CLINICAL CHEMISTRY LECTURE

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ELECTROLYTES TO ACID-BASE BALANCE
ELECTROLYTES
• Minerals found in the blood and other body fluids that carry an electrical charge
• They exhibit significant function and involvement in various processes in the body
KEY FUNCTION MAIN ELECTROLYTES INVOLVED
Volume and osmotic regulation Sodium, Potassium, Chloride
Myocardial rhythm and contractility Potassium, Magnesium, Calcium
Cofactors in enzyme activation (activators) Calcium, Magnesium, Zinc, Chloride
Regulation in ATPase ion pumps Magnesium
Acid-base balance Bicarbonate, Potassium, Chloride
Blood coagulation Calcium, Magnesium
Neuromuscular excitability Potassium, Calcium, Magnesium and Sodium
Production and use of ATP from glucose Magnesium and Phosphate

•
SODIUM
Main cation in the ECF, representing 90% of all extracellular cations
• It is the main determinant of plasma osmolality (295 mOsm/kg; approx. 275 mOsm is contributed by
sodium)
(135-145 mmol/L) • Contributors to plasma osmolality (main extracellular electrolytes): sodium, chloride and bicarbonate
• Concentration in the plasma is mainly dependent on water intake and excretion
• Three processes are of primary importance in the regulation of plasma sodium:
• The intake of water as response to thirst as stimulated or suppressed by plasma osmolality
- ↑ Plasma osmolality: thirst center is activated; ADH released; increased in cases of dehydration
- ↓ Plasma osmolality: inactivated
• The excretion of water largely affected by ADH release in response to changes in either blood volume or osmolality
• The blood volume status, which affects sodium excretion through aldosterone, angiotensin II, and atrial natriuretic peptide
• Renal regulation: minor control

2 hormones greatly affecting sodium values in the plasma:

ALDOSTERONE ATRIAL NATRIURETIC PEPTIDE
• Promotes sodium retention by • Released from cardiac atria; released in response to blood pressure
increasing its reabsorption in • Released when blood pressure is high
the DCT • Blocks aldosterone and renin secretion (their activation increase BP)
• Increases potassium • An endogenous antihypertensive agent secreted by the cardiac atria
excretion • Blocks aldosterone and renin secretion
• ↑ aldosterone: ↑ sodium, ↓ • Inhibits the action of angiotensin II and vasopressin resulting to natriuresis
potassium • NATRIURESIS: increased sodium secretion (also the release of water which lowers down blood pressure)

HYPONATREMIA (<135 mmol/L)

INCREASED SODIUM LOSS INCREASED WATER RETENTION WATER IMBALANCE
Aka DEPLETIONAL HYPONATREMIA (differentiated Aka DILUTIONAL HYPONATREMIA • Excess water intake
thru urine sodium) • SIADH
URINE SODIUM (≥ 20 mmol/dl) URINE SODIUM (≥20 mmol/d) • Pseudohyponatremia
• Hypoadrenalism • Renal failure
• Potassium deficiency
• Diuretic abuse URINE SODIUM (≤ 20 mmol/d)
• Ketonuria • Nephrotic syndrome
• Salt-losing nephropathy • Hepatic cirrhosis
URINE SODIUM (≤20 mmol/dl) • Congestive heart failure
• Prolonged vomiting/diarrhea/burns
CAUSE SERUM NA URINE NA URINE OSM SERUM K 24-H URINE NA
Overhydration ↓ ↓ ↓ N or ↓ ↓
Diuretic abuse ↓ ↓ ↓ ↓ ↑
Adrenal failure ↓ Mildly ↑ N ↑ ↑
SIADH ↓ ↑ ↑ N or ↓ ↑
Bartter’s syndrome ↓ ↓ ↓ ↓ ↑
Diabetic hyperosmolarity ↓ N N ↑ N
• 24-h urine Na: differentiates overhydration from diuretic abuse • SIADH: hypothalamic tumor; keeps on retaining
• Bartter’s syndrome: similar with diuretic abuse water, which dilute the electrolytes (↑ plasma water;
• Diabetic hyperosmolarity: metabolic cause of hyponatremia electrolytes are diluted; ↓ volume of urine)
• Diuretics: blocks chloride pump on ALH; can’t reabsorb chloride and sodium • When encountering hyponatremic px: measure
• Adrenal failure: can no longer produces aldosterone leading to low sodium levels; serum osmolality
Addison’s disease
CLASSIFICATION OF HYPONATREMIA BY OSMOLALITY
LOW OSMOLALITY NORMAL OSMOLALITY HIGH OSMOLALITY
Increased sodium loss Hyperlipidemia Lithium excess Hyperglycemia (DM
Increased water retention Hyperproteinemia Multiple myeloma hyperosmolality)
SIADH Increased monosodium cations Severe hyperkalemia Mannitol infusion
Severe hypermagnesemia Pseudohyperkalemia
PSUEDOHYPONETREMIA
• Can occur when sodium is measured using indirect ion-selective electrode (ISE) in a px who is hypoproteinemic or hyperlipidemic
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(colloidal; occupies space meant for sodium; results to water displacement)

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• When water is displaced, sodium is also displaced

ELECTROLYTES TO ACID-BASE BALANCE RABAGO, FRANCZESCA FAITH

 CLINICAL CHEMISTRY LECTURE
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ELECTROLYTES TO ACID-BASE BALANCE
• An indirect ISE dilutes the sample prior to analysis and as a result of plasma/serum water displacement; the ion levels are falsely
decreased
• REMEDY: measure sodium using direct ISE; not affected by high protein and lipid levels
HYPERNATREMIA (>150 mg/dl)
EXCESS WATER LOSS DECREASED WATER INTAKE INCREASED INTAKE OR RETENTION
• Dehydration • Older persons • Hyperaldosteronism: Cushing’s, Conn’s
• Diabetes insipidus: opposite of SIADH; receptors of • Infants • Sodium bicarbonate excess
ADH are resistant • Mental impairment • Dialysis fluid excess
• Renal tubular disorder
• Prolonged diarrhea
• Profuse sweating
CAUSE SERUM NA URINE NA URINE OSM SERUM K 24-H URINE NA
Dehydration ↑ ↑ ↑ N Var
Diabetes insipidus ↑ ↓ ↓ N ↓
Hyperaldosteronism ↑ ↓ N ↓ ↓
HYPERNATREMIA RELATED TO URINE OSMOLALITY
< 300 mosm/kg: diabetes insipidus 300 – 700 mosm/kg >700 mosm/kg
• Neurogenic: nonproduction of ADH • Partial defect in ADH/AVP • Loss of thirst
• Nephrogenic: ADH receptors at the CD are release • Insensible water loss (skin, fever, breathing =
unresponsive • Osmotic diuresis: ↑urine hyperventilation)
output because of ↑ of solutes • Extrarenal water loss
• GI loss
• Excess sodium intake
Hyponatremia is correlated with plasma osmolality while hypernatremia is correlated with urine osmolality

•
Major intracellular cation
POTASSIUM •
Only 2% of its total body concentration found in the plasma (20% greater inside cells)
•
It is the chief countercurrent of sodium
(3.5-5.2 mmol/L)
•
Most important analyte wherein any abnormality is life-threatening
- Involved in neuromuscular excitability and myocardial contraction
Renal maintenance of normal serum potassium is done by:
• Proximal convoluted tubules: almost all the potassium in the ultrafiltrate is absorbed
• Distal convoluted tubules: potassium is excreted in exchange to sodium under the aldosterone influence

ABNORMALITIES IN POTASSIUM LEVEL

HYPOKALEMIA HYPERKALEMIA
GI LOSS CELLULAR SHIFT DECREASED RENAL EXCRETION CELLULAR SHIFT INCREASED INTAKE
• Vomiting and • Alkalosis • Acute or chronic renal failure: • Acidosis • Oral or IV
diarrhea • Insulin overdose MOST COMMON • Muscle cellular injury potassium
• Gastric suction • Use of β2 agonist • Hypoaldosteronism • Chemotherapy replacement
• Intestinal tumor drugs (propranolol) • Diuretics: original diuretics were • Leukemia therapy: most
• Malabsorption • These conditions tend not potassium-sparing • Hemolysis common cause
• Cancer therapy to increase Na, K, • Most common cause in • Vigorous exercise of hyperkalemia
• Large doses of ATPase pump activity nondialysis px: • Digitalis intoxication: in hospitalized px
laxatives • Potassium plasma is HYPORENINEMIC inhibits NaK ATPase
taken up inside the HYPOALDOSTERONISM pump
cell; lowers K+ plasma
RENAL LOSS DECREASED INTAKE ARTIFACTUAL
Diuretics abuse • Sample hemolysis: most common cause of pseudohyperkalemia (slight hemolysis:
Nephritis 50 mg/dl; potassium levels are increased by 3%; heavy/gross hemolysis: 500 mg/dl of
Renal tubular acidosis Hb; potassium is increased by 30%)
Hyperaldosteronism • Serum K is 0.1-0.7 mmol/L higher than plasma K
• Whole blood is stored at room temperature (cold temp: promotes release of K from the
cells)
• Thrombocytosis
• Prolonged tourniquet use: hemoconcentration
• Excessive clenching of fists
• EDTA contamination: majority exists as K EDTA
• HEPARINIZED PLASMA: anticoagulant of choice

•Most abundant anion in the ECF

CHLORIDE •
•
Chief counterion/counterbalance of sodium
It works with sodium in the maintenance of water balance and osmolality (maintenance of electroneutrality)
(98-107 mmol/L)
•It has a close relationship with bicarbonate in the maintenance of acid-base balance
•If a particular condition affects sodium, it can also affect chloride since both are extracellular
ABNORMALITIES IN CHLORIDE LEVEL
HYPOCHLOREMIA HYPERCHLOREMIA
• Prolonged vomiting • Renal tubular acidosis
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• Aldosterone deficiency • Diabetes insipidus

• Metabolic alkalosis • Salicylate hyperthyroidism
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• Salt-losing nephropathy • Metabolic acidosis

• Post-prandial: used in the production of gastric acid (HCl) • Prolonged diarrhea
ELECTROLYTES TO ACID-BASE BALANCE RABAGO, FRANCZESCA FAITH
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ELECTROLYTES TO ACID-BASE BALANCE
- Chloride levels are decreased after eating
- Chloride is also an activator of amylase – an enzyme used to digest or break down starches
- - production of ALKALINE TIDE (decreased Cl; increased HCO3: inverse relationship)
- After eating: metabolic alkalosis

•
BICARBONATE •
Second most abundant anion in the ECF
Accounts for 90% of the total CO2 at physiologic pH
(22-26 mmol/L) • Blood specimen for bicarbonate determination must be collected anaerobically

MECHANISMS AND CAUSES OF INCREASED BICARBONATE CONCENTRATION IN THE ECF

• Loss of HCl from the stomach
• Postprandial metabolic alkalosis: state where Cl levels are low, which is why HCO3 levels are increased
• Administration of bicarbonate and its precursors
• Shift of the hydrogen ions in the cells
• Water volume depletion
• Potassium depletion
• Increased renal excretion of acid
• Hyperaldosteronism

CELLULAR SHIFT
• Aka Hamburger’s phenomenon
• Occurring in the tissues
• As a result of cellular respiration, tissue cells release CO2 every time they receive O2
• This CO2 combines with water in the plasma forming carbonic acid which increases blood acidity
• Some of the CO2 enters the cell. With the aid of carbonic anhydrase bicarbonate is generated and released into the plasma to neutralize the
excess acid
• Chloride shifts into the cells to establish neutrality

Explanation:
• RBCs send O2 to tissues; every time tissues receive O2, they release CO2; some of it enters the RBCs and bind with water forming
CARBONIC ACID
• With the help of carbonic anhydrase, carbonic acid will be broken down into HC03 an H+; HCO3 is thrown outside the RBCs
• The release of HCO3 (base) from the RBCs will neutralize the forming acid in the plasma
• When a negatively charged ion is released from the RBCs, it must be exchanged with another (-) charged ion which is why after HCO3 leaves
the cell, Cl- goes inside to maintain electroneutrality

•
CALCIUM •
Most abundant cation in the body
1% is found in the ECF because almost 99% is deposited in the bones and teeth
(8.6-10 mg/dl) • Maximally absorbed in the duodenum favored by acid pH
iCa: 4.6-5.3 mg/dl • Calcium levels in the blood is dependent on plasma protein
- Hypoalbuminemia can cause hypocalcemia (every 1 g/dl ↓ in albumin, there is 0.2 mmol/L ↓ in
total calcium)
Three forms of calcium: 1% in ECF
• Ionized (active calcium): 50%; sensitive and specific marker for calcium disorders
• Protein-bound calcium: 40%
• Complexed with ions: 10% (mainly phosphate)

ABNORMALITIES IN CALCIUM LEVEL

HYPOCALCEMIA HYPERCALCEMIA
• Alkalosis • Primary hyperparathyroidism: MAIN CAUSE
- Blood pH is one factor affecting calcium homeostasis; ALKALOSIS • Cancer (lung and breast): 2ND COMMON
promotes deposition of calcium in the bones, which is why there is a ↓ levels CAUSE; from the release of PTH-related peptide
of Ca2+ in the blood • Acidosis
• Vitamin D deficiency • Increased vitamin D
• Primary hypoparathyroidism: PTH is the main hormone responsible for ↑ calcium • Multiple myeloma
• Acute pancreatitis • Sarcoidosis
• Hypomagnesemia: both hyper/hypomagnesemia can cause low calcium levels • Hyperthyroidism
- Can inhibit secretion of PTH • Milk-alkali syndrome
- Impair PTH action at its receptor site in bones
- Causes vitamin D resistance
- Hypermagnesemia: hypocalcemia + hypercalciuria
• Malabsorption syndrome
• Renal tubular failure, nephrotic syndrome, chronic liver disease, malnutrition

•
PHOSPHATE Main anion inversely related to calcium (ABSOLUTE INVERSE RELATIONSHIP)
•
80-85% in the bones and 15-20% in the ECF
(2.7-4.5 mg/dl) inorganic •
Total phosphate: 12 mg/dl (mostly organic)
ABNORMALITIES IN PHOSPHATE LEVEL
HYPOPHOSPHATEMIA HYPERPHOSPHATEMIA
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Alcohol abuse Avitaminosis D Hypoparathyroidism Increased vitamin D

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Primary hyperparathyroidism Renal failure

Myxedema Lymphoblastic leukemia

ELECTROLYTES TO ACID-BASE BALANCE RABAGO, FRANCZESCA FAITH

 CLINICAL CHEMISTRY LECTURE
:
ELECTROLYTES TO ACID-BASE BALANCE
CALCIUM-PHOSPHATE HOMEOSTASIS
There are 2 factors/systems that affect calcium-phosphate homeostasis: blood pH and hormones
Alkalosis: promotes bone absorption; calcium phosphates are made at an alkaline medium
Acidosis: promotes bone resorption
Major factor affecting homeostasis are hormones

The endocrine control of calcium and phosphate levels are mainly regulated by the ff. hormones:

PARATHYROID HORMONE
• Produced by the parathyroid gland
• Acts as the main regulator of calcium-phosphate homeostasis (emphasizes inverse relationship)
• It is considered as the main hypercalcemic hormone of the body
• Can elicit function in GIT, kidneys, bone
- GIT: ↑ absorption in calcium and phosphate
- Bone: promotes bone resorption, promotes osteoclastic activity
- Kidneys: ↑ reabsorption of calcium; ↓ reabsorption of phosphate
• Net effect: INCREASE CALCIUM, DECREASE PHOSPHATE
CALCITONIN
• Produced by the parafollicular C cells of the thyroid gland
• Acts as the main hypocalcemic hormone of the body
• Used as a tumor marker for metastatic thyroid carcinoma
• Can elicit function in GIT, kidneys, bone
- GIT: ↓ absorption in calcium and phosphate
- Bone: promotes bone absorption, promotes osteoblastic activity
- Kidneys: ↓ reabsorption of calcium; ↓ reabsorption of phosphate
• Net effect: DECREASE CALCIUM AND PHOSPHATE

ACTIVE VITAMIN D
• Formed from 7-dehydrocholesterol in the skin upon irradiation to sunlight
• Cholecalciferol is sent to the liver (25-hydroxycholecalciferol) and into the kidneys where it is converted to its active form: 1, 25-
dihydroxycholesterol
• Activation of vitamin D occurs in the kidneys; its proform is found in the SKIN
• Only influences GIT and kidneys
• Often times associated with bone strength but has no direct effect on the bone; it simply increases the net effect of Ca2+ and PO4- which
promotes bone strength
GIT (absorption) BONE KIDNEYS (excretion, reabsorption) NET EFFECT
PTH ↑ Ca2+ and PO4- Resorption ↑ Ca2+, ↓ PO4- ↑ Ca2+, ↓ PO4-
CALCITONIN ↓ Ca2+ and PO4- Absorption ↓ Ca2+ and PO4- ↓ Ca2+ and PO4-
ACTIVE VIT D ↑ Ca2+ and PO4- ↑ Ca2+ and PO4- ↑ Ca2+ and PO4-

•
Second most abundant ICF cation and the 4th most abundant in the body
•
Vasodilator causing decrease uterine hyperactivity in eclampsia and increase uterine blood flow
MAGNESIUM •
It is important in maintaining DNA, RNA, and ribosomal structures and involved in the synthesis of CHO,
CHON, and lipids
(1.2-2.1 mmol/L) - Cofactor of polymerase (included in the reagents for PCR)
• An electrolyte that is usually monitored in cases of eclampsia, preeclampsia, and MI (used as a medication
in these cases; serve as a vasodilator)
Hormones affecting magnesium values in the plasma:
• PTH: increases intestinal absorption and renal reabsorption of magnesium
• ALDOSTERONE and THYROXINE: promotes renal excretion (lowers plasma magnesium)
• 53% in bones, 46% in muscles and other organs; <1% in serum and RBCs
Magnesium in serum (1%):
- Protein bound (albumin): 33% or 1/3
- Ionized or free: 61%
- Complexed with other ions: 5% (PO4- or citrate)

ABNORMALITIES IN MAGNESIUM LEVEL

HYPOMAGNESEMIA HYPERMAGNESEMIA
• Glomerulonephritis • Decreased excretion
• Pyelonephritis • Acute or chronic renal failure
• Chronic alcoholism • Hypothyroidism
• Malabsorption syndrome (sprue) • Hypoaldosteronism
• Hyperparathyroidism: there is increased renal excretion of
magnesium due to excess calcium ions

APPROACHES IN ELECTROLYTE DETERMINATION

• Flame emission photometry: yellow; obsolete
SODIUM • Ion selective electrode: most routinely used
• Atomic absorption spectrophotometry: reference method
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• Colorimetric method: obsolete; Albanese Lein

• Flame emission photometry: violet
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POTASSIUM • Ion selective electrode: current method of choice; uses valinomycin

• Atomic absorption spectrophotometry
ELECTROLYTES TO ACID-BASE BALANCE RABAGO, FRANCZESCA FAITH
 CLINICAL CHEMISTRY LECTURE
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ELECTROLYTES TO ACID-BASE BALANCE
• Colorimetric method: Lockhead and Purcell; Hillman and Beyer
• Spectrophotometric method
CHLORIDE • Mercurimetric titration: Schales and Schales
• Coulometric amperometric titration: Cotlove chloridometer; involves generation of silver ions that are complexed with
chloride
• Ion selective electrode: most common; uses ion exchange membrane that selectively binds chloride
• Flame emission photometry: red-orange
• Colorimetric method: most common
CALCIUM - O-cresolphthalein dye: contains hydroxyquinoline – prevent Mg interference
- Arsenazo III dye
• Ion selective electrode: measures ionized or free calcium
• Atomic absorption spectrophotometry: reference method
• May use serum or heparinized (dry lithium heparin) plasma; liquid chelates calcium
Fiske-subbarow method (common method)
PHOSPHORUS - Involves the formation of ammonium phsphomolybdate (colorless) complex that is measured at 340 nm;
reduced to molybdenum blue measured at 600-700 nm
• Flame emission photometry: blue
• Dye-lake method: Titan yellow
• Atomic absorption spectrophotometry: reference method
MAGNESIUM • Colorimetric method: most common method
- Calmagite: measured at 532 nm (reddish violet)
- Formazan dye: measured at 660 nm
- Methylthymol blue
Ca2+ shelter: prevents Ca2+ interference

ANION GAP
•Difference between unmeasured anions and unmeasured cations
•Useful in indicating an increase in one or more of the unmeasured anions in the serum and also as a form of quality control for the analyzer
used to measure these electrolytes
ACCEPTABLE FORMULA AG = Na – (Cl + HCO3); normal values: 7.16 mmol/L
FOR ANION GAPS AG = (Na + K) – (Cl + HCO3); normal values: 10-20 mmol/L
DECREASED ANION GAP INCREASED ANION GAP
• When there is a decrease in unmeasured anions; increased • When there is an in increase in unmeasured anions
cations • Mnemonic: PUDILS
• Hypoalbuminemia • Poisoning: methanol, ethanol, ethylene glycol, salicylate
• Severe hypercalcemia • Uremia
• Multiple myeloma: increased production of cationic proteins • Diabetic ketoacidosis
• Severe dehydration
• Lactic acidosis
• Instrument error

ACID-BASE BALANCE
• Maintenance of physiologic pH is significant in order for the metabolic processes of the body to work optimally
• The normal pH of the blood is between 7.35 to 7.45. this is maintained principally by the existing blood buffering mechanisms of the body
and is affected by exchange of gases specifically carbon dioxide and O2
ACID BASE
• Increases the concentration of hydrogen ion • Increases the concentration of hydroxyl ions
• Donates a proton in a reaction • Accepts protons in a reaction
• Accepts a pair of electrons • Donates a pair of electrons
BUFFER SYSTEMS
Bicarbonate-carbonic acid buffer system
• Considered as the most important buffer in the body
• Under physiologic conditions, there is a 20:1 ratio between bicarbonate and carbonic acid
• 90% of the CO2 in the blood exists as bicarbonate ion

Biphosphate-dihydrogen phosphate buffer system

• Under normal conditions, the ratio of biphosphate to dihydrogen phosphate is 4:1
• Hemoglobin: capable of transporting gases and exchange of ions
• Plasma proteins: brought about by their amphoteric nature

HENDERSON-HASSELBALCH EQUATION
• This equation states the relationship between acid and base and relates the pH of a solution to the dissociation properties of the weak acid
• Expresses the blood pH depends on the ratio of bicarbonate and pCO2
• Presents that if the kidneys and lungs are properly functioning, a 20:1 ratio of HCO3 to H2CO3 will be maintained

pH = 6.1 + HCO3 (nominator, base, metabolic)

H2CO3 (denominator, acid, respiratory)
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H2CO3: pCO2 x 0.03 (dissolution constant)

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LUNGS (respiratory) = Pco2 (acid)

KIDNEYS (metabolic) = HCO3 (base)
ELECTROLYTES TO ACID-BASE BALANCE RABAGO, FRANCZESCA FAITH
 CLINICAL CHEMISTRY LECTURE
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ELECTROLYTES TO ACID-BASE BALANCE
ACID-BASE DISORDERS
PRIMARY CAUSE PRIMARY COMPENSATION DISEASE/CONDITIONS
Metabolic acidosis Bicarbonate loss Hyperventilation Diabetic ketoacidosis; lactic acidosis; renal failure; diarrhea
Metabolic alkalosis Bicarbonate excess Hypoventilation Vomiting
Respiratory acidosis Hypoventilation Bicarbonate reabsorption COPD, pneumonia, CNS disease, stroke, drug overdose,
botulism, myxedema
Respiratory alkalosis Hyperventilation Bicarbonate excretion Anxiety, severe pain, aspirin overdose, hepatic cirrhosis
Kidney problem: metabolic dysfunction
- METABOLIC ACIDOSIS: When you are losing bicarbonate, you are losing base; which is why the body becomes acidic; LUNGS
compensate by lowering pCO2 thru hyperventilation
- METABOLIC ALKALOSIS: When there is excess bicarbonate, there is an excess base; body compensates thru the lungs by
hypoventilation to prevent release of pCO2
Lung problem: respiratory dysfunction
- RESPIRATORY ACIDOSIS: In hypoventilation, body has excess CO2 which results to accumulation of acid; kidney increases base by
reabsorbing HCO3
- RESPORATORY ALKALOSIS: in hyperventilation, there is an increased amount of O2 that enters in the body resulting to alkalosis;
kidney increases excretion of HCO3 to lower down the base

IDENTIFYING ACID-BASE DISORDERS

NORMAL VALUES
PH PCO2 HCO3 TOTAL CO2 PO2 O2 SATURATION
7.35-7.45 35-45 mmHg 22-26 mmol/L 23-27 mmol/L 80-100 mmHg 95-100%

1. Check pH
If above the normal range: alkalosis
If below the normal range: acidosis

2. Check pH and pCO2 if opposite: respiratory

Check pH and pCO2 if parallel: metabolic

3. Identify expected compensation

if not yet present: uncompensated
if already present: compensated

4. Check pH again
Still out of range: partial
Within normal range: fully

BLOOD GAS ANALYSIS

• Specimen for blood gas analysis: heparinized arterial blood
• It must be collected under anaerobic condition and sample must be placed in ice water or ice bath
• The specimen must be refrigerated if not tested within 20 minutes

ELECTRODES OF BLOOD GAS ANALYSIS

pH Glass electrode connected to a reference electrode (potentiometry)
pCO2 Severinghaus electrode; a modified pH electrode (potentiometry)
pO2 Clark electrode, composed of O2 permeable membrane with electrode composed of a platinum cathode and silver-silver chloride anode
(polarography/amperometry)
HCO3: derived or solved value

ERRORS IN BLOOD GAS ANALYSIS

• Room air is composed of 20-22% O2. This atmospheric air may enter the specimen causing an increase
Specimens exposed to room air in O2 while displacing CO2 in the process
• Presence of bubbles; misplaces CO2
• Effect: ↑ pH, ↑ pO2, ↓pCO2
• Changes are due to the presence of blood cells utilizing glucose and O2 at room temperature, causing
Sealed specimen left at RT the formation of acid products and CO2
• Effect: ↓ pO2
Excess heparin • Heparin is an acid mucopolysaccharide which would lead to acidic pH of blood specimen

ABG results in myocardial • pO2 is significantly reduced

infarction • metabolic acidosis ensues
• pCO2 is usually normal or low to compensate for metabolic acidosis
ABG results in fever • For every 10C increase in temperature PO2 decreases by 7% and PCO2 increases by 3%
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ELECTROLYTES TO ACID-BASE BALANCE RABAGO, FRANCZESCA FAITH

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LIVER TO CARDIAC FUNCTION ASSESSMENT
LIVER
• Largest internal organ, weighing approximately 1,200 to 1,500 grams
• Extremely vascular organ, receives 27% of the total cardiac output or 1500 ml/min of blood from 2 major blood vessels
• Screens substances that enter via the portal circulation
• Bilobed organ (not paired; left side is larger than the right); separated by the talciform ligament
• PORTAL VEIN: approx. 75%; provides nutrient-rich blood; arises from the GIT
• HEPATIC ARTERY: approx. 25%; provides O2-rich blood

3 SYSTEMS
HEPATOCELLULAR: responsible for metabolic reactions as macromolecular synthesis (proteins) and degradation and metabolism of xenobiotics
(drugs)
- Drugs are taken in their proform and must pass through the liver to be taken up by the body (first pass)
HEPATOBILIARY: involved with the metabolism of bile salts and bilirubin
RETICULOENDOTHELIAL: concerned with the immune system and the production of heme and globin metabolites; liver is part of the RES; Kupffer
cells (macrophages) play a role in the immune system

BIOCHEMICAL FUNCTIONS OF THE LIVER

FUNCTION DESCRIPTION
SYNTHETIC production of biological compounds such as proteins (coagulation factors), CHO, and lipids
EXCRETORY Processing and excretion of exogenous and endogenous substances into the bile and urine
In measurement of BILIRUBIN
DETOXIFICATION Gatekeeper between the substances absorbed in the GIT and released into the circulation
STORAGE Conversion of biological compounds into a storage form; glucose as glycogen

BILIRUBIN
BILIRUBIN 1 BILIRUBIN 2
Unconjugated, indirect, nonpolar, water insoluble, free bilirubin, slow Conjugated, direct, polar, water soluble, prompt, regurgitative, bilirubin
bilirubin, prehepatic diglucuronide, posthepatic
Noncovalently attached to albumin

DELTA BILIRUBIN: conjugated bilirubin tightly bound to albumin; obstruction

• Iron and globin will settle back to the storage pool for future use
• Protoporphyrin IX is converted to B1 and will make use of albumin to be transported to the
liver where they will be conjugated
• Liver: albumin cannot enter; its transport protein would be LIGANDIN
• B1 will be sent to the smooth endoplasmic reticulum by the hepatocytes wherein B1 is
conjugated to 1 or 2 molecules of glucuronic acid
• Conjugation is aided by the enzyme uridyl diphosphate (UDP)-glucuronyltransferases
• B2 (conjugated bilirubin) must be sent to the canaliculi; for it to enter, there must be a portal
or mode of transport
• Hepatocytes have their canaliculi for the B2 to enter which is the CMOAT – canalicular
multispecific organic anion transport
• From the several canaliculi of hepatocytes, B2 will be drained into the bile duct
• Bile duct is connected to the duodenum; in the duodenum, with the aid of the normal flora, B2 is converted to urobilinogen (20% goes back into
the circulation, remaining 80% is converted to urobilin and stercobilin (normal stool color)
• The 20% urobilinogen that went back into the circulation must go back to the liver to be further metabolized; in its way going back to the liver, it
passes through the kidneys where it is excreted (this explains why urobilinogen is never reported as negative in urinalysis)
• Once urobilinogen (20%) is oxidized, it becomes urobilin which contributes to the normal color of urine

JAUNDICE: condition characterized by yellow discoloration of skin, sclera, and mucous membranes. Most commonly caused by increased bilirubin, not
clinically seen until bilirubin values exceeds 3mg/dl
COVERT JAUNDICE: abnormal bilirubin level; not yet manifesting as jaundice

DERANGEMENT IN BILIRUBIN METABOLISM

PREHEPATIC: hemolytic anemia, hemolytic disease of the newborn; increased RBC destruction; liver is essentially normal but overly compensates;
there is an increase in the rate of conjugation (increased B1, N B2, ↑ urobilinogen (B2 is constantly converted into urobilinogen from the increased rate
of conjugation)
- Negative B2 (URINE BILIRUBIN); will only be positive if there is B2 that goes back into the circulation

HEPATIC
• Unconjugated hepatic hyperbilirubinemia
• B1 is responsible for the jaundice
GILBERT’S SYNDROME: transport CRIGLER-NAJJAR: conjugation defect LUCY-DRISCOLL: presence of
defect with UDPGT deficiency due to UDPGT deficiency antibodies against UDPGT
• Defective hepatic uptake of bilirubin • Type 1: absolute UDPGT - (+) Circulating anti-UDPGT
• Transport deficit with UDPGT deficiency; pathologic neonatal antibodies
UNCONJUGATED deficiency jaundice • Increased B1 (unconjugated),
• UDPGT: conjugates B1 with - Physiologic neonatal normal B2, normal urobilinogen,
1

glucuronic acid jaundice: normal; liver of negative urine bilirubin

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neonates is still immature and

cannot conjugate; during
pregnancy, mother’s liver
LIVER TO CARDIAC FUNCTION ASSESSMENT RABAGO, FRANCZESCA FAITH
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:
LIVER TO CARDIAC FUNCTION ASSESSMENT
compensates for the
conjugation in fetus; subjected
to phototherapy
• Type 2: partial UDPGT deficiency
(clinically the same with Gilbert’s;
neonatal condition, most likely to be
associated with Crigler)
• Viral hepatitis, cirrhosis, hepatic carcinoma; affects not just the conjugation process, but the handling of conjugated bilirubin
COMBINED • ↑B1 and B2; since there is a problem with the liver, the (20%) urobilinogen that goes back into the liver is also affected
• ↑ urobilinogen; (+/-) urine bilirubin
• There is formation of B2 but they cannot be sent into the canaliculi and cannot be drained into the bile duct
• B2 goes back into the circulation
• Conjugated hepatic hyperbilirubinemia
• Excretory/secretory defect
• LIVER BIOPSY: done to differentiate Dubin from Rotor
- N B1, ↑ B2, N urobilinogen, (+) urine bilirubin (both cases present this result)
CONJUGATED - LIPOFUSCIN PIGMENTS: aka wear and tear pigments; absent in ROTOR, (+) in DUBIN; abnormal gall bladder in
DUBIN; normal in ROTOR
DUBIN-JOHNSON SYNDROME: impaired transport of B2 into ROTOR SYNDROME: reduction in the concentration/activity of
the canaliculi ligandin
• Defect in ATP binding cassette/CMOAT system • Normal gall bladder function; absence of dark
• Abnormal gall bladder function; presence of dark pigmentation of liver
pigmentation in the liver • Believed to be of VIRAL origin
• LIGANDIN: transport protein of bilirubin in the liver
POST HEPATIC: obstruction in the bile flow; may be due to the presence of bile stones, tumor, cancer
• Pancreatic cancer, cholestasis, cholelithiasis
• Bile duct and pancreatic duct have the same outlet in the duodenum; whenever the pancreas is enlarged, it can also cause a constriction in the
bile duct
• Explains why px with pancreatic cancer also presents JAUNDICE
• Normal B1, ↑ B2, ↓ urobilinogen (nothing to be processed since B2 is recirculated back), (+) urine bilirubin
• Bishop (ref book): increased B1; not true to all conditions (a possibility only); when there is an obstruction in the bile duct, accumulation of bile
flow happens (B1 also flows back into the circulation)
• Stool s clay colored/gray; no urobilinogen, therefore no presence of urobilin and stercobilin

BILIRUBIN DETERMINATION METHODS

GENERAL REACTION
Based on the Van den Berg reaction (diazo reaction)
Diazo reagent: diazotized sulfanilic acid
- The only fraction that reacts is B2 (direct bilirubin)
Accelerator: solubilizer or dissociating agent; it dissociates B1 from the albumin

1. Bilirubin + diazo reagent = azobilirubin (only bilirubin formed is B2)

2. Bilirubin + accelerator + diazo reagent = azobilirubin (can measure total bilirubin)

B1 FRACTION = total bilirubin – B2 (result of the 2nd reaction – the first reaction)

EVELYN-MALLOY METHOD JENDRASSIK GROF METHOD

Preferred sample is serum; subject to PROTEIN interferences More sensitive than Evelyn; proposed REFERENCE METHOD; not
• pH: acid affected by PROTEIN OR HB interferences
• Accelerator: methanol • pH: alkaline
• End color: red/reddish purple • accelerator: caffeine-sodium benzoate
• Wavelength: 560 nm • end color: blue
• wavelength: 600 nm
• most commonly used methods today are modifications of the EVELYN-MALLOY METHOD
• most common principle used: EVELYN-MALLOY METHOD

LIVER DISEASES
HEPATOCELLULAR DISEASES: damage with the hepatocytes
Enzymes most affected: AST and ALT
Alcoholic liver disease Hepatitis Cirrhosis
• Caused by long-term alcoholism • Liver inflammation • Destruction of the normal liver architecture
• Hepatotoxic effects of acetaldehyde • Infection; toxicity (exposure to heavy due to scarring (FIBROSIS)
(product of ethanol metabolism) metals, salicylates) • Scarring impairs blood flow in the liver
• Acetaldehyde: hangover effect • <80%: degree of liver damage (NECROSIS)
• ↑ AST, lipoprotein, bilirubin, ketones, TAG • ↑ AST, ALT, LD, ALP, bilirubin • End-stage
• ↓ glucose, albumin, transferrin • Normal: total protein, albumin, ammonia • >80%: degree of liver damage
• ALT will not increase; requires B6 (AST • Increased De Ritis ratio; not as high as in
requires B6 to function); ALT, however, alcoholic liver disease
requires B6 to actually be produced • ↑ bilirubin, ammonia
2

• AST>ALT during alcoholic liver disease • ↓ total protein, albumin

• De Ritis ratio: >2.0 (implies that AST is • Normal AST, ALT, LD, ALP (can be slightly
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greater than ALT) ↑) ; enzymes may be low from the depletion

of energy source
LIVER TO CARDIAC FUNCTION ASSESSMENT RABAGO, FRANCZESCA FAITH
 CLINICAL CHEMISTRY LECTURE
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LIVER TO CARDIAC FUNCTION ASSESSMENT
TESTS FOR HEPATOCELLULAR DISEASES (can be used for hepatobiliary)
Serum bilirubin level Capacity to conjugate bilirubin and secrete bile
Ratio of B2 and total bilirubin Capacity to conjugate bilirubin; assess hemoglobin turnover
Serum albumin level Capacity to synthesize protein
Serum globulin level Abnormal processing of exogenous and/or autologous antigens
Capacity to synthesize coagulation proteins and/or biliary obstruction
PT and response to Vit K PT: prolonged if there is deficiency in coagulation proteins
Vit K: fat soluble; must be aided by the secretion of bile so it can be emulsified and absorbed into the circulation
Bile obstruction: no production of bile; cannot absorb fats leading to Vit K deficiency
Serum AST and ALT Hepatocellular damages and necrosis
BSP excretion Hepatocellular uptake; conjugating and secretory capacity; patency of biliary ducts
Fasting blood glucose Capacity to synthesize glucose and glycogen storage (rough indication)
Blood urea Loss of detoxifying capacity
Blood ammonia Loss of detoxifying capacity; integrity of portal circulation; quantity of colonic bacteria

HEPATOBILIARY DISORDERS
Stones, tumor, constriction (pancreatic enlargement)
Normal: total protein, albumin, AST, ALT, LD
BILIARY OBSTRUCTION ↓: urobilinogen
↑: GGT, ALP, B2
Enzymes noted: ALP and GGT

TESTS FOR HEPATOBILIARY DISORDERS

Patency: unobstructed biliary duct
Serum bilirubin level Overall capacity to transport bile
Ratio of B2 and total bilirubin Patency of biliary ducts; hepatocellular metabolism of bilirubin
Serum bile acids/bile salts Overall patency of biliary ducts
Fecal color and fat content Patency of biliary ducts
Fecal urobilinogen Patency of biliary ducts; quantity of bilirubin processed
Urine urobilinogen Patency of biliary ducts; quantity of bilirubin processed; hepatocellular excretory capacity
Serum ALP Abnormality of bile duct epithelium
Excretion of BSP Patency of bile ducts and hepatocellular function
Urine bilirubin Patency of biliary ducts; hepatocellular bilirubin metabolism

Hepatitis A, B antigens and A, B, C antibodies: viral hepatitis

Alpha-fetoprotein: hepatocellular proliferation (tumor, regeneration); also increased in degeneration of liver
Other specific determinations Alpha-antitrypsin: early developing cirrhosis (JUVENILE CIRRHOSIS)
Ceruloplasmin: Wilson’s disease; deficiency is associated with accumulation of copper in the liver → cirrhosis
Serum iron/ferritin: hemochromatosis
To check for viability of transplanted liver tissue, the ff. must be tested:
Liver transplants - AST, ALT, GGT
- Bilirubin, bile acid, and coagulation tests

CARDIAC FUNCTION ASSESSMENT

CORONARY HEART DISEASE RISK FACTORS (+)
LABORATORY CLINICAL
• LIPIDS: cholesterol, TAG, and specific lipoprotein fractions Age Obesity
• HOMOCYSTEINE: amino acid that exacerbates thrombosis (promotes thrombin Gender Hypertension Cigarette
formation → embolism) Race DM smoking
• C-REACTIVE PROTEIN: inflammatory marker that reflects severity or contributes to Family history of CHD Sedentary lifestyle
the pathogenesis of coronary heart disease (hsCRP: >3 mg/dl; high risk)
• HDL: inversely proportional to the risk for CVD

MARKERS OF AMI
MARKER INITIAL RISE PEAK NORMALIZE REMARKS
Myoglobin 1-3 hr 5-12 hr 18-30 hr Not cardiac specific; earliest cardiac marker
Troponin I 3-6 hr 12-18 hr 5-10 days Troponin T: 3-4 hr; 10-24 hr peak; normalize w/in 7 days; gold std/reference method
CK-MB: 4-8 hr; 12-24 hr; 2-3 days; most cardiac specific CK; used in conjunction with
CK 6-8 hr 24 hr 3-4 days Trop I; it is possible that CK-MB is undetected in the presence of Trop I (it is normalized
earlier than trop I)
Represents earliest enzyme marker
AST 6-8 hr 24 hr 5 days Intermediate presentation
LD 12-24 hr 48-72 hr 10 days Late presentation
• Myoglobin and troponin I: structural proteins
• Troponin complex: I, T, C; responsible of transmitting calcium signals which trigger muscle contraction
• Trop I: inhibits the binding of actin and myosin
• Trop T: binds the tropomyosin complex to tropomyosin; covers the receptors of actin
• Trop C: binds to Ca2+, reversing the inhibitory effect of troponin I; when it binds, tropomyosin moves exposing actin receptors → muscle
3

contraction
• Enzyme markers: cornerstone of post-MI management
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• Brain natriuretic peptide: marker of congestive heart failure

LIVER TO CARDIAC FUNCTION ASSESSMENT RABAGO, FRANCZESCA FAITH

 CLINICAL CHEMISTRY LECTURE
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ENDOCRINOLOGY TO TDM
HYPOTHALAMUS
• Located in the 3rd ventricle directly above the pituitary gland
• Connected with the pituitary gland via the infundibulum or pituitary stalk
• Contains neurosecretory cells that produce releasing and inhibiting hormones

HORMONES PRODUCED:
Corticotropin-releasing hormone Growth hormone releasing hormone
Thyrotropin releasing hormone Growth hormone inhibiting hormone
Gonadotropin-inhibiting hormone Melanocyte inhibiting factor
Prolactin-inhibiting hormone Antidiuretic hormone
Prolactin-releasing hormone Oxytocin

PITUITARY GLAND
• Aka hypophysis (under the hypothalamus)
• Resides in the depression of the sphenoid bone called sella turcica
• Connected to the hypothalamus thru the pituitary stalk
• Master gland

Divided to 3 lobes:
• Anterior pituitary (ADENOHYPOPHYSIS): true endocrine gland; hormone producer
• Posterior pituitary (NEUROHYPOPHYSIS): do not produce hormone; stores ADH and oxytocin
• Intermediate lobe (RUDIMENTARY)

HORMONES PRODUCED BY THE ANTERIOR PITUITARY GLAND

ACTH • Initiates steroidogenesis by stimulating the adrenal cortex
• A tropic hormone
FSH • Stimulates ovulation in females and aids spermatogenesis in males; tropic
LH • Stimulates corpus luteum development for progesterone production in females; tropic
• Stimulates sperm production in males
TSH • Stimulates thyroid gland to produce T3 and T4; tropic
• Produced by the lactotrophs or mammotrophs in the adenohypophysis
PROLACTIN • Stimulate development of the breast tissues needed for lactation
• Stimulated by stress
• Produced by the somatotrophs; most abundant of all pituitary hormones
GROWTH • Stimulates synthesis of new proteins; stimulates lipolysis
HORMONE • Stimulates IGFs or somatomedin production of the liver
• Effector/non-tropic hormone
• DEEP SLEEP: main stimulus
↑ GH: physiologic stress, amino acids ↓ GH: emotional stress, glucose loading, insulin deficiency, thyroxine
GIGANTISM: GH excess; occurs before closure of epiphyseal plates deficiency
ACROMEGALY: also in excess; occurs after closure of bones DWARFISM: GH deficiency
HORMONES STORED IN POSTERIOR PG
ADH/AVP Stimulates cells in collecting ducts to increase water reabsorption
Primarily stimulated by increase plasma osmolality detected by the hypothalamus (site of action: COLLECTING DUCTS)
Increases water level, blood pressure, but decreases sodium level (dilutional effect)
OXYTOCIN Most active in pregnant women; causes milk ejection and uterine contractions during labor
Stimuli are distension of uterus and neonatal suckling of the mother’s nipple
Prolactin, GH, ADH, Oxytocin: all considered as effector and non-tropic hormones

THYROID GLAND
• Bilobed gland centered in the trachea at the level of the 2nd, 3rd, and 4th tracheal rings; reddish brown, weighing 15-25 g and measures 3-5 cm
long
• Fundamental unit: thyroid follicle
• Parafollicular cells: produce calcitonin
THYROID HORMONE SYNTHESIS
• Iodide trapping: uptake of iodide
• Oxidation: iodide to iodine
• Organification: incorporation of iodine (element) with tyrosine residues (amino acid) of thyroglobulin
• Coupling: combination of MIT and DIT
• Release: release into circulation thru the action of proteases

HORMONES PRODUCED
• Main hormone release from the thyroid glands
THYROXINE/ • Most abundant thyroid hormone
TETRAIODOTHYRONINE/ • Distribution: 70% TBG (thyroid-binding globulin), 20% TBPA (thyroid-binding prealbumin or transthyretin), 10%
T4 TBA (thyroid-binding albumin)
• Major transport protein: TBG
• Most active thyroid hormone
1

• Less tightly bound to serum proteins; no affinity to TBPA

TRIIODOTHYRONINE/T3 • Majority comes from the peripheral deiodinization of T4
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• T3: iodine removed from α portion

• rT3: iodine removed from β portion
ENDOCRINOLOGY TO TDM RABAGO, FRANCZESCA FAITH
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ENDOCRINOLOGY TO TDM
CALCITONIN • Produced by the parafollicular C cells
• Hypocalcemic hormone
• Marker for medullary thyroid carcinoma
No way of measuring TRH alone; differentiates secondary from tertiary
TRH STIMULATION ASSAY:
• TRH is given to px w tertiary hypothyroidism; stimulates TSH in PG, produces T3 and T4; there is CORRECTION
• Secondary hypothyroidism: no correction; low T3 and T4

TR UPTAKE TEST
• Principle how much is TMG taking from the budget
• T3 level is directly proportional to T3 uptake
• TBG is inversely proportional to T3 uptake
• ↑thyroid hormones: TBG is saturated
• Hypothyroidism: low T3 uptake

SELECTED THYROID CONDITIONS

HASHIMOTO’S • Primary hypothyroidism (increased TSH, low T3 and T4)
THYROIDITIS • Association with anti-microsomal Ab, anti-TPO, anti-thyroglobulin Ab
• Cold intolerance, weight gain, low basal metabolic rate and sympathetic response
• Thyroid hormones are inversely proportional to lipids
GRAVES DISEASE • Associated with the presence of anti-TSH receptor / thyroid stimulating Ig (diagnostic of Graves), anti-TPO Ab, anti-
thyroglobulin Ab
• Heat intolerance, weight loss, increased basal metabolic rate and sympathetic response
• Anti-TSH receptor acts as the TSH receptor which is why there is an increase in T3 and T4 (mimics function of
TSH)
• Example of primary hyperthyroidism
EUTHRYOID SICK • Characterized by normal thyroid but unusually low T3 and T4; often found in critically ill, hospitalized px
SYNDROME • Characteristic lab finding: increased Rt3
SUBCLINICAL • Values are normal, but there are impending changes in levels of TH
• SUBCLINICAL HYPOTHYROIDISM: N T3 and T4; increased TSH
• SUBCLINICAL HYPERTHYROIDISM: N T3 and T4; low TSH

ADRENAL GLANDS
• Pyrimidal structure above kidney
• Weights approx. 4-6 grams

ADRENAL CORTEX:
• Zona glomerulosa: outermost; produces sex; testosterone
• Zona fasciculata: middle, thickest, produces cortisol (glucocorticoids)
• Zona reticularis: produces androgens

ADRENAL MEDULLA:
• Not influenced by the HPT axis
• Not influenced by ACTH from the hypothalamus
• Part of the sympathetic nervous system

HORMONES PRODUCED BY THE ADRENAL CORTEX

• Promotes sodium and water reabsorption by the kidney to help maintain blood pressure and tonicity
• Regulated by the RAAS
ALDOSTERONE • HPT may influence release of aldosterone; however, whenever aldosterone is low, the one that regulates is RAAS
• Main mineralocorticoid of the body
• Exhibits diurnal variation; regulated by the ACTH production thru the HPA axis
CORTISOL • Peak= 8 AM; trough: 10 PM
• When anterior PG releases ACTH, it stimulates entire adrenal cortex to produce its products
• When cortisol drops, HPA axis regulates its levels
ANDROGENS • Androgens, estrogens; involved in the development of secondary sexual characteristics
HORMONES PRODUCED BY THE ADRENAL MEDULLA (CATECHOLAMINES)
An example of a lipid hormone – fast acting; 1st responders to stress
NOREPINEPHRINE/ • Produced by the sympathetic ganglia; highest concentration in the CNS
NORADRENALINE • Acts as a neurotransmitter in both the CNS and SNS (-nor: CNS)
• Metabolites: VMA; MMHPG (Methylhydroxyphenylglycol)
EPINEPHRINE / • Produced from norepinephrine; comes only from the adrenals
ADRENALINE • Metabolites: VMA (major), normetanephrines, HVA
• Produced from the decarboxylation of 3,4-dihydroxyphenylalanine
DOPAMINE • Highest concentration in the brain
• Only catecholamine found in the urine
• Metabolites: HVA
SELECTED ADRENAL GLAND CONDITIONS
2

• Group of clinical and metabolic disorders characterized by adrenocortical hyperfunction

CUSHING’S SYNDROME • Findings: Hirsutism, obesity, hypertension, buffalo hump, moon-shaped face
Page

PITUITARY CUSHINGS ADRENAL CUSHINGS

• Secondary • Primary
ENDOCRINOLOGY TO TDM RABAGO, FRANCZESCA FAITH
 CLINICAL CHEMISTRY LECTURE
:
ENDOCRINOLOGY TO TDM
(Adrenal cortex • Pituitary adenoma (↑ACTH, ↑ CORTISOL) • Adenoma in adrenal gland (↑ CORTISOL,
hyperfunction) • Referred as Cushing disease ACTH ↓)
• Androgens and aldosterone will also increase; when
ACTH stimulates the cortex, all of its products will be
produced
ADDISON’S DISEASE • Decreased aldosterone, cortisol and other steroids
(Adrenal Hypofunction) • Can be due to effect in hypothalamus, pituitary pr adrenal gland
CONN’S DISEASE • Aldosterone-secreting adrenal adenoma
• Primary aldosteronism (isolated increase in aldosterone)
• Tumor of the adrenal medulla or sympathetic ganglia resulting to overproduction of catecholamines
PHEOCHROMOCYTOMA • Symptoms: hypertension, tachycardia, headache, sweating and tightening of chest
• Diagnostic test: 24-hour urinary metanephrines
• Commonly affects adult (30-50 years of life)
• Fatal malignant condition in children; results to excessive norepinephrine production
NEUROBLASTOMA • Elevated urinary excretion of HVA or VMA or both, and dopamine
• Diagnostic test: serum or plasma catecholamines

GONADS
• Most potent male androgen
TESTOSTERONE • Functions for growth and development of the reproductive system, prostate and external genitalia
• Needed in spermatogenesis
• Synthesized by the Leydig cells under the influence of the LH
• Arises from the structural alteration of testosterone
• Promotion of breast development, maturation of external genitalia

3 FORMS
ESTROGEN • ESTRONE (E1): most abundant in post-menopausal women; produced from the adrenal cortex
• ESTRADIOL (E2): most potent estrogen; most abundant in pre-menopausal women; comes from the ovaries
• ESTRIOL (E3): abundant during pregnancy; found in maternal urine; produced by the placenta

• Follicular phase: ↑ estrogen; Luteal phase: ↑ progesterone

Best hormone to determine ovulation
PROGESTERONE Prepares the uterus for pregnancy and breast lobules for lactation
Produced by the granulosa cells of the corpus luteum
SELECTED GONADAL CONDITIONS
MALES FSH LH TESTOSTERONE
Klinefelter’s syndrome Congenital condition wherein you have an extra Y chromosome (XXY) ↑ ↑ ↓
Primary hypogonadism (decreased testosterone because of a problem in the
gonads)
Panhypopituitarism Secondary hypogonadism; problem with the pituitary gland ↓ ↓ ↓
Testicular tumor Primary Hypergonadism ↓ ↓ ↑
Precocious puberty Secondary Hypergonadism; PG produces excessive LH and FSH ↑ ↑ ↑
FEMALES FSH LH ESTROGEN
Menopause Primary hypogonadism ↑ ↑ ↓
Sheehan’s syndrome Secondary hypogonadism; loss of blood after child delivery; affected PG ↓ ↓ ↓
Aka postpartum hypopituitarism
Feminizing ovarian tumor Primary hypergonadism ↓ ↓ ↑
Gonadotropin-producing Secondary hypergonadism ↑ ↑ ↑
tumor

THERAPEUTIC DRUG MONITORING

• Common indications of therapeutic drug monitoring:
• Identifying non-compliance in patients
• Preventing the consequences of under/overdosing
• Maximizing the therapeutic effect, particularly when there is a narrow dose range between therapeutic and toxicity
• Optimizing a dose regimen based on drug-drug interactions or a change in the patient’s physiologic state that may unpredictably affect
circulating drug concentrations

PHARMACOLOGICAL PRINCIPLES AND TERMS

PHARMACODYNAMICS Deals with the relationship between the drug concentration at the receptor site and response of tissues to the drug; effects
of the drugs on the body
PHARMACOKINETICS Deals with the relationship between the drug dose and drug blood levels how the body handles the drug
MEDIAN EFFECTIVE Measure of the effectiveness of the drug; dose of the drug to produce a specified effect in 50% of the animal population
DOSE (ED50)
MINIMUM EFFECTIVE Lowest concentration of the drug that will give us the desired effect
CONCENTRATION
MINIMUM TOXIC Lowest concentration of the drug that is capable of giving adverse reactions
CONCENTRATION
3

MEDIAN LETHAL Measure of the toxicity of the drug; dose of the drug required to kill 50% of the animal population
DOSE (LD50)
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THERAPEUTIC INDEX / Ratio of ED50 to LD50; measure how selective the drug is in producing the desired effect
MARGIN OF SAFETY
HALF-LIFE Time required to reduce the drug into half its original concentration; basis of dose interval
ENDOCRINOLOGY TO TDM RABAGO, FRANCZESCA FAITH
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ENDOCRINOLOGY TO TDM
BIOAVAILABILITY • Fraction of the drug that reaches the circulation/blood; highest bioavailability (100%): Intravenous
• Lowest: drugs given orally (undergo first pass effect; metabolized in the liver)
• Time during which the concentration of the drug in the body stays consistent
STEADY STATE • Important in drugs that are given in multiple doses
• Reached after 4-7 doses (measure peak and trough levels; make sure that it won’t exceed peak levels and won’t go
below the trough of therapeutic range)
• Screens for drug toxicity; specimens are collected when the highest serum concentration of the drug is anticipated
• 1 hour after the dose (depends on the characteristic of the drug and the manner into which it is taken in the body)
PEAK LEVEL • Given IV: 30 min
• IM: 45 min
• Orally: 1-2 hr
• In general, spx is collected an hour after the initial dose
• Monitored to ensure that levels of the drug stay within therapeutic range. Specimens are collected when the lowest
TROUGH LEVEL serum concentration of the drug is expected
• Collected right before the next dose

PROCESSES INVOLVED IN DRUG DISPOSITION

Liberation Release of the drug
Absorption Rate at which the drug leaves the administration site
Transport of the drug from the administration site to the blood
Distribution Refers to the equilibrium of drug with the body tissue and plasma protein
Refers to the delivery of drug tissues
Metabolism Process of chemical modification of drugs by cells; usually occurring in the liver
Also known as: Biotransformation
Elimination/excretion Drugs and its metabolites are excreted from the body; primarily occurs in the liver

• Age and sex

Factors considered in deciding dose of prescribed drug • Renal function
• Concurrent administration of other drugs
• Spectrophotometric, colorimetric and fluorometric techniques
TDM techniques/assays • Immunoassays such as RIA, EIA, and FIA
• Chromatographic such as GC and HPLC; utilized for multiple assays
• GC-MS: gold standard for drug monitoring (sensitive, specific)
• Serum or heparinized plasma: therapeutic drug monitoring
Specimens • Urine: drug of abuse
• Whole blood: tacrolimus, cyclosporine
PHARMACOKINETICS
Rate of absorption exceeds distribution and elimination: increase in serum concentration of the drug
Rate of elimination and distribution exceeds absorption: decrease in serum concentration

THERAPEUTIC DRUGS
CARDIOTROPHIC DRUGS: for treating arrhythmias and CHF
Cardiac glycoside used in the treatment of CHF
DIGOXIN Leads to a decrease in intracellular potassium; leads to an increase in intracellular calcium
Functions by inhibiting membrane Na, K ATPase, increasing calcium
QUINIDINE Naturally occurring drug that is used to treat cardiac arrhythmic situations
70-80% of absorbed fraction is bound to serum proteins
PROCAINAMIDE Used to treat cardiac arrhythmia
Undergoes N-acetylation in the liver to form N-acetyl procainamide (NAPA) – metabolite
PROPANOLOL Anti-adrenergic beta blocker drug: suppresses conversion of T4 to T3
Toxic effect: Raynaud’s type
DISOPYRAMIDE Used to treat cardiac arrhythmias
Commonly used as a quinidine substitute 9when the adverse effects of quinidine are excessive)
ANTIEPILEPTIC DRUGS: treatment of seizures, grand mal, petit mal, and psychomotor seizures
• Slow-acting barbiturate that effectively controls several types of seizures
• Reaches peak level 10 hours after administration (oral)
PHENOBARBITAL • PRIMIDONE: inactive proform; absorbed much faster; usually given when effect of phenobarbital must be given right
away
• Total potential: primidone (parent drug) + phenobarbital (metabolite) = measured both
• Metabolite must also be measured because there is a possibility that the parent drug is converted to its metabolite
PHENYTOIN OR • Commonly used treatment for seizure disorders
DILANTIN • Also used as a short-term prophylactic agent in brain injury to prevent loss of functional tissue
• Proform: FOSPHENYTOIN; injectable proform
VALPROIC ACID • Used as a monotherapy for the treatment of petit mal and absence seizures
CARBAMAZEPINE • Treatment for various seizure disorders with serious adverse effects
OR TEGRETOL • Less frequently used; except when patients do not respond to other drugs
ETHOSUXIMIDE OR • Used for controlling petit mal seizures
ZARONTIN •
4

Drug of choice for petit mal seizure

ANTI-ASTHMATICS: bronchodilators for treatment of asthma; for prevention of attacks and treatment of symptomatic exacerbations
Page

THEOPHYLLINE • Acts as phosphodiesterase inhibitor to maintain a high cAMP

• Causes relaxation of bronchial smooth muscle; crosses the placenta
• THEOBROMINE: bronchodilator; given to neonates experiencing dyspnea
ENDOCRINOLOGY TO TDM RABAGO, FRANCZESCA FAITH
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ENDOCRINOLOGY TO TDM
ANTI-INFLAMMATORY: prevents prostaglandin synthesis
ACETOMINOPHEN • Acts in the hypothalamus by inhibiting prostaglandin synthase
(PARACETAMOL) • TOXIC TO THE LIVER (AST/ALT)
• Non-steroidal anti-inflammatory drug
ASPIRIN/ • Prevents prostaglandin synthesis by inhibiting the cyclooxygenase pathway (same pathway where thromboxane A2 is
ACEYTLSALYCYLIC produced: needed for platelet function)
ACID • Anti-inflammatory at higher doses; anticoagulant at lower doses
• No aspirin intake within 48 hours prior to blood donation
• Measured using the Trinder’s reaction

IMMUNOSUPPRESSIVE DRUGS: prevention of GVHD

• Drug of maintenance of allografts
CYCLOSPORINE • Acts by inhibiting selectively T-helper cell function with sparing and augmentation of the T-suppressor cell population
• Inhibits T helper production of IL-2 (link in humoral and cell immunity)
• Suppression of host vs. graft rejection transplant
• OL-2: influence function of plasma cells to release antibodies
TACROLIMUS • Orally administered immunosuppressive drug that is 100 times more potent than cyclosporine
• Lesser dosage requirement
SIROLIMUS OR • An antifungal agent with immunosuppressive activity
RAPAMYCIN • Commonly used in conjunction with cyclosporine or tacrolimus
MYCOPHENOLIC • Lymphocyte proliferation inhibitor
ACID • Used most commonly as supplemental therapy in renal transplant patients
• Administered in the form of MYCOPHENOLATE MOFETIL

PSYCHOACTIVE DRUGS: for psychiatric affective disorders

• Orally administered drug used to treat manic depression (bipolar disorder)
• Acts by competing with other monovalent cations and divalent cations (calcium, magnesium)
• Treatment for the prevention of Alzheimer’s disease
• Positive risk factors (enzymes) for the development of Alzheimer’s disease are magnesium dependent (uses it as
LITHIUM a cofactor); lithium binds to the enzymes to treat Alzheimer’s
• Bipolar disorder: accumulation of inositol to the brain; inositol phosphatase requires magnesium and its end
product (inositol) may accumulate in the brain
• Lithium prevents bipolar disorder by binding to the receptors and by competing with magnesium
• Lithium and magnesium: diagonal relationship; lithium can bind to the receptors of magnesium
TRICYCLIC • Drugs used to treat depression, insomnia, extreme apathy, and loss of libido
ANTIDEPRESSANTS • Examples are imipramine, amitriptyline, and doxepin
(TCADs)
CLOZAPINE • Atypical antipsychotic used to treat otherwise treatment-refractory schizophrenia, including its negative symptoms,
suicidal tendencies, and various types of cognitive deficiencies associated with the disease
OLANZAPINE • A thienobenzodiazepine derivative that effectively treats schizophrenia, acute manic episodes, and the recurrence
of bipolar disorders
ANTINEOPLASTIC: chemotherapeutic drugs
METHOTREXATE • Inhibits DNA synthesis in all cells
• Efficacy of treatment is dependent on a controlled period of inhibition, one that is selectively detrimental to
neoplastic cells
• LEUCOVORIN: reverses the actions of methotrexate at a specific time after methotrexate infusion (leucovorin
rescue)
ANTIBIOTICS: for bacterial infections
AMINOGLYCOSIDE • Treatment of infections with gram-negative bacteria
• May cause cranial nerve damage, nephrotoxicity and ototoxicity
VANCOMYCIN • Glycopeptide antibiotic that is effective against gram-positive cocci and bacilli
• Toxicities include red man syndrome, nephrotoxicity and ototoxicity
• Drug of choice in cases of MRSA infection

DRUGS OF ABUSE
OPIATES: derived from Popver somniferum (opium poppy)
MORPHINE • Powerful analgesic; acts by binding to the U receptors in the CNS
• Used for the treatment of HF by lowering venous return to the heart
CODEINE • Mild analgesic and antitussive (found in cough syrup)
HEROINE • Induces pleasant, euphoric state and is highly addictive
• Withdrawal symptoms: hypothermia, palpitations, cold sweats and nightmares
• Intravenously administered
TRANQUILIZERS
DIAZEPAM • A benzodiazepine and is used as a minor tranquilizer (downer)
(VALIUM) • Induces GABA secretions to inhibit conduction of dopaminergic neurons
• Used to counter effects of drugs and induce tranquil states
• Intoxication can lead to somnolence, confusion, seizure and coma
• Counters amphetamines
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SEDATIVE-HYPNOTICS
BARBITURATES • Derivative of barbituric acid; fat soluble thus can pass easily thru the BBB
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• Classified based on the length of time they exert on pharmacological effects

PHENYTOIN • Anticonvulsants; structurally and functionally similar to phenobarbital
ENDOCRINOLOGY TO TDM RABAGO, FRANCZESCA FAITH
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DOPAMINERGIC STIMULANTS (UPPERS)
• Derived from coca plant, also called “CRACK”
COCAINE • Administered thru snorting
• Hepatic metabolism: primary product is benzoylecgonine – cleared within 2 days
• Used as local anesthesia during nasopharyngeal surgery
• Similar effects with androgenic amines, epinephrine and norepinephrine
AMPHETAMINES • Acts as a competitive inhibitor of the enzyme monoamine oxidase (MAO) which inactivates androgenic neurotransmitters
• Crystal meth; MDMA – methylenedioxymethylamphetamine (ecstasy); MDEA – methylenedioxy-N-ethylamphetamine
(Eve)
HALLUCINOGENS
• Analgesic, anesthetic, and stimulant
PHENCYCLIDINE • Interacts with cholinergic, androgenic, GABA-secreting, serotoninergic and opiate neuronal receptors
• Abused therapeutic drug
• Angel dust/hair
METHAQUALONE • Sedative-hypnotic properties
• Anticonvulsant, antispasmodic, local anesthetic, antitussive and weak antihistamine activities
• Semi-synthetic indolalkylamine; potent even in low doses
LSD (LYSERGIC • Acts on presynaptic serotonin receptor, decreasing activity of serotonin
ACID • CNS hyperarousal
DIETHYLAMIDE) • Most commonly abused hallucinogen in the US; effects: panic reactions, bad trip
• Derived from an ergot mushroom
• Oldest and widely used mind-altering drug
MARIJUANA OR • Hashish: more potent product by extraction of the resin from the plant; more concentrated
CANNABIS • Tetrahydrocannabinol (THC): principal psychoactive agent; half-life is 1 week; tested in the URINE

ALCOHOLS
• Most common drug of abuse; has sedative-hypnotic effect
ETHANOL • Metabolized in the liver to form acetaldehyde and acetic acid
• Fatal dose: 300-400 ml taken in less than an hour
• Legally intoxicated: if blood ethanol >1000µg/mL or 100 mg/L (2.1 mmol/L)
ETHYLENE • Predominant ingredient in anti-freeze and car radiators
GLYCOL • 3 toxic metabolites: glycol-aldehyde, glycolic acid, and glyoxylic acid
METHANOL • Metabolized in the liver to form acetaldehyde and formic acid
ISOPROPYL • Metabolized to form acetone
ALCOHOL
• When intoxicated by methanol: antidote is ethanol; methanol itself is not toxic unless converted to formic acid; ethanol consumes alcohol
dehydrogenase to avoid producing formic acid
• Ethylene glycol poisoning: monohydrate calcium oxalate

STAGES OF IMPAIRMENT BY ALCOHOL

BLOOD ALCOHOL (%) SIGNS AND SYMPTOMS
0.01-0.05 No obvious impairment; some changes observable in performance testing
0.03-0.12 Mild euphoria; decreased inhibitions, some impairment of motor skills
0.09-0.25 Decreased inhibitions, loss of critical judgment, memory impairment, diminished reaction time
0.18-0.30 Mental confusion, dizziness, strongly impaired motor skills (staggering and slurred speech)
0.27-0.40 Unable to stand or walk, vomiting, impaired consciousness
0.30-0.50 Coma and death

WHISKEY BLOOD CONCENTRATION INFLUENCE

1-2 10-50 mg/dl None to mild euphoria
3-4 50-100 mg/dl Mild influence on stereoscopic vision and dark adaptation
4-6 100-150 mg/dl Euphoria, disappearance of inhibition, prolonged reaction time
6-7 150-200 mg/dl Moderate severe poisoning, reaction time greatly prolonged, loss of inhibition and slight disturbances
in equilibrium and coordination
8-9 200-250 mg/dl Severe degree of poisoning, disturbances of equilibrium and coordination, retardation of thought
processes and clouding of consciousness
10-15 250-400 mg/dl Deep, possibly fatal, coma

5-PANEL URINE DRUG TEST

• Cocaine
• THC
• Opiates
• Amphetamines
• Phencyclidine

TOXICOLOGY
Study of drugs or poisons encountered in households, environment, industries and in the workplace
ACUTE TOXICITY CHRONIC TOXICITY
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Usually associated with a single, short-term exposure to a substance, the Caused by repeated frequent exposure for extended periods at doses that
dose of which is sufficient to cause immediate toxic effects are insufficient to cause an immediate acute response
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Responds immediately; effect is seen immediately

ENDOCRINOLOGY TO TDM RABAGO, FRANCZESCA FAITH

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ENDOCRINOLOGY TO TDM
REINSCH TEST
Procedure: immerse copper wire in urine specimen for 30 minutes and observe for the stain imparted; specimen: URINE
ANTIMONY SELENIUM MERCURY BISMUTH ARSENIC
Bluish black Gray-silver Silver upon rubbing Shiny Flat gray to black

TOXIC AGENTS/POISONS
• Common suicidal agent; binds iron in ferric state of cytochromes and Hb
CYANIDE • Inhibits cellular respiration by binding with respiratory enzymes of the electron transport system
• Odor of bitter almonds
• Most common gaseous poison
CARBON MONOXIDE • Binds with Hb being 210x stronger than O2 to form carboxyhemoglobin
• Causes tissue hypoxia in brain and heart; shift to the right in the hemoglobin-O2 dissociation curve
• Odorless, tasteless, colorless gas
• Romantic poison, favorite homicidal poison; protoplasmic poison
• High affinity to keratin in hair, nail and outer layer of skin
ARSENIC • Can cause cyanosis, hypotension, tachycardia, ventricular arrhythmia
• Can cross placenta
• Chronic poisoning: HAIR and NAILS
• Garlic odor, metallic taste
• Poisoning occurs when inhaled or absorbed in the skin
MERCURY • Inhibits catecholamine-O-methyltransferase
• Causes respiratory and CNS toxicity; deposits in the kidney
• Interferes with heme synthesis by blocking D-ALA-synthase, ALA-dehydrase, coproporphyrinogen decarboxylase
and ferrochelatase
LEAD • Inhaled or ingested
• Characteristics of INORGANIC LEAD poisoning:
- Increased ALA in urine; decrease ALA activity in RBCs
- Increase FEP; increase zinc protoporphyrin (excellent screening test)
- Microcytic, hypochromic anemia
- Basophilic stippling
• Widely used as pesticides in agriculture
• Interfere with neurotransmission by inhibiting the enzyme acetylcholinesterase which hydrolyzes the neurotransmitter
acetylcholine
ORGANOPHOSPHATE • Aid in respiration; most affected: LUNGS
• Chronic: decreased acetylcholinesterase; Acute: pseudocholinesterase

Symptoms (parasympathetic manifestations):

• Salivation, lacrimation, urination, defecation, papillary constriction, bradycardia

TRACE ELEMENTS AND VITAMINS: deficiency is detrimental; micronutrients

IRON COPPER
• Human body contains around 3-5 grams; approximately 80% is • Normally 50-120 mg; with highest concentration in the liver,
found in RBCs brain, heart and kidneys
• Storage form: Ferritin (reversible); hemosiderin (irreversible; stored • Component of metalloenzymes
in excess) • Transport protein: ceruloplasmin
• Diurnal variation (highest in the morning) • Wilson’s disease: ceruloplasmin deficiency
• Transport protein: transferrin • Menke’s disease: severe copper deficiency
Wilson’s Menke’s
STEPS IN SPECTROPHOTMETRIC IRON DETERMINATION: Serum copper ↓ (serum copper cannot ↓
1. Acidification be seen bc of lack in
2. Reduction transport protein)
3. Colorimetry Serum ↓ ↓ (no ceruloplasmin because
ceruloplasmin of a lack in copper)
+; deposited in liver, Affected keratinization; kinky
Copper brain, kidneys hair
deposits Kayser-Fleischer rings
ZINC CHROMIUM
• Normally the body contains about 2.5 grams mainly found in muscles • Takes part in maintenance of normal metabolism of glucose, fat and
and skeleton cholesterol
• Cofactor to 300 enzymes • Important part of glucose tolerance factor
MANGANESE MOLYBDENUM
• Essential component of metalloenzymes • Occurs as a molybdenite, wulfenite, and powellite
• Serves as an enzyme activator • A cofactor for xanthine oxidase, aldehyde oxidase, and sulfite oxidase

SELENIUM
• Involved in the metabolism of thyroid hormones
• Takes part in the cellular defense against free radicals (oxidizing agents)
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• When exposed to mercury: selenoenzymes are depleted

• KESHAN DISEASE: endemic cardiomyopathy; usually affects children and women of childbearing age
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• KASHIN-BECK DISEASE: endemic osteoarthritis; affects pre/adolescents

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ENDOCRINOLOGY TO TDM
FAT SOLUBLE VITAMINS: longer half-life; stored in adipose tissues, deficiency is not common
VIT A Maintenance of good vision; deficiency: night blindness, growth retardation; RETINOL
VIT D Absorption of dietary calcium; deficiency: hypocalcemia, rickets, osteomalacia; CHOLECALCIFEROL
VIT E Antioxidant of dietary respiration; deficiency: mild hemolytic anemia, ataxia; TOCOPHEROL
VIT K Cofactor of anticoagulants; deficiency: bleeding disorders, hemorrhage; PHYTOMENADIONE

WATER SOLUBLE VITAMINS: easily cleared; deficiency is common

B1 Enzyme cofactor; deficiency: Beri-beri, Wernicke-Korsafoff syndrome; THIAMINE
B2 Enzyme cofactor; deficiency: angular stomatitis, dermatitis, photophobia; RIBOFLAVIN
B3 Enzyme cofactor; deficiency: depressed immune system, muscle weakness; PANTHOTENIC ACID
B6 Enzyme cofactor; deficiency: facial seborrhea; PYRIDOXAL PHOSPHATE
B12 DNA and folate synthesis; deficiency: megaloblastic abnormalities; CYANOCOBALAMIN (for proper DNA synthesis)
- Nuclear plasmic asynchrony (deficiency)
C Hydroxylation of collagen; deficiency: scurvy; ASCORBIC ACID; prone to bleeding disorders from decreased strength of collagen
BIOTIN Enzyme cofactor; deficiency: hair loss, depression, dermatitis
FOLIC Synthesis of amino acids and DNA; VIT B9 (PTEROYLGLUTAMIC ACID)
ACID Deficiency: megaloblastic anemia
NIACIN Enzyme cofactor; deficiency: pellagra; NICOTINIC ACID OR NICOTINAMIDE
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ENDOCRINOLOGY TO TDM RABAGO, FRANCZESCA FAITH