. Finally, the large intestine alters to such an
ial incidence of Crohn’s disease takes place in 40 % extent that the typical haustra disappear. Regener-
of cases. Genetic impact may determine the type of ating islands of mucosa surrounded by areas of ulcer-
immune reaction. Genetic predisposition is proved ations can be so pronounced that the condition leads
by the occurrence of inflammatory bowel diseases in to the formation of pseudopolyps lacking the signs
monozygotic twins. Until now, no evidence has been of a neoplastic process. If, however, the duration
acquired proving the infectious etiology of inflam- of the inflammatory process is prolonged, dysplastic
matory bowel diseases. The theory that an immune changes with signs of malignity may take place in
mechanism may be involved is based on the pres- epithelial cells. However, carcinoma rarely appears
ence of antibodies against the colonic epithelial cells, in coincidence with ulcerative colitis. More frequent
histological changes, and the recovery of the clini- are the strictures or fistulae.
cal state after the immunosuppressive therapy. It is The acute ulcerative colitis is manifestant by diar-
believed that the cause of inflammation resides in rhea, rectal bleeding, fever, weight loss and abdomi-
epithelial immunoregulatory defects. Intestinal mu- nal pain. These signs are considered to represent the
cosa contains an increased amount of T helper cells cardinal symptoms. However, the clinical manifesta-
and a decreased amount of T supressor cells. Psy- tion of the disease can be modest residing only in an
chological factors are assumedly applied albeit incur- increased frequency of stool per day, especially when
ring deterioration of the clinical state by assisting localised in the rectum (ulcerative proctitis).
the maintainance of the disease. Various external The state of a patient principally depends on
factors, such as toxins that are present in the liv- the extent of diarrhea. Ulcerations, extreme hy-
ing and working environment, can participate as the pokalaemia, anaemia, leukocytosis and fever can de-
triggering factors in the development of the disease. velop. The signs of toxicity appear – weakness,
In ulcerative colitis and Crohn’s disease the in- anorexia, tachycardia and hypotension. The ab-
flammatory process is involved having many com- domen can be diffusedly distended, although de-
mon signs, however it differs in its clinical manifes- markated resistances are not present. In approxi-
tation and histological findings. mately 10–15 % of patients the disease begins very
abruptly and requires immediate hospitalisation.
7.14.1 Ulcerative colitis The patients are at risk to develop severe complica-
tions such as megacolon, shock, hypokaliaemia, hy-
The acute stage of ulcerative colitis is characterized poalbuminaemia, or perforation of the colon.
by a diffuse superficial inflammation of the colonic
mucosa and submucosa. In addition to the large
7.14.2 Crohn’s disease
intestine, the rectum is usually involved (95 % of
cases). Inflammatory reaction may involve the entire Crohn’s disease is sometimes referred to as regional
large intestine, as well as the terminal ileum. Inflam- enteritis. The inflammatory process involves all in-
matory foci are infiltrated by neutrophils. In a ma- testinal layers including the serous surface. The in-
jority of cases, the mucosa is afflicted by a diffuse in- flammatory process is often discontinuous; severely
flammation. In addition to the latter, the superficial involved segments of bowel are separated from each
defects are present in the mucosa. Sometimes more other by areas of apparently normal bowel. In ap-
profound linear ulcerations develop. The surround- proximately 90 % of Crohn’s disease, the rectum may
ing of crypts is covered by multiple microabscesses. be spared. In addition to the intestine, there may
Intestine with noticeable inflammatory changes is be diffuse ulceration of the other parts of GIT (oral
significantly distended (more than 6 cm in diameter). cavity, oesophagus, stomach and duodenum). Ap-
528 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

proximately one third of the patients is constituted by other vascular disorders, surgical interventions,
by those with the involvement of the ileum, one third dissecting aortic aneurysm, marked decrease in the
with involvement of the large intestine and one third heart output, vasculitis, or hypercoagulation. Is-
of patients is afflicted by lesions in the ileum and chaemia is mostly marked in the interface between
large intestine. Inflammation of the intestinal serous the chief inflowing arteries – in the spleenic flexure
surface incurs the development of adhesions between and rectosigmoid area (flexura lienalis, area rectosig-
intestinal loops, or adhesions of intestines with other moidea). Ischaemic colitis is a consequence of hypop-
organs. Strictures and fistulae are frequently present, erfusion, however, not in coincidence with a complete
foremostly in the perirectal area. Various patho- obstruction. The rectum is usually spared because
logical structures are detectable by palpation. The of rich collateral blood flow. The clinical course
macroscopical appearance of the mucosa may be nor- of disease may be acute or chronic with all transi-
mal. Profound linear ulcerations are present along tory stages between those two extreme conditions.
the longitudinal axis of the intestine. In addition Acute ischaemic colitis usually begins very abruptly
to neutrophils, the inflammatory infiltration contains with abdominal pains and bloody stools. Fever may
also lymphocytes and macrophages. Granulomas de- be present, as well as hypotension, tachycardia and
velop in 50 % of cases. Fibrosis and formation of symptoms of peritoneal irritation. It is very difficult
stenoses occur in conseqence of an excessive produc- to differentiate the acute stage of ischaemic colitis
tion of collagen. Epithelial dysplasia is not observed. from ulcerative colitis. Angiographic, or X-ray ex-
The clinical manifestation in Crohn’s disease aminations with contrast enema would represent an
greatly resembles that of ulcerative colitis but patho- unreasonable hazard. Surgical intervention may be
logical changes are sparing rectum. Only in 10 % of required when signs of perforation are present.
cases are inflammation in rectum and even more of- Subacute and subchronic colitis begin inconspic-
ten as pararectal – perianal fistulae. According to uously. Patients develop abdominal pain and diar-
ileum involvement (site of B12 vitamin absorption) rhea. Anxiety arises in coincidence with food intake
macrocytic anaemia can occur and as well protein resulting in evident weight loss. Chronic states re-
malabsorption. However, all symptoms are much sult in the narrowing of some segments of the large
more moderate. With involvement of ileum, the intestine.
symptoms reflecting variable degrees of intestinal
stenosis may occur. A colicky pain sometimes arises 7.14.4 Diverticulitis
following the food intake. Less frequently, the right
lower quadrant can display a palpably detectable Diverticula in the large intestine occur especially in
resistance. Marked rectal bleeding is rare, the oc- the aged. Diverticula are, in fact, pouches in form of
cult bleeding however, is frequent. The beginning of small sacks which maintain all components of the in-
Crohn’s disease in young people can simulate acute testinal wall. Diverticula develop most frequently in
appendicitis. With involvement of the large intes- the site of the entrance of arteriole into the intesti-
tine, diarrhea is present together with perirectal ab- nal wall. The intestinal wall in these sites is weak-
scesses, fistulae and fissures. In such case (large in- ened. The development of diverticula is enhanced by
testine involvement), the manifestation includes ex- several factors, foremostly by a chronically increased
traintestinal symptoms. Toxic megacolon can even intraluminal pressure frequently in coincidence with
develop. In contrast to ulcerative colitis, the pa- a diet deficient in fiber or roughage. Stool in such
tients with Crohn’s disease more frequently develop cases is low in volume. The majority of divertic-
strictures and fistulae, and adversely, perforation and ula develop in the sigmoid colon. They are usually
haemorrhage develop less frequently. asymptomatic. Diverticula may, however, be the
cause of infection. The vessels surrounding the di-
verticula can rupture easily thus causing bleeding, in
7.14.3 Ischaemic colitis
most cases moderate.
In elderly people the ischaemic colitis can simulate Diverticulitis is a state, in which infection develops
an inflammatory intestinal disease. The cause of inside and around the diverticula. Such a state can
ischaemic colitis resides in extensive atherosclero- result in diverticular micro- or macro-perforation.
sis. Ischaemic colitis is less frequently brought about The inflammation is incurred by colonic bacteria.
7.15. Tumours of the GIT 529

Bacterial overgrowth in chronic states can lead to tis than with the Crohn’s disease. Patients with
B12 vitamin consumption as it is in all blind loops Crohn’s disease more frequently develop cholelithi-
and could be a reason of macrocytic anaemia devel- asis. Cholelithiasis is especially enhanced in cases
opment. Gradually, microabscesses can develop. Mi- where ileum is involved, namely in consequence of
croabscesses are inclined to perforate spontaneously, decreased reabsorption of bile acids.
thus causing localised, or less frequent generalised The symptoms of inflammatory intestinal dis-
peritonitis. If the perforation results in peritonitis, ease more frequently include episcleritis, iritis and
there is a risk of the development of a large abscess uveitis. Approximately 5 % of patients develop
and its penetration into adjacent organs. Acute di- erythema nodosum. Renal disorders are observ-
verticulitis can be clinically manifestant as appen- able as urolithiasis with the formation of calcium-
dicitis localised to the left. The symptoms frequently oxalate stones. Further symptoms include obstruc-
appear during defecation. In addition to the intesti- tive uropathy, kaliopenic nephropathy and amyloi-
nal symptoms, the overall clinical picture includes dosis. The patients with inflammatory intestinal
fever, leukocytosis, and palpable resistance. Bleed- diseases are inclined to the development of throm-
ing is not massive. Repeated attacks of diverticulitis bophlebitis. Inflammatory intestinal diseases can be
result in the development of fistulae. complicated by osteoporosis and osteomalacia.
Extraintestinal manifestation can, in special cases,
precede the development of intestinal symptoms.
7.14.5 Extraintestinal manifestation It is not simple to assess the correct diagnosis on
of inflammatory intestinal dis- the basis of clinical manifestations. Ulcerative col-
eases itis and Crohn’s disease must be differentiated es-
pecially from bacillary dysentery, amoebiasis, pseu-
Extraintestinal manifestation of ulcerative colitis and domembranous colitis, ischeamic colitis, neoplastic
Crohn’s disease greatly resemble each other. Nutri- processes, angiodysplasia and specific forms of coli-
tional deficiency appears in consequence of anorexia, tis.
fever, blood loss and malabsorption. This state re-
sults in an abrupt weight loss which at a young age
brings about developmental retardation. The inflam-
matory bowel disease can be associated with two
forms of athritis, often referred to as enteropathic
arthritis. The first form is so-called non-deformating
7.15 Tumours of the GIT
acute arthritis of big joints. The second form is
sacroiliitis and ankylosing spondylitis which appear
in patients with HLA B27. The articular affliction Neoplastic processes of the gastrointestinal tract
can precede the clinical manifestation of intestinal in- are the most frequent malign tumours. This chapter
flammation even months or years prior to the latter. will be devoted to tumours of GIT, in addition to the
The characteristic symptoms include mono or oligo- tumours of pancreas and liver.
arthritis and asymmetrical synovitis of the knee or
ankle joints. Sacroiliitis and ankylosing spondylitis
persist also in cases where resection was performed
7.15.1 Carcinoma of the oesophagus
due to Crohn’s disease. The oesophageal tumours are usually malign. Solely
Extraintestinal manifestation of inflammatory in- 10 % of tumours localised in the oesophagus are be-
testinal diseases can include also hepatobiliary nign. Oesophageal tumours occur approximately
changes. Many patients have moderate pericholan- 4 times more frequently in black people and as many
gitis which is manifestant by an increase in alkaline as 30 times more frequently in the northern China
phosphatase. The occurrence of extra and intra- and the surroundings of the Kaspian Sea. The ex-
hepatic sclerotising cholangiitis manifestant by ob- act cause of this phenomenon is unknown. They
structive jaundice, is less frequent. Slower progres- often occur in smokers, alcoholics, and in persons
sion brings about cirrhosis. Sclerotising cholangi- with gastro-oesophageal reflux. The incidence of oe-
itis is more often associated with ulcerative coli- sophageal carcinoma is higer in patients with gluten-
530 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

sensitive enteropathy. The mechanism, as to the rea- third of stomach. Their growth is sometimes diffuse
son why carcinoma develops in coincidence with the and infiltrative ( they are usually referred to as linitis
reflux and enteropathies, is unknown. plastica) and they can exulcerate.
Oesophageal carcinoma is manifestant by dyspha- At its onset, the gastric adenocarcinoma is man-
gia. Patients with dysphagia above 40 years of age ifestant by unspecific symptoms. Epigastric pain
must be examined bearing in mind the possibility arises among the initial symptoms. The pain is
of the presence of oesophageal carcinoma. Contrast significantly variable. Sometimes it resembles that
radiographs, oesophagoscopy, cytologic and bioptic arising in coincidence with gastric ulcers. However,
examinations are used to distinguish strictures and more frequently it is associated with epigastric dis-
benign tumours from carcinomas. Dysphagia pro- comfort, nausea and sensation of satiety even after a
gresses gradually. At the beginning, the difficculties small meal. All patients display anorexia and weight
appear in coincidence with the swallowing of solid loss. Vomiting is present especially in cases when
food. Six months after the onset of this symptom, carcinoma is localised in the distal part thus caus-
the difficulties arise in association with the swallow- ing gradual pyloric obstruction. A tumour in the
ing of fluids as well. In turn, anorexia and sub- area of cardia can infiltrate the gastro-oesophageal
sequent weight loss appear. Regurgitation of food juction and therefore cause dysphagia. Gastric tu-
and its subsequent aspiration entail the development mours frequently bleed, thus causing iron deficiency
of bronchopneumonia. Dysphagia brings about sub- and the development of hypochromic anaemia. Hae-
sternal pain. Its appearance represents the signal matemesis sometimes occurs. In such cases, the pa-
that carcinoma begins to overgrow the mediastinal tient suffers from overall weakness with pronounced
structures. Approximately 5 % of these tumours are hypotension. Metastases can cause obstructive jaun-
associated with an abrupt bleeding. The affliction of dice, malign ascites, or gastrocolic fistula.
laryngeal innervation affects the voice which becomes Endoscopic examination associated with cytologic
noticeably hoarse. Paraneoplastic endocrine abnor- and bioptic examinations have not been overcome
malities rarely appear. Oesophagotracheal and oe- by any other diagnostic methods in coincidence with
sophagobronchial fistulae are more frequent. Metas- gastric carcinoma. Surgical therapy depends on the
tases appear in regional lymphatic nodes, liver and presence of metastases. The palliative measures of-
lungs. ten prevail therapeutical interventions. Less than
10 % of patients survive a period of five years.
7.15.2 Carcinoma of the stomach
Gastric carcinomas most frequently involve adeno- 7.15.3 Carcinoma of the large intes-
carcinomas. Only 5 % of patients develop primary tine
lymphoma of the stomach, or leiomyosarcoma. Be-
nign tumors of the stomach rarely occur. Adenocarcinoma is the most frequent malignity of
The past 30 years have yielded a dramatic decrease the large bowel. Following carcinomas of the lungs
in the occurrence of gastric carcinoma in the USA and breast carcinoma, the carcinoma of the large
and western Europe. Japan, South America and bowel is the most freqeunt carcinoma in both men
eastern Europe continuously yield high occurrence and women in western Europe. The precise cause is
of this disease. In addition to these geographical fac- unknown. However, circumstances and factors which
tors, it is known that gastric carcinoma occurs more enhance the incidence of carcinomas are known. A
frequently in men than in women. The incidence is higher incidence is reported to be in patients who ac-
higher in black people and persons with blood group cept food with low contents of fiber and high contents
A. Infavourable dietary factors include nitrates, salt, of animal fat and proteins. It is held that on the basis
insufficiency of fresh vegetables and fruit. Carcinoma of such a diet, the intestinal microbial flora produces
occurs more frequently in patients who have suffered carcinogenes which are in contact with the mucosa
from atrophic gastritis. for a long time. When exposed to critical judgement,
Adenocarcinoma grows from the mucosal cells. It these ideas appear to be rather speculative. Similarly
grows neither from parietal, nor from chief cells. it is expected that the possible protective effect of
Tumours are most frequently localised in the distal selenium, ascorbic acid and alpha-tocopherol will be
7.16. Bleeding from GIT 531

confirmed. Many risk factors are known to have an Familial polyposis of the large bowel is a disease
impact increasing with age. The forefront factors in- of low incidence. Polyps begin to develop already in
clude inflammatory intestinal diseases, familial poly- children at school age. They result from activation
posis and colorectal carcinoma occuring in the first of a precisely defined oncogene. The intestine may
level of kinship. Risk factors include also the multi- contain as many as 1000 polyps ranging from micro
focal malignity in first level of kinship, especially the to macroscopic size. They are potentially malign and
malignities in female genital organs. Activation of therefore prior to their surgical removal it must be
oncogenes can play a crucial role in the development taken into account that total colectomy will have to
of colorectal tumors. be performed.
Regarding the histologic aspect, adenocarcinomas
of the large intestine are greatly variable. However,
their prognosis depends more on the extent of inva-
sion than on the histologic picture. They are pre-
dominantly localised in the descending and sigmoid
colons and in the rectum. Early symptoms of colorec-
7.16 Bleeding from GIT
tal carcinoma are unspecific and alternation of con-
stipation with diarrhoea, and tenesmus are observed.
Haematochezia with anaemia are significant symp- Bleeding from GIT is a severe, and frequent symp-
toms. They are associated with weakness, weight tom. As to the quantity, the bleeding per se may be
loss and anorexia. More scarce is the development massive and acute, or occult. It may be of episodic
of peritonitis in consequence of tumor invasion, or character. In approximately 80 % of cases, the acute
due to perforation of the intestinal wall. Abdominal bleeding stops spontaneously. If the bleeding re-
pain, alterations in stool shape, haematochezia and occurs or persists, may be life-threating. The treat-
anaemia induced by iron deficiency in persons above ment of gastrointestinal bleeding must therefore re-
40 years of age require diagnostical consideration of solve the hypovolaemia, cease the bleeding and pre-
colorectal carcinoma. Bright blood in stool can be vent the relapses. Acute bleeding can be manifestant
put into association with haemorrhoids and diverti- by symptoms as follow:
culitis solely after exclusion of malignity. The find-
ing of occult bleeding, although without pronounced 1. Haematemesis refers to vomiting of blood. Oe-
symptoms can contribute to an early diagnosis of ma- sophageal varices often result in vomiting of
lignity. Clinical examinations supported by bioptic bright red blood. However, if the blood, prior
examination are sufficiently reliable. Resection of tu- to being vomited gets into contact with gastric
mor should be followed by a check-up detection of the acid its appearance resembles the sediment of
plasma carcinoembryonic antigen which serves as a black coffee.
marker of relapse.
2. Melena (melas Gr. black) refers to a black
colouring of stool caused by the presence of
7.15.4 Polyps in GIT blood. It appears due to bleeding from any part
of GIT extending from the oral cavity to the
Polyps in GIT result from excessive growth of lu- large intestine. Melena is usually present in co-
minal epithelial cells. The occurrence is sporadical incidence with bleeding from the portion above
or familal. Polyps may be both benign or malign, the ligament of Treitz. The black colouring of
single or multiple. After 65 years of age, they are stool is caused by haem, namely due to its oxi-
detectable in two thirds of the population. Benign dation by intestinal and bacterial enzymes. The
polyps almost never progress to malignity. They are haem becomes oxidated within 8 hours. Melena
often accidentally detected in coincidence with other develops when the bleeding from GIT reaches
examinations as an accidental finding. Clinical man- 50–100 ml per day.
ifestation of polyps includes bleeding, anaemia and
abdominal pain. Large polyps may lead to intestinal 3. Haematochezia is a symptom of bright red blood
obstruction or cause profuse diarrhea. being present in stool. It is caused by bleeding
532 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

from the large intestine, rectum or anal aper- is complicated by another significant fact. Patients
ture. The source of bright red blood in stool with cirrhosis develop defects in blood coagulation.
may be also in higher parts of GIT, namely in Bleeding in such cases represents a life-endangering
coincidence with fast intestinal passage. When situation and its treatment is intricate.
the blood remains in the lumen for more than Further causes of bleeding from the upper part of
8 hours, its presence is manifestant as melena, gastrointestinal tract may include oesophagitis, car-
even in cases when the bleeding is localised in cinomas and other gastric tumours. The bleeding
the lower parts of GIT. may be chronic, but also acute with massive ham-
orrhage. The bleeding may sometimes develop in
Chronic gastrointestinal bleeding can be detected
coincidence with repeated vomiting. It is referred to
accidentally in coincidence with stool examination,
as Mallory-Weiss tear. Trauma of mucosa develops
or intentionally on the basis of the suspicion of such
in the area of oesophago-gastric junction. Which is
bleeding. The signals indicating to gastrointesti-
typical for this syndrome, is that haematemesis does
nal bleeding include overall weakness, dyspnoe, syn-
not develop during the first attack of vomiting, but
cope and in elderly patients problems resembling the
occurs during its subsequent attacks.
symptoms of the ischaemic heart disease. The above
mentioned symptoms, in particular, lead to the sus- Bleeding below the ligament of Treitz most fre-
picion of hypochromic anaemia developing in conse- quently originates in the anorectal area and colon.
quence of chronic bleeding. A small amount of bright red blood on the toilet
According to its localisation, gastrointestinal tissue or coating the stool usually comes from haem-
bleeding can be divided into two groups: bleeding orrhoids, anal fissures and fistulae. Proctitis due to
proximal to the ligament of Treitz and that local- infection frequently occurs in homosexuals. It usu-
ized distal to the ligament of Treitz. The assess- ally results in haematochezia.
ment of the site of bleeding simultaneously indicates Carcinoma of the large intestine, and polyps are
to its chief etiology. Bleeding above the ligament associated with chronic blood losses, but abrupt
of Treitz constitutes as many as 90 % of all cases bleeding may also take place. Bleeding in ulcerative,
of gastrointestinal bleeding. Bleeding due to pep- bacterial and ischaemic colitis is associated with di-
tic ulcer may come from the stomach, duodenum, arrhea. Bacterial colitis is accompanied with fever
or anastomosis after surgical intervention (ulcus in and weakness. Stool contains mucus and leukocytes.
anastomosis). Another cause of gastric bleeding may Ischaemic colitis occurs in the aged. Stool is typically
be due to erosive gastritis. It appears after alcohol liquid with an admixture of blood.
abuse or in coincidence with antiinflammatory drugs, Another cause of bleeding can reside in divertic-
such as acetylsalicylic acid, indomethacine, ibupro- ula. Diverticula localised in the sigmoid colon are
fen and other NSAIDs. Gastric erosions often de-
most frequent, but they rarely bleed. Inversely, the
velop in patients hospitalized due to severe trauma, diverticula in the ascending colon occur a little less
after massive burns and head injuries. In these cases frequently, but frequently represent the cause of mas-
stress-induced haemorrhagic gastritis develops. It sive bleeding. Inflammation of diverticula – diverti-
may develop also due to abrupt systemic diseases. culitis may be the cause of bleeding.
Regarding to the height of its mortality rate, haemor-
rhage due to erosive gastritis is very dangerous. The Elderly people may develop bleeding in conse-
mortality rate in hospitalized patients is reported to quence of vascular ectasias (not neoplasms) in the
reach 20 %. submucosal area of the colon. They are referred to
Bleeding from oesophageal varices is very fre- as angiodysplastic lesions. Angiodysplasia of aged
quent. It appears suddenly and is of massive char- people is more frequently present in association with
acter. Oesophageal varices result from portal hyper- aortic atherosclerosis. Diagnosis of angiodysplasia,
tension which develops in cirrhosis, most frequently in association with bleeding, is very difficult to as-
in that of alcoholic etiology. These relations are very sess.
significant. As many as 70 % of patients with portal Small intestine disorders rarely cause gastrointesti-
hypertension due to cirrhosis suffer from repeated nal bleeding. The Meckel’s diverticulum (a persis-
bleeding from oesophageal varices. This situation tent omphalomesenteric duct) which may be the
7.17. Abdominal pain 533

source of bleeding, occurs in two per cent of the pop- Spinal sensoric neurons receive information also
ulation. from non-sensoric neurons. Consequently, abdomi-
Finally, bleeding from GIT can be due to dis- nal pain can as well be perceived in extraabdominal
turbed haemostasis and haemocoagulation. There- parts of the body.
fore, bleeding occurs in cases of impaired coagula- Localisation, time of occurrence and progression of
tion (haemophilia, disseminated intravascular coag- abdominal pain are significant facts which are of im-
ulation), in vascular malformations (Osler-Weber- portant diagnostic value. Abdominal pain has one of
Rendu) and in vasculitis (Henoch-Schönlein pur- the following three properties, or their mutual com-
pura). binations:

1. Visceral pain is usually dull, inaccurately lo-

calised due to multisegmental and bilateral in-
nervation of abdominal organs. Therefore it is
frequently perceived in the central line. It has
7.17 Abdominal pain its origin in visceral organs. It may, however, be
of crampy and carving character.

2. Parietal pain is of somatic character. It is very

Pain is a general symptom which arises in conse- intensive, well localised and lateralised. The
quence of tissue impairment. In coincidence with pain is usually evoked by inflammation in the
gastrointestinal diseases, pain is the cause which parietal peritoneum.
drives the patient to the physician. Specific signs
of pain can facilitate the assessment of the correct 3. Transferred pain is localised superficially. It
diagnosis. Particular types of pain are specific for manifests irritation of visceral organs perceived
some diseases. Hence, e.g. the diagnosis of appen- as pain in more remote areas. The involved ar-
dicitis can be asessed on the basis of the character of eas are innervated by the same spinal segments.
pain even when the result of computer tomography The pain is usually associated with hyperaesthe-
is negative. Sensitive neurons lead information from sia.
visceral organs and peritoneum via the sympathetic
Visceral pain, as mentioned above, is not precisely
fibers into the spinal sensoric neurons. Their affer-
localised. Despite this fact it is possible to make out
ent endings terminate in smooth muscles of hollow
a list of pain characteristics classifying the relation
organs, in organ capsules, peritoneum and intraab-
of particular pain to individual visceral organs. Pain
dominal vessels. Abdominal organs per se are not
originating in oesophagus is localised substernally. If
sensitive to stimuli of cutting, traction and burns.
it is abrupt, it can be projected to the back, or to the
Only three stimuli are able to induce the pain in the
left arm. The pain coming from the stomach, duode-
digestive tract:
num and pancreas is localised in the epigastrium, or
• Distension or increased tension in the wall of right upper quadrant of the abdominal cavity. Pain
hollow organs or tension in capsules of solid or- from the gallbladder and bile ducts can be trans-
gans. It arisses due to strong muscular contrac- ferred below the lower angle of the right shoulder
tion in these organs, their spasms, distension, or blade. Pain due to subphrenic or hepatic abscesses
traction. can be transferred to the upper margin of the right
shoulder blade. Jejunal and ileal pains are often lo-
• Inflammation, owing to which, substances such calised periumbilically. Pain from the terminal ileum
as bradykinin, prostaglandins, histamine and can be perceived in the right lower quadrant. Pain
serotonin are released. These substances stimu- from the large intestine is not precisely demarkated.
late the sensitive endings of nerves. It is perceived in the hypogastrium, or lower abdom-
inal area, as if coming from organs within the pelvic
• Ischaemia brings about a release of tissue me- cavity. Pain in the left upper quadrant resembling
tabolites. These products, in the same way, sti- that which arises due to ischaemic heart disease is
mulate the sensitive endings of the nerves. present due to affliction of the transverse colon. Pain
534 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

in the area of the left hip joint appears due to dis- and peritonitis. These states stimulate the triggering
eases of the transverse and descendent colons. Rup- zones in medulla oblongata via the vagus nerve by
ture due to appendicitis can be manifestant by pain afferentation. The triggering zones induce vomiting.
in the lumbal and gluteal areas. Pain from the rec- In this way, drugs and irritation of the gastric mucosa
tum is perceived in the sacral region. can induce vomiting. Other impairments associated
In addition to its localisation, pain is determi- with vomiting include the increase in intraabdomi-
nated also by its progression and quality. Pain due nal pressure, psychogenous vomiting, hypersecretion
to oesophageal reflux is of burning character. The of gastric acid, morning vomiting in alcoholics, preg-
pain appearing in coincidence with peptic ulcers may nant women and patients with uraemia.
be of burning or cutting character. It is related to Abdominal pain often occurs in the irritable bowel
the intake of food or antacids. Pain arising due to syndrome. The clinical picture is dominated by ab-
intestinal obstruction is sharp, crampy with alternat- dominal pain, constipation or alternation of consti-
ing periods with and without severe pain. Patients pation and diarrhea. The organic foundation of these
are anxious. Pain arising in coincidence with biliary symptoms is not present. Possible changes in the
or cystic obstruction is permanent without interrup- large intestine are nonspecific. Currently, two fac-
tion. The pain evoked by inflammation, especially tors are considerated as being decisive:
by that of the parietal peritoneum is of permanent 1. Abnormal motility of the large intestine. The
equal quality, and is perceived in a demarkated site, latter is manifestant by high amplitudes of seg-
providing the peritoneum is irritated focally. It oc- mental contractions. They are very pronounced
curs in coincidence with appendicitis and gallbladder especially after the intake of food, in coincidence
inflammation. Pain is diffuse when the inflammation with emotions, mechanical distension and some
itself is diffuse and the peritoneal cavity contains pus, drugs.
blood, gastric or intestinal contents. Irritation of
the peritoneum is associated with muscular rigidity 2. Increased sensitivity to physiological stimuli,
above this area. Patients usually choose to remain such as normal amount of intestinal gas or nor-
in horizontal position in order to minimize the dis- mal intraluminal pressure in the sigmoid colon.
comfort. The pain caused by intestinal ischaemia is Intensity of the pain varies and it is usually lo-
abrupt, weakly localised and permanent. Pain aris- calised in the lower quadrants. The pain may be
ing due to the rupture of dissecting aortic aneurysm related to the intake of food. After defecation
arises suddenly and the afflicted person describes it and release of gases it becomes more moderate.
as being unbearable.
The stool is of marble-like appearance, or pellet-
Some types of abdominal pain are characterized like. It can contain a greater amount of mucus.
by its course. Thus, e.g. an abrupt onset of pain Bleeding is not observed, providing haemorrhoids
which becomes generalised, with subsequent devel- are not the causal condition. The clinical picture
opment of symptoms of peritoneal irritation often displays particular individual patterns. The disease
signalises that the perforation of a hollow organ has afflicts people with emotional instability, lethargy,
brought about peritonitis. Inversely, acute appen- headache, a certain degree of psychic rigidity and
dicitis or cholecystitis begin as a weakly localised anxiety. Laboratory examinations and examina-
pain in the central line. The pain is projected above tions of the entire digestive tract are negative. The
the afflicted organ with subsequent symptoms of medicamentous therapy has no chances to be success-
peritoneal irritation. ful. Spasmolytic drugs relieve the pain. The symp-
Abdominal pain is often associated with nausea toms appear in original intensity even after a lapse
and vomiting. Vomiting appears most frequently in of time following a special diet. In such cases the
coincidence with obstruction and distention of the condition is to be treated by patient’s re-education
stomach and intestine. It occurs especially due to under the physician’s supervision and aimed at the
obstruction of the pylorus or that of the small in- psychoneurotic essence of this state. According to
testine. Sometimes the cause resides in motility im- some statistical studies, as many as 5 % of all gas-
pairment, e.g. in diabetic gastroparesis. Nausea and troenterologic outdoor patients suffer from this con-
vomiting are incurred also by peritoneal irritation dition.
7.18. The Liver (D. Maasová) 535

Acute abdominal pain always represents an urgent 4. excretion of larger and more hydrophobic
situation. It is an intricate and serious problem. It metabolites, foreign substances and a number
may represent a significant symptom of a condition of drugs
which if not treated immediately ends up by death
of the afflicted patient. Acute abdominal pain re- Optimal procurement of these mutually distinct
quires rapid and precise diagnosis and in many cases functions is in accord with hepatic structure, includ-
it is inevitable to operate. Therefore, despite the fact ing the blood and bile pathways. The overall blood
that it would be possible to object that the discourse perfusion via the liver represents one fourth of the
on acute abdominal pain belongs to the domain of cardiac output at rest. The blood inflow is procured
clinical medicine, we are going to present several im- by the hepatic artery (25 %) which brings in blood
portant matters on this symptom. rich in oxygen, and the portal vein (75 %) which sup-
Acute abdominal pain most frequently occurs in plies the liver with blood rich in nutrients from the
the diseases of the digestive tract as follow: acute ap- splanchnic area. Both vessels enter the liver and ter-
pendicitis, cholecystitis, pancreatitis, intestinal ob- minaly reache the sinusoids. The sinusoids already
struction, perforation of hollow organs, intestinal in- contain mixed blood which directly bathes the hep-
farction, intestinal strangulation, acute diverticulitis. atocytes. The blood delivers important metabolic
Acute abdominal pain can arise also due to dis- products. After taking up some nutrients and elimi-
turbances of other than digestive organs. It may nated waste products (some waste products are taken
be due to: rupture of aortic aneurysms, rupture up, whereas others are excreted by hepatocytes) the
in extrauterine pregnancy, pneumonia, renal stones, blood is drained through the central veins (venae
haemolytic crisis, acute hepatitis and acute por- centrales) which represent the beginning of the effer-
phyria. ent blood pathways subsequently merging into the
The judgement of abdominal pain requires to inferior vena cava. The hepatic parenchyma micro-
take into consideration the onset of pain, its course scopically appears as a system of hexagonal lobuli,
and accompanying symptoms, such as fever, nausea, the centres of which contain a central vein.
vomiting, constipation and diarrhea. The latter rep- However, regarding the functional aspect, the hep-
resents a supremely valuable symptom which aids to atic parenchyma is divided into acini. The acinus is
assess the correct and qualified diagnosis. localised among several central veins and its centre is
constituted by so-called portobiliary space (terminal
triad), which contains the terminal branch of the por-
tal vein, terminal branch of the hepatic artery and
the bile duct. The functional efficiency, resistance,
7.18 The Liver as well as the enzymatic equipment of hepatocytes
is determined by its localisation – its distance from
the portobiliary space. The periportal zone (zone 1)
resides in the close vicinity of terminal triad and it is
The liver is the largest parenchymatous organ in perfused by blood being still rich in oxygen and nutri-
the human body. Its task in organism is irreplace- ents. The function of the intermediary zone (zone 2)
able. Liver failure, or experimental hepatectomy in- changes according to the overall supply of the liver
curs death in several hours. Hepatic functions can by blood. The central zone (zone 3) is localised in the
be divided into four groups: vicinity of central vein, i.e. at the periphery of acini.
The blood flowing to the cells of the latter zone is
1. synthesis of a large amount of special proteins, poor in oxygen and nutrients which have been taken
carbohydrates and lipids up in the previous two zones. Therefore the cells
2. regulation of the balance between GIT and sys- of this zone are predominantly liable to impairment
temic circulation which maintains a stable level in coincidence with e.g. shock and other disorders of
of amino acids and glucose circulation. According to the enzymatic equipment,
the cells of the periportal zone primarily synthesize
3. production of bile salts and bicarbonate neces- proteins, the cells of the central zone carry out glycol-
sary for the correct digestion in GIT ysis, lipogenesis and processes of biotransformation.
536 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

The following text is going to deal with the mi- in the pericanalicular cytoplasm under the condi-
croanatomic localisation of the terminal blood path- tion of increased bile secretion. In the proximity of
ways and the onset of bile ducts in relation to hepa- the canalicular membrane, microfilaments are con-
tocytes, as well as with the structure of hepatocytes centrated. The microfilaments are contractile struc-
regarding their function. tures constituted of polymerized actin. They form a
pericanalicular network. A coordinated contraction
It is within the acinus that arteriole empties into
of this network (possibly involving changes in cytoso-
the portal venule and the mixed blood percolates
lic calcium concentration) bring about a peristaltic
through the sinusoid toward the central vein. The si-
wave which shifts the bile into larger collecting struc-
nusoid is lined by endotelial and phagocytic Kupffer
tures. The canaliculi gradually gain their own wall,
cells. Unusually large fenestrae in the endotelial cells
thus changing into ductules (cholangioles) which co-
facilitate an easy transgression of large molecules
alesce and form larger biliary ducts. Both right and
from the blood to the hepatocyte plasma mem-
left hepatic ducts emmerge from the hepatic port and
brane. The capillary space, which occurs between
constitute the common hepatic duct (ductus hepati-
the endotelial lining cells and hepatocytes (space of
cus communis) which is joined by the cystic duct
Disse), represents the onset of the lymphatic path-
from the gallbladder, thus constituting the common
ways. The sinusoidal membrane, that portion of
bile duct merging into the duodenum. In this site
hepatocyte plasma membrane bordering the space
common bile duct contains a muscular sphincter of
of Disse – constitutes rich microvilli which enlarge
Oddi which inhibits an uncontrollable leakage of bile
the surface of resorption of substances brought in by
into the duodenum.
the blood. The lateral portion of sinusoidal mem-
brane, bordering the intercellular space, is relatively
flat. The canalicular membrane, which consists of 7.18.1 Metabolism in liver
many irregularly spaced microvilli, carries out inten-
sive processes of elimination. The canalicular mem- 7.18.1.1 Metabolism of proteins
branes of two adjanced hepatocytes joined by junc-
The liver is the main site of the synthesis of the ma-
tional complexes circumscribe the canalicular space
jority of plasma proteins as well as the main site of
– canaliculus. The different plasma membrane do-
their degradation. Among the number of proteins
mains differ in their assotiated transport systems and
sythesized within the liver, the greatest significance
in their physical properties. Canalicular membrane,
in relation to hepatic diseases resides in albumin and
as compared with the sinusoidal membrane, has a
prothrombin. Albumin’s main function is to main-
higher content of the sialic acid, higher molar choles-
tain the intravascular oncotic pressure and the trans-
terol/phospholipids ratio and lower fluidity. These
fer of substances soluble in water, such as fatty acids,
special properties assumedly facilitate the secretion
bilirubin, hormones and drugs. Since albumin has a
of bile acids and lipids and protect the membrane
relatively long halftime of breakdown (cca 21 days),
from the detergent effect of canalicular bile.
its level almost does not change in coincidence with
Hepatocytes contain multiple mitochondria. This acute hepatic diseases. Long-term reduction of the
fact suggests that the hepatocytes have functions albumin synthesis in chronic liver diseases, however,
that are energetically demanding. The smooth part evokes hypoalbuminaemia with all consequences in-
of the endoplasmic reticulum is the site where the cluding the development of ascites. Serum albumin is
detoxication and conjugation processes are carried therefore the sensitive marker of the synthetic func-
out together with the synthesis of enzymes. The tion of the liver and a significant indicator of the
granulated part of the endoplasmic reticulum pro- severity of chronic hepatic diseases.
cures the synthesis of proteins (albumin, coagula- An insufficient synthesis of prothrombin is exter-
tion factors). Lysosomes contain hydrolytic enzymes nally manifestant in dependence on the function of
and acid phosphatases, as well as accumulated pig- other coagulation factors, a majority of which are
ments (lipofuscin, ferritin, bilirubin, copper). The synthesized in the liver. A common symptom of
Golgi complex participates in the transport of cer- impaired synthesis is a prolonged blood coagulation
tain solutes from blood to bile (bile acids, biliru- time. The liver receives amino acids from GIT and
bin). This fact is proved by its dense occurrence muscles, and regulates their plasma levels by pro-
7.18. The Liver (D. Maasová) 537

cesses of glyconeogenesis and transamination. The enzymes responsible for the synthesis and oxidation
liver is responsible for the modification of plasma of fatty acids, the synthesis of cholesterol, phospho-
amino acids composition. Aromatic amino acids – lipids and the apoprotein part of plasma lipoproteins.
phenylalanine, tyrosine, methionine – are preferen- They are also the singular site of beta-oxidation of
tially transformed to urea, whereas amino acids with fatty acids with the production of ketone substances.
branched chains – valine, leucine, isoleucine – are They take up free fatty acids from circulation. The
selectively shifted to the periphery, where they are free fatty acids serve as the substrate for the synthe-
preferentially metabolized in muscles. This selectiv- sis of phopholipids and triacylglycerols.
ity disappears in severe diseases of the liver. It is pos- The liver has a major part in the metabolism of
sible that the resultant change in the ratio of plasma transport lipoproteins. Lipoproteins with high den-
concentrations of these two groups of amino acids sity (HDL) are synthetized in the liver and intestines.
can incur damage to the metabolism of brain neu- Their major share is represented by protein and a
rotransmitters and contribute to the development of their minor share by triacylglycerols. They represent
portosystemic encephalopathy. the most important system of transport of phospho-
Amino acids are degraded in the liver by transam- lipids. In addition to the kidneys, the liver is the
ination and oxidative deamination, giving way to the main site of HDL catabolism.
formation of ammonia, which in turn is further con- Lipoproteins with low density (LDL) are produced
verted to urea and eliminated by the kidneys. Severe in the plasma during catabolic processes of lipopro-
hepatic impairments coincide with the failure of this teins with very low density (VLDL). They are the
chief pathway of elimination of the nitrogenous waste chief transporters of cholesterol. A majority of them
from organism. are degraded in the liver after their binding with
high-affinity receptors. VLDL which contain as much
7.18.1.2 Metabolism of saccharides as 60 % of triacylglycerols, are synthetised foremostly
in the liver and represent the endogenous synthesis
The maintenance of the stable level of glucose in the of triacylglycerols.
blood represents the further function of the liver. It Chylomicrons have the lowest density. Together
acts as the entrance gate for glucose accepted by or- with VLDL, they are considered as being the main
ganism with food. An excess of glucose which is lead carriers of triacylglycerols. They are produced in
in from GIT during digestion is converted to glyco- the cells of intestinal mucosa and represent the chief
gen. However during fasting, the latter represents form of transport of fat from food. They appear in
the source of glucose. The main metabolic path- the plasma during the postprandial period and dis-
way is glycogenolysis. After the depletion of glyco- appear in several hours. They are catabolised by the
gen reserves, it is foremostly the lactate, pyruvate, lipoprotein lipase in peripheral tissues and by the
glucogenic amino acids and glycerol originating from hepatic lipase in the liver. The next significant role
fat reserves by lipolysis. As long-term fasting de- of the liver resides in the metabolism of cholesterol.
pletes the above mentioned sources, the organism The liver takes up a major part of the exogenous
utilises ketone substances and fatty acids as alter- cholesterol and at the same time it is the main site of
native sources of energy, and tissues adapt to the the synthesis of the endogenous cholesterol. Choles-
lower consumption of glucose. The main tool of the terol is eliminated from the liver by both blood and
metabolic control of glycaemia maintenance are hor- bile. The main product of cholesterol catabolism are
mones as insulin, glucagon, catecholamines and glu- the bile acids.
cocorticoids. The supply of glucose by gluconeogen-
esis under conditions of hepatic diseases is well pre- 7.18.1.4 Metabolism of bile acids
served. Hypoglycaemia represents a threat solely in
severe liver failures. Bile acids (BA) are synthetized in hepatocytes from
cholesterol. The limitating factor of the velocity of
7.18.1.3 Metabolism of lipids its synthesis is the cholesterol-7alpha-hydroxylase.
Primary bile acids – cholic and chenodeoxycholic
The liver has a special position in the metabolism acids conjugate with glycine and taurine in the endo-
of lipids. Hepatocytes are abundantly equipped by plasmic reticulum. The conjugation increases their
538 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

solubility, thus enabling their elimination into bile inhibits their entrance into the systemic circulation.
and currently makes the molecule more resistant to Solely a small, relatively stable fraction of BA es-
precipitation by divalent cations (e.g. Ca2+ ). The capes. This fraction is taken up during the repeated
conjugation significantly decreases the possibility of perfusions via the liver (thereby the concentration
passive absorption from the biliary tract and small of BA in the systemic circulation is directly propor-
intestine. Conjugated BA are too large to penetrate tional to the load of bile acids that are lead into the
paracellular junctions and their charge hinders their liver from intestine in each moment – their level in
movement through the lipid parts of apical mem- blood increases during digestion and decreases be-
branes of the biliary and intestinal epithelia. This tween meals, however does not exceed 8 µM). The
enables them to pass through the intestine in high half-time of BA in the systemic circulation is only
concentration and to reach the terminal ileum. In the several minutes. Binding of BA to plasma albumin
intestine, the bile acids act as detergents – their main (70–99 %) inhibits their entrance into the extracellu-
function is to solubilize lipids. Approximately 90 % lar space and glomerular filtrate. A small fraction of
of bile acids are reabsorbed in the terminal ileum. bile acids which escapes into the glomerular filtrate is
A small part of bile acids which has passed through efficiently reabsorbed in the renal tubules, and that is
the ileocecal valve, enters the anaerobic environment why they are not present in urine of healthy people.
of the cecum. Herein, under the influence of bac-
terial enzymes, secondary bile acids – deoxycholic 7.18.1.5 Metabolism of bilirubin
and lithocholic acids are produced. A small part of
bile acids deconjugates, partly under the influence of Bilirubin is the terminal product of degradation
bacterial enzymes. Primary and secondary bile acids of haemoproteins, especially that of haemoglobin.
return back to the liver. They are taken up by hep- Heme is converted to biliverdin and further to biliru-
atocytes. According to the actual needs, they are bin by mononuclear phagocytic cells which include
conjugated and again secreted into bile (enterohep- also the Kupffer cells of the hepatic sinusoids. The
atic circulation). The remnant 5–10 % are excreted produced lipophilic, insoluble bilirubin (nonconju-
daily in stool, and therefore their overall pool must gated) circulates in plasma bound tightly to albu-
be repleted by de novo synthesis. min. The contact with hepatocytes brings about
the dissociation of the bilirubin-albumin complex.
The enterohepatic circulation of bile acids rep-
After the transgression through the membrane it
resents a continuous flow of transporting molecules
is transported by means of cytoplasmic transport
which transfer lipids and substances soluble in fat
proteins (Y protein, ligandin) to the endoplasmic
from the intestinal lumen into intestinal mucosa and
reticulum where it conjugates in presence of uri-
cholesterol from the liver to intestine, thus enabling
dine diphospho-glucuronosyltransferase (UDP-GT)
thus its elimiation by stool. This movement is en-
to bilirubin monoglucuronide and bilirubin diglu-
hanced during digestion and hindered during fasting,
curonide. Conjugated bilirubin is soluble in water
but never ceases.
which enables its active secretion into bile. The in-
The enterohepatic circulation of bile acids includes testinal flora in terminal ileum brings about its hy-
chemical pumps (transport systems of hepatocytes drolysis and an immediate reduction to colour-less
and enterocytes), mechanical pumps (biliary tract, tetrapyrols, commonly referred to as urobilinogens.
small intestine, blood circulation), valves (sphincter Approximately 20 % of the formed urobilinogen is ab-
of Oddi, ileocecal valve) and storing spaces (gallblad- sorbed, returned by portal circulation into the liver
der, small intestine). The enterohepatic circulation where it is partially degraded and secreted into bile.
is thereafter enabled by the impermeability of the Only a minimal amount of urobilinogen escapes from
cellular membranes for conjugated BA. The relative liver and is eliminated into urine.
impermeability or the epithelial lining of the biliary
pathways and proximal part of the small intestine 7.18.1.6 Production of bile
maintain the concentration gradient of BA, which is
a thousand-fold higher in the bile and small intestine The production of bile resides in the movement of
than in the surrounding cells. An efficient extraction water, electrolytes and other bile constituents from
of bile acids by hepatocytes from the portal blood the sinusoid blood (or from hepatocytes) into the
7.18. The Liver (D. Maasová) 539

canaliculus. Their movement from the sinusoid into ities are decreased. These processes are referred to
the canalicular space can be carried out in two ways: as metabolic detoxification or biological transforma-
transcellular movement – through the sinusoidal (or tion. Since the liver catabolizes a large amount of
lateral) and canalicular membranes, or paracellular hormones (steroids, insulin, glucagon, thyroxin), the
movement – from the intercellular space through the chronical impairment of hepatic functions is usually
tight junctions between the adjacent hepatocytes. accompanied by the signs of hormonal disbalance. A
Since these tight junctions are relatively permeable severe consequence of a decrease in the amount or
for anorganic ions, this pathway leads the majority activity of microsomal enzymes, is the delay in inac-
of Na+ , Cl−, and K+ ions. tivation and elimination of xenobiotics. However, a
The main driving force of the canalicular produc- simultaneous administration of two drugs, metabo-
tion of bile resides in bile acids. They are actively lized by the same microsomal system can also lead to
transported through the canalicular membrane into modification, augmentation or decrease in the phar-
the canaliculi where they undergo condensation. In macological effect of one of the drugs or both.
consequence of this process their density becomes ap- Under certain circumstances, the final products
proximately 1000–fold higher than that in plasma. of detoxification can have a further toxic impact.
This condition produces an enormous osmotic gra- E.g., owing to a high intake of alcohol, the produced
dient for water diffusion. Water under basal con- acetaldehyde damages mitochondria of hepatocytes
ditions foremostly moves by transcellular pathways. and the produced hydrogen ions cause an accumula-
The conjugated bilirubin is transferred through the tion of fat in hepatocytes (steatosis).
canalicular membrane by its own transport system.
Its elimination, however, depends to a certain extent
7.18.1.8 Liver enzymes
on the elimination of bile acids. The secretion of
phospholipid-cholesterol vesicles into bile depends as Liver diseases usually bring about changes in the
well on the secretion of bile acids. It is maximal un- amount of enzymes which belong to the hepatic en-
der high enterohepatic circulation of bile acids. The zymatic equipment, or the synthesis of which takes
smaller component of bile production, independent place in the liver. This fact is being used in both
from bile acids, takes place on the level of canali- routine and special enzymatic diagnostics. Since the
culi and ductuli. The membrane ATP-ase in canali- investigated enzymes are from various cellular parts
culi pumps ions into bile. By this process the ions (cytosol, mitochondria, nembranes, lysosomes), the
gradually seize a certain amount of water. The bile changes in concentrations of individual enzymes in
is supplemented by fluid rich in bicarbonates which the blood and their mutual combinations can ren-
is eliminated into bile through the walls of ductuli. der certain information on the character and stage
This process takes place under the impact of secretin. of liver impairment.
Bile acids are strong detergents which solubilize bile
lipids by enclosing them into micelles (mixed mi-
Cytosolic and mitochondrial enzymes
celles are conglomerates of cholesterol, fatty acids
and lecithin surrounded by polar molecules of bile ALT (alanine aminotransferase) is a specific en-
acids). The formation of micelles is also important zyme of the hepatic tissue. It exclusively occurs in
for the elimination of cholesterol and phospholipids cytosol. This enzyme leaves the cell already in coinci-
into bile and for the transport of bilirubin. The bond dence with a moderate impairment merely increasing
of bilirubin with micelles decreases its concentration the permeability of the cellular membrane.
in the non-micellar phase of bile and decreases thus AST (aspartate aminotransferase) is constituted
the possibility of its backward diffusion through the of cytosolic and mitochondrial fractions. In addition
membranes of biliary pathways. to the liver, it also occurs in a greater amount in
the cardiac and skeletal muscles. Increased plasma
7.18.1.7 Detoxification functions of the liver levels of AST therefore occur in coincidence with an
impairment of hepatocytes, cardiomyocytes and my-
Both endogenous and exogenous chemical substances ocytes. A moderate impairment of hepatocytes asso-
undergo transformation processes in the liver. Owing ciated only with an increased permeability of mem-
to these processes their toxicity, or biological acitiv- branes singly allows the cytosol fraction to enter the
540 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

blood. Therefore, the increased level in AST can oc-

cur e.g. due to septicaemia, or other states in which
hypoperfusion and anoxia lead to a transient impair- 7.19 Pathophysiology of the
ment of hepatocytes. The recovery of circulation liver
very quickly lowers the AST plasma level. Necrosis
of hepatocytes brings about also the mitochondrial
fraction, and the level of AST in blood is high.

Membrane enzymes
7.19.1 Acute hepatitis
They occur especially on the canalicular mem-
brane of hepatocytes. Therefore they foremostly Acute impairment of the hepatic parenchyma can be
react to the changes concerning the composition caused by many factors. Histologic changes in the
and excretion of bile. To a greater extent, they parenchyma, however, essentially resemble in coin-
can be synthetised due to the effect of insufficiently cidence with various etiologic causes. Hepatocytes
hydroxylated BA. The detergent effect of BA releases that yield degenerative changes (oedema, vacuoliza-
them to a greater extent from the membraneous sur- tion, cytoplasmic granulation) succumb to necrosis
face. and are quickly replaced. The distribution of these
ALP (alkaline phosphatase) occurs not only in changes in the parenchyma depends to a certain ex-
the liver, but also in other tissues (bone, intestines, tent on the etiologic cause, but necrosis foremostly
placenta). The hepatic isoenzyme is localised es- occurs in the zone 3. The extent of hepatocellular
pecially in the canalicular part of the hepatocytic impairment can significantly vary in dependence on
membranes. Its increased serum level is a sensitive the etiologic cause and interindividually. The same
indicator of both segmental and complete biliary ob- factor can in one patient cause e.g. necrosis of only
structions as the isoenzyme enters the blood by the a small group of hepatocytes and in another it can
reflux due to its increased production above the site entail an extensive necrosis of the parenchyma lead-
of obstruction. If, together with the ALP increase, ing to a fulminant liver failure. Acute diseases of
the abnormalities in gammaGT occur, it is assumed the liver usually yield the presence of centrilobular
that ALP is of the hepatic origin. cholestasis. The extent of the inflammatory infiltrate
varies, but portal and periportal tracts are infiltrated
GammaGT (gamma glutamyltransferase) is spe-
especially by lymphocytes.
cific only to a small extent, but it is an outstand-
The most frequent type of acute hepatic impair-
ingly sensitive enzyme. Its serum activity already
ment is an inflammatory disease – acute hepati-
increases due to minimal cholestasis. Furthermore,
tis. Its cause can reside in: viruses (viral hepatitis,
its activity is increased by xenobiotics and alcohol.
mononucleosis. cytomegaly), bacteria (leptospirosis,
In case of ALP being normal, the increase in gam-
tuberculosis, brucellosis), toxic substances (alcohol,
maGT is a reliable marker of alcohol abuse. A mod-
organic solvents, herbal poisons, drugs). In addition
erate increase in gammaGT is common even after the
to the above mentioned factors, sepsis, inflammation
intake of a small amount of alcohol and therefore it
in the abdominal cavity and inflammation in the vas-
does not inevitably have to indicate an impairment
cular bed of the portal vein or in draining biliary
of the liver, providing all other tests are normal.
pathways can evoke the so-called secondary hepati-
BGL (betaglucuronidase) is a lysosomal enzyme. tis. In our environment the most frequent types of
Its increased activity in the blood already occurs acute hepatitis are of viral etiology.
in coincidence with the initial phase or moderate
form of intrahepatic cholestasis. It is explained by 7.19.1.1 Viral hepatitis
metabolic activation of lysosomes per se without the
membraneous permeability having to be necessarily Acute viral hepatitis is a systemic infection which af-
impaired. flicts foremostly the liver. Under common conditions
none of the hepatotropic viruses damages the hepa-
tocytes directly. The liver injury develops in con-
sequence of the immunologic reaction between the
7.19. Pathophysiology of the liver (D. Maasová) 541

virus and the host organism. The common cause hepatocytes and activation of the mesenchyma
of liver impairment resides in the attack of lympho- take place. Number of cells with phagocytic
cytes to viable, antigen expriming hepatocytes. Typ- abilities, including the Kupffer cells, increases.
ical morphological changes in hepatitis include infil- Histiocytes, plasmocytes and granulocytes en-
tration of lobules by mononuclear cells ( small Ly, ter the periportal spaces. Later, fibroblasts de-
plasma cells, eosinophils), degeneration and necro- velop, causing thus the proliferation of collage-
sis of hepatocytes, hyperplasia of the Kupffer cells nous fibers. This histologic picture is main-
and various degrees of cholestasis. In addition to the tained practically until the recovery of the clin-
above mentioned changes, the regeneration of hepa- ical state (6–8 weeks) takes place.
tocytes with the development of rosettes and pseu-
During the subsequent period, the jaundice
doacini currently take place.
withdraws and in a majority of cases the dis-
• Viral hepatitis A (VHA) is a frequent type of vi- ease retreats during 3–6 weeks. Simultaneously
ral hepatitis. It is spread world-wide and occurs with the disappearance of jaundice, the phys-
in epidemies especially in children and young ical and psychical activities return. Sometimes
people. The source of infection resides in con- the patient still suffers from weakness, increased
taminated food and the transmission takes place tiredness, arthralgia or dyspeptic disturbances
by the oral pathway. for several months after the termination of the
disease. This state is referred to as posthepatitis
The virus of hepatitis A is a RNA virus. Its syndrome. It involves a functional disturbance
replication takes place in the liver. Hepatitis A and the afflicted patients are especially young
virus is also present in bile, stool and blood (at neurovegetatively unstable people. The VHA
the end of the incubation period and in acute prognosis is very good as the majority of pa-
phase of VHA). Antibodies against the virus be- tients are completely healthy. A severe course
long to the IgM class, in later period to that of of the disease with fulminant hepatic necrosis
IgG. Carriership does not exist. and hepatic coma leading to death is exceptional
In addition to the liver, the disease afflicts also (0.1 %). VHA never progresses into chronicity.
other organs, e.g. the heart, gastrointestinal
tract, pancreas and spleen. The preicteric (pro- • Viral hepatitis B (VHB). It is estimated that the
dromal) phase lasts for two weeks. Viraemia hepatitis B virus (HBV) is present in 300 mil-
in this period causes anorexia, nausea, vomit- lions of carriers, foremostly in Africa and the
ing, diarrhoea, headache, malaise, and febril- Far East. HBV is transmitted by blood (trans-
ity. During this phase the AST serum level in- fusions, contaminated needles) or by sexual in-
creases. Urine contains bilirubin and urobilino- tercourse, foremostly in homosexuals (the virus
gen. Yet, the serum bilirubin does not increase is present in the semen and saliva). The ver-
significantly. tical transmission from mother to child during
birth or soon after birth is the most world-wide
The icteric period lasts for 2–3 weeks. The de-
frequent pathway of transmission.
velopment of icterus usually brings about an
improvement in the patient’s subjective state. The virus of hepatitis B is a DNA virus. The
Urine becomes darker and stools are lighter due entire virus appears in the electrone microscope
to the cholestasis. The serum bilirubin increases as so-called Dane particle which is constituted
and its level manifests the stage of icterus. 1– of the internal nucleus formed by the nucleus
2 weeks after the appearance of jaundice, the of hepatocyte and the external superficial layer
serum AST reaches its maximal values. The (HBsAg) formed by multiplication in the cy-
blood yields leukopenia with relative lympho- toplasm. The internal nucleus contains DNA,
cytosis. The liver is moderately enlarged. The DNA-polymerase, nuclear antigen (HBcAg) and
pathological changes in hepatocytes vary and antigen e (HBeAg). Replication takes place ex-
occur simultaneously. Necrosis may be of soli- clusively in the liver and it is possible to assume
tary, focal or diffuse characters. Simultane- that the virus becomes a component of the nu-
ously with the latter, the regeneration of some clear protein of the host cell. In this way it
542 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

can take part in the development of hepatic tu- • Viral hepatitis E (VHE) is transmitted in faecal-
mours – hepatomas. It is possible to detect the oral manner and occurs in epidemies in Asia,
virus in blood in form of nuclear (HBcAg and south Africa and Mexico. It is characteristic by
HBeAg) and mainly superficial (HBsAg) parti- high mortality rate in pregnant women (20 %).
cles. The superficial particles contain further A majority of cases terminate with no conse-
antigenic subdeterminants (a, d, y, w, r), charac- quences and do not bring about chronic hepatic
terising the geofraphical differencies. In relation impairment.
to hepatitis B, it is necessary to mention the
virus of hepatitis D (delta-antigen). Hepatitis D Hepatitis F and G have already been described
virus is a defective RNA virus which needs the too.
virus of hepatitis B for its own transmission. It
occurs in the nuclei of hepatocytes and occa-
sionally in the cytoplasm. It can be transiently
7.19.2 Chronic hepatitis
identified in coincidence with acute VHB, espe- The hepatitis lasting for more than 6 months is de-
cially in narcotic addicts. Its main significance fined as being chronic. The most frequent causes of
resides in the fact that it can cause a severe hep- chronic hepatitis include: viruses of B and C hepati-
atitis in the carriers of the hepatitis B virus. tis, alcohol, xenobiotics and autoimmune processes.
The clinical signs of chronic hepatitis vary. Most
The clinical picture of VHB is the same as frequently they involve permanent tiredness, malaise
that of VHA. Furthermore, the prodromal phase associated with depression and gastrointestinal diffi-
can be manifested by the immune response culties – inappetence, nausea, meteorism. Since this
with transient urticaria, maculopapulose ex- disease is frequently asymptomatic, the basic crite-
anthem or polyarthritis afflicting small joints. rion for the assessment of the diagnosis of chronic
The disease can proceed more severely than hepatitis resides in the persistence of histological
that of VHA. Occasionally, arthritis or glomeru- changes. On the basis of the latter, two main types
lonephritis occur due to the formation of extra- of chronic hepatitis are distinguished: chronic per-
hepatic immune complexes. The course of the sistent hepatitis and chronic active hepatitis.
disease depends on a number of factors, includ-
ing the virulence of the virus and both immuno- • Chronic persistent hepatitis (CPH) is a benign
competence and the age of the patients. The state with a relatively good prognosis. It is
disease usually terminates by a complete recov- frequently asymptomatic. Laboratory tests dis-
ery. Approximately 1 % of cases manifest the play only a moderate increase in AST. The liver
symptoms of fulminant hepatitis. A proportion biopsy reveals the chronic inflammatory infil-
of hepatitis cases (5–10 %) progresses to chronic- trate which is present in the enlarged portal
ity and patients become permanent carriers of tracts. The basic architecture of the liver is how-
the virus. ever intact. Only in rare cases, solitary necroses
of hepatocytes (piecemeal necrosis) or moder-
ate fibrosis are present. This state can persist
• Viral hepatitis C (VHC), earlier referred to for several months or years, with no tendency
as non-A, non-B hepatitis, is caused by an of progression. A majority of patients develop
RNA virus and is responsible for a majority of neither chronic active hepatitis, nor cirrhosis.
post-transfusion hepatitis in countries where the
blood is not tested for VHB markers. It also • As well as the latter, the chronic active hepati-
occurs in drug addicts and homosexuals. Acute tis (CAH) can similarly proceed asymptomati-
hepatitis has a more moderate course than those cally, but in contrast to CPH, it is character-
of VHA and VHB. The extrahepatic manifesta- ized by progression of the pathological process in
tion includes arthritis, agranulocytosis, aplastic the hepatic parenchyma which can lead to liver
anaemia, as well as diffuse neurological prob- failure. Therefore CAH was previously referred
lems. Fulminant hepatic failure is rare, but the to as chronic aggressive hepatitis. Approxi-
progression to chronicity is frequent (50 %). mately 3 % of patients with hepatitis B progress
7.19. Pathophysiology of the liver (D. Maasová) 543

to CAH, especially if superinfection with delta- disintegration of hepatocytes results in the collapse
virus is involved. In addition to hepatitis C, of the reticulin net. The portal triads remain intact.
the further important triggering etiologic fac- The inflammatory reaction can be surprisingly
tors include also some drugs (methyldopa, isoni- moderate. The progressive loss of liver tissue can re-
azid, nitrofurantoin). The main histological sign duce its weight to 500 g and the liver is transformed
of CAH resides in minute disseminated necro- to a small tender organ covered by a wrinkled and a
sis of hepatocytes on the interface between the too large capsule. Fulminant hepatitis is foremostly
parenchyma and inflammatory infiltrate. The manifested by icterus, encephalopathy, coagulopa-
inflammatory infiltrate constituted of lympho- thy with bleeding, renal failure with disturbances
cytes and plasma cells penetrates from the por- in the electrolyte balance, cardiovascular instability,
tal space into the lobule. This process brings ARDS, sepsis etc. . According to the severeness of
about disruption of hepatocytic plates around the affliction and immunity abilities of the organism,
the portal triads and changes the architecture the mortality rate varies between 25 and 90 per cent.
of the lobules. Fibrous septa develop isolating If the patient survives several weeks, the regenerative
small groups of hepatocytes. abilities of the remnant hepatocytes can be applied.
The regenerative process can entirely restore the for-
The cellular immune mechanisms play dominant mer architecture of the tissue. Massive destruction
role in the pathogenesis of CAH. It is assumed that of the liver, however, results in the irregular regener-
lymphocytes become sensitive to the changed or new ation with the development of nodules (postnecrotic
antigens which are exprimed from the surface of hep- cirrhosis).
atocytic membranes. Humoral immune mechanisms
can be responsible for some extrahepatic impair-
ments in CAH. Out of them e.g. arthritis, rash, and 7.19.4 Chronic hepatic failure
glomerulonephritis can take place in consequence of
the deposition of the circulating immune complexes. Chronic hepatic failure develops in consequence of a
Since CAH is a serious progressive disease, it is im- wide scale of acute and chronic liver diseases. If the
portant to distinguish it from CPH which does not activity of the pathological process in these states ex-
require therapy. Untreated CAH often terminates ceeds the regenerative abilities of the liver, the hep-
fatally within five years, the cause of death residing atic functions are slowly and gradually deteriorated.
in liver failure. Death in the later period usually oc- Chronic hepatic failure is characterized by a slow de-
curs in consequence of complications associated with velopment of symptoms, fluctuating progression, and
liver cirrhosis. sometimes also by a transient disappearance of symp-
toms.
The biochemical markers of hepatic functional im-
7.19.3 Acute hepatic failure pairment are accompanied especially by the neu-
If the liver disease progresses to hepatic encephalopa- ropsychical (hepatic encephalopathy) and haemato-
thy within several days or 2–3 weeks, it is referred to logical (haemorrhage) symptoms. Bleeding is caused
as fulminant hepatic failure. Fortunately, acute fail- by a decreased synthesis of the factors of coagulation,
ure is rare and takes place due to viral hepatitis and decreased number of thrombocytes and (providing it
hepatitis caused by drugs (isoniazid, antidepressives, is present) by increased pressure in the portal vas-
halothane) and toxic substances (e.g. mycotoxins of cular bed. The deterioration of this state usually in-
Ammanita phalloides, phosphorus, carbon tetrachlo- duced by exogenous factors can lead to hepatic coma
ride). with high mortality.
The development of hepatic failure significantly
varies. It especially depends on the liver condition 7.19.5 Hepatic cirrhosis
and the age of a patient. All inducing factors in-
deed cause identical morphological changes. Necro- Cirrhosis is an irreversible change in the structure
sis of hepatocytes is either dispersed in the entire of the liver, representing the ultimate stage of the
parenchyma, or afflicts individual irregular areas. A large group of liver diseases of various etiology. The
complete destruction of the adjacent lobules with the most frequent cause of cirrhosis is represented by
544 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

chronical ethylism (historically referred to as Laen- mediators of inflammation (TNF-alpha, TNF-beta,

nec’s cirrhosis), progressive chronical hepatitis (es- IL-1). However, since fibrosis can develop without
pecially B,C,D), endogenous metabolic impairments, apparent inflammation, it is also necessary to admit
long-term cholestasis (biliary cirrhosis) and venosta- a direct stimulation of the production and deposition
sis due to heart failure (cardiac cirrhosis). of collagen by toxic substances.
The diffuse alterations of the parenchyma are char-
The pronounced changes in the hepatic structure
acterized by chronic inflammation with extensive fi-
create the foundation for severe functional impair-
brotisation and impairment of the normal structure
ments. The reduction and destruction of the vascular
of the liver. Hepatocytes succumb to degenerative
bed brings about hypoxia of the parenchyma which is
changes, even necrosis. Proliferation of hepatocytes
of permanent and progressive charater. This process
results in a solitary development of so called hy-
results in a decrease in the overall metabolic capacity
perplastic (regenerative) nodules. This substitution,
of the liver. The reduction of the sinusoid surface,
however, is not fully functionally valuable, therefore
compression of the vessels by islets or regenerating
this obsolete designation of regenerative nodules is
tissue and fibrotic narrowment of portal vessels rep-
currently abandoned. The histologic picture distin-
resent a presupposition for the development of por-
guishes:
tal hypertension. The altered structure of the biliary
• micronodular cirrhosis in which hyperplastic tract causes impairments in bile drainage.
nodules are smaller than 3 mm. They are sur- The symptoms of cirrhosis do not correlate pre-
rounded by fibrous septa. Cirrhosis diffusively cisely with the stage of impairment and the disease
afflicts all lobules and is most frequently caused is often latent for a long period. Merely, uncon-
by alcoholic impairment, spicuous dyspeptic difficulties arise, accompanied by
• macronodular cirrhosis, in which the size of physical and psychical fatigue. The fatigue and ady-
nodules varies from 3 mm to several centime- namia graduate in subsequent stages. Exacerbation
ters. Among the nodules it is possible to find of the disease takes place together with icterus vary-
normal lobules. This type is the most frequent ing in intensity. The typical changes in the skin –
consequence of hepatitis B. spider naevi are manifestant in the area of the su-
perior vena cava (neck, chest, arms). Assumedly
Since the main problem of cirrhosis resides in the the cause resides in inappropriate vasodilatation or
progressive fibrosis, it is necessary to solve the ques- high activity of oestrogens (spider naevi are normal
tion: which factor initiates and preserves this pro- findings in pregnant women and they occur also in
cess ? In normal liver, the interstitial collagens I women using contraceptives). Palmar and plantar
and III are concentrated especially in portal triads. erythemas document an overall impairment of the
The collagenous net among hepatocytes is consti- vasomotor tonus. Leukonychia (white and fragile fin-
tuted of fine fibers of type IV localised in space of ger nails) documents low level of serum albumin and
Disse. In cirrhosis, collagens I and III accumulate is not specific for the diseases of the liver. Femi-
in all parts of the lobule and bring about a serious nisation in men characterized by gynecomastia, tes-
restriction of blood flow and disables the diffusion of ticular atrophy and reduction in axillar, chest and
solutes between the hepatocytes and plasma. The pubic hair is common especially in alcoholic cirrho-
accumulation of collagen within the space of Disse sis and haemochromatosis. It is caused not only by
is associated with a loss of fenestration of sinusoid high level of oestrogens, but also by complex gonadal
endothelial cells. This process then deteriorates the and hypothalamic dysfunction. Women with cirrho-
movement of proteins. The main source of this exces- sis develop amenorrhea. Deteriorated blood coagu-
sive collagen appears to reside in so-called Ito cells. lation is manifestant by skin haemorrhages ranging
During the development of cirrhosis these cells are from petechiae to suffusions and gingival bleeding.
activated and transformed into cells similar to fibrob- Biochemical changes do not have to be necessarily
lasts with contractile properties, participating thus pronounced. However, they are distinctly positive
in the deterioration of the blood flow in the cirrhotic foremostly during the activation of the process. The
liver. The stimuli for the deposition of fibrous tissue activity of transaminases increases (especially AST).
are not yet known, but a significant role is played by The activity of alkaline phospatases is suppressed
7.19. Pathophysiology of the liver (D. Maasová) 545

in coincidence with cholestasis. The concentration the liver (portal vein thrombosis), or in the liver be-
of albumins decreases and that of plasma gamma- fore the sinusoids (e.g. in schistosomiasis). Similarly,
globulins increases. The prothrombin time is pro- the postsinusoid obstruction can be localised in the
longed and the concentrations of coagulatory factors hepatic parenchyma (venoocclusive disease with af-
(V, VII, IX and X) decrease. The blood examination fliction of the central veins), or as far as behind the
displays moderate anaemia. More significant and se- liver (on the level of hepatic veins, or inferior vena
vere biochemical findings appear in the late stage in cava). If the resistance in the portal system is due
coincidence with hepatic insufficiency. to hepatic cirrhosis, it is localised on the level of si-
Patients with advanced cirrhosis, regardless to nusoids. The compression of vessels by the islets of
the inducing cause, gradually develop syndromes regenerating tissue, the reduction of sinusoid surface
which represent serious complications. Firstly, the and fibrotic narrowment of portal vessels in this case
syndrome of intrahepatic portal hypertension is in- increase the resistance and have a decisive impact on
volved. The further development of the disease the size of portal hypertension. The portal hyperten-
is accompanied with symptoms of fluid retention sion coincides to a certain extent with an increased
with edema and ascites. Further deterioration of portal inflow. Hyperdynamic splanchnic circulation
metabolic fucntions of the liver brings about hepatic is currently considered to be a component of the over-
(portosystemic) encephalopathy. all hyperdynamic state with the increased stroke vol-
The intermediate cause of a majority of deaths re- ume of the heart and low vascular resistance which
sides in: can be observed in patients with portal hypertension.
It is assumed that the development of hyperdynamic
1. progressive liver failure circulation is induced by several chemical mediators,
e.g. vasodilatatory prostaglandins, gastrointestinal
2. some of the complications in coincidence with peptides, especially though by glucagon, serum bile
portal hypertension acids and adenosine. Glucagon and bile acids en-
ter the systemic circulation to a greater extent in
3. hepatocellular carcinoma coincidence with the development of the collateral
circulation and has a direct vasodilatatory effect on
7.19.6 Portal hypertension the splanchnic arterioles. In addition to the portal
hypertension, a decreased responsiveness to endoge-
Portal hypertension is defined as a permanent in- nous vasoconstricting substances (noradrenalin, an-
crease in the pressure within the portal vein above giotensin II, vasopressin) was detected. This condi-
the normal values. Normal values of the portal pres- tion is caused by postreceptor defect.
sure range from 5 to 10 mmHg (0.6–1.2 kPa). Portal
hypertension is considered to take place when the An increased pressure in the portal vein brings
pressure increases above 22 mmHg (2.75 kPa, 30 cm about the development of collateral circulation in
of water column). the effort to deviate the blood from the high pressure
Portal venous system begins in the intestinal cap- portal vascular bed into the surrounding low pressure
illaries and terminates in the hepatic sinusoids and veins which merge into the inferior vena cava. The
includes all veins which drain the blood from the developed, so-called porto-caval anastomoses func-
abdominal part of the digestive tract, spleen, pan- tion as an advantageous shunt. The collateral vas-
creas and gallbladder. Since the resistance of the cular bed is developed in sites where the portal vas-
sinusoid wall is minimal and the portal venous sys- cular system is in close neighbourhood with the ve-
tem has no valves, these facts imply that any in- nous system which drains the blood from the infe-
crease in resistance between the splanchnic vascular rior or superior venae cavae. In these areas, the ve-
bed and the right heart, retrogradely elevates the nous junctions which under normal conditions have
pressure in all vessels on the intestinal side from the no significant function, acquire the clinical impact
site of obstruction. The position of the pathological in portal hypertension. The involved veins include
resistance in relation to the sinusoids is referred to the veins in submucosa of the oesophagus and stom-
as being presinusoid, sinusoid or postsinusoid. Ob- ach, veins in the submucosa of the rectum, veins of
struction in the presinusoid area can occur before the anterior abdominal wall and the left renal vein.
546 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

The porto-caval anastomoses which develop in sub- formed by renal factors. The retention of sodium
mucosa of the oesophagus cause the development of and water by the kidneys is assumedly determined
oesophageal varices, whereas those in the submucosa by systemic haemodynamic changes in cirrhosis. It
of the stomach can entail the development of gastric foremostly involves a low peripheral vascular resis-
varices. Anastomoses in the submucosa of the rec- tance caused by circulating vasodilatory substances.
tum can rarely result in the development of haemor- Vasodilation leads to a not complete filling of the ar-
rhoids. Anastomoses can develop also in the anterior terial vascular space causing the barroreceptor stim-
abdominal wall, where under normal conditions the ulation of the renin-angiotensin-aldosteron system,
functionless umbilical vein can act as a junction. In sympathetic activation and the release of ADH in
coincidence with portal hypertension the umbilical the effort to increase the plasma volume. The por-
vein connects the portal vein with epigastric veins. tal hypertension is then responsible for the redistri-
The junctions between these two systems form char- bution of the maintained fluid into the peritoneal
acteristical vessels radially branching from the um- cavity. Therefore, the recovery of the circulating
bilicus – caput Medusae. volume does not supervene and the stimulus of ac-
The main clinical symptoms of portal hyper- tivation of the renin-angiotensin-aldosteron system
tension include haemorrhage from the gastrooe- persists. The velocity of ascites development varies
sophageal varices, ascites, splenomegaly and hepatic from several days to several weeks. Ascites is pre-
encephalopathy. Their range depends to a certain dominantly accompanied by a moderate abdominal
extent on the development of portal-systemic collat- pain and overall discomfort. A pronounced ascites
eral circulation. can cause a shortening of breath by compressing the
diaphragm. However, the most severe complication
7.19.7 Ascites leading to a higher mortality is the infection of as-
citic fluid (assumedly via blood or lymph) causing
Ascites signifies the presence of excessive amount of the bacterial peritonitis.
fluid in the peritoneal cavity. Most frequently it de-
velops in cirrhosis, but it can occur also in coinci-
dence with other diseases. 7.19.8 Hepatic encephalopathy
Despite the fact that the prior impulse trigger- Hepatic (portalsystemic) encephalopathy (PSE) is a
ing the development of ascites is still not precisely dreaded complication of acute and chronic hepatic
known, it is proved that the accumulation of fluid failure. It is considered to be a complex neuropsy-
is enhanced by several factors. An increased hy- chiatric syndrome caused by metabolic impairment
drostatic pressure in portal hypertension and de- of the central nervous system and neuromuscular sys-
creased plasma oncotic pressure caused by hypoal- tem. In a majority of cases, only minimal morpho-
buminaemia in the liver diseases facilitate the trans- logical changes (edema, reaction of astrocytes) are
gression of fluid into the peritoneal cavity. A signifi- identifiable in the brain. Especially two main impair-
cant role in these processes is played by the change in ments are responsible for the development of PSE:
the velocity of the output and drainage of the hep-
atic lymph. The thin endothelial lining of sinusoids 1. severe impairment of hepatocellular functions
in a healthy liver enables the leakage of plasmatic
proteins already due to a small increase in sinusoid 2. intrahepatic, or extrahepatic shunts of portal ve-
pressure. In contrast to other capillaries the oncotic nous blood into the systemic circulation
pressure in sinusoids only slightly differs from the
extravasal pressure and therefore a majority of fluid These two abnormalities result in the fact that ni-
remains in interstitium. Under normal conditions, trogen substances are absorbed in the intestine and
this fluid returns into the vessels by means of the are not sufficiently detoxicated by the liver, caus-
lymphatic system of the liver. If, however, the veloc- ing thus changes in the brain metabolism. The en-
ity of the output exceeds the velocity of resorption by trance of toxic substances into the brain is assumedly
lymphatic vessels, the fluid leaks into the peritoneal facilitated also by an increased permeability of the
cavity. blood-brain barrier. The most aggressive toxic sub-
The maintainance of ascites is predominantly per- stance is considered to be ammonia developing in
7.20. Jaundice (D. Maasová) 547

the process of the break down of proteins by intesti- syndrome is typically heralded by oliguria, associ-
nal bacteria. Further factors co-acting in the de- ated with the increase of urea and creatinine con-
velopment of encephalopathy are mercaptanes, free centration in the blood. Pathophysiology of the renal
fatty acids, intestinal endotoxins, activation of the failure remains unclear. The decrease in glomerular
inhibitory neurotransmitter system GABA and as- filtration and in elimination of sodium are evident.
sumedly also the accumulation of false neurotrans- There are hints that the pathogenetic cause can re-
mitters (octopamine). side in the disbalance of metabolites of the arachi-
Acute onset of PSE, e.g. in cirrhosis in a stable donic acid.
state, has a predominantly apparent inducing cause. In acute hepatic failure or advanced chronic liver
Most frequently it involves bleeding into GIT which disease the renal insufficiency can quickly progress to
is a massive source of nitrogen substances absorbed death.
in the intestine. A similar situation is developed due
to a diet rich in proteins. The disturbances of elec-
trolyte balance can significantly contribute to the
development of PSE. Foremostly the hypokalemic
metabolic alkalosis, but also the metabolic alkalosis
alone increases the NH3 : NH4 ratio. Hypokalemia,
often caused by intensive diuretic therapy, stimulates
7.20 Jaundice
the renal production of ammonia. Further inducing
factors include the drugs which affect the CNS func-
tions, hypoxia and acute infections, assumedly by
means of the protein-catabolic effect. Jaundice (icterus) signifies a yellow colouring of
PSE is manifestant by a wide range of distur- sclerae, skin and mucosae determined by accumula-
bances of conciousness from inconspicuous changes in tion of the bile pigment – bilirubin. Jaundice devel-
behaviour through marked confusion to heavy coma. ops in pathological states of various etiology. They
These disturbances can be accompanied by neuro- are commonly characteristic by the disbalance be-
logical symptomatology, e.g. by non-specific changes tween the production and excretion of bilirubin.
in EEG, rigidity, hyperreflexia. A very characteris- Physiological level of the total bilirubin in the plasma
tical symptom is the coarse tremor of fingers, which of adults is 3–21 µmol/l. When the concentration
later develops into flapping tremor (tremor of hands in the plasma increases c. three-fold, bilirubin infil-
from the wrist). The cause of the flapping tremor is trates the tissues. It accumulates predominantly in
considered to reside in a sudden intermitent inhibi- the tissues with high contents of elastine, to which it
tion of the motor tonus. Alterations in personality, has a significant affinity, but penetrates also into the
mood disturbancies, loss of social barriers, confusion, somatic fluid with high contents of proteins (e.g. ex-
inability to concentrate, apraxia and daytime somno- udate). The accumulation of bilirubin in organism
lence are further symptoms of the amount of clinical takes place due to:
symptoms of the hepatic encephalopathy.
1. increased production of bilirubin – prehepatic
7.19.9 Hepatorenal syndrome jaundice,

Hepatorenal syndrome signifies renal insufficiency in

2. hepatic impairment, providing the hepatocytes
the patients with a severe impairment of the liver,
are not normally able to take up, conjugate,
whereas the kidneys do not display any morpholog-
or secrete bilirubin, or bile, or if bile stagnates
ical cause of this state. This definition involves nei-
within the liver on the level of minute bile ducts
ther simultaneous impairments of both organs, nor
– intrahepatic jaundice,
the cases of cirrhosis during which the circulatory
collapse has brought about acute tubular necrosis
with subsequent renal failure. 3. reduction or stopping of the drainage of bile due
The renal functions promptly improve after the to mechanical obstruction in extrahepatic bile
recovery of liver functions. The development of the pathways – posthepatic jaundice.
548 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

7.20.0.1 Prehepatic jaundice 1. Disturbances of bilirubin uptake

The Gilbert’s syndrome (icterus iuvenilis inter-
This group includes the impairments which develop
mittens) is characterized as a functional impair-
by an excessive production of bilirubin. If the supply
ment of the transport of organic anions in hepato-
of bilirubin excceds the maximal conjugation capac-
cytes. This dominantly hereditary disease resides in
ity of the liver, it accumulates in the blood (hyper-
the decrease of bilirubin uptake, assumedly due to
bilirubinaemia). Overproduction of bilirubin takes
a decreased binding capacity of the transport pro-
place due to:
tein (ligandin). At the same time the process of
conjugation is hindered due to the defect of UDP-
• increased haemolysis (hereditary or acquired
glucuronosyltransferase (so called infantile conjuga-
haemolytic anaemias, posttransfusion haemoly-
tion system). This moderate hereditary disturbance
tic reaction),
is manifestant usually as late as in the second decade
of life. A permanently subicteric patient develops a
• resorption of excessive haematomas (injury, pronounced jaundice usually only due to stress (in-
catheterisation, rupture of vascular aneurysm) tercurrent infection, physical exercise, fasting, alco-
or excessive infarction (pulmonary infarction), hol).
Transient non-conjugated hyperbilirubinaemia
• ineffective erythropoiesis, when the produced which develops after administration of drugs (certain
haemoglobin is not effective in peripheral tissues tetracyclines), x-ray contrast substances, pigments
and has been broken down already in the bone (bromsulphthalein) is explained by a competitive in-
marrow. This group referred to as shunt hyper- hibition of the ligandin. This mechanism assumedly
bilirubinaemia, includes megaloblastic anaemia evokes also a moderate hyperbilirubinaemia in coin-
caused by the deficiency of the intrinsic fac- cidence with fasting, when the produced metabolites
tor (pernicious anaemia, resection of stomach, compete with bilirubin in binding to ligandin.
polyposis of the stomach) or deficiency of folic
acid and vitamin B12 (resection of the terminal 2. Impairments of bilirubin conjugation
ileum, blind intestinal loop, intestinal diverticu- Impairments of bilirubin conjugation develop due
losis, fuctional intestinal impairments). A pro- to absolute or relative insufficiency of UDP-
nounced jaundice in this group of hyperbilirubi- glucuronosyl transferase (UDP-GT). An impairment
naemia is rare. of bilirubin conjugation most frequently occurs in
newborns in whom it is already possible to find sev-
Prehepatic jaundice is characterized by an in- eral differences:
creased level of non-conjugated bilirubin in the
blood. As the liver takes up and degradates the • conjugation system during the intrauterine de-
high amount of pigment, the bile and stools are velopment of the foetus matures already in the
dark (pleiochromic bile, hypercholic stool). Uro- tenth lunar months and closely after birth it is
bilinogen produced and absorbed in the intestine in still relatively incapable of increasing its activ-
an increased amount is not taken up by overloaded ity appropriately. Ligandin is similarly ”imma-
hepatocytes and it appears in urine. Also in se- ture”.
vere anaemia, when complicated by e.g. hypoxaemia, • in this period the foetal haemoglobin is broken
fever or vascular collapse, the liver ability to elimi- down implying an increased bilirubin supply
nate bilirubin decreases.
• binding capacity of serum albumin to bilirubin
is lower,
7.20.0.2 Intrahepatic jaundice • the blood-brain barrier is still not sufficiently
mature which enables the entrance of bilirubin
Due to didactic purposes it is wise to divide intra-
into CNS
hepatic jaundice into groups according to the site of
the most marked disturbance taking place during the The above mentioned facts imply that the pres-
metabolism and transport of bilirubin. ence of jaundice in 50 % of healthy newborns is not
7.20. Jaundice (D. Maasová) 549

considered to be a pathological state (physiological UDP-GT and the neonatal jaundice can be prolonged
jaundice of the newborn). It supervenes on the sec- for weeks or months.
ond or third day after birth, and in consequence of Crigler-Najjar syndrome is an especially severe
a rapid increase in the conjugation capacity it dis- congenital disease. It occurs in two forms:
appears up to six days. The level of unconjugated
bilirubin in the blood is on the upper limits of the • Type I, originally described by Crigler and Naj-
physiological standard for newborn (130 µmol/l). jar is an autosomally recessive disease caused by
the absence of the genetic equipment for UDP-
In the premature infant, the glucuronosyltrans-
GT. The unconjugated bilirubin exceeds 15–20-
ferase activity is less, and the neonatal jaundice may
fold its normal values and if therapy is not ap-
be more pronounced. It supervenes also on the sec-
plied immediately, the child dies due to the con-
ond or third day, but fades away slower in accordance
sequences of the bilirubin encephalopathy.
with the process of maturing of the conjugation sys-
tem. The most difficult cases can yield an increase • Type II is an autosomally dominant form with
in bilirubin above the critical value of 340 µmol/l. a moderate clinical course. It involves a par-
Such values indicate that unconjugated bilirubin is tial deficiency of UDP-GT. In comparison with
apt to enter CNS. The deposition of bilirubin in form I it ussually does not occur in newborns,
the basal ganglia rich in lipids leads to the develop- but in adolescents and adults. Therefore the
ment of bilirubin encephalopathy (kernicterus). Ker- neurologic complications are uncommon. The
nicterus is the most severe complication of unconju- bile contains a variable amount of conjugated
gated hyperbilirubinaemia. It is manifestant by in- bilirubin with a significant increase in monocon-
appetence, apathy, hypotonia, decreased tendon re- jugates.
flexes, tonic spasms. If the infant survives, it usually
remains permanently handicapped (rigidity, chorea, All types of jaundice of this group show an in-
deafness for high tones, etc.). The danger of the de- creased level of unconjugated bilirubin in the blood.
velopment of bilirubin encephalopathy in newborn
increases the presence of substances in the blood 3. Impairments of elimination through the
which compete with the unconjugated bilirubin in canalicular membrane
its bond to albumin (organic anions in acidosis, sal-
A. Isolated impairments in bilirubin secretion
icylates, sulphonamides, some antibiotics). In such
a case the proportion of the free fraction of the un- Dubin-Johnson syndrome is a genetically deter-
conjugated bilirubin is higher, and can lead to the mined disorder of the excretion of the conjugated
entrance of pigment into CNS already at values of bilirubin and other organic anions (e.g. bromsulph-
total bilirubin being 150–200 µmol/l. thalein) from hepatocytes into bile. The impairment
resides in the transport systems on the canalicular
Some substances of steroid nature can cause a
membrane of the cell. The disease is characterized
transient inhibition of UDP-GT, assumedly by com-
by chronic jaundice caused by an increased level of
petition. A typical representation of this dis-
the conjugated bilirubin in the blood. In the liver
turbance is familial neonatal hyperbilirubinaemia
the striking feature is the presence of a dark brown
(Lucey-Priscoll syndrome). Essentially it is a tran-
pigment in the hepatocytes localised centrilobullarly
sient inhibition of UDP-GT by steroid factor, present
(so-called black liver). Patient with Dubin-Johnson
in the maternal serum. Jaundice appears already af-
syndrome may be asymptomatic with the exception
ter birth.
of jaundice. Despite the icteric colouring, the patient
In some breast-fed infants, jaundice has been as- does not suffer from pruritus, hence already the clin-
cribed to the presence in breast milk of pregnane– ical picture gives the hint of isolated impairment of
3 beta, 20 alpha-diol, an inhibitor of glucuronosyl- the excretion of pigment.
transferase. Jaundice supervenes later, and persists Rotor syndrome in many aspects resembles the
for more than three weeks. When the infant is re- Dubin-Johnson syndrome, however the brown pig-
moved ved from the breast, the ”breast-milk jaun- ment is not present in hepatocytes. This rare dis-
dice” subsides. ease is inherited as an autosomal recessive trait
Hypothyreoidism delays the normal maturation of and is genetically distinct from the Dubin-Johnson
550 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

syndrome. The presented functional hyperbilirubi- in urine. Stool is hypocholic or completely acholic.
naemias (Gilbert, Dubin-Johnson, as well as Rotor Urobilinogen in urine is present only if the stasis of
syndrome) have the attribute of being benign. Even bile is not total. In case of total stasis, the reappear-
a long-term observation of patients with these im- ance of urobilinogen in urine is a good sign of the
pairments (15 and more years) has not revealed any recovery of bile flow.
signs of hepatic damage.
4. Intrahepatic mechanic cholestasis
B. Impairment of bile secretion (intrahepatic
The cause of this type of intrahepatic cholesta-
functional cholestasis)
sis is an impairment at the level of the minute bile
This disease includes an extensive group of patho- ducts – canaliculi and ductuli. Under the influence
logical states which are characterized by a de- of pathological reactions their lumen becomes narrow
creased, or blocked transport of all components of by hypersensitive reaction in their walls and periduc-
bile through the canalicular membrane. The canalic- tal oedema or cellular reaction in their surround-
ular membrane is energetically very demanding and ing. This mechanic obstacle of bile flow consequently
therefore also the most vulnerable site of the hepa- brings about bile stagnation and condensation lead-
tocyte. The functional impairment of bile elimina- ing to the formation of bile plug.
tion comes into consideration in all states leading to Intrahepatic cholestasis of pregnancy (reccurrent
hepatocyte injury. The conjugation processes do not jaundice of pregnancy) appears in a small percentage
have to be damaged for a length of time and the of pregnant women usually in the last trimester but
impairment supervenes in the later phases of cellu- may develope any time after the seventh week of ges-
lar damage. The components of bile stagnate before tation. It is assumed that in these women an abnor-
the canalicular membrane and regurgitate into the mal metabolism of oestrogens produces a cholestati-
blood. This type of cholestasis occurs in: cally effective metabolites. Jaundice often reappears
• all types of hepatitis (viral, alcoholic, drug- not only in subsequent pregnancies, but also after
induced, toxic, non-specific) contraceptives. This fact suggests an equal, or simi-
lar mechanism of cholestasis development. The clin-
• cirrhosis (postinfectious, congestive) ical features consist primarily of pruritus and jaun-
dice. Pruritus is explained by retention of bile salts
• focal lesions of the liver (toxoplasmosis, malaria,
while the decisive factor resides in the local increase
etc.)
in concentration of bile salts in the skin. These symp-
The listed impairments of the liver are not char- toms of cholestasis quickly fade out after parturition.
acterized only by jaundice, but (and furthermore) Drug-induced cholestasis may occur in some pa-
by a wide scale of manifestations of functional hep- tients following the use of oral contraceptives (oe-
atic impairment from moderate dyspepsia to hepatic strogens), anabolic steroids and drugs, e.g. chlor-
coma. The decrease or even absence of bile acids in promazine. In contrast to cholestasis after oestro-
the intestine results in an disturbance in the resorp- gens, the cholestasis after administration of anabolic
tion of fat and vitamins. The deficiency in vitamin K steroids can transgress to chronicity. Chlorpro-
is manifestant by a coagulopathy which is enhanced mazine is a typical example for the development of
also by the inability of the damaged hepatocytes to idiosyncratic reaction. In about 1 % of patients re-
synthesize prothrombin sufficiently. Since the excre- ceiving chlorpromazine, intrahepatic cholestasis with
tory step is the one which is rate-limiting and most jaundice develops after 5 weeks of treatment. It is as-
readily affected by injury, significant amounts of con- sumed that the metabolisation of the drug results in
jugated bilirubin and bile acids reenter the systemic free radicals which on the sensitive terrain change the
circulation. Later also the conjugation process be- structure of minute biliary ducts. The walls become
comes retarded. The cause can reside in the profound antigenic, which is the cause of the development of
impairment of cells and/or feedback suppression of local immune reaction. The development of the id-
the activity of UDP-GT by the accumulated conju- iosyncratic reaction was anticipated on the grounds
gated bilirubin in hepatocytes. The laboratory ex- of the presence of eosinophilia.
aminations reveal an increase in both forms of biliru- Cholestasis in the culminating phase of the vi-
bin in the blood, and that of conjugated bilirubin ral hepatitis can be explained by the fact that the
7.20. Jaundice (D. Maasová) 551

functional impairment of the canalicular membrane blood. Total enclosures do not bring about urobilino-
which is present in hepatitis, leads to the increase gen in urine.
in its permeability with the penetration of macro-
mulecules and condensation of bile. The dense bile 7.20.0.4 Postoperative jaundice
stagnates and irritates the adjacent structures thus
causing inflammation and fibrosis. This condition Owing to the performance of gradually more de-
results in the narrowment of the ducts. Despite the manding surgical interventions, the problem of post-
final functional recovery of hepatocytes this mechan- operative jaundice appears in the centre of attention.
ical factor disables the free drainage of bile for a cer- After so-called major surgical procedures, 17 % of pa-
tain period. tients develop a moderate and 4 % exhibit a strongly
Patients with intrahepatic mechanic cholestasis pronounced jaundice. Pathogenic mechanisms par-
usually present with signs and symptoms of cholesta- ticipating in the development of jaundice have their
sis, but without pronounced signs of hepatic damage foundations in the overproduction of bilirubin, hep-
(with the exception of viral hepatitis). atocellular damage and/or extrahepatic obstruction.
Overproduction of bilirubin is caused most fre-
quently by transfusion of stored blood. After the
7.20.0.3 Posthepatic jaundice (extrahepatic transfusion, within 24 hours, approximately 10 % of
biliary obstruction) the administered erythrocytes break down. That
Posthepatic jaundice develops due to partial or total means that 500 ml of blood provides c. 430 µmol
obstruction of extrahepatic bile ducts. It most fre- of bilirubin which a healthy liver eliminates with-
quently involves an obstructions of large bile ducts out any problems. Transfusions repeated closely
(common bile duct and ductus hepaticus communis). one after another transgress however the capacity of
The functional reserve of the liver is large, and there- the liver to eliminate bilirubin. The further source
fore partial enclosures result in jaundice only in cases of bilirubin resides in the resorption of the blood
of obstructions taking place in a larger number of bil- from extravascular spaces. Rarely, e.g. in patients
iary ducts (75 % of draining ducts under experimen- with the glucoso-6-phosphate-dehydrogenase defect,
tal conditions). Mechanical obstacle can be caused haemolytic anaemia occurs after anaesthesia, drugs,
by an intraductal enclosure (stones, parasites, struc- or after surgical intervention per se.
tures) or compression of the biliary ducts from the Hepatocellular impairment varying in its degree
outside (tumours, scars). A severe and long-lasting develops due to a number of causes. It can develop as
obstacle of bile drainage damages the walls of biliary a reaction to the administered drugs or anaesthetics,
ducts by a retrograde increase in the pressure of the e.g. halotane. Repeated anaesthesia, in rare cases,
stagnating bile. This condition results in regurgita- incur hepatitis which is put into association with the
tion of bile. After the transgression of the pressure hypersensitivity to halotane. Moderate reactions are
in biliary ducts above 25 mmHg (3.1 kPa), the su- however more frequent, especially in obese patients
pervening condition then ranges from disturbances as fat-soluble halotan accumulates in the fat tissue
to a complete failure of hepatocytes to secrete bile. and slowly floats away. Hepatocellular necrosis may
Later, the accumulation of bilirubin in hepatocytes follow profound shock. With lesser degrees of hy-
and high pressure negatively influence also the pro- potension or hypoxaemia, significant impairment of
cess of conjugation. hepatic function may occur. Renal impairment due
A total enclosure of biliary pathways is character- to hypotension and hypoxaemia may enhance the de-
ized by a pronounced icterus, generalized pruritus gree of jaundice because the renal excretion of conju-
and increased bleeding due to the deficiency of vita- gated bilirubin is decreased. Sepsis as well can pro-
min K. Stools are acholic and contain fat (steator- duce the impairment of hepatocytes and bring about
rhea). Biochemical examinations reveal an increased jaundice, often of a cholestatic type.
level of conjugated bilirubin, bile acids, cholesterol Extrahepatic obstruction may occur in conse-
and alkaline phosphatase in the blood and bilirubin quence of a surgical intervention in the abdominal
in urine. After a certain period, in accordance with cavity.
the suppression of the process of conjugation, also
the level of unconjugated bilirubin increases in the
552 Chapter 7. Pathophysiology of the gastrointestinal tract ( I. Hulı́n, I. Ďuriš et al.)

increased degradation of cholic acid in the intes-

tine to deoxycholic acid which is reabsorbed to a
7.21 Diseases of the gallblad- greater extent. An important role is ascribed to
the nucleation of cholesterolmonohydrate crystals,
der which is significantly accelerated in lithogenic bile.
It may be due to either an excess of pronucleating
factors (mucin glycoproteins, lysine phosphatidyl-
choline), or a deficiency of antinucleating factors
(apolipoproteins, other glycoproteins). Nucleation
7.21.1 Cholelithiasis of cholesterol-monohydrate crystals probably occurs
within the mucin gel layer. The formation of bile
The presence of bile stones in the biliary pathways stones is also supported by a decreased evacuation
– cholelithiasis – is one of the most frequent causes and stagnation of bile.
of the diseases of the gastrointestinal tract. The bile Bile stones can be solitary, growing to the size
stones are crystalline structures formed by concre- of a walnut, or multiple. They are localised most
tion or accretion of normal or abnormal bile con- frequently in the gallbladder (cholecystolithiasis), or
stituens. They are divided into three types: choles- in ductus choledochus (choledocholithiasis), rarely in
terol stones, mixed stones and pigment stones. The minute extrahepatic and intrahepatic biliary ducts.
cholesterol stones and mixed stones which most fre- The symptomatology of the presence of bile stones
quently occur in our population contain more than varies greatly. The dyspeptic syndrome – the sen-
70 % of cholesterol. The rest of stones are formed sation of fullness in epigastrium, meteorismus, dif-
by calcium and bile salts, proteins, fatty acids, phos- fuse moderate abdominal pain which binds to dietary
pholipids and bilirubin. Pigment (bilirubin) stones faults are very frequent in cholelithiasis. If the stone
are composed primarily of calcium-bilirubinate; they migrates from the gallbladder into the cystic duct
contain less than 10 % of cholesterol. Pigment stones or choledochus, it can cause obstruction with retro-
are common in the Orient and Asia. In Europe they grade augmentation of intraluminal pressure and dis-
occur mostly in patients with chronic haemolytic tension. This state is manifestant by biliary colic –
states which display higher concentrations of biliru- sudden and intensive abdominal pain lasting for sev-
bin in bile. Deconjugation of soluble bilirubin may eral minutes or hours accompanied by nausea and
be mediated by bacteria. vomiting.
The formation of the so-called lithogenic (stone- Cholelithiasis is a very frequent cause of further,
developing) bile is based on several mechanisms. more severe diseases in extrahepatic biliary path-
The most important is the increased biliary secretion ways. Cholelithiasis may cause cholecystitis, cholan-
of cholesterol (drugs, obesity, high-caloric diet). Sim- gitis, cholestasis, as well as acute haemorrhagic
ilarly decreased hepatic secretion of bile acids and necrosis of the pancreas.
phospholipids in rare inborn errors of metabolism
or conditions affecting the enterohepatic circulation
7.21.2 Cholecystitis
of bile acids (ileal diseases, parenteral alimentation)
contribute to the formation of lithogenic bile. In Acute inflammation of the gallbladder develops most
this association the patients often appear to have a frequently in consequence of cholelithiasis (calculous
reduced activity of cholesterol-7-alpha-hydroxylase, cholecystitis). The bile stone can stick in the drain-
the rate-limiting enzyme for primary bile acids syn- ing part of the gallbladder or in the cystic duct which
thesis. disables the free draining of bile and causes chemi-
Hence, the bile stones develop due to the disbal- cal irritation and inflammation. Chemical inflam-
ance between the levels of cholesterol and bile acids mation is caused by the release of lysolecithin (due
plus phospholipids. This disbalance may be due to to the action of phospholipase on lecithin in bile)
hypersecretion of cholesterol, hyposecretion of bile which is toxic for the mucosa. The normal glyco-
acids, or both. Still, a certain role is played by protein layer is impaired and the epithelium is di-
the change in the mutual ratio of the cholic and rectly exposed to the detergent effect of bile salts.
deoxycholic acids in bile. The cause resides in an The inflammatory process in the mucosa and wall of
7.22. Gastrointestinal hormones (I. Ďuriš) 553

the gallbladder is enhanced also by prostaglandins with dyspeptic difficulties after dietary faults, with
which are released from the distended wall. The dis- infrequent acute exacerbations. A prolonged total
tension and increased intraluminal pressure simulta- obstruction of the cystic duct causes that the lumen
neously result in ischaemia of the gallbladder mucosa of the obstructed gallbladder fills and progresively
and wall. These chemical and mechanical influences distends with mucus (mucocele) or clear transudate
cause inflammation even prior to the bacterial con- (hydrops) produced by mucosal epithelial cells.
tamination which usually takes place later. The gall-
bladder at the culmen of inflammation is thickened,
oedematous and hyperaemic, filled with turbid bile
containing a large amount of fibrin and pus. The
state of the gallbladder containing only pus is re-
ferred to as gallbladder empyema. The gallbladder
7.22 Gastrointestinal
in severe cases changes into a greenish black necrotic hormones
sack with larger or smaller perforations – gangrenous
cholecystitis.
Approximately 5–10 % of cases of acute cholecysti-
The contacts of the human organism with the sur-
tis develop without the presence of bile stones (acal-
rounding environment are intermediated by compli-
culous cholecystitis). The causes of the inflammation
cated neurohumoral pathways. The neurohumoral
include serious trauma and burns, difficult parturi-
connection with the gastrointestinal tract represents
tions, simultaneous failure of several organs, sepsis,
an extensive labyrinth, the junctions of which are
etc. The gallbladder is usually large and tense, with
only partially known.
evident weakness and slowness of evacuation. The
main cause is considered to be the ischaemic impair- The major contact of the gastrointestinal tract
with the external environment represents the food
ment of the gallbladder as the cystic artery is the
intake. Almost all gastrointestinal hormones are se-
terminal artery without collateral circulation.
creted as a response to the accepted food.
Acute cholecystitis usually begins as an attack of Gastrin is produced by G cells of the antral glands
biliary colic which does not withdraw and is accom- of the duodenum and small intestine. Coffein and
panied by fever and further signs of inflammation wine (not destilates) stimulate its release similarly
(leukocytosis, high rate of erythrocyte sedimenta- as proteins and amino acids (especially fenylalanine
tion). Anorexia associated with vomiting can lead and tryptophane). GRP (gastrin-releasing peptide)
even to extracellular volume depletion. The appear- and its equivalent in apmhibians – bombesin, have
ance of jaundice signifies either obstruction of the a stimulating effect whereas somatostatin (SMS) su-
biliary pathways by a stone, or a state when the presses its release. Gastrin belongs to the strongest
oedematous inflammation involves the bile ducts and secretogogues of the gastric juice. It affects the
surrounding lymph nodes. Acute cholecystitis can motility and trophics of the gastric and intestinal
be the cause of severe complications. The bile stasis mucosae. The antagonist of gastrin – proglumid –
is inclined to become complicated by e.g. bacterial inhibits the growth of the cellular line of colorectal
superinfection which spreads via lymphogenic and carcinoma in tissue cultures.
ascendent pathways and causes an inflammation of Cholecystokinin (CCK) is produced by I cells of
intrahepatic biliary ducts (cholangitis), perforation the duodenum and upper jejunum. As most im-
with the development of abscess, rupture with gen- portant function is considered to be the stimula-
eralized peritonitis, fistula with bile or stone drainage tion of the secretion of pancreatic juice, induction
into the adjacent organs etc. of the contractions of the gallbladder and relaxation
Chronic cholecystitis develops in 90 % of cases in of Oddi’s sphincter, as well as the lower oesophageal
consequence of repeated acute cholecystitis or due sphincter. CCK stimulates the peristalsis of gastric
to permanent mechanical irritation of the wall of antrum, small and large intestines, causes hypertro-
the gallbladder. The gallbladder is shrunk, its wall phy and hyperplasia of the pancreatic cells, improves
is thickened, fibrotically changed and physiologically the lymphatic flow and moderately stimulates the
unfunctional. The disease often has a latent course gastric secretion. It belongs to the so-called hor-
Chapter 8

Pathophysiology of bones and joints

organic matrix is the homogeneous ground substance

containing, above all, the vitamin K- dependent pro-
8.1 Introduction tein osteocalcin (Gla- protein) binding the calcium,
the phosphoprotein osteonectin forming the connec-
tion between collagen and calcium, and other pro-
teins and lipids in less quantity. The ground sub-
The skeleton has several functions in the organ- stance serves as medium for exchange of nutrients,
ism: it forms the supporting framework of the body, oxygen, minerals, and waste products of metabolism
protects the organs, and forms cavities where the between the bone tissue and blood. It is supposed
bone marrow is localized. From pathophysiological that it participates also in the regulation of inorganic
point of view however, the most important function salts deposition into the bone matrix.
of skeleton is that it serves as a rich reservoir of mi- The inorganic component of bone containing ma-
neral ions, above all of calcium, phosphate, magne- inly the calcium and phosphate in form of hydroxya-
sium and sodium. Under physiological conditions all patite crystals is localized in close proximity to the
these functions operate in well balanced mutual in- surface of collagen fibers and among them. The ratio
teraction. Under pathological conditions the partic- Ca/P changes according to the nutrition conditions
ipation of bones in maintainance of chemical home- in adults being about 1.67. The hydroxyapatite crys-
ostasis (e.g. during calcium deficiency) may lead to tals provide the bones with extraordinary strength.
progressive bone demineralization which can nega- On the surface of hydroryapatite crystals a brisk ex-
tively influence the supportive function of the skele- change of ions occurs. Therefore they could be con-
ton. The complicated relations between the bone sidered to some degree as a ion exchanger or buffer
and extracellular milieu being mediated mainly by system. The inorganic bone component is completed
hormones, enable the development of a large variety by magnesium, sodium and potassium ions but they
of pathological conditions where the initiating factor have not been identified in crystalline form. It seems
may be any component involved (e.g. kidney, GIT, that they conjugate with hydroxyapatite. The prop-
endocrine gland, bone). erty to conjugate with bone crystals have also the
ions foreign for the human body e.g. lead, stron-
8.1.1 Remarks to the anatomy and tium, gold or radioactive substances. Deposition of
radioactive substances in bones leads to prolonged ir-
physiology of bones radiation with the risk of development of neoplasms
The bone consists of a firm organic matrix (30 per in bones.
cent) strengthened by deposition of calcium salts (70 The bones are throughout the life constantly re-
per cent). The organic matrix contains mainly the modelled by two alternating processes: continuous
collagen fibers with high content of glycine, proline bone resorption and formation. After the end of
and hydroxyproline. The collagen fibers are arranged growth period both processes function in equilib-
in the direction of the pressure forces acting on the rium. The continuity of bone remodelling is impor-
bone. They ensure the bone elasticity. The rest of tant from two points of view, at least:

557
558 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

1. it ensures optimal stability of skeleton during from monocytes of bone marrow. Under physiologi-
changing external conditions by prompt adap- cal conditions they operate in small groups on less
tation response to the magnitude and direction than 1 per cent of bone surface. The resorption
of the load exerting its action on the bone is performed by amply ruffled border of osteoclasts
releasing proteolytic enzymes (from lysosomes) and
2. by continual release and reuptake of calcium into
acids e.g. lactic and citric acids (from mitochodria).
the mineral component of bone tissue it con-
The enzymes dissolve the organic matrix and the
tributes to the maintainance of calcium blood
acids dissolve the inorganic salts. The result of os-
level stability.
teoclast activity is a tiny cavity or canaliculus (How-
The bone formation and resorption are performed ship’s lacuna) with the length of some few millime-
by bone cells. The osteoblasts are present on the ters and diameter of about 1 millimeter. They are
outer bone surface and in the bone cavities. They immediately occupied by osteoblasts and the bone
are responsible for the bone new-formation. They formation starts again. Considering the functional
secrete the collagen monomers and proteoglycans point of view the above mentioned processes are
of the ground substance. The collagen monomers termed: basic multicellular unit, BMU. It is a func-
rapidly polymerize forming collagen fibers. In few tional unit in which every cycle is characterized by
days the calcium salts begin to precipitate on the osteoclast activation leading to bone resorption and
surface of collagen fibers. Small agglomerations of by subsequent activation of osteoblasts performing
precipitates grow and increase quickly in number. the bone formation. Since the osteoblastic bone for-
The elementary amorphous substance of the precip- mation is associated with precedent osteoclastic bone
itate is a mixture of various salts. During weeks or resorption (osteoblasts need place for their action)
even months it is changed into hydroxyapatite crys- the remodelling rate is determined by the osteoclast
tals by substitution and addition of atoms and by activation rate. The close coupling of bone resorp-
complicated processes of reabsorption and reprecip- tion and formation processes indicates that between
itation. It is very important for the organism that both types of cells i.e. the osteoblasts and osteoclasts
about 25 per cent of salts remain permanently in exchange of information occurs. The mechanism of
the amorphous form. Only in this form they can be this communication is not known however several,
deposited or released to maintain constant calcium mainly local factors (e.g. prostaglandins, growth fac-
level in ECF. The response is in so far prompt that tors and even the partly decomposed components of
the release or uptake of the necessary quantum of osteoid) participate in this process.
ions from blood occurs actually during a sole blood
Continual remodelling performed by balanced in-
flow trough the bone. Total amount of in this way
teraction of osteoblasts and osteoclasts enable the
available calcium represents 5 to 10 g.
bone to change its architecture in response to me-
The activity of osteoblasts results in osteoid for-
chanical load. During the exposure of the bone tis-
mation. Osteoblasts remain in osteoid permanently
sue to the load action its new formation increases.
changing functionally and morphologically (in shape
That is why the bones of hard working people and
and function) into osteocytes localized in the osseous
of sportsmen are substantially heavier. On the con-
lacunae. The osteocytes do not form new bone sub-
trary the bones of immobilized limbs become dur-
stance. They communicate with one another and
ing several weeks lighter by 30 per cent. Thus the
with osteoblasts via long processes forming a dense
permanent physical load stimulates the osteoblastic
network (so called osteocytic membrane system) in
activity and calcification of the bone.
bone canaliculi. Since they are in close connection
with capillaries and in immediate contact with the The overload of bone elasticity and firmness causes
bone fluid rich in nutritive substances they partic- fracture. Periost and the blood vessels of the bone
ipate actively in transfer of minerals in the lacunar marrow, compact bone tissue and neighboring soft
wall. They can be reactivated into osteoblasts if need tissues become disrupted. Haematoma develops
arises. along the medullar cavity, among the broken ends
Simultaneously with bone formation the bone re- of the bone, and under the periost. The bone tissue
sorption occurs performed by the activity of osteo- in the immediate proximity to the fracture is affected
clasts. Osteoclasts are large phagocytic cells derived by necrosis. stimulating an intense inflammatory re-
8.1. Introduction 559

sponse characterized by vasodilatation, plasma ex- 8.1.2 Hormones influencing the

sudation and infiltration with leukocytes and mast bone tissue
cells. After 48 Hs the blood vessels from surround-
ing tissues and bone marrow begin to infiltrate the Constant calcium and phosphate levels in blood are
inflammatory focus and the blood circulation re- critically important for vital functions. Responsible
stores progressively. The activated cells of periost, for their maintainance are, above all, the hormones
endosteum and bone marrow produce subperiostal influencing the reservoir of these ions (bones) and
procallus bridging the fracture surfaces and form- the organs of ion intake (GIT) and excretion (kid-
ing the non osseal connection. Osteoblasts of pro- neys). Dominant role in hormonal regulation play
callus synthesize collagen and other components of parathormone and calcitriol.
matrix which begin to mineralize and to form callus Parathormone (PTH) secretion from parathyroid
(in about 3 weeks). As the healing process contin- glands is extremely sensitive to changes in blood con-
ues the unnecessary callus is resorbed. New bone centration of calcium ions. The secretion of PTH
trabeculae are formed arranged in the direction of rises when the calcium ion concentration in blood
pressure forces action. This process lasts for weeks falls and vice versa (negative feedback mechanism).
to months.The healing duration can be negatively The end- effect of PTH action is the calcium blood
influenced by several factors. To the general fac- level elevation achieved by influencing the:
tors belong the advanced age, insufficient nutrition,
1. absorption of calcium and phosphates from bo-
(starving or malabsorption leading to protein, cal-
nes
cium, vitamin D and C deficiency). As the most
frequent local factors should be mentioned the in- 2. excretion of calcium and phosphates via kidneys
correct apposition of the broken bone ends and in-
sufficient immobilization which can lead owing to the 3. calcitriol
repeated moving to formation of fibrotic connection
– the pseudoarthrosis. Further local causes of re- ad 1) The effect of PTH is realized in two pha-
tarded healing may be the infection and insufficient ses. During the fast phase lasting some minutes
blood supply given also by anatomic localization of PTH stimulates existing osteoblasts and osteocytes
the fracture e.g.: equipped with receptors for PTH to reabsorb the cal-
cium salts. Binding of PTH to the receptors induces
• the nutrient artery enters the bone far from the the rise in cAMP concentration via adenylcyclase ac-
site of fracture, or it is impaired by the fracture tivation and subsequent phosporylation of regulative
(head of femur, carpal scaphoid bone) proteins. These processes result in enhanced per-
• fracture is localized in region where periost is meability of osteocyte membrane to calcium. Cal-
absent (collum femoris) cium present in the bone fluid enters the osteocyte
governed by the steep concentration gradient. The
• minimal amount of adjacent soft tissue (tibia) transfer of calcium from cells into the extracellular
fluid (ECF) is performed by Ca-pumps. The cal-
The process of healing is retarded also in patho- cium concentration in the bone fluid decreases. To
logic fractures. This term is used in cases of frac- maintain the equilibrium the surrounding amorphous
tures caused by preexisting bone disease. It occurs salts are dissolved. Such a process – the osteocytic
in diseases with decreased bone density: osteoporo- osteolysis – does not cause resorption of the organic
sis, Paget’s disease, osteogenesis imperfecta, and tu- matrix of bone (see the figure 8.1).
mours of bone. In these cases due to decreased During the slow phase lasting days to weeks PTH
bone density or alterations in bone tissue composi- induces an indirect activation of osteoclasts which
tion lower, in extreme cases minimal external force are not equipped whith PTH receptors. It is sup-
is sufficient to disrupt the bone continuity. posed that the activated osteoblasts and osteocytes
emit a till unknown signal inducing activation of
present osteoclasts and simultaneous formation of
new osteoclasts. The result is an increased rate of
osteoclastic resorption of the whole bone tissue i.e. of
560 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

sides the parathormone the second most effective reg-

ulator of bone metabolism. Vitamin D3 – cholecalcif-
erol is formed in the skin from endogenous precursor
by the action of ultraviolet radiation (sunlight). Vi-
tamin D in small amount is ingested in food as ergo-
calciferol (D2 ) differing from vitamin D3 only in the
length of the side chain. The biologically inert chole-
calciferol is transported via blood flow into the liver
where it is oxidized to an intermediate product – 25-
hydroxyvitamin D3 exhibiting low biologic activity.
After being released into the blood it is metabolized
(1-alpha-hydroxylation) in the cells of renal proxi-
mal tubule to thousand times more active calcitriol.
Calcitriol fulfills criteria to be considered as hormone
from more than one points of view, above all, because
it acts in a manner characteristic of steroid hormones
i.e. it binds to a specific intracellular receptor in the
target cells.
The formation of calcitriol is under physiological
circumstances strictly controlled by PTH. Parathor-
mone induces enhancement of calcitriol formation by
Figure 8.1: Osteolytic osteolysis stimulation of the 1-alpha-hydroxylation in kidneys.
Further regulating factor of calcitriol formation are
the levels of ionized calcium and inorganic phosphate
both components: the mineral salts and organic ma- in blood. Hypocalcaemia (acting directly on kid-
trix. ney and indirectly mediated by PTH effects) and
Skeleton contains about thousand times more cal- hypophosphataemia also stimulate the calcitriol for-
cium than is its total amount present in ECF. That mation.
is why even the maximal increase in calcaemia in-
duced by PTH does not lead to evident alterations Calcitriol increases the concentration of ionized
in bones. Long-term duration of PTH hyperproduc- calcium and in a less degree the phosphate concen-
tion (months to years) however, leads to osteoporo- tration in blood by its action on the target organs
sis characterized by presence of large cavities filled i.e. intestine, kidney and bone. It enhances the cal-
with osteoclasts. Progressive bone resorption results cium absorption and in a less degree also the phos-
in secondary stimulation of osteoblasts, nevertheless phate absorption by increasing the permeability of
the resorption prevails over the bone formation. the brush border, the calcium binding protein syn-
thesis, and the active transport across the basolateral
ad 2) PTH increases in kidneys the tubular cal- cell membrane in the intestinal wall.
cium reabsorption (ascending limb of Henle’s loop,
Calcitriol stimulates the calcium reabsorption in
distal tubule and collecting tubule) and simultane-
kidneys mediated by specific receptors for calcitriol
ously it inhibits the phosphate reabsorption in the
in distal parts of nephron.
proximal tubule. By combination of these effects
PTH enables to increase the calcium level and to In the bone calcitriol stimulates the osteoclastic
excrete simultaneously excess of phosphates released bone resorption in the same way as does PTH in
from bone minerals (should the product of calcium slow phase of its action: it augments the number
and phosphate remain constant, the increase in con- and the activity of osteoclasts. Since the osteoclasts
centration of one ion entails the fall of the other and lack the specific calcitriol receptors, it probably stim-
vice versa). ulates the differentiation of mononuclear precursor
Calcitriol (1,25–dihydroxyvitamin D3 ) Active cells to the mature osteoclasts. The activity of os-
hormonal form of vitamin D3 the calcitriol – is be- teoclasts is simultaneously modulated by neighbo-
8.1. Introduction 561

ring osteoblasts equipped with specific intracellular 1. stimulation of calcitonin

calcitriol receptors.
2. inhibition of bone resorption induced by PTH
Calcitriol is inevitably necessary for initiation and
regular continuation of osteoid mineralization. This 3. positive influence on calcitriol activation in kid-
effect is realized probably by influencing the calcium neys
ion transport through the membranes of osteoblasts
Androgens are responsible for the achievement of
and osteocytes. It supports indirectly the bone min-
peak bone mass in men. Androgens together with
eralization increasing the calcium and phosphate ab-
estrogens and growth hormone influence the growth
sorption in the intestine. Calcitriol and PTH real-
and the epiphyseal closure.
ize their effects on bone by an evidently common
Glucocorticoids are in physiological doses impor-
final mechanism. Evidence of it is given by the fact
tant regulators of bone growth. Glucocorticoids in-
that during calcitriol deficiency the responsiveness of
fluence both, the osteoclasts and the osteoblasts. In
the bone to PTH is reduced and on the contrary in
excess however, they reduce the bone mass density
PTH deficiency even hundred times more calcitriol
(osteoporosis). This final effect results from their
is needed to calcium and phosphate mobilization.
direct action on bone (inhibition of replication and
Besides both mentioned major hormones there are
differentiation of osteoblasts and increase in numbers
further hormones and local modulatory factors influ-
and activity of osteoclasts) and from indirect action
encing the bone metabolism. However their physio-
(inhibition of intestinal calcium absorption and stim-
logical function is still not well understood. Their
ulation of calcium excretion via kidneys).
effect on bone becomes manifest only under certain
The mechanism of thyroxine effects on bone is not
circumstances.
well understood. Nevertheless it is well known that
Calcitonin is a hormone secreted by C-cells of pa-
the untreated thyrotoxicosis may lead to osteoporosis
rathyroid gland. Effects of calcitonin on plasmatic
and the hypothyroidism on the contrary is associated
levels of calcium are in contrary to those of PTH
with decreased metabolic turnover in the bones.
and calcitriol. Calcitonin achieves the decrease in
Somatotropin (STH) action on bone is important
plasmatic calcium level by acting on the bone tissue.
mainly in the period of growth. It induces prolif-
1. It immediately suppresses the resorbing activ- eration of chondrocytes. Experiments in vitro have
ity of osteoclasts by binding to the specific re- shown that its effect is rather indirect, mediated by
ceptors and influences simultaneously the os- stimulation of the liver to form somatomedin (soma-
teocytic membrane system resulting in calcium totropin mediator). This peptide circulates in blood
deposition into the rapidly exchangeable amor- firmly bound to proteins. Since its structure and
phous salts. This effect of calcitonin is evident activity is similar to insulin it is named recently –
only when high metabolic turnover in bones is the insulin-like growth factor (IGF). It occurs in two
present e.g. in growing period or in Paget’s dis- forms:
ease (see further). • IGF1 strongly dependent on somatotropin
2. By long-lasting effect calcitonin decreases the • IGF2 less dependent on somatotropin and more
new-formation of osteoclasts. Because the os- similar to insulin.
teoclastic bone resorption leads to secondary
stimulation of osteoblastic activity reduced People which are resistent to the PTH effects e.g.
numbers of osteoclasts result in reduced num- Pygmies have a normal level of PTH but low level of
bers of osteoblasts. Resulting effect of long-term IGF1 in blood.
calcitonin action is the bone remodelling retar- Vitamin C participates in collagen and acidic mu-
dation. copolysaccharide synthesis. Vitamin K is neces-
sary for the biosynthesis of Ca-binding proteins (in
Estrogens influence positively the bone metabo- plasma, kidney, liver), and for the osteocalcin biosyn-
lism. Decrease in, or absence of estrogen secretion thesis in bones. Vitamin A sustains the osteoclastic
leads to the loss of the bone mass. The action of bone resorption and by its action on the acidic mu-
estrogens on the bone is directly mediated by specific copolysaccharides it influences the stage of calcifica-
receptors, or indirectly by: tion.
562 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

Various local factors contribute considerably to tological examinations can be manifest only at one
the maintainance of the tender balance in activi- or more sites of the skeleton. Thus, the vertebral col-
ties of single types of bone cells. Topically produced umn alterations might have the look of local lesions,
prostaglandins e.g. PGE2 may directly act on the they however are indicative of generalized skeleton
bone metabolism by stimulation of osteolytic pro- disease. The genuine real local disorders are caused
cesses or by inducing synthesis of further local factors by:
(epidermal growth factor, platelet-derived growth
factor). Interleukin-1 is a very effective substance 1. immobilization of one part of the skeleton leads
stimulating the bone resorption. Similar to the in- to local atrophy developing the sooner the
terleukins is the osteoclast activating factor. Further higher is the metabolic turnover in affected bone
cytokines e.g. the gamma interferon exert also topi-
2. disorder of circulation (local obliteration or ob-
cal regulative effects on bone tissue. By osteoblasts
turation of blood vessel, or A-V anastomosis
produced TGF beta (transforming factor beta) stim-
lead to trophic disorders of bone)
ulates the mitogenesis and collagen synthesis. The
majority of these factors is involved also in the heal- 3. tumours of bones (every tumour of bone includ-
ing and reparation of microfractures. Besides the ing the cyst whether it originates in bone or has
hormones and topically acting factors the trophic in- been metastasized is substantially of local char-
fluence of nervous system has a substantial impor- acter, even if a multiple dispersion is involved
tance in bone metabolism regulation. When the ner- because the bone among the metastases is nor-
vous system is excluded the bone formation is re- mal).
duced and bone resorption enhanced (bone atrophy).

8.2.1 Skeleton balance disorders

8.2.1.1 Negative balance of skeleton
Osteoporosis The term osteoporosis is reserved
8.2 Generalized skeleton dis- for bone mass loss per bone volume unit. The com-
orders position of bone remains however normal as show the
histological and biochemical findings.
The bone mass quantity is determined by mutual
proportion of bone formation and resorption pro-
By evaluation the bone diseases the fact should be cesses. Positive, neutral or negative bone balance are
taken into consideration that in bones a continuous observed in various periods of life. In childhood and
process of remodelling takes place. The bone remod- adolescence the bone formation preponderates evi-
elling does not occur however at identical velocity in dently over the bone resorption. In adults are both
all parts of skeleton. Therefore the disorder becomes processes in equilibrium (remodelling). The peak
manifest first in those parts of skeleton where the bone mass is attained in age of 30 to 35 years. In
metabolic turnover is maximal. Intensity of remod- men are the peak values substantially higher than in
elling has a declining tendency: mostly affected is women, so they are in black population in compar-
the vertebral column, afterwards pelvis, ribs, lower ison to the white people. Genetic factors however
extremities, shoulder girdle, upper extremities and predetermine the peak bone mass in every individ-
at least the skull. Generalized process with identical ual. Following five to ten years a slow decline in
manifestations in all parts of skeleton does not exist. total bone mass begins. At the beginning the veloc-
The term – generalized process – indicates a biolog- ity of the decrease is identical in both sexes. Subse-
ical process occurring at the molecular level, it does quent bone loss in women is during the menopause
not indicate clinical manifestations. A metabolic dis- significantly accelerated. In advanced age is the rate
turbance induced mostly by hormonal or nutrition of bone loss again identical in both sexes. The less
disorders is always involved. Specification as a pro- the attained peak bone mass the sooner osteoporosis
cess at molecular level is important because the bone will develop.Therefore are the white postmenopausal
affection assessed in clinical, radiological an even his- women at greatest disadvantage.
8.2. Generalized skeleton disorders 563

Osteoporosis is the most common bone disease. It bone resorption. The number and activity of os-
develops in majority of cases (about 80 per cent) teoclasts rises. The major etiologic factor of these
in consequence of progressive bone mass loss depen- alterations is the postmenopausal decrease in estro-
dent on age. Moderate degree of bone atrophy is gen level. Physiological estrogen level before the
a physiological phenomenon and belongs to involu- menopause exert by direct or indirect influence on
tional manifestations of aging. Only when the symp- other hormones an inhibitory effect on bone resorp-
toms become intensified and the bone density falls by tion. Estrogen deficiency or complete loss enhances
more than 25 per cent the condition is considered to the bone responsiveness to PTH effect causing the
be pathologic. It is reported that as much as 20 per bone resorption and probably negatively influences
cent of people more than 60 years old are affected the calcitriol synthesis in kidney.
by osteoporosis. The involutional osteoporosis can
Other types of osteoporosis are less frequent, nev-
be of type II – senile, and type I – postmenopausal.
ertheless not less severe. The juvenile osteoporosis
Both types of disease belong to important medical
may arise reversibly in young people during the pe-
problems in advanced countries where owing to the
riod of accelerated growth. Its cessation is sponta-
higher age achievement higher percentage of popula-
neous, nevertheless during the active phase fractures
tion is affected by osteoporosis. Clinical manifesta-
may occur. Osteoporosis due to inactivity develops
tion appears frequently as late as the bone density
during complete immobilization. According to the
is reduced to such a degree that the bones are ex-
intensity of bone metabolism in the given patient se-
tremely fragile and prone to spontaneous fractures.
vere bone atrophy develops during weeks to months.
Because during the menopause the process of resorp-
Inactivity of muscles leads to vasodilatation in pe-
tion attacks mainly the spongy bone tissue, typical
riost resulting in massive osteoclastic bone resorp-
for the postmenopausal osteoporosis is the fracture
tion as shown in animal experiments. The mechan-
or osteoporotic break down of vertebra. Unlike to
ical stimulus for compensatory bone new formation
this situation in advanced age the bone loss equally
is lacking. This mechanism seems to be important in
affects the spongy and the trabecular bone tissue
weightlessness as confirmed by rapidly developing os-
hence typical for senile osteoporosis is the fracture
teoporosis frequently accompanied with fractures of
of femur. The most frequent clinical manifestation
collum femoris in astronauts. Hypogonadism leads
of osteoporosis is pain behind which a fracture or in-
to osteoporosis mainly in trabecular bones. Hypogo-
fraction of a brittle bone are hidden. Long-term and
nadism may originate in primary affection of gonades
repeated fractures of vertebrae result in spinal col-
or in secondary disorders induced by deficiency of go-
umn deformities (characteristic are outstanding loss
nadotropins. It occurs frequently in women with hy-
of body height and severe kyphosis).
pothalamic amenorrhea. In sportswomen, the run-
Osteoporosis originates either from reduced bone ners above all, having amenorrhea due to physical
formation or increased bone resorption. exertion in top performance, reduced mineral con-
In the age-related bone osteoporosis is the bone tent in vertebral column was also found. Estrogen
new formation reduced. The osteoblasts and osteo- deficiency in them predominates obviously the posi-
clasts become less active. Reduced renal functions tive effect of physical activity on the bone formation.
occurring in aged people participate to a certain de- Hypogonadism in men predispose them to osteoporo-
gree in the pathogenesis of osteoporosis of type II. sis. Major factor responsible for the reduced bone
The mechanism is indirect: by influencing the vita- density in men is the testosterone deficiency.
min D metabolism in kidney is the calcium absorp- Osteoporosis induced by glucocorticoid excess ap-
tion through the wall of intestine impaired. In elderly pears in Cushing’s disease or during long term gluco-
is also the intake of calcium in food insufficient and corticoid administration in high doses (e.g. in severe
the occurrence of further deficiency states is more bronchial asthma). In the first phase the excess of
frequent. In bones the circulatory and neurotrophic glucocorticoids increases the number and activity of
disturbance arise and in bone collagen structural al- osteoclasts accompanied with massive destruction of
terations typical of old age may be seen. bone. Later follows the phase of reduced bone for-
The postmenopausal osteoporosis is characterized mation with depressed osteoblastic activity. This di-
by high metabolic turnover in bones and increased rect effect on bone is supported by further indirect
564 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

effects of glucocorticoids as: antianabolic effect on bone marrow. Any kind of the subtle bone vessel
proteins, antagonism against the calcitriol formation system damage can result in regional osteoporosis.
in kidneys, and enhancement of calcium excretion.
In hyperthyroidism osteoporosis occurs infrequently. Osteitis fibrosa cystica is thank to the present
Excess of thyroid hormones stimulates the bone me- status of medical care an extremely rare bone dis-
tabolism. During this process the bone resorption ease appearing at advanced stage of primary or
is more effective than the bone formation. Long- infrequently secondary hyperparathyroidism. The
lasting heparin admininistration leads to osteoporo- metabolic turnover in bones is enhanced by influ-
sis because according to the today’s opinions hep- ence of long- term continual PTH hypersecretion.
arin either depresses the collagen synthesis in bone The bone resorption prevails due to considerable in-
or enhances its degradation. Calcium deficiency is an crease in osteoclastic activity. The endosteum and
important factor in osteoporosis development. Bone the trabecular bone tissue are the most responsive
atrophy can be induced in animal experiments by sites to the excess of PTH. Increased number of tra-
elimination of calcium from the food. The calcium becular surfaces exhibit resorption and their den-
absorption from intestine decreases with age. Unifor- sity progressively declines. Conglomerations of os-
mity of nutrition without sufficient participation of teoclasts produce cysts and cyst-like formations (so
useful components in elderly may also lead to neg- called brown tumours). The bone cysts are filled
ative calcium balance. Lactose intolerance can be with fluid and bordered by fibrous tissue. They occur
responsible sometimes for the negative calcium bal- mainly in subperiostal region. Brown tumours form
ance. Patients suffering from this disease are unable a solid non calcifying tissue mass consisting mainly of
to utilize the calcium present in milk and milk prod- polynuclear osteoclasts. Proliferation of osteoclasts
ucts. It is because these patients have diarrhea after and fibroblasts is evident also in bone marrow cav-
ingestion of milk or its products, thus this condi- ities. PTH leads also to enhancement of osteocytic
tion is associated with calcium malabsorption. The osteolysis enlarging the lacunae around the osteo-
underlying cause of the lactose intolerance is the ab- cytes. Thus, the resulting manifestation of osteitis
sence of lactase, an enzyme enabling the absorption fibrosa cystica is the generalized osteopenia and in-
of monosaccharides derived from di- or polysaccha- creased bone resorption with occurrence of cysts and
rides. In patient with atrophic gastritis or following so called brown tumours.
gastrectomy osteoporosis occurrence is not seldom.
It seems the cause might be the gastric acid defi- 8.2.1.2 Positive balance of skeleton
ciency and GIT motility disturbances. Deficiency of
proteins and vitamins, vitamin C and D above all, Osteopetroses (osteoscleroses) Osteopetroses
contributes to the development of osteoporosis. are very seldom bone diseases characterized by exces-
sive bone tissue formation. In contrast to the osteo-
Regional osteoporosis arises most commonly ow- porosis the bone formation predominates the bone
ing to the extremity immobilization after fracture, resorption, thus by positive bone balance the bone
tendon injury, arthritis etc. The underlying cause mass becomes excessive. Positive bone balance can
of osteoporosis in immobilized region is mainly the be induced by several mechanisms.
reduced afferent signalization arising from various Albers-Schönberg disease (so called marble bone
receptors i.e. the decrease in trophic influence of disease) results from failure of normal coupling be-
NS. Significant symptoms of osteoporosis may ap- tween bone formation and resorption. The bone
pear in about 8 weeks in patients 20 to 50 years density is greater with occurrence of sclerotic foci.
old but they can develop sooner. The reduced or Impairment of physiological function of osteoclasts
interrupted trophic effect of nervous system is also leads to defective modelling and remodelling pro-
the cause of bone atrophy following dissection of pe- cesses. Numerous osteoclasts are present on the
ripheral nerves (postdenervation atrophy). Regional bone surface, nevertheless without signs of activity.
osteoporosis may be due to inadequate number of The mechanism of osteoclast activity disorder at the
osteoblasts and osteoclasts in a certain bone region molecular level is not known till now. It was found,
since the complete remodelling cycle requires contin- however, that the transfusion of healthy haematopoi-
uous and sufficient supply of precursor cells from the etic stem cells to mice with osteopetrosis leads to
8.2. Generalized skeleton disorders 565

healing, and on the contrary, the transplantation of Fluorosis In endemic regions with high content of
bone marrow from mice with osteopetrosis to healthy fluoride (in water or soil) is the occurrence of flu-
mice results in osteopetrosis. Definitive evidence of orosis already many years known. On the basis of
”inoculation” has been referred by Coccia et al. in experimental results it is supposed that fluoride re-
the case of an affected girl after transplantation of places the hydroxyl ions in the deposition into the
bone marrow from her HLA-identic brother. In os- apatite crystals causing their enlargement and re-
teoclasts in girls bones chromosome Y was present duced solubility. Long-term observations in people
(confirming their origin), while in osteoblasts it was showed that fluoride in high doses stimulates the os-
not present. The Albers-Schönberg disease has sev- teoblasts. Calcium balance becomes positive, new
eral types: trabeculae of osteoid are formed and calcified in de-
pendence on fluoride dosis.
• Infantile osteopetrosis (lethal). It is an ex-
Acromegaly The growth hormone is the single hor-
tremely rare disease with autosomal recessive in-
mone which induces new formation in adult skeleton.
heritance which begins to develop immediately
This effect is probably mediated by somatomedins
after the birth. Generalized osteosclerosis leads
(IGF-1, IGF-2). Acromegaly is associated with en-
rapidly to obliteration of bone marrow spaces
hanced bone metabolism leading to rise in bone den-
and to aplastic anaemia and excessive com-
sity. The consequence of STH overpoduction in
pensatory hematopoiesis associated with hep-
adulthood is the enlargement and thickening of acral
atosplenomegaly. The epiphyseal growth plates
parts of skeleton. At least in 30 per cent of ills suffer-
become calcified. Increased density of cranial
ing from acromegaly the syndrome of carpal tunnel
bones narrows down the foramina for cranial
develops with compression of nervus medianus by hy-
nerves what may lead to blindness, deafness,
pertrophic bones and soft tissue of the forearm distal
paresis n. facialis, hydrocephaly etc. Increased
part. Enlargement in height and width of vertebrae
fragility of bones may result in pathologic frac-
by periostal bone apposition is sometimes observed.
tures. Disease ends with death within the first
These alterations may cause compression of spinal
decade of life.
nerve roots in foramina vertebrales and stenosis of
• Osteopetroses with early onset (non lethal). On spinal canal.
the contrary to the severe autosomal recessive
form these types of osteopetroses in childhood 8.2.2 Disorders of ground substance
are not lethal. Because of positive bone balance
and moderately reduced bone marrow spaces Seldom conditions, in majority of genetic origin, are
only mild anaemia and rare pathological frac- included in this group of diseases. Not only the
tures are associated with this condition. Com- growth and the bone composition irregularities are
plete absence of carbonic anhydrase II in ery- involved but more often outstanding disorders of
throcytes has been found in many patients. Be- other tissues and organs.
sides, this form of osteopetrosis is frequently ac- Disturbances in acidic mucopolysaccharid meta-
companied with renal tubular acidosis and sim- bolism occur in hereditary disorders of acidic mu-
ilar defect of carbonic anhydrase II. It seems coplysaccharide degradation. In all eight till now rec-
therefore possible that in osteoclastic bone re- ognized types of mupolysaccharidoses the affection of
sorption even the carbonic anhydrase II plays the skeleton (dysostosis multiplex) being the conse-
an important role. Chronic acidosis reduces the quence of defective composition of ground substance
manifestations of osteopetrosis because it sup- is combined with mucopolysaccharide deposition into
ports conditions for continual osteolysis. various extraskeletal sites. These alterations can lead
to e.g. pseudoatherosclerosis due to involvement of
• Osteopetrosis with late onset is more frequent blood vessel tunica intima, to valvular heart diseases,
but less severe condition with autosomal domi- thickening of articular capsulae and ligamenta, sple-
nant inheritance in comparison with the above monegaly etc. Clinical manifestations of skeleton in-
mentioned infantile form. It remains long volvement depend on type of disease. In general, dis-
time hidden or becomes manifest by moderate orders of ossification are included accompanied with
anaemia and by pathological fractures. retardation or cessation of growth, kyphoses caused
566 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

by vertebral deformities, thicker and shorter diaphy- orrhea, chronic disorders in bile secretion, in syn-
ses of long bones, and chest deformities. Similar al- dromes arising following gastrectomy, etc.). All these
terations can be observed in some types of hereditary conditions may reduce considerably the absorption of
disturbances in glycoprotein degradation (e.g. mu- vitamin D, calcium and less the phosphate from GIT.
colipidosis I, II, III, aspartylglucosaminuria, man- Decreased calcium level in serum leads to secondary
nosidosis). hyperparathyroidism. Nevertheless, parathormone is
The collagen anomalies occur in several genetic not able to enhance the calcium absorption from in-
diseases. testine under these circumstances. By its effect on
Osteogenesis imperfecta is a hereditary disease kidneys it aggravates even more the condition: the
with mutations in one or two structural genes coding phosphate level becomes more reduced.
the protocollagen of type I. Presence of anomalous Further underlying causes of osteomalacia or rick-
collagen III or V and alterations in cross bindings ets are disturbances of vitamin D transformation into
of collagen fibrils have been found in bones. Defec- calcitriol :
tive collagen synthesis leads to typical bone fragility
• 25-hydroxylation of vitamin D3 in the liver is
(brittle bones) resulting in deformities and fractures.
retarded in hepatocellular diseases
The extraskeletal manifestations include: blue scle-
rae, deafness, thin skin, valvular heart diseases, de- • 1-alpha-hydroxylation of 25-hydroxy-vitamin
fective dentin. All these signs are manifestations of D3 in kidneys is significantly reduced mainly
collagen synthesis disturbance. Further seldom ge- during chronic renal failure.
netic diseases involving the collagen anomalies are:
Ehlers-Danlos syndrome characterized by loose and Osteomalacia belongs to the uraemic bone syn-
infirm network of collagen fibers (manifested by lax- drome and is associated mostly with further
ness of joints), Marfan’s syndrome with characteris- metabolic osteopathies (see later). 1-alpha hydrox-
tic phenotypic manifestation – a long and thin skele- ylation is reduced also in parathyroid hormone defi-
ton. Vitamin C deficiency (scorbut) leads in child- ciency. Another very infrequent cause is the inher-
hood to disorders in collagen synthesis with resulting ited disorder of 1-hydroxylase (vitamin-D dependent
bone atrophy. Ascorbic acid is probably required for rachitis of type I).
collagen hydroxylation. Anomalies of receptors for calcitriol in target tis-
sues occur rarely, if present they cause the vitamin-
dependent rachitis of type II.
8.2.3 Disorders of mineralization Hypophosphataemic osteomalacia develops when
8.2.3.1 Insufficient osteoid mineralization reduced capacity of tubular phosphate reabsorption
is present e.g. in inherited tubular disorders, or in
Osteomalacia (rachitis) The term osteomalacia Fanconi’s syndrome. Excessive and long-lasting in-
expresses a condition characterized by defective os- gestion of antacids reducing the phosphate reab-
teoid mineralization. The remodelling cycle passes sorption in gut may be a further cause of hyphos-
normally to the osteoid formation, nevertheless, the phataemia. In these cases the organism is lacking
calcification and deposition of minerals is retarded. for phosphorus a very important ”building stone” of
The bone size remains unchanged but the new bone osteoid mineralization. In addition the already com-
consists of soft osteoid instead of firm, hard bone pletely formed bone begins to demineralize. Calcium
tissue. When this condition develops in childhood is released from the skeleton in order to maintain
in the period of growth it is called rachitis (rickets). calcium- phosphate equilibrium in extracellular fluid.
Many etiologic factors may participate in the devel- Every metabolic acidosis of long duration con-
opment of osteomalacia, however, the most impor- tributes at last to the bone demineralization. The
tant is the vitamin D deficiency. Vitamin D sup- most typical example is the so called renal tubular
ports the mineralization by stimulation of calcium acidosis persisting during the life of the patient. Min-
and phosphate absorption from intestine. Deficiency eralization disorder occurs either because of calcium
of vitamin D in food is in our country infrequented. deficiency due to defective vitamin D metabolization
Frequent is, however, its insufficient resorption in or because the bones compensate constantly the aci-
syndromes of malabsorption (chronic diarrhea, steat- dosis (phosphate anions exchange the Ca2+ for H+ ).
8.2. Generalized skeleton disorders 567

Clinical symptoms of osteomalacia and rachitis The first step in the pathogenic process is probably
can be deduced from the pathogenesis of these dis- the retention of phosphates due to reduced glomeru-
eases. The soft bone does not break but it is bend- lar filtration. High plasmatic level of phosphates
ing under the action of minimal load. This leads to causes a reciprocal decrease in calcium level in or-
stretching or even to disrupting of periost associated der to maintain the product Ca · P unchanged. De-
with severe pain. At advanced stage of the disease creased calcium level leads to enhanced secretion of
the pains are present in the whole skeleton. Defor- PTH by feedback mechanism. PTH stimulates the
mations sometimes of bizarre even grotesque forms phosphate excretion via kidneys and thus restores
occur owing to the pathologic flexibility of bones. the Ca · P product to normal value. Always when a
On the sites of maximal load action and thus of rela- further decrease in glomerular filtration occurs a new
tively most intense bone metabolism pseudofractures equilibrium is established but only if the secondary
occur. They appear in form of fatigue fractures (the parathyroidism is present. By these processes is the
callus during the healing process never calcifies) or organism able to sustain the phosphate balance as
in form of permanent fractures induced by pulsation late as the glomerular filtration falls to about 25 ml
of adjacent artery. per minute. The price of this compensation, how-
ever, is the progressive bone resorption induced by
8.2.3.2 Excessive mineralization of osteoid PTH – the osteitis fibrosa cystica. With progressing
renal failure further nephrons disappear and the re-
This term has theoretical meaning and is mentioned maining nephrons are not able to excrete sufficient
only to complete the scheme of classification con- amount of phosphates in spite of stimulating PTH
cerning the logical and didactic approaches. Exces- effect. Plasmatic phosphates begin to rise again and
sive mineralization leading to osteosclerosis develops the calcium level falls again. Calcium malabsorp-
namely only when there has been previously to much tion makes the hypocalcaemia significantly worse. It
osteoid formed. Hence, the item of overmineraliza- appears when the renal failure progresses to a de-
tion is included into the item of positive balance of gree when the 1-alpha-hydroxylation of vitamin D
skeleton (see part 8.2.1.2). is significantly reduced. This is caused partially by
the renal parenchyma loss (including the loss of cells
containing the 1-alpha-hydroxylase) and partially by
8.2.4 Renal osteodystrophy – a com-
the suppressive effect of hyperphosphataemia on 1-
bined disturbance of mineral alpha-hydroxylation. Deficiency of calcitriol and azo-
metabolism taemia too, decrease the calcium absorption from
One of the most complicated bone diseases arises as GIT. Owing to this in some uraemic patients de-
a result of long-term renal failure. It is observed creased osteoid calcification appears and osteoma-
in patients who are regularly dialyzed. Since in lacia develops. It is not proven if it is a direct con-
these cases heterogeneous (mixed) histological find- sequence of calcitriol deficiency, or it reflects the de-
ings are observed the most convenient terms are: re- fective collagen synthesis. It can result also from
nal osteodystrophy or renal bone syndrome. Renal by uraemia induced disturbances in calciumphos-
osteodystrophy occurs in uraemic patients and in- phate transformation to hydroxyapatite. Aluminium
cludes: essential disturbances in metabolism of diva- present in solution used for dialysis accumulating in
lent ions, metabolic bone disorders (osteitis fibrosa bones contributes considerably to the development
cystica, osteomalacia, and osteosclerosis), hyperpla- of osteomalacia.
sia of parathyroid glands, and calcifications in tis-
sues. In about 10 per cent of patients the regional os-
teosclerosis can be observed mainly in vertebral col-
The pathogenesis of renal dystrophy is complex.
umn trabecular bones. It is probably the conse-
Many factors are involved, the most important being:
quence of temporary, transient interruption of 1-al-
• the retention of phosphates pha-hydroxylation inhibition in kidneys.

• reduced 1,25 dihydroxy vitamin D3 synthesis in The progress of renal osteodystrophy is accelerated
kidneys by metabolic acidosis if it is prolonged.
568 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

drocephalus. In untreated patients secondary hyper-

parathyroidism may develop during the phase of high
8.3 Localized bone disorders calcium utilization due to enhanced bone formation.
Paget’s disease is relatively frequently complicated
by various types of malignant or benign bone tu-
mours.
The underlying cause of Paget’s disease is not well
8.3.1 Locally enhanced bone resorp- known. From the several existing hypotheses is at
tion present the mostly accepted the hypothesis of viral
origin of disease (slow viruses). Viral pathogenesis
8.3.1.1 Osteitis deformans (Morbus Paget) is supported by geographical and familial occurrence
of disease, findings of inclusions in osteoclasts, and
Osteitis deformans is characterized by excessive
by identical stage of disease development if it occurs
anomalous remodelling affecting skeletal bones. The
in more than one bones. This phenomenon might
pathologic process is initiated by osteoclasts present
be caused by a single episode of viral infection of os-
in the given focus in great amount. The osteoclasts
teoclast precursors which have been transferred into
are functionally and structurally altered – they are
one or more bones. Continual replication of virus
large, polynuclear and contain plenty of cytoplas-
in affected cells associated with transfer via cell fu-
matic and nuclear particles. These anomalous osteo-
sion (normal property of osteoclasts) might explicate
clasts exert the bone resorption regardless of normal
why is disease localized meanwhile the other bones
anatomical limitations. After the initial excessive
are not affected.
bone resorption an increase in osteoblastic activity
follows associated with bone formation. Medullar
cavities in the focus are occupied with fibrous tissue
extremely rich in blood vessels. Combination of a
chaotic bone resorption with bone formation results 8.3.2 Local disorders of blood supply
in the typical mosaic pattern in the affected site. De-
fective structure of bone makes it more fragile. The 8.3.2.1 Avascular necrosis
most frequently affected bones are : the axial skele-
ton, lumbar part of vertebral column, bones of pelvis, The bone responds to severe decrease in, or interrup-
the ribs, sternum,cranial bones, and femur. The non tion of blood supply similarly as other tissues, i.e. by
affected bones reveal normal structure even in severe ischaemia and necrosis. The underlying cause of dis-
forms of disease. That is why the condition is classi- orders of blood supply in certain part of bone may be
fied among the localized bone diseases. trauma impairing the integrity of vessels, thrombosis
Osteitis deformans occurs mainly in middle-aged or embolism. Bone infarction occurs with predilec-
men. Although even 3 per cent of population (mainly tion in regions supplied via the end artery, hence the
in Western Europe and USA) are involved. The pro- most exposed is the subchondral region at the ends of
gression of disease has slow onset and remains long long bones. Most frequently affected are the collum
time asymptomatic. Clinical manifestations are de- femoris and the coxal joint. In patients with sickle
termined by combination of anomalous bone struc- cell anaemia necrosis of femoral head occurs due to
ture with enhanced blood flow in the affected bone. artery occlusion by defective erythrocytes. Local
Anomalous bone structure is the cause of deformi- ischaemia resulting from end artery occlusion may
ties and fractures. The enhanced blood flow trough have as underlying cause hyperlipidaemia, arthritis
the affected bone acts as a powerful A-V shunt and urica, m. Gaucher or prolonged application of corti-
may lead even to heart failure. Pathologic bone al- coids. The posttraumatic avascular necrosis of epi-
terations may result in neurological complications physis in childhood may lead to growth retardation
e.g. by involvement of middle vear bones (ossicles) on the epiphyseal plate and to joint disorders. In
or by compression of n. acusticus deafness develops, adults becomes the healing process of fractures re-
the pressure of cervical vertebrae on the basis cranii tarded and complicated and may result in irreparable
(platybasia) leads to vertigo, ataxia eventually to hy- joint impairment.
8.4. Disorders of joints (I. Šulková, M. Bakošová) 569

8.3.2.2 Sudeck’s syndrome nutrients from blood vessels, except the articulating
portions of the articular cartilages, disks and menisci.
Sudeck’s syndrome – the posttraumatic atrophy of Synovial cavity contains folds of synovial mem-
extremity – is known more than 200 years. It is brane that secretes the thick synovial fluid lubri-
an acute localized bone atrophy accompanied with cating the synovial cavity. It is an adapted con-
inflammatory alterations in the surrounding soft tis- nective tissue, the cells are covered with small villi.
sues. The underlying cause of Sudeck’s syndrome The surface of synovial membrane is smooth, moisty
are circulatory disorders in the affected region of ex- and sheeny. Synovial membrane also plays an im-
tremity induced by reflex action. The pain stimuli portant role in exchange of substances between the
after the trauma induce by reflex action an increase joint and blood vessels and participates in the nutri-
in the tonus of adrenergic nervous system leading to tion of cartilages. The cells on the surface of synovial
local spasm of venules and resulting in blood stasis in membrane- the lining cells produce hyaluronic acid
capillaries. During the persistence of circulatory dis- important for the exchange of proteins between syn-
order dystrophy of all tissue layers is developing. At ovial membrane and joint cavity. There exist two
further stage local excessive bone resorption occurs types of these cells.
owing to the osteoclast accumulation in the site of
impairment which leads to the painful posttraumatic • Type A – these cells are very simillar to macro-
osteoporosis. The pain progressively rises, hence the phages and contain a lot of cytoplasmatic lyso-
circulus vitiosus closes sustaining the disorder of va- somes.
soregulation up to the last ischaemic stage. The af-
• Type B – they are very close in their structu-
fected extremity does not bear longer any loading
re to cells acting in proteosynthesis. The syno-
and the following immobilization further impairs the
vial membrane participates also in elimination
tissue metabolism. Atrophy of the bone and soft tis-
of waste products of joint metabolism.
sues associated with contractures may lead to com-
plete loss of functional ability. The metabolic activity of synovial membrane is
Diabetic osteopathy seems to be similar to the very low, but it can be rised in pathologic condi-
Sudeck’s syndrome. The underlying cause of this tions, e.g. in rheumatoid arthritis. The increase in
type of osteopathy are as well the disorders of circu- metabolic activity is accompanied by proliferation of
lation. lining cells. It is assumed that the proliferation of lin-
ing cells is the determinig factor of raised metabolism
in inflammatory processes of synovial membrane.
The synovial fluid is a clear, viscous, amber-
collored liquid present in human joints in small
amounts. It has two essential functions:
8.4 Disorders of joints
1. the participation in the nutrition of cartilages,
2. lubrication of the synovial cavity.

The composition is the same as that of intersti-

8.4.1 Some remarks on anatomy and tial fluid except of the presence of hyaluronic acid.
physiology Hyaluronic acid is responsible for the viscosity rate
in synovial fluid. Decrease in viscosity is typical for
Most of the permanent joints in the body are syn- inflammatory processes of joints. In noninflamma-
ovial. In synovial joints the ends of the bones are tory processes the viscosity increases and in haemor-
covered with smooth hyaline articular cartilage. The rhagic conditions the viscosity value varies. A part
joint is lubricated by a thick synovial fluid and is en- of calcium present in the synovial fluid is bound with
closed by a flexible articular capsule. The four basic hyaluronic acid in form of calcium hyaluronate which
structures of a synovial joint are the synovial cav- represents an important buffer system for mainte-
ity, the articular cartilage, the articular capsule and nance of slightly alkalic pH in synovial fluid. The
ligaments. All the tissues of synovial joints receive normal pH range in synovial fluid is 7.31 to 7.64. All
570 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

the components of synovial fluid except hyaluronic Articular capsule is a fibrous capsule that lines the
acid are products of plasma filtration. The normal synovial cavity in the noncartilaginous parts of the
synovial protein level represents one third of plasma joint. The inner linning of the capsule is the synovial
protein level, no fibrinogen and other coagulation membrane, the outer layer is a fibrous membrane
factors are found. The concentration of lipids is very which reinforces the capsule. The articular capsule is
low compared with plasma, it rises in pathologic con- lax and pliable and permits considerable movement.
ditions. Electrolytes are distributed between plasma Ligaments are fibrous thickenings of the articular
and synovial fluid according to electrolyte balance capsule. Most of them are inelastic, but yet are pli-
principles Chlorides and bicarbonates are present able enough to permit considerable movement. They
in synovial fluid in higher concentration, anorganic prevent excessive movement and strain. They are
phosphorus in the same and natrium, potassium and richly supplied by sensory nerves and in this way
ionized calcium in lower concentrations as in serum. they prevent a person from stretching the ligaments
The concentrations of other substances (glucose, uric excessively.
acid) are the same as in serum. The synovial fluid cell Two other structures associated with joints are
count is similar to that of interstitial fluid. Mononu- bursae and tendon sheaths. Bursae resemble flat-
clear phagocytes, mainly responsible for the elimina- tened sacs and are filled with synovial fluid. They
tion of detritus, predominate. Besides cells irregular are helpful in elimination of friction arising by mus-
amorphous particles are present which are probably cle rubbing against another one. They facilitate the
fragments of articular cartilage and fibrous fragments movement of muscles over bones.
of synovial membrane. The amount of detritus in Tendon sheaths are modifications of bursae They
synovial fluid depends on the degree of degenerative are also filled with synovial fluid and their function is
changes. to reduce friction so that the tendos can slide easily.
Degenerative disorders of joints are characterized
by clear synovial fluid without spontaneous coagula- 8.4.2 Degenerative disorders of the
tion. In inflammatory diseases the effusion is turbid
joints
with increased white cell count and polymorphonu-
clear leukocyte predominance, the protein is elevated 8.4.2.1 Osteoarthritis
and viscosity is low.
Osteoarthritis, or degenerative arthritis is the most
Articular cartilage is a smooth and sheeny sur- common form of arthritis. It is a slowly progressive
face of the bones facing the synovial cavity. Because degeneration of the articular cartilage that generally
of its thickness and elasticity it acts like a shock is manifested in the weight-bearing joints such as the
absorber, it mitigates mechanical stress when the hip, knee and lumbar region of vertebral column and
joint is loaded. With increasing age its elasticity de- in fingers of elderly individuals. The disease is not a
creases. The articular cartilage itself is insensitive to single nosologic entity, but rather a group of disor-
pain, since it has no nerve supply, it has also no blood ders that have in common the mechanical destruction
supply. Its basic components are cells, fibres and ma- of a joint.
trix. The matrix is composed of collagen and proteo- It was often called degenerative joint disease be-
glycans captured in collagen web. Proteoglycans are cause of the progressive degradation of articular car-
responsible for load whithstand and elasticity, col- tilage that leads to joint narrowing, subchondral
lagen provides tensile strength. When the cartilage bone thickening, and eventually, a nonfunctioning,
is loaded, proteoglycans are compressed and water is painful joint. Although it is not primarily an in-
released. After removal of pressure water returns and flammatory process, a mild inflammatory reaction
the cartilage increases its volume. This mechanism may occur within the synovium. Ostephytes, large
is essential for cartilage elasticity. peripheral nodules of bone represent the bones at-
Besides articular cartilage within some joints there tempt to grow a new articular surface. In the early
are articular disks. These disks may act as shock stages the cartilage is thicker than normal because
absorbers to reduce the effect of shearing upon a joint of chondrocyte replication, but with progression the
and to prevent jarring between bones. They also degree of cell replication is not enough to keep pace
adjust the unequal articulating surfaces of the bones. with the continuing stress and the joint surface thins
8.4. Disorders of joints (I. Šulková, M. Bakošová) 571

down, the cartilage softens and the integrity of the of cartilage degradation seems to play interleukin 1
surface is breached. Remodeling and hypertrophy (IL-1), a cytokine produced by mononuclear cells and
of bone are also major features. There are also im- synthesized by chondrocytes. IL-1 stimulates the
portant changes of soft tissue present. They include synthesis and secretion of latent metalloproteinases
chronic synovitis and thickening of the joint capsule and tissue plasminogen activator. In addition to its
and periarticular muscle wasting, which may further catabolic effects, at concentrations even lower than
restrict the movement. those needed to stimulate cartilage degradation, IL-
The factors that play a major role in the etiology 1 suppresses PG synthesis by chondrocyte, inhibit-
of osteoarthritis include: ing matrix repair. The activity of these potentially
very destructive substances is limited by at least two
1. an increased unit load on the joint inhibitors:tissue inhibitor of matalloproteinase and
2. inferior material properties of the cartilage. plasminogen activator inhibitor 1, both synthesized
by the chondrocyte. If they are destroyed or present
The increased unit load may result from a num- in insufficient concentrations, the cartilage degrada-
ber of factors, but it is often attributable to incon- tion by these substances is started.
gruties of the joint secondary to various pathological Chondrocyte metabolism in normal cartilage can
conditions. For example, in congenital hip dyspla- be modulated also directly by mechanical loading.
sia the socket of the acetabulum is shallow, cover- Whereas static loading and prolonged cyclic loading
ing only 30 to 40 % of the femoral head (normally inhibit synthesis of Pgs and protein, loads of rela-
50 %). As a result there is less surface area cov- tively brief duration may stimulate matrix biosyn-
ered by cartilage and an increased load on articular thesis.
cartilage. Some congenital disorders, slipped cap-
ital femoral epiphysis and other similar conditions 8.4.2.2 Pathophysiology of cartilage changes
may lead to increased joint congruity and to con- in osteoarthritis
centration of dynamic loads. In general, the earli-
est progressive degenerative changes occur at those The biochemical changes of osteoarthritis primarily
sites within the joint, which are subject to greatest involve proteoglycans. There is a decrease in pro-
compressive loads. So, the mentioned subtle congen- teoglycan content and aggregation. There exists a
ital or developmental changes in combination with strong evidence supporting the concept that lysoso-
repetitive impact loading can soon lead to joint fail- mal and neutral metalloproteinases are responsible
ure. Repetitive overloading can often lead to os- for much of the loss of cartilage matrix in osteoarthri-
teoarthritis at specific sites related to vocational or tis. It is not sure whether their synthesis is stimu-
avocational overload (e.g., ankles of ballet dancers, lated by IL-1 or other factors, but an imbalance ap-
metacarpophalangeal joints of boxers, knees of bas- pears to exist between the levels of active enzymes
ketball players). and their inhibitors. This leads to serious loss of car-
The inferior material properties of the cartilage tilage matrix and so alters the important properties
are related to the biochemical structure. As men- of the cartilage.
tioned above, the articular cartilage is composed of The collagen fibres are thicker than normal and
two major macromolecular species: proteoglycans there are apparent changes in their arrangement
(PGs), which are responsible for stiffness of the tis- present, but no alterations in collagen content occur.
sue and its ability to withstand load, and colla- In the early stages of osteoarthritis, synthesis of
gen, which provides tensile strength and resistance to matrix by chondrocytes is augmented, presumably
shear. There are lysosomal proteases present within as a reparative reaction. This marked biosynthetic
the cells and matrix of normal articular cartilage, activity may lead to an increase in PG concentration,
but their low pH optimum asures that their pro- which may be associated with thickening of the carti-
teoglycanase activity will be confined to intracellu- lage and maintain the joint in a reasonable functional
lar sites. However, cartilage also contains a fam- state for years, however the repair tissue is often infe-
ily of metalloproteinases, which can degrade all the rior to normal hyaline cartilage. As the osteoarthri-
components of the extracellular matrix at neutral tis progresses, protein synthesis tends to decrease,
pH. Very important role in the biochemical processes suggesting that the cell reaches the point where it
572 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

fails to respond to reparative stimuli. The cell meta- 8.4.3 Inflammatory disorders of the
bolism gradually diminishes, as does cell replication joints
and end stage osteoarthritis develops with full loss
of cartilage. Rheumatoid arthritis
The most common form of osteoarthritis is id- Rheumatoid arthritis is a systemic, chronic, in-
iopathic (primary) osteoarthritis, in which no pre- flammatory disease that involves the joints. Char-
disposing factor is apparent. But several risk acteristic clinical feature of rheumatoid arthritis is
factors may play important role in the develop- persistent inflammatory synovitis which can lead to
ment of the disease. The most important are cartilage destruction and bone erosions. It usually
the age, female sex, race, genetic factors, major involves matching joints on opposite sides of the
joint traumas, repetitive stress, obesity, congeni- body. Most susceptible are the peripheral joints-
tal/developmental defects, prior inflammatory joint fingers, wrist and knee. The course of the disease is
diseases and metabolic/endocrine disorders. variable, and is often punctuated with remissions and
exacerbations. The broad spectrum of clinical man-
The age represents the most powerful risk factor in
ifestations ranges from barely discernible and mild
osteoarthritis. With increasing age progressive rise
forms to severe, destructive, and mutilating disease.
in incidence of osteoarthritis occurs. In radiographic
Rheumatoid arthritis affects less than 1 % of the
survey the prevalence in women older than 65 years
adult population, its incidence is greater in women
was 68 %.
than in men(with ratio 3 : 1). A genetic origin for the
Genetic predisposition plays important role in disease is suggested by the association of HLA-DR4
generalized primary osteoarthritis with HeberdenŽs and related B cell aloantigen, HLA-DRW4, with se-
nodes(osteophytes at the distal interphalangeal vere seropositive rheumatoid arthritis in white peo-
joints in the fingers). The heredity is linked to one ple. As many as 70 % of patients with classic or
gene, dominant in women and recessive in men. definite rheumatoid arthritis express HLA-DR4 com-
Obesity represents an important risk factor for pared with 28 % of control individuals.
knee osteoarthritis as recently was clearly proved. The cause of rheumatoid arthritis is unknown. In-
Major trauma and repetitive overloading represent fectious bacteria or viruses have never been detected
the most common risk factors for the development of in the joints of patients with rheumatoid arthritis.
osteoarthritis. Damage to the articular cartilage may It is thought that immunologic mechanisms play an
occur at the time of injury or subsequently during use important role in the pathogenesis of the disease.
of the affected joint. It has been suggested that rheumatoid arthri-
tis might be the manifestation of the response
The leading clinical feature of osteoarthritis is
to an infectious agent in a genetically susceptible
joint pain. It is a deep, aching pain aggravated by
host. There have been suggested several causative
joint movement and relieved at rest. The articular
agents, e.g. Mycoplasma, Epstein-Barr virus, cy-
cartilage has no nerve supply, so other structures are
tomegalovirus, parvovirus and rubella virus but no
responsible for joint pain in osteoarthritis. It can
convincing evidence supports this theory. The mech-
be the synovium – its inflammation due to cartilage
anism by which an infectious agent can cause RA
particles, subchondral bone – its microfractures or
remains also unclear.
medullary hypertension, osteophytes which stretche
One theory supposes a persistent presence of in-
the periostal nerve endings, stretching of ligaments,
fection of articular structures or retention of micro-
muscle spasm and joint instability leading to stretch-
bial products in the synovial tissues which generates
ing of the joint capsule or inflammation of capsule.
a chronic inflammatory process. Another possibil-
Other important clinical feature is stiffness of the ity is that microorganisms might induce an immune
joint upon arising in the morning or after a period response to components of the joint, because they
of inactivity. Primary osteoarthritis has no systemic disturb its integrity and reveal antigenic peptides. It
manifestations. can also be a break down in normal self-tolerance
Secondary osteoarthritis has the same clinical pat- leading to reactivity to self-antigens in the joint or
tern, but develops on the basis of preexisting under- the infecting microorganism might prime the host to
lying cause. cross-reactive determinants expressed on joint struc-
8.4. Disorders of joints (I. Šulková, M. Bakošová) 573

tures. In summary, a pathogenetic theory maintains as the predominance of CD4+ T cells in the syn-
that, initially, in a joint or elsewhere, an unknown ovium, increased amounts of IL-2 receptors, a prod-
agent, possibly a virus, stimulates the formation of uct of activated T cells, in blood and synovial fluid
antibodies(immunoglobulins). These immunoglobu- and also administration of monoclonal antibodies
lins act as a new antigens, triggering the produc- against T cells or CD4+ T cell subset that has sup-
tion of autoantibodies reactive with the Fc portion pressed rheumatoid inflammation in some patients.
of IgG (the rheumatoid factor). Immune complexes, T lymphocytes produce a number cytokines that can
which contain rheumatoid factors (IgG-IgG-RF, IgG- lead to activation of macrophages and also increased
IgM-RF), are phagocytosed by leukocytes, which re- expression of HLA molecules, also cytokines which
lease lysosomal enzymes and other products. Simi- promote B cell proliferation and differentiation into
larly, mononuclear phagocytes within the synovium antibody-forming cells. This results in the produc-
may also phagocytise the immune complexes. The tion of immunoglobulin and rheumatoid factor and
rheumatoid synovium is characterized by the pres- in formation of immune-complex and consequent ac-
ence of a number of secreted products of activated tivation of complement and exacerbation of the in-
lymphocytes, macrophages and other cell types. The flammatory process by the production of anaphyla-
local production of these cytokines appears to be toxins, C3a and C5a. It is, however, unclear whether
responsible for many clinical manifestations of RA. this represents a response to a persistent exogenous
These cytokines include those that are derived from antigen or to altered autoantigens such as collagen,
T lymphocytes such as interleukin 2 (IL-2), IL- immunoglobulin, or one of the heat shock proteins.
6, granulocyte-macrophage stimulating factor (GM- It could also be a persistent responsiveness to ac-
CSF), tumour necrosis factor a and transforming tivated autologus cells that might occur as a result
growth factorb, those originating from activated of Epstein-Barr virus infection or persistent response
macrophages-including IL-1, tumour necrosis factor to a foreign antigen or superantigen in the synovial
a, IL-6, IL-8, GM-CSF, macrophage CSF, platelet tissue.
derived growth factor, insulin-like growth factor, and
those secreted by other cell types in the synovium, The exudative synovial fluid in RA contains mo-
such as fibroblasts and endothelial cells-IL-1, IL-6, re polymorphonuclear leukocytes than mononuclear
IL-8, GM-CSF, macrophage CSF. The infiltrating T cells. The exudation is stimulated by a number
cells appear to be activated, since they express ac- of mechanisms. It is the local production of im-
tivation antigens such as HLA-DR and in addition mune complexes which can activate complement and
they appear to have proliferated locally in the syn- generate anaphylatoxins and chemotactic factors.
ovial tissue, perhaps in response to sequestered anti- Mononuclear phagocytes produce factors such as IL-
gen. 1, tumour necrosis factor a and leukotriene B4 which
can together with activated complement stimulate
The activity of these above mentioned cytokines
the endothelial cells of postcapillary venules to bind
is supposed to be responsible for many features of
circulating cells. TNF-α, IL-8, C5a and leukotriene
rheumatoid synovitis, such as synovial tissue in-
B4 stimulate the migration of polymorphonuclear
flammation, synovial proliferation and cartilage and
leukocytes into the synovial site. Vasoactive medi-
bone damage, as well as the systemic manifestations
ators such as histamine produced by mast cells that
of RA. On the other hand, local factors are produced
infiltrate synovium may also facilitate the exudation
that tend to slow the inflammation, such as trans-
of inflammatory cells into the synovial fluid as well as
forming growth factor β, which inhibits many of the
prostaglandin E2 with its vasodilatory effects. Poly-
features of rheumatoid synovitis including T cell ac-
morphonuclear leucocytes in the synovial fluid in RA
tivation and proliferation.
are able to ingest the immune complexes and in this
It has been suggested that the propagation of RA way produce reactive oxygen metabolites and other
is an immunologically mediated process, but the ini- inflammatory mediators. In summary, changes in
tiating stimulus has not been characterized. It is the synovial fluid include a massive increase in vol-
possible, that the inflammatory process is started ume, increased turbidity, and decreased viscosity be-
by the CD4+ helper-inducer T cells infiltrating the cause the lysosomal enzymes degrade hyaluronate,
synovium. Many findings support this theory, such the protein content is increased with relative in-
574 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

Figure 8.2: Pathogenesis of rheumatoid arthritis

creases in larger molecules, such as IgG. The number hypertrophy, it creeps over the surface of the ar-
of white blood cells in the synovial fluid is markedly ticular cartilage and adjacent structures. The in-
increased, with a polymorphonuclear predominance flammatory processes lead to formulation of pannus,
of about 70 %. The synovial fluid may also contain vascular granulation tissue composed of proliferat-
lymphocytes, macrophages, and the exfoliated lining ing fibroblasts, small blood vesels and variable num-
cells of the synovium. Fragments of of synovial villi, ber of mononuclear cells. Pannus produces a large
fibrin and particles of collagen may be also present. amount of degradative enzymes such as collagenase
and stromelysin, that may facilitate tissue damage.
The pathomechanism of bone and cartilage de- Very important role in the mechanism of bone and
struction is not fully understood. The synovial lining cartilage destruction play two cytokines, IL -1 and
cells, which are normally one to three layers thick, tumour necrosis factor α (TNF-α). They stimulate
undergo hyperplasia and form layers 8 to 10 cells the pannus cells to produce collagenase and other
thick. As the synovium undergoes hyperplasia and
8.4. Disorders of joints (I. Šulková, M. Bakošová) 575

neutral proteases causing erosion of cartilage, ac- produce myocardial infarction, cerebrovascular oc-
tivate chondrocytes in situ and stimulate them to clusion, renal failure or mesenteric infarction.
produce proteolytic enzymes degrading the cartilage,
they may activate osteoclasts and so cause deminer-
8.4.4 Arthritis urica (gout)
alization of bone. The characteristic bone- loss of
rheumatoid arthritis is juxta-articular, probably re- Gout represents a heterogenous group of diseases
lated to a factor elaborated locally by the rheumatoid in which the common denominator is an increased
synovium. The pannus invades the joint and sub- serum uric acid level. Recurrent attacks of acute
chondral bones and eventually the joint is destroyed arthritis are associated with the deposition of urate
and undergoes fibrous fusion, or ankylosis. crystals in and about the joints of the extremities.
For systemic manifestations is the release of in- The most striking feature of gout is the acute attack
flammatory substances, such as IL-1, TNF-α IL-6, of monarticular arthritis.
from synovium responsible. Hyperuricaemia, or increased serum uric acid level,
is defined as a plasma urate concentration greater
Since rheumatoid arthritis is a systemic disorder
than 420 µmol/L. It can be the result of increased
that predominantly affects the joints, the clinical fea-
production of urate, decreased elimination of uric
tures can be divided into two groups: articular ma-
acid, or combination of these two processes. In-
nifestations and extraarticular (systemic) manifesta-
creased uric acid level in serum leads to formation
tions.
of crystals and their tissue deposition.
Articular manifestations are the result of inflam-
mation of the joint structures. They involve pain
8.4.4.1 Increased production of urate
in affected joints aggravated by movement, swelling,
tenderness warmth and erythema of the affected In order to understand the pathogenesis of gout, a
joints. Almost invariable is morning stiffness with brief discussion of purine metabolism is necessary.
duration more than 1 hour. Initially motion is lim- Uric acid is produced by the oxidation of hypoxan-
ited by pain, the inflammed joint is held in flexion thine and xanthine, catalyzed by xanthine oxidase.
to minimize distention of the capsule. Later, fibrous These purines arise either from the breakdown of en-
or bony ankylosis or soft tissue contractures lead to dogenous nucleic acids, or the catabolism of dietary
fixed deformities. Muscle atrophy and weakness de- purines, or as a result of an increased synthesis of
velop as a result of motion restriction. purines in the liver, caused by loss of regulation in
The majority of patients develop constitutional several steps. Each of these three processes can lead
symptoms such as weakness, easy fatigability, to overproduction of uric acid.
anorexia, and weight loss. Conditions such as leukaemic blast crises, cyto-
toxic therapy for malignancy, haemolysis, or rhab-
Extraarticular manifestations involve rheumatoid
domyolysis, which are characterized by rapid cell
nodules, rheumatoid vasculitis, pleuropulmonary
turnover, proliferation or cell death, lead to accel-
manifestations and osteoporosis.
erated purine nucleotid metabolism and in this way
The rheumatoid nodule resembles a granuloma- to uric acid overproduction. Accelerated breakdown
tous reaction to a centrally located core of so-called of ATP is the cause of hyperuricaemia in myocar-
”fibrinoid necrosis”, which is a mixture of fibrin and dial infarction, smoke inhalation, strenuous physical
other proteins, such as degraded collagen. Midzone exercise or status epilepticus. Diet provides an ex-
consists of histiocytes arranged in a radial, or pal- ogenous source of purines. Foods rich in nucleic acid
isading fashion. Granulation tissue forms outer zone. content such as liver or kidney, have a significant ef-
These nodules are usually located on periarticular fect on the serum urate level.
structures, extensor surfaces and in other areas of Biosynthesis of purines takes place in the liver.
pressure, but they can also develop in visceral or- The formation of a purine ring is an 11-step pro-
gans. The most common locations are the olecranon cess. The first step is catalyzed by amidophospho-
bursa, the proximal ulna, the Achilles tendon, and ribosyltransferase (amidoPRT) activity. The rate of
the occiput. purine biosynthesis is determined, for the most part,
Vasculitis may affect virtually any organ, it can by this enzyme, which is regulated by the substrate
576 Chapter 8. Pathophysiology of bones and joints ( D. Maasová et al.)

phosphoribosylpyrophosphate(PRPP) which stimu- Urate crystals activate complement, Hageman factor

lates the reaction and the end products of biosyn- and contact system of coagulation that leads to gen-
thesis that inhibit the reaction. One of the causes of eration of bradykinin, kallikrein and plasmin. Urate
gout is the increase in activity of the enzyme PRPP crystals also react with neutrophils and it leads to re-
synthetase which leads to increased PRPP produc- lease of lysosomal enzymes, oxygen-derived free radi-
tion and accelerated de novo biosynthesis. It is an cals, collagenase and protease. These substances are
inborn error of metabolism with overproduction of responsible for the development of synovitis. When
purines, hyperuricaemia, hyperuricaciduria and de- synovitis develops, larger molecules, such as lipopro-
velopment of gout before the age of 20. The disorder teins, enter the joint space, bind to urate crystals,
is X-linked similarly as hypoxanthine phosphoribo- and perhaps, play a role in terminating the attack.
syltransferase(HRTP) deficiency that also causes hy- Tophi, aggregates of monosodium urate monohy-
peruricaemia, hyperuricaciduria and gout because of drate crystals generally surrounded by foreign body
urate overproduction. HRTP catalyzes the combina- giant cells, are formed in extraarticular and articular
tion of the purine bases hypoxanthine and guanine structures. They cause deformities and destruction
with PRPP to form the respective ribonucleotides. of hard and soft tissues.
In HRTP deficiency PRPP is accumulated and pro-
The typical course of the disease involves progres-
vides increased substrate for amidoPRT and de novo
sion through asymptomatic hyperuricaemia, acute
synthesis which leads to increased urate levels. In
gouty arthritis, interval or intercritical gout, and
addition, decreased formation of ribonucleotides de-
chronic or tophaceous gout. Renal stones may oc-
creases feedback inhibition on amidoPRT.
cur in any stage except the first.
8.4.4.2 Decreased elimination of uric acid Acute gouty arthritis is a painful condition that
usually involves one joint. The painful joint is ac-
Since renal excretion is an important regulator of companied by signs of intense inflammation : swel-
serum levels of uric acid, renal abnormalities may ling, erythema, warmth, and exquisite tenderness.
affect its metabolism. Urate is completely filtered However, later in the course of the disease, polyartic-
by the glomerulus and reabsorbed in the proxi- ular involvement with fever is common. Commonly
mal nephron. It is then secreted at a more distal the gouty attack begins at night, and the exquisitely
site in the tubule and, in turn, is partially reab- painful, inflamed joint may simulate an acute bacte-
sorbed. Decreased urate clearence is caused by all di- rial infection. The duration of the attack is about
uretics(except spironolactone), low doses of aspirin, 7–10 days. The first metatarsophalangeal joint is in-
pyrazinamide, ketone bodies, lactate and chronic volved in over 50 percent of first attacks.
lead nephropathy. Diuretic therapy leads to en-
hanced reabsorption of uric acid distal to the site The intercritical period is the asymptomatic phase
of excretion. Renal insufficiency can decrease urate that represents the interval between the initial acute
clearence as a result of impaired glomerular filtra- attack and subsequent attacks. These periods may
tion. Decreased proximal tubular secretion of urate last up to 10 years, but later attacks may be increas-
may cause the hyperuricaemia in individuals with ingly severe and prolonged.
gout and no evidence of urate overproduction, and Chronic gout is characterized by persistent pol-
also causes the secondary hyperuricaemia of acidosis. yarticular low-grade pain with attacks of acute pain.
Combination of these two mechanisms may also Tophi are present in the cartilage, synovial mem-
contribute to hyperuricaemia as it is in deficiency of branes, tendos and soft tissues and become apparent
glucose-6-phosphate, hereditary fructose intolerance on physical examination.
or excesive alcohol consumption. Renal dysfunction, manifested by albuminuria, oc-
curs in up to 90 % of patients and is due to crystal
8.4.4.3 Pathogenesis deposition in the renal interstitial tissue and obstruc-
Acute gout is the result of the interaction between tion of the collecting tubules by the uric acid crys-
urate crystals and polymorphonuclear leukocytes. tals.
Chapter 9

Inflammation and fever

view inflammation is the key reaction of the innate
immune response but in fact, inflammation is more
9.1 Inflammation than this, since it can lead to death, as in anaphy-
lactic shock, or debilitating diseases, as in arthritis
and gout.
According to different criteria, inflammatory re-
sponses can be divided into several categories. The
criteria include:
9.1.1 Principles of inflammation
1. time – hyperacute (peracute), acute, subacute,
A human or animal must defend itself against mul- and chronic inflammation;
titude of different pathogens including viruses, bac-
teria, fungi, and protozoan and metazoan parasites 2. the main inflammatory manifestation - alter-
as well as tumours and a number of various harmful ation, exudation, proliferation;
agents which are capable to derange its homeostasis.
3. the degree of tissue damage - superficial, pro-
For this, a plenty of effector mechanisms capable of
found (bordered, not bordered);
defending the body against such antigens and agents
have developed and these can be mediated by sol- 4. characteristic picture - nonspecific, specific;
uble molecules or by cells. If infection occur as a
consequence of the tissue damage, the innate and, 5. immunopathological mechanisms
later, the adaptive immune systems are triggered to
• allergic (reaginic) inflammation,
destroy the infectious agent.
Inflammation is a complex stereotypical reaction • inflammation mediated by cytotoxic anti-
of the body expressing the response to damage of its bodies,
cells and vascularized tissues. In avascular tissues, • inflammation mediaded by immune com-
e.g. in normal cornea, the true inflammation does plexes,
not occure. • delayed-type hypersensitivity reactions.
The discovery of the detailed processes of inflam-
mation has revealed a close relationship between in-
9.1.1.1 The response to injury and infection
flammation and the immune response.
The five basic symptoms of inflammation - red- Inflammation is the body’s reaction to invasion by
ness (rubor), swelling (tumour), heat (calor), pain an infectious agent, antigen challenge or even just
(dolor) and deranged function (functio laesa) have physical, chemical or traumatic damage.
been known since the ancient Greek and Roman era. The mechanism for triggering the response the
These signs are due to extravasation of plasma and body to injury is extremely sensitive. Responses are
infiltration of leukocytes into the site of inflamma- to tissue damage that might not normally be thought
tion. Early investigators considered inflammation of as injury, for example when the skin is stroked
a primary host defence system. From this point of quite firmly or if some pressure is applied to a tissue.

577
578 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

In addition, the body has the capacity to respond in some situations, for example to reduce or stop
to both minor injuries such as bruising, scratching, the lost of blood, whereas tissue repair and recon-
cuts, and abrasions, as well as to major injuries such struction can begin a little later. Therefore, a wide
as severe burns and amputation of limbs. variety of interconnected cellular and humoral (sol-
Depending on the severity of the tissue damage uble) mechanisms are activated when tissue damage
resulting from an injury, the integrity of the skin or and infection occur. On the other hand if the injury
internal surfaces may be breached and damage to the is negligible, the body must have mechanisms which
underlying connective tissue and muscle, as well as are able to stop the tissue damage when the injury
blood vessels can occur. In this situation infection agent was removed.
can, and frequently does result because the normal The development of inflammatory reactions is con-
barrier to the entry of harmful organisms has been trolled by cytokines, by products of the plasma en-
broken. It is obviously most important that the body zyme systems (complement, the coagulation cloth-
can respond to injury by healing and repairing the ing, kinin and fibrinolytic pathways), by lipid medi-
damaged tissue, as well as by eliminating the infec- ators (prostaglandins and leukotrienes) released from
tious agents that may have entered the wound and different cells, and by vasoactive mediators released
their toxins. It is also important that the appropri- from mast cells, basophils and platelets. These in-
ate response to the tissue damage and infection can flammatory mediators controlling different types of
be made: it is no use bringing all of the body’s de- inflammatory reaction differ. Fast-acting media-
fences into action to repair a minor scratch, just as tors, such as vasoactive amines and the products
one would not expect a single mechanism to be able of the kinin system, modulate the immediate re-
to deal with the sudden loss of a limb or a major sponse. Later, newly synthesized mediators such as
infection. leukotrienes are involved in the accumulation and
The inflammatory reaction is phylogenetically and activation of other cells. Once leukocytes have ar-
ontogeneticaly the oldest defence mechanism. The rived at a site of inflammation, they release media-
cells of the immune system are widely distributed tors which control the later accumulation and acti-
throughout the body, but if an infection or tissue vation of other cells.
damage occurs it is necessary to concentrate them
However, in inflammatory reactions initiated by
and their products at the site of damage. Three ma-
the immune system, the ultimate control is exerted
jor events occur during this response :
by the antigen itself, in the same way as it controls
1. An increased blood supply to the tissue ”in dan- the immune response itself. For this reason, the cel-
ger”. It is performed by vasodilation. The in- lular accumulation at the site of chronic infection,
flamed tissue looks like containing greater num- or in autoimmune reactions (where the antigen can-
ber of vessels. not ultimately be eradicated), is quite different from
that at sites where the antigenic stimulus is rapidly
2. Increased capillary permeability caused by re- cleared.
traction of the endothelial cells. This permit The nervous system can also participate in the
larger molecules than usual to escape from the control of inflammation, especially axon reflexes, but
capillaries, and thus allows the soluble media- inflammation may be realized in denervated tissues
tors of immunity to reach the site of inflamma- as well.
tion.
Inflammation can become chronic. In certain set-
3. Leukocytes migrate out of the capillaries into tings the acute process, characterized by neutrophil
the surrounding tissues. In the earliest stages infiltration and edema, gives way to a predomi-
of inflammation, neutrophils are particularly nance of mononuclear phagocytes and lymphocytes.
prevalent, but later monocytes and lymphocytes This probably occurs to some degree with the nor-
also migrate towards the site of infection. mal healing process but becomes exaggerated and
chronic when there is ineffective elimination of for-
For the possibility of surrounding tissue damage, eign materials as in certain infections (e.g. tuber-
inflammatory responses must be well ordered and culosis) or following introduction of foreign bodies
controlled. The body must be able to act quickly (e.g. asbestos) or deposition of crystals (e.g. urate
9.1. Inflammation 579

crystals). Chronic inflammation is often associated may result as a tissue atrophy. In other cases, hy-
with fusion of mononuclear cells to form multinu- pertrophy or hypoplasia is the compensatory mecha-
cleated gigant cells, which eventually become granu- nism for this situation. The altered cellular activities
loma. Chronic inflammation is seen under conditions may lead to metaplasia, dysplasia, or neoplasia be-
of delayed hypersensitivity. cause aging cells are more susceptible to destruction
Main humoral and cellular components involved in of their DNA, RNA and vital proteins.
the amplification and propagation of both acute and Extremly low temperature is able to form crystals
chronic inflammation are showed in Table 9.1. inside the cell. Mild decrease in temperature causes
paralysis of vasomotors and an increase in perme-
9.1.1.2 Factors involved in cell damage ability of vessels. Blood viscosity rises proportion-
ally with the lowering temperature and cells are de-
There are two categories of factors capable to induce stroyed by hypoxia. Low temperature acting for a
the damage of cells and tissues - endogenous and ex- longer time provokes the destruction of myelin in ex-
ogenous. Endogenous damaging factors include im- posed area. Microthrombi are produced in vessels
munopathological reactions, and some neurological and they are the cause of gangrene.
and genetical disorders. Exogenous factors can be
High temperature increases the permeability of
divided into:
cell membranes. Very high temperature is respon-
sible for the coagulation of vessels and denaturation
• mechanical (traumatic injury),
of vital biopolymers, especially proteins.
• physical (extremely low or high temperature, According to the dose and the way of expo-
ionising irradiation, microwaves), sition ionizing irradiation may primarily damage
haematopoietic, gastrointestinal or neural tissues.
• chemical (caustic agents, poisons, venoms, geno- Whole-body irradiation produces nonspecific im-
toxic and proteotoxic compounds), munosupression which is the cause of increased sensi-
tivity to infection. The infection is developed mainly
• nutritive (deficiency of oxygen, vitamins and ba- due to leukopenia and the loss of physical integrity
sic nutrients), of mucosal membranes especially in the gastroin-
testinal tract. Whole-body irradiation eliminates
• biological (viruses, microorganisms, protozoan
and metazoan parasites). most of the mature lymphocytes of the immune sys-
tem while preserving the more radiation-resistant el-
Immunopathological reactions may be also trig- ements such as the thymic epithelium. Ionizing ra-
gered by exogenous antigens. Genetically caused al- diation is also used for the treatment of patient with
terations leading to inflammation are manifested by cancer and sometimes in the form of local graft irra-
destruction of membrane structures, by derangement diation. An alternative form of radiation therapy is
of transport mechanisms, or by defective activity of total lymphoid irradiation e.g. for the treatment of
some enzymes and mediators. Cell damage also oc- Hodgkin’s disease. Lethally irradiated persons can
curs during ageing. It is very complicated process be given immature bone marrow cells to reconstitute
in which genetic, metabolic, immunologic, neurolog- the immune systems.
ical and other factors are involed. In ageing cells, On the cell level, irradiation destroy important
probably metabolic intermediates such as different biopolymers (DNA, proteins) and biological mem-
free radicals, aldehydes, ketones, and their reaction branes. At first, the degenerative changes of nu-
products, or on the contrary non-degradable com- cleus and chromosomal aberrations can be seen. The
pounds are accumulated. This results in a serious increased membrane permeability and activation of
defect in the integrity and physiological homeostasis hydrolytic lysosomal enzymes disrupt cell structures
of cells and tissue. and compartments. Irreversible damage of irradiated
It seems that aging cells are losing their multi- cells causes their complete destruction, necrosis.
plication capacity at a particular generation. For in- Some chemicals, namely caustic agents and min-
stance, cultivated fibroblasts lose their ability to mul- eral acids are able to damage tissues directly, other
tiply between 40 and 60 generations. The cell aging such as heavy metals, poisons and venoms mainly
580 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

Process Effector cells and molecules

Antigen recognition:
Specific T lymphocytes, antibodies (immunoglobulins)
Nonspecific Professional phagocytes (neutrophils, eosinophils, monocytes and tissue
macrophages), alternative complement pathway, Hageman factor (coagulation
cascade)

Amplification Complement system, arachidonate products, mast cell products, platelet-

activating factor (PAF), bradykinin, serotonin, coagulation cascade, cytokines
(IFN-γ, TNF-α, IL-1, IL-6, IL-8, IL-11, chemokines, growth factors), lysosomal
contents of neutrophils

Antigen destruction Neutrophils, eosinophils, macrophages, cytotoxic lymphocytes, terminal com-

plement components and other perforins, reactive oxygen and nitrogen inter-
mediates.

Table 9.1: Components of inflammation

derange important enzymatic reactions. Metabolic sodium-potassium pump loses its operating capac-
homeostasis of cells and tissues is also disturbed by ity. This leads to the intracellular accumulation of
the action of genotoxic and proteotoxic agents. To sodium and the leakage of potassium from cells. Ac-
the often observed defects belong: destruction of cell cumulation of sodium induces the transfer of ions and
membranes, decrease of intracellular pH, release of water into cell. It is the reason of endoplasmic retic-
lysosomal enzymes and changes similar as in hypoxia ulum dilatation. The dilatation provides complete
(decrease of oxidative phosphorylation). Lysosomal damage to ribosomes and blocks proteosynthesis.
enzymes and free radicals derived from oxygen (re-
If the hypoxia continues, the whole cell is overfilled
active oxygen intermediates - ROI) or from nitrogen
with water, sodium, and chlorides. This state is still
(reactive nitrogen intermediates - RNI) have an es-
reversible, after the renewing of oxygen transport,
sential role in the damage of cell structures especially
the cell should recover. In the others cases, vacuoles
during the injuring inflammation. These substances
in the cytoplasm and the damage of mitochondrial
may be also activated by the action of many am-
membrane appear. Now, it is the irreversible pro-
phiphilic detergents that are components of different
cess. Because of the membrane damage, the extra-
cleaning and washing preparations and tooth pastes.
cellular calcium may enter the cell and accumulate in
They are dangerous if they reach inside the body
mitochondria. The production of ATP is completely
in the inappropriate amount or in the inappropriate
terminated that is thought to be the real death of
way.
cell. The cell or tissue death is performed as necro-
The oxygen deficiency is manifested in 3–5 min-
sis.
utes. In mitochondria, oxidative phosphorylation is
very quickly impaired and insufficient production of Cell damage may be also caused by different
ATP appears. Deficiency of ATP activates anaerobic gasses, especially by nitrogen oxides, sulphur dioxide,
metabolism in which ATP is formed from glycogen. carbon monoxide, formaldehyde, chlorine, etc. Car-
But the reserves of glycogen are again quickly de- bon monoxide is bound by hemoglobin with 300times
pleted. Because of persistent ATP insufficiency the higher affinity than oxygen. Therefore the exposure
9.1. Inflammation 581

to CO develops the secondary oxygen deficiency due 3. Reactions of the immune complex type. The
to the termination of oxygen transport to cells. complement system is also activated by the im-
Infections are often involved in cell damage. Viru- mune complexes. During the activation, chemo-
lence of microorganisms and the induction of inflam- tactic factors are formed which attract granulo-
mation depend on their ability to replicate in human cytes to the inflammation area. Neutrophils de-
or animal body and to destroy cellular structures. stroy target cells by released lysosomal enzymes,
During growth and multiplication, microorganisms especially by proteinases, and free radicals of
can produce and release different exotoxins which oxygen.
are potent injuring agents. Other microorganisms, 4. Reactions of delayed or cell-mediated hypersen-
after destruction or lysis, release from phospholipid sitivity. Specific subpopulation of T lympho-
and lipopolysaccharide envelops toxins known as en- cytes and several cytokines are involed in these
dotoxins. The term ”endotoxin” is generally used processes.
to refer to the thermostable polysaccharide toxin,
firmly bound to the bacterial cell, in contrast to 5. Cytotoxic reactions influencing the function of
the thermolabile protein ”exotoxin”, secreted into cell receptors. They are also mediated by au-
toantibodies that may have a function of ago-
the external environment. Endotoxin (lipolysaccha-
nists or antagonists. Hence, the autoantibodies
ride, LPS) is responsible for many pathophysiological
symptoms observed during gram-negative bacterial can pathologically stimulate and/or block the
infections. They include pyrogenicity (the ability to transfer of specific signal through the receptor.
cause an increase in body temperature), changes in It follows that cell damage following the inflamma-
the number of circulating leukocytes (leukocytope- tory reaction may be useful or harmful. The useful
nia, leukocytosis), complement activation, activation activities include:
of macrophages, aggregation of platelets, increase
of capillary permeability and others. In addition, 1. destruction of injuring and infectious agents and
LPS induces an immune response. Administration their elimination from the inflammatory site;
or release of a higher dose of endotoxin may pro- 2. limitation of spreading of injuring factors;
duce lethal shock. All these biological activities are
mediated through the endogenous mediator – tumor 3. stimulation of the specific immune response;
necrosis factor-α (TNF-α).
4. help in the healing process.
Viruses do not produce exotoxins or endotoxins.
They are typical intracellular parasites and use cells To the harmful inflammatory reactions belong au-
for their own replication. During this, damage of cell toimmune and other immunopathological processes.
structures leading to the death of cell is observed. In
addition viruses may be responsible for the tumorous 9.1.1.3 The phases of inflammation
transformation of cells.
The main purpose of inflammation, this immensely
During the immune responses, the cells may be
complex response seems to be to bring fluid, proteins,
damaged by effector cells and molecules participating
and cells from the blood into the damaged tissues. It
in immune mechanisms. From this point of view they
should be remembered that the tissues are normally
are thought to be the immunopathological responses.
bathed in a watery fluid (extracellular lymph) that
They include:
lacks most of the proteins and cells that are present
in blood, since the majority of proteins are too large
1. Immediated allergic anaphylactic reactions me- to cross the blood vessel endothelium. Thus there
diated by IgE antibodies (reagines). have to be mechanisms that allow cells and proteins
to gain access to extravascular sites where and when
2. Cytotoxic reactions during which complement they are needed if damage and infection has occured.
is activated by IgG or IgM antibodies reacting The main features of the inflammatory response
with antigens of self cells and structures (au- are, therefore: vasodilation, i.e. widening of the
toantigens) which immediately damage the tar- blood vessels to increase the blood flow to the in-
get cells and surrounding tissues. fected area; increased vascular permeability, which
582 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

allows diffusible components to enter the site; cellu- the vessel is damage, fibrinogen and fibronectin
lar infiltration by chemotaxis, or the directed move- are deposited at the site of injury, platelets ag-
ment of inflammatory cells through the walls of blood gregate and become activated, and the red cells
vessels into the site of injury; changes in biosynthetic, stack together in what are called ”rouleau” to
metabolic, and catabolic profiles of many organs; help stop bleeding and aid clot formation. The
and activation of cells of the immune system as well dead and dying cells contribute to pus forma-
as of complex enzymatic systems of blood plasma. tion.
Of course, the degree to which these occur is nor-
mally proportional to the severity of the injury and 3. If the damage is sufficiently severe, a chronic
the extent of infection. cellular response may follow over the next few
Inflammation can be divided into several phases. days. A characteristic of this phase of inflamma-
The earliest, gross event of an inflammatory re- tion is the appearance of a mononuclear cell in-
sponse is temporary vasoconstriction, i.e. narrowing filtrate composed of macrophages and lympho-
of blood vessels caused by contraction of smooth cytes. The macrophages are involved in micro-
muscle in the vessel walls, which can be seen as bial killing, in clearing up cellular and tissue de-
blanching (whitening) of the skin. This is followed bris, and they also seem to be very important in
by several phases that occur over minutes, hours and remodelling the tissues.
days later, outlined below.
4. Over the next few weeks, resolution may occur,
1. The acute vascular response follows within sec-
meaning that the normal tissue architecture is
onds of the tissue injury and last for some min-
restored. Blood clots are removed by fibrinoly-
utes. This results from vasodilation and in-
sis, and if it is not possible to return the tissue to
creased capillary permeability due to alterations
its original form, scarring results from in-filling
in the vascular endothelium, which leads to in-
with fibroblasts, collagen, and new endothelial
creased blood flow (hyperaemia) that causes
cells. Generally, by this time, any infection will
redness (erythema) and the entry of fluid into
have been overcome. However, if it has not been
the tissues (oedema). This phase of the in-
possible to destroy the infectious agents or to re-
flammatory response can be demonstrated by
move all of the products that have accumulated
scratching the skin with a finger-nail. The
at the site completely, they are walled off from
”wheal and flare reaction” that occurs is com-
the surrounding tissue in granulomatous tissue.
posed of (a) initial blanching of the skin due to
A granuloma is formed when macrophages and
vasoconstriction, (b) the subsequent rapid ap-
lymphocytes accumulate around material that
pearance of a thin red line when the capillaries
has not been eliminated, together with epith-
dilate; (c) a flush in the immediate area, gener-
eloid cells and gigant cells (perhaps derived from
ally within a minute, as the arterioles dilate; and
macrophages) that appear later, to form a ball
(d) a wheal, or swollen area that appears within
of cell.
a few minutes as fluid leaks from the capillar-
ies. It is usually terminates after several tens
Inflammation is often considered in terms of acute
minutes.
inflammation that includes all the events of the acute
2. If there has been sufficient damage to the tis- vascular and acute cellular response (1 and 2 above),
sues, or if infection has occured, the acute cellu- and chronic inflammation that includes the events
lar response takes place over the next few hours. during the chronic cellular response and resolution
The hallmark of this phase is the appearance or scarring (3 and 4).
of granulocytes, particularly neutrophils, in the In addition, a large number of more distant ef-
tissues. These cells first attach themselves to fects occur during inflammation. These include: the
the endothelial cells within the blood vessels production of acute phase proteins, including com-
(margination) and then cross into the surround- plement components, by the liver; fever, caused by
ing tissue (diapedesis). During this phase ery- pyrogens acting on the hypotalamus in the brain;
throcytes may also leak into the tissues and a and systemic immunity, resulting in part from lym-
haemorrhage can occur (e.g. a blood blister). If phocyte activation in peripheral lymphoid tissues.
9.1. Inflammation 583

9.1.2 Exudation and swelling ceed efficiently, activated Hageman factor activates
prekallikrein via a series of prekallikrein activators,
9.1.2.1 Fluid exudate resulting in the production of kallikrein. The gener-
ation of kallikrein triggers kinin production, includ-
In acute inflammation, the pressure in postcapil-
ing the formation of bradykinin, which is responsible
lary venules may overcome the osmotic pressure of
for induction pain, increasing vascular permeability,
plasma proteins. Therefore fluid and low molecular
and causing vasodilation. Kallikrein also activates
substances have the tendency to penetrate into the
the fibrinolytic pathway, leading to the removal of
surrounding area. The vascular permeability for pro-
blood clots.
teins and some smaller molecules differs from tissue
The complement cascade, as a part of the innate
to tissue. For example, the brain and thymus vessels
immune response, may be activated via the alter-
are less permeable. The sinusoids in liver and sinuses
native and/or collectin (lectin) pathway to destroy
in spleen are highly open vessels even at normal con-
some invading microorganisms. In addition, during
ditions.
activation of complement, important opsonins (C3b),
The increased capillary permeability for plasma chemotactic factors for neutrophils and mononuclear
proteins is the key factor for the production of in- phagocytes (C5a), and anaphylatoxins (C5a, C3a)
flammatory exudate. In the interstitial area, high-
are formed. They all participate in inflammation
molecular proteins may be split into smaller frag- during phagocytosis or immediate allergic reactions.
ments that participate in the raising of osmotic pres-
Immunoglobulins may act as specific or nonspe-
sure of interstitial fluid. In addition, the alteration
cific opsonins facilitating thus the process of phago-
of general matrix is observed. It becomes more fluid
cytosis, or may participate in antibody-dependent
which helps to make easier the diffusion of exudate.
cell-mediated cytotoxicity (ADCC) by which target
On the other hand, a sudden increase of pressure in
cells are destroyed by killer cells.
tissue is thus prevented.
In the fluid infiltrate, all components of plasma,
There are two phases of inflammatory infiltration. including administered drugs, are present. There-
The immediate temporary phase with a peak be- fore it is important to administer effective antibiotic
tween 8 and 10 min and duration about 30 min. It or other chemotherapy as soon as possible in order
is developed by the release of fluid from venules me- to reach the inflammatory area in the concentration
diated by histamine. This is followed by immediate similar to that in plasma.
prolonged phase which is similar, only the time of Exudative infiltrate contributes to the general
duration is greater – a few days. The second delayed signs of inflammation. It is responsible for edema
phase needs a few hours for its development. The (swelling, tumour). The increased pressure in tissue
damage to capillaries and venules is observed. may participate in the production of pain (dolor).
In the fluid exudate, all components of plasma, Actually, the pain is observed before the occurrence
including fibrinogen, kinins, complement, im- of greater edema, since also other factors such as
munoglobulins etc., are present. Fibrinogen is impor- the acidic pH of exudate, the accumulation of potas-
tant for clot formation and the prevention of further sium ions and the presence of bradykinin, serotonin
loss of blood. Fibrin, which is originated from fib- or other mediators take part in this process.
rinogen, acts as the beginning of a scaffold on which
tissues may subsequently be repaired and on which
9.1.2.2 Cellular exudate
new capillaries can be constructed, a process known
as angiogenesis. Although the rapid response of the Cellular exudate is formed during the second and the
coagulation pathway is essential, the extent of blood third phase of inflammation – acute and chronic cel-
clothing must be limited so that it does not progress lular response. During the former, neutrophils are
to undamaged vessels. In addition, the clots must ul- prevalent, whereas mononuclear cells (macrophages
timately be removed from the area of damage. This and lymphocytes) overcome later. Cell composition
is controlled by fibrinolysis (fibrin breakdown) due of exudate differ not only depending on the phase
to the enzyme plasmin. of inflammation but also on the type of inflamed
The kinins are important mediators of inflam- tissue and factors triggering inflammatory process.
matory responses. For kinin generation to pro- Central effector and regulatory functions in acute in-
584 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

flammation posses neutrophils. They are also dom- and control. The white blood cells leave the postcap-
inant when a pyogenic bacterial infection or local illarly venule by extending pseudopodia between ap-
deposition of immune complexes containing IgG are posing endothelial cells and pulling themselves into
the cause of inflammation. Mononuclear phagocytes the subendothelial space and the adjacent interstitial
represent the main infiltrating cells in subacute and compartment. This complex event, which is often
chronic phase of the majority of inflammatory reac- termed leukocyte extravasation, emigration, or dia-
tions, and in the case of infection with intracellularly pedesis, is dependent not only on an array of cellu-
parasitizing microorganisms as well. Eosinophils and lar processes including adhesion molecule expression
basophils are predominant when inflammation has and activation, but also on cytoskeletal reorganiza-
been initiated by immediate alergic reactions or by tion, and alteration in membrane fluidity.
parasites.
So, a number of different cell types are recruited 9.1.3 Cells participating in inflamma-
into the area where damage has occured, and these tion
are responsible for inactivation and removing of the
invading infectious agents, for removing the damaged 9.1.3.1 Mast cells and basophils
tissues, for inducing the formation of new tissue, and Mast cells and basophils play a central role in in-
reconstructing the damaged cell matrix, including flammatory and immediate allergic reactions. They
basement membranes and connective tissue. A new are able to release potent inflammatory mediators,
blood supply to the area is also established during such as histamine, proteases, chemotactic factors, cy-
the repair process. tokines and metabolites of arachidonic acid that act
Professional phagocytes (neutrophils, eosinophils, on the vasculature, smooth muscle, connective tis-
monocytes and tissue macrophages) are essential sue, mucous glands and inflammatory cells.
performing phagocytosis, lymphocytes are involved Mast cells settle in connective tissues and usually
in the specific immune responses, endothelial cell do not circulate in the blood stream.
in the regulation of leukocyte emigration from the Basophils are the smallest circulating granulocytes
blood into inflamed tissue and platelets with mast with relatively the least known function. They arise
cells in the production od early phase mediators. in the bone marrow, and following maturation and
The accumulation of leukocytes in inflamed tis- differentiation, are released into the blood circula-
sue results from adhesive interactions between leuko- tion. If they are adequately stimulated they may
cytes and endothelial cells within the microcircu- settle in the tissues.
lation. These adhesive interactions and the exces- Both mast cells and basophils contain special cy-
sive filtration of fluid and protein that accompa- toplasmic granules which store mediators of inflam-
nies an inflammatory response are largely confined mation. The extracellular release of the mediators is
to one region of the microvasculature – postcap- known as degranulation and may be induced by:
illary venules. The nature and magnitude of the (a) physical destruction, such as high temperature,
leukocyte-endothelial cell adhesive interactions that mechanical trauma, ionising irradiation, etc.;
take place within postcapillary venules are deter-
mined by a variety of factors, including expression of (b) chemical substances, such as toxins, venoms,
adhesion molecules on leukocytes and/or endothelial proteases;
cells, products of leukocyte (superoxide and other
ROI) and endothelial cell (nitric oxide) activation, (c) endogenous mediators, including tissue prote-
and the physical forces generated by the movement ases, cationic proteins derived from eosinophils
of blood along the vessel wall. The contribution of and neutrophils;
different adhesion malecules to leukocyte rolling, ad- (d) immune mechanisms which may be IgE-
herence, and emigration in venules will be discussed dependent or IgE-independent. The former is
later. elicited by aggregation of IgE bound to high-
This process is similar for granulocytes, mono- afinity receptors (Fc
RI) on the surface of these
cytes, and lyphocytes only different chemotactic fac- cells. Specific antigen (allergen) is responsible
tors and cytokines may be involved in its initiation for the IgE aggregation. In the IgE-independent
9.1. Inflammation 585

way, the anafylatoxins C5a, C3a and C4a are motryptic enzymes (chymase and cathepsin G-like
formed during activation of complement. Then, protease) and one mast cell carboxypeptidase en-
the degranulation is triggered through C5a- zyme, and at least two genes encoding tryptase pep-
receptors on the surface of mast cells and ba- tides have been detected. The gene encoding chy-
sophils. mase resides on chromosome 14, closely linked to
the gene encoding cathepsin G, an enzyme appar-
There are two categories of inflammatory (ana- ently expressed in mast cells and various myelomono-
phylactic) mediators in mast cells and basophils. cytic cells, and to the genes encoding granzymes,
Preformed mediators, stored in secretory granules which are expressed in cytotoxic T lymphocytes and
and secreted upon cell activation, include a bio- natural killer cells. Two types of mast cells have
genic amine, typically histamine, proteoglycans, ei- been found by immunohistochemical analyses. The
ther heparin, over-sulphate chondroitin sulphates or MCTC type contains tryptase, chymase, cathepsin G
both, and a spectrum of neutral proteases. Re- like protease and mast-cell carboxypeptidase, and
leased histamine acts at H1, H2 and H3 receptors predominates in normal skin and intestinal submu-
on cells and tissues, and is rapidly metabolized ex- cosa, whereas the MCT type contain only tryptase,
tracellularly. The proteoglycan, which imparts the and predominates in normal intestinal mucosa and
metachromatic staining characteristic of mast cells lung alveolar wall. Nearly equivalent concentrations
when exposed to certain basic dyes such as toluidine of each type are found in nasal mucosa. In MCTC
blue, has two functions: it may package histamine cells, tryptase, chymase and mast-cell carboxypepti-
and basic proteins into secretory granules, and in dase reside in macromolecular complexes with pro-
human mast cells it appears to regulate the stability teoglycan, but interestingly, tryptase reside in a sep-
of the protease called tryptase. Neutral proteases, arate complex from that in which chymase and mast-
which account for the vast majority of the granule cell carboxypeptidase are found.
protein, serve as markers of mast cells and of differ-
ent types of mast cells. The biological function of mast cell neutral pro-
Newly generated mediators, often absent in the teases, like mast cells themselves, remain to be fully
resting mast cells, are typically produced during IgE- clarified. In serum, elevated levels of tryptase are de-
mediated activation, and consist of arachidonic acid tected in systemic mast-cell disorders, such as ana-
metabolites, principally leukotriene C4 (LTC4 ) and phylaxis and mastocytosis. Ongoing mast-cell ac-
prostaglandin D2 (PGD2 ) and cytokines. Of partic- tivation in asthma appear to be a charakteristic of
ular interest in humans is the production of tumour this chronic inflammatory disease. It is detected by
necrosis factor (TNF-α), IL-4, IL-5 and IL-6. In the elevated levels of tryptase and PGD2 in bronchoalve-
cytoplasma of both mastocytes and macrophages are olar lavage fluid, higher spontaneous release of his-
special organelles – lipid bodies – where metabolism tamine by mast cell obtained from the bronchoalve-
of arachidonic acid occur and where their products, olar lavage fluid of asthmatics than non asthmat-
including leukotrienes, may be stored. ics, and ultrastructural analysis of mast cell in pul-
Mast cells are heterogeneous – two types of them, monary tissue.
mucosal and connective tissue, were reported in ro- The number of basophils and mast cells increase
dent tissue back in the 1960’s on the basis of his- at sites of inflammation. To reach these areas, ba-
tochemical and fixation characteristics that reflect, sophils must migrate from the blood into tissue sites.
in part, whether heparin proteoglycan was present A crucial step in this process is the adherence of
in secretory granules. Neutral proteases better re- cells to the endothelium. Cell adherence is medi-
flect the heterogeneity or plasticity of mast cells in ated by several families of adhesion molecules and
vivo and in vitro, particularly in humans where his- adhesion receptors in the surface of basophils and
tochemical heterogeneity is less apparent (Table 9.2). mast cells that can mediate binding to other cell
In murine mast cells, five chymases ( mouse mast and to the extracellular matrix (ECM) glycoproteins.
cell protease – MMCP-1, -2, -3, -4 and -5), one mast Upon stimulation, basophils and mast cells release
cell carboxypeptidase and two tryptases (MMCP-6 cytokines, including TNF-α and IL-4, that can mod-
and -7) have been reported. ulate adhesion molecules on endothelial cells. Acti-
In human mast cells, genes encoding two chy- vated endothelial cells express the intercellular adhe-
586 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

Mast cell type Biogenic amine Neutral protease Proteoglycan

Mouse:
Mucosal H MMCP-1,-2 Chondroitin sulphate E
Connective tissue H + 5-HT MMCP-3,-4,-5,-6, Heparin
Carboxypeptidase

Human:
MCT cells H Tryptase Heparin, chondroitin sulphate
MCTC cells H Tryptase, chymase, Heparin, chondroitin sulphate
cathepsin G-like protease,
carboxypeptidase

H: histamine; 5-HT: serotonin; MMCP: mouse mast cell protease

Table 9.2: Predominant granule mediators of mast cells

sion molecule (ICAM-1), endothelial-leukocyte ad- mast cells. Adherence of mast cells to fibroblasts,
hesion molecule (ELAM-1) and vascular cell adhe- other cells or to ECM proteins can transduce signals
sion molecule (VCAM-1) on their cell surface. Hu- that affect cell growth and differentiation.
man basophils express integrins as receptors for these The increase in the number of mast cells and ba-
molecules. sophils, and the enhanced secretion at sites of in-
flammation, can accelerate the elimination of the
Until recently, the effects of adherence on cell func-
cause of tissue injury or, paradoxically, may lead to a
tion were believed to result only from changes in cell
chronic inflammatory response. Thus, manipulating
shape and cytoskeletal organization. However, in ad-
mast-cell and basophil adhesion may be an impor-
dition to cell spreading, aggregated adhesion recep-
tant strategy for controlling the outcome of allergic
tors transduce a variety of intracellular signals that
and inflammatory responses.
regulate cell function. These signals include protein
tyrosine phosphorylation, phosphoinositide hydroly-
sis, changes in intracellular pH or calcium concentra- 9.1.3.2 Eosinophils
tion and the expression of several genes. The adhe-
The eosinophil is a terminally differentiated, end-
sion properties of basophils and mast cells regulate
stage leukocyte that resides predominantly in sub-
their migration, localization, proliferation and phe-
mucosal tissue and is recruited to sites of specific
notype.
immune reactions, including allergic diseases. The
Different mechanisms could contribute to the in- mean generation time for eosinophils in the bone
crease in the number of mast cells at sites of tissue marrow is approximately 2-6 days. They mainly set-
injury: mast cells or their progenitors could migrate tle in the tissue where their number is about one
to these sites; or resident mast-cell precursors could hundred times higher than in the blood. Like other
proliferate. Adhesion receptors and their ligands also granulocytes, they posses a polymorphous nucleus,
play a role in the localization and migration of mast although with only two lobes and no nucleolus. The
cells in normal tissues. ECM proteins that are the eosinophil cytoplasm contains large ellipsoid granules
ligands for adhesion receptors are chemotactics for with an electron-dense crystalline nucleus and par-
9.1. Inflammation 587

tially permeable matrix. In addition to these large mediators, leukotriene C4 (LTC4 ) and platelet acti-
primary crystalloid granules, there is another granule vating factor (PAF). Both mediators contract airway
type that is smaller and lacks the crystalline nucleus. smooth muscle, promote the secretion of mucus, alter
These large specific granules are the principal in- vascular permeability and elicit eosinophil and neu-
dentifying feature of eosinophils. They contain four trophil infiltration. In addition to the direct activ-
distinct cationic proteins which exert a range of bi- ities of these eosinophil-derived mediators, MBP by
ological effects on host cells and microbial targets: a non-cytotoxic mechanism can stimulate the release
major basic protein (MBP), oesinophil cationic pro- of histamine from basophils and mast cells, and EPO
tein (ECP), eosinophil derived neurotoxin (EDN), from mast cells. Thus, once stimulated, eosinophils
and eosinophil peroxidase (EPO). Basophils contain can serve as a local source of specific lipid mediators
about one fourth as much MBP as did eosinophils as well as induce the release of mediators from mast
and detectable amounts of EDN, ECP and EPO. cells and basophils.
Small amounts of EDN and ECP were also found The processes that lead to the accumulation of
in neutrophils. eosinophils within tissue sites of specific inflam-
These proteins have major effects not only on the mation, as for other leukocytes, involve numerous
potential role of eosinophils in host defence against sequential interactions that enable eosinophils to
helminthic parasites, but also in contributing to tis- adhere to and then transmigrate through the en-
sue dysfunction and damage in eosinophil related in- dothelium and to respond to local chemoattractants.
flammatory and allergic diseases. As MBP lack en- The adhesion of eosinophils to endothelium include
zymatic activity, one mechanism whereby this highly CD18-dependent pathways, interaction between E-
cationic polypeptide may exert its toxic activities selectin and P-selectin and adherence to VCAM by
is by interactions with lipid membranes leading to means of very late antigen 4 (VLA-4) expressed on
their derangement. Both MBP and EPO have been the eosinophil.
shown to act as selective allosteric inhibitors of ago- The eosinophil granule content is released follow-
nist binding to M2 muscarinic receptors. Thus, these ing similar stimuli to neutrophil granules (e.g. during
proteins may contribute to M2 receptor dysfunction phagocytosis of opsonized particles and by chemotac-
and enhance vagally mediated bronchoconstriction tic factors). However, whereas the neutrophil lyso-
in asthma. EDN specifically damage the myelin coat somal enzymes act primarily on material engulfed in
of neurons. phagolysosomes, the eosinophil granule content act
In addition, histaminase and a variety of hy- mainly on extracellular target structure such as par-
drolytic lysosomal enzymes are also present in the asites and inflammatory mediators.
large specific granules. The eosinophil functional activity, like the im-
Among the typical small granule enzymes are aryl mune response in general, may be beneficial or harm-
sulphatase, acid phosphatase and a 92 kDa metallo- ful for the organism. Compared to neutrophils,
proteinase, a gelatinase. eosinophils have limited phagocytic activity which is
Only recently has it been recognized that mainly aimed at killing multicellular parasites. An-
eosinophils are capable of elaborating cytokines other beneficial activity is the inactivation of me-
which include those with potential autocrine growth- diators of anaphylaxis. Thus, for example, acyl-
factor activities for eosinophils and those with po- sulphatase B may inactivate the slow-reacting sub-
tential roles in acute and chronic inflammatory re- stance of anaphylaxis (SRS-A, a mixture of LTC4 ,
sponses. Three cytokines have growth-factor activi- LTD4 and LTE4 ), phospholipase D destroys the
ties for eosinophils: granulocyte-macrophage colony- platelet lytic factor, histaminase degrades histamine
stimulating factor (GM-CSF), IL-3 and IL-5. Other and lysophospholipase (phospholipase B) may inac-
cytokines produced by human eosinophils that may tivate the membrane-active lysophosphatides.
have activities in acute and chronic inflammatory re- In addition to the acute release of protein, cytokine
sponses include IL-1α, IL-6, IL-8, TNF-α and both and lipid mediators of inflammation, eosinophils
transforming growth factors, TGF-α and TGF-β. likely contribute to chronic inflammation, includ-
Eosinophils also participate in hypersensitivity re- ing the development of fibrosis. Eosinophils are
actions, especially through two lipid inflammatory the major source of the fibrosis-promoting cytokine
588 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

TGF-β in nodular sclerosing Hodgkin’s disease. Ad- state of preactivation that enable a more powerful
ditional roles for the eosinophil in modulating extra- response to be generated once microbial activity is
cellular matrix deposition and remodeling are sug- initiated.
gested by studies of normal wound healing. During
dermal wound healing eosinophils infiltrate into the
wound sites and sequentially express TGF-α early, 9.1.3.3.1 Neutrophil granules The neutrophil
and TGF-β later, during wound healing. granules are of major importance for neutrophils
function. When referring to phagocytes or leuko-
cytes in general, the term granule is used more often
9.1.3.3 Neutrophils, central cells in acute in- than lysosome. The terms are not fully equivalent;
flammation the term granules was originally derived from mor-
Neutrophils, which are also known as polymorphonu- phological observations whereas the term lysosomes
clear leukocytes (PMN), represent 50 to 60 % of the is based on functional and biochemical characteris-
total circulating leukocytes and constitute the ”first tics of these cell organelles. Not all organelles that
line of defence” against infectious agents or ”non- look like granules are necessarily typical lysosomes.
self” substances that penetrate the body’s physical The granules of neutrophils are generated during cell
barriers. Once an inflammatory response is initiated, differentiation; they are produced for storage rather
neutrophils are the first cells to be recruited to sites than continually. On the basis of function and en-
of infection or injury. Their targets include bacteria, zyme content, human neutrophil granules can be di-
fungi, protozoa, viruses, virally infected cells and tu- vided into three main types - azurophil, specific and
mour cells. Their development in the bone marrow small storage granules. Their function is not just
takes about two weeks; during this period, they un- to provide enzymes for hydrolytic substrate degra-
dergo proliferation and differentiation. During mat- dation - as in classical lysosomes – but also to kill
uration, they pass trough six morphological stages: ingested bacteria and, finally, to secrete their con-
myeloblast, promyeloblast, myelocyte, metamyelo- tents to regulate various physiological and patho-
cyte, non-segmented (band) neutrophil, segmented logical processes, including inflammation. Individual
neutrophil. The segmented neutrophil is a fully func- granule populations can be characterized morpholog-
tionally active cell. It contains cytoplasmic granules ically (e.g. azurophil granules are larger and contain
(primary or azurophil and secondary or specific) and more electron-dense material than specific granules),
a lobulated chromatin-dense nucleus with no nucle- or biochemically using enzyme markers or other sub-
olus. The bone marrow of a normal healthy adult stances (Table 9.3).
produces more than 1011 neutrophils per day and Neutrophil granules contain antimicrobial or cy-
more than 1012 per day in settings of acute inflam- totoxic substances, neutral proteinases, acid hydro-
mation. Upon release from the bone marrow to the lases and a pool of cytoplasmic membrane receptors.
circulation the cells are in a nonactivated state and Among azurophil granule constituents myeloperox-
have a half-life of only 4 to 10 h before marginating idase (MPO) is a critical enzyme in the conversion
and entering tissue pools, where they survive for 1 of hydrogen peroxide to hypochlorous acid. Together
to 2 days. Cells of the circulating and marginated with hydrogen peroxide and a halide cofactor it forms
pools can exchange with each other. Senescent neu- the most effective microbicidal and cytotoxic mech-
trophils are thought undergo apoptosis (programmed anism of leukocytes - the myeloperoxidase system.
cell death) prior to removal by macrophages. The MPO is responsible for the characteristic green color
viability is significantly shorter in individuals suffer- of pus.
ing from infectious or acute inflammatory diseases Defensins, which constitute 30 to 50 % of
when the tissue requirement for newly recruited neu- azurophilic granule protein, are small (molecule
trophils increases considerably. weight < 4 000) potent antimicrobial peptides that
Subpopulations of neutrophils have been identi- are cytotoxic to a broad range of bacteria, fungi and
fied by various criteria. These cells exist not only in some viruses. Their toxicity may be due to mem-
dormant (resting) or activated states but also in var- brane permeabilization of the target cell which is
ious intermediate stages. For, example, priming is a similar to other channel-forming proteins (perforins).
mechanism whereby dormant neutrophils acquire a Bacterial permeability-increasing (BPI) protein is
9.1. Inflammation 589

Constituents Granules

Azurophil Specific Small storage

Antimicrobial Myeloperoxidase Lysozyme

Lysozyme Lactoferrin
Defensins
BPI

Neutral proteinases Elastase Collagenase Gelatinase

Cathepsin G Complement Plasminogen
Proteinase 3 activator activator

Acid hydrolases Cathepsin B Cathepsin B

Cathepsin D Cathepsin D
β-D-Glucuronidase β-D-Glucuronidase
α-Mannosidase α-Mannosidase
Phospholipase A2 Phospholipase A2

Cytoplasmic membrane CR3, CR4

receptors FMLP receptors
Laminin receptors

Others Chondroitin Cytochrome b558 Cytochrome b558

-4-sulphate Monocyte-chemotactic factor
Histaminase
Vitamin B12
binding protein

BPI: bactericidal permeability-increasing protein

FMLP: N-formylmethionyl-leucyl-phenylalanine

Table 9.3: Enzymes and other constituents of human neutrophil granules

also a member of perforins. It is highly toxic to gram- Serine proteases such as elastase and cathepsin G
negative bacteria but not to gram-positive bacteria hydrolyze proteins in bacterial cell envelopes. Sub-
or fungi and can also neutralize endotoxin, the toxic strates of granulocyte elastase include collagen cross-
lipopolysaccharide component of gram-negative bac- linkages and proteoglycans, as well as elastin com-
terial cell envelope. ponents of blood vessels, ligaments, and cartilage.
Cathepsin D cleaves cartilage proteoglycans, whereas
Lactoferrin sequesters free iron, thereby prevent- granulocyte collagenases are active in cleaving type I
ing the growth of ingested microorganisms that sur- and, to a lesser degree, type III collagen from bone,
vive the killing process and increases bacterial per- cartilage, and tendon. Collagen breakdown prod-
meability to lysozyme.
590 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

ucts have chemotactic activity for neutrophils, mono- Opsonization is a process, in which opsonins ad-
cytes, and fibroblasts. sorb to the surface of bacteria or other particles and
Regulation of tissue destructive potential of lysoso- facilitate their adherence to the phagocyte cytoplas-
mal proteases is mediates by protease inhibitors such mic membrane through opsonin receptors. Specific
as α2 -macroglobulin and α1 -antiprotease. These an- binding between the particle and phagocyte which
tiproteases are present in serum and synovial flu- occurs during immune phagocytosis is mediated by
ids. They are thought to function by binding to immunoadherent receptors. There are two types
and covering the active sites of proteases. Protease- of immunoadherent receptors: Fc-receptors mainly
antiprotease imbalance is probably important in the for IgG antibodies (FcR) and complement receptors
pathogenesis of emphysema. (CR1, CR3). It means that function of opsonins in
the first case is realized by antibodies and in the sec-
Azurophil granules function predominantly in the
ond case by iC3b. Specific binding between the par-
intracellular milieu (in the phagolysosomal vacuole),
ticle and phagocyte may be also performed by lectins
where they are involved in the killing and degrada-
and lectin receptors (lectinophagocytosis).
tion of microorganisms. On the other hand, neu-
trophil specific granules are particularly susceptible To the phagocytosis itself chemotaxis of phago-
to release their contents extracellularly and appear cytes precede into the site where phagocytosable ma-
to have an important role in initiating inflammation. terial occurs. This is regulated by chemotactic fac-
Specific granules represent an intracellular reservoir tors generated by infectious agents themselves, as
of various plasma membrane components including well as those release as a result of their initial con-
cytochrome b558 (component of NADPH oxidase, en- tact with phagocytes and other components of the
zyme responsible for the production of superoxide), immune system.
receptors for complement fragment iC3b (CR3, CR4) Phagocytosis is a complex process composed of
for laminin, and formylmethionyl-peptide chemoat- several morphological and biochemical steps. Af-
tractants. In addition, there is also histaminase ca- ter recognition and particle binding to the phagocyte
pable for the degradation of histamine, vitamin B12 surface, ingestion (engulfment), phagosome origina-
binding protein, plasminogen activator (responsible tion, phagolysosome formation (fusion of phagosome
for plasmin formation and cleavage of C5a from C5) with lysosomes), killing and degradation of ingested
and others. cells or other material proceed. Simultaneously with
The importance of neutrophil granules in inflam- the recognition and particle binding a dramatic in-
mation is apparent from studies of several patient crease in oxygen consumption (the respiratory burst)
with congenital abnormalities of the granules. Pa- is observed. It is responsible for the production of
tients with Chédiak-Higashi syndrome have a pro- superoxide and other oxygen radicals, and also for
found abnormality in the rate of establishment of the secretion of a variety of enzymes and biologically
an inflammatory response and have abnormally large active substances controlling inflammatory and cy-
lysosomal granules. The congenital syndrome of spe- totoxic reactions.
cific granule deficiency is an exceedingly rare disorder During phagocytosis, cytosolic granules (lyso-
characterized by diminished inflammatory responses somes) fuse with the invaginating plasma membrane
and severe bacterial infections of skin and deep tis- (around the engulfing microorganism) to form a
sues. phagolysosome into which they release their con-
tents, thereby creating a higly toxic microenviron-
ment. This step is of the first importance because
9.1.3.3.2 Neutrophils in host defence The during it two categories of cytotoxic substances,
major role of neutrophils is to phagocytose and de- present in the preformed state in azurophil and spe-
stroy infectious agents but they also limit the growth cific granules and synthesized de novo during the
of some microbes, thereby buying time for adaptive respiratory burst, arrive at the same cell compart-
(specific) immunological responses. With many mi- ment. This degranulation normally prevents release
crobes, however, neutrophil defences are ineffective of the toxic components into the extracellular milieu.
in the absence of opsonins and various agents that However, some target may be too large to be fully
amplify the cytotoxic response. phagocytosed or they avoid engulfment, resulting in
9.1. Inflammation 591

frustrated phagocytosis in which no phagosome is with the anhanced respiratory burst has been de-
formed. These may be killed extracellularly. How- tected in the blood of people with an acute bacte-
ever, tissue damage occurs when neutrophil microbi- rial infection and patients with the adult respira-
cidal products are released extracellularly to such an tory distress syndrome (ARDS). This is a good ex-
extent that host defences (antioxidant and antipro- ample of the neutrophil paradox. Neutrophils have
tease screens) in the immediate vicinity are over- been implicated in the pathology of this condition
whelmed. because of the large influx of these cells into the
The importance of neutrophils in fighting bacterial lung and the associated tissue damage caused by
and fungal infections is well recognized. Recently, it oxidants and hydrolytic enzymes released from ac-
has been shown that neutrophils are in abundance tivated neutrophils. The impairment of neutrophil
also in virally induced lesions. Neutrophils bind to microbicidal activity that occurs as the ARDS wors-
opsonized viruses and virally infected cells via anti- ens may be a protective response on the part of the
body (Fc) and complement (iC3b) receptors. Viruses host, which is induced locally by inflammatory prod-
such as influenza can be inactivated by neutrophils ucts. This ”down-regulation” of neutrophil function
trough damage to viral proteins (e.g. hemagglutinin may explain why many of these patients eventually
and neuraminidase) mediated by the myeloperoxi- die from overwhelming pulmonary infections.
dase released during degranulation. In contrast to The acute phase of thermal injury is also associ-
these acute diseases, chronic influenza infections can ated with neutrophil activation, and this is followed
diminish or exhaust the microbicidal potency of neu- by a general impairment in various neutrophil func-
trophils. tions. Activation of neutrophils by immune com-
plexes in synovial fluid contributes to the pathology
of rheumatoid arthritis. Chronic activation of neu-
9.1.3.3.3 Neutrophils and host tissue dam-
trophils may also initiate tumour development be-
age Although neutrophils are essential to host de-
cause some ROI generated by neutrophils damage
fence, they have also been implicated in the pathol-
DNA and proteases promote tumour cell migration.
ogy of many chronic inflammatory conditions and
ischemia-reperfussion injury. Hydrolytic enzymes of In patient suffering from severe burns, a strong
neutrophil origin and oxidatively inactivated pro- correlation has been established between the onset
tease inhibitors can be detected in fluid isolated of bacteremic infection and reduction in the propor-
from inflammatory sites. Under normal conditions, tion and absolute numbers of neutrophils positive for
neutrophils can migrate to sites of infection with- antibody and complement receptors.
out damage host tissues. This damage may occur Oxidants of neutrophil origin have also been shown
through several independent mechanisms. These in- to oxidize low-density lipoproteins (LDL) which are
clude premature activation during migration, extra- then more effectively bound to the plasma membrane
cellular release of toxic products during the killing of of macrophages through specific scavenger receptors.
some microbes, removal of infected or damage host Uptake of these oxidized LDL by macrophages is
cells and debris as a first step in tissue remodeling, or thought to initiate atherosclerosis.
failure to terminate acute inflammatory responses. In addition, primed neutrophils have been found
Ischemia-reperfusion injury is associated with an in people with essential hypertension, Hodgkin’s
influx of neutrophils into the affected tissue and sub- disease, inflammatory bowel disease, psoriasis, sar-
sequent activation. This may be triggered by sub- coidosis, and septicaemia, where priming corre-
stances released from damaged host cells or as a con- lates with high concentrations of circulating TNF-α
sequence of superoxide generation through xantine (cachectin).
oxidase. Hydrolytic damage to host tissue and therefore
Under normal conditions, blood may contain a chronic inflammatory conditions may occur only
mixture of normal, primed, activated and spent neu- when antioxidant and antiprotease screens are over-
trophils. In the inflammatory site, mainly activated whelmed. Antiprotease deficiency is thought to be
and spent neutrophils are present. Activated neu- responsible for the pathology of emphysema. Many
trophils have enhanced production of reactive oxygen antiproteases are members of the serine protease in-
intermediates (ROI). A subpopulation of neutrophils hibitor (SERPIN) family. Although the circulation is
592 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

rich in antiproteases, these large proteins may be se- cells. The first type is represented by reactive oxy-
lectively excluded at sites of inflammation because gen intermediates which are formed in neutrophils by
neutrophils adhere hightly to their targets. Ox- the activity of NADPH oxidase, the enzyme of the
idative stress may initate tissue damage by reduc- respiratory burst. The second type includes reactive
ing the concentration of extracellular antiproteases nitrogen intermediates, the first member of them, ni-
to below the level required to inhibit released pro- tric oxide being produced by nitric oxide synthase.
teases. Chlorinated oxidants and H2 O2 can inacti-
vate antiproteases such as α1 -protease inhibitor and Reactive oxygen intermediates (ROI)
α2 -macroglobulin (which are endogenous inhibitors Upon activation neutrophils and mononuclear
of elastase) but, surprisingly, simultaneously acti- phagocytes have increased oxygen consumption, a
vate latent metalloproteases such as collagenases and process known as the respiratory burst. During this,
gelatinase, which contribute to the further inactiva- oxygen is univalently reduced by NADPH oxidase to
tion of antiproteases. superoxide anion or its protonated form, perhydroxyl
Cytoplasmic constituents of neutrophils may also radical, which then is catalytically converted by ac-
be a cause of formation of specific anti-neutrophil cy- tion of superoxide dismutase to hydrogen peroxide:
toplasmic antibodies (ANCA) which are closely re-
lated to the development of systemic vasculitis and O2 + e− + H+ −→ HO·2 = · O−
2 +H
+
glomerulonephritis. ANCA are antibodies directed · O− + · O− + 2H+ −→ O + H O
against enzymes that are found mainly within the 2 2 2 2 2

azurophil or primary granules of neutrophils. There

are three types of ANCA that can be distinguished NADPH oxidase is an electron transport chain
by the patterns they produce by indirect immunoflu- found in the wall of the endocytic vacuole of pro-
orescence when tested on normal ethanol-fixed neu- fessional phagocytes and in B and T lymphocytes.
trophils. Diffuse fine granular cytoplasmic fluores- It is so called because NADPH is used as an elec-
cence (cANCA) is typically found in Wegener’s gran- tron donor to reduce oxygen to superoxide and hy-
ulomatosis, in some cases of microscopic polyarteri- drogen peroxide. NADPH oxidase is a complex en-
tis and Churg Strauss syndrome, and in some cases zyme composed at least of five members. Two of
of crescentic and segmental necrotising glomeru- them are p21phox and gp91phox subunits of a very un-
lonephritis, but is rare in other conditions. The tar- usual flavocytochrome b558 in the cytoplasmic mem-
get antigen is usually proteinase 3. Perinuclear fluo- brane. Two cytosolic proteins (p47phox , p67phox ), a
rescence (pANCA) is found in many cases of micro- qiunone, and a Rac-related GTP-binding protein are
scopic polyarteritis and glomerulonephritis. These thought to be the other functional components of this
antibodies are often directed against myeloperoxi- electron transport system. (phox meas ”phagocyte
dase but other targets include elastase, cathepsin G, oxidase”, p – protein, and gp – glycoprotein). The
lactoferrin, lysozyme and β-D-glucuronidase. The NADPH oxidase system is dissociated and thus in-
third group designated ”atypical” ANCA includes active in dormant neutrophils. While some com-
neutrophil nuclear fluorescence and some unusual cy- ponents are membrane bound, others are stored in
toplasmic patterns and while a few of the target anti- the cytosol. Upon activation, the cytosolic compo-
gens are shared with pANCA, the others have not nents translocate to the plasma membrane to assem-
been identified yet. ble the active oxidase. The absence of, or an ab-
pANCA are also found in a third of patients with normality in, any one of these components result in
Crohn’s disease. The reported incidence of ANCA chronic granulomatous disease (CGD) characterized
in rheumatoid arthritis and SLE varies considerably by the absence of respiratory burst from neutrophils
but the patterns are predominantly pANCA and and monocytes of these patients. The children suf-
atypical ANCA. fer from repeated infections that respond poorly to
conventional therapy and almost invariably lead to
early death.
9.1.3.3.4 Free radicals produced by neu- Superoxide anion (· O−2 is both a one-electron re-
trophils Two types of free radicals are produced ductant and a one-electron oxidant that can pass
by neutrophils, macrophages, endothelial and other through cell membrane via anion channels. It apears
9.1. Inflammation 593

that superoxide does not have direct toxic effects on ditions. For example pulmonary diseases in which
targets but, rather exerts its toxicity by penetration oxygen radicals are thought to be involved include
to important sites where it subsequently is converted ARDS, hyperoxia, asbestosis, silicosis, paraquat tox-
to other ROI. Hydrogen peroxide (H2 O2 ), hydroxyl icity, bleomycin toxicity, cigarette smoking, ionizing
radical (· OH) and singlet oxygen are of the first im- radiation and others.
portance of them. ROI are highly toxic also for producing cells.
Hydrogen peroxide interacts with myeloperoxi- Therefore neutrophils have to contain large reserves
dase (MPO), contained in neutrophil azurophil gran- of endogenous antioxidants such as glutathione and
ules to produce hypochlorous acid, which is metabo- ascorbate. Their ability to maintain these antioxi-
lized to hypochlorite (bleach) and chlorine: dants in the reduced state during phagocytosis may
MPO
prevent death from oxidative suicide.
H2 O2 + Cl− + H+ −→ H2 O + HOCl
Reactive nitrogen intermediates (RNI)
 H+ + OCl−
HOCl 
They are sometimes also called reactive oxynitro-
HOCl + Cl− −→ Cl2 + OH− gen intermediates (RONI). The pathway by which
they are originated is an oxidative process in which
Hydroxyl radical (· OH) is formed by several ways short-lived nitric oxide (NO· ) is derived from the
from which decomposition of H2 O2 catalyzed by guanidino nitrogen in the conversion of L-arginine
Fe2+ is the most important: to L-citrulline. This reaction is catalysed by NO·
synthase and, like the respiratory burst, it involves
Fe2+ + H2 O2 −→ Fe3+ + OH− + · OH oxygen uptake.
Three distinct isoform of nitric oxide synthase
This reaction is supposed to be involved, for in- (NOS) representing three distinct gene products have
stace, in asbestosis because asbestos contains high been isolated and purified. The three isoforms vary
concentrations of iron. The toxicity of · OH is be- considerably in subcellular location, structure, ki-
lieved to result from the ability of · OH to serve as a netics, regulation, and hence functional roles (Ta-
powerful one-electron oxidant capable of abstracting ble 9.4).
electrons from a large variety of compounds with the Two of the enzymes are constantly present and
formation of a new radical, which can oxidize other termed constitutive NOS (cNOS). The endothelial
substances: cNOS is mostly membrane bound and formed only
in endothelial cells. The neuronal cNOS was identi-
· OH + R −→ OH− + R· fied in the cytosol of central and peripheral neurons.
NO· derived from the cNOS isoform act as a physio-
Hydroxyl radical and hypochlorite are the most logic regulator by relaxing vascular smooth muscle or
powerfull substances involved in microbicidal and cy- by functioning as a neurotransmitter. These isoforms
totoxic reactions. HOCl is 100 to 1000 times more ef- produce small amounts of NO· for short periods in
fective than H2 O2 . Furthermore, HOCl-induced cell a calcium/calmodulin dependent manner upon stim-
death occurs very rapidly in comparison to that me- ulation. Endothelial cNOS with the endothelial cell
diated by H2 O2 . acting as a signal transducer, releases NO· contin-
Singlet oxygen (1 O2 ) is an oxygen form whose elec- uously in varying amounts to regulate blood vessel
trons are excited at a higher energy level compared to tone and thus also the blood flow and pressure. Large
the normal (ground) triplet oxygen. When returning amounts of NO· produced in a prolonged time may
to the ground state they emit light (chemiluminis- cause vasodilalation and hypotension, whereas insuf-
cence) which may have antimicrobial and cytotoxic ficient NO· formation may be involved in hyperten-
effects. sion. It seems that NO· plays a fundamental role in
These oxidants also promote the margination of the regulation of the cardiovascular system. The or-
neutrophils by triggering the expression of adhesion ganic nitrates used as vasodilatation drugs for many
molecules on endothelial cells. years spontaneously release or are biotransformed to
ROI are involved in a variety of pathological con- the active form which is NO· Within the CNS, NO·
594 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

Characteristic Endothelial cNOS Neuronal cNOS Inducible NOS

Depency on Ca2+ , calmodulin Ca2+ , calmodulin Independent

Molecular weight x103 150–160 150–160 132

Chromosomal location 7q35–36 12q24.2 17q11–12

Producing cells Endothelial Neurons Macrophages, monocytes,

Kuppffer’s cells neutrophils,
hepatocytes, myocytes,
chondrocytes, smooth
muscle cells

Inductors of No No LPS, TNF–α, IL–1,

biosynthesis IFN–γ, GM–CSF

Inhibition by Yes Yes Yes

L–arginine analogs

Inhibition by No No Yes
glucocorticoids

Table 9.4: Isoforms of human NO· synthase and their characteristics

is released in response to increases in intracellular observed in the case of IL-4, IL-8, IL-10, TGF-
Ca2+ that follow stimulation of glutamate receptors β (transforming growth factor), PDGF (platelet-
and may be classified as a mediator of slow synap- derived growth factor) and MDF (macrophage de-
tic transmission. A second function for NO· within activating factor).
the CNS may relate to the toxic effects because its NO· may react with superoxide to form highly
increased release may lead to epileptic seizures and toxic peroxynitrite anion:
brain damage.
The third isoform of NOS is not present in rest- NO· + · O−
2 −→ ONOO
−

ing cells but instead the cells must be induced to

express the enzyme, thus the name inducible NOS which may be transformed in an acid milieu to
(iNOS). Stimuli typically include cytokines and/or peroxynitrite acid and then to hydroxyl radical:
lipopolysaccharide (LPS), and once expressed the
enzyme generates large amounts of NO. A number ONOO− + H+ −→ ONOOH
of cytokines is involved in the production of iNOS.
Among them IFN-γ, IL-1, IL-6, THF-α, GM-CSF ONOOH −→ · OH + NO· −→ NO− + H+2 3
(granulocyte-macrophage colony stimulatory factor)
and PAF (platelet activating factor) exert the stim- Independent pathways are involved in the sythe-
ulatory effect whereas the suppression has been sis of ROI and RNI. Dormant neutrophils produced
9.1. Inflammation 595

NO· continuously but activation arrest this pathway Induced NO· synthesis was reported in inflam-
in favor of the oxidative burst. Thus, although the matory responses initiated by microbial products
ROI and RNI pathways are independent, they may or autoimmune reactions and also in the systemic
compete for common substrates such as NADPH inflammatory response, also referred to as sepsis.
and O2 and exert other modulating effects on each NO· likely participates in the inflammatory reaction
other. The steady-state production of these species and subsequent joint destruction in some types of
may dictate the anti/proinflammatory balance. Mi- arthritis. For instace synovial fluid from patients
crobial killing appears to ROI dependent in normal with osteoarthritis exhibits elevated nitrate concen-
neutrophils but RNI may play a role in cells with trations (nitrate are end products of the L-arginine-
deficiences in the NADPH oxidase/MPO pathways. NO synthase pathway). There is also evidence for
Nitric oxide may also contribute to the microbicidal chronic expression of iNOS in the smooth muscle in
activity of neutrophils by reacting with ROI to form atherosclerotic aortic aneurysms, a disease in which
secondary cytotoxic species such as peroxynitrite. there is progressive dilatation and destruction of the
The main role of neutrophil-derived NO· may be aortic wall leading often to fatal rupture.
to facilitate the migration of neutrophils from blood
vessels to surrounding tissue by causing vasodilata- 9.1.3.3.5 Regulation of neutrophil function
tion. NO· facilitates relaxation of vascular smooth Under normal conditions, neutrophils roll along mi-
muscle, and ROI initiate vasoconstriction through crovascular walls via low affinity interaction of se-
the production of superoxide, which removes NO. In lectins with specific endothelial carbohydrate lig-
addition NO· inhibits neutrophil adhesion to vascu- ands. During the inflammatory response, chemotac-
lar endothelium and this may prevent inflammatory tic factors of different origin and proinflammatory cy-
and ischemia-reperfusion injuries. tokines signal the recruitment of neutrophils to sites
of infection and/or injury. This leads to the activa-
The basis of the functional activity of NO· is tion of neutrophil β2 -integrins and subsequent high-
its dual actions on some enzymes of target cells. afinity binding to intercellular adhesion molecules on
The small amount of NO· released by cNOS iso- the surface of activated endothelial cells in postcap-
forms is adequate to activate the known NO- illary venules. Under the influence of a chemotac-
sensitive enzymes (guanylate cyclase and ADP- tic gradient, generated locally and by diffusion of
ribosyl-transferase) and participate in NO signal- chemoattractants from the infection site, neutrophil
ing pathways. The larger amounts of NO· gener- penetrate the endothelial layer and migrate through
ated by iNOS may also activate the NO-sensitive connective tissue to sites of infection (diapedesis),
enzymes, but in many cell types the high out- where they finally congregate and adhere to extra-
put of NO· also exceed the necessary concentra- cellular matrix components such as laminin and fi-
tion threshold to inhibit the action of certain iron- bronectin. A wide variety of adhesion molecules have
containing enzymes, namely aconitase, NADPH- been characterized on the surface of phagocytic cells
ubiquinone oxidoreductase, succinate-ubiquinone ox- and will be shown later.
idoreductase, ribonucleotide reductase, NADPH oxi-
Cytokines are basic regulators of all neutrophil
dase and glyceraldehyd-3-phosphate dehydrogenase.
functions. Many of them including hematopoietic
Activation of soluble guanylate cyclase by NO· growth factors and pyrogens have shown to be potent
leads to the synthesis of cGMP, which leads to re- neutrophil priming agents. Neutrophils also synthe-
laxantion of vascular smooth muscle cells, inhibition size and secrete small amounts of some cytokines in-
of platelet adherence, aggregation, inhibition of neu- cluding IL-1, IL-6, IL-8, TNF-α, and GM-CSF; they
trophil chemotaxis, and signal transduction in the may act in an autocrine or paracrine manner. The
central and peripheral nervous system. pyrogenic cytokines, IL-1, TNF-α, and IL-6 all prime
NO· causes autoribosylation of glyceraldehyde-3- various pathways that contribute to the activation of
phosphate dehydrogenase, which inactivates this gly- NADPH oxidase. Pro-inflammatory cytokine IL-8,
colytic enzyme. NO· also inhibits three mitochodrial which is also known as neutrophil-activating factor,
enzymes: aconitase of the Krebs cycle and NADPH is also a potent chemoattractant; it synergizes with
ubiquinone oxidoreductase and succinate-ubiquinone IFN-γ, TNF-α, GM-CSF, and G-CSF to amplify
oxidoreductase of the electron transport chain. various neutrophil cytotoxic functions. Cytokines
596 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

also increase the microbiostatic and killing capac- catecholamines are involved in the neutrophil regula-
ities of neutrophils against bacteria, protozoa and tion. Growth hormone primes the oxidative burst of
fungi. IFN-γ and GM-CSF independently amplify human neutrophils. This is initiated by growth hor-
neutrophil antibody-dependent cytotoxicity. Anti- mone to the prolactin (and not the growth hormone)
inflammatory cytokines, IL-4 and IL-10 inhibit the receptor on neutrophils in a zinc-dependent process.
production of IL-8 and the release of TNF-α and The growth-promoting effects of growth hormone are
IL-1 which reflects in the blockade of neutrophil ac- mediated through insulin-like growth factor 1, which
tivation. is also a strong neutrophil-priming agent. Prolactin,
Furthermore, some cytokines prolong neutrophil which shares considerable functional and structural
survival. The acute inflammatory response may similarities with growth hormone, is also a strong
be terminated by the secretion of macrophage in- immunopotentiating agent. Prolactin primes the ox-
flammatory protein-1α (MIP-1α) from neutrophils; idative burst of neutrophils and macrophages to the
this protein may signal mononuclear cell recruit- same intensity as that induced by growth hormone.
ment and clear neutrophils from the affected tis- Although glucocorticoids and opioids may enhance
sue site. All these cytokines are produced by neu- some immune responses at very low concentrations,
trophils themselves and/or by lymphocytes, mono- they are generally considered to be immunosuppres-
cytes/macrophages or endothelial cells. sive. These contrasting responses may be controlled
Along to cytokines other mediators, including by the presence of multiple receptors for the same
bioactive lipids, neuroendocrine hormones, his- mediator that are coupled to stimulatory and in-
tamine, and adenosine, are also involved in the reg- hibitory pathways. In fact, containment of the stress
ulation of neutrophil activation. response may be the principal role of glucocorticoids.
Bioactive lipids originate mainly from arachi- Glucocorticoids severely impair the phagocytic and
donic acid which is an abundant constituent of cytotoxic activities of neutrophils and macrophages,
neutrophil membranes. Arachidonic acid is me- their capacity to produce ROI and to induce iNOS,
tabolized to prostaglandins, leukotrienes and lipox- and secrete lysosomal enzymes in response to acti-
ins. LTB4 is a strong neutrophil chemoattractant vation. Oxidative burst of professional phagocytes
that may play a role in the priming process. Va- is also inhibited with epinephrine and β-endorphin
soactive leukotrienes LTC4 , LTD4 and LTE4 in- which activity is mediated via nonopioid receptors.
crease microvascular permeability and may con- Histamine is a potent inhibitor of neutrophil mi-
tribute to ischemia-reperfusion injury. In contrast crobicidal activity. Adenosine provides an interest-
to leukotrienes, prostaglandins suppress most neu- ing example of how a single mediators may play
trophil functions, possibly through their ability to el- dual roles. Adenosine, a vasodilator, is a potent
evate intracellular cAMP. Lipoxins LXA4 and LXB4 anti-inflammatory agent released from damaged host
are potent inhibitors of neutrophil microbicidal ac- cells. Neutrophil chemotaxis is activated by adeno-
tivity. sine occupancy of A1 receptors and inhibition of
In many inflammatory conditions, the level of the respiratory burst triggered through A2 receptors.
platelet-activating factor (PAF) rise in the affected Adenosine suppresses the respiratory burst only if it
tissues, but injury can be attenuated by PAF antag- is added before the triggering agent, but it has no
onists. PAF directly primes superoxide generation effect on the initiation or progress of degranulation.
and elastase release. The interactions between platelets and neutrophils
The major ”stress hormones” are involved in the are essential for both cell types. Activated platelets
regulation of inflammation at both the systemic can bind to neutrophils and stimulate the oxidative
and, perhaps, local levels. The bidirectional in- burst while themselves synthesize vasoconstrictive
teractions of cytokines and neurotransmitters with leukotrienes. Like prostaglandins, many immuno-
nervous and immune cells, respectively, provide a suppressive mediators use cAMP as a second messen-
means of indirect chemical communication between ger. Increased intracellular cAMP in neutrophils is
the neuroendocrine and immune systems. From associated with decreases in a number of microbicidal
the neuroendocrine hormones mainly growth hor- functions. Phagocyte priming and activation may, in
mone, prolactin, β-endorphin, glucocorticoids and fact, be controlled by shifts in the intracellular ratio
9.1. Inflammation 597

of cGMP to cAMP, since cGMP is stimulatory. Macrophages can be divided into normal and
inflammatory macrophages. Normal macrophages
9.1.3.4 Macrophages and monocytes includes macrophages in connective tissue (his-
tiocytes), liver (Kupffer’s cells), lung (alveo-
Originally, monocytes and macrophages were clas- lar macrophages), lymph nodes (free and fixed
sified as cells of the reticulo-endothelial system - macrophages), spleen (free and fixed macrophages),
RES (Aschoff, 1924). Van Furth et al. (1972) pro- bone marrow (fixed macrophages), serous fluids
posed the mononuclear phagocyte system – MPS, (pleural and peritoneal macrophages), skin (histio-
and monocytes and macrophages became basic cell cytes, Langerhans’s cell) and in other tissues.
types of this system. Their development takes in The macrophage population in a particular tis-
the bone marrow and passes through the following sue may be maintained by three mechanisms: in-
steps : stem cell - committed stem cell - monoblast - flux of monocytes from the circulating blood, local
promonocyte - monocyte (bone marrow) - monocyte proliferation and biological turnover. Under nor-
(peripheral blood) - macrophage (tissues). Monocyte mal steady-state conditions, the renewal of tissue
differention in the bone marrow proceeds rapidly macrophages occurs through local proliferation of
(1.5 to 3 days). During differentation, granules are progenitor cells and not via monocyte influx. Orig-
formed in monocyte cytoplasma and these can be di- inally, it was thought that tissue macrophages were
vided as in neutrophils into at least two types. How- long-living cells. More recently, however, it has been
ever, they are fewer and smaller than their neutrophil shown that depending on the type of tissue, their
counterparts (azurophil and specific granules). Their viability ranges between 6 and 16 days.
enzyme content is similar. Inflammatory macrophages are present in various
The process of haematopoiesis is controlled by exudates. They may be characterized by various spe-
a group of at least 11 growth factors. Three of cific markers, e.g. peroxidase activity, and since they
these glycoproteins initiate the differentiation of are derived exclusively from monocytes they share
macrophages from uni- and bipotential progenitor similar properties. The term exudate macrophages
cells in the bone marrow. The progression from designates the developmental stage and not the func-
pluripotential stem cell to myeloid-restricted pro- tional state.
genitor is controlled by IL-3, which generates dif- Macrophages are generally a population of ubiqui-
ferentiated progeny of all myeloid lineages. As tously distributed mononuclear phagocytes respon-
IL-3-responsive progenitors differentiate, they be- sible for numerous homeostatic, immunological, and
came responsive to GM-CSF and M-CSF, the two inflammatory processes. Their wide tissue distri-
growth factors giving rise to monocyte/macrophage- bution makes these cells well suited to provide an
restricted progeny. After lineage commitment, cells immediate defence against foreign elements prior to
are completely dependent on these growth factors for leukocyte immigration. Because macrophages par-
continued proliferation and viability. More recently, ticipate in both specific immunity via antigen pre-
TNF-α has also been implicated in growth regulation sentation and IL-1 production and nonspecific im-
for macrophage precursors. munity against bacterial, viral, fungal, and neoplas-
The blood monocytes are young cells that al- tic pathogens, it is not surprising that macrophages
ready possess migratory, chemotactic, pinocytic and display a range of functional and morphological phe-
phagocytic activities, as well as receptors for IgG Fc- notypes.
domains (FcγR) and iC3b complement. Under mi-
gration into tissues, monocytes undergo further dif-
ferentiation (at least one day) to become multifunc- 9.1.3.4.1 Heterogeneity and activation of
tional tissue macrophages. Monocytes are generally, macrophages Macrophage heterogeneity is a
therefore, considered to be immature macrophages. well-documented phenomenon, perhaps first ob-
However, it can be argued that monocytes represent served by Metchnikoff, who described a progression
the circulating macrophage population and should be of infiltrating cell types in inflammatory exudates.
considered fully functional for their location, chang- It has also long been recognized that macrophages
ing phenotype in response to factors encountered in isolated from different anatomical sites display a
specific tissue after migration. diversity of phenotypes and capabilities. Because
598 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

macrophage function is dependent in part on sig- CSF-derived macrophages are more cytotoxic against
nals received from the immediate microenvironment, TNF-α-resistant tumour targets, express more MHC
it is suggested that macrophage heterogeneity may class II antigen, more efficiently kill Listeria mono-
arise from unique conditions within specific tissues. cytogenes, and constitutively secrete more PGE2 .
Obviously, the sterile, anaerobic environment of the The production of functionally distinct macro-
spleen or peritoneum will impart different constraints phage populations gives the nonspecific immune sys-
on resident macrophages than does the aerobic en- tem added flexibility to respond to immunological
vironment of the alveolar macrophage, which con- or inflammatory stimuli. It is probable that the na-
tains numerous external factors. Antibodies di- ture of an immune response is dictated in large part
rected against specific membrane antigens have been by the functional phenotype(s) of the macrophages
used to compare macrophage from different tissues. present within the lesion. The existence of distinct
For instance, human breast milk macrophages ex- subsets of helper T lymphocytes (TH cells) also sug-
press an antigen not observed on monocytes, alve- gest that the predominance of TH 1 (IFN-γ and IL-2
olar macrophages, or peritoneal cells. Furthermore, producing) or TH 2 (IL-4 and IL-10 producing) cells
human alveolar macrophage express high levels of may, in turn, favor the production or activation of a
MHC class II antigen, whereas the opposite is found particular macrophage subset.
for peritoneal macrophages.
In addition, the orchestration and regulation of
It has been just as quickly recognized that cytokine production during inflammatory responses
macrophages isolated from a given tissue display het- constitute a key determinant of both the resolution
erogeneous function. For example, only a portion of challenge and the limitation of host tissue damage.
of peritoneal macrophages express low levels of 5’- Hence, the sequential appearance within inflamma-
nucleotidase, and immune elicitation of peritoneal tory lesions may allow the most appropriate response
macrophages results in predominantly macrophages at a given stage of an immune response. Analysis of
with low 5’-nucleotidase activity, presumably be- temporal production of cytokines during immune re-
cause of an influx of monocytes. Thus, functional sponses suggests that different macrophage popula-
heterogeneity results from the spectrum of matura- tions participate at various stages, or that the chang-
tional states in a given isolate because of the influx ing conditions within the lesion differentially affect
of monocytes and/or local proliferation. the functions of distinct macrophage populations.
Because macrophages are responsible for numer- Several studies correlate the presence of certain
ous inflammatory processes, it becomes impor- macrophage populations with disease states. Hu-
tant to distinguish between normal or steady-state man macrophages expressing an undefined antigen
haematopoiesis and induced haematopoiesis associ- detected by the 27E10 monoclonal antibody are
ated with immunological challenge. Production of observed in acute inflammatory exudates in cases
the macrophage lineage from bone marrow progeni- of contact dermatitis, gingivitis, and psoriasis, but
tors is normally controlled by M-CSF, which is con- are absent in chronic inflammation arising from os-
stitutively produced by many cell types. In re- teoarthritis, tuberculoid leprosy, and rheumatoid
sponse to invasive stimuli and inflammation, mono- arthritis. In human liver, heart, and kidney grafts,
cyte numbers increase dramatically, as do serum lev- strong infiltration of 27E10-positive macrophages is
els of M-CSF. In addition, GM-CSF appears in the associated with acute rejection, whereas the RM3/1-
serum. Although there appear to be a large overlap positive phenotype is associated with an uncompli-
of macrophage progenitors able to respond to M-CSF cated clinical course. Accumulation of 25F9-positive
or GM-CSF, the very different structures and signal macrophages correlates with tumour progression and
transduction mechanisms of the receptors for M-CSF poor prognosis. These studies suggest that pheno-
and GM-CSF suggest that the differentiation path- typic analysis of macrophage subsets might be of
ways they initiate, would be dissimilar. use diagnostically, even if the specific role of these
M-CSF-derived macrophages are larger, have a macrophage populations is unclear.
higher phagocytic capacity, and are highly resistant It follows that the term macrophage refers to a het-
to infection by vesicular stomatitis virus compared erogeneous population of cells that differ in their ori-
to GM-CSF-derived macrophages. Conversely, GM- gin, development stage (differentiation), local adap-
9.1. Inflammation 599

tation and thus also in their function and pur- secretion of IL-1. Moreover, the process of tumour
pose. The nomenclature of individual macrophage cell lysis is a multistep event, determined by the sen-
types (particularly inflammatory) is rather confus- sitivity of the target cell itself. Thus, activation to
ing and terms such as stimulated, activated, induced, kill one target does not necessarily include the ability
elicited etc. are often used interchangeably. Basi- to kill all targets.
cally, two main macrophage groups can be distin- When human (but not murine) macrophages are
guished: resident (normal) and inflammatory (exu- expossed to IFN-γ they express a 1-hydroxylase.
date) macrophages. This enables them to convert inactive circulating
The term activated macrophages is reserved for 25-hydroxycholecalciferol into the active metabolite,
macrophages possesing specifically increased func- 1,25-dihydroxycholecalciferol (also known as vitamin
tional activity. The process of differentiation is not D3 or calcitriol). Macrophages have receptors for this
to be confused with activation, the process trough derivative, and it exerts additional activating effects
which differentiated macrophages acquire an increase on these cells, and perhaps some negative feedback
ability to perform specific functions. Characteristi- on lymphocytes. This pathways is of some impor-
cally, resident tissue macrophages are relatively qui- tance in man, since production of calcitriol can be
escent immunologically, having low oxygen consump- so great that it leaks from the site of macrophage
tion, low levels of major histocompatibility complex activation into the peripheral circulation, where it
(MHC) class II gene expression, and little or no cy- can exert its better known effects on calcium and
tokine secretion. Resident macrophages are, how- phosphate balance. Detectable hypercalcaemia can
ever, phagocytic and chemotaxic and retain some result.
proliferative capacity. There is also evidence that activated macrophages
can be deactivated. Prostaglandin E may have this
There are two stages of macrophage activation,
effect, and some effector mechanisms (but not all) are
the first being a primed stage in which macrophages
steroid sensitive. Recently a macrophage deactivat-
exhibit enhanced MHC class II expression, anti-
ing factor (MDF) has been purified from a tumour
gen presentation, and oxygen consumption, but re-
cell supernatant. This cytokine block activation by
duced proliferative capacity. The agent that primes
IFN-γ of increased capacity for production of ROI
macrophages for activation is IFN-γ, a product of
and, to some extent, of nitric oxide. So too do IL-4,
stimulated TH 1 and TH 0 cells. But many other fac-
calcitonin gene related peptide (CGRP), and TGF-β.
tors, including IFN-α, IFN-β, IL-3, M-CSF, GM-
CSF and TNF-α, can also prime macrophages for
selected functions. 9.1.3.4.2 Biological functions of macropha-
ges Macrophages are involved at all stages of the
Primed macrophages respond to secondary stim- immune response. First, as already outlined, they
uli to become fully activated, a stage defined by act as rapid protective mechanism which can re-
their inability to proliferate, high oxygen consump- spond before T cell-mediated amplification has taken
tion (through NADPH oxidase), killing of faculta- place. Activated macrophages play a key role in
tive and intracellular parasites, tumour cell lysis, host defence against intracellular parasitic bacteria,
and maximal secretion of mediators of inflamma- pathogenic protozoa, fungi and helminths as well
tion, including TNF-α, PGE2 , IL-1, IL-6, reactive as against tumours, especially metastasing tumours.
oxygen species, and nitric oxide produced by iNOS. After phagocytosis, macrophages prevent intracellu-
Agents capable of providing secondary signals are larly parasitic organisms from replication at least by
diverse and include LPS, heat-killed gram-positive three ways:
bacteria, yeast glucans, GM-CSF and phorbol es-
ters. The distinction between primed and fully ac- 1. Intracellular environment is unsuitable for mi-
tivated macrophages is usually arbitrary, depending crobial reproduction due to low pH and lack of
in large part on the stimulus used and the functional nutrients in a phagolysosome.
assessed. 2. The toxic reaction may be activated to
Macrophages stimulated for tumouricidal activity against dividing organisms. This include ROI,
show decreased MHC class II gene transcription and hypochlorite, NO· , myeloperoxidase, neutral
are generally poor presenters of antigen, despite their proteases and lysosomal hydrolases.
600 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

3. Macrophages may also produce microbiostatic of LTC4 , LTD4 and LTE4 became known as slow-
effector molecules at a steady-state and thus reacting substance of anaphylaxis (SRS-A). These
maintain intracellular microorganisms in the leukotrienes are important mediators of bronchial
non-replicating state. This latent infection asthma, since they provoke long-term contractions of
is generally observed only in such individuals bronchial smooth muscles. More detailed data about
whose macrophages cannot be sufficiently ac- bioactive lipids, complement, clotting factors and cy-
tivated. Generally, macrophages represent the tokines will be in next chapters.
second line of defence against different agent in- Macrophages secrete not only cytotoxic and in-
cluding pathogenic microorganisms. flammation controlling mediators but also sub-
stances participating in tissue reorganization. They
In addition, macrophages are important killer cells include enzymes, as hyaluronidase, elastase, and
(K cells); by means of antibody-dependent cell- collagenase, inhibitors of some of them (antipro-
mediated cytotoxicity (ADCC) they are able to kill teases), regulatory growth factors and others.
or damage extracellular targets. They also take part Hyaluronidase, by destroying hyaluronic acid, an im-
in the initiation of T cell activation by processing and portant component of connective tissue, reduces vis-
presenting antigen. Finally they are central effector cosity and thus permits greater spreading of material
and regulatory cells of the inflammatory response. in tissue spaces. Hyaluronidase is therefore some-
To fulfil these functions, macrophages in their acti- times designated the ”spreading factor”. Elastase
vated state are able to produce more than one hun- and collagenase are enzymes capable to split colla-
dred of different substances (Table 9.5). gen and elastin, the basic members of connective pro-
· teins.
Monocytes lose their myeoloperoxidase activity
during conversion to tissue macrophages, therefore
microbicidal and cytotoxic activity of macrophages 9.1.3.4.3 The role of macrophages in angio-
is performed mainly through ROI, NO· and other genesis An important component of inflammatory
substances which are similar to those in neutrophils reactions and subsequent repair and remodelling pro-
with the exemption of thymidine, arginase and TNF- cesses is angiogenesis or neovascularization – the for-
α. However, macrophages may acquire MPO from mation of new capillaries from preexisting blood ves-
their environment by pinocytosis or from ingested sels. It is also commonly observed during physio-
neutrophils. In this way, especially macrophages logical growth processes and during embryogenesis,
in inflammatory site with the intensive cell destruc- where the formation of new blood vessels from an-
tion, can gain myeloperoxidase (or other peroxidase). gioblasts is referred to as vasculogenesis. Some dis-
Such peroxidase then participates in cytotoxic mech- eases, such as arthritis and diabetic retinopathy, are
anisms of macrophages. maintained by persistent neovascularization. Inter-
Macrophages are important producers of arachi- est in neovascularization was originally evoked by the
donic acid and its metabolites. Upon phagocytosis phenomenon of tumour angiogenesis: Tumours do
macrophages release up to 50 % of their arachidonic not grow beyond 2-3 mm3 and cannot metastasize
acid from membranous esterified glycerol phospho- unless vascularized. From the many cells and cell
lipid. It is immediately metabolized into different products as inducers or modulators of angiogenesis,
types of prostanoids. From them prostaglandins, es- macrophages have emerged as a major protagonist.
pecially PGE2 , and prostacyclin (PGI2 ) are charac- The angiogenic activity of macrophages is associated
terized as pro-inflammatory agents: they induce va- with their secretory activity and needs specific acti-
sodilatation, act synergeticly with complement com- vation.
ponent C5a and LTB4 , mediate fever and myalgia Among the potential activators of macrophages,
response to IL-1, in the combination with bradykinin LPS is known to induce angiogenic activity but does
and histamine they contribute to erythema, oedema, not appear to be a general stimulus of angiogenesis.
and pain induction. Tromboxan TXA2 is considered More specific activation signals could be provided by
as an inflammatory mediator; it facilitates platelet the particular metabolic conditions found in wounds.
aggregation and triggers vasoconstriction. LTB4 is Macrophages became angiogenic when exposed to
the efficient chemoatractant substance. A mixture low oxygen tensions or to woundlike concentrations
9.1. Inflammation 601

Group of substances Individual products

Microbicidal and cytotoxic:

Reactive oxygen intermediates Superoxide, hydrogen peroxide, hydroxyl radical,
hypohalite, chloramines
Reactive nitrogen intermediates Nitric oxide, nitrites, nitrates
Oxygen independent Neutral proteases, acid hydrolases, lysozyme, defensins

Tumouricidal: H2 O2 , NO· , TNF-α, C3a, proteases, arginase, thymidine

Tissue damaging: H2 O2 , TNF-α, NO· , neutral proteases

Fever inducing:
Pyrogenic cytokines IL-1, TNF-α, IL-6

Inflammation regulators:
Bioactive lipids Prostaglandins (PGE2 , PGF2α ), prostacyclin (PGI2 ), trom-
boxans, leukotrienes (LTB4 , LTC4 , LTD4 , LTE4 )
Bioactive oligopeptides Glutathione
Complement components C1,C4,C2,C3,C5, factors B,D,P,I,H
Clothing factors V, VII, IX, X, prothrombin, plasminogen activator, plasmino-
gen activator inhibitors
Cytokines IL-1, IL-6, IL-8, TNF-α, INF-γ.
Macrophage inflammatory proteins (MIP-1, MIP-2, MIP-3).
Regulatory growth factors (M-CSF, GM-CSF, G-CSF, PDGF).

Neutral proteinases Elastase, collagenase, angiotensin convertase, stromelysin

Protease inhibitors α2 -Macroglobulin, α-1-proteinase inhibitor, plasmin and colla-
genase inhibitors, plasminogen activator inhibitors
Acid hydrolases Acid proteases (cathepsin D and L), peptidases, lipases,
lysozyme and other glycosidases, ribonucleases, phosphatases,
sulphatases
Stress proteins Heat shock proteins (HSP)

Participating in tissue reorgani- Elastase, collagenase, hyaluronidase, regulatory growth fac-

zation: tors, fibroblast growth factor (FGF), transforming growth fac-
tors (TGF-α, TGF-β), angiogenesis factors

Other: Apolipoprotein E, IL-1 inhibitors, purine and pyrimidine

derivates (thymidine, uracil, neopterin)

Table 9.5: Effector and regulatory products of macrophages

of lactate, pyruvate, or hydrogen ions. They can also Certain mature or immature macrophage-like cell
be activated by cytokines such as IFN-γ, GM-CSF, lines obtained from mice or humans have different
PAF, or MCP (monocyte chemoattractant protein). angiogenic activities. Differences in angiogenic acti-
602 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

vity also depend on the developmental and largely nases) and serine proteases (e.g. elastase and plas-
on the activation stage. minogen activator). As mentioned above, these en-
The formation of new capillaries proceeds through zymes can degrade ECM molecules, modulate me-
a series of steps. The sequence of events for endothe- chanical structures, and liberate ECM-bound growth
lial cells begins with destruction of the basement factors. Plasminogen activator has been found to
membrane and local degradation of the extracellular be indispensable for tube formation of microvascu-
matrix (ECM). This allows endothelial cells to mi- lar cells in vitro. Its inhibition subsequently leads
grate by extending cytoplasmic buds in the direction to suppression of angiogenesis. As proteolytic en-
of chemotactic factors. Simultaneously, inflamed and zymes are capable to degrading almost all compo-
neoplastic tissues present leakage of capillaries with nents of the ECM, control mechanisms are necessary,
exudation of fibrin, which also serves as a migratory such as activation-dependent release of proteinases.
matrix for endothelial and other cells. For elongation Macrophages themselves also synthesize tissue in-
of new capillaries, migrating endothelial cells must be hibitors of metallo- and serine proteases.
replaced by newly divided endothelial cells. Eventu- Macrophages release monokines that influence
ally migration and mitosis have to be stopped while changes in the ECM other than inducing protease
capillary sprouts differentiate into mature capillaries release by endothelial cells. Some of these cytokines
with a new basement membrane. Macrophages are also have direct angiogenic effects. TGF-β, which
able to promote all phases of the angiogenic process both stimulates and inhibits angiogenesis in vitro,
by virtue of their secretory products. modulates the expression of fibronectin or collagen
type I and their incorporation into the ECM. Other
Local degradation of the ECM appears to entail
macrophage-derived cytokines with angiogenic po-
more than opening up a way for migrating cells. The
tential and modulating effects on the ECM are an-
ECM has been suggested to have a controlling role in
giotropin, platelet-derived growth factor (PDGF),
a variety of physiological and biochemical processes
and IL-6.
including angiogenesis. Some ECM molecules be-
In summary, macrophage can change the compo-
come angiogenic after hydrolytic degradation. For
sition of the extracellular matrix:
instance, fragments of hyaluronic acid, as opposed
to the complete molecule, have been shown to induce 1. by releasing degrading enzymes,
neovascularization. Similarly, fibrin, after digestion
by plasmin, can provoke an angiogenic response. 2. by synthesizing ECM molecules such as fi-
Macrophages release several proteases, among them bronectin or proteoglycans, and
plasminogen activator, whose actions could yield an-
giogenic fragments from ECM molecules. 3. by releasing monokines with modulating effects
on the ECM.
Several soluble growth factors (basic fibroblast
growth factor – bFGF, TGF-β, GM-CSF) are stored Macrophages produce several factors, other than
in the ECM by being bound to, for example, heparin- proteases, that induce migration of endothelial cells.
like glycosaminoglycans. Their enzymatic release Most of them also support other stages of the an-
would make them available for endothelial cells. giogenic process such as mitosis or differentiation of
Macrophages are able to degrade heparan sulphate endothelial cells. However, two factors appear to
and to release ECM-bound bFGF by expression of have predominantly chemotactic effects: human an-
urokinase-type tissue plasminogen activator. giogenic factor (HAF) and angiotropin. Their migra-
The composition of the ECM determine the shape tory effects are sufficient for initial neovasculariza-
of endothelial cells, thereby dictating their respon- tion as migrating endothelial cells can form sprouts
siveness to individual growth factors. Changes in without proliferating. Angiogenin, another well-
shape of endothelial cells with subsequently modified characterized nonmitogenic angiogenic factor does
responsiveness towards growth factors were achieved not appear to be released by macrophages.
by mere mechanical forces. Macrophages secrete sev- Macrophages secrete or produce several fac-
eral enzymes and cytokines that cause changes of the tors that induce mitoses of capillary endothelium.
molecular or mechanical structure of the ECM. They Whereas the mitogenic effects of bFGF, TGF-
are a rich source of metalloproteases (e.g. collage- α, GM-CSF, M-CSF, vascular endothelial growth
9.1. Inflammation 603

factor/vascular permeability factor (VEGF/VPF), it is not known whether they are chemotactic, mito-
IL-8, and substance P are well characterized, the genic, or lead to change in the ECM. As an exam-
proliferative actions of insulin-like growth factor I ple may serve angiotensin-converting enzyme (ACE).
(IGF-I, somatomedin C) and PDGF on endothelial ACE converts angiotensin I to angiotensin II. The
cells may need further confirmation. latter caused marked neovascularization after being
The heparin-binding (fibroblast) growth factors implanted into rat cornea or in the chorioallantoic
have shown prominent angiogenic activity in almost membrane assay. The nature of this angiogenic ef-
any bioassay for angiogenesis. Basic FGF stimulates fect is unknown and may be indirect by causing an in-
directed migration and proliferation of cultured en- flammatory infiltrate, as ACE promotes neither mi-
dothelial cells and promotes formation of differenti- gration nor proliferation of endothelial cells. Most
ated capillary tubes in vitro. These effects are as- macrophages exhibit only low activity of angiotensin-
sociated with selective up-regulation of integrins on converting enzyme, but macrophages of sarcoido-
endothelial cells and induction of protease such as sis granulomas present higher activities. This may
plasminogen activator. be important view of a marked angiogenic effect of
macrophages in sarcoidosis.
Activated macrophages are the only blood cells
besides platelets producing platelet-derived growth Inhibition of neovascularization is necessary to re-
factor (PDGF). PDGF is a family of dimeric pro- strict the extent of the new vascular network and
teins consisting of A chain and/or a B chain. Ac- to facilitate differentiation of capillary sprouts into
tivated monocytes and macrophages, but not rest- functionally mature capillaries. Macrophages re-
ing monocytes, express the B-chain gene of PDGF. lease several factors that inhibit migration or mito-
Direct angiogenic effects of PDGF are not unequiv- sis of endothelial cells: monocyte-derived endothe-
ocal. Controversial effects of PDGF on endothelial lial cell inhibitory factor (MECIF), macrophage-
cells may derive from the heterogeneity of endothe- derived endothelial cell inhibitor (MD-ECI), throm-
lial cells. Capillaries that respond to PDGF have bospondin I, IFN-α, and IFN-γ. These cytokines
PDGF-B-type receptors, whereas endothelial cells of could thereby promote the differentiating effects of
large vessels do not respond to PDGF. Apart from otherwise chemotactic and mitogenis factors such as
its direct effects on endothelium, PDGF has effects angiotropin, bFGF, GM-CSF, or M-CSF.
on other cells involved in wound healing. It is a po- Thrombospondin 1 (TSP 1) is one of several ECM
tent chemoattractant and mitogen for mesenchymal proteins that are produced by macrophages. Its
cells. It also activates macrophages and stimulates expression has been linked to a cancer suppressor
synthesis of ECM components. gene in several cells that is down-regulated during
Vascular endothelial growth factor (VEGF), also tumourigenesis. It inhibits migration, proliferation,
called vascular permeability factor (VPF) or vascu- and capillary tube formation of endothelial cells in
lotropin, is a PDGF-related protein whose mitogenic vitro, where it is associated with quiescent but not
activity is apparently specific for endothelial cells, proliferating endothelial cells. TSP 1 also suppress
the only cells that normally express VEGF/VPF neovascularization in vivo. Since TSP 1 performs
receptors. Besides stimulating proliferation of en- several other functions in wound (serving as migra-
dothelial cells, it markedly increases vascular perme- tory matrix, enhancing neutrophil chemotaxis, in-
ability and induces serine and metalloproteinases in hibiting proteases) its role in angiogenesis is likely to
endothelial cells. depend on regulatory effects of the other mediators
Macrophages release several factors that do not present during inflammation.
directly induce angiogenesis in coresponding assays Histological examination of tissue sections with
but act indirectly by attracting or activating an- ongoing angiogenesis has shown that the presence
giogenic cells. This applies for each phase of the of granulocytes and macrophages is a prerequisite
angiogenic process. Since angiogenesis is a com- for the neovascularization. Neutralization or deple-
ponent of inflammatory processes, all macrophage- tion of either type suppressed the formation of new
derived mediators of inflammation have to be con- blood vessels. The angiogenic activity of granulo-
sidered at least as indirect angiogenesis factors. An- cytes, however, appeared to be inferior to that of
other macrophage-derived factors are angiogenic, but macrophages and apparently was not associated with
604 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

the release of diffusible factors. Also the half-life of mally present in the plasma in an inactive form, such
extracellular granulocytes is extremely short. Mast as peptide fragments of some components of com-
cells or T lymphocytes, on the other hand, do not ap- plement, coagulation, and kinin systems. Mediators
pear to be relevant for outgrowth of vascular sprouts of inflammatory responses are also released at the
in inflammatory angiogenesis. Instead, mast cells site of injury by a number of cell types that either
may have an important role in tumour angiogenesis, contain them as preformed molecules within storage
and the angiogenic activity of T lymphocytes seems granules, e.g. histamine, or which can rapidly switch
to be relevant in graft-versus-host reaction. on the machinery required to synthesize the media-
tors when they are required, for example to produce
9.1.4 Mediators of inflammation metabolites of arachidonic acid.
Mononuclear phagocytes (monocytes and
Once leukocytes have arrived at a site of infection or macrophages) are central to inflammation, as they
inflammation, they release mediators which control produce many components which participate in or
the later accumulation and activation of other cells. regulate the different plasma enzyme systems, and
However, in inflammatory reactions initiated by the hence the mediators of the inflammatory response.
immune system, the ultimate control is exerted by They are also actively phagocytic and are involved
the antigen itself, in the same way as it controls the in microbial killing, as are neutrophils. While the
immune response itself. For this reason, the cellular latter can be thought of as short-lived kamikaze cells
accumulation at the site of chronic infection, or in au- that need to be continually replaced from the bone
toimmune reactions (where the antigen cannot ulti- marrow, mononuclear phagocytes are long-lived and
mately be eradicated), is quite different from that at some can proliferate in situ. Other cells such as mast
sites where the antigenic stimulus is rapidly cleared. cells and basophils are much less phagocytic, but to-
There are four major plasma enzyme systems gether with platelets, these cells are particularly im-
which have an important role in haemostasis and portant for secretion of vasoactive mediators. The
control of inflammation. These are the complement function of these cell types is at least partially un-
system, the clotting system, the fibrinolytic (plas- der the control of cytokines. All inflammatory cells
min) system and the kinin system. have receptors for Fc domains of immunoglobulins
Inflammatory mediators are soluble, diffusible and for complement components, and they possess
molecules that act locally at the site of tissue damage specialized granules containing an immerse variety of
and infection, and at more distant sites. They can be products that are released perhaps by common mech-
divided into exogenous and endogenous mediators. anisms. Cytotoxic T lymphocytes and NK cells, in
Bacterial products and toxins can act as exogenous general, also possess granules which are important
mediators of inflammation. Notable among these is for their cytotoxic function. In general, lymphocytes
endotoxin, or LPS of Gram-negative bacteria. The are involved in the adaptive response to inflamma-
immune system of higher organisms has probably tion, and the early events of inflammation are me-
evolved in a veritable sea of endotoxin, so it is per- diated in part by molecules produced by cells of the
haps not surprising that this substance avokes pow- innate arm of the immune system.
erful responses. For example, endotoxin can trigger Early phase mediators are produced by mast cells
complement activation, resulting in the formation of and platelets. They are especially important in acute
anaphylatoxins C3a and C5a which cause vasodila- inflammation and include mainly histamine, sero-
tion and increase vascular permeability. Endotoxin tonin and other vasoactive substances. Platelets may
also activates the Hageman factor, leading to acti- contribute to inflammatory responses resulting as a
vation of both the coagulation and fibrinolytic path- consequence of tissue injury, through a variety of
ways as well as the kinin system. In addition, en- mechanisms including:
dotoxin elicit T cell proliferation, and have been de- 1. the release of vasoactive amines and other per-
scribed as superantigen for T cells. meability factors,
Endogenous mediators of inflammation are pro-
duced from within the (innate and adaptive) immune 2. the release of lysosomal enzymes,
system itself, as well as other systems. For example, 3. the release of coagulation factors which lead to
they can be derived from molecules that are nor- localized and generalized fibrin deposition, and
9.1. Inflammation 605

4. the formation of platelet aggregates or trombi the bone marrow – are associated with readily de-
which result in the blocking of vessels and cap- tected changes in circulating levels of certain medi-
illaries. ators of inflammation. For example, TNF-α peaks
within two hours and is likely the predominant py-
To the early phase mediators also belong chemoa- rogen associated with the febrile response. Plasma
tractants (e.g. C5a) and cytokines such as IL-1, IL-6, levels of the chemoattractant IL-8 increase early and
and TNF-α. peak by four hours. Early increases in IL-8 may re-
Late phase mediators are responsible for the regu- late to the transient decrease in the neutrophil count
lation of vascular events occuring later – from about at 30 min (margination).
6–12 hours after initiation of inflammation. The later Mediator accumulation at local inflammatory pro-
vascular events are mediated, at least in part, by cesses in skin blisters is somewhat different from
products of arachidonic acid. the systemic effects following intravenous endotoxin.
The chemical mediators of inflammation are sum- Mediators detected in blister fluid within 3 to 5 hr of
marized in Table 9.6. There is considerable func- the inflammatory response included LTB4 , C5a, IL-8
tional redundancy of the mediators by inflammation. and IL-6. In contrast IL-1β, GM-CSF, and TNF-α
This explains why certain patients may have com- were not detected until after 8 hr in the blister. Thus
plete absence of a humoral component (e.g., com- the endotoxin and skin blister models of inflamma-
plement component C3), yet minimal problems with tion demonstrate that there are clear differences in
increased susceptibility to infection. the mediators that can be detected systemically and
Edema formation can be separated from phago- locally.
cyte recruitment. Vasodilation in response to his-
tamine, bradykinin, PGE2 and PGI2 , and comple-
9.1.4.1 Histamine and serotonin
ment fragments C3a and C5a results from a direct
action of these substances on endothelial cells and The most important vasoactive mediators that are
smooth muscle vasculature with resulting leakage of stored in mast cell and basophil granules are
plasma. This is accompanied by release of mediators, histamine in man, as well as serotonin or 5-
such as C5a, LTB4 , and PAF, that act directly on hydroxytryptamine in rodents. They both are also
the phagocytic cells. In addition N-formyl peptides present in human platelets. Histamine is stored in
are released from bacteria and mitochondria of dam- mast cells and basophils largely complexed to mu-
aged tissues. These mediators are potent chemoat- copolysaccharide (glycosaminoglycans) such as hep-
tractants that mobilize neutrophils, monocytes, and arin. Histamin has diverse functions including pri-
eosinophils, cause release of lysosomal contents, and mary, local dilation of small wessels; widespread ar-
activate the respiratory burst of the phagocytes with teriolar dilatation; local increased vascular perme-
resulting production of toxic oxygen products. ability by contracting endothelial cells; the contrac-
Following intravenous endotoxin, a characteristic tion of nonvascular smooth muscle; chemotaxis for
change in body temperature and white blood count eosinophils; and blocking T lymphocyte function. A
is observed. The body temperature begins to in- number of different cells of the body have recep-
crease after about one hour and reaches a maximum tors for histamine. These can be of three types –
at about four hours. The leukocyte count shows a H1, H2, and H3. The H1 receptors mediate acute
characteristic decrease at about 30 min, due to neu- vascular effects together with smooth muscle con-
trophil and monocyte adherence to endothelial cells striction in the bronchi (histamine act as a ”spasmo-
in the lung and spleen. This is followed by a leuko- gen”) and the stimulation of eosinophil chemotaxis.
cytosis characterized by the presence of immature In constrast, the H2 receptors mediate a number of
neutrophils at about four hours, which can persist anti-inflammatory effects, including the inhibition of
throughout 24 hr with gradual return to baseline eosinophil chemotaxis, but cause the vasodilatation.
by 48 hr. The leukocytosis is predominantly due The H3 receptor is mainly involved in the control of
to mobilization of immature neutrophils from the histamine release by different producing cells.
bone marrow. The critical components of the in- Serotonin is also capable of increasing vascular
flammatory response – fever, neutrophil margination permeability, dilating capillaries and producing con-
in the circulary vessels, and then mobilization from traction of nonvascular smooth muscle. Most sero-
606 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

Function Mediators

Increased vascular permeability Histamine, serotonin, bradykinin, C3a, C5a, PGE2 , LTC4 ,
of small blood vessels LTD4 , prostacyclins, activated Hageman factor, high-
molecular-weight kininogen fragments, fibrinopeptides

Vasoconstriction TXA2 , LTB4 , LTC4 , LTD4, C5a, N-formyl peptides

Smooth muscle contraction C3a, C5a, histamine, LTB4 , LTC4 , LTD4 , TXA2 , serotonin,
PAF, bradykinin

Increased endothelial cell IL-1, TNF-α, MCP, endotoxin, LTB4

stickiness

Mast cell degranulation C5a, C3a

Phagocytes
Stem cell proliferation IL-3, G-CSF, GM-CSF, M-CSF
Recruitment from bone narrow CSFs, IL-1
Adherence/aggregation iC3b, IgG, fibronectin, lectins
Chemotaxis C5a, LTB4 , IL-8 and other chemokines, PAF, histamine (for
eosinophils), laminin, N-formyl peptides, collagen fragments,
lymphocyte-derived chemotactic factor, fibrinopeptides
Lysosomal granule release C5a, IL-8, PAF, most chemoattractants, phagocytosis
Production of reactive oxygen C5a, TNF-α, PAF, IL-8, phagocytic particles;
intermediates IFN-γ enhances
Phagocytosis C3b, iC3b, IgG (Fc portion), fibronectin; IFN-γ increases Fc
receptor expression
Granuloma formation IFN-γ, TNF-α, IL-1

Pyrogens IL-1, TNF-α, PGE2 , IL-6

Pain PGE2 , bradykinin

Table 9.6: Mediators of inflammation

tonin is stored in the gastrointestinal tract and cen- tion and degrade phospholipids to arachidonic acid.
tral nervous system but a large amount is also stored Arachidonic acid has a short half-life and can be me-
in the dense granules of platelets. tabolized by two major routes, the cyclo-oxygenase
and lipoxygenase pathways. The cyclo-oxygenase
9.1.4.2 Lipid mediators pathway produces prostaglandins, prostacyclin, and
thromboxanes; the lipoxygenase pathway produces
The major constituent of cell membranes are phos-
in one branch leukotrienes and in the second branch
pholipids. Cellular phospholipases, especially phos-
lipoxins (Figure 9.1).
pholipase A2 and C, are activated during inflamma-
9.1. Inflammation 607

Figure 9.1: The metabolic pathway of arachidonic acid

(HPETE: hydroperoxy-eicosatetraenoic acid; HETE: hydroxy-eicosatetraenoic acid)

PHOSPHOLIPIDS IN CELL MEMBRANES

Phospholipases A2 and C

ARACHIDONIC ACID

cyclooxygenase

15-lipoxygenase 5-lipoxygenase
TXB2 ← TXA2 ← PGG2 → PGI2
5-HPETE, 5-HETE
THROMBOXANES PROSTACYCLIN

PGH2 15-HPETE

LTA4 LTB4 LTC4 LTD4 LTE4 LTF4

PGD2 PGE2 PGF2
LEUKOTRIENES
LXA4 LXB4
PROSTAGLANDINS

LIPOXINS

The prostaglandins (PG) are a family of lipid- ve effects on release of mediators by mast cells, lym-
soluble hormone-like molecules produced by different phocytes, and phagocytes.
cell types in the body. For example, macrophages Thromboxane A2 (TXA2 ) is produced by mono-
and monocytes are large producers of both PGE2 cytes and macrophages, as well as by platelets. It
and PGF2 , neutrophils produce moderate amounts causes platelets to aggregate and constrict blood ves-
of PGE2 , mast cells produce PGD2 . It is important sels and airways. These effects are somewhat op-
to note that, unlike histamine, prostanglandins do posed by the action of prostacyclin (PGI2 ) which is
not exist free in tissues, but have to be synthesized a potent vasodilator.
and released in response to an appropriate stimulus. Leukotrienes. LTB4 and 5-hydroxyeicosatetrano-
PGE2 enhances vascular permeability, is pyrogenic, ate (5-HETE), causes the chemotaxis (directed lo-
increases sensitivity to pain, and stimulates leuko- comotion) and/or chemokinesis (general cell move-
cyte cAMP, which can have an important suppressi- ment) of a number of cell types including neutrophils.
608 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

The synthesis of LTB4 is inhibited by colchicine, an nal components C5-C9 that form membrane attack
anti-inflammatory agent used for treatment of gout. complex (MAC) – C5b678(9)n. C3 also participates
The mixture of LTC4 , LTD4 and LTF4 originally in all pathways.
called slow reacting substance of anaphylaxis (SRS- Activation of each of the components results from
A), is produced by a wide variety of cells, including a proteolytic cleavage event in a cascade mechanism
monocytes and macrophages. They are spasmogenic which fragments the native molecule into two frag-
and cause contraction of smooth muscle, mainly in ments. The fragment which participates further in
the bronchus, and they have effects on mucous secre- the complement cascade is designated the b fragment
tion. (e.g. C3b) and is usually larger than the another a
Lipoxins LXA4 and LXB4 stimulate changes in mi- fragment (e.g. C5a) which posseses other biological
crocirculation. For example, LXA4 induces rapid activities.
arteriolar dilation and can also antagonize LTD4 -
The complement system influence the activity of
induced vasoconstriction. It suggest that LXA4 may
numerous cells, tissues and physiological mechanism
regulate the action of vasoconstrictor leukotrienes.
of the body. These effects may involve either the
LXA4 can block neutrophil chemotaxis induced by
whole complement, or only individual components
both LTB4 and N-formyl-oligopeptides. Both LXA4
or fragments. Activation of the complement cascade,
and LXB4 inhibit cytotoxicity of natural killer cells.
with the formation of the effector MAC unit, results
Platelets produce a group of acetyl-alkylglycerol
in cytotoxic and cytolytic reactions. Target cells for
ether analogs of phosphatidylcholine called platelet-
MAC action may be heterologous erythrocytes, nu-
activating factors (PAFs). PAFs cause platelet ag-
cleated cells (autologous or foreign), bacteria (Gram-
gregation and are potent phagocyte chemoattrac-
negative, susceptible to serum), microscopic fungi,
tants and stimuli of lysosomal enzyme release and
viruses with a surface envelope and virus-infected
reactive oxygen product formation by neutrophils,
cells.
eosinophils, and macrophages. In addition, PAFs in-
crease the stickiness of endothelial cells for leuko- The result of cytotoxic complement reaction may
cytes. be beneficial for the body (elimination of the infec-
The basic activities of bioactive lipids are listed in tious agent or damaged cells) or harmful (damage to
Table 9.7. autologous normal cells by immunopathological re-
actions).
9.1.4.3 Products of the complement system Different fragments, released from individual com-
ponents during complement activation, operate by
Complement is a complex system containing more a non-cytolytic mechanism through specific recep-
than 30 various glycoproteins present in serum in tors present on various cell types. The direction
the form of components, factors, or other regulators and intensity of the biological response depend on
and/or on the surface of different cells in the form the state of the receptors (affinity and density) and
of receptors. These are present in the blood serum on the function of cells bearing receptors. From the
in an inactive state and are activated by immune functional standpoint, complement receptors can be
complexes (the classical pathway), by carbohydrates divided into two types: the adherent type and the
(the lectin pathway), or by other substances, mainly other receptors. Adherent receptors mediate adher-
of bacterial origin (the alternative pathway) – Fig- ence of cells and other particles with bound C3b or
ure 9.2. C4b fragments and are known as CR1 to CR5. Ad-
The components of the classical pathway are num- herence reaction mediated through the CR receptors
bered 1 to 9 and prefixed by the letter C, e.g. C1, on phagocytes lead to stimulation of phagocytosis,
C2. . . .C9. C1 is composed of three subcomponents activation of metabolism and secretory function and
C1q, C1r, and C1s. The early components of the movement of phagocytes into the inflammatory site.
alternative pathway are known as factors, and each These receptors, present on the other cells of the im-
molecule is named by a letter, for example factor B, mune system, are involved in a variety of immunoreg-
D, P. The lectin pathway is the same as the classi- ulatory reactions. CR1 on erythrocytes may bind
cal pathway, only C1q is omited. All these pathways circulating immune complexes (that had activated
use in the later stages of activation the same termi- complement) and transport them to the liver where
9.1. Inflammation 609

Activity Lipid mediators

Pyrogenicity PGE2

Vasoconstriction TXA2

Vasodilatation, increase of vascular PGI2 , PGE2 , PGD2 , PGF2

permeability

Contraction of smooth muscle, LTC4 , LTD4 , LTE4

increase of vascular permeability

Chemotaxis of phagocytes LTB4 , 5-HETE, PAF

Platelet aggregation TXA2 , PAF

Table 9.7: Lipid mediators and their basic activities

the immune complexes are partially degraded and The production of anaphylatoxins follows not only
thus become more soluble. from complement activation, but also from activa-
The second group of receptors reacts with small tion of other enzyme system which may directly
complement fragments (C4a, C3a, C5a) as well as cleave C3, C4 and C5. Such enzymes include plas-
with C1q, Ba, Bb and factor H. Stimulation of these min, kallilrein, tissue and leukocyte lysosomal en-
receptors results in various biological effects (chemo- zymes, and bacterial proteases.
taxis, secretion of vasoactive amines, mediators of The anaphylatoxins have powerful effects on blood
the inflammatory and anaphylactic reaction etc.). vessel walls, causing contraction of smooth muscle
The main functions of the complement cascade and and an increase in vascular permeability. These ef-
its role in the acute inflammatory reaction are sum- fects show specific tachyphylaxis (i.e. repeated stim-
marized in Table 9.8. ulation induces diminishing responses) and can be
The complemet system is a potent mechanism blocked by antihistamines; they are probably medi-
for initiating and amplifying inflammation. This ated indirectly via release of histamine from mast
is mediated through fragments of complement com- cells and basophils. C5a is the most powerful, ap-
ponents. To the most well-defined fragments be- proximately 100 times more effective than C3a, and
long anaphylatoxins. Anaphylatoxins are proteolytic 1000 times more effective than C4a. The smooth
products of the serine proteases of the complement muscle contraction in the lungs is primarily medi-
system: C3a, C4a and C5a. They are polypeptides ated by LTC4 and LTD4. This activity decrease in
containing approximately 75 amino acid residues and the following order:
meet all the criteria which characterize local hor-
mones. The C-terminal arginine in the molecule of C5a > histamine > acetylcholine > C3a >> C4a
C3a is of fundamental importance for its biological
activity. As soon as arginine is removed, the biolog- C5a is extremely potent at stimulating neutrophil
ical activity disappears completely. In the case of chemotaxis, adherence, respiratory burst genera-
C5a, the removal of C-terminal arginine (C5adesArg ) tion and degranulation. C5a also stimulates neu-
only decreases its biological activity. trophils and endothelial cells to express more adhe-
610 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

Figure 9.2: Different activation pathways of the complement system

(MBP: mannan-binding protein; MASP: MBP-associated serine protease; B: factor B; D: factor D;
P: properdin; MAC: membrane attack complex)

CLASSICAL PATHWAY LECTIN PATHWAY ALTERNATIVE PATHWAY

Immune complexes Carbohydrates, Activating surfaces

Collectins

C1q MBP C3b

C1r C1r P
C1s MASP C1s D
C4 C4 C4 B
C2 C2 C2

C3

C3b

C5b678(9)n (MAC)

sion molecules. Ligation of the neutrophil C5a recep- deficiency. All such children were found either to
tor is followed by mobilization of membrane arachi- lack MBP, or to have very low concentrations of the
donic acid which is metabolized to prostaglandins lectin. MBP has been found to initiate complement-
and leukotrienes including LTB4 , another potent mediated lysis of mannan-coated erythrocytes and
chemoattractant for neutrophils and monocytes. Fol- this lysis requires the presence of the classical path-
lowing ligation of monocyte C5a receptors, IL-1 is way complement component C4, but not C1q. This
released. Thus the local syntesis of C5a at sites of new lectin pathway of complement activation is
inflammation has powerful pro-inflammatory prop- important not only for the killing of microorgan-
erties. isms through the interaction of carbohydrates on
their surfaces and MBP or other collectins (humoral
At the same time, C3b and C4b fragments act
lectins found in humans and other mammals) but
as opsonins enhancing phagocytosis. In addition to
also for the opsonizing activity.
inducing phagocytosis, ligation of complement re-
ceptors on neutrophils, monocytes and macrophages The complement cascade also interacts with other
may also stimulate exocytosis of granules containing triggered-enzyme cascade: coagulation, kinin gener-
powerful proteolytic enzymes, and free radical pro- ation and fibrinolysis. There is another connection
duction through the respiratory burst. between these systems: the regulatory protein, C1
inhibitor, inhibits not only C1r and C1s but also Fac-
Recently it has been shown that mannan-binding
tor XIIa of the coagulation system, kallikrein of the
protein (MBP) is the main opsonin in the human
kinin system and plasmin of the fibrinolytic cascade.
blood serum. This was confirmed by observations
on infants with recurrent infections due to opsonin Under some circumstances the consequences of
9.1. Inflammation 611

Activity Components and fragments

Increase of vascular permeability C5a, C3a, C5adesArg , C4a

Smooth muscle contraction
Degranulation of mast cells and basophils

Neutrophil activation and chemotaxis C5a, C5adesArg

Stimulation of prostaglandin and leukotriene production

Opsonization of bacteria and immune complexes leading C3b, C4b

to phagocytosis

Stimulation of the respiratory burst of professional phago- C3b, C5a, C5adesArg , C1q
cytes

Lysis of bacteria and foreign cells C5b678(9)n

Solubilization of circulating immune complexes C3b, CR1

Table 9.8: The biological functions of complement and its role in the acute inflammatory reactions

complement activation in vivo may be deleterious also cause complement activation. Abundant depo-
rather than beneficial. The state of shock that may sition of membrane attack complex may be readily
follow becteraemia with Gram-negative organisms seen in tissue following ischaemic injury. A possi-
may, in part, be mediated by complement, which is ble pathophysiological role for complement activa-
extensively activated by endotoxin. The large quan- tion following tissue ischaemia was demostrated in
tities of C3a and C5a which result from this cause ac- experimental models of myocardial infarction: com-
tivation and degranulation of neutrophils, basophils plement depletion reduced the size of tissue injury
and mast cells. These anaphylatoxins may stimu- and infusion of soluble CR1 has recently been shown
late intravascular neutrophil aggregation leading to to have a similar effect.
clothing and deposition of emboli in the pulmonary
microvasculature. At this site neutrophil products, The activation of complement by immune com-
including elastase and free radicals, may cause the plexes is normally beneficial. Immune complexes
condition of shock lung. This condition is char- bearing C3b are efficiently removed from tissues and
acterized by interstitial pulmonary oedema due to from the circulation by monocytes and other phago-
damage to small blood vessels, exudation of neu- cytes. However there are circumstances in which im-
trophils into alveoli, and arterial hypoxaemia. Ex- mune complex production continues at a high level;
tracorporeal blood circulation, for example through complement activation by immune complexes may
heart-lung bypass machines, or over cuprophane dial- then prove deleterious. Such complexes may form
ysis membranes, may similarly cause activation of in tissues, for example in glomeruli of patients with
complement, accompanied by transient leukopenia, autoantibodies to glomerular basement membrane
thought to be caused by aggregation of neutrophils (Goodpasture’s syndrome) or at motor end-plates
in the lungs. in patients with autoantibodies to acetylcholine re-
ceptors (myasthenia gravis). Alternatively, immune
Tissue injury following ischaemic infarction may complexes may become trapped in blood vessel walls
612 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

having travelled trough the circulation. This occurs, The intrinsic pathway is activated when blood
for example in systemic lupus erythematosus, and comes into contact with sub-endothelial connective
in bacterial endocarditis in which an infected heart tissues or with negatively charged surface that are
valve provides the source of immune complexes which exposed as a result of tissue damage. Quantitatively
deposit in the kidney and other microvascular beds. it is the most important of the two pathways, but
Complement mediates inflammation in these dis- is slower to cleave fibrin than the extrinsic path-
eases by two major pathways: way. The Hageman factor (factor XII), factor XI,
prekallikrein, and high molecular weight kininogen
1. by activated leukocytes, which are attracted to (HMWK) are involved in this pathway of activation.
sites of immune complex deposition by locally- Thus this pathway provides a further of the interre-
produced anaphylatoxins C5a and C5adesArg lationship between the various enzyme cascade sys-
and which bind to C3b and C4b fixed to the tems in plasma. The first step is the binding of Hage-
immune complexes; man factor to a sub-endothelial surface exposed by
an injury. A complex of prekallikrein and HMWK
2. by the membrane attack complex (MAC),
also interacts with the exposed surface in close prox-
which cause cell lysis and thus stimulates
imity to the bound factor XII, which becomes acti-
prostaglandin synthesis from arachidonic acid,
vated. During activation, the single chain protein of
mobilized from perturbed cell membranes.
the native Hageman factor is cleaved into two chains
These two mechanisms of damage are well exempli- (50 and 28 kDa), that remain linked by a disulphide
fied by considering two types of glomerular disease. bond. The light chain (28kDa) contains the active
Autoantibodies to glomerular basement membrane site and the molecule is referred to as activated Hage-
cause inflammation which can be inhibited by either man factor (factor XIIa). There is evidence that the
complement depletion or by neutrophil depletion. In Hageman factor can autoactivate, thus the pathway
contrast, membranous nephritis, (which may be in- is self-amplifying once triggered (compare with the
duced experimentally by antibodies to subepithelial alternative pathway of complement).
antigens), is unaffected by neutrophil depletion, but Activated Hageman factor in turn activates
almost totally abrogated in animals deficient in C5. prekallikrein. The kallikrein produced can then also
In this disease the basement membrane is presumed cleave factor XII, and a further amplification mech-
to act as a physical barrier to neutrophil exudation, anism is triggered. The activated factor XII remains
so that the heavy proteinuria is caused by deposition in close contact with the activating surface, such that
of membrane attack complex. it can activate factor XI, the next step in the intrinsic
pathway which, to proceed efficiently, requires Ca2+ .
9.1.4.4 The coagulation mechanism Also involved at this stage is HMWK, which binds to
factor XI and facilitates the activation process. Acti-
The blood clothing system or coagulation pathway,
vated factors XIa, XIIa, and kallikrein are all serine
like the complement system, is a proteolytic cas-
proteases, like many of the enzymes of the comple-
cade. Each enzyme of the pathway is present in
ment system.
the plasma as a zymogen, in other words in an inac-
tive form, which on activation undergoes proteolytic Eventually the intrinsic pathway activates factor
cleavage to release the active factor from the pre- X, a process that can also be brought about by the
cursor molecule. The coagulation pathway functions extrinsic pathway. Factor X is the first molecule of
as a series of positive and negative feedback loops the common pathway and is activated by a com-
which control the activation process. The ultimate plex of molecules containing activated factor IX, fac-
goal of the pathway is to produce thrombin, which tor VIII, calcium, and phospholipid which is pro-
can then convert soluble fibrinogen into fibrin, which vided by the platelet surface, where this reaction
forms a clot. The generation of thrombin can be di- usually takes place. The precise role of factor VIII in
vided into three phases, the intrinsic and extrinsic this reaction is not clearly understood. Its presence
pathways that provide alternative routes for the gen- in the complex is obviously essential, as evidenced
eration of factor X, and the final common pathway by the serious consequences of factor VIII deficiency
which results in thrombin formation (Figure 9.3). experienced by haemophiliacs. Factor VIII is mod-
9.1. Inflammation 613

Figure 9.3: The intrinsic, extrinsic, and common pathways of the coagulation (clotting) cascade
614 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

ified by thrombin, a reaction that results in greatly is involved in fibrinolysis or clot removal. Activated
enhanced factor VIII activity, promoting the activa- Hageman factor and its peptides can also initiate
tion of factor X. the formation of kallikrein from plasma prekallikrein,
The extrinsic pathway is an alternative route for and this triggers the release of bradykinin from
the activation of the clothing cascade. It provides a kininogens in the plasma. Kinins are responsible for
very rapid response to tissue injury, generating acti- dilating small blood vessels, inducing a fall in blood
vated factor X almost instantaneously, compared to presssure, triggering smooth muscle contraction, and
the seconds or even minutes required for the intrinsic increasing the permeability of vessel walls. In addi-
pathway to activate factor X. The main function of tion, activation of the coagulation pathway produces
the extrinsic pathway is to augment the activity of a vascular permeability factor, as well as chemotactic
the intrinsic pathway. peptides for professional phagocytes.
There are two components unique to the extrinsic 9.1.4.5 Fibrinolysis
pathway, tissue factor or factor III, and factor VII.
Once haemostasis is restored and the tissue is re-
Tissue factor is present in most human cells bound
paired, the clot or thrombus must be removed from
to the cell membrane. The activation process for tis-
the injured tissue. This is achieved by fibrinolytic
sue factor is not entirely clear. Once activated, tis-
pathway. The end product of this pathway is the
sue factor binds rapidly to factor VII which is then
enzyme plasmin, a potent proteolytic enzyme with
activated to form a complex of tissue factor, acti-
a broad spectrum of activity. Plasmin is formed by
vated factor VII, calcium, and a phospholipid, and
activation of the proenzyme, plasminogen by either
this complex then rapidly activates factor X.
plasma or tissue activators. Tissue plasminogen acti-
The intrinsic and extrinsic systems converge at vators are found in most tissues, except the liver and
factor X to a single common pathway which is ul- the placenta, where they are synthesized by endothe-
timately responsible for the production of thrombin lial cells and are found concentrated in the walls of
(factor IIa). blood vessels. The two best characterized are vascu-
Clot formation. The end result of the clotting lar activator (commonly known as tissue plasmino-
pathway is the production of thrombin for the con- gen activator – tPA) and urokinase. There is great
version of fibrinogen to fibrin. Fibrinogen is a dimer interest in using tPA as a therapeutic agent for dis-
soluble in plasma. Exposure of fibrinogen to throm- solving blood clots: the gene for tPA has now been
bin results in rapid proteolysis of fibrinogen and the cloned and the expressed gene product is avaible for
release of fibrinopeptide A. The loss of small pep- clinical trials. Plasminogen activator is also a prod-
tide A is not sufficient to render the resulting fibrin uct of macrophages. The level of tissue activator in
molecule insoluble, a proces that is required for clot the plasma is normally low, but can be increased by
formation, but it tends to form complexes with adja- exercise and stress.
cent fibrin and fibrinogen molecules. A second pep- Two forms of plasminogen are present in the
tide, fibrinopeptide B, is then cleaved by thrombin, plasma; one has a glutamic acid at the N-terminal
and the fibrin monomers formed by this second pro- of the polypeptide chain, and is called native or glu-
teolytic cleavage polymerize spontaneously to form plasminogen, and the other a lysine. The latter form
an insoluble gel. The polymerized fibrin, held to- arise as a result of partial degradation of the parent
gether by noncovalent and electrostatic forces, is sta- molecule by autocleavage.
bilized by the transamidating enzyme factor XIIIa, Triggering of fibrinolysis occur when the plasmino-
produced by the action of thrombin on factor XIII. gen activator, plasminogen, and fibrin are all in close
These insoluble fibrin aggregates (clots), together proximity. Both plasminogen and its activator bind
with aggregated platelets (thrombi), block the dam- avidly to fibrin as the clot forms. This close associ-
aged blood vessel and prevent further bleeding. ation prevents inhibition of plasmin activity by in-
There is an interrelationships between the coagu- hibitor, and allows proteolysis of the fibrin to pro-
lation pathway and other plasma enzyme systems. ceed after the production of lys-plasminogen. Plas-
Contact activation of the coagulation pathway, in min inhibitors (antiplasmins) which can control plas-
addition to promoting blood clotting, results in the min activity include: α1 -antitrypsin, α2 -antiplasmin,
generation of plasminogen activator activity, which C1 inhibitor, antithrombin III.
9.1. Inflammation 615

Plasmin attacks fibrin at a number of different trolled internally by the presence of inhibitors for
sites, at least 50, reducing its size such that it no each of the active components. C1 inhibitor con-
longer has haemostatic activity. Many fragments are trols the activity of the activated Hageman fac-
formed during this process, and some retain the ca- tor, while α2 -macroglobulin and C1 inhibitor act as
pacity to polymerize, thus some of the early degrada- kallikrein inhibitors. There are a variety of enzymes
tion products can compete with fibrinogen for throm- in plasma that control bradykinin activity, including
bin and act as inhibitors of clot formation. This may carboxypeptidase N, which removes the C-terminal
prevent the clot being removed before the tissue is arginine residue, thus inactivating the peptide.
repaired. Kallikrein also act directly on the complement
pathway with direct cleavage of the chemotactically
9.1.4.6 The kinin-forming system active peptide C5a from the complement component
C5. Cleavage of fibrinogen by plasmin results in
The kinins, bradykinin and lysylbradykinin, are im- a number of products including fibrinopeptide B,
portant mediators of inflammatory responses. They which potentiates the action of bradykinin and has
are liberated from precursor molecules, kininogens, also chemotactic activity for phagocytic cells.
by the action of various proteases, collectively known
as kininogenases. Three types of kininogen have
9.1.4.7 Cytokines mediating inflammatory
been identified: high- and low-molecular weight
and effector functions
kininogen (HMWK and LMWK respectively), and
T-kininogen. These molecules are synthesized by Cytokines are soluble (glyco)proteins, nonim-
hepatocytes and are released into the plasma, where munoglobulin in nature, released by living cells of
in addition to releasing kinins, they function as (i) co- the host, which act nonenzymatically in picomolar
factors in the coagulation pathway; (ii) inhibitors of to nanomolar concentrations through specific recep-
cysteine protease enzymes; and (iii) part of the acute tors to regulate host cell function. Cytokines make
phase response. The kinins are potent vasoactive up the fourth major class of soluble intercellular sig-
basic peptides and their properties are wide rang- naling molecules, alongside neurotransmitters, en-
ing, including the ability to increase vascular perme- docrine hormones, and autacoids. They possess typ-
ability, cause vasodilation, pain, and the contraction ical hormonal activities:
of smooth muscle, and to stimulate arachidonic acid
metabolism. 1. they are secreted by a single cell type, react
Three different pathways may lead to kinin for- specifically with other cell types (target cells)
mation during inflammation: (i) the generation of and regulate specific vital functions that are
bradykinin as a result of activation of the Hage- controlled by feedback mechanisms;
man factor and the production of plasma kallikrein;
2. they generally act at short range in a paracrine
(ii) the production of lysylbradykinin by tissue
or autocrine (rather than endocrine) manner;
kallikreins; and (iii) the action of cellular proteases
in kinin formation. 3. they interact first with high-affinity cell sur-
The mechanism of bradykinin formation in plasma face receptors (distinct for each type or even
and in tissues is summarized in Figure 9.4. subtype) and then regulate the transcription
In brief, HMWK and prekallikrein circulate in of a number of cellular genes by little under-
plasma as a 1:1 stoichoimetric complex. This com- stood second signals. This altered transcription
plex, together with the Hageman factor, binds to (which can be an enhancement or inhibition) re-
negatively charged surface or collagen. Once they sult in changes in cell behaviour.
are exposed by tissue damage, the Hageman factor
is activated, prekallikrein is converted to kallikrein, Target cells, on which cytokines transform their in-
and HMWK itself is digested to release bradykinin, formation signal, may be localized in any body com-
a nine amino acid peptide. partment (sometimes a long distance from the site of
As bradykinin is such a potent vasoactive pep- secretion). Other type of these molecules act mostly
tide, its activity and its formation must be care- on neighbouring cells in the microenvironment where
fully controlled. Activation of the pathway is con- they have been released. These are characterized as
616 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

Figure 9.4: The kinin pathway forming bradykinin

local hormones and their secretion is brought about munoregulatory products, (lymphokines, monokines,
by autocrine (only the cell or organ of secretion interleukins and other cytokines), despite being of lo-
is affected) or paracrine mechanisms. During the cal hormone character, may act in fact systemically.
paracrine secretion some cytokines may escape cell Cytokines are synthesized, stored and transported
binding and may spill over into general circulation by various cell types not only inside of the im-
via lymph or plasma. This is important, especially mune system (lymphokines, interleukins, monokines,
for the products of lymphoid cells, which are mobile tumour necrosis factors, interferons) but also by
after having picked up the message in the microenvi- other cells which are mainly studied in haematology
ronment throughout the body and therefore their im- (colony-stimulating factors), oncology (transforming
9.1. Inflammation 617

growth factors), and cell biology (peptide growth fac- ulatory and antitumour activities but when TNF-α
tors, heat shock and other stress proteins). The main circulates in higher concentrations beyond the organ
types of cytokines are listed in Table 9.9. of origin, it may be involved in the pathogenesis of
Lymphokines are cytokines secreted mainly by ac- endotoxic shock, cachexia and other serious diseases.
tivated TH lymphocytes and the term monokines From the point of inflammation view there are
refers to analogous immunoregulators produced by two main groups of cytokines: proinflammatory and
activated macrophages and monocytes. In order to anti-inflammatory (Table 9.10). Proinflammatory
unify the terminology of these factors, the term in- cytokines are produced predominantly by activated
terleukin was accepted. Besides the term expressing macrophages and are involved in the up-regulation
their origin, cytokines may be also named according of inflammatory reactions. Anti-inflammatory cy-
to their function, as are interferons, growth and dif- tokines belong to the T cell-derived cytokines and
ferentiation factors, colony-stimulating factors, etc. are involved in the down-regulation of inflammatory
The central role of cytokines is to control the direc- reactions.
tion, amplitude, and duration of immune responses
The central role in inflammatory responses have
and to control the (re)modeling of tissues, be it devel-
IL-1 and TNF-α, because the administration of their
opmentally programmed, constitutive, or unsched-
antagonists, such as IL-1ra (IL-1 receptor antago-
uled. Unscheduled remodeling is that which accom-
nist), soluble fragment of IL-1 receptor, or mono-
panies inflammation, infection, wounding, and re-
clonal antibodies to TNF-α and soluble TNF recep-
pair. Individual cytokines can have pleiotropic (mul-
tor, all block various acute and chronic responses
tiple), overlaping and sometimes contradictory func-
in animal models of inflammatory diseases. Some
tions depending on their concentration, the cell type
of these antagonists are beginning to utilize as anti-
they are acting on, and the presence of other cy-
inflammatory agents in diseases such as sepsis and
tokines and mediators. Thus the information which
rheumatoid arthritis. IL-1 and TNF-α together
an individual cytokine conveys depend on the pat-
with IL-6 serve as endogenous pyrogens. The up-
tern of regulators to which a cell is exposed, and not
regulation of inflammatory reaction is also performed
on one single cytokine. It is supposed that all cy-
by IL-11, IFN-α , IFN-β , and especially by the
tokines form the specific system or network of com-
members of chemokine superfamily. On the other
munication signals between cells of the immune sys-
hand, anti-inflammatory cytokines (IL-4, IL-10, IL-
tem, and between the immune system and other or-
13) are responsible for the down-regulation of in-
gans. In this inter-cell signalling network, the signal
flammatory responses. They are able to suppress
is usually transfered by means of a special set of cy-
the production of proinflammatory cytokines. Their
tokines.
strong anti-inflammatory activity suggest possible
Because of the potent and profound biological ef- utilization in management of many inflammatory dis-
fects of cytokines, it is not surprising that their activ- eases, including sepsis, rheumatoid arthritis, inflam-
ities are tighly regulated, most notably at the levels matory bowel disease, psoriasis, T cell-mediated au-
of secretion and receptor expression. Additional reg- toimmune diseases such as type I diabetes, as well
ulatory mechanisms are provided by the concomitant as in acute graft-versus-host disease. IL-10 is ca-
action of different cytokines and the presence in bi- pable of effectively protecting mice from endotoxin-
ological fluids of specific inhibitory proteins, soluble induced shock, a lethal inflammatory reaction medi-
cytokine-binding factors and specific autoantibodies. ated by TNF-α and IL-1. The production of most
The cytokine system is a very potent force in lymphokines and monokines such as IL-1, IL-6 and
homeostasis when activation of the network is lo- TNF-α is also inhibited by transforming growth fac-
cal and cytokines act vicinally in surface-bound or tor β (TGF-β). But, on the other hand, TGF-β
diffusible form, but when cytokine production is has a number of proinflammatory activities includ-
sustained and/or systemic, there is no doubt that ing chemoattractant effects on neutrophils, T lym-
cytokines contribute to the signs, symptoms, and phocytes, and unactivated monocytes. TGF-β has
pathology of inflammatory, infectious, autoimmune, been demonstrated to have in vivo immunosupres-
and malignant diseases. TNF-α is an excellent exam- sive and anti-inflammatory effects as well as proin-
ple of such dual action. Locally it has important reg- flammatory and selected immunoenhacing activities.
618 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

Cytokine types Individual cytokines

Lymphokines MAF (macrophage inhibition factor), MMIF (macrophage migra-

tion inhibitiom factor), MCF (macrophage chemotactic factor),
LMIF (leukocyte migration inhition factor), HRFs (histamine re-
leasing factors), TF (transfer factor)

Interleukins IL-1, IL-2, . . . ., IL-15

Tumour necrosis factors TNF-α (cachectin), TNF-β (lymphotoxin)

Interferons IFN-α, IFN-β, IFN-γ, IFN-ω, IF-τ

Colony stimulating factors G-CSF (granulocyte colony stimulating factor), GM-CSF

granulocyte-macrophage CSF), M-CSF (macrophage CSF), multi-
CSF (IL-3)

Polypeptide growth factors aFGF (acidic fibroblast growth factor), bFGF (basic fibroblast
growth factor), EGF (epidermal growth factor), NGF (nerve
growth factor), PDGF (platelet-derived growth factor), VEGF
(vascular endothelial growth factor)

Transforming growth factors TGF-α, TGF-β

α-Chemokines IL-8, NAP-2 (neutrophil-activating protein 2), PF-4 (platelet fac-

tor 4), βTG (β-thromboglobulin)

β-Chemokines MCP-1 (monocyte chemoattractant protein 1), MCP-3, MIP-1α,

MIP-1β (macrophage inflammatory protein 1β), RANTES

Stress proteins HSPs (heat shock proteins), GRPs (glucose-regulated proteins),

ubiquitin, superoxide dismutase (Mn)

RANTES: Regulated upon Activation Normal T Expressed and presumably Secreted chemokine

Table 9.9: Main types of cytokines

When administered systemically, TGF-β acts as an cells, endothelial cells, smooth muscle cells, fetal hep-
inhibitor, but if given locally can promote inflamma- atocytes, and myeloid, erythroid, and lymphoid cells.
tion. Generally, TGF-β stimulates neovasculariza- TGF-β is a potent immunosupressive cytokine that
tion and the proliferation and activities of connective supresses cell-mediated as well as humoral immunity
tissue cells and is a pivotal factor in scar formation (including tumour immunity).
and wound healing. But TGF-β has antiproliferative
effects on most other cell types including epithelial
9.1. Inflammation 619

Group Individual cytokines

Proinflammatory cytokines
Endogenous pyrogens IL-1, TNF-α, IL-6
Up-regulation IL-1, TNF-α, IL-6, IFN-α, IFN-β, chemokines
Stimulation of the production of IL-1, IL-6, IL-11, TNF-α, INF-γ, TGF-β, LIF, OSM,
acute phase reactants CNTF

Chemoattractant cytokines
CXC chemokines IL-8, PF-4, PBP, NAP-2, β-TG
CC chemokines MIP-1α, MIP-1β, MCP-1, MCP-2, MCP-3, RANTES
C chemokines Lymphotactin
Stimulation of proinflammatory IL-12
cytokines

Anti-inflammatory cytokines
Inhibition of production of proin- IL-4, IL-10, IL-13
flammatory cytokines

TGF-β: transforming growth factor; LIF: leukemia inhibitory factor; OSM: oncostatin M;
CNTF: ciliary neurotrophic factor; PF-4: platelet factor 4; PBP: platelet basic protein;
NAP-2: neutrophil activating protein 2; β-TG: β-thromboglobulin; MIP: macrophage in-
flammatory protein; MCP: monocyte chemoattractant protein; RANTES: Regulated upon
Activation Normal T Expressed and presumably Secreted chemokine

Table 9.10: Cytokines involved in inflammatory reactions

9.1.4.7.1 Chemokines Chemokines (a shorten- tent inducers of other cytokines and exhibit more
ing of chemoattractant cytokines) represent a super- specialized functions in inflammation and repair.
family of about 30 chemotactic cytokines acting as
vital initiators and promulgators of inflammatory re- The chemokine molecules share structural similari-
actions. They range from 8 to 11 kD in molecular ties, including four conserved cysteine residues which
weight, are active over a 1 to 100 ng/ml concen- form disulphide bonds in the tertiary structure of
tration range, and are produced by a wide variety the proteins. Traditionally, the chemokine super-
of cell types. The production of chemokines is in- family has been divided into two subgroups: C-X-C
duced by exogenous irritants and endogenous me- (where X is any amino acid) and C-C, according to
diators such as IL-1, TNF-α , PDGF, and IFN-γ . whether an intervening residue spaces the first two
The chemokines bind to specific cell surface recep- cysteines. This structural distinction has been shown
tors and can be considered second-order cytokines to delineate a general, though not absolute, distinc-
that appear to be less pleiotropic than first-order tion in the biological properties of these molecules:
proinflammatory cytokines because they are not po- most C-X-C chemokines are chemoattrastants for
neutrophils (and to some extent lymphocytes) but
620 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

not monocytes, whereas C-C chemokines appear to acterized pathologically by the infiltration of neu-
attract monocytes, basophils, eosinophils, and lym- trophils and/or mononuclear cells and proliferation
phocytes (including NK cells) but not neutrophils. of mesangial cells, whereas the latter lacks such find-
Recently, the third ”C” branch of these molecules ings. Immunohistochemical analyses demonstrated
has been discovered. Lymphotactin, the representa- the detection of IL-8 protein in inflammatory cells
tive of these C chemokines, is clearly chemoattrac- infiltrated into glomeruli in IgA nephropathy, sug-
tant for lymphocytes and NK cells, but it does not gesting that IL-8, produced in glomeruli, promotes
attract either monocytes or neutrophils. The list of the infiltration of neutrophils into glomeruli, thereby
main chemokines is in the Table 9.10 and 9.11. inducing renal injury.
Not all of the known properties of the chemo- Monocyte chemoattractant protein – 1 (MCP-1) is
kines involve leukocyte migration. For example a chemoattractant for human monocytes with the op-
chemokines have been reported to have roles in timal agonist concentration of 10−9 mol/L and may
haematopoietic precursor cell cycling regulation and play a role in the accumulation of monocytes over a
differentiation. On the other hand, their involve- period of 24-48 hours after interaction of antigen and
ment in such processes as leukocyte trafficking and sensitized lymphocytes. MCP-1 is nearly as effective
inflammatory processes further suggest that the as C5a, and much more potent than IL-8, in the de-
chemokines are important in a number of disease granulation of basophils, resulting in histamine re-
states. It is now clear that certain C-C chemokines, lease. This may play an important role in the patho-
namely RANTES, MCP-1, MCP-3 and MIP-1 ex- genesis of the late phase of allergic disorders such as
hibit potent promigratory and activating potentials atopic food allergies, asthma, and chronic urticaria.
for eosinophils, basophils and T cells, the cells most Histamine release also occurs after stimulation with
often associated with respiratory pathologies and al- two other C-C chemokines, RANTES and MIP-1α .
lergic disorders, including asthma and nasal polypo-
sis. These observations are now being coupled with 9.1.4.8 Chemotactic factors
an emerging body of evidence showing that these
mediators can be localized to affected tissues during The term chemotaxis refers to the movement of
these pathologies. leukocytes (or cells in general), induced by a chemo-
tactic stimulus. Besides chemotaxis (stimulated, di-
IL-8 and MCP-1 are more widely produced than
rected migration), leukocytes also posses two other
other chemokines and there is a suggestion that they
types of movement: random migration (undirected,
represent the first line of defence.
spontaneous migration) and chemokinesis (stimu-
Interleukin-8 is a polypeptide consisting of 72 lated, undirected migration). A chemotactic stimu-
amino acids in its mature form. The biological profile lus is provided by substances that can either attract
of activity of IL-8 is very similar to that of the classi- or repulse the cells. Thus, chemotactic cell move-
cal chemotactic peptides C5a and FMLP (N-formyl- ment can be either positive or negative, i.e. the cells
methionyl-leucyl-phenylalanine). It is able to induce may move towards the source of chemotactic sub-
the full pattern of responses observed in chemotac- stances (towards an increasing concentration gradi-
tically stimulated neutrophils, i.e. activation of the ent) or in the opposite direction. The positive move-
motile apparatus and directional migration, expres- ment is typical for leukocytes. Substances possessing
sion of surface adhesion molecules, release of lyso- chemotactic activity are called chemotactic factors
somal enzymes, and production of reactive oxygen (chemotaxins, chemoattractants).
intermediates. IL-8 is not species-specific and is a Leukocyte chemotaxis (leukotaxis) is mainly re-
potent angiogenic factor. sponsible for their mobilization at the inflammatory
Recently, elevated urinary IL-8 levels were ob- site. Both exogenous and endogenous chemoattrac-
served in patients with several types of glomerulone- tant participate in this event (Table 9.11). Exoge-
phritis including IgA nephropathy, acute glomerulo- nous chemotaxins include bacterial oligopeptides of
nephritis, purpura nephritis, membranous prolifera- the FMLP type, lectins, denutured proteins, some
tive glomerulonephritis, and lupus nephritis, but not lipids and lipopolysaccharides. Endogenous chemo-
in patients with focal glomerulosclerosis and mem- taxins are produced by the host organism and are of
branous nephropathy. The former groups are char- humoral (complement fragment C5a, C5desArg and
9.1. Inflammation 621

Chemoatractant Ne Mo/Ma Eo Ba Ly NK

Exogenous
FMLP + + – – – –

Endogenous
C5a + + + – – –
LTB4 , PAF + + – – – –
PDGF + + – – – –
IL-3, IL-5 – – + + – –
TGF-β + ± – – + +

Chemokines CXC
IL-8, NAP-2 + – – – ± –

Chemokines CC
MCP-1 – + – + + +
MCP-3, MIP-1, RANTES – + + + + +

Chemokines C
Lymphotactin – – – – + +

Ne: neutrophils; Mo: monocytes; Ma: macrophages; Eo: eosinophils; Ba: basophils;
Ly: lymphocytes (T cells); NK: NK cells; FMLP: N-formylmethionyl-leucyl-phenylalanine

Table 9.11: The main chemotactic factors for leukocytes

Ba, fibrinopeptides, kallikrein and plasminogen acti- from a round to a triangular shape that is oriented
vator) or cellular type (from different cells – LTB4 , along the direction of chemotactic gradient. Reorga-
PAF, chemotactic cytokines etc.) nization of cytoskeletal contractile elements, partic-
Interaction between the chemotactic factor and its ularly actin microfilaments and microtubular struc-
corresponding receptor triggers a series of coordi- tures, contributes to this shape change. Activation
nated biochemical events which include changes in of the contractile cell system not only results in mi-
the cell transmembrane potential, altered cyclic nu- gration but also in other form of movement such as
cleotide levels and ion flow across the cytoplasmic enhanced adherence, spreading, endocytosis and se-
membrane and increased glucose utilization and oxy- cretion of lysosomal enzymes.
gen consumption. The composition of membrane
phospholipids is altered and arachidonic acid, re- 9.1.4.9 The acute phase reactants
leased by phospholipases, is metabolized into a num-
ber of biologically active intermediates and prod- Within the spectrum of systemic reaction to inflam-
ucts. Within a few minutes, the leukocyte changes mation two physiological responses in particular are
622 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

regarded as being associated with acute inflamma- to synthesize the induced APRs. The list of APRs is
tion. The first involves the alteration of the tempera- in Table 9.12.
ture set-point in the hypotalamus and the generation APRs have a wide range of activities that con-
of the febrile response. The second involves alter- tribute to host defence: they can directly neutral-
ations in metabolism and gene regulation in the liver. ize inflammatory agents, help to minimize the ex-
Three cytokines that are released from the site of tis- tent of local tissue damage, as well as participate
sue injury – IL-1, TNF-α and IL-6 are considered to in tissue repair and regeneration. There is a rapid
regulate the febrile response, possibly as a protective increase in the plasma concentration of many com-
mechanism. These cytokines mediate fever through plement cascade components the activation of which
the induction of PGE2 . At the same time, IL-1 and ultimately results in the local accumulation of neu-
IL-6 can act on the adrenal pituitary axis to generate trophils, macrophages and plasma proteins. These
adrenocorticotropic hormone (ACTH) and, subse- participate in the killing of infectious agents, the
quently, induce the production of cortisol. This pro- clearance of foreign and host cellular debris, and the
vides a negative feedback loop, since corticosteroids repair of damaged tissue. Coagulation components,
inhibit cytokine gene-expression. such as fibrinogen, play an essential role in promot-
It is important to consider the acute phase re- ing wound healing.
sponse (and inflammation) as a dynamic homeostatic Proteinase inhibitors neutralize the lysosomal pro-
process that involves all of the major systems of the teases released following the infiltration of activated
body, in addition to the immune, cardiovascular and neutrophils and macrophages, thus controlling the
central nervous system. Normally, the acute phase activity of the proinflammatory enzyme cascades.
response lasts only a few days; however, in cases of The increased plasma levels of some metal-binding
chronic or recurring inflammation, an aberrant con- proteins help prevent iron loss during infection and
tinuation of some aspects of the acute phase response injury, also minimizing the level of haem iron avaible
may contribute to the underlying tissue damage that for uptake by bacteria and acting as scavenger for
accopanies the disease, and may also lead to further potentially damaging oxygen free radicals.
complications, for example cardiovascular diseases or The major APRs in mammals include serum amy-
protein deposition diseases such as reactive amyloi- loid A (SAA) and either C-reactive protein (CRP)
dosis. or serum amyloid P component (SAP) depending on
The second important aspect of the acute phase the species. Ironically, of all the APRs, the activities
response is the radically altered biosynthetic profile of these three are among the least well-known. Nev-
of the liver. Under normal circumstances, the liver ertheless, their interactions with other well-defined
synthesizes a characteristic range of plasma proteins defence systems and the magnitute and rapidity of
at steady state concentrations. Many of these pro- their induction following an acute phase stimulus, to-
teins have important functions and higher plasma gether with their short half-lifes, suggest a particu-
levels of these acute phase reactants (APRs) or acute larly critical requirement for these proteins very early
phase proteins (APPs) are required during the acute in the establishment of host defence. Significantly,
phase response following an inflammatory stimulus. individuals unable to synthesize these proteins have
Although most APRs are synthesized by hepato- not been described; these major APRs are therefore
cytes, some are produced by other cell types, in- likely to be of considerable clinical importance.
cluding monocytes, endothelial cells, fibroblasts and CRP and SAP are pentraxins, proteins with a
adipocytes. Most APRs are induced between 50 % characteristic pentameric organization of identical
and several-fold over normal levels. In contrast, the subunits arraged as single and double annular pen-
major APRs can increase to 1000-fold over normal tagonal discs, respectively. Generally, only one of
levels. This group includes serum amyloid A (SAA) these proteins is an APR in a given mammalian
and either C-reactive protein (CRP) in humans or species: in humans, normal plasma SAP levels are
its homologue in mice, serum amyloid P compo- approximately 30 mg.L−1 and remain constant dur-
nent (SAP). So-called negative APRs are decreased ing inflammation but CRP levels can increase up to
in plasma concentration during the acute phase re- 1000-fold from approximately 1 mg.L−1 , depending
sponse to allow an increase in the capacity of the liver on the disease and its severity. CRP was originally
9.1. Inflammation 623

Group Individual proteins

Positive APRs
Major APRs Serum amyloid A, C-reactive protein, serum amyloid P component
Complement proteins C2, C3, C4, C5, C9, B, C1 inhibitor, C4 binding protein
Coagulation proteins Fibrinogen, von Willebrand factor
Proteinase inhibitors α1 -Antitrypsin, α1 -antichymotrypsin, α2 -antiplasmin, heparin cofac-
tor II, plasminogen activator inhibitor I
Metal-binding proteins Haptoglobin, haemopexin, ceruloplasmin, manganese superoxide dismu-
tase
Other proteins α1 -Acid glycoprotein, haeme oxygenase, mannose-binding protein, leuko-
cyte protein I, lipoprotein (a), lipopolysaccharide-binding protein

Negative APRs Albumin, pre-albumin, transferin, apoAI, apoAII, α2 -HS glycoprotein,

inter-α-trypsin inhibitor, histidine-rich glycoprotein

Table 9.12: Acute phase reactants

named for its ability to bind the C-polysaccharide of thrombin-induced platelet activation, as well as in-
of Pneumococcus and has since been shown to have hibition of the oxidative burst in neutrophils, which
a number of calcium-dependent binding specificities would help prevent oxidative tissue destruction.
and biological avtivities related to nonspecific host
The exquisite responsiveness of CRP to acute
defence. It acts as an opsonin for bacteria, parasites
phase stimuli, along with its wide concentration
and immune complexes, and can activate the classi-
range and ease of measurement, have led to plasma
cal pathway of complement. SAP is the circulating
CRP levels being used to monitor accurately the
form of amyloid P component, which is a constituent
severity of inflammation and the efficacy of disease
of all types of amyloid deposits.
management during an infection. Conversely, some
diseases (e.g. systemic lupus erythematosus) are as-
SAA is the collective name given to a family of
sociated with relatively low plasma levels of CRP.
polymorphic proteins encoded by multiple genes in a
number of mammalian species. Functionally, SAAs SAA and SAP are archetypal examples of plasma
are small apolipoproteins that associate rapidly dur- proteins that are likely to be beneficial during the
ing the acute phase response with the third fraction transient acute phase response but which have detri-
of high-density lipoprotein (HDL3), on which they mental effects in chronic inflammation. These ma-
become the predominant apolipoprotein. SAA en- jor APRs have been implicated in a number of clini-
hances the binding of HDL3 to macrophages during cal conditions. Secondary, or reactive amyloidosis is
inflammation, concomitant with a decrease in the the occasional consequence of a variety of chronic
binding capacity of HDL3 to hepatocytes. It suggest and recurrent inflammatory diseases, for example
that SAA may remodel HDL3 and act as a signal to leprosy, tuberculosis, systemic lupus erythematosus
redirect it from hepatocytes to macrophages, which and rheumatoid arthritis. It is characterized by the
can then engulf cholesterol and lipid debris at sites ultimately fatal deposition of insoluble fibrils in a
of necrosis. Excess cholesterol could thus be redis- number of tissues, including spleen, liver and kidney.
tributed for use in tissue repair or excreted. Other Secondary amyloid deposits are composed mainly of
putative protective roles for SAA are the inhibition amyloid A derived (probably by proteolysis) from the
624 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

precursor SAA. Amyloid P component (AP), derived through junctions between endothelial cells, and pen-
from SAP, is associated with secondary AA plaques etrate the basement membrane before gaining entry
and all other forms of amyloid deposits, including into, and migrating through the tissue spaces. The
those present in Alzheimer’s disease, AP has also nature and magnitude of the leukocyte-endothelial
been shown to act as an elastase inhibitor, which sug- cell adhesive interactions that take place within post-
gest a role for SAP on amyloid deposit in protecting capillary venules are determined by a variety of fac-
the fibrils from degradation by proteolytic enzymes. tors, including expression of adhesion molecules on
APR synthesis is under control performed by in- leukocytes and/or endothelial cells, signaling by cy-
flammatory mediators from which several cytokines tokines and chemotactic factors, products of leuko-
and hormones specifically regulate the transcription cyte (superoxide) and endothelial cell (nitric oxide)
of human APRs (Figure 9.5). activation, and the physical forces generated by the
These include TNF-α, IL-1, IL-6, IL-11, IFN-γ, movement of blood along the vessel wall.
LIF, OSM, CNTF, TGF-β, and glucocorticoids. In
addition, insulin and akadaic acid have recently been 9.1.5.1 Adhesion molecules
shown to act as inhibitors of the cytokine-driven in-
duction of some APRs. There is considerable het- During an inflammatory response adhesion molecules
erogeneity in the response of individual APR genes serve to enhance pairing between many less avid re-
to the listed cytokines. An important feature of the ceptors and their ligands and transmit signals that
acute phase response is that IL-1 and TNF-α stim- direct specific effector functions. At least four su-
ulate, via the CNS, the synthesis of glucocorticoids perfamilies of adhesion molecules participate in these
by the adrenal glands, which results in co-operative events: the selectins, the integrins, certain members
enhancement of the IL-1 and TNF-α-mediated in- of the immunoglobuline superfamily and cadherins.
duction of APR synthesis in the liver. This effect The selectin family is composed of three mem-
is coincident with the glucocorticoid-mediated down bers named according to the cells in which they
regulation of IL-1 synthesis by macrophages, thereby were originally discovered. L-selectin (CD62L) is
creating a negative-feedback loop between the im- constutively expressed on leukocytes and its tar-
mune and CNS systems to reduce de novo cytokine get cells are activated endothelial cells. E-selectin
synthesis. Most of the increase (or decrease, in the (CD62E) is produced exclusively by endothelial cells
case of negative APRs) in APR biosynthesis is due after cytokine activation and its counter-receptors
to increased (or decreased) gene transcription. are on neutrophils, monocytes, eosinophils, lym-
phocyte subsets and some tumour cells. P-selectin
(CD62P) is preformed and stored for rapid release in
9.1.5 Molecular mechanisms of the the granules of platelets or the Weibel-Palade bod-
acute cell-mediated inflamma- ies of endothelial cells but in the latter P-selectin
tory reaction is expressed only after cytokine activation. Its
target cells are the same as those for E-selectin.
The accumulation of leukocytes in inflamed tissue Each selectin receptor molecule contains a lectin-
results from adhesive interactions between leuko- like N-terminal domain, followed by an epidermal
cytes and endothelial cells within the microcircula- growth factor–like motif, a series of consensus re-
tion. These adhesive interactions and the excessive peats similar to those in complement-regulatory pro-
filtration of fluid and protein that accompanies an teins, a transmembrane domain, and a cytoplasmic
inflammatory response are largely confined to one re- tail. The lectin domain is directly involved in mediat-
gion of the microvasculature: postcapillary venules. ing cell-cell contact through Ca2+ -dependent inter-
This process is quite complicated and broadly in- actions with cell-surface carbohydrates, particularly
clude four distinct components: circulation, adhe- the sialyated Lewis X antigen (sLex ).
sion, diapedesis, and migration. First, leukocytes The integrins are a large family of heterodimeric
must overcome haemodynamic forces in order to ad- glycoproteins which can be subdivided according to
here to the endothelial cell surface lining the typi- the particular β subunit they possess, which is shared
cal vessel wall. Having done this, they must crawl by all members of the group. On this basis, this
their way along the endothelial cell surface, migrate family can be subdivided into the β1, β2, and β3
9.1. Inflammation 625

IL-6 IL-11 IFN-γ LIF OSM CNTF TGF-β

FEVER

+
✛ TNF-α ✲
Hypothalamic
anterior pituitary- ✛ IL-1 ✲
adrenal axis + LIVER

✲ Glucocorticoids ✲
E
✛ Insulin
✛ Okadaic acid

ACUTE PHASE PROTEINS

Abbreviations: + stimulation of activity; – inhibition of activity; E: enhancement of activity;

LIF: leukemia inhibitory factor; OSM: oncostatin M; CNTF: ciliary neurotrophic factor.

Figure 9.5: Inflammatory mediators that modulate hepatic APR synthesis in humans

integrins. The β2 integrins are expressed particu- CD11b/CD18 is the complement receptor type 3,
larly by leukocytes, giving rise to their alternative CR3, and CD11c/CD18 is CR4 (also called p150,95).
name, the leukocyte integrins, whereas the others, Both CR3 and CR4 are expressed by myeloid cells.
in general, are more widely distributed. The β 2 There are two or more ligands for LFA-1, those
leukocyte integrins are represented by three het- defined to date being ICAM-1 (CD54) and ICAM-2
erodimeric molecules: LFA-1 (CD11a/CD18), CR3 (CD102), which are members of the immunoglobu-
(DC11b/CD18), and CR4 (CD11c/CD18). Each of lin superfamily. CR3 can bind fragments of comple-
them contains the same 95 kDa β2 integrin subunit, ment components, particularly iC3b, and it mediates
also designated CD18 and different α chains des- phagocytosis of complement-coated particles by pro-
ignated CD11a (180 kDa), CD11b (165kDa), and fessional phagocytes.
CD11c (150kDa). The intact CD11a/CD18 molecule
Alongside with intercellular adhesion molecules
is the lymphocyte function-associated antigen-1,
ICAM-1 and ICAM-2 there is additional mem-
LFA-1 and is expressed by lymphocytes (including
ber of the diverse immunoglobulin superfam-
T cells), myeloid cells (monocytes, macrophages,
ily - platelet-endothelial cell adhesion molecule,
and granulocytes), and a variety of other cell type.
PECAM-1 (CD31). Both ICAM-1 and ICAM-2
626 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

are expressed by endothelial cells, PECAM-1 has posure to inflammatory mediators including com-
been indentified on neutrophils, monocytes, platelets plement fragments (C5a), cytokines such as IL-1,
and is present in large amounts on endothelial cells IL-8 and TNF-α, and lipopolysaccharide or clas-
(about 106 copies per cell), where it is concentrated sical chemoattractants such as formylated methio-
at cell-cell junction. nine – leucine - phenylalanine (FMLP) leading to
The main adhesion molecules participating in their microvascular sequestration due in part to de-
the interactions between neutrophils and endothe- creased deformability (i.e. increased cell stiffness)
lial cells of postcapillary venules are shown in Ta- and in part to increased adhesiveness of the circu-
ble 9.13). lating leukocytes. Endothelial cells are similary acti-
vated, leading to enhanced expression of several ad-
9.1.5.2 Leukocyte mobility and chemotaxis hesion molecules. Platelet activating factor (PAF)
produced by endothelial cells may act on nearby neu-
The emigration of circulating leukocytes from the trophils to potentiate their adhesion to the endothe-
blood into inflamed tissues have been refined into a lium.
”three step” process comprising: (a) rolling of leuko- Transmigration of neutrophils across the endothe-
cytes along the vasculature (mediated through tran- lial barrier involves interaction between leukocyte in-
sient interactions between selectin proteins and their tegrins and endothelial ICAM, and between glycosy-
carbohydrate ligands), followed by (b) activation of lated aminoglycans on the neutrophil plasma mem-
both neutrophils and endothelial cells and a high brane and PECAM-1, which is localized in the inter-
affinity interaction between β2 integrins and glyco- cellular junctions of endothelial cells. In extravascu-
proteins of immunoglobulin superfamily, leading ul- lar locations, interaction between extracellular ma-
timaely to (c) extravasation (crawling along the en- trix proteins and adhesion molecules, possibly by ac-
dothelium, diapedesis, and migration into tissue) in tivation of cytosolic tyrosine kinases, facilitate the
response to a chemoattractant gradient (Figure 9.6). release of large quantities of toxic oxygen radicals
Rolling leukocytes are generally defined as white and proteolytic enzymes.
cells that move through microvessels at a rate that Chemokines due to their selective chemoattrac-
is lower than that of red blood cells. In 30 µm diam- tant activities for different types of leukocytes (Ta-
eter postcapillary venules, the red blood cell velocity ble 9.11) play an important role in the process of
is usually 1-3 mm/s, whereas leukocytes roll at veloc- transmigration. The model of chemokine involve-
ities ranging between 5 and 300 µm/s, with the most ment in leukocyte trafficking might be summarized
frequently observed rolling velocities lying between as follows:
20 and 60µm/s. Rolling leukocytes are not always
commited to either firmly adhering to the vessel wall (a) a chemokine, sequestered in solid phase on the
or rolling along the entire vessel length; rolling leuko- endothelial cell surface, is presented as a signal
cytes frequently detach and return to the mainstream to trap a specific type of leukocyte as the cell is
of flowing blood. Leukocyte rolling is likely to occur undergoing selectin-mediated rolling along the
also under normal physiological conditions in all tis- endothelium;
sues (gastrointestinal mucosa, skin, lung) that are (b) the leukocyte is selectively activated by the
continually exposed to extermal inflammatory stim- chemokine so that the cell stops rolling and be-
uli that are physical and/or chemical in nature. come firmly adhered;
In inflamed tissue, leukocyte rolling frequently
(but not always) leads to a stationary state in which (c) the adhered leukocyte rather ”crawls” than
the leukocyte remains firmly attacked to the en- swims along the chemotactic gradient formed by
dothelial cell surface, without rotation motion. This the chemokines on the endothelium;
strong (high-affinity) adhesive interaction is often re-
(d) the leukocyte undergoes diapedesis and migrates
ferred to as leukocyte sticking, firm adhesion, or ad-
into the tissue space, while still responding to a
herence, terms that denote the absence of movement
chemotactic gradient.
of the leukocyte along the length of the venule.
In the initial phase of an acute inflammatory re- In general, cell mobility represents the integra-
sponse, circulating leukocytes are activated by ex- tion of many processes including adhesion (integrin-
9.1. Inflammation 627

Adhesion receptor Counter-receptor Implicated in

on neutrophils on endothelial cells

Selectin p150sLex (CD15) P-selectin(CD62P) Leukocyte rolling,

interactions sLex (CD15s), E-selectin(CD62E), binding to high endothe-
L-selectin(CD62L) GlyCAM-1 and others lial venules
neutrophil addressins

Integrin– LFA-1, ICAM-1(CD54), Secondary adhesion

immunoglobulin (CD11a/CD18), ICAM-2(CD102), (sticking), spreading,
superfamily in- VLA-4, VCAM-1(CD106) homing to inflamed tissue
teractions (CD49d/CD29)

Immunoglobulin PECAM-1(CD31), PECAM-1(CD31) Potentiating adhesion,

superfamily in- transendothelial migration
teractions HCAM(CD44) Receptor binding hyaluro-
nate and other molecules of
connective tissue

GlyCAM: Glycosaminoglycan–cell adhesion molecule; HCAM: homing cell adhesion molecule;

ICAM-1, ICAM-2: intercellular adhesion molecule 1,2; LFA-1: leukocyte function associated
antigen 1; PECAM: platelet endothelial adhesion molecule; sLex: sialylated Lewis antigen X;
VCAM-1: vascular cell adhesion molecule; VLA-4: very late antigen 4

Table 9.13: Adhesion molecules involved in leukocyte binding to endothelium

dependent), lamellar protrusion (actin-dependent), fections with high mortality (patients seldom survive
deadhesion (integrin-dependent), and contraction beyond two years of age). The moderate deficiency is
(actin and possibly myosin-dependent). Moving neu- accompanied by partially β2 integrin expression; pa-
trophils assume a polarized morphology with an an- tients express 2.5 to 6.0 % of normal LFA-1, CR3 and
terior lamellipodium extended in the direction of CR4 levels and usually have only recurrent skin in-
movement, a cell body that is elongated parallel to fections. Leukocytes from patients with LAD-2 syn-
the axis of lamellar protrusion, and a knob-like tail drome failed to express sLex (CD15s) and therefore
or ”uropod”. they are not able to bind to E-selectin and P-selectin.
Consistent with the proposed role of selectins, there
The importance of leukocyte adhesion molecules
was a marked reduction in the rolling of leukocytes
may be documented by the existence of leukocyte ad-
from these patients. This clearly indicates a require-
hesion deficiency (LAD), a congenital disorder man-
ment for the carbohydrate ligands recognized by the
ifest as LAD-1 and LAD-2 syndromes. Leukocytes
selectins. The LAD-2 patients, are suffering from re-
of patients with LAD-1 syndrome lack β2 integrin
current bacterial infections but they can survive into
expression. It occurs in two main forms: one with
childhood, with short stature and mental retardation
severe and the other with moderate clinical mani-
due to disorder of fucose metabolism since fucose is
festations. In severe form, both α- and β-chains in
an important component of sLex .
the molecule of the LFA-1 subfamily are completely
lacking. The severe deficiency affecting both boys
and girls, is manifested by severe, life-threatening in-
628 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

Figure 9.6: Mechanisms of leukocyte adherence to and transmigration across the endothelium (arranged
according to G.P.Downey, 1994); PECAM: platelet endothelial cell adhesion molecule

9.1.6 Categories of inflammation me- tribute to the sustained nature of the inflammatory
diated by the immune system process.
Coombs and Gell divided inflammatory responses
The immune processes are probably ongoing and, mediated by the immune system into four categories,
in most cases, lead to the elimination of antigens called I, II, III, and IV, which represent four dis-
without producing clinically detectable inflamma- tinct immune mechanisms that result in tissue injury.
tion. The development of clinically apparent inflam- These same four processes represent mechanisms of
mation indicates that the immune system has en- immune protection from infectious agents:
countered either an unusually large amount of anti-
gen, antigen in an unusual location, or antigen that
I. Immediate hypersensitivity (allergic, or reaginic
is dificult to digest. In some diseases, such as rhe-
acute inflammation).
matoid arthritis, the iniciating agent is unknown or
may be normal host tissue components. In oth-
ers (e.g. systemic lupus erythematosus), inherent or II. Cytotoxic (inflammation mediated by cytotoxic
acquired immunoregulatory abnormalities may con- antibodies).
9.1. Inflammation 629

III. Immune complex (inflammation mediated by express atopic diseases and another does not. At
immune complex). least two reasons exist – environmental exposure and
genetics. A third reason – an external event that
IV. Delayed hypersensitivity (chronic inflammation alters IgE regulation – may be important in certain
mediated by lymphocytes and macrophages). clinical situation but may represent a rare cause of
atopic diseases.
9.1.6.1 Allergic (reaginic) acute inflamma- The atopic diseases, allergic rhinitis, asthma, and
tion atopic dermatitis have a genetic component. Some
or all of these clinical syndromes can be present in
Type I hypersensitivity is characterized by an aller- a single member or in several member of the same
gic reaction that occurs immediately following con- family. The natural history of atopic diseases is not
tact with antigen, which is referred to as the aller- known, but it appears that atopic individuals appear
gen. The term allergy means ”changed reactivity” to have a relatively high frequency of food allergy be-
of the host when meeting an ”agent” on a second fore the age of two years; food allergy then becomes
or subsequent occasion. In some individuals certain rarer but the patients develop IgE antibodies to in-
allergens have a propensity to stimulate production halant allergens and manifest allergic rhinitis and/or
of IgE antibodies. IgE antibodies bind nonspecifi- asthma.
cally, via their high affinity Fc receptors, to mast cells
In general, atopy is a hereditary feature manifested
and basophils. Subsequent attachment of antigen to
by abnormal immediated – type hypersensitivity to
the Fab portion of cell-bound IgE antibodies results
a certain allergen or a group of allergens.
in release of contents of cytoplasmic granules from
mast cells and basophils (e.g. histamine), as well as Anaphylaxis denotes an acute systemic immediate
in synthesis and secretion of biologically active prod- reaction to allergen, typically mediated by IgE anti-
ucts of arachidonic acid (e.g. leukotrienes). Mast bodies. The mildest form of anaphylaxis, involving
cell products increase vascular permeability and con- only the skin, is termed urticaria or ”hives”. More
strict bronchial smooth muscle. A wheal and flare re- severe reactions involve the mucous membranes and
action occurs within seconds to minutes. Neutrophils the gastrointestinal, pulmonary, and cardiovascular
and eosinophils characteristically predominate and organs. Anaphylaxis may be life-threatening. The
mononuclear cells can also be seen. manifestations range from urticaria to angioedema
Reaginic reactions are responsible for such allergic (swelling of mucous membranes, for example, of the
phenomena as urticaria, seasonal rhinitis, asthma, lips, tongue, palate, and larynx), nausea and vom-
and in settings where large amounts of antigens (al- iting (edema and smooth muscle contraction of gas-
lergens) enter the host circulation, systemic anaphy- trointestinal tract), asthma (bronchial smooth mus-
laxis. These occur when an IgE response is directed cle contraction), and hypotension (increased vascu-
against innocuous enviromental antigens, such as lar permeability resulting in a loss of blood volume
pollen, house-dust mites or animal dander. The re- into tissue and thus a fall in blood pressure; reducing
sulting release of pharmacological mediators by IgE- contractility of the heart also contributes to hypoten-
sensitized mast cell produces an acute inflammatory sion). Life-threatening reactions involve laryngeal
reaction with symptoms such as asthma or rhinitis. edema, severe asthma, or severe hypotension and cir-
The importance of type I reactions in protection from culatory collapse. Agents that induce IgE-mediated
infectious organisms is uncertain, although the in- anaphylaxis include penicillin, insect venoms, foods,
creased vascular permeability mediated by these re- and occasionally immunotherapy (i.e. injection of al-
actions probably facilitates the capacity of antibody lergen to which a person is allergic, in order to treat
and inflammatory cells to arrive at the infected site. allergic diseases.
In addition, homocytotropic IgE antibodies and cells Identical symptoms, which are not immune medi-
containing inflammatory mediators probably partic- ated, are sometimes termed anaphylactoid. Anaphy-
ipate in the defence against large, non-phagocytable lactoid reactions may be caused by radiocontrast dye
organisms, most notably the multicellular helminthic (used for x-ray studies) and exercise.
parasites. Although antigen-IgE antibody interaction is the
There is an important question why one individual major cause of anaphylaxis, other immune mecha-
630 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

nisms may occasionally induce the syndrome. Thus trophils, eosinophils and generally, K cells, by means
immune complexes may mediate anaphylaxis in some of Fc receptors on these effector cells. This is so-
patients who are IgA-deficient and receive infusions called antibody-dependent cell-mediated cytotoxic-
of IgA, which interacts with preformed anti-IgA anti- ity (ADCC). Alternatively, the antibodies after bind-
body. Anaphylactoid reactions may also occur after ing to tissue antigens can interact with complement
repeated intravenous administration of normal hu- by activating C1 of the classical pathway. This
man immunoglobulin preparation that contain more results in the deposition of the C5b678(9)n mem-
than 5 % of IgG aggregates in agammaglobulinaemic brane attack complex and following lysis of antibody-
or hypogammaglobulinaemic patients. These ag- sensitized cells.
gregates activate complement to produce C5a and Both the complement fragments and IgG can act
C3a anaphylatoxins which stimulate mediator release as opsonins bound to host tissues or to microorgan-
from basophils and perhaps some subsets of mast isms, and phagocytes take up the opsonized parti-
cells. cles. By enhancing the lysosomal activity of phago-
cytes, and potentiating their capacity to produce re-
9.1.6.2 Acute inflammation mediated by cy- active oxygen intermediates, the opsonins increase
totoxic antibodies the phagocytes’ capacity to destroy pathogen, but
also increase their ability to produce immunopatho-
Type II, or antibody-dependent cytotoxic hyper- logical damage in hypersensitivity reactions. For ex-
sensitivity occurs when antibody binds to either ample, neutrophils from the synovial fluid of patients
self antigen or foreign antigen on cells, and leads with rhematoid arthritis produce more superoxide
to phagocytosis, killer cell activity or complement- when stimulated than neutrophils from the blood.
mediated lysis. This is thought to be related to their activation, in
Both type II and type III hypersensitivity are the rheumatoid joint, by mediators which include im-
caused by IgG and IgM antibodies. The main dis- mune complexes and complement fragments.
tinction is that type II reactions involved antibodies The accumulation of inflammatory cells (neu-
directed to antigens on the surface of specific cells trophils), with release of neutrophil lysosomal en-
or tissues, whereas type III reactions involve anti- zymes and generation of toxic oxygen intermedi-
bodies against widely distributed soluble antigens in ates, together with complement-mediated tissue ly-
the serum. Thus, damage caused by type II reac- sis, leads to destruction of tissues as in the glomeru-
tions is localized to a particular tissue or cell type, lar and pulmonary basement membrane damage
whereas damage caused by type III reactions affects in Goodpasture’s syndrome or in the autoimmune
those organs where antigen-antibody complexes are haemolytic anemia and immune-mediated thrombo-
deposited. cytopenia of systemic lupus erythematosus.
These hypersensitivity reactions are related to nor- There are three main subtypes of cytotoxic hyper-
mal immune responses seen against microorganisms sensitivity:
and larger multicellular parasites. Indeed, in mount-
1. Type II reactions between members of the same
ing a reaction to a pathogen, exaggerated immune
species. They are caused by isoimmunization
reactions may sometimes be as damaging to the host
and include transfusion reactions after transfu-
as the effects of the pathogen itself. In such cases
sion of blood incompatible in the AB0 system,
the bordeline between a normal, useful immune re-
haemolytic disease of the newborn due to rhesus
sponse and hypersensitivity is blurred. Hypersensi-
incompatibility and/or transplantation reaction
tivity reactions may also occur in many other con-
provoked by antibodies in the recipient directed
ditions involving immune reactions, particularly au-
against surface transplantation antigens on the
toimmunity and transplantation.
graft.
In type II hypersensitivity, antibody directed
against cell surface or tissue antigens forms immune 2. Autoimmune type II hypersensitivity reactions
complex which interacts with complement and a are evoked by antibodies in the host directed
variety of effector cells to bring about damage to against his own cell or tissue antigens (autoanti-
the target cells. Antibodies can link the target bodies). As an example may serve autoimmune
cells to effectors cells, such as macrophages, neu- haemolytic anaemia caused by autoantibodies
9.1. Inflammation 631

to the patient’s own red cells; Hashimoto’s thy- 9.1.6.3 Acute inflammation mediated by im-
roiditis with autoantibodies against thyroid per- mune complexes
oxidase surface antigen; idiopathic thrombocy-
Type III hypersensitivity develops when immune
topenic purpura manifest by platelet destruction
complexes are formed in large quantities, or cannot
evoked by anti-platelet antibodies; Goodpas-
be cleared adequately by the reticulo-endothelial sys-
ture’s syndrome in which complement-mediated
tem, leading to serum-sikness type reactions.
damage to basement membrane due to specific
Repeated cutaneous injection of antigen was
autoantibodies is observed.
shown by Arthus in 1903 to initiate, within hours,
acute local inflammation. This form of inflamma-
Many diseases are caused by autoantibodies tion, called the ”Arthus reaction”, was ultimately
against hormone receptors. Recently, they are shown to require immune complexes. Deposition of
also known as type V hypersensitivity reac- immune complexes in local tissues with resultant in-
tions. Autoantibodies directed against recep- flammation is common in rheumatic diseases. The
tors can have the function of agonist resulting in combination of IgM or IgG antibodies with antigen
stimulatory hypersensitivity and/or of antago- activates the complement cascade, generating active
nist leading to the blockade of signal transmited peptides such as C5a, which, in addition to dilat-
through the receptor occupied by such an au- ing capillaries and increasing vascular permeability,
toantibody. The example of stimulary hypersi- contracts smooth muscle and mobilizes phagocytic
tivity is thyrotoxicosis where pathological stim- cells. Binding of immune complexes to neutrophils
ulation of TSH receptor occurs, whereas to the and macrophages also activates the respiratory burst
blocking hypersensitivity belong primary myx- with generation of toxic oxygen products such as
oedema (blockade of TSH receptor) or myasthe- hydrogen peroxide, hydroxyl radical, hypochlorous
nia gravis (blockade of acetylcholine receptor). acid, and chloramines. Lysosomal proteolytic en-
zymes, together with toxic oxygen products, produce
a potent system that can damage protein and lead
to blood vessel damage with haemorrhagic necrosis
3. Type II drug reactions are very complicated. and local tissue destruction.
Drugs may become coupled to body compo- When large amounts of antigen enter the circu-
nents and thereby undergo conversion from a lation (as following administration of heterologous
hapten to a full antigen which may sensitive serum), a serum sickness reaction may ensue. As an-
certain individuals. If, during this response, tibody is produced, antigen-antibody complexes are
IgE antibodies are produced, anaphylactic re- formed. Such complexes may localize to small ves-
actions can result. In some circumstances, cell- sels, resulting in local inflammation and vasculitis.
mediated hypersensitivity may by induced. In Phagocytosis of immune complexes by macrophages
other cases where coupling to serum proteins oc- can result in release of cytokines, such as IL-1 and
curs, the possibility of type III immune complex- TNF-α, which initiate fever. Deposition of im-
mediated reactions may arise. Finally, the drug mune complexes in the glomerular basement mem-
antigenic complex with a molecule on the surface brane can lead to glomerulitis. By similar mech-
of host cells may evoke the production of anti- anisms arthritis may result. Rheumatoid arthritis
bodies which are cytotoxic for the cell-drug com- has many characteristics of a local immune complex
plex. Examples of this mechanism have been reaction, whereas systemic lupus erythematosus has
seen in the haemolytic anaemia sometimes asso- many clinical features of serum sickness.
ciated with continued administration of chlor- Diseases resulting from immune complex forma-
promazine or phenacetin, in the agranulocytosis tion can be placed broadly into three groups:
asociated with the taking of amidopyrine or of 1. The combined effects of a low-grade persis-
quinidine, and now classic situation of thrombo- tent infection (such as occur with α-haemolytic
cytopenic purpura which may be produced by a Streptococcus viridans or staphylococcal infec-
sedative edormid. When the drug is withdrawn, tive endocarditis, or with a parasite such as
the hypersensitivy is no longer evident. Plasmodium vivax, or in viral hepatitis), to-
632 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

gether with a weak antibody response, leads stimulated to elaborate lymphokines which mediate
to chronic immune complex formation with the a range of inflammatory responses. Other aspects of
eventual deposition of complexes in the tissues. DTH reactions are seen in graft rejection and allergic
contact dermatitis. DTH is used as a general cate-
2. Immune complex disease is a frequent compli- gory to describe all those hypersensitivity reactions
cation of autoimmune disease where the contin- which take more than 12 hours to develop, and which
ued produced of antibody to a self-antigen leads involve cell-mediated immune reactions rather than
to prolonged immune complex formation. The humoral immune reactions. Whereas allergic reac-
mononuclear phagocyte, erythrocyte, and com- tions occur within seconds and minutes and immune
plement systems (which are responsible for the complex reactions occur within several hours to one
removal of complexes) become overloaded and day, DTH reactions peak at 2 to 3 days.
the complexes are deposited in the tissues, as
occurs in systemic lupus erythematosus. Unlike other forms of hypersensitivity, type IV hy-
persensitivity cannot be transferred from one animal
3. Immune complexes may be formed at body to another by serum, but can be transferred by T
surfaces, notably in the lungs following re- cells (TH 1 cells in mice). In humans, transfer from a
peated inhalation of antigenic material from sensitized to a non-sensitized individual can be also
moulds, plants or animals. This is exemplified in achieved only by T lymphocytes and, interestingly,
Farmer’s lung and Pigeon fancier’s lung, where by a low molecular weight material extracted from
there are circulating antibodies to the actino- them (transfer factor). Delayed type hypersensitiv-
mycete fungi found in mouldy hay, or to pigeon ity is obviously associated with T cell protective im-
antigens. Both diseases are forms of extrinsic munity but does not necessarily run parallel with
allergic alveolitis, and they only occur after re- it – there is not always a complete correlation be-
peated exposure to the antigen. tween delayed hypersensitivity and protective immu-
nity. The T cells necessary for producing the delayed
The main diseases in which immune complexes response are cells which have become specifically sen-
are important are summarized in Table 9.14. The sitized to the particular antigen by a previous en-
sites of immune-complex deposition are partly de- counter, and they act by recruiting other cell types
termined by localization of the antigen in the tissue, to the site of the reaction.
and partly by how ciculating immune complexes be-
Three types of delayed hypersensitivity reac-
come deposites.
tion are recognized: Contact hypersensitivity and
Experimental models are avaible for each of the
tuberculin-type hypersensitivity both occur within
three mains types of immune complex disease de-
72 hours of antigen challenge, whereas granuloma-
scrined above: serum sickness induced by injections
tous reactions develop over a period of weeks. The
of foreign antigen, to represent the presence of a per-
granulomas are formed by the aggregation and pro-
sistent infection; the NZB/NZW mouse, for autoim-
liferation of macrophages, and may persist for weeks.
munity; and the Arthus reaction, for local damage
This reaction is, in terms of its clinical consequences,
by extrinsic antigen. Care must be taken when inter-
by far the most serious type of delayed type hyper-
preting animal experiments as the erythrocytes of ro-
sensitivity response. The position is complicated be-
dents and rabbits lack the receptor for iC3b (known
cause these different types of reaction may overlap, or
as CR1) which readily binds immune complexes that
occur sequentially following a single antigenic chal-
have fixed complement. This is present on primate
lenge.
erythrocytes.
The delayed type hypersensitivity reactions are
probably important for host defence against in-
9.1.6.4 Chronic inflammation (delayed-type
tracellular parasites such as tuberculosis and cer-
of hypersensitivity reaction)
tain viruses and are prevalent in certain disease
Type IV or delayed type hypersensitivity (DTH), such as sarcoidosis, Wegener’s granulomatosis, and
is most seriously manifested when antigens (for ex- polymyositis. In some diseases, such as chronic gran-
ample those of tubercle bacilli) are trapped in a ulomatous disease of childhood, granuloma forma-
macrophage and cannot be cleared. T cells are then tion can lead to obstruction of vital structures such
9.1. Inflammation 633

Site of deposition

CIC VS Kidneys Joints Skin Others

Autoimmune diseases

Systemic lupus erythematosus + + + + + Brain

Rheumatoid arthritis + + +
Polyarteritis + + + Muscle, liver
Cutaneous vasculitis + + +
Polymyositis/dermatomyositis + + Muscle
Fibrosing alveolitis + Lungs
Cryoglobulinaemia + + + + +

Diseases due to microbial antigens

Bacterial endocarditis + + + Heart

Leprosy + + + + Eyes
Malaria + +
Hepatitis + + + + Liver
Trypanosomiasis (African) + + + Heart, brain
Dengue haemorrhagic fever + + +

CIC: circulating immune complexes; VS: the vascular system

Table 9.14: Some of the main diseases in which immune complexes are implicated

as the esophagus or ureters. The contact dermatitis as a perivascular cuffing with mononuclear cells fol-
is caused by sensitization to certain simple chemicals. lowed by a more extensive exudation of mononuclear
and polymorphonuclear cells. The latter soon mi-
Perhaps the best known example of cell-mediated grate out of the lesion leaving behind a predomi-
hypersensitivity is the Mantoux reaction obtained by nantly mononuclear cell infiltrate consisting of lym-
injection of tuberculin into the skin of an individual phocytes and cells of the monocyte - macrophage se-
in whom previous infection with the mycobacterium ries. This contrasts with the essentially ”polymorph”
had induced a state of cell-mediated immunity. The character of the Arthus reaction.
reaction is characterized by erythema and induration
which appears only after several hours and reach a
maximum at 24–48 hours, thereafter subsiding. His-
tologically the earliest phase of the reaction is seen
634 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

of thermoregulation to higher values. Hyperthermia

means overheating of an organism caused only by
9.2 Fever exogenic causes (e.g. hot environment, hot bath).
In this case the center of thermoregulation doesn’t
change its setting up.
Heat is lost from an organism in several ways. The
biggest loss is by conduction. It depends on the gra-
9.2.1 Regulation and control of body dient between the body temperature and the temper-
temperature ature of the surrounding environment. The second
way is by radiation. The third way is by evaporation.
In a healthy individual, body temperature is kept It is used especially during increased production of
constant in a very small range despite of big differ- heat. Distribution of heat is done by blood circu-
ences in temperature of the surroundings and also lation. Heat goes from each cell to the surrounding
those in physical activity. Very perfect regulation of liquid and afterwards to the circulated blood. Modu-
body temperature, necessary for optimal progress of lating factor of heat loss is the amount of blood that
enzymatic reactions, is developed in all homoiotermic circulates through the body surface. The big flow
animals. It doesn’t apply to poikilothermic animals. through the subcutaneous area and the skin secures
During the most variable changes in human organ- the income of heat that may be given to the envi-
ism, the body temperature may increase. Fever is ronment through the body surface. Sweating helps
a natural reaction during a number of illnesses. In delivering the heat. Sweat glands are controlled by
several cases, absence of the natural reaction is more cholinergic impulses through the sympathetic fibers.
alarming sign than the presence of fever itself. Fever During intensive sweating, up to one liter of sweat
is usually accompanied by different general symp- may be formed. When the humidity of the environ-
toms, such as sweating, chills, sensation of cold, and ment is higher, a loss of heat by sweating is easier.
other subjective sensations. Missing of these symp- When it is necessary to accumulate the heat in an
toms during high temperature may be a sign of a organism, adrenergic stimuli cause reduction of the
serious illness. blood flow through the skin. The skin becomes an
The main task in heat production has thermoge- isolator decreasing the heat loss to minimum. Con-
nesis caused by the effect of thyroid hormones. Hor- trol mechanisms regulate the production of heat and
mones of thyroid gland stimulate Na+ − K+ ATP-ase its loss. Production and handover (loss) of heat are
found in cytoplasmic membranes. Increased produc- controlled from the center in the hypothalamus. It
tion of heat is achieved by increasing the metabolic works on the principle of negative feedback control
processes in which energy is released in the form of and includes:
heat. The greatest importance is splitting of ATP
when 54 kJ are released from one mol of ATP. Skele- 1. Receptors registrating central temperature
tal muscles, liver, splanchnic organs, and brain are
2. Effector mechanisms composed of vasomotors,
the biggest producers of heat in an organism. In
metabolic effectors, and controls of sweat glands
the heat production the muscles have especially im-
portant role. Because of their weight, they are able 3. Structures recording whether the actual temper-
to produce very large amount of heat very quickly. ature is not too high or too low
Increased production of heat takes place in skeletal
muscles during increased physical activity. During Increased central temperature activates mecha-
the digestion, an increased production of heat oc- nisms enabling the heat loss. Low central temper-
curs also in the GIT. Constant body temperature ature activates mechanisms enabling the accumula-
is achieved by perfect nervous regulation. Nervous tion of heat. These mechanisms work as the thermo-
system maintains the optimal intensity of metabo- stat.
lism and at the same time regulates the amount In healthy individuals, the body temperature (oral
of heat loss. In early postnatal development, the temperature) is somewhere between 36,5oC and
thermoregulation is inadequate because of immature 37,5o C. It slightly increases during the day since
CNS. Fever is always achieved by reset the center the morning (from 6:00 a.m.). The peak is reached
9.2. Fever (I. Hulı́n) 635

at 6:00 to 10:00 p.m. The lowest temperature is be- heat is released. Glycerol and FFA remain in the cell
tween 2:00 and 4:00 a.m. Diurnal variation depends and can perform the resynthesis after some time. An
on the activity throughout the day. Diurnal varia- adult person has little brown fat.
tions don’t change in persons that work at night and
sleep during the day. Such a diurnal variation is also 9.2.2 Pathogenesis of fever
kept when fever occurs. Fever reaches the peak in the
evening, and in the morning even a very sick patient If the body temperature is above 37,2o C and is asso-
may have almost normal temperature. Body tem- ciated with sweating, hyperventilation, and vasodi-
perature changes are more intensive in young person latation in the skin, we speak of fever. At the be-
than in old people. The temperature may slightly ginning, gradual increase in body temperature is ob-
or temporarily increase in hot environment. Phys- served together with muscle shivering, vasocontric-
ical activity may also increase the body tempera- tion in the skin, and piloerection. This situation is
ture. In extreme effort, the increase may be very called chills. Increased body temperature is achieved
high. The temperature in marathon runners may by lowered loss of heat. Vasoconstriction in the skin
increase to 39o C to 41o C. The temperature may and subcutaneous tissue is the cause of pale color
increase slightly if vasodilatation, hyperventilation, and dryness, the affected person has a feeling of cold-
and other compensation mechanisms fail. Small in- ness. At the same time the production of heat in the
crease in temperature may occur if the surrounding organism increases. The muscle tonus increases, the
temperature is lower or the jogging is done early in spasms accur. Spasms may occur mainly in children.
the morning. When the vasodilatation starts in the skin, the feel-
ing of warmth and sweating occurs.
Organism uses simple mechanism for temperature
Fever may be provoked by many stimuli. Most of-
regulation. It is the blood flow through the skin and
ten, they are bacteria and their endotoxins, viruses,
subcutaneous area. Vasoconstriction allows the in-
yeasts, spirochets, protozoa, immune reactions, sev-
creased accumulation of heat, and vasodilation se-
eral hormones, medications, and synthetic polynu-
cures its quick loss. Changes in temperature up
cleotides. These substances are commonly called ex-
to 3o C don’t cause an interuption of physiological
ogenic pyrogens. Cells stimulated by exogenic py-
functions. Spasms may occur during high fever in
rogens form and produce cytokines called endogenic
children. If the body temperature is increased over
pyrogens. Endogenic pyrogens centrally affect the
42,2oC, irreversible changes in the brain occur. In
thermosensitive neurons in the preoptic area of the
humans the temperature usually doesn’t overcome
hypothalamus increase the production of heat and
41,1oC. Uncontrolled decrease in temperature be-
decrease in heat loss. The body temperature incre-
low 32,8o C is accompanied by confusions and grad-
ses until it reaches the set point. This information
ual loss of consciousness. If the decrease continues
is transferred by temperature of blood that flows
under 30o C, the fibrilation of ventricles occur that is
around the hypothalamus. The decrease of tempera-
the sign of fatal termination of this condition.
ture is controlled by activation of mechanisms regu-
Brown fat that differs from the white one in struc- lating increased outcome of heat to the surrounding
ture and sites of location has an important function area. Increased outcome continues in favourable case
in thermogenesis in newborns and children. It is until the new equilibrium is achieved.
found between scapulas, on the neck, in axils, around The most important endogenic pyrogens are IL-1,
the aorta and the kidneys. It is highly vascularized, IL-6 and cachectin also called the tumour necrosis
and it has large mitochondria in its cells. One could factor-α (TNF-α). These are glycoproteins that also
say that while the white fat acts as feather-bed, the have other important effects. They are produced es-
brown one is an electrical pillow. Receptors of cold pecially by monocytes and macrophages but also by
conduct the information to the center of thermoreg- endothelial cells and astrocytes. Also the interferons
ulation. From this center the impulses run in the α, β and γ display the pyrogenic activity.
sympathetic nerve fibers and lead to the release of After administration an endotoxin in an experi-
norepinephrine in the brown fat. Norepinephrine ac- ment, the level of plasmatic TNF-α increases and
tivates the enzyme lipase. Activated lipase splits the fever occurs. Increased concentrations of IL-1 and
fat to glycerol and free fatty acids (FFA) and the TNF-α are also found in sepsis. The production of
636 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

these cytokines is regulated by the positive feedback that the fever can be supposed as a positive factor.
mechanism. Besides this, macrophages activated by Fever and specific effects of IL-1 and TNF-α form to-
IFN-γ may increase the production of IL-1 and TNF- gether highly integrated processes that are involved
α primary induced by other stimuli. On the other in the response to infection and acute inflammation
hand, glucocorticoids and prostaglandins of group E processes.
may display inhibitory effect on the production of IL- Interferons, and especially IFN-γ (formed by
1 and TNF-α. Released IL-1 and TNF-α are trans- T lymphocytes and NK cells) may enhance this re-
ported by blood. They affect the target cells in the ponse. Several parts of this complex response have
close proximity or in distant sites. The target cells protective and the others may have malignant con-
have specific receptors for IL-1 and TNF-α. In the sequences. Septicemia, or septic shock is an overshot
hypothalamus, IL-1 and TNF-α trigger the synthe- response of the organism. In this complicated reac-
sis of prostaglandis of group E from the arachidonic tion of the organism, it is not easy to decide whether
acid of cytoplasmic membranes of target cells. Pre- fever should be treated by antipyretics or not. By an-
cise mechanism by which prostaglandin PGE2 reset tipyretics the symptoms of fever may be suppressed
the central thermostat, is not known. Aspirin and but it is uncertain if it is reasonable to suppress also
the non-steroidal antiphlogistics display antipyretic the positive efects of fever and everything that is
activity by inhibiting the cyclo-oxygenase, an en- connected with it. This complex process (fever) mo-
zyme responsible for the synthesis of PGE2 (these bilizes not only the immune system but also those
antipyretics don’t inhibit the production of TNF- processes that improve the nutrition of cells and have
α or IL-1). Glucocorticoids work antipyretically by protective importance on their activity.
inhibiting the production of IL-1 and TNF-α, and In the majority of diseases, fever is caused by pyro-
by inhibiting the metabolic processes of arachidonic gens. There are situations, when fever may be caused
acid. directly by changes in the center of thermoregula-
tion without the participation of exogenic and may
In the process of fever, IL-1 and TNF-α play the
be also endogenic pyrogens. This occurs in brain tu-
central role. Except introduced activity in fever,
mours, intracranial bleeding, and thrombosis.
they interfere with many mechanisms in an organ-
ism. Some of their effects are executed with the par-
ticipation of metabolites of arachidonic acid. IL-1 9.2.3 Causes of fever
and TNF-α affect myelopoesis, release of neutrophils Such a change is considered to be a cause of fever
and enhancement of their functions. They cause va- that initiates the production of endogenic pyrogens.
sodilatation and the increase the adhesivity of cells, Generally, these changes may be divided into several
increase the production of PAF and thrombomodulin groups:
by endothelial cells, proteolysis and glycogenolysis
in muscles, mobilisation of lipids from adipocytes, 1. infections caused by bacteria, ricketsia, chlamy-
proteosynthesis and glycogenolysis in the liver, in- dia, viruses, and parasites
duce proliferation of fibroblasts, activate osteoclasts
2. immune reactions, including the defects in colla-
and the release of collagenase from chondrocytes, in-
duce slow wave sleeping activity in the brain, the gen, immunological abnormalities and acquired
release of ACTH, beta endorfins, growth hormone immunodeficiency
and vasopressin, the release of insulin, cortisol, and 3. destruction of tissues, such as trauma, local
catecholamines. TNF-α and partially also IL-1 in necrosis (infarction), and inflammatory reaction
longlasting operation may cause cachexia mainly by in tissues and vessels (flebitis, arteritis), pul-
decreasing the appetite. It is so in chronic infections, monary infarction, cerebral and myocardial in-
inflammatory processes, and in neoplastic processes. farction, and rhabdomyolysis
Beside that, TNFα and IL-1 significantly increase 4. specific inflammations (sarcoidosis, granuloma-
the immune response by activation of T-cells and tous hepatitis)
stimulation of IL-2 production. IL-1 enhances B-cells
proliferation. It is interesting that these processes 5. inflammation of intestine and intraabdominal
have the temperature optimum at 39,5oC. It follows inflammatory processes
9.2. Fever (I. Hulı́n) 637

6. neoplastic processes with the participation of sick person has a feeling of cold. Thermogenesis par-
lymphoendothelial system and hemopoetic sys- ticipates in this process through thyroxin and triio-
tem, solid tumours (Grawitz tumour of the kid- dine thyronine. In consequence of thyroxin thermo-
ney, carcinoma of the pancreas, pulmonary and genesis and the activation of sympathicus, the effect
skeletal tumours, hepatoma) Fever is present of cardiovascular and respiratory systems increases
in complications of solid tumours, usually in together the basal metabolism. These changes may
metastases that are associated with necrosis of be measured by increased utilization of oxygen in the
the tumour, obstruction of ducts, or with infec- organism.
tion The third stage is called the climax phase (stadium
acme). Climax means that the body temperature
7. acute metabolic failures such as arthritis urica, culminates. At culmination of fever, such a temper-
porfyria, Addison’s crisis, thyreotoxic crisis, and ature is achieved to which the thermoregulatory cen-
feochromocytoma ter is reset. The center is washed by blood that has
the temperature originally adjusted. Because of this,
8. administration of some drugs
the activation of sympathetic compartments stops.
However, the parasympathetic compartment of the
9. dehydration or admistration of salts. That’s
thermoregulatory center is activated. Subsequently,
why fever occurs together with diarrhea.
the impulses cause vasodilatation of skin vessels and
10. administration of foreign proteins (e.g. globu- the decrease in peripheral vascular resistance. These
linum antitetanicum-antitoxic fraction of horse changes are the reason of decreased blood pressure
serum) may be the reason of fever’s origin. and increased pressure in the pulmonary artery. The
pressure in the pulmonary artery increases because
of vasoconstriction of pulmonary arteriols. The pa-
9.2.4 Progress of the fever and tient has warm and red skin, he sweats, and looses
accompanying symptoms heat by conduction, radiation, and evaporation.
The fourth stage is called the descent stage (sta-
Typical fever runs in certain stages that may be
dium decrementi). This stage starts from the peak
called phases. As first phase is entitled prodromal
of fever and is characterized by the decrease of the
phase or pre-report phase that occurs for about 15 body temperature. The decrease of fever may be lyt-
to 90 minutes. In this stage, the release of endogenic
ical or critical. Critical decrease means the situation
pyrogen occurs on the basis of exogenic pyrogen’s
when the fever decreases to normal temperature in 1
effect. Endogenic pyrogen mediated through PGE2
or 2 hours. With the decrease of fever, also the fre-
affects the thermosensitive neurons of thermoregu-
quency of puls and respiration is decreased. Sudden
latory center in hypothalamus. In this stage, the descrease especially of longlasting fever may cause
resetting of thermoregulatory center for a different
temperature crisis. Expressive decrease of fever, de-
temperature take place.
creased puls, and decrease in peripheral vascular re-
The second stage is called the phase of increase sistance may cause the failure of circulation. This is
(stadium incrementi). It is thought that in this stage especially dangerous for persons with cardiovascular
the thermoregulatory center is reset. The thermoreg- disease and for old persons.
ulatory center has probably two compartments. The
Some diseases are characterized by certain stereo-
impulses from the sympathetic compartment that
typic consequence of temperature changes. Accord-
are sent by sympathetic fibers to the whole organism
ing to the temperature curve, we may distinguish
are operating in this stage. In cutaneous and sub-
several types of fever.
cutaneous vessels, they cause vasoconstriction, thus
they decrease the the heat outcome. On the other
hand, muscles, liver, and heart, under the influence 1. febris continua is fever in which the temperature
of sympathetic compartment, increase production of changes are less than 1o C in 24 hours
heat that forms, together with decreased outcome of
heat, the optimal situation for heat accumulation in 2. febris septica-hectica is fever in which the swings
an organism. Body temperature increases, but the are 3 to 5o C
638 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

3. febris remittens is fever with big temperature Oxidative processes speed up during the fever
swings what may be demonstrated by the incresed utiliza-
tion of oxygen. During the fever or after its finish,
4. febris intermittens is fever characterized by sev- hyperglycemia may be ascertained. In general, the
eral hours lasting apyretic periods catabolism of proteins with negative nitrogen bal-
ance increases leadeing to the losses of protein that
5. febris recurrens is fever that reccurs after several may reach 300 to 400 grams per day. Decreased di-
days
uresis associated with increased protein catabolism
6. febris undulans is fever in which the halwave often leads to the rise in metabolic acidosis. These
lasts several days metabolic changes may be improved in the phase of
polyuria that starts after the decrease of fever.
7. fever inversa means that fever is higher in the When the body temperature increases by 6o C a
morning than in the evening. This is typical for situation not compatible with life is formed. Subjec-
patients suffering from tuberculosis. tive feeling of fever is highly variable. Some persons
percieve already a small increase in body tempera-
In fever, important changes occur in the function ture, others don’t feel even the increase of temper-
of organism. As a direct consequence, tachycardia is ature to high values. This occurs in persons with
observed. Increased frequency in heart beats by 10 longlasting increase of body temperature. A pa-
to 15 beats means the increased in the body temper- tient with tuberculosis sometimes doesn’t even feel
ature by 1o C. Except tachycardia, extrasystols may the temperature of 39o C. In most cases, the fever is
also occur during fever. These may have toxic or in- associated with subjective dyscomfort such as uncer-
fectious origin or may be the sign of myocardial de- tain headache, arthralgia, pain in muscles and in the
generation at longlasting fever. The blood pressure back. The cause of these symptoms is not completely
increases in the period of inceasing fever . In the pe- clear.
riod of decreasing fever, the blood pressure decreases Chills may accompany any fever. It is typical for
because of the decrease of peripheral vascular resis- pyogenic infections associated with bacteremia. It
tance and the simultaneously present bradycardia. may also occur in noninfectious diseases such as vas-
Oligemia, caused by evaporation and sweating, culitis or lymphoma. Chills may be provoked by an-
may participate in worsening of cardiovasculr func- tipyretics that cause sudden decrease of body tem-
tions. In intial stages of fever, up to its culmina- perature. This effects of antipyretics is seen espe-
tion, the frequency of breathing increases. During cially if they are given in the phase of increasing
the fever, or after its finish, pathological components- temperature.
proteins, hyaline casts, and creatinine are present in
Sweating. Diffuse sweating usually occurs in cul-
the urine. Probably, this is caused by the direct dam-
mination of fever. It may be very unpleasant for
age to the kidneys by the fever itself. Experimentally
some persons. However, it is the natural reaction at
it was observed that warm water bath of 40o C last-
the process of fever.
ing for several hours doesn’cause similar changes in
urine and general condition as fever. Fever has un- Changes in mental condition are present in very
favourable influence on the function of the digestive young and very old persons. They may be very
tract. The defect in secretion of digestive juices is ob- mild or may develop into delirant state. Expressive
served. This is associated with motor disorder and changes in mental condition may be sometimes ob-
the disorder of absorption. Such changed functions served in alcohol drinkers, cardiovascular patients,
of GIT may cause the constipation with catastroph- and senile persons. TNF-α and IL-1 cause the re-
ical effects especially in old people. Hypoptialism is lease of β-endorfins in the brain that may participate
the part of decreased secretory function of the gas- on changed mental condition.
trointestinal tract. At hypoptialism, inflammation Spasms are present in children to 5 years of age.
of buccal mucosa and the tongue is present as well. Most often they develop in the phase of increasing
In general, the patient loses appetite what is caused body temperature.
by direct activity of TNF-α but also by functional Herpes labialis. Increased body temperature may
changes in the digestive tract. activate latent virus of herpes simplex. From unclear
9.2. Fever (I. Hulı́n) 639

reasons, it often occurs in pyogenic bacterial infec- acteristcs: sudden start of fever, temperature over
tions (pneumococcal, streptococcal, meningococcal), 38,5o C, fever without chills, symptoms of respiratory
in malaria, and in ricketsioses. Herpes labialis to infection, muscle and joint ache, headache, nausea,
some extent a sign of suppressed cellular immunity. vomitting, diarrhea, enlarged lymph nodes or spleen,
Utility of fever. Fever slightly increases im- meningeal symptoms, and dysuria.
mune reactions, increases chemotactic, phagocytic, Similarly to infectious diseases, acute leukemia or
and bactericidal activity of polymorphonuclear leu- vasculitis may manifest in the same way.
cocytes. Up to certain value, it stimulates the pro- Long duration (weeks or months) is always a very
cesses of antibody production. serious problem. If it is not possible to determine
Concomitantly, it slows down the proliferation of the cause of fever at the beginning, it is called the
microorganisms. Increased body temperature causes fever of unknown origin (FUO). This term is used to
a decrease in the amount of plasmatic iron, zink, describe fever lasting at least 2 weeks, reaching tem-
and copper. This decrease is not favourable for the peratures above 38,2oC, and the cause of the origin
growth of microbes. High temperature causes de- is uncertain.
struction of lysosomes and the whole cells. This is Fever may last long in some infections with suba-
a way by which the body defendes itself against mi- cute or chronic course. Those may be hired abscess
crobes but also against reglication of viruses. The in the abdominal cavity or in the abdominal organs
increased production of interferons also acts against (abscess of the liver, spleen, subfrenic abscess, diver-
viruses. ticulitis and an abscess in the small pelvis).
In general, fever is considered to be a pathologi- Longlasting fever may also occur in renal infec-
cal reaction. However, it belongs to compensatory tions and in intravascular infections (acute infections
mechanisms and has important roles in defence pro- of the urinary tract, bacterial endocarditis).
cesses. Therefore, medication of actual fever can’t be Unwanted are the iatrogenic infections at
the target of treatment. Infectious disease without catheterisation or at fistula treatment. They cause
fever means a prognostically bad medical finding. big troubles and may have untypical course associ-
Harmfull effects of fever. They may come into ated with fever.
consideration at high temperatures, if fever lasts too Deep mycosis and tuberculosis, complications of
long, and especially if the patients are suffering from AIDS, complications of immunosuppressive treat-
an additional disease, too. Increased basal metabol- ment are accompanied by fever. Viral infections,
sim, minute heart volume, and water and salt loses ricketsioses and chlamydia infections are accompa-
may complicate other basic illnesses. Very high tem- nied by fever and lymphadenopathy.
perature suppress immune mechanisms. Longlasting
Neoplastic processes are very serious problem.
fever causes dysfunctions of parenchymal organs. It
In some of them, fever of unknown origin may be
is so in malignant (extreme) fever, febrile spasms,
present for a long time. Sometimes after months or
epilepsy, cardiac problems, and the disease of the
even after year or two, other symptoms of neoplastic
central nervous system. Fast decrease of fever may
disease may be detected. In several cases fever has
endanger the patient by fast lowering of the blood
typical progress (Pel–Ebstein fever at Hodgkin’s lym-
pressure.
phoma). Acute leukemia may be, at the beginning,
considered to be an infectious disease. The tempera-
9.2.5 Fever from the clinical point of ture reaches up to 40o C. Fever may accompany also
the solid tumours. The cause may be the obliteration
view
of glandular ducts or necrosis of the tumour and/or
Fever may have certain signs in relation to its course. metastatic spread.
It has diagnostic importance and certain information Diseases of connective tissue are accompanied by
value. Is several disease, however, it doesn’t neces- fever. It’s present at rheumatic arthritis, periarteri-
sarily have certain characteristics. tis nodosa, systemic lupus erythematosus, and in
Fever in infectious diseases usually is of short du- polymyalgia rheumatica.
ration. Generally, it is limited to 2 week period. Dur- There are many other disorders and changes of or-
ing infectious diseases fever has the following char- ganism in which fever develops. Those may be hid-
640 Chapter 9. Inflammation and fever ( I. Hulı́n, M. Ferenčı́k, V. Štvrtinová, J. Jakubovský)

den hematomas, hemolytic crisis, pulmonary em- Drug-induced fever is a serious problem. If we
bolisation, and thermoregulatory dysfunction at take into consideration that the patient with infec-
metabolic and endocrine disorders. Sometimes psy- tion is treated by antibiotics that may cause fever,
chogenic fever may occur. It happens in patients we find out that it’s an excessive complex problem.
with psychopathology or in pharmacofags. In these Of medications that cause the fever the antibiotics
cases the frequency of heart beats even at high tem- are most frequent (especially β-lactamase antibiotics
peratures increase only slightly. and penicilins) but also sulfonamids, nitrofurantoin,
Habitual hyperthermia (37,2–38oC) is detected in antituberculotics, barbiturates and laxatives. Drug-
children and young women. It is associated with induced fever doesn’t have characteristic features.
the signs of psychoneurosis, asthenia, complete weak- Most often it occurs 5 to 10 days after the start of
ness, and insomnia. They often have different un- treatment but it may occur also right after the first
pleasant subjective feelings that force them to think dose. Most probably, the drug acts like an exogenic
about their high temperature. pyrogen.
Chapter 10

Pathophysiology of malignant disease

include chemicals, hormones, drugs etc. They may

induce some alterations in initiated cells, such as al-
10.1 Carcinogenesis teration of cell surface sensitivity to various growth
factors, alteration of cell surface glycoproteins and
glycolipids, alteration of cell morphology, increase
phospholipid and glucose metabolism, stimulation of
In the last years cancer research has provided an DNA synthesis and cell proliferation, increase pro-
enormous amount of information. But a unitary
duction of free oxygen radicals, activation of a latent
theory of carcinogenesis has not been created still
provirus DNA, induction of disproportionate DNA
today.
replication within one cell cycle with gene amplifica-
The study of carcinogenesis has historically been tion, etc.
devided into two major areas:
A classic example of initiation and promotion is
1. carcinogenesis induced by chemical and physical such model, in which the carcinogen (polycyclic aro-
agents matic hydrocarbon, benzo(a)pyren) is applied to
2. viral carcinogenesis mouse skin. Following this croton oil or acetone
is repeatedly applied. Croton oil produced a more
Within the last decade has been found that these significant increase in malignant tumor formation
two areas of carcinogenesis are in fact closely related. compared to acetone. Initiator is represented by
Chemical and physical agents as well as viruses act benzo(a)pyren and promoters include croton oil and
via the alteration of a limited number of target genes acetone.
– activation of protooncogenes and inactivation of Perhaps the best example of the multistage, mul-
tumor supressor genes. tifactorial nature of cancer in humans is the interac-
In cellular transformation process, by which nor- tion of asbestos and cigarette smoking in the etiology
mal cell becomes a cancer (malignant) cell, two of lung cancer, with the combined factors increasing
clearly separated stages were defined: initiation and the risk almost 900-fold compared to that in non-
promotion. (Fig. 10.1) smoking nonasbestos workers.
Initiation is induced by carcinogens. Carcino- It is accepted that human cancer does not arise
gens (initiators) include chemical agents, irradiation, all of a single mutation, but there is still controversy
viruses and hormones. Carcinogen causes an irre- concerning the actual relevant number of exposures
versibile DNA damage, which predisposes to cancer. to initiators and promoters that must occur in incu-
DNA changes induced by carcinogens include inter- bation period of cancer.
ruptions of the DNA chain, errors in DNA repair, For many human cancers the probability that all
elimination of a base pair etc. Promotion is media- target genes will be altered by environmental factors
ted by cocarcinogens (promoters). These agents are is closely associated with age. IndividualÝs age de-
not themselves mutagenic or carcinogenic but acce- termines how long the cell has been subjected to en-
lerate or promote the transformation when applied vironmental carcinogenic factors and therefore can-
repeatedly after a carcinogen (initiator). Promoters cer incidence increases with age.

641
642 Chapter 10. Pathophysiology of malignant disease ( B. Mladosievičová)

Figure 10.1: Two-stage carcinogenesis: initiation and promotion

There are many experts who claim that as much as 1. Polycyclic aromatic hydrocarbons (i.e. ben-
90 % of all human cancers are of environmental origin zoapyrene)
(caused by chemicals, radiation, hormones, viruses).
2. Nitrosamines (i.e. dimethylnitrosamine)

10.1.1 Chemical carcinogenesis 3. Aromatic amines (i.e. beta-naphtylamine)

The number of known chemical carcinogens grows. 4. Heavy metals (i.e. arsenic)
The problem of their identification in humans is due
to by long latent periods (even 20 and more years) 5. Alkylating agents (i.e. melphalan)
between exposure to these agents and the first ap-
6. Toxins (i.e. aflatoxin)
pearance of cancer. It may be the time required for a
sequence of promoting events. Chemical carcinogens 7. Others (i.e. vinyl chloride)
include naturally ocurring and synthetic compounds.
The higher incidence of human cancer is associated A wide range of different chemicals associated
with approximately 30 chemicals. Some substantial with cancer induction requires metabolic activation
groups of carcinogens are as following: for reactivity with DNA. The process of metabolic
10.1. Carcinogenesis 643

activation requires cellular enzymes, which are in- tem. The risk of developing lung cancer is increasing
duced by the carcinogen. Individuals vary in their also in passive smokers.
abilities to activate chemical carcinogens. This ge- Smoking contributes also to esophagus, bladder,
netically determined variability in the degree of in- pancreas, larynx and other cancers.
ducibility of the activating enzymes may be corre- High incidence of cancers falls in those individuals
lated with cancer susceptibility. who stopped smoking.
One system of such activating enzymes is aryl hy-
drocarbon hydroxylase system, which converts pro- 10.1.2 Radiation carcinogenesis
ximate carcinogen benzo(a)pyrene, a component of
Ultraviolet light and ionizing irradiation are the
cigarette smoke, into its ultimate carcinogenic form.
Individuals with lung cancer appear to have a ge- most universal carcinogenic factors.
netically higher level of inducibility of this enzyme Radiation damages DNA directly, causing muta-
system than those smokers without lung cancer. tions. In support of this theory is the frequent oc-
curence of multiple skin tumours after exposure to
Chemical carcinogens are dose-dependent. Many
of them have been shown to induce cancer when used ultraviolet light in individuals with xeroderma pig-
mentosum. In this rare hereditary defect the cellu-
in high concentrations. But little is known about
lar enzymes reparing ultraviolet-induced mutations
the effects of these carcinogenes when humans are
within cellular DNA are missing. Deffective DNA re-
exposed to minimal amounts of these agents in the
pair mechanism is associated with the early develop-
environment over a period of many years.
ment of skin cancer on skin exposed to sunlight. Ra-
Many chemical carcinogens are present in the food,
diation can also act through the formation of highly
air and water.
reactive free-oxygen radicals that have capability of
peroxidating cellular molecules. Radiation may also
10.1.1.1 Nutritional factors and carcinogen- activate cancer-causing viral DNA sequences present
esis within the genetic code of individuals. Another ob-
Some carcinogenic agents are formed in the food servation in the exposed population is the higher
through cooking and charcoal broiling. Any burnt than expected presence of chromosomal abnormal-
food may have carcinogenic potential. Carcinogenic ities.
potential of food may depend upon, how it is stored Skin cancer results from sunlight exposure. Nega-
and its age when consumed. Extremely dangerous tive effects of ultraviolet light and increased risk of
carcinogens, such as aflatoxin, may be produced by skin cancer may be associated also with damage of
food molds. Some food preservatives and additives the ozone layer of the earth.
used at high concentrations are associated with car- Radiation damage is a linear response to dose re-
cinogenic activity. ceived.
Other dietary elements, such as high fiber diet, Human radiation carcinogenesis caused by ionising
vitamins A, E, C and selenium, have been shown to irradiation has been studied in the survivors of the
inhibit carcinogenic potential of food. atomic bombings of Hiroshima and Nagasaki. The
incidence of leukaemia was greater than in nonex-
posed Japanese populations and were characterized
10.1.1.2 Cigarette smoking and carcinogen-
by a latency period even of 20 to 30 years after ex-
esis
posure.
Cigarette smoke contains about 7000 chemical sub- Another groups of patients developing malignan-
stances including many different types of carcino- cies with greater than average frequency are those
gens, such as benzo(a)pyren, nitrosamines, aromatic who received radiation therapy. The incidence peaks
amines etc. The incidence of lung cancer appears to 4 to 8 years following radiation. Also therapeutic in-
be 10 fold higher in smokers than in non-smokers. jection of bone-seeking radioactive isotopes such as
224
After smoking of approximately 200 000 cigarettes Ra also leads to high incidence osteogenic tumors.
there is 30 fold increased risk of lung cancer. Cancer The most common sites for radation induced can-
in smokers may be associated with cigarette smoke cer are the lymphoid system, the thyroid, the female
chemicals and irritating of mucose in respiratory sys- breast and the lung.
644 Chapter 10. Pathophysiology of malignant disease ( B. Mladosievičová)

10.1.3 Viral carcinogenesis oncogenes of their own. If the proviral DNA is inte-
grated in the proximity of a target gene - protoonco-
In 1911 Peyton Rous described Rous sarcoma virus, gen, also these viruses without v-onc could begin to
an agent that induced malignant tumors – sarcomas regulate the expression of proto-oncogenes.
in inoculated chickens. The gene responsible for the
tumor inducing capabilities of Rous sarcoma virus Viral infection may also contribute to carcino-
was isolated in the 70’s. This gene was named ac- genesis undirectly, not only directly – by insertion.
cording virus from which this oncogene was isolated Viruses may stimulate cell proliferation associated
– v-src. It has been identified more than 20 onco- with normal repair or healing process. Actively di-
genes, most of which are carried by RNA viruses. viding cells are at high risk of mutations induced by
RNA viruses are replicative and very minimally carcinogenes. During some viral infection, the host’s
transforming or nonreplicative and highly trans- immune system is compromised and thus cancer like-
forming. Highly oncogenic retroviruses have evolved lihood increases.
from their non-oncogenic retrovirus counterparts. Oncogenic viruses (mostly from RNA family) are
This evolution include several steps: responsible for many animal malignancies (in chick-
RNA viruses contain a gene (pol gene) for enzyme ens, mice, monkeys, cats etc.)
reverse transcriptase. Using this enzyme RNA virus
makes a complementary DNA copy of its own RNA. Only one human cancer has been unequivocally
(For this reason these viruses containing reverse tran- shown to be result of a retroviral infection – adult T
scriptase are called retroviruses.) Thus virus can in- cell leukaemia (ATL) caused by C type RNA viruses,
corporate its own viral DNA into the genome of the human T cell leukaemia-lymphoma viruses – HTLV I
host cell in a form of provirus. Only in an integrated and II. Epidemiological data indicate that there is
form oncogenic virus may cause cell transformation. a consistent association between HTLV I and II in-
Provirus contains also genes for structural proteins fection and adult T-cell leukaemia. The HTLV I
(gag, env gene), for transcription (long term repeat provirus sequences integrated in genome of tumor
– LTR) etc. cells have been detected in patients with ATL from
During process known as transduction the virus different parts of the world. These include the south-
incorporates part of the cellular DNA material into western islands of Japan and the Caribbean. Ap-
its own viral genome. Accidental viral and proto- proximately 5 % of the normal population and 100 %
oncogenes combination may occur. Somewhere of patients with ATL have a high titer of HTLV anti-
along this path proto-oncogene mutates and viral bodies. Patients who develop ATL have a higher titer
oncogene may arise de novo. Also such changes of antibodies to the HTLV viruses. Transmission of
as removal of signals for transcription termination HTLV I by close contact is suggested by the greater
and other rearrangements of cellular DNA may oc- antibody prevalence in family members of HTLV–
cur. The virus now becomes oncogenic. Viral onco- positive patients compared to the prevalence in the
genes are mutants of normal cellular genes – proto- general population. The infection with members of
oncogenes. Proto-oncogenes are cellular prototypes the HTLV family may also produce immunosupres-
– progenitors of viral oncogenes. Viral oncogenes are sion. HTLV I and II are members of the same family
not homologues with proto-oncogenes as was initially as the virus that causes AIDS (HTLV III and HIV.)
suspected. For example c-myb is a cellular progeni- The close relationship is supposed between
tor of viral oncogene – v -myb, however structure and Burkitt’s lymphoma (malignancies of jaw region
expression of v-myb is not identical with the struc- found predominantly in Central Africa) and the
ture and expression of c-myb (Fig. 10.2). Epstein-Barr virus, (EBV is a DNA, herpes like virus
Oncogenicity of viral-oncogenes is due to their infected B lymphocytes – causative agent of infec-
products – the quantitative or qualitative altered tious mononucleosis). High titer of antibodies to
transforming proteins. They are protein-kinases res- the EBV and EBV provirus sequences have been de-
ponsible for alterations in cellular morphology and tected in DNA of malignant cells. The antibody titer
growth. against the EBV rises and falls with tumor progres-
Another family of viruses – replication competent sion and regression. Despite this evidence, however,
viruses (slowly transforming viruses) do not carry
10.1. Carcinogenesis 645

Figure 10.2: A comparison of structure and expression of c-myb and v-myb (a: DNA, b: RNA, c: protein
encoded by RNA)

it is not clear if the virus is a cause of the lymphoma ers than in matched controls. It is suggested that
or whether other oncogenic stimuli produce the can- these tumors appear after about 35 years of persis-
cer in infected cells. tent HBV infection.
The applications of the new hepatitis B vaccines
Infection of the liver with hepatitis B virus (HBV)
are promising in prevention not only viral infection
is associated with an increased incidence of primary
but also the hepatoma.
liver cancer (hepatoma). In areas of the world where
there is a high prevalence of HBV carriage, there It seems also likely that viral infection may depress
is a corresponding high prevalence of hepatoma (in the detoxification of chemical carcinogens in liver and
Southeast Asia, Central and South Africa). The fre- by this way it may contribute to carcinogenesis.
quency of finding persistent HBV infection in he- Herpes simplex type II virus and papillomavirus
patoma patients is 10 to 40 times higher than in can cause genital infection, which has been shown in
controls living in the same area. Chronic infection females to be associated with the later development
with HBV often leads to cirrhosis. Prospective stud- of cervical cancer. Patients who develop malignancy
ies have shown that that HBsAg-positive patients have a higher titer of antibodies to the virus and the
with cirrhosis will develop liver cancer with more fre- malignant cells contain viral DNA, RNA and pro-
quency in contrast to HBsAg-negative cirrhosis pa- teins.
tients (e.g. those with alcoholic cirrhosis). In other Human breast cancer is associated with B type
prospective studies the risk of developing hepatoma RNA virus infection – Bittner factor.
was about 250 times higher among the virus carri- Viruses are often suspected also in acute leukaemia
646 Chapter 10. Pathophysiology of malignant disease ( B. Mladosievičová)

causation because a nonspecific viral like illness cha- ral oncogene (e.g. c-src, c-myc, c-myb etc). They
racterized by fever, malaise, leukocytosis, respiratory are not cancer genes. The term ”proto-oncogenes” is
symptomes etc. Viral infection may also decrease the used to denote their ability to require an oncogenic
immunologic capability of the individual to protect potential.
against cancer. In normal cells they have functions in cell growth
and differentiation: They
10.1.4 Hormones and carcinogenesis • code for phosphorylate proteins
Hormones are supposed to be carcinogenic agents, • influence DNA replication
especially when elevated.
Estrogens may be responsible for development of • control mRNA production
breast cancer and endometrial cancer. Some malig-
nant cells of breast cancer appear to have estrogen • bind GTP
hormone receptors that allow binding to hormone Since the retroviral oncogenes are mutants of nor-
molecules to take place, which then causes cellular mal proto-oncogens, they have provided a key to
division and growth. Also endometrial cancer may open a door to understand proto-oncogene – onco-
be associated with estrogen replacement therapy. gene conversion. It was accepted that following
Diethylstilbestrol administered to prevent abor- crucial events may be responsible for conversion of
tion has been linked to an increased incidence of proto-oncogenes to ”cancer” genes:
vaginal and testicular cancer in children of women
with such treatment in pregnancy. • mutations (point mutations of proto-oncogenes
Elevated levels of hormones may act as promoters or their regulatory genes caused by chemicals,
by increasing of normal cellular proliferation or they radiation, viruses)
may promote also tumor growth and dissemination.
• amplifications

10.1.5 Irritation and carcinogenesis • translocations (proto-oncogene is placed in

proximity to a strong promoter)
Irritation may also play a role in carcinogenesis.
Continous irritation of skin or mucose may promote An example is found in Burkitt’s lymphoma,
malignancy. It is well known that irritation sup- where the translocation of c-myc proto-oncogene
port development of malignant melanoma from a pre- from chromosome 8 to chromosome 14 is often ob-
viously benign pigmented mole. Also using intraute- served. In this instance, the oncogene c-myc of chro-
rine devices may subject uterus to prolonged irrita- mosome 8 becomes activated when is transcripted in
tion and may increase risk of development of cancer. tandem with either heavy chain genes (IgH genes) of
Some components of smoke and alcohol may promote chromosome 14 or with immunoglobulin light chain
carcinogenesis acting as irritating factors. genes of chromosomes 2 and 22.
Altered c-myc play an important role in B cell
tumorigenesis. Normal proto-oncogene c-myc is ex-
pressed in normal proliferating lymphoid cells and
presumably this expression is a signal for conti-
nued growth. In terminally differentiating B cells,
10.2 Cellular oncogenes c-myc transcription is arrested, resulting in a non-
proliferating plasma cell. However, when chromoso-
mal rearrangements bring c-myc into the proximity
of an immunoglobulin gene locus, c-myc transcrip-
Mammalian cells possess a set of normal cellular tion can be positively driven by that locus, thus pro-
genes – proto-oncogenes (c-onc) and tumor supres- viding continued proliferation to plasma cell.
sor genes. Another example is the translocation 9, 22 in
Proto-oncogenes are termed also as celullar onco- 90 % patients with chronic myelogenous leukemia,
genes (c-onc) with acronyme from corresponding vi- where the proto-oncogene c-abl from chromosome 9
10.3. Characteristics of cancer cells 647

is translocated to the abbreviated chromosome 22 morphological and biochemical events which can re-
known as the Philadelphia chromosome (Ph1 ). In sult in the proliferative response. For example c-
this disorder an abnormal transcription of c-abl has sis proto-oncogene encodes for PDGF, which parti-
been found. cipates in a normal repairing process by stimulating
Detection of chromosomal abnormalities using growth of fibroblasts and by influencing of platelet
high resolution chromosome techniques are very im- aggregation. If proto-oncogene c-sis is altered, it may
portant for diagnosis and prognosis. On the basis code for a polypeptide similar in function to PDGF
of such detection acute nonlymphocytic leukaemia – PDGF like transforming factor, which is able to
can be subdivided into 17 categories with prognosis disrupt normal cell proliferation (Fig. 10.3). Proto-
varying from poor to long survival. Chromosomal oncogene c-erb encodes another polypetide epider-
abnormalities predisposing to cancer are inherited mal growth factor receptor. Altered c-erb may code
or acquired (Tab. 10.1 and Tab. 10.2). for truncated form of EGF receptor which may be re-
sponsible for generating an uncontrolled proliferative
signal. Altered c-erb is associated with squamose cell
cancer and glioblastoma.
Many of the normal proto-oncogene products have
a tyrosine kinase activity. This activity leads to self-
posphorylation and phosphorylation of other pro-
teins. Tyrosine phosphorylation is an important me-
diator of growth regulatory mechanisms and mor-
phological cell phenotype.
Product of another proto-oncogene exhibits
GTPase activity.
Alteration of one proto-oncogene is not sufficient
for development of malignancy, but a cascade of se-
quential proto-oncogene alterations may be neces-
sary.

10.3 Characteristics of cancer

Figure 10.3: Production and action of transforming cells
growth factors (TGFs)

Mutated, inappropriately amplified or translo-

cated proto-oncogenes may encode for The cancer cells show cellular and nuclear pleo-
morphism, they loss of normal arrangement of cells,
1. excessive, unregulated quantity or
they develope changes in the cell membranes and or-
2. chemically altered quality of gene products. ganelles (Fig. 10.4), they exhibit abnormal mitoses
and chromosomal abnormalities.
Of particular interest in neoplastic transforma- Increased motility of malignant cells may be asso-
tion is a role of such gene products as polypeptide ciated with increased amounts of contractile proteins
growth factors and their receptors. The growth fac- in their microfilaments, with loss of contact inhibi-
tors implicated are the platelet-derived growth fac- tion (probably caused by alteration in calcium ion
tor (PDGF) and epidermal growth factor (EGF). concentration in the malignant cell membrane).
Polypetide growth factors potently stimulate normal Interrupted cellular adhesiveness (for the solid
cellular proliferation. The interaction of growth fac- surface) and contact inhibition (among cells) may
tors with their specific receptor starts a cascade of result from changes in the cell surface glycoproteins
648 Chapter 10. Pathophysiology of malignant disease ( B. Mladosievičová)

Inherited chromosomal abnormalities Tumor type

Down’s syndrome (trisomy 21) Acute leukaemia

Klinefelter’s syndrome (47,XXY) Breast cancer
Anirida–Wilm’s syndrome (11p− ) Wilm’s tumor
Mosaicism (45XO,46XY) Gonadoblastoma
Multiple malformations (13q− ) Retinoblastoma

Table 10.1: Inherited chromosomal abnormalities and malignancy

Acquired chromosomal abnormalities Tumor type

Translocation (8;14) Burkitt’s lymphoma

Translocation (9;22) Chronic myelogenous leukaemia
Translocation (15;17) Acute promyelocytic leukaemia
Deletion (5) Acute nonlymphocytic leukaemia
Deletion (6) Acute lymphocytic leukaemia

Table 10.2: Acquired chromosomal abnormalities and malignancy

and the poorly developed tight junctions and desmo- 2. loss of specialization and differentiation of the
somes in malignant cells. Changes in motility, adhe- cell
siveness and contact inhibition may promote inva-
sion and subsequent establishment of secondary ma- 3. ability to move from the original site and estab-
lignant growth – metastasis. lish new malignant growth at other tissue sites
The cancer cells exhibit differences in metabolism (metastasis)
as compared to normal cells. The metabolism of ma- 4. capacity to invade and destroy normal tissue
lignant cells is usually more anaerobic than that of
normal non-rapidly dividing cells and is greatly ac-
celerated. Malignant cells may be able to withstand 10.3.1 Tumor cell markers
hypoxic conditions. They may have increased glu- The cancer cells have ability to produce some sub-
cose and amino acid uptake. These cells have high stances – tumor cell markers – that are found on
levels of hexokinase increasing their glucose utiliza- tumor cell membranes and in cytoplasm. These sub-
tion. stances may be detected in the blood, urine or spinal
The cancer cells loss capabilities to synthesize spe- fluid.
cialized proteins typical for differentiated cells. En- Immunochemical analysis of serum levels of tumor
zymes and other proteins produced by cancer cells cell markers enabled us:
are needed for the tumor growth.
The standard characteristics of cancer cells are: 1. to identify individuals at high risk of cancer
1. loss of regulation of mitotic rate (Fig. 2.5) 2. to diagnose the specific type tumor
10.3. Characteristics of cancer cells 649

Figure 10.4: Characteristic features of malignant cell (adapted from McCance KL, Mooney KH, Roberts LK:
Pathophysiology, 1990)

3. to follow the clinical course of malignant disease cofetal antigens have also been observed in pregnant
women, heavy cigarette smokers, patients with acute
4. to assess effectiveness of therapy viral hepatitis etc.
Some tumors inappropriately produce hormones
Tumor cell markers include antigens, enzymes and
and enzymes. Detection of these tumors occurs
hormones. (Tab. 10.3)
through abnormal serum levels of these markers.
Some cancer cells may produce oncofetal antigens,
such as alpha-fetoprotein and carcinoembryonic anti-
gen. These proteins are participated in embryogene- 10.3.2 Similarity of embryonic and
sis, however in the mature organisms their produc- malignant cells
tions quickly declines after birth. However, titers of
antibodies to carcinoembryonic antigen (CEA) are Carcinogenesis may be a caricature of normal his-
detectable in 90 % patients with cancer of the pan- togenesis observed in the developing embryo as it
creas, in 70 % patients with cancer of the colon and differentiates toward a mature organism.
in 35 % patients with breast cancer. Only approx- Some characteristics of the cancer cells are rem-
imately 5 % of normal individuals have detectable iniscent of the embryonic cells. Cancer cells re-
CEA reactive antibody titers. Increased levels of on- semble embryonic cells in motility, decreased con-
650 Chapter 10. Pathophysiology of malignant disease ( B. Mladosievičová)

Markers Tumor type

Antigens
Carcinoembryonic antigen (CEA) adenocarcinomas
Alfa fetoprotein (AFP) testicular, ovarian,
hepatic carcinomas
Tissue peptide antigen (TPA) carcinomas
Squamous cell carcinoma antigen (SCCA) epidermoid carcinomas
Antigenic determinants detected by pancreatic, breast,
monoclonal antibodies (CA 15-3, ovarian carcinomas
CA 125, CA 19-9)

Hormones
Human chorionic gonadotropin (HCG) trofoblastic tumors
Calcitonin (CT) thyroid, oat cell lung
carcinomas
Adrenocorticotrophic hormone (ACTH) oat cell lung carcinomas
Insulin, gastrin pancreatic carcinomas
Parathormone (PTH) oat cell lung carcinomas

Enzymes
Acid phosphatase prostatic carcinomas
Alkaline phosphatase bone tumors
Lactate dehydrogenase leukaemias
Thymidine kinase lymphomas, leukaemia
Neuron specific enolase neuroblastomas, oat cell
lung carcinomas

Table 10.3: Tumor cell markers

tact inhibition, invasiveness (which can be compared It has been observed that malignant tumors de-
to the invasive penetration of the endometrium by velop more readily in undifferentiated tissue. These
the trophoblast of the embryo), anaerobic metabo- tumors have a higher grade of malignacy. Risk of de-
lism, anaplasia (loss of differentiation), release of an- velopment of such tumors is associated with prenatal
giogenic (blood vessel-forming) substances, produc- exposure to radiation, stilbestrol therapy, certain vi-
tion of embryonic proteins (such as carcinoembryonic ral infections during pregnancy etc.
antigen).
10.4. Tumor growth and development 651

be insufficient in tumors with rapid rate of growth.

Later the tumor necrosis with releasing of necrotox-
10.4 Tumor growth and deve- ins may develop. A slowing down of tumor growth
may result from the depletion of oxygen and nutri-
lopment ents.

10.4.4 Pathogenesis of metastasis

A typical characteristic of malignancy is metastasis.
10.4.1 Tumor classification Metastasis is the dissemination of clumps of cancer
Tumors (abnormal formation of tissue) are classi- cells from a primary site of origin to a secondary site.
fied as malignant (cancer-producing) or benign (non- 50 % of newly diagnosed patients with malignant tu-
cancer producing). mors have occult metastases that are not readily de-
Tumors are named according to the tissue from tectable.
which they arise. Carcinomas are malignant tumors Malignant cells disseminate by these routes
derived from epithelial tissue, sarcomas from connec- • through lymphatic vessels (invasion into small
tive tissue and lymphomas from lymphatic tissue. lymphatic vessels)
Leukaemias usually involve an abnormal prolifera-
tion of blood-forming cells, in which malignant cells • through blood vessels (invasion into venules and
are widely dispersed and infiltrate bone marrow and capillaries)
lymphatic tissue.
• through serous surfaces of body cavities (im-
plantation in the peritoneal, pleural space etc.)
10.4.2 Malignant tumor growth
The process of metastasis involves several steps:
Malignant tumors arise as a result of uncontrolled
autonomous proliferation of the cancer cells. A typi- 1. local invasion of the surrounding tissue
cal feature of malignant tumor growth is invasion
of surrounding host tissue, which is accompanied by 2. penetration of tumor cells into blood vessels or
some cell surface changes of malignant cells. Tu- lymphatics
mor growth rates vary and are influenced by vas-
3. transport in the blood or lymph circulation
cular supply, immune surveillance mechanisms, by
occurence of non-proliferating cells, by proteolytic 4. arrest in capillary bed of organs
enzymes, growth factors etc.
Most tumors are considered to be monoclonal. 5. adherence to vascular wall
However, during the course of tumor growth het-
6. escape from vessels
erogenous mixture of cells can occur resulting from
angiogenesis, cell differentiation etc. Some subpopu- 7. proliferation of cells at the secondary site
lation of tumor cells may remain in non-reproductive
stage (G0 phase). These non-proliferating cells may Release of cancer cells from primary tumor can be
be resistant to therapy. associated with palpation, puncture and surgery and
therefore manipulation of the tumor must be careful.
However, many millions of cancer cells may break
10.4.3 Tumor angiogenesis
off primary tumor and never set up metastases be-
Tumor angiogenesis is new growth of blood vessels to cause of most die within lymphatics or bloodstream.
vascularize tumor by penetration of the capillaries Metastatic cells may exhibit differences from cells
from the edges of tumor. Malignant cells produce tu- of primary tumor. These differences may be asso-
mor angiogenesis factor (TAF), promoting growth of ciated with some tissue characteristic of secondary
the network of blood vessels in the tumor (Fig. 10.6). sites.
Also decreased pO2 in central parts of tumor may Metastases occur frequently in the liver, lungs
play a role in angiogenesis. Tumor angiogenesis may (Fig. 10.7), brain, bones etc. Destruction of these
652 Chapter 10. Pathophysiology of malignant disease ( B. Mladosievičová)

Figure 10.5: Mitotic activity and differentiation of normal and malignant cells (from Groer MW: Basic
pathophysiology, 1989)

Figure 10.6: Tumor angiogenesis (adapted from McCance, Mooney KH, Roberts LK: Pathophysiology, 1990)
10.5. Predisposing factors of cancer cells 653

prostate, kidney metastasize to bone, melanoma-skin

cancer metastasizes to liver). The mechanical theory
of metastasis explain the spread of cancer cells to
certain organs to such factors as metastatic cell size,
pressure, size of vessels, direction of bloodstream or
lymphatic drainage etc. The selective affinity theory
of metastasis correlates higher afinity of metastatic
cells to certain enviroment with immunologic chara-
cteristics, local growth factors, specific glycoprotein
surface components of favorable tissue cells etc.

10.5 Predisposing factors of

cancer cells

Epithelial tissue sometimes shows such deviation

from normal tissue growth as hyperplasia, metapla-
sia and dysplasia. These changes may predispose to
cancer. They occur as dysplasia of cervix uteri, poly-
posis coli, chronic cystic mastitis etc.
Carcinoma in situ represents preinvasive epithelial
tumor with atypical cell changes without disruption
of basement membranes. Some preinvasive lesions
may progress to invasive forms, some are unchanged
and some may spontaneously regress.

10.6 Characteristics of benign

tumors

Benign tumor is classified on the basis of well dif-

ferentiated cells, which do not invade and cannot
set up a new growths – metastases. Benign tumors
Figure 10.7: Pathogenesis of metastasis (from Poste are usually separated from the surrounding host tis-
& Fidler, 1980) sue by a capsule of connective tissue. Benign tumor
growth is slow. Necrosis and ulcerations of these tu-
mors are unusual. However, benign tumor can repre-
organs can often be found in cancer patients with sent sometimes extremely serious problem (if it ob-
metastases. structs a bronchus, vessel, truct, if it interferes with
Some tumor types preffer certain sites of secondary oxygenation, nutrition or elimination, if it has func-
growths (e.g. breast carcinoma and carcinoma of the tional endocrinal activity etc.)
654 Chapter 10. Pathophysiology of malignant disease ( B. Mladosievičová)

Figure 10.8: Factors contributing to cachexia in cancer patients

features that reflect the degree of differentiation.

There are four grades of malignancy from tumors
which are well differentiated and have low degree of
10.7 Pathophysiology of ma- malignancy (grade I.) to very poorly differentiated
tumors with no resemblance to tissue of origin, with
lignant disease high mitotic activity and great cellular variability
with high degree of malignancy (grade IV.).
TNM system is international accepted classifica-
Systemic and organ-specific signs and symptoms tion of stage of malignant disease. Tumor progres-
of tumor growth and dissemination are included in sion is related to three components included in this
malignant disease. Grading (degree of malignancy) classification (T–tumor, N–nodes, M–distant metas-
and staging (stage of development of malignant dis- tases).
ease) are helpful in diagnosis of malignant disease. Cancer patients have often suffered from cachexia,
Tumors are graded by biopsy according structural pain, infection, anaemia, ulceration, compression,
10.7. Pathophysiology of malignant disease 655

Figure 10.9: Factors predisposing to infection in cancer patients

obstruction, destruction of vital organs, skin and as meat, chocolate etc.) Hyperglycaemia, hyper-
connective tissue abnormalities etc. proteinaemia (results of abnormal metabolism) and
specific anorexigenic polypeptides (produced by tu-
mors) can act directly on hypothalamic satiety cen-
10.7.1 Cachexia ter. Cachexia may result from special competitive
Cachexia is closely related to anorexia. Cachexia is uptake of specific nutrients by malignant tumor that
manifested by weight loss, wasting, weakness, loss of results in lack of nutrients in host. Several factors
mobility, fluid and electrolyte dysbalance, anaemia, contributing to cachexia are shown on Fig. 10.8.
malnutrition. Cachexia is observed in at least 2/3
of oncologic patients and may be the first symptom. 10.7.2 Infection
Cachectic wasting is the most common cause of death
particularly in patients with stomach, colon, rectum Infection is one of the most serious complication and
or breast cancer. common cause of death in cancer patients. Fac-
Anorexia can be due to pain, depression, altered tors predisposing to infection are shown on Fig. 10.9.
taste sensations, aversion to certain foods (such Common agents causing infection in cancer patients
656 Chapter 10. Pathophysiology of malignant disease ( B. Mladosievičová)

Figure 10.10: Factors associated wit anaemia in cancer patients

are E. coli, Pseudomonas, Klebsiella, Staphylococ- 10.7.4 Leukopenia and thrombocyto-

cus, Candida, Streptococcus, Proteus, Clostridium, penia
viruses and protozoa.
Leukopenia and thrombocytopenia can be caused by

10.7.3 Anaemia • direct tumor invasion and metastasis to bone

marrow
Anaemia may develop in most of cancer patients.
Approximately 20 % of all cancer patients have • myelotoxic chemotherapy and radiotherapy
anaemia with Hgb lower than 9 g/dl. Factors causing
anaemia in cancer patients are shown on Fig. 10.10. • disseminated intravascular coagulation
10.7. Pathophysiology of malignant disease 657

Figure 10.11: Factors contributing to pain in cancer patients

Figure 10.12: Protection of malignant cell from immunologic surveillance. Antibodies produced by B lym-
phocytes block the cell from destruction by T lymphocytes. (From Groer MW, Basic Pathophysiology, 1989)
658 Chapter 10. Pathophysiology of malignant disease ( B. Mladosievičová)

10.7.5 Pain 3. suboptimal number of Tc cells (tumor grows at

increased rate)
Pain is unusal symptom in the early stages of malig-
nant disease, but pain does affect 60-80 % patients 4. stimulation of supressor T lymphocytes (block-
with advanced cancer. Pain may be enhanced by ing immune response)
anxiety, sleep loss, fatigue etc. Mechanisms causing
pain in cancer patients are shown on Fig. 10.11. 5. immunosupressive substance prostaglandin E is
Serious complications induced by nephrotoxic, produced by some tumors (PgE acts by increas-
myelotoxic, cardiotoxic, neurotoxic chemoterapy and ing c AMP levels in lymphocytes and thus blocks
radiotherapy are also of considerable importance in their proliferation)
oncologic patients.
6. B-lymphocytes may transfer antibodies block-
ing T lymphocyte receptors on malignant cells,
therefore T lymphocytes cannot destroy these
cancer cells (Fig. 10.12)
10.8 Immune surveillance and 7. cachexia
cancer
8. immunosupressive therapy

There is an increased cancer risk in individuals

Immune system plays an important role in im-
with immunodeficiency (inherited or acquired). Such
munologic surveillance for the emergence of cancer
individuals have 14-fold increased risk of developing
cells. A normal immunologic surveillance recognizes
lymphomas, 4-21-fold increased risk of skin cancer,
altered cell surface (specific and non-specific) tumor
11-fold increased risk of stomach cancer, 13-fold in-
antigens and reacts against them. Up to 10 million
creased risk of uterine cervix cancer, 2-fold increased
malignant cells can be destroyed by immune system.
risk of urinary bladder cancer.
(Tumor 1 cm in diameter contains approximately 109
cells after 30 doubling-times.) Of particular interest in cancer research and clin-
A wide range of cell mediated and humoral im- ical practice are mind-body relationships studied in
mune responses can protect the host against cancer psychoneuroimmunology.
cells – cytotoxic T lymphocytes (Tc cells), natural Stressors may supress the immune system through
killer (NK) cells, macrophages, helper T lympho- several mechanisms (release of catecholamines and
cytes, B lymphocytes, cytotoxic antibodies and com- corticosteroids, central mechanisms etc.). Immuno-
plement system. supression results in increased susceptibility to ma-
However, cancer cells are capable to escape im- lignancy with negative influence on incidence and
munologic surveillance. Escape mechanisms include: mortality from malignant disease.
1. antigenic modulation (by capping with antibo- However, ability to cope with stressors plays also
dies, masking by glycocalyx coat, shedding) an important role. Several studies demonstrated
that ”fighting” and denial patients are associated
2. non-antigenic subclone of cells (which may arise with longer survival than non-fighting and depressed
during tumor progression) patients.
Chapter 11

Fluids and electrolytes

1. Urine. The kidneys are the most important reg-

ulation mechanism for the elimination of water
and in this way for maintainance of homeosta-
11.1 Fluid disorders sis. They excrete all superfluous substances to
urine and resorb necessary solutes from primary
urine. Diuresis ranges between 1200–1500 ml a
day.
All the biochemical processes in organism, neces-
sary for life, take place in aqueous environment. The 2. Perspiration. Nearly 600–800 ml of water is lost
organism gains water in three ways: daily during perspiratio insensibilis. It might be
even more in some specific situations. Appart
• Receiving pure water. Organism receives 1200– from extreme climatic and working conditions
1500 ml of pure water daily. This input is easily it is the fever which increases the loss of water
balanced. during perspiration. Old people with fever may
even develop a dehydration.
• Receiving water by food intake. The amount
of water in food is variable. Organism receives 3. Respiration. 400–500 ml of water is lost daily by
1000 ml of water daily in this way. When no food respiration. We have to mention that it is the
is taken, we have to substitute not only the daily loss of pure water without electrolytes in this
intake of water but the amount of water released case.
from food as well.
4. Stools. 100 ml of water is lost daily by stools.
• Gaining water from biochemical processes. Wa- The loss of water and also electrolytes might be
ter is released in the process of oxidation. At extreme during diarrhoea.
about 35 ml of water is released during oxida- 5. Vomiting. The clinic result of water loss might
tion of 100g of proteins, 60 ml of water during be very serious during some patological condi-
oxidation of 100 g of glycids and 107 ml of wa- tions. Very important is the loss of chlorides,
ter is released during oxidation of 100 g of lipids. which dominates in the clinic symptoms, and
We can estimate that the daily water intake is also the loss of sodium and H+ .
300–500 ml in this way and in case of destructive
metabolism even more. Water, that represents 60 per cent of body weight
in males and 50 per cent in females, doesn’t exist as
The total water intake is approximately 2500 ml pure water in the organism. It contains a lot of sol-
a day, but it is very variable. The organism adapts uble substances – solutes which are mostly osmotic
to this variability by adaptation of the elimination active. According to the qualitative and quantitative
processes. differences in content of soluble substances we clas-
Elimination of water. Water is eliminated by uri- sify the total body water into several compartments
ne, perspiration, respiration, stools and vomiting. (spaces) where reciprocal exchange take place.

659
660 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

It is common and usefull to divide the total body the change of the capillary permeability is one of
water in the organism into extracellular and intra- the mechanisms that might lead to imbalance be-
cellular. tween extra- and intracellular space. The capillary
wall may be so alterated by inflammation or physical
11.1.1 Extracellular fluid (ECF) or chemical trauma that a large amount of proteins
can move to the interstitial fluid.
The extracellular fluid represents all the fluid outside
the cells. Its total amount is approximately 14 litres 11.1.2 Fluid in other extracellular
in a 70 kg person (1/3 of total body fluid-TBF). We
divide the extracellular fluid into: interstitial fluid, spaces
plasma, cerebrospinal fluid, intraocular fluid, gas- Cerebrospinal fluid is found in the brain and sub-
trointestinal fluid and fluid in potential space. arachnoid spaces surrounding the brain and the
Interstitial fluid represents the fluid in space be- spinal cord. Due to a limited diffusion through the
tween cells. The small part of it is free and flows blood brain barrier (bbb) and due to the active se-
through, but the bigger part is firmly captured in the cretion of some substances from the choroidal plexus
space by hydrated substances. For example, collagen as well, this fluid is slighly different from interstitial
fibres absorb a large amount of fluid and the poly- fluid and plasma. But the difference is not very large,
merised hyaluronic acid absorbs even a larger part and the cerebrospinal fluid can be considered to be
of fluid. Hyaluronic acid forms a gelly substance a part of interstitial fluid.
between cells of most body tissues. Despite these Intraocular fluid has got similar characteristics to
bounds, soluble substances move freely by diffusion the cerebrospinal fluid. It is a product of both diffu-
in the fluid. sion and secretion.
Plasma is a part of extracellular fluid which con- There are many spaces in the organism, containing
tinuously communicates with the interstitial fluid only a small amount of fluid normally. But in some
through capillary pores. The total capillary surface pathological conditions the amount of fluid can be
is extremely large and reaches 5000 square metres very large in these spaces. They are known as po-
by estimation. It is easy to imagine the large part of tential spaces. For example it is the space between
fluid which can move from intravascular to extravas- the visceral and parietal pleura. Under physiological
cular space and vice versa. Keeping a relatively sta- conditions this space contains only 10–15 ml of vis-
ble volume of intravascular fluid is conditioned by cous fluid but during disease this amount can reach
presence of proteins in plasma. Protein molecules are several litres. Other potential spaces are the peri-
too big for crossing the capillary wall freely. The per- toneal cavity, pericardial cavity, joint cavities and
sistance of proteins in vascular space creates an on- bursae. The fluid in these potential spaces commu-
cotic power which has the tendency to retain water. nicate freely with the surrounding interstitial fluid
The presence of oncotic pressure, which acts against and so we consider it to be a part of interstitial fluid.
the hydrostatic pressure, forms a base of Starling’s The fluid in gastrointestinal tract is extracellular
thesis concerning factors which regulate exchange of fluid as well.
fluid between vascular and extravascular space. The amount of this liquid varies according to the
Many factors are involved in the regulation of fluid intake and digestion of food. So it is possible to find
exchange between extra- and intravascular spaces. nearly 1 litre of fluid in GIT. In certain pathologi-
They are discussed in pathological conditions sep- cal conditions, for example ileus, the amount of fluid
arately. Their effect on disorders in the fluid dis- can reach nearly 10 liters. The gastrointestinal fluid
tribution between intra and extracellular spaces is (except secretions of some glands) is, regarding elec-
not always clearly understood. For example there trolytes, similar to the interstitial fluid and so it is
is a very week correlation between venous pressure considered as a part of it.
and edema when only venous pressure is changed.
The relation between hypoproteinemia and edema
11.1.3 Intracellular fluid (ICF)
in nephrotic syndrom is known. But this edema may
subside without measurable changes in concentra- About 25–40 liters of fluid (2/3 of the TBF) is called
tion of plasma proteins. These facts signalize that the intracellular fluid. The fluid in each cell con-
11.1. Fluid disorders (H. Sapáková) 661

tains its specific mixture of different components, but K+ is one of the most energy demanding processes
the concentration of these components is very sim- in the cells, provided by transport mechanisms.
ilar. Due to this fact, the intracellular fluid of all
the different types of cells is considered as one big
compartment of fluid, even if it is an aggregate of Plasma Interstitial Intracellular
trillions small compartments. Substance (mmol/l) fluid fluid
(mmol/l) (mmol/l)

11.1.4 The characteristic of the main Na+ 142 142 ±10

K+ 4,5 4,75 160
body fluid compartments Ca2+ 2,5 1,25
Mg2+ 1 0,5 20 (+Ca)
The knowledge of the individual compartments is
Cations 150,0 148,5 (180)
essential for the understanding of the physiological
mechanisms of homeostasis, for estimating the dose Cl− 103 114 ±2
of different drugs and diagnostic substances and for HCO− 3 25 27,5 ±8
the understanding of many pathological situations PO3−
4 1,0 1,5 120 (+SO4 )
as well. For example, the relative portion of ECF to SO2−
4 0,5 0,5
Proteins 16 0 50
the whole body weight in newborn is higher than in Organic 4,5 5
adult. That is the reason why the newborn can not acids
regulate the volume of ECF, and is relatively more Anions 150,0 148,5 180
susceptible to dehydration.
The composition of fluids determines the presence
of osmotic forces which are important for the main- Table 11.1: Substantial components of blood plasma,
tainance of volume in the main compartments of to- interstitial fluid, and intracellular fluid
tal body fluid (TBF).
They can by devided into three groups: The osmolarity of each compartment always
ranges between 290±10 mmol/l. This value is a little
1. Low molecular organic substances, that can lower than theoretically calculated osmotic concen-
cross the cellular membrane relatively fast. For tration of ions. This difference is due to the fact that
example we can mention urea, glucose, or amino the dissociation of electrolytes in biological fluids is
acids that only slightly contribute to the dis- not perfect and a part of the ions is in a nondifusible
tribution of water in the body in physiological (bound) form. Because of the high permeability of
conditions. the biological membranes, the deviations in the os-
molarity of one compartment will quickly be reflected
2. High molecular organic substances , mainly pla- in other compartments. Increase in the concentra-
sma proteins, are very essential in the exchange tion of solutes is hyperosmolarity, and a decrease in
of water between circulating blood and intersti-
the concentration of solutes is hypoosmolarity.
tial fluid due to their oncotic pressure.
For the constant osmotic pressure in body fluids,
3. Inorganic substances (electrolytes) are the most volume of water and amount of solutes must equili-
important constituents of body fluids. They brate. Though the concentration of particular ions in
considerably contribute to distribution and re- body fluids is variable, the resulting molar concentra-
tention of water in separated compartments of tion, determining osmotic pressure, is almost similar.
body fluids. Under normal conditions, the intracellular and the
interstitial fluids are isoosomotic with the plasma.
The composition of intracellular fluid differs from As seen in the table above 11.1, Na+ dominates the
the composition of blood plasma in many cases. It is extracellular fluid (plasma, interstitial fluid). Other
because Na+ is the main cation and Cl− is the main cations are present in small amounts. For the practi-
anion of ECF, whereas the intracellular fluid contains cal purpose we might consider Na+ to the sole cation
mainly K+ and P− (especially its phosporylated or- in extracellular fluid. As Na+ is the most important
ganic forms) together with protein anions. The cation in ECF, any change of its amount is accom-
maintainance of transmembral gradients for Na+ and panied with the change of anions amount. That is
662 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

the principle of electroneutrality. At the same time, The renal hormones, regulating homeostasis, are
every change of Na+ amount results in the change mostly renin-angiotensin-aldosteron system, kalli-
of ECF osmolarity. As the organism tries to main- krein-kinin system and prostaglandins.
tain the osmolarity, all changes of Na+ amount re-
sult in changes of water amount. So we can say that 11.1.5 Changes in the volume of body
the amount of ECF depends on the amount of Na+
fluids
mainly.
Changes of osmolarity on one side of membrane Changes in the volume of body fluid are typical of all
appear immediately on the other side of membrane. serious diseases. During the etiopathogenic analysis
So the dilution of ECF (by intake of a large amount we have to keep in mind following:
of water or by infusion containing hypoosmolar fluid)
• The close relation between ECF and ICF, which
will transfer water from ECF, where osmotic pressure
means, that changes in the volume and chemi-
has dropped, into the cells, where osmotic pressure
cal composition of one compartment will usually
is greater. When ECF osmolarity increases, water
cause identical changes in the other one.
will move from the cells to ECF according to the
osmotic gradient. For example, this shift can occur • The dependence of ECF volume on composition
upon intake of hyperosmolar solution, or upon an in- of ions of internal environment (this condition
adequate water intake. The stability of ECT osmotic concerns other body fluids as well).
pressure is an important factor for normal cell func-
tions. Any change of ECF osmolarity will lead to the • The volume of total body fluid and division of
disturbance of water balance both in ECF and inside fluid into particular compartments.
the cells.
• The close relationship between water metabo-
The pH value of arterial blood is 7.40±0.04. The lism, electrolyte composition and acid-base bal-
pH value of interstitial fluid is similar to blood pH. ance of body fluids as well.
The ECF pH is maintained by the buffer systems,
pulmonary ventilation and kidney and this provides So it is very difficult to talk about isolated changes
the required stability of pH in body fluids. of ECF, not only according to pure water, but chem-
These mechanisms take place in appearance, de- ical composition as well. Even though we practically
velopment and culmination of many serious patho- distinguish many states with accumulation or loss of
logical states, because each cell can normally exist body fluids, basically it is hyperhydration or hypo-
only in optimal physical and chemical conditions. To hydration (respectively dehydration).
maintain normal course of enzymatic and metabolic
reactions it is necessary to have a constant acid-base 11.1.6 Dehydration
balance as well.
Under physiological conditions, the fluid intake and
The composition of internal environment is strictly output is in equilibrium. If a disorder occurs, lead-
maintained by the regulatory and compensatory ing to decreased body fluid volume (respectively neg-
mechanisms of organism, even if the composition of ative water balance), dehydration develops. Dehy-
the external environment varies considerably. These dration can be devided into isoosmotic (isotonic),
regulation mechanisms work mainly on the feed- hypoosmotic (hypotonic) and hyperosmotic (hyper-
back effect (e.g. increase of ECT osmolarity −→ os- tonic).
moreceptors −→ hypothalamus −→ hypophysis −→
ADH −→ H2 O retention −→ normalization of osmo-
11.1.6.1 Isoosmotic dehydration (isotonic)
tic pressure in body fluids). Cannon called the main-
tainance of stable internal environment in higher or- This kind of dehydration occurs as a result of wa-
ganisms homeostasis. The extrarenal hormones, par- ter loss directly related to salt loss, so there is a
ticipating in electrolyte and volume homeostasis, are loss of isoosmotic fluid. The most common causes
mainly antidiuretic hormone (ADH – adiuretin or of isoosmolar fluid loss are: diseases of gastrointesti-
vasopresin), aldosteron, and atrial natriuretic factor nal tract accompanied by diarrhea and vomiting (py-
(ANF). lorostenosis, gastroenteritis, colitis), accumulation of
11.1. Fluid disorders (H. Sapáková) 663

fluid in the abdominal cavity (peritonitis) or in in- lutes, intake of pure water can lead to decrease in
testine (ileus), fistulae. It can be caused by draining internal environment’s osmolarity, accompanied by
the gastric or intestinal content as well. From re- water inflow into the cells. Decrease of ECF osmotic
nal causes there are kidney diseases associated with pressure leads to decrease of ADH secretion, result-
isostenuria and polyuria and administration of di- ing in water diuresis what means excretion of taken
uretics, too. From the causes of blood circulation it water. Simultaneously with loss of water a small
is a blood loss. Burns and excessive transsudation amount of sodium is lost, too. That’s why receiv-
from wounds can also cause the loss of isoosmolar ing pure water or glucose solutions not only doesn’t
fluid. improve, but even might worsen patient’s condition.
The loss of body fluids is limited to extracellular Optimal therapy requires isoosmolar solutions. It is
space. So haemodynamics is affected mostly and the very important to estimate the ions loss. Vomiting or
clinical features of circulation disorder dominates. gastric lavage will cause isoosmolar loss of fluid and
The cardiac output is decreased and as a result some metabolic alkalosis as well. Diarrhea on the other
changes of blood distribution in particular organs ap- hand causes metabolic acidosis and potassium defi-
pear. The blood flow in kidneys and skin decreases. ciency.
Skin turgor and intraocular pressure decreases as
well. The failure of peripheral circulation – hypo-
volemic shock – is mostly dangerous in isoosmotic 11.1.6.2 Hypoosmotic (hypotonic) dehydra-
dehydration. The circulation reacts to low cardiac tion
output by vasoconstriction. So diastolic blood pres- This condition occurs when electrolyte loss (mainly
sure might increase a little and systolic blood pres- sodium) exceeds water loss. The extracellular space
sure decreases due to low cardiac output. The pulse shrinks and osmolarity of ECF decreases. As a con-
is fast and weak (so called thready pulse). Mucus sequence, water will enter cells. This process con-
membranes are dry and tongue is coated. Subjec- tinues till osmotic pressure becomes equal on both
tively patient feels exhausted and weak. sides of the cellular membrane. The cells become
The osmotic pressure of plasma is not changed and swallen. This type of dehydration can occur upon
so there is no stimulation for releasing ADH from hy- chronic pyelonephritis (the risk increases by salt free
pophysis at first. Diuresis will not decrease a much diet), polyuric phase of chronic renal insufficiency,
till there isn’t a marked decline of ECF volume. The chronic adrenal insufficiency (Addison’s disease), in
decline of ECF volume leads to low renal perfusion upon CNS diseases (encephalitis, damage in the re-
and to increase of aldosteron secretion with resulting gion of paraventricular and supraoptic nuclei). Hy-
reabsorption of sodium and water. In the beginning, potonic dehydration might occur while using large
even thirst is not a dominating symptom. So the doses of diuretics and laxatives, too. Salt loss occurs
loss of isoosmolar ECF can reach a considerable level upon rectal tumors and long lasting salt free diet.
without appearance of dehydration signs (marked Substitution of fluid loss by pure water (for example
thirst, oliguria, ect.). Later occurs thirst, probably after long lasting vomiting and diarrhea and in states
as a result of high aldosteron release. Low renal per- accompanied by enormous sweating) can cause this
fusion can be associated with decreased catabolite kind of dehydration as well.
excretion and with accumulation of urea nitrogen,
Symptoms of hypoosmotic dehydration are result-
that means with extrarenal azotemia. The diagno-
ing from the decrease of ECF and from the loss of
sis might be assisted with evaluation of haematocrit.
Na+ (possibly K+ ), and resulting water flow into the
The haematocrit increases as loss of fluids is limited
cells. The symptoms are: general weakness, sunken
to ECF (except from posthaemorrhagic states).
eyes, low skin turgor, low blood pressure and thready
Newborns are most susceptible to this form of de- pulse. The developing clinical picture is similar to
hydration. The total volume of ECF is small in new- shock accompanied with spasms of particular mus-
borns, and then common gastrointestinal problems cles, mainly of legs. The patient might fall into delir-
associated with diarrhea can lead to a relatively large ium or coma when the loss of electrolytes is contin-
loss of fluids. uous and very high.
According to the loss of Na+ and other ECF so- The laboratory tests reveals decrease of Na+ be-
664 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

low 130 mmol/l in serum. Erythrocytes, haemat- erythrocytes, Hb, total poteins, but a diminution of
ocrit, and proteins are relatively increased. The ther- erythrocyte’s size (due to intracellular dehydration).
apy consists of restoration of body fluids with hyper- Haematocrit is normal or a bit higher. Hypovolemic
osmolar solution (according to hypoosmolarity) and shock is the most dangerous consequence of plasma
correction of possible acid base disorders. volume decline and high plasma density. Therapy
consists of water substitution in form of glucose so-
11.1.6.3 Hyperosmotic (hypertonic) dehy- lution without electrolytes.
dration
11.1.7 Hyperhydration
Hyperosmotic dehydration, so called hypersalemia
(water defficiency in organism), occurs when wa- Hyperhydration is a general increase of body fluids
ter loss exceeds electrolytes loss. The consequence volume. It appears as a result of an excessive intake
of hyperosmotic dehydration affects all body com- of salt and fluids, failure of excretory mechanisms
partments. First of all ECF hyperosmolarity causes and increase of their retention.
transfer of fluid from relatively hypoosmolar cells to Depending on changes of electrolyte composition,
interstitium and plasma. So the osmotic pressure is hyperhydration is divided into:
equilibrated in all body compartments. Nevertheless • isoosmotic (isotonic) hyperhydration,
the osmotic pressure is still higher than in normal
conditions. • hypoosmotic (hypotonic) hyperhydration,
This type of dehydration results from low water • hyperosmotic (hypertonic) hyperhydration.
intake (unconsciousness, abscence of thirst in case of
CNS anomalies and in old people, hydrophobia or
11.1.7.1 Isoosmotic (isotonic) hyperhydra-
cases of drink and swallow disabilities). It occurs in
tion
conditions associated with high water loss (hyperven-
tilation, profuse sweating, polyuria in diabetes mel- Isoosmotic hyperhydration is characterized by an ex-
litus and diabetes insipidus) as well. cessive blood plasma volume and interstitial volume
The shift of water from cells into ECF maintains as well. As ECF osmolarity is unchanged, ICF vol-
the necessary volume of intravascular fluid. That’s ume remains unchanged, too.
why the viscosity of blood, hematocrit value and con- The surplus of plasma volume, manifested by de-
centration of plasma proteins is normal initially. On crease of haematocrit, hemoglobin and plasma pro-
the other hand, due to the shift of water from in- teins (so called hemodilution), overloads the heart.
tracellular to extracellular spaces, intracellular de- The total raise of ECF volume can be the result
hydration results. The increase of osmolarity stimu- of administration of an excessive amount of isoosmo-
lates osmoreceptors. As a result more ADH is re- lar solutions. This occurs usually upon a fast par-
leased and consequently more water in kidneys is enteral application of a large amount of solutions
reabsorbed. The amount of urine decreases and its (blood transfusion, plasma transfusion and blood
specific gravity is increased. Although the transfer of substituents). The consequences are mostly haemo-
water from cells into circulating blood maintains the dynamic. Their range and seriousness depends on
blood volume, metabolic processes inside the cells are the given amount of fluid, speed of administration
disturbed. If water loss is considerably high, clinical and ability of heart to increase cardiac output. Car-
status becomes serious. The patient experiences se- diac failure may develope.
vere thirst. His salivary glands secretion is decreased, General edema is the most common condition of
mucous membranes are dry, voice is harsh, tongue is isoosmolar fluid’s retention and increase in ECF vol-
dry, skin turgor is low, and his temperature increases ume. General edema occurs together with cardiac
(due to low evaporation from skin). Later some failure, nephrotic syndrome and liver cirrhosis. The
psychological disturbances (desorientation, halluci- ECF volume can be several times larger than normal
nation and eventually convulsions and coma) occur. ECF volume. The optimal therapy is elimination of
Laboratory tests reveal high serum Na+ , high urea the underlying disease (heart, liver, kidneys). It is
nitrogen (due to decreased glomerular filtration) and important to decrease water and Na+ intake. Os-
high serum chlorides as well. Tests reveal surplus of motic diuretics are very helpfull.
11.1. Fluid disorders (H. Sapáková) 665

11.1.7.2 Hypoosmotic (hypotonic) hyperhy- 11.1.7.3 Hyperosmotic (hypertonic) hyper-

dration hydration
The surplus of water in organism causes hypoosmotic Hyperosomotic hyperhydration is defined as a con-
hyperhydration. Hypoosmolarity of the extracellu- dition where both the volume and the osmolarity of
lar space (due to surplus of water) results in water the ECF are increased. This leads to a shift of water
shift to a relatively hyperosmolar cells. In this con- from the intracellular space into the ECF. It will con-
dition the volume of all body fluids (ICF and ECF) tinue till a new osmotic balance between ECF and
increases equally, but the solute concentration in flu- ICF is established. Intracellular dehydration results.
ids decreases. There are two possible causes for hyperosmotic hy-
Hypoosmotic hyperhydration can result from: perhydration: increased intravenous administration
of NaCl (in case of renal insufficiency) and an exces-
1. Excessive infusions of glucose solutions (gaining sive introduction of infusions (such as hyperosmolar
water from glycid metabolism). salts or hyperosmolar sugar solutions). In the former
case, the plasma Na+ is increased and might reach
2. Excessive water intake or infusion therapy in pa- 147 mmol/l, in the latter case this value is normal
tients with oliguria and anuria. or decreased (the hyperosmolarity is caused by the
osmotic activity of the sugars). Laboratory param-
3. Covering water and electrolyte loss by an exces- eters show decreased number of RBC, low Hb and
sive amount of pure water, resp. 5 per cent glu- haematocrit, and a decreased RBC volume.
cose. The most common cause of hypoosmotic
hyperhydration is substitution of pure water in
case of an excessive sweating. Water defficiency Water surplus

4. The increase of ADH, due to an overproduction loss of weihgt weight increase

(Schwartz-Bartter syndrome) or due to deficient thirst cephalalgia
degradation in altered liver. oliguria disorientation
concentrated urine nauzea
5. The overproduction of ADH resulting from pain acidosis vomiting
during postoperation stress. Another cause of fever edema
ADH overproduction might be bronchial tumor muscle clones muscle spasms
and brain lesion. cardiorespiratory failure unconsciousness

The consequences of water overproduction depend

on the speed of its development. When the develop- Table 11.2: Consequences of both hypohydration
ment is rapid, pulmonary edema might occur. and hyperhydration
Other symptoms of so called water intoxication,
probably due to brain edema, are headache, in- Etiological factors of hyperosmotic hyperhydration
adequate behaviour with disorientation resulting in are e.g. adrenal tumors, acute renal failure, acute
unconsciousness (coma). Intracranial hypertension glomerulonephritis, as well as high doses of steroid
leads to nauzea and vomiting. The plasmatic Na+ hormones.
concentration is low, and the Na+ and Cl− content The clinical symptomatology of hyperosmotic hy-
in urine is low. perhydration is similar to the hypoosmotic hyperhy-
The therapy consists of limiting the water intake, dration.
treating the underlying disease, and administrating During the therapy it is very important to find out
osmotic diuretics. Application of hyperosmolar so- the etiology of the disorder. The correction of the
lutions, always recommended in the past, comes to fluid volume should be accompanied with the correc-
consideration only when brain edema might develop. tion of the osmolarity, the ionic concentrations and
In anuria, water retention is the second most impor- the pH.
tant indication for haemodialysis (first being potas-
sium retention).
666 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

Sodium is found in two fractions in organism, ex-

changeable and non exchangeable.
11.2 Electrolyte balance and The exchangeable fraction is represented by so-
its disturbances dium in extracellular fluid, intracellular fluid, and 15
per cent of bone sodium (on bone surface).
The non exchangeable fraction is fixed inside the
bones, and do not share the sodium functions men-
The trace elements and minerals are necessary for tioned above.
the maintenance of biochemical reactions inside the Under normal conditions, the amount of sodium
cells. Their most important roles are: is constant in particular body fluid compartments.
The concentration gradient between ICF and ECF
• to maintain the suitable osmolarity and volume is maintained by sodium pump, transporting the
of body fluids, sodium outside the cell using the ATP energy. About
10 per cent of all the sodium in organism exists in-
• to maintain the appropriate acid-base balance, tracellulary.
• to create the suitable physico-chemical environ- Sodium can be mobilized from bones, to supply
ment for cellular functions. Excitability of ner- the loss from extracellular fluid. In acidosis, sodium
vous and muscular fibers and, generally, normal is excreted by urine together with acid radicals. As a
functions of glandular, muscular and nervous result the shift of sodium from bones to extracellular
cells depend on the ionic composition and the fluid occurs. In positive sodium balance, sodium is
balance between intracellular and extracellular deposited inside the bones, on contrary.
compartments. Sodium balance. The amount of sodium remains
nearly constant under physiological conditions. The
• being a part of important compounds with spe- sodium food intake ranges between 140–260 mmol
cific functions in organism (iron, iodine, zinc, daily. As the sodium intake is regulated only a little
and magnesium). (by the actual taste of food), the regulation depends
on elimination of sodium.
It is important to concentrate on element’s intake, The sodium loss via the skin is not significant when
elimination, and concentration in ECF or ICF during the temperature of outside environment is comfort-
investigation their turnover. able. Approximately 10 mmol Na+ a day is lost by
sweating in basal conditions. This amount rises in
11.2.1 Sodium hot conditions, mostly in fever. Sodium loss via stool
represents only 1–2 per cent (nearly 10 mmol/day) of
Sodium represents more than 90 per cent of ca- total Na+ loss. This way becomes more important in
tions in the extracellular fluid (its concentration is diarrhea, where elimination of Na+ and other elec-
140 mmol/l in ECF and 3–35 mmol/l in ICF, de- trolytes rises extremely. Kidneys are most important
pending on type of tissue). That is why sodium de- in regulation of sodium elimination. Approximately
termines the osmotic pressure together with corre- 120–240 mmol Na+ a day is excreted by kidneys.
sponding anions. As a result, the amount of sodium The kidneys are able to excrete urine both with
is responsible for the volume of extracellular fluid. very high or very low sodium content. Many factors
As there exists a balance between extra and intracel- affect the natriuresis. For example, haemodynamic
lular fluid, any change of Na+ concentration causes and physical factors, aldosterone, renin-angiotensin
the shift of water between cells and extracellular en- system, kallikrein-kinin system, prostaglandins, and
vironment. newly discovered natriuretic substances (ANF, natri-
Sodium has an important role in the maintainance uretic hormon ?) as well.
of acid-base balance. The concentration of sodium
determines the amount of needed bases. 1. Haemodynamic factors – changes of blood
The presence of Na+ is important for the main- flow in kidneys with the resulting affection of
tainance of normal membrane potentials and normal glomerular filtration. This mechanism takes
cardiac function. place in fast and short term changes of Na+
11.2. Electrolyte balance and its disturbances (H. Sapáková) 667

excretion, but the maintainance of glomerulo- During a limited salt intake, the tubular cells do not
tubular balance prevents further continuation of respond to the stimuli of sodium retention. As a re-
these changes. sult a progressive hyponatremia and hypochloremia
occur.
2. Physical factors – oncotic pressure, which de- A large amount of sodium is lost during a diuretic
creases during albumin’s concentration decline. therapy in normal kidneys. The saluretic’s aim is to
This results in slower resorption of Na+ and wa- induce a negative sodium balance. If they are applied
ter in tubules. intermittently, organism compensates this loss. The
3. Aldosterone, which increases the resorption of application of saluretics daily for a long time might
Na+ from primary urine. cause an electrolyte wastage.
In pathological conditions, a serious loss of Na+
4. Renin-angiotensin system. The constriction of from gastrointestinal tract may occur. The pan-
vas afferens decreases the renal blood flow. As creatic juice, bile and secretions from small intes-
a result, decrease of glomerular filtration and de- tine contain sodium nearly in the same concentra-
crease of Na+ amount in primary urine occurs. tion as plasma. Under normal conditions, sodium is
Finally sodium excretion is decreased. On the resorbed from the intestine, and only a small loss of
other hand, angiotensin supresses the resorption Na+ by stool appears. In diarrhea the sodium loss
of sodium from primary urine by a direct effect reaches a considerable level.
on tubules and so contributes to a higher Na+ Sodium retention is accompanied by the increase
excretion. Clinical features and conditions de- in total body sodium. The sodium surplus does not
termines the dominating mechanism. lead to hypernatremia and hyperosmolarity, because
the resulting stimulation of ADH leads to retention
5. Kallikrein-kinin system which increases the of water. Water and sodium are retained in the prox-
blood flow in kidneys, the diuresis and natri- imal tubuli, too. As a result an expansion of ECF
uresis. occurs, so the actual level of plasma Na+ doesn’t
6. Prostaglandins, contributing to a higher Na+ change. During a considerable sodium retention,
elimination. Vas efferens is suggested to be their edema or accumulation of fluid in body cavities may
target place. develop. The relationship between sodium retention
and hypertension is a subject of an intense investi-
7. Natriumuretically acting substances (ANF- gation.
atrial natriuretic factor and natriuretic hor- The most common causes of an excessive total
mone), which suppress the Na+ resoption in sodium are: high intake, low elimination, and Na+
tubules and so increase Na+ excretion. sequestration.

Sodium disorders. Despite the precise regulatory 1. High Na+ intake.

mechanisms of Na+ turnover, sodium disorders are The organism may receive a large amount of
quite a common clinical problem. sodium per os, by a nasogastric probe or par-
The loss of sodium by excessive sweating leads to enterally. While using a nasogastric probe, a
hyponatremia indirectly. Since sweat contains less sufficient amount of fluid must be administered
sodium than plasma the water loss is greater than as the organism can not provide the appropriate
sodium loss with resulting hyperosmolarity of ex- excretion of Na+ in a small volume of urine.
tracellular fluid. In Addison’s disease the inability
to retain sodium in kidneys occurs. As a result a 2. Low Na+ elimination.
negative sodium balance with hypovolemia, hypona- It is a common cause of positive Na+ balance
tremia, and hyperkalemia appears. Then an intake occuring upon heart failure, liver cirrhosis with
of mineralocorticoids is required. ascites, nephrotic syndrome, renal insufficiency
A number of kidney diseases result in inabili- and delayed gestosis or endocrine disorders.
ty of salt retaining (salt loosing nephritis, chronic
pyelonephritis, ect.). In this conditions, the plasma (a) Heart failure is probably the most common
sodium is maintained only by a higher salt intake. cause of Na+ retention.
668 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

(b) Liver cirrhosis. Na+ retention results from Changes of chlorides intake are immediatly re-
hypoproteinemia, secondary hyperaldos- flected in changes of their excretion by kidneys. Dur-
teronism, decreased renal function and ing acid base disturbances, the concentration of chlo-
most probably from other tubular disor- ride changes more then concentration of Na+ . It
ders. results from the fact that total amount of cations
should be equal to total amount of anions to main-
(c) Nephrotic syndrome. Na+ retention results
tain electroneutrality. Anions have only two main
from hypoproteinemia with resulting hy-
variable constituents: HCO− −
3 and Cl .
povolemia and from secondary hyperaldos-
Changes in acid base balance caused by a primary
teronism.
change of the amount of bicarbonate are accompa-
(d) Oligoanuric phase of renal insufficiency nied with the opposite change of chlorides. Sec-
(mostly acute renal failure and terminal ondary changes of the amount of bicarbonate occur
stage of chronic renal insufficiency). during hypo- or hyperventilation. In these condi-
tions plasma chloride concentration changes indepen-
(e) Endocrine disorders. Mainly two groups of
dently on plasma sodium concentration.
disorders cause low sodium elimination. It
is primary and secondary hyperaldostero- Disorders of chlorides turnover occur simultane-
nism and natriuretic hormone defficiency. ously with disorders of Na+ turnover. The most
Natriuretic hormone: The low Na+ elim- common cause of chloride disturbances is the loss of
ination results from inadequate produc- gastric juice, occuring mainly upon an excessive vom-
tion or function of natriuretic hormone. iting or a permanent suction of gastric juice. The loss
At least two natriuretic hormones are de- of chlorides is much bigger than the loss of Na+ and
scribed in literature. It is suggested that a K+ . Resulting decrease in plasma chloride concen-
hormone retaining sodium exists as well. tration and simultaneous increase in plasma bicar-
bonate concentration occurs. Hypochloremia leads
3. Sequestration of Na+ . to alkalosis with resulting decrease in the ionized
calcium in plasma. Tetany may develop. H+ and
It is caused by an unequal distribution of Na+ (eg.: Na+ enter the cells and push the K+ outside. It is
in hollow organs, in burns and bruises of soft tissues). necessary to apply chlorides, potassium, sodium and
Symptoms of hypovolemia are present. water to correct this disorder.

11.2.2 Chlorides 11.2.3 Potassium

The daily food intake of potassium ranges between
Daily food intake of chlorides is 140–260 mmol. Their
30–80 mmol. The resorbed K+ is distributed in ECF
total amount in organism is around 1400 mmol.
in a low concentration (4.5 mmol/l). Despite this
Elimination of chlorides via urine is only a bit lower
fact, the concentration of K+ in ICF is high and vari-
than their intake, because nearly 10 mmol Cl−/day
able in different tissues. Potassium concentration in
is excreted by sweating. Nearly the same amount
ICF ranges between 100–160 mmol/l.
is excreted by stool. Chlorides are distributed in
ECF, forming its main anion. Plasma Cl− concen- About 90 per cent of potassium in organism is ex-
tration is around 100 mmol/l. The shift of chlorides creted by urine and 10 per cent is excreted by stool.
between ICF and ECF appears in pathological con- These values can be variable, for example the amount
ditions, such as heart failure and disturbances of acid of K+ in stool considerably increases in diarrhea. To
base balance. maintain the K+ balance in the organism intact kid-
neys are necessary.
The concentration of chlorides in organism is reg-
ulated similarly as sodium concentration. In oppo- Potassium is the main intracellular cation. Nearly
site, chlorides are not resorbed actively in kidneys, all processes in cells are depended on gradients of
but along the electrochemical gradient of Na+ . Chlo- potassium and natrium on both sides of the cellular
rides are resorbed actively only in ascendent arm of membrane.
Henley’s loop. Many metabolic processes are responsible for the
11.2. Electrolyte balance and its disturbances (H. Sapáková) 669

shift of potassium between intra- a extracellular smooth muscles (stomach atonia, urinary bladder
fluid. atonia, and paralytic ileus) and also to some serious
The glucose enters the cells accompanied with po- cardiac disorders. Hypokalemic alkalosis might de-
tassium. Investigations performed on human ery- velop. In experiments performed on rats, the potas-
throcytes show that during the entrance of 0,5– sium defficiency leads to myocardial necrosis with
1,0 mmol glucose 1 mmol of potassium enters the resulting fibrotic changes. The ECG reveals flatten-
RBC at the same time. ing or even inversion of T wave, depression of ST
segment, and prolongation of QT interval, as well.
Glycogenolysis leads to the release of intracellular
potassium on the contrary. Potassium defficiency is closely related to the hy-
pokalemic familiar periodic paralysis. In this heredi-
Tissue growth and regeneration also require po-
tary disturbance the paroxysmal hypotonic paralysis
tassium. The building of a new protein in cells makes
of skeletal muscles and the affection of cardiac func-
potassium entering the cell. On the other side, pro-
tion occur. The paralytic paroxysms are closely re-
tein degradation leads to the release of potassium
lated to the decrease in potassium concentration and
from intracellular space. Cellular injury or cellular
to the decrease in creatinin and phosphate plasma
hypoxia results in leak of potassium from cells.
concentration as well. Intravenous or peroral ad-
In alkalosis, H+ leaves the cells and enters the ex- ministration of KCl improves the muscular functions.
tracellular fluid, while potassium enters the cells. Al- The paroxysms occur spontaneously and mainly fol-
kalosis becomes mitigated but hypokalemia develops. lowing a tiring muscle work. They occur namely dur-
Even the primary hypokalemia can stimulate the H+ ing the supply of consumpted glycogen, which is ac-
entering the cells (the result is hypokalemic alkalosis, companied by the decrease in anorganic phosphate
too). and potassium. The application of insulin or glu-
Short term shift of potassium occurs during depo- cose leads to development of paralytic paroxysm in
larization and repolarization of cellular membranes predisposed individuals. A certain relation between
in excitable structures, related to the spread of im- paroxysmal muscular paralysis and primary hyper-
puls. aldosteronism (Conn’s syndrome) is assumed. Pa-
Kidneys have the most important role in the regu- tients with familiar paroxysmal muscular paralysis
lation of potassium turnover in organism, too. How- were noticed to have a little higher aldosterone level
ever, kidneys are not as perfect in sparing potassium, in urine.
as in sparing sodium and chlorides. So, disorders of The symptomatology of hypokalemic familiar pe-
potassium balance occur more often. riodic paralysis is similar to hypokalemic states,
In pathological conditions an accumulation or which are clinically marked as states of potassium
wastage of potassium with resulting serious distur- defficiency. Adynamia, hyporeflexia or areflexia,
bances of cell metabolism develope. The symptoms paresis, disturbances of heart rate, polyuria due to
of potassium disorders depend mainly on the con- kaliopenic nephropathy and rarely mild edema oc-
centration of plasma sodium. Having a certain con- cur. Kaliopenic nephropathy is granular, hydropic
centration of plasma potassium and different con- and vacuolar degeneration of tubular cells, which can
centrations of plasma sodium, clinical symptoms are be caused by long lasting hypokalemia.
usually different. The symptoms of hypokalemia are Upon chronic diarrhea not only sodium but also a
more prominent, if the concentration of sodium is considerable amount of potassium is lost. It is due to
normal or increased. Similarly, symptoms of hy- the fact, that potassium is found in higher concentra-
perkalemia are intensified by low sodium concen- tion in intestinal juice than in plasma. Defficiency of
tration, and supressed by hypernatremia. Calcium potassium is not substituted by the supplementation
also antagonizes some physiological effects of potas- of water and salt only. On the contrary, the infu-
sium, mainly those concerning the neuromuscular ex- sion of large amount of sodium chloride solution can
citability and heart function. decrease the plasma potassium concentration even
Potassium defficiency. Potassium defficiency leads more. The decrease of potassium can be manifested
to serious alteration of striated muscles (adynamia, by muscle weakness and by paralysis of diaphragm
hyporeflexia, and paralysis of skeletal muscles), of in certain conditions.
670 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

The most common cause of potassium defficiency Hyperkalemia occurs mainly in situations with
is insulin therapy of diabetic ketoacidosis. Several massive cellular degeneration, for example hemoly-
gramms of cellular potassium are excreted daily by tic crisis, crush syndrome ect.
urine during diabetic ketoacidosis. Since the diabetic Hyperkalemia appears also in Addison’s disease,
coma develops slowly, large amount of potassium can where it is accompanied by low plasma sodium con-
be lost. Starting with insulin therapy, glucose enters centration resulting from defficiency of mineralocor-
the cells accompanied by potassium, with resulting ticoids.
considerable decline of plasma potassium. Hyperkalemia in renal diseases associated with
Less common is potassium defficiency caused by oliguria or anuria is caused by altered K+ excre-
chronic or acute renal diseases (Potassium-losing tion. This condition can be even life threatening.
nephropathy). This condition is noticed in the The disease is usually manifested by the loss of ap-
polyuric stage of tubular necrosis. Due to severe in- petite, nausea and vomiting. The inadequate intake
jury of tubular apparatus, the coordination between of food and the toxic effect of waste products (due
potassium elimination and potassium resorption is to renal retention) result in higher glycogen and pro-
altered. tein degradation leading to increase of potassium in
The iatrogenic states of potassium deficiency extracellular fluid.
(caused by the medical staff) are very important. The untreated diabetes mellitus with acidosis is
Long lasting administration of ACTH, cortisol, pred- another cause of hyperkalemia with shift of potas-
nisolon, prednison, etc. leads to hypokalemia due to sium from the cells to the extracellular fluid. In
higher potassium excretion. this condition potassium is leaving the cells due to
The administration of saluretics can lead to hy- glycogenolysis and proteolysis and due to loss of
pokalemia after few days even in therapeutic doses. bases from extracellular fluid as well. Dehydration,
The long lasting use of laxatives can lead to hy- associated with acidosis, increases the stage of hy-
pokalemia due to a relatively high level of potassium perkalemia even more.
in intestinal juice (especially if the food is not rich of
Iatrogenic hyperkalemia occurs mainly upon the
potassium).
administration of potassium drugs for stimulation of
Hypercorticism is another cause of potassium de- diuresis in progressive renal insufficiency with edema.
ficiency in organism. Mineralocorticoids stimulate
both sodium resorption and potassium excretion in
renal tubules.
Hyperkalemia. Experimentally, a higher concen-
11.2.4 Calcium and Magnesium
tration of potassium in washing solution can result in
These two elements do not exceed 5 per cent of the
disappearance of neuromuscular excitability. Upon
total cation amount in extracellular fluid. So they
doubling the plasma K+ concentration, signs and
participate only a little on the maintainance of body
symptoms of paralysis can occur. The clinical signs
fluids osmolarity and volume. They are also not
of hyperkalemia are similar to signs of hypokalemia:
very important in the regulation of acid-base bal-
adynamia, paresthesia and even paralysis. ECG is
ance. But calcium and magnesium ions are impor-
very good differential diagnostic method. We can
tant for their specific effect.
notice the following in hyperkalemia:
The calcium concentration in the internal environ-
• Raising of T wave with steep edges and narrow ment is regulated by parathyroid hormon and thyreo-
base. calcitonin. Calcium metabolism is markedly affected
by vitamin D and other substances which either in-
• Widening of QRS complex, mainly the S wave, crease or decrease its resorption in the upper part of
so the picture of right sided bundle branch block small intestine. The factors enhancing vitamin D re-
(Wilson’s block) occur. sorption are: HCl in stomach, aminoacids and prod-
ucts of milk fermentation. The factors decreasing
• The disappearance of P wave, and finally vitamin D resorption are: surplus of phosphates and
oxalates, disturbances of fatty acids resorption and
• cardiac arrest diarrhea.
11.2. Electrolyte balance and its disturbances (H. Sapáková) 671

11.2.4.1 Calcium Nearly 99 per cent of total calcium amount is de-

posited in bones. Calcium blood level is relatively
Calcium is a component of all body fluids and tissues.
stable and ranges between 2.25–2.75 mmol/l. Prac-
It has an important role in different processes such
tically all the blood calcium is present in plasma,
as:
existing in 3 forms:
• blood coagulation
• bound to plasma proteins (nearly 50 per cent).
• teeth and bones formation Calcium binds mainly to albumin and less to
globulin fraction. The binding makes it nondif-
• enzymatic activity (myosine ATPase) fusible through the capillary membrane.
• cardiac rhythm • combined with other substances in plasma and
interstitial fluid (eg. citrate), diffusible through
• neuromuscular excitability capillary membranes, but non ionized (about 5
• muscle cell excitation-contraction coupling per cent),

• cell membranes permeability • diffusible and ionized calcium (45 per cent).
Particularly this form is needed for most of the
• milk secretion functions mentioned previously.

Calcium is provided in food in organic or inorganic The ratio between ionized and non ionized calcium
form, but most probably it is resorbed only in inor- depends on the plasma pH. The lower is the plasma
ganic form. The resorption of calcium takes place pH, the higher is the ionization and vice versa. This
mainly in the upper part of small intestine. The pH relationship can be expressed by the following equa-
of intestinal juice is very important in this process, as tion by Ron–Takahashi:
calcium ions are well dissolved in acid medium but
they are not dissolved in alkalic medium. Sugars, [ H+ ]
[ Ca2+ ] = K ·
mainly lactose, which raises the amount of organic [ HCO− 3 ]
acids during digestion, helps in calcium resorption.
Fats (without vitamin D) decrease calcium resorp- Changes of ionized calcium level are more impor-
tion, most probably due to the formation of nonsol- tant than changes of its total amount. Changes in
uble calcium soaps. Vitamin D markedly enhances ionized calcium level lead to the signs and symp-
the calcium resorption from intestine. toms of hyper- or hypocalcemia. On the other
The best source of calcium is milk, but a consid- hand, changes of total plasma calcium (regardless
erable amount of calcium can be obtained by intake the cause), usually lead to corresponding changes of
of hard water. Some vegetables such as spinach and its ionized fraction.
oxalis contain oxalacetic or benzoic acid which form The fraction of the diffusible nonionized calcium
nonsoluble substances with calcium. In this way increases in renal insufficiency. It is important to
they worsen calcium resorption. Cereals also contain keep in mind that massive transfusion of stored
a substance (inositol hexaphosphatic acid) forming blood, containing citrate to prevent coagulation,
nonsoluble salts with calcium and magnesium. This can markedly decrease the level of ionized calcium.
explains the decalcifying effect of some cereals. Mainly patients with liver disorders who can not
Calcium balance means the difference between cal- metabolise citrate fast enough are at risk.
cium food intake and calcium elimination by urine Hypercalcemia. The signs and symptoms of hy-
and stool. The balance is positive in growth, preg- percalcemia are variable and many of them result
nancy, acromegaly or in a period following calcium from decreased muscle excitability. Elevated ion-
defficiency. A negative calcium balance is noticed ized calcium level increases the electrical resistance of
in rachitis, coeliac disease, renal rachitis, osteomala- cell membranes and the potential of myoneural junc-
cia, hyperparathyroidism, hyperthyroidism, starva- tion. Patients complain of tiredness, backache, weak-
tion or calcium defficiency in food and usually during ness due to muscular hypotonia and walking prob-
lactation. lems as well. Headache, confusion, depression and
672 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

sleeplessnes often mislead to the diagnosis of psy- carpopedal spasms, spasm of the glottis leading to
chosis. Keratopathies and sight disorders are com- inspiratory stridor and spasm of mimic and mastica-
mon. Hypercalcemia leads to polyuria and poly- tory muscles – trismus.
dipsia. Polyuria results from inadequate calcium As mentioned previously, spasms might also in-
resorption in tubular apparatus. Osmotic diuresis volve smooth musculature. For example, spasms of
with sodium, potassium, chloride and bicarbonate the smooth vessel muscles can be manifested as is-
wastage occur. The loss of potassium might lead to chemic pain in digits. The spasm might affect the
hypokalemia. Hypercalciuria predispose to the de- coronary vessels with resulting myocardial ischemia
velopment of nephrolithiasis. as well.
Hyperparathyroidism is usually the most com- Tetany also occurs when the total plasma calcium
mon cause of hypercalcemia. But it is not the only is normal but its ionized fraction is decreased due
one. Hypercalcemia can be caused by osteolytic bone to the shift of pH into the alkaline side (vomiting,
tumors, myelomas, malignant bronchial tumors se- hyperventilation). Hypocalcemia and tetany might
creting substances identical to parathyroid hormone, occur in renal insufficiency as well, because calcium
overdose of vitamin D, hypersensitivity to vitamin D is bound to acid organic radicals and then excreted
(e.g. in sarcoidosis) and long lasting immobilization by urine.
during bone diseases (such as Paget’s disease). Hy- In conditions, associated with long lasting negative
percalcemia can also be found in patients with peptic calcium balance and resulting release of calcium from
ulcer, receiving a large amount of milk and sodium bones, osteoporosis and osteomalacia develop. The
bicarbonate as well. bones become soften and deformed and spontaneous
The effect of hypercalcemia can be observed when fractures might result.
calcium plasma level exceeds 3,75 mmol/l. If the
increase continues, a life-threatening hypercalcemic 11.2.4.2 Magnesium
crisis with dehydration may develope. Such crisis
Chlorophyll is the most important source of daily
appears in patients with hyperparathyroidism or in
magnesium requirement. Magnesium is resorbed in
women with a disseminated mastocarcinoma. Vom-
the upper part of intestine, and is excreted via bile
iting, tachycardia, fever and finally coma can appear.
and large intestine, and to a less extent via urine.
Oliguria is responsible for the raise of plasma phos-
The same carrier assists in resorption of both mag-
phate and urea.
nesium and calcium from intestine. So a low calcium
Hypocalcemia occur mostly in hypoparathyroi- intake stimulates the resorption of magnesium and
dism, rachitis, chronic acidosis and steatorrhoe. It vice versa. The parathyroid hormon increases mag-
is manifested by latent or symptomatic tetany. The nesium resorption from intestine, whereas calcitonin
neuromuscular tetany appears when ionized calcium has an opposite effect.
decreases to half of its normal level or when total Magnesium is an important cofactor for many en-
calcium level reaches 1.75 mmol/l. zyme systems participating in the metabolism of gly-
The latent tetany is manifested by the following cides and in muscle contraction. It activates plasma
trias: positive Trousseau’s sign (so called obstetric and bone alkaline phosphatase, inhibits calcification
hand formed upon compressing the arm by manome- and modulates the neuromuscular excitability.
ter – flexed forearm in wrist joint, extended fingers Magnesium defficiency increases neuromuscular
in the metacarpophalangeal joints and thumb op- excitability. Tetany due to magnesium defficiency
position); positive Chvostek’s sign (a slight muscle might develop. Developed tetany can not be clin-
clonus on the homolateral side upon hitting the angle ically distinguished from tetany caused by calcium
of mandible by a neurological hammer); Erb’s sign defficiency. Experimentally, this kind of tetany was
( increased neuromuscular excitability upon galvanic introduced in rats, dogs and cattle. Calves, mainly
current). feeded with milk containing a low magnesium level,
A symptomatic tetany is manifested by spasms of often develope a severe tetany and can even perish
both striated and smooth muscles. Spasms of the due to convulsions. On the other hand, in human,
skeletal muscles are: muscle twitch up to generalized hypomagnesemia without hypocalcemia doesn’t usu-
convulsions common in children and rare in adults, ally lead to tetany. Several cases are described
11.2. Electrolyte balance and its disturbances (H. Sapáková) 673

where administration of magnesium improves clin- calcium level; by parathyroid hormone, calcitonin,
ical symptoms of tetany, but administration of cal- vitamin D, and by calcium plasma level. A relation-
cium doesn’t. In human, hypomagnesemia occurs in ship exists between calcemia and phosphatemia: the
severe steatorrhoe, after the resection of a large part product of total plasma calcium in mmol/l and inor-
of small intestine, in chronic malnutrition, chronic ganic plasma phosphorus in mmol/l is constant. This
alkoholism, diabetic acidosis and in chronic renal in- solubility product ranges between 30–40 in adults
sufficiency, when glomerular filtration exceeds tubu- and 40–55 in children. So, the increase in calcium
lar reabsorption. Sometimes, low plasma magnesium concentration results in the decrease of phosphorus
occurs in hyperparathyroidism, and especially after concentration and vice versa. It was proved that chil-
surgical extirpation of parathyroid adenoma. After dren develop rachitis when the solubility product is
extirpation, salts are fastly deposited to the bone below 35 and clinical improvement appears when it
tissue, magnesium resorption is decreased and mag- is above 40.
nesium elimination by kidneys increases. Chronic Some pathological conditions lead to changes in
magnesium defficiency leads to degenerative changes phosphorus plasma level.
in myocard, kidneys and skin.
Hypophosphatemia occurs in:
Neuromuscular excitability is decreased and mus-
cle weakness appears upon raised magnesium plasma • Hyperparathyroidis
level. When magnesium plasma level exceeds
2.5 mmol/l, hypotonic status, paralysis of striated • Hypovitaminosis D
muscles, and even deep coma might develope. The
• Inadequate phosphorus food intake
depressive effect of magnesium can be removed by
administration of calcium. During hypermagnesemia • Steatorrhoe
hyperglycemia and glycosuria might develop, proba-
bly due to magnesium effect on the enzymes of glu- Hyperphosphatemia occurs in:
cose metabolism.
• Hypoparathyroidism

11.2.5 Phosphorus • Hypervitaminosis D

The total amount of phosphorus is about 1 per cent • Renal insufficiency
of total body weight. Phosphorus is distributed
mostly in bones and teeth (80–85 per cent). A small • Severe diabetes mellitus
part is distributed in cells and ECF in form of or- • Bone fractures
ganic and inorganic compounds.
The most important functions of phosphorus are: Phosphatases, enhancing the hydrolysis of phos-
phoric acid esters, play an important role in meta-
• participation in bone ossification as calcium
bolism of phosphorus. They can be found in all body
phosphate and magnesium phosphate
cells and tissues.
• buffer system of ECF as primary and secondary
sodium phosphate
• regulation of the intermediary metabolism of
carbohydrates, fats and proteins.
The phosphorus metabolism is closely related to
the calcium metabolism. This relationship appears
during absorption of phospohorus from intestine.
The calcium surplus in food inhibits the phosphorus
resorption by creating a low soluble calcium phos-
phates.
The inorganic phosphorus level in adults is lower
than in children. This level is regulated similarly as
674 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

apparatus is very acidic (pH < 5.0). On the con-

trary, mitochondrial compartment is slightly more
11.3 Disorders of acid-base basic than the cytosole (pH 6.7–7.2). It is difficult
to measure the intracellular pH. As a consequence,
homeostasis only measurements of pH of ECF(blood or plasma)
are used in clinical praxis.

11.3.1.1 Sources of hydrogen ions

11.3.1 Regulation mechanisms of There are two main sources of hydrogen ions in hu-
man body:
acid-base homeostasis
1. the metabolism of proteins and phospholipids
One of the conditions to maintain the stability of
inner environment is the isohydria, i.e. the stabil- and the incomplete metabolism of fatty acids
and carbohydrates. Formed acids (so called non-
ity of hydrogen ion concentration in the organism.
volatile acids) are no further dissociated, and
Since the concentration of hydrogen ions in body flu-
they must be eliminated by kidneys,
ids represents a very small number (e.g. in the blood
0.00004 meq/l), it is commonly expressed as pH. The 2. the complete metabolism of fatty acids and
pH is defined as the negative decadic logarithm of the carbohydrates, whereby CO2 is formed. Even
molar H+ concentration: pH = − log H+ . The pH in though CO2 is not an acid, in the solution it is
biological systems has a specific significance. The hydrated to carbonic acid which is the source of
electrochemical potential of ions is proportional not H+ : CO2 + H2 O → H2 CO3 → H+ + HCO− 3.
to their concentration but to its logarithm. For this Carbonic acid is called volatile acid because this
reason the responses of the sensors or receptors in reaction is reversible, and the acid can be elim-
the body are more likely to be proportional to pH inated by expiration in form of CO2 .
than to concentration.
The concentration of H+ is the main determinant
11.3.1.2 Transport and neutralisation of hy-
of many physiological and biochemical processes. Al-
drogen ion
ready in physiological pH range, the activity of en-
zymes varies due to the changes in protein charge Approximately 40 mmol of nonvolatile acids and
and conformation. The influence of pH values on 20 000 mmol of CO2 are daily formed in the cells
proteins leads further to consequent changes in mem- and delivered into the circulation. To maintain a
brane transport systems activity for metabolites and normal value of H+ concentration (40 nmol/l), the
ions. The dissociation of many physiologically and hydrogen ions in body fluids have to be promptly
pharmacologically important weak acids and bases and sufficiently neutralised. There are efficient ex-
depends on the value of pH. Changes of their dis- tracellular (plasma) and intracellular (erythrocytes)
sociation can lead to alterations in their distribution buffers acting in the blood. The main intracellular
in compartments separated by lipid membrane. That buffer is haemoglobin. The main buffer of plasma is
is why the pathological changes in pH disturb many bicarbonate-carbonic acid buffer system followed by
important functions of organism. other, less important systems (phosphates, plasma
Hydrogen ions are components of chemical - proteins). Protein system plays an important role in
anatomical structures, and their activity in individ- keeping the pH of tissue cells. Phosphate system is
ual compartments varies. The physiological pH value involved in maintaining the pH of tissue cells, ery-
of arterial blood is 7.40, the pH of venous blood and throcytes, and tubular urine. Bicarbonate-carbonic
interstitial fluid is 7.35 due to increased amount of acid buffer system, consisting of weak carbonic acid
carbon dioxide. Intracellular pH depends on the type and its strong natrium salt, plays an important role
of cells and their metabolism, it usually reaches the in keeping the pH of extracellular fluid.
value of 6.9. Subcellular organelles also maintain the Henderson–Hasselbalch’s equation derives the
value of pH on the level necessary for their optimal blood pH from the equation:
function. The inner space of lysosomes and Golgi pH = pK + log[HCO− 3 ]/[H2CO3 ]
11.3. Disorders of acid-base homeostasis (D. Maasová, Š. Navarčı́ková) 675

Since H2 CO3 is in equilibrium with dissolved CO2 , ion accompanying bicarbonate, phosphate, sul-
and CO2 is in equilibrium with pCO2 , we can use the phate anions, and the anions of other nonvolatile
term pCO2 instead of H2 CO3 . From the equation acids in the urine.
follows that the pH of extracellular fluid depends on
the reciprocal relation between [HCO− Immensely important for the excretion of H+ is
3 ] and pCO2
and not on their absolute amounts. Bicarbonate- ammoniagenesis. It takes place primarily in the
carbonic acid buffer system is very efficient one be- proximal tubular cells. Since the excretion of hy-
cause of its greatest amount in extracellular fluid, drogen ions is limited by tubular fluid acidity (limit
and mainly because it is an ”open system” i.e. – both of pH 4.5), natrium ion, in excess of strong acid‘s
its components are regulated by lungs and kidneys salts in the urine, is exchanged for H+ after its con-
according to the demands of organism. nection with NH3 to NH+ 4 . This reaction helps to
Except the introduced physical-chemical buffers avoid the rise of strong acids in urine, and excretion
also others, so called biological buffers, operate in of hydrogen ions is not restricted.
the organism, e.g. metabolic reactions consuming or
producing hydrogen ion, if they, as an response to 11.3.2 Classification of acid-base
pH shift, change their speed in order to maintain disturbances
homeostasis. Another mechanism is the transport
of protons by proton pumps through the lipid mem- The acid-base disturbances arise as a result of dis-
branes. They maintain the pH of intracellular com- balance in production, buffering and final excretion
partments (cytosole, mitochondria, lysosomes, Golgi of hydrogen ions.
apparatus) on a level unresponding to passive dis- Increased activity of H+ (pH < 7.36) is called aci-
tribution according to the electrochemical gradient. dosis.
The most important proton pumps act in the mito- Decreased activity of H+ (pH > 7.44) is called al-
chondrial and lysosomal membrane. kalosis.
The values of pH that are suitable for living or-
11.3.1.3 Excretion of hydrogen ion ganisms are 7.0 to 7.8. Very important is the speed
of development of the disorder. Acute disorders are
Two basic mechanisms are responsible for definite worsely tolerated.
excretion of hydrogen ions : Using the equation pH = pK+log[HCO− 3 ]/[CO2 ],
it is obvious that the shift in pH is due not to the
1. Removal of CO2 by lungs. The quantity of
absolute amount, but due to the disturbance in re-
ventilation is regulated by respiratory centre in
ciprocal ratio of these two components in the extra-
medulla oblongata, responding to changes in
cellular fluid. HCO− 3 is the metabolic part of the
pCO2 and pH. Under physiological condition,
buffer, and pCO2 the respiratory part. Therefore
the pCO2 is kept on the value 5.3 kPa.
the states with primary change in [HCO− 3 ] are called
2. Excretion of hydrogen ion by tubular cells of metabolic disturbances, and the states with primary
kidneys. The H+ is formed in the tubular cells change in pCO2 are respiratory disturbances. From
of proximal and distal tubule by the dissociation this point of view, we can define four basic acid-base
of carbonic acid. Carbonic acid is formed in the disturbances:
reaction of CO2 and H2 O catalyzed by carbon
• metabolic acidosis (shift in pH to the acidic side
anhydrase. The amount and activity of carbon
due to primary decrease in [HCO− 3 ] without a
anhydrase is one of the factors determining the
change in pCO2 )
speed of H+ production in the tubular cells. It
is necessary to realise that also HCO−
3 is formed • respiratory acidosis (shift in pH to the acidic
by the dissociation of carbonic acid. Simultane- side due to primary increase in pCO2 without a
ously with hydrogen ion elimination to the tubu- change in [HCO− 3 ])
lar fluid, HCO− 3 returns to the blood (therefore
expression ”kidney eliminates H+ ” means the • metabolic alkalosis (shift in pH to the alkalic
same as ”kidney saves bicarbonate”). The elim- side due to primary increase in [HCO−
3 ] without
inated hydrogen ion is exchanged for natrium a change in pCO2 )
676 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

• respiratory alkalosis (shift in pH to the alkalic 11.3.3.2 Participation of kidneys in compen-

side due to primary decrease in pCO2 without a satory processes
change in [HCO− 3 ]).
The degree of compensation in respiratory distur-
bances depends on the speed of the respiratory dis-
order development.
11.3.3 Compensation of acid-base In acute respiratory disorders (lasting about 6 ho-
disturbances urs) only immediately reacting chemical buffers of
extracellular fluid help to correct pH. These non-
The organism reacts by compensatory processes to
bicarbonate buffers (plasma proteins, haemoglobin,
changes in metabolic or respiratory component of the
phosphates, sulphates) bind or release H+ , that is
buffer system. The purpose of compensatory pro- demonstrated by an unimportant change in HCO− 3
cess is the appropriate shift of the other, originally concentration. Relatively weak total activity of these
unchanged component so that pH returns closer to
buffers is the cause of uncomplete compensation of
normal value. This process leads to compensation of
acute respiratory disorders.
the disorder. But even maximal compensatory effort
In chronic respiratory disorders, kidneys take part
can not return pH on the physiological value (ex-
in the compensation. The compensatory activity of
cept chronic respiratory alkalosis that can be com-
kidneys is held by increased or decreased secretion of
pensated by kidneys to physiological pH).
H+ and, simultaneously, by increased and decreased
reabsorption of bicarbonate. In this way, the level of
bicarbonate adjusts to the changed value of pCO2 ,
11.3.3.1 Participation of respiratory system
and pH returns toward the normal standard. Regu-
in compensatory processes
lation processes need enzyme reconstruction of tubu-
Pathological changes in pH, caused by primary lar cells (carbon anhydrase). The maximal compen-
change in HCO− satory effort of kidneys is then achieved after 5 days,
3 concentration in extracellular fluid
(metabolic acidosis and alkalosis), are compensated and it remains for the same time after the removal
by the change in depth and frequency of respira- of a disorder. Compensation of chronic respiratory
tion. In this way, the primary change in bicar- disorders by healthy kidneys is very effective.
bonate concentration induces a respiratory response To understand the typical shifts of several other
which changes plasma CO2 in the same direction. ions that will be mentioned in individual acid-base
Metabolic acidosis is compensated by hyperventila- disturbances, it is necessary to remember:
tion, metabolic alkalosis, on the contrary, by hy- 1. Hydrogen ions in surplus remove potassium ions
poventilation. However, respiratory compensation from the cells to the extracellular fluid. This
for metabolic alkalosis is relatively weak because its shift (sc. distributive hyperkalemia) often ac-
limitation by hypoxemic hypoxia. Respiratory cen- companies metabolic acidosis. On the other
tre, regulating the process, is sensitive to changes in hand, in alkalosis potassium enters the cells, but
pCO2 and pH. In the compensatory process, the res- this effect is short lasting. If the alkalosis lasts
piratory centre reacts only to the pH shift caused by longer, increased loss of potassium by kidneys
the change in HCO− 3 concentration, because in pri- occurs, which leads to mild deficiency of potas-
mary metabolic disturbances the value of pCO2 does sium in the organism. Typical relationships are
not change. Bicarbonate anion is slowly diffusible – acidosis – hyperkalemy, alkalosis – hypokalemy.
the equilibration of its changed level between blood These relationships are not always present, it de-
and liquor is slow. Therefore, the compensatory pro- pends on underlying cause of the disorder and
cess starts 1 hour after the rise of the disorder and is other circumstances of it’s development.
developed to it’s maximum in 12 to 24 hours. On the
contrary, sudden and total therapeutical correction 2. To maintain the electroneutrality, the number of
of bicarbonate plasma level in compensated patient cations has to be equal to the number of anions.
causes dangerous shift of pH to the other side, be- The major plasma cation is Na+ , while other
cause of compensatory process sustaining for longer cations (K+ , Mg2+ , Ca2+ ) form the nonessen-
period of time. tial part of the cationic pool. The major plasma
11.3. Disorders of acid-base homeostasis (D. Maasová, Š. Navarčı́ková) 677

anions are HCO− −

3 and Cl , and there are also This close relation is not present in acidosis
anions of nonvolatile acids in the pool. We can caused by accumulation of organic acids.
express basic relationship: Na+ = HCO− 3 +Cl
−

(+ anions of nonvolatile acids). Therefore, in • Administration of ammonium chloride and ly-

primary change of chloride concentration, ap- sine or arginine hydrochloride. The cations of
propriate amount of HCO− 3 originates or disap- these drugs enter the metabolism, while chloride
pears. This reaction is accompanied with pH anions cause the extinction of adequate amount
change. On the other hand, primary change of bicarbonate anions in order to maintain elec-
in bicarbonate will be accompanied with the troneutrality.
retention or excretion of chloride (hyper- and
hypochloremy in some metabolic acid-base dis-
Increased production of nonvolatile acids
turbances).
3. Plasma sodium plays an important role in keep- Ketoacidosis:
ing pH as well as in maintaining the volume of
• Diabetic ketoacidosis: In diabetes mellitus, due
body fluids. Maintaining the stable volume of
to altered carbohydrate and lipid metabolism,
body fluids is vitally important, and it has pref-
ketoacids are produced more rapidly than they
erence in the kidneys before regulation of pH.
can be metabolised. Formed nonvolatile ke-
This fact is the direct cause of some pH distur-
toacids are the source of H+ which binds with
bances owing to decrease of body fluid volume
HCO− 3 . Simultaneously, hydrogen shifts potas-
(see metabolic alkalosis).
sium out from the cells into the blood and dis-
4. The activity of H+ is one of the factors influ- tributive hyperkalemia occurs. In patients with
encing the ionisation of plasma calcium. De- uncontrolled diabetes, blood glucose can over-
crease in H+ activity lowers the ionisation of shoot the renal threshold and osmotic diuresis
plasma calcium (tetany in severe alkalosis); in- arises. During osmotic diuresis, normal reab-
crease in H+ activity increases the ionisation of sorption of potassium is impossible because of
calcium (in acidosis with hypocalcemia, symp- rapid flow of tubular fluid. Primary distributive
toms of tetany are ”masked”, until the moment hyperkalemia can be gradually decreased what
when acidosis is therapeutically repaired). represents, however, total potassium depletion.
Drugs, used in treatment of diabetic ketoaci-
11.3.4 Metabolic acidosis dosis (insulin, glucose) cause shift of potassium
from extra- to intracellular space and therefore
Metabolic acidosis is characterized by decrease of pH sudden, life-threatening hypokalemia can arise.
below 7.35 due to primary decrease in plasma bicar-
bonate below 22 mmol/l. • Starvation (i.e. long-lasting fever with anorexia)
The main reasons of metabolic acidosis: may cause mild ketoacidosis. Reduced carbo-
hydrate intake leads to low insulin and high
Intake of substances producing H+ glucagon levels. These hormonal changes favour
• Intoxication by salicylates: salicylates create a glycolysis and ketogenesis.
metabolic block, which leads to production of
a mixture of endogenous organic acids. At the • Alcoholic ketoacidosis: The main causes of ke-
same time, salicylates have the additional effect toacidosis are prolonged restriction of food in-
of direct respiratory centre stimulation, which take, vomiting and alcohol intake.
leads to independent respiratory alkalosis.
Lactic acidosis: It arises most often in severe cir-
• Intoxication by inorganic acids: resulting acido- culatory or respiratory failure as a result of hypoxia
sis is characterised by close relation between the due to hypoperfusion of peripheral tissues. During
decrease in pH and degree of hyperkalemia (de- the insufficiency of peripheral circulation, certain de-
crease of pH by 0.1 causes the increase of potas- gree of acidosis is advantageous since haemoglobin,
sium in extracellular fluid by cca 0.8 mmol/l). at lower pH, easier releases oxygen to hypoperfused
678 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

tissues. Another cause of lactic acidosis may be se- moderate acidosis by increasing bicarbonate loss
vere anaemia because of diminished blood oxygen- in the urine.
carrying capacity, and intoxication by drugs (ethy-
lene glycol, paraldehyde) which are metabolised into Clinical pattern in metabolic acidosis is due to un-
lactate. Overproduction of lactate by neoplastic tis- derlying disorder. Acidosis per se has a negative
sue is probably the cause of lactic acidosis associated inotropic effect on the heart that is, hovewer, hid-
with tumours. den by increased production and excretion of kate-
cholamines. It also causes the constriction of veins
Reduced excretion of H+ that results in increased venous return with the risk
of pulmonary edema. When pH is lowered to 7.0,
• Renal failure: It seems that the main defect depression of CNS ranging from fatigue to confusion
is the failure of amoniagenesis, decreased renal and coma is present. The compensation of acido-
proton secretion and decreased number of func- sis is hyperventilation. In acute metabolic acidosis,
tional nephrons. For this reason the excretion hyperventilation may be very intensive (Kussmaul’s
of phosphates, important acceptors of hydrogen respiration).
in tubular urine, fails. In these, usually chronic
conditions, the plasma bicarbonate rarely falls
11.3.5 Metabolic alkalosis
below 10 mmol/l because the formed acids are
partially buffered by phosphate and carbonate Metabolic alkalosis is characterized by increased pH
from bones. above the value 7.45 due to primary increase in
plasma bicarbonate above 26 mmol/l.

Increased losses of HCO–3 The basic reasons of metabolic alkalosis:

• Severe diarrhea or intestinal malabsorption cau- Increased supply or production of bicarbonate

se loss of bicarbonate, potassium, sodium and
water by the stool. Hyperchloremic, hy- • Metabolic alkalosis can originate in long-term
pokalemic acidosis and volume depletion result. parenteral application of substances containing
Dehydration is very dangerous especially in new- organic anions (natrium lactate, natrium cit-
born and infants. rate). The organic anions are metabolised, and
remaining cations are the reason of correspond-
• Chronic vomiting, in which there is a loss of ing increase of bicarbonate to maintain the elec-
gastric contents accompanied by a loss of alka- troneutrality. Transfusion of larger amount
lic duodenal contents. If the loss of HCO− 3 is of conserved blood, that contains natrium cit-
higher than the loss of acids (e.g. during hypo- rate, ammonium and potassium, can lead to
or anacidity of gastric juice), and there is almost metabolic alkalosis. Therapeutical correction of
no food intake, acidosis, usually accompanied by metabolic acidosis or an overdose of bicarbonate
dehydration, arises. and other alkalising substances can lead to the
development of metabolic alkalosis.
• Renal tubular acidosis is the term used to de-
scribe metabolic acidosis which is caused by a Chloride depletion
disorder of the renal tubules. It is due to de-
creased ability of tubular cells to secrete H+ and • Loss of hydrochloric acid in gastric contents by
therefore to reabsorb an appropriate amount of vomiting (e.g. patients with increased gastric
the filtered bicarbonate. Sodium is in increased acid secretion or pyloric stenosis),or by gastric
amounts exchanged for potassium, and potas- aspirate, leads to increased concentration of bi-
sium depletion results. Typical clinical finding is carbonate to maintain the electroneutrality.
hyperchloremic metabolic acidosis and increased
urinary HCO− • Low intake of chlorides in patients with restric-
3 excretion.
tion of NaCl in the diet. The kidneys, in order
• Carbon anhydrase inhibitors, such as acetazo- to maintain the volume of ECF reabsorb sodium
lamide, have similar effect. They cause mild to in increased amounts. If only small amount of
11.3. Disorders of acid-base homeostasis (D. Maasová, Š. Navarčı́ková) 679

sodium in form of NaCl is available, its reabsorp- in most cases the symptoms of underlying disorder
tion is increased by exchanging for H+ , what are dominating.
however leads to increased reabsorption of bicar-
bonate and to the shift of pH to alkalic values.
11.3.6 Respiratory acidosis
• An overdose of diuretics that primarily sup-
Respiratory acidosis is characterized by decrease in
presses the reabsorption of chlorides (”loop” di-
pH below 7.36 due to primary increase in pCO2 (hy-
uretics). Kidneys, that cannot reabsorb sodium
percapnia) over 5.8 kPa.
in form of NaCl in sufficient amounts, compen-
sate its reabsorption by exchange for H+ that There is no disorder known characterized by over-
leads to increase in blood bicarbonate. production of CO2 . Thus, all causes of respiratory
acidosis have in common a defect in the excretion of
• Metabolic alkalosis is most often formed as a re- CO2 .
sult of extracellular volume depletion. During Central depression of respiration. The causes of
volume depletion, renal conservation of sodium decreased activity of respiratory centre may be:
takes priority over the other homeostatic mech-
anisms. Kidneys maximally increase the reab- • drugs (hypnotics, sedatives, morphium) supress-
sorption of sodium in the form of NaCl, by ex- ing the activity of respiratory centre
change for H+ and by exchange for K+ influ-
enced by aldosterone. • local damage of the respiratory centre by in-
flammation, tumour, trauma, as well as by is-
Reduced elimination of HCO-3 chemia during embolisation or during thrombo-
sis of a. vertebralis
• Primary hyperaldosteronism. Aldosterone stim-
ulates the reversed reabsorption of Na+ in the Impaired respiratory mechanics: deformities of
tubular cells by stimulating the secretion of K+ , thorax, high position of diaphragm, morbus Bech-
H+ , Mg2+ , and ammonium ions. Pathological terev, pain after chest traumas etc.
graduation of this mechanism leads to minimal Pulmonary disorders. The most common cause
or moderate hypokalemic alkalosis. Patients are of chronic respiratory acidosis is chronic obstructive
not volume- or chloride-deficient. lung disease (chronic bronchitis and emphysema),
in which ventilation and perfusion are mismatched
• Primary potassium depletion causes increased
and effective alveolar ventilation is decreased. Other
loss of H+ by kidneys. It seems that there is
diseases (pneumonia, pulmonary edema, bronchial
a relation between the elimination of K+ and
asthma, pneumothorax, haemothorax, atelectasis,
H+ that compete for common transport mecha-
chronic pulmonary fibrosis) usually cause respira-
nism. It means that the deficit of one cation
tory alkalosis. In these conditions, hypoxia stimu-
leads to increased elimination of another one.
lates ventilation and since CO2 is much more dif-
Hypokalemia is the reason for increased secre-
fusible than oxygen, excretion of CO2 is enhanced
tion of H+ . However, only chronic and severe
(hypocapnia). Respiratory acidosis occurs only with
hypokalemia may generate metabolic alkalosis.
respiratory fatigue in advanced stages of the above
Clinical pattern. Metabolic alkalosis directly en- mentioned disease.
hances neuromuscular irritability. This effect, rather Neuromuscular disorders: muscular dystrophy,
than the decrease in ionized plasma calcium induced myasthenia, poliomyelitis, botulism etc.
by alkalosis, is the major cause of tetany. Alkalosis Clinical manifestations of respiratory acidosis de-
may cause slight increase of myocardial contractil- pend on the speed of it’s development. In acute dis-
ity as well as increased sensibility of myocardium to orders dominate confusion up to loss of conscious-
heart glycosides. Severe alkalemia has been associ- ness. If the respiratory acidosis develops more slowly,
ated with cardiac arrhytmias. The relationship be- it is characterized by symptoms that are typical for
tween alkalosis and potassium depletion is complex, cerebral vasodilation caused by hypercapnia: somno-
and it is still not sufficiently explained. Symptoms lence, headache, papilledema, dilatation of conjunc-
of metabolic alkalosis are generally inexpressive, and tival and superficial facial blood vessels. Influence of
680 Chapter 11. Fluids and electrolytes ( H. Sapáková, D. Maasová )

acidemia on cardiovascular system was described in hypocapnia causes constriction of small vessels in
the part considering metabolic acidosis. the brain. This condition is clinically manifested by
Acute respiratory acidosis is nearly always accom- headache, dizziness and light-headedness. Severe res-
panied by hypoxemia, i.e. cardiopulmonary arrest is piratory alkalosis may cause confusion or loss of con-
a combination of respiratory acidosis and metabolic sciousness. Alkalosis, in combination with hypocap-
lactic acidosis. nia, enhances neuromuscular excitability that is typ-
ically manifested by paresthesias around mouth and
11.3.7 Respiratory alkalosis on the fingers. In some cases, severe symptoms of
CNS irritation may occur. Irritation is manifested
Respiratory alkalosis is characterised by increase in e.g. as extreme nervousness or convulsions (in epilep-
pH over 7.44 due to primary decrease of pCO2 tics purposely performed hyperventilation may in-
(hypocapnia) under 4.8 kPa. duce seizures that are clinically used to determine
The basic reasons of respiratory alkalosis: the degree of seizure emergency).
Disorders of CNS
• Cerebrovascular incidents with hypoxia in the 11.3.8 Therapeutical principles of
surroudings of the respiratory centre. Local de- acid-base disturbances
crease of pH in the area of respiratory centre
causes hyperventilation and consequent decrease Disorders of acid-base balance may accompany var-
of pCO2 in the blood ious diseases and they are not detectable by clin-
ical observation alone. It is necessary, especially
• Trauma, tumour and inflammation of CNS
in acutely ill patients, to determine the value of
when causing an irritation of respiratory centre
pH, pCO2 , and bicarbonate in capillary blood.
• Drugs (salicylates, progesterone) cause hyper- Analysators of blood gases measure pH and pCO2
ventilation by direct stimulation of medullary directly by specific electrodes. The equipment auto-
respiratory centre matically calculates the concentration of bicarbonate
using Henderson-Hasselbalch equation. The value
• Extreme anxiety and hysterical fit. Strong hy- is usually expressed as ”standard bicarbonate” that
perventilation is conditioned by the sensation of represents the theoretical concentration of bicarbon-
air shortage, and it may be as intensive as to ate in the blood saturated with oxygen, at pCO2
cause the tetanic spasm. 5.3 kPa and temperature of 37o C. After applying
Diseases of lungs with the failure of alveolo- the obtained value to nomogram, we can determine
capillar oxygen transfer or with reduced respiratory the concentration of ”actual bicarbonate”, the con-
surface area. Decrease of pO2 causes irritation of the centration at actual pH, pO2 , pCO2 , and tempera-
chemoreceptors, leading to hyperventilation. Respi- ture of patient’s blood. This determination, in clin-
ratory alkalosis occurs during initial stages of the dis- ical practice, is sufficient for accurate and relatively
eases, e.g. during mild pulmonary embolism, pneu- rapid classification of pure or combined acid-base dis-
monia, mild pulmonary edema or asthma. If the dis- turbances.
order causes failure of CO2 exhalation, respiratory The appropriate therapy is choosed considering
acidosis with hypoxia arises. the type and the stage of the disorder. As discussed
Irritation of the respiratory centre from the pe- above, acid-base disturbance is in almost all cases
ripheral receptors during localized pulmonary and secondary one. Therefore, the optimal therapy is the
pleural diseases. elimination of the underlying disorder. If it is not
Mountain sickness. Lower pO2 in the inhaled air possible and patient’s health requires a rapid correc-
stimulates the medullar respiratory centre. During tion of pH, the application of substances normalising
hyperventilation, highly diffusible carbon dioxide es- the surplus of acids or bases is justified.
capes in greater amounts and hypocapnia occurs. Immediate and rapid arrangement of acidosis is
Clinical manifestations of respiratory alkalosis de- indicated only in acute intoxication. Alkalisation
pend on its severity and acuteness. Hyperventila- of extracellular fluid, and hence of urine, simulta-
tion may or may not be clinically apparent. Acute neously helps to eliminate the acids more quickly.
11.3. Disorders of acid-base homeostasis (D. Maasová, Š. Navarčı́ková) 681

Intravenous application of sodium bicarbonate is rec- To correct the alkalosis, ammonium chloride per
ommended if pH falls below 7.2, or plasma bicarbon- os can be used. After the resorption into the blood,
ate falls below 10 mmol/l. Intravenous application of the NH4 is metabolised to urea in the liver. This
bicarbonate requires considerable attention because reaction releases HCl that immediately reacts with
it changes the pH very strongly and suddenly. We the buffers of extracellular fluid and shifts pH to the
apply only one third or one half of calculated amount acidic side. Intravenous application of ammonium
over the period of 24 hours, and we lean on the ac- chloride is dangerous because of its toxicity. An-
tivity of compensatory mechanisms of the body. other substance commonly used, is monohydrochlo-
For slowlier neutralisation of acid surplus in aci- rid lysine. During acidifying therapy, enhancement
dosis, a larger amount of sodium bicarbonate per os of diuresis for the elimination of bicarbonate is re-
can be applied. After absorption from GIT to the quired.
blood, pH is shifted to the alkalic side. In therapeutical approach of acid-base distur-
For slow alkalisation of body fluids, substances bance, it is necessary to regulate other components
metabolised in the body (sodium lactate or sodium of body fluids simultaneously (potassium, calcium,
gluconate) can be used. Lactate or gluconate part of sodium, chlorides). It is important to think of the
the molecule is metabolised, and sodium remains in outlast of compensatory processes and to eliminate
the extracellular fluid as sodium bicarbonate. the underlying disorder to maximal possible extent.