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Handbook of Clinical

Biochemistry
Second Edition

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Handbook of Clinical

Biochemistry
Second Edition

R Swaminathan
St Thomas Hospital, UK

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HANDBOOK OF CLINICAL BIOCHEMISTRY

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Acknowledgement

My sincere gratitude to all who commented and suggested changes.

This include Miss A. Sankaralngam, Dr. Rashim Slota, and many
students who did a special study module (also called student selected
component) with me on the subject of chemical pathology (clinical biochemistry). Special thanks to Ms Julie Clayton who helped with the
manuscript.
Ms. Jihan Abdat of World Scientific Publishing helped in many
ways to get this book published. My sincere thanks to her. Finally, this
book would not have been possible without the help, encouragement
and support from my family (Kamala, Suresh, Abirami and Ramesh).
Any errors and inaccuracies in this book are no ones fault but
mine.

v
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Preface

In writing this revised edition, the overall aim of the book remains the
same as the first edition. The text in this second edition has been thoroughly revised and where necessary, new material has been added.
One of the new features of this edition is the addition of
summary/key points at the end of each chapter to facilitate revision.
Self-assessment questions including traditional multiple choice questions and extended matching questions are introduced at the end to
help with revision and examination preparation.
At the end of each chapter some key references for further reading are given to help readers.

vii
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Contents

Acknowledgement

Preface

vii

Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter

1
2
3
4
5
6
7
8
9
10

Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter
Chapter

11
12
13
14
15
16
17
18
19
20
21
22
23

Interpretation of Biochemical Tests

Disorders of Fluid Balance
Potassium
Disorders of AcidBase Balance
The Kidneys
Calcium Metabolism
Magnesium Metabolism
Disorders of Phosphate Metabolism
Metabolic Bone Disease
Carbohydrate Metabolism and Its
Disorders
Lipids and Lipoproteins
Hypertension and Cardiovascular Disease
Clinical Enzymology
Proteins
The Liver
The Gastrointestinal Tract
Nutrition
Vitamins and Trace Elements
The Hypothalamus and the Pituitary
The Reproductive System
The Adrenal Gland
The Thyroid
Clinical Biochemistry of Haematology

1
23
59
81
111
157
191
205
219
237
273
299
325
349
379
413
433
451
475
497
523
553
577

ix
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Contents

Chapter 24
Chapter 25
Chapter 26
Chapter 27
Chapter 28
Chapter 29

Malignancy and Clinical Biochemistry

Therapeutic Drug Monitoring
and Toxicology
Inherited Metabolic Diseases
Disorders of Purine Metabolism
Clinical Biochemistry in Paediatrics
and Geriatrics
Cerebrospinal Fluid and the Nervous System

599
623
655
673
687
709

Questions and Answers

719

Index

765

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chapter

Interpretation of Biochemical Tests

Introduction

iochemical tests are now an important part of investigation and

management of patients. Understanding the factors which influence laboratory results and how laboratory results could be used for
the diagnosis and treatment, is important for the rational and effective use of laboratory tests. As with other investigations, biochemical
results should be taken in the context of patients clinical features
(signs and symptoms) and other relevant findings.
Biochemical tests are performed for four main reasons diagnosis, management, prognosis and screening. When used appropriately,
biochemical tests can contribute substantially to the overall care of the
patient. However, when used inappropriately, it can lead to unnecessary further investigations, pain and suffering to the patient and
increased costs to the health service.
Diagnosis
Clinical diagnosis is usually based on history, physical examination
and results of investigations. History and examination are the important elements in arriving at a diagnosis and studies show that up to
80% of cases can be diagnosed from history and clinical findings
alone. Biochemical tests very often help to confirm the diagnosis or
identify a metabolic syndrome. Seldom are they diagnostic except in
a few instances, such as inherited disorders of metabolism.

1
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Chapter 1

Management
Biochemical tests are most often used in the management of patients.
Approximately 6070% of all biochemical tests are used for monitoring
treatment or to follow the progress of the disease. Serial measurements are valuable in management, e.g. in patients with diabetic
ketoacidosis, frequent measurements of blood glucose help to assess
the response to insulin and to adjust dosage; in hypothyroid patients
on thyroxine replacement therapy, regular measurements of thyroid
function tests guide the adequacy of thyroxine replacement.
Biochemical tests are also useful in assessing the severity of the
disease. The degree of abnormality in biochemical tests is (usually but
not always) related to the severity of the disease. For example, in renal
failure, the greater the plasma urea and creatinine, the more severe the
reduction in renal function.
Prognosis
Biochemical tests, either individually or in combination, can give an
indication of the prognosis, e.g. in patients with malignant tumours,
serial measurements of tumour markers are of value in assessing the
response to treatment and the possibility of recurrence.
Screening
When tests are done to detect the presence of a disease before clinical
features are evident, it is described as screening. Screening may be
applied to a population (population screening), to a selected subgroup of a population (selective screening), individuals (individual
screening) or it could be opportunistic.
Population screening
These tests are done in an apparently healthy population to identify
those who may have subclinical disease or those who are at risk of

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Interpretation of Biochemical Tests

developing a disease. Population screening programmes should satisfy

the following criteria:
1. The disease should have a significant effect on the quality of life
or life expectancy, e.g. screening for Gilberts syndrome, an inherited disorder of bilirubin metabolism, is of no value as it has no
long-term effect on the health of the patient.
2. The screening test can detect the disease before irreversible damage has occurred.
3. Effective treatment is available and is acceptable for asymptomatic
patients.
4. The screening test should be effective (specific and sensitive) and
acceptable to the population to be screened.
5. The prevalence of the disease and the benefits of treatment should
justify the cost of screening.
6. The population at risk can be defined.
Unequivocal benefits of screening have only been established for
a few conditions. These include screening for phenylketonuria and
hypothyroidism in the newborn and cervical screening for the detection of cervical carcinoma.
Selective screening
Screening can also be applied to a subgroup of the population known
to be at risk of developing that disease, e.g. family members of a
patient with hypercholesterolaemia or premature coronary heart
disease could be screened for high cholesterol.
Individual screening
Here an individual is screened for a particular disease or diseases based
on the individuals history. An example is antenatal screening of a foetus for inherited disease when a previous child of the parents has been
found to have that disease or when there is a strong family history of
that disease.

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Chapter 1

Opportunistic screening
Opportunistic screening is when a patient is screened for certain diseases
when he presents to the doctor with an unrelated condition, e.g.
detection of hypertension.

Other Uses of Laboratory Tests

Biochemical profiling
With the availability of multichannel analysers, it is now possible to
analyse a small blood sample for a large number of biochemical tests.
When a group of tests is applied to otherwise healthy individuals or
to all admitted to hospitals, it is termed biochemical profiling. In
general, this type of approach has caused more harm than good as the
efficiency of detection of a disease is low. Unnecessary investigations
may follow when non-specific abnormalities in test results are found.
It has been argued that admission profiling can detect potentially
treatable diseases at an early stage. Diseases that can be detected by
screening hospital patients include hyperparathyrodism, hypothyroidism, diabetes mellitus, renal disease and liver disease (alcoholism).
However, the value of such admission screening is yet to be established as this approach can detect diseases, which may not manifest in
the lifetime of the patient.

Baseline
Biochemical tests are often also used as a baseline before starting
treatment to detect any harmful effects of treatment or to monitor the
treatment.

Collection of Specimens
Biochemical investigations are done in body fluids, most often in
plasma or serum. It is essential that blood samples are collected
appropriately to prevent artefacts. In patients receiving intravenous
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Interpretation of Biochemical Tests

therapy, blood should be collected from a different site to avoid

contamination of the blood sample with the infusion fluid.
Tourniquet is often used to obstruct venous blood flow in order to
make the venepuncture easy. However, if the tourniquet is applied too
long, the increased pressure will cause transfer of water and small
molecular weight constituents into the interstitial compartment. This
will often result in an increase in the concentration of large molecular
weight substances such as proteins and in protein-bound substances
such as calcium in the serum sample.
While transferring the blood from the syringe into the bottle, care
should be taken to avoid haemolysis.
Once the blood is taken, it should be put into appropriate bottles
containing the appropriate preservatives. Most investigations are
now done in serum. However, there are some investigations for
which plasma is required, e.g. measurement of fibrinogen requires
plasma. Inappropriate use of anticoagulants has often led to spurious
results, e.g. taking blood sample for electrolytes into an EDTA tube
will cause very high potassium and low calcium concentrations.
Blood for the measurement of glucose concentration should be
taken into a fluoride tube; otherwise the blood glucose will artificially decrease due to continued glycolysis by red cells. Once the
blood is collected, it should be transported to the laboratory within
a specified time to prevent artificial results, e.g. if the blood sample
is left at room temperature for several hours, it will lead to high
potassium concentration. Storing samples below room temperature
has similar effects.
Some investigations are done in urine a random or a 24-hour
urine collection. Appropriate preservatives should be used to avoid
artefactual results, e.g. urine for calcium should be collected in a container with acid preservative to prevent precipitation of calcium
phosphate. When 24-hour samples are required, patients should be
given appropriate instructions on how to collect the urine samples. In
investigations done on 24-hour samples, the most important source of
error is incomplete urine collection. Measurement of urine creatinine
concentration is sometimes used to check whether urine collection is
complete.
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Chapter 1

Identification of Patient Specimens

It is essential that the sample is collected from the correct patient.
Many errors have occurred due to improper identification of the
patient. Once collected, the sample should be correctly labelled and
accompanied by a properly completed request form.

Interpretation of Laboratory Results

In interpreting laboratory results, one of two questions is usually
asked:
(i) Is the result normal or abnormal?
(ii) Has the result changed significantly from a previous result?
In answering the first question, the result is compared to a range
(reference range).
Reference Ranges
Reference ranges can be either population-based or risk-based.
Population-based reference ranges
To determine the population-based reference range, blood samples
are taken from a defined population usually healthy individuals,
but it can be from any defined population. If the analyte concerned is
known to be affected by sex and age, the population should be
divided according to these two factors. Once the blood is analysed, the
results are examined to see whether it follows a Gaussian (symmetrical)
distribution. If the result fails to follow a Gaussian distribution, transformations such as a log transformation can be done. The reference
range is calculated as mean 2 standard deviation (SD), but often the
range is taken as the value that represents 95% of the population
(2.597.5%) when the values are ranked. This type of reference range
excludes 5% of the population who are apparently healthy. It is also possible that some subjects with an undiagnosed disease may be included

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Interpretation of Biochemical Tests

in the population used to establish the reference range (for example,

undiagnosed diabetes mellitus).
The probability of finding abnormal results in a healthy population increases if multiple tests are done at the same time, especially if
the tests are not dependent on each other. If 20 independent tests are
done, the probability of finding at least one result outside the reference value is 64%.
Risk-based reference range
Reference range is sometimes based on disease risk. The reference values for cholesterol are based on the risk of developing coronary heart
disease. Epidemiological studies have shown that a cholesterol value
of 4.0 mmol/L or lower carries a low risk of coronary heart disease.
It is important to remember that results within the reference
range do not exclude disease and results outside the reference
range do not always indicate the presence of a pathological disease.
However, the more abnormal the result, the greater the chance that
there is a disease process. The diagnosis is seldom based solely on
biochemical results. Test results should be taken in conjunction with
clinical findings and usually there is no absolute demarcation or cutoff values between disease and normal.
Detection of a Significant Change
The second question asked about a test result is whether there is a
significant change from a previous result. In deciding whether a significant change has occurred, several factors need to be taken into
account. These include analytical variation, biological variation
related to the time of sampling and the procedure used. Ideally biological variation should be minimised by taking the sample under
identical conditions of time, posture, etc. Other preanalytical factors
should be minimised by using exactly the same techniques. When
these factors are minimised, the variation between two results
depends on the imprecision of the assay. If the difference between two
results is equal to or more than 2.8 times the standard deviation (SD)
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Chapter 1
Table 1.1

Calculation of total variation

Serum free thyroxine concentration measured in a subject 2 months

apart were 12 and 18 pmol/L. Is this difference significant?
The analytical variation for free thyroxine measurement is 1 pmol/L
and the biological variation 1.2 pmol/L.
Total variation = (SD2A + SDI2) = (12 + 1.22),
= (1 + 1.44) = 2.44 = 1.6.
For a difference between two values to be significant at 5% level, the
two results should be greater than 2.8 the total variation.
In this case, 2.8 1.6 = 4.48.
The difference observed is 6 pmol/L and therefore this change is
clinically significant.

of the method, the difference is significant at 5% confidence limit. For

example, if the analytical SD for serum sodium is 2 mmol/L, a change
less than 5.6 mmol/L is within the limit of the analytical variation.
In order to decide whether the change is clinically significant,
biological variation should be taken into account. Total variation (biological and analytical) is calculated from the analytical and biological
variations using the formula:
SD2Total = SD2A + SD2I
where SDTotal is the total variation, SDA is the SD of analytical variation
and SDI is the SD of biological variation (Table 1.1).

Factors Affecting Test Results

Test results can be affected by preanalytical, analytical and postanalytical factors. Preanalytical factors may be biological factors or factors
related to the collection of specimen. The latter has already been
discussed.

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Interpretation of Biochemical Tests

Biological Factors (Table 1.2)

Age
Many biochemical variables vary with age, and an appropriate agerelated reference range should be used to interpret results of these
tests. Examples of tests which vary with age include alkaline phosphatase, phosphate and gonadotrophins.
Sex
Tests such as sex hormones, serum creatinine, urate and GGT show
differences between sexes.
Body composition
Body fat and lean body mass can influence some results. Creatinine
and creatine kinase, which are derived from muscle, are said to be
related to muscle mass. Triglycerides tend to be higher in obese
individuals.

Table 1.2

Biological factors affecting biochemical results

Factors
Age
Sex
Body composition
Race/Ethnicity
Time
Posture
Stress
Food intake
Alcohol
Exercise
Drugs in vivo effects

Biochemical tests
Alkaline phosphatase, uric acid, creatinine
Gonadotrophins, gonadal steroids, creatinine
Creatinine, creatine kinase, triglycerides
Creatine kinase, prostate specific antigen
Cortisol
Protein, renin, aldosterone
Prolactin, cortisol
Glucose, triglycerides
Triglycerides
Creatine kinase
Phenytoin gamma-glutamyl transferase
Thiazides potassium
Oestrogens sex hormone-binding globulin

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Chapter 1

Ethnicity/race
The range found in healthy individuals from different ethnic groups
vary for some analytes. Prostate specific antigen (PSA) is higher in
African Americans and lower in Japanese compared to Caucasians.
Serum creatine kinase (CK) values in African Americans are higher
than in Caucasians.
Time of day
Cortisol, osteocalcin, parathyroid hormone, etc. show a circadian
rhythm. Some analytes show seasonal changes, e.g. plasma 25hydroxycholecalciferol.
Stress
Stress causes the release of cortisol, ACTH, prolactin, growth hormone, catecholamines, etc. Thus, it is very important to avoid stress
when taking samples for these measurements.
Posture
Posture increases aldosterone and renin activity. Plasma proteins and
protein-bound compounds tend to be higher on attaining a standing
posture. This is due to the movement of fluid from the vascular compartment to the interstitial compartment.
Food intake
Glucose, triglycerides and insulin are examples of substances affected
by food.
Drugs
Drugs can influence results by either interfering with the analysis
or by physiological mechanisms. For example, in patients taking
phenytoin, serum gamma-glutamyl transpeptidase (GGT) is higher
due to enzyme induction.
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Interpretation of Biochemical Tests

11

Exercise
Exercise and trauma release CK and myoglobin.

Intrinsic biological variation

Although many biochemical variables are tightly controlled, there is
variation within an individual. This individual variation is small for
some analytes and large for others. For example, serum iron concentration fluctuates rapidly within the same individual whereas serum
sodium, creatinine and calcium concentrations show less variation
(Figure 1.1). For analytes which have a low intraindividual variation,
the serum concentration may change within the reference range and

Figure 1.1 Within individual variation for (a) serum creatinine and (b) serum iron
in four individuals. The circle represents the mean for the individuals and the lines
indicate the range found in that individual (adapted from Fraser and Stevenson, 1998
with permission).

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Chapter 1

become abnormal for that individual. For analytes with low intraindividual variation, population reference ranges are less useful.
Analytical Factors
All analytical methods have errors inaccuracy and imprecision
(Figure 1.2). Inaccuracy refers to how close the result is to the true
value. Imprecision refers to the reproducibility of the result and is
usually expressed as coefficient of variation. To estimate imprecision,
a sample is analysed several times and the mean and standard deviation (SD) are calculated. Coefficient of variation (CV) is derived using
the formula:
CV =

SD
100.
Mean

The Diagnostic Value of an Investigation

The diagnostic value of a test is described in terms of sensitivity, specificity and predictive value. The sensitivity of a test is the frequency
with which a positive result is found in patients known to have the disease i.e. true positive (TP) rate. The specificity of a test is a measure
of the frequency of negative results in patients (or persons) known to
be free of the disease, i.e. true negative (TN) rate. A sensitivity of 90%
implies that 90% of patients with the disease will have a positive result
and 10% of people with disease will not show a positive result; a false
negative (FN) result. A specificity of 95% means 95% of people without the disease will show a true negative result and 5% of the

**
Precise but inaccurate

Figure 1.2

*
Imprecise and inaccurate

Precise and accurate

Diagram illustrating accuracy and imprecision.

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Interpretation of Biochemical Tests

13

population without the disease will have a positive result, a false positive (FP) result. An ideal test should be 100% sensitive and 100%
specific. However, in practice, no such test exists. Specificity and
sensitivity can be calculated from the following formulae:
true negative
100.
false positive + true negative
true positive
100.
Sensitivity =
true positive + false negative

Specificity =

The predictive value of a positive test is a measure of the likelihood

of having the disease under consideration when the test is positive.
The predictive value of a negative result is the likelihood of not having the disease when the test result is negative. In determining the
specificity, sensitivity and predictive values, it is important to be able
to assign subjects to the right categories, i.e. patients should be allocated to a particular disease based on independent diagnosis. For
some diseases, histological confirmation may be the only way of
confirming the diagnosis. Calculation of predictive values is illustrated
in Table 1.3.
In the preceding discussion, it has been assumed that the prevalence of the disease is 50%. When establishing the diagnostic value
of a new test, it is not unusual to apply the test to selected groups
of equal sizes a group with the disease and a control group a
prevalence of 50%. In clinical practice however, the test will be
applied to a larger number of people where the prevalence will be
lower. The example given in Table 1.4 illustrates the effect of prevalence on the predictive value of a test, which has a sensitivity of 99%
and specificity of 99%. When the prevalence is 50%, the predictive
value of a positive result is 99%. However, when the prevalence is
1%, the predictive value falls to 50%. The predictive value of a test
falls with decreasing prevalence. One way of improving the efficacy
of a test would be to use the tests more selectively, i.e. by applying
the test only on sound clinical grounds, thus increasing the prevalence of the disease.
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Chapter 1
Table 1.3

Calculation showing predictive value of a test

TP
100.
TP + FN
TN
Specificity =
100.
TN + FP
TP
100.
Predictive value of a positive result =
TP + FP
TN
Predictive value of a negative result =
100.
TN + FN
TP + TN
100.
Efficiency =
(TP + FP + TN + FN)
Sensitivity =

Example

Disease
Health

Positive

Negative

Total

(TP) 90
(FP) 5
95

(FN) 10
(TN) 95
105

100
100
200

*TP = True positive; TN = True negative;

FD = False positive; FN = False = negative.

90
100 = 94.7%.
(90 + 5)
95 100
95
= 90.5% =
100 = 90.5% .
Predictive value of a negative result =
(95 + 10)
(95 + 10)
Predictive value of a positive result =

Efficiency =

(90 + 95)
100 = 92.5%.
200

Cut-off Value
In the discussion thus far, the test result was designated as positive or negative. As biochemical results are usually quantitative, the cut-off value, the
concentration at which the test is considered as positive, can be varied.
Selection of the cut-off value will depend on the purpose of the
test. In circumstances where the consequences of not diagnosing the
diseases is great, it is important to select a cut-off value so as not to
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Interpretation of Biochemical Tests

Table 1.4

15

Effect of prevalence on the predictive value

Sensitivity of the test = 99%
Specificity of the test = 99%

Population of 1000 with a prevalence of 50%

+ve results

ve test

Total

Disease
Without the disease

4950
50

50
4950

5000
5000

Total

5000

5000

10,000

Predictive value of a +ve result =

4950
100 = 99%
4950 + 50

Prevalence of 1% Population 10 000 with a prevalence of 1%

Disease
Without the disease
Total

+ve results

ve test

Total

99
99

1
9801

100
9900

198

9802

10,000

Predictive value of a +ve result =

99
100 = 50%
99 + 99

miss any individual with the disease, i.e. to keep false negatives as low
as possible. Hence, a lower cut-off value to ensure a sensitivity of
100%, should be chosen. An example of this situation is in the screening for phenylketonuria (PKU), when missing the diagnosis of PKU
has grave consequences. This approach however, will reduce specificity and will give a larger number of false positive results. In
circumstances where it is important not to cause unnecessary anxiety
and investigations, a high specificity is required and a high cut-off
value should be selected.
To compare the performance of two tests, receiver operating characteristic (ROC) curves can be used. The sensitivity and specificity at
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Chapter 1

Figure 1.3 Receiver operating characteristic (ROC) curve for prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) in the diagnosis of prostatic carcinoma.
The area under the curve for PSA is greater than PAP showing the PSA is a better test.

different cut-off values for each test are calculated and plotted as
shown in Figure 1.3. The area under the curve is a measure of the performance the greater the area under the curve, the more specific
and sensitive the test.
Likelihood Ratios
Likelihood ratios are an alternative way of summarising the usefulness of a diagnostic test. The ratio tells us how many more (or less)
times patients with the disease are likely to have that particular
result than patients without the disease. Likelihood ratios can be
calculated for a positive (LR+) or a negative (LR) results by the
following equations:
The likelihood for a positive result is calculated as
LR + =

sensitivity
.
1 - specificity

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Interpretation of Biochemical Tests

17

The likelihood for a negative result is calculated as

LR - =

1 - sensitivity
.
specificity

The higher the likelihood ratio of a positive result, the greater the
chances of finding the disease. Likelihood ratios above 10 and below
0.1 are considered strong evidence to rule in or rule out diagnoses
respectively.

General Principles
Steady State vs. Transient State
In order to understand the pathophysiology of diseases, it is important to explain the difference between steady state and transient state.
This principle can be illustrated by the following case example:
In a patient with chronic renal failure, the following blood results
are found:
Sodium (mmol/L)
Potassium (mmol/L)
Bicarbonate (mmol/L)
Chloride (mmol/L)
Urea (mmol/L
Creatinine (mol/L)

138
5
18
102
35
565

135145
3.55.0
2332
90108
3.57.2
4060

If students are asked about the urinary excretion of creatinine in this

patient, most students will say that the excretion of creatinine will be
low due to the low glomerular filtration rate. Similarly, if students
were asked about the excretion of carbon dioxide in a patient with
chronic obstructive airways disease, most would answer that it would
be decreased and the arterial partial pressure of carbon dioxide is
increased. However, in both these examples, it is likely the excretion
will not be low as these patients are in a steady state. This can be
explained using the diagram below (Figure 1.4).
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Chapter 1

Figure 1.4 Theoretical changes in plasma concentration, GFR, production rate

and urinary excretion of creatinine before and after a reduction in GFR. (Reproduced
with permission.)

When the patient is healthy, the amount of creatinine excreted is

equal to the amount produced (which depends on the persons muscle mass). As creatinine is excreted by filtration without reabsorption
or significant secretion, the amount excreted is equal to the amount
filtered (Equation 1).
Amount produced = amount excreted = amount filtered,
= GFR plasma creatinine.

(1)

If the GFR falls, the amount filtered will fall resulting in less excretion. This will increase the plasma concentration. As the plasma
concentration increases, the filtered amount will increase thus excretion will increase. Eventually, the amount excreted will be equal to the
amount produced, and the plasma concentration will be steady at a
higher value. In this new steady state, input (production of creatinine
in this case) will be equal to the output (urinary excretion).
In the steady state if there is a transient increase in input (e.g. sudden increase in potassium intake), the plasma concentration and the
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Interpretation of Biochemical Tests

19

Figure 1.5 Changes in plasma concentration, input and output with time of potassium following a transient increase in input, (a) in the normal steady state and (b) in
an abnormal steady state; chronic renal failure with reduced glomerular filtration rate.

excretion will increase until the load is excreted and the plasma concentration will come back to the previous level (Figure 1.5a). If the
steady state is an abnormal one (like the patient with chronic renal
failure described above), the increase in plasma concentration will
be greater and it will take a longer time before the steady state is
re-established (Figure 1.5b).
The following general principles will be of help in the understanding of changes in plasma concentration:
1. A change in plasma concentration of a substance is the result of
either a change in input rate (production or intake) or due to a
change in the output rate (metabolism or excretion).
2. When the steady state is disturbed, plasma concentration and output will change until input and output are equal a new steady
state.
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Chapter 1

3. In the steady state, irrespective of weather, this is a normal or

abnormal state, input and output are equal.
4. A transient increase in input when the steady state is abnormal will
be handled at a different rate than when the steady state is normal.
Concentration vs. Amount
Most clinical biochemistry investigations are done in plasma or serum
and what is measured is the concentration. A change in concentration
of an analyte can be due to a change in the amount of substance in
plasma or due to a change in the volume of fluid. It is a common mistake to assume that when the plasma sodium concentration is low, the
amount of sodium in the body is low. However, very often a low
plasma sodium concentration is due to an increase in water content.
Concentration vs. Activity
In many circumstances, we measure the total concentration of a substance in serum or plasma. However, the substance may be partly
bound to proteins, and very often, it is the unbound or free analyte
which is the physiologically important fraction. For example, calcium
in serum is bound to proteins (mainly albumin) and the physiologically active form is ionised calcium. The total concentration however,
may change due to changes in the binding protein concentration, e.g.
in pregnancy, the concentration of binding protein for thyroxine
increases due to increased synthesis and this will cause the total
thyroxine concentration to be high with normal free thyroxine concentration. Therefore, in interpreting the total concentration of an
analyte, it is important to bear in mind that the total concentration
may change without a change in the active fraction.
Urinary Excretion
When the excretion or concentration of a substance is measured in
the urine, it is important to remember that there is no reference
range. This is particularly true for urine electrolytes, urea and
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Interpretation of Biochemical Tests

21

osmolality. The concentration of electrolytes in serum is highly regulated such that, if there is a change in serum concentration,
homeostatic mechanism(s) will return the serum concentration
back to the original value. Urinary excretion, on the other hand, is
a method of regulating plasma concentration. Therefore, one
cannot determine a reference value for it. In the steady state,
urinary excretion is a reflection of input. In the case of electrolytes,
it is a reflection of intake. For example, a urinary excretion of
100 mmol/d of sodium implies that the person is taking 100 mmol
per day of sodium . On the other hand, if we know that the person
is taking 50 mmol of sodium per day, a urinary excretion of
100 mmol/d of sodium tell us that he is losing sodium through his
kidneys. Interpretation of urinary values should be done in relation
to the input (intake) and/or in relation to the clinical state. For
example, if a person is volume depleted (extracellular volume is
low), the bodys response is to increase sodium reabsorption and the
urinary exertion should be very low (usually < 20 mmol/L or d).
Any value higher than this implies that the person is losing sodium
through his kidneys.

Further Reading
1. Fraser CA, Stevenson HP. Production and use of data on biological variation in laboratory medicine. CPD Bulletin in Clin Biochem 1998; 1: 1417.
2. Fraser CA. Biological Variation: From Principles to Practice 2001. AACC
Press.
3. Payne RB, Morgan DB. Sodium, water and acidbase balance: Teaching
transient and steady states. Med Educ 1977; 11:133135.

Summary/Key Points
1. Biochemical tests are useful in the diagnosis, monitoring, screening and prognosis of disease. Most biochemical tests are done for
monitoring treatment or to detect complications of treatment.
Biochemical screening of healthy subjects are of little value except
in a few well-defined situations.
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2. A test result can vary due to biological and analytical variation.

Analytical variation or imprecision is assessed by the standard
deviation (or coefficient of variation).
3. When interpreting results, they are usually compared to a reference range, which encompasses 95% of values in a healthy
population. For analytes such as serum cholesterol and serum
25-hydroxyvitamin D concentration, this approach is not valid
and risk-based value is used to compare results.
4. A test result within the reference range does not necessarily imply
that there is no disease and a test result outside the reference
range does not indicate disease.
5. Tests results can vary due to many physiological factors such as
age, gender, ethnicity, time of day, body size, etc.
6. Even when these physiological factors are controlled, there is
intrinsic variation within an individual. This intraindividual variation is large for some analytes (e.g. iron, cortisol) and low for
others (e.g. sodium, calcium and thyroxine).
7. For an analyte with low within person biological variation, a change
within the reference range is potentially clinically significant.
8. The diagnostic value of a test is described by sensitivity (percentage of positive results in a group with the disease) and specificity
(percentage of negative results in a group without the disease).
The predictive value of a test is influenced by the prevalence of the
disease in the population. For a disease with low prevalence, even
a test, which is highly specific and sensitive, will give a large number of false positives.
9. The value of two tests can be compared using the receiver operating characteristic curves (ROC) in which specificity is plotted
against sensitivity.

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chapter

Disorders of Fluid Balance

Introduction
Distribution and Composition of Body Fluids

ater accounts for approximately 60% of body weight in young

men and 55% in young females. In newborn infants, the total
body water (TBW) may be as high as 75% of body weight and it
progressively reduces to 60% of body weight by 10 years of life. TBW,
as a percentage of body weight, decreases steadily with age and in
obesity. In obese subjects, it can be as low as 45%. Expressed as a
percentage of lean body mass, total body water accounts for 75% of
lean body mass in adults.
Water is distributed between intracellular (ICF) and extracellular
(ECF) compartments separated by the cell membrane. The extracellular
compartment is further divided into plasma water, interstitial water (outside the circulation) and a small amount of transcellular water which is
water in specialised spaces such as cerebrospinal fluid space, pleural space,
synovial space, intra-ocular spaces and the lumen of the gut (Table 2.1).
Composition of Extracellular Fluid
The main extracellular cation is sodium (Table 2.2). Concentration of
ions in plasma is usually expressed as mmol/L of plasma. However, these
ions are distributed in plasma water which forms only 93% of plasma.
Hence, the concentration of ions in plasma water is higher (sodium concentration in the plasma water is 153 mmol/L). If the amount of solids
(proteins and lipids) is grossly elevated, as in hyperlipidaemia or hyperproteinaemia, the concentration of ions expressed per litre of plasma may
23
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Chapter 2
Table 2.1

Distribution of body water in a 70-kg adult man

Volume (L)

% of body weight

42
28
14
3
10
1

60
40
20
5
14
1

Total Body Water

Intracellular Water
Extracellular Water
Plasma Water
Interstitial Water
Transcellular Water

Table 2.2

Composition of intracellular and extracellular compartments (mmol/L)

Extracellular fluid
Intracellular fluid

Plasma/Serum

Interstitial

Cations
Sodium
Potassium
Calcium (ionised)
Magnesium (ionised)

10
160
1
13

140*
4
1.2
1.0

145
4
1.2
1.0

Anions
Chloride
Bicarbonate
Phosphate & others
Protein

3
10
106
65

102
27
1.0
16

117
27
1.0
0

Total

368

292

302

*Concentration in plasma water is 153 mmol/L.

be artificially low (i.e. pseudohyponatraemia). The concentration of

sodium in plasma and interstitial fluids are very similar the small
difference is accounted for by the Gibbs-Donnan equilibrium due to the
presence of a higher protein concentration in plasma.
The total volume of transcellular fluid at any one time is small
about one litre. However in the gastrointestinal tract, a much larger
volume (58 litres) is secreted and reabsorbed each day (Table 2.3).
In pathological states, e.g. diarrhoea, fistula and vomiting, the loss of
these fluids can produce serious fluid and electrolyte abnormalities.
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Disorders of Fluid Balance

Table 2.3

N+
K+
Cl+
HCO3

25

Composition of transcellular fluids (mmol/L)

Saliva

Gastric
juice

Bile
fluid

Pancreatic
fluid

Ileal
fluid

Colonic
fluid

Sweat

2080
1020
2040
2060

20100
510
120160
0

150
510
4080
2040

120
510
1060
80120

140
5
105
40

140
5
85
60

65
8
39
16

Composition of Intracellular Fluid

The main intracellular cations are potassium and magnesium while
the main intracellular anions are phosphate and proteins (Table 2.2).
The sodiumpotassium pump maintains low intracellular sodium and
high potassium concentrations. The higher total ion concentration in
ICF compared to ECF (368 vs. 300 mmol) is due to the GibbsDonnan effect of high concentration of non-diffusible anions
proteins and organic phosphate.

Distribution of Water between ICF and ECF

Osmotic forces chiefly determine the movement of water across the
cell membrane, which are freely permeable to water. Cell volume,
which is essential for normal cell functions, is thus regulated by the
regulation of plasma osmolality.

Osmolality
Osmolality is the number of osmoles per kg of water and osmolarity
is number of osmoles per litre of solution. In clinical practice, the difference between osmolality and osmolarity is negligible.
The number of particles dissolved in body fluids determines its
osmolality, which is held within narrow limits. In the ECF, sodium
and its anions are the major contributors to osmolality. Plasma
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Chapter 2

osmolarity can be calculated from plasma electrolytes, glucose and

urea:
Calculated plasma osmolarity = 2[Na+ + K+] + glucose + urea.
(All in mmol/L)
In most circumstances, the calculated osmolarity and measured osmolality differ very little. However, in the presence of unmeasured osmotically
active molecules (e.g. alcohols, mannitol, etc.) or in the presence of
excessive lipids or proteins, which may cause pseudohyponatraemia, calculated values will be lower than measured osmolality. This difference is
sometimes referred to as an osmolar gap.
Although sodium, glucose and urea contribute to the osmolality
of ECF, not all of these molecules are physiologically active.
For example, urea is diffusible across the cell membrane and therefore
an increase in osmolality produced by high concentration of urea does
not cause movement of water. Effective osmolality or tonicity of ECF
is mainly due to sodium and it anions.
If water is added to the ECF, osmolality of ECF will decrease and
water will move into cells, resulting in an increase in the volume of ICF
and ECF until the osmolalities are equal (Figure 2.1a). On the other
hand, if isotonic saline is added to ECF, osmolality of the ECF will not
change and the ECF volume will increase without changing ICF volume (Figure 2.1b). Loss of water will cause a decrease in ICF and ECF,
while loss of isotonic saline will cause a decrease in ECF only. If sodium
(without water) is added to ECF, osmolality of the ECF will increase
and this will result in water moving out of cells, causing an increase in
ECF and a decrease in ICF volume. These experiments illustrate that
the plasma sodium concentration does not reflect ECF volume changes.
Plasma sodium concentration is a reflection of the water content. On
the other hand, the amount of sodium determines the ECF volume.

Regulation of Total Body Water

Total body water is regulated by the intake and excretion of water,
which are in turn determined by osmolality. Typical values for water
intake and output in a normal adult man are illustrated in Table 2.4.
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Disorders of Fluid Balance

ICF 28L

Addition of 3 L of water

ECF 14L

27

ICF 30L

ECF 15L
(a)

ICF 28L

Addition of 3 L of saline

ECF 14L

ICF 28L

ECF 17L

(b)
Figure 2.1

(a) Addition of 3 L of water. (b) Addition of 3 L of isotonic saline.

Table 2.4

Typical water balance in a normal adult man

Intake (ml/d)

Water in diet
Ingestion of water
Water of oxidation

850
1400
400

Total

2600

Output (ml/d)
Urine
Skin
Respiratory tract
Faeces

1500
500
400
200
2600

Water loss through the skin and lungs (insensible loss) is

determined by thermoregulation. Evaporation of water accounts
for approximately a quarter of the heat lost from the body.
Of the 1500 mls of urine, a small proportion (500 ml) is obligatory loss, which is required to excrete the osmolar load. This
obligatory amount of urine volume increases with the demand for
solute excretion (e.g. during intake of a high protein diet). Thus
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approximately 1.5 litres of water is obligatory loss. As 500 ml of

water is produced as a result of metabolism, about 1 litre of water
intake is obligatory.
Water intake and output are controlled by osmoreceptors in the
hypothalamus via influences on thirst and the secretion of antidiuretic
hormone (ADH/AVP). An increase in plasma osmolality (sodium) of
as little as 1% will stimulate thirst and increase ADH secretion. Other
stimuli to thirst are a decrease in ECF volume and angiotensin II. A
small decrease in the ECF volume does not cause thirst or increased
ADH secretion, whereas a decrease greater than 10% to 15% in blood
volume or ECF volume will. Angiotensin II is also an important stimulus for thirst and it acts directly on the brain, causing an increase in
water intake.
ADH regulates water reabsorption at the collecting tubules of the
kidney. Isotonic fluid reabsorption occurs in the proximal segment of
renal tubules. This is followed by the production of a hypotonic fluid
as a result of the countercurrent mechanism. In the collecting tubules,
in the presence of ADH, water will move out due to the high osmolality of the medulla. By this mechanism, osmolality of the urine can
be altered from 50 to 1400 mosmol/kg. The ability of the kidney to
alter the osmolality of the urine depends on several factors and these
are listed in Table 2.5. Osmotic diuresis, e.g. due to the presence of
glucose in urine, prevents the development of medullary hyperosmolality thus, urine cannot be concentrated or diluted (Figure 2.2).
When the osmolar load is high, the ability to dilute as well concentrate the urine is limited and the urine osmolality is fixed close to that
of plasma (Figure 2.2).

Table 2.5 Factors essential for the production of

hypertonic urine
Adequate fluid reaching the loop of Henle
Countercurrent mechanism
Presence of ADH
Responsiveness of collecting tubular cells to ADH
Medullary hyperosmolality

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29

1400
1200
URINE CONCENTRATION
mOsm/Kg

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Disorders of Fluid Balance

1000
800
600
400

Maximal ADH
Plasma

200
No ADH

0
2

Figure 2.2

6
8
10
SOLUTE EXCRETION
mOsm/min/1.73m2

12

14

Effect of osmotic diuresis on urine concentrating and diluting abilities.

Table 2.6 Factors influencing the secretion of

antidiuretic hormone
Osmolality
ECF volume
Nausea
Pregnancy
Hypoglycaemia
Drugs alcohol, nicotine, morphine

Secretion of ADH is also stimulated by non-osmotic factors such

as volume depletion and stress (e.g. surgery or trauma) (Table 2.6).
One of the important non-osmotic stimuli for ADH secretion is
ECF volume depletion. Figure 2.3 shows the ADH response to
volume depletion and changes in ECF osmolality. A small change
in ECF volume does not cause an increase in the secretion of
ADH but a large decrease in ECF volume (greater than 15%) will
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25

PRESSURE

20
BASAL
Plasma ADH (ng/L)

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VOLUME
OSMOLALITY
15

10

0
30

20
10
0
Percentage change (%)

10

Figure 2.3 Effect of changes in ECF volume, blood pressure and osmolality on the
secretion of ADH.

result in a dramatic increase in ADH secretion. Hypotension has a

similar effect to that of hypovolaemia (Figure 2.3). Surgical stress is a
common cause of an increase in ADH secretion in hospitalised
patients. Nausea, but not vomiting, is a powerful stimulus for ADH
excretion.

Regulation of ECF Volume

ECF volume is determined by the amount of body sodium, which in
turn is regulated primarily through renal sodium excretion. A normal
70-kg adult man has approximately 4000 mmol of sodium, most of
which is in the ECF. About 30% of the bodys sodium is found in the
bone, but only 60% of this is exchangeable. Sodium intake, which is
determined by habit, varies widely (50300 mmol/day) and sodium
balance is maintained by renal excretion with small amounts excreted
in the stools and sweat. In a healthy person, large amounts of sodium
are filtered daily (25,200 mmol approximately six times the total
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Disorders of Fluid Balance

31

body sodium) and only 100150 mmol is excreted: a reabsorption

rate of 99.4%. The renal reabsorption of sodium is finely regulated to
maintain sodium balance and consequently to maintain ECF volume.
As the maintenance of ECF volume and hence blood volume is crucial, there are several sensitive and powerful homeostatic mechanisms
involved in regulating renal sodium excretion.
Changes in the ECF volume are sensed by volume receptors in the
carotid sinus, aortic arch and afferent glomerular arterioles as changes in
the effective circulating volume (ECV). ECV refers to the part of ECF
in the vascular space that effectively perfuses the tissues. ECV is not a
measurable entity and under normal circumstances, ECF varies directly
with ECF volume. However, in disease states, e.g. heart failure, ECV
may be reduced with increased ECF volume. Stimulation of these volume receptors will cause the stimulation of several systems, including the
sympathetic system and the reninangiotensin system. Stimulation of the
sympathetic system will cause haemodynamic changes in order to maintain the ECV and indirectly increase sodium reabsorption. Other factors
influencing sodium reabsorption are given in Table 2.7.
Aldosterone, a steroid hormone secreted by the zona glomerulosa
of the adrenal cortex is controlled by angiotensin II. Renin, a proteolytic enzyme secreted by the macula densa cells in the kidney acts
on circulating angiotensinogin to convert it to angiotensin I, which
in turn, is converted to angiotensin II by angiotensin-converting
enzyme. Renin secretion is increased by sodium deficiency and
Table 2.7

Factors influencing sodium reabsorption

Hormonal factors
Aldosterone
Atrial natriuretic peptide (ANP)
Sodium transport inhibitor (ouabain-like factor)
Dopamine
Kinins
Prostaglandins
Haemodynamic factors
GFR
Peritubular capillary haemodynamics

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Chapter 2

volume depletion. Hyperkalaemia can also stimulate the secretion of

aldosterone. Aldosterone acts by increasing the reabsorption of
sodium in exchange for potassium and/or hydrogen ion secretion.
Angiotensin II, in addition, has vasoactive actions, thereby minimising the effects of a decrease in plasma volume.
A variety of natriuretic factors can increase sodium excretion. Atrial
natriuretic peptide (ANP), secreted by the myocytes is one of the wellcharacterised natriuretic factors. ANP increases sodium excretion by
inhibiting sodium reabsorption in the inner medullary collecting tubules
via a cyclic GMP-mediated mechanism. ANP, by a direct effect on vascular smooth muscles, has a hypotensive effect. In addition to ANP, two
other natriuretic peptides have been described: brain natriuretic peptide
(BNP) and C-type natriuretic peptide (CNP). BNP, first described in the
brain, is synthesised and secreted from the ventricles of the heart. The
biological effects of BNP are similar to that of ANP. CNP appears to be
a neuropeptide rather than a cardiac peptide. In addition to these natriuretic peptides, many other natriuretic factors have been described; one
of these is a sodiumpotassiumATPase inhibitor.
As the mechanisms responsible for ECF volume regulation are
many and powerful, it is impossible to get clinical sodium depletion
by decreased intake. Sodium depletion almost always follows abnormal losses. As the amount of body sodium determines the ECF
volume, sodium depletion manifests as volume depletion without
necessarily changing plasma sodium concentration.

Distribution of Fluid between Plasma

and Interstitial Fluid
The movement of fluid between plasma and interstitial fluid (IF) is
important as it supplies nutrients and remove waste products from the
cells. This movement of fluid is controlled primarily by capillary
hydrostatic pressure and plasma oncotic pressure, as capillaries are
permeable to water and solutes (Figure 2.4).
At the arteriolar end of the capillary, fluid passes out into the IF
as the hydrostatic pressure is higher than the oncotic pressure. At the
venous end, plasma oncotic pressure is greater than the hydrostatic
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Disorders of Fluid Balance

Arterial end

Hydrostatic
pressure:
35 mm Hg

33

Venous end

Plasma oncotic pressure: 25 mm Hg

Hydrostatic
pressure:
35 mm Hg

Oncotic pressure of interstitial fluid: 5 mm Hg

Hydrostatic pressure of interstitial fluid: 5 mm Hg
Figure 2.4

Haemodynamic factors controlling fluid movement across capillary wall.

pressure and fluid is reabsorbed. Some fluid is returned by lymphatics. This movement of fluid in and out of IF is rapid about 75% of
plasma is exchanged every minute.
Although the fluid moving through the capillary wall is relatively
protein-free, albumin does slowly pass into the interstitial space and
return to the circulation by the lymphatics. Permeability of capillaries
varies in different organs, with the hepatic sinusoids being more permeable. It is important to note that although albumin concentration
in IF is low, about 50% of total body albumin is extravascular since the
volume of IF is 34 times greater than the plasma volume.
A small increase in hydrostatic pressure or decrease in oncotic
pressure will be expected to cause accumulation of IF. However, this
does not happen until there are gross changes due to the following
safety factors:
1. Increased lymphatic flow.
2. When fluid enters the interstitial compartment, it will decrease the
oncotic pressure of the IF. This will minimise the gradient for further fluid entry.
3. Increase in IF volume will raise interstitial hydrostatic pressure
and oppose the entry of fluid.
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Chapter 2

Disorders of Water Metabolism

Any excess or deficit of water in the body is shared between ICF and
ECF and can be detected by changes in plasma sodium concentration.
For example, if 6 litres of water is lost, 2 litres will be lost from ECF and
the plasma sodium concentration will increase by 20 mmol/L to
160 mmol/L. Similarly a gain of 6 litres of water will result in a
decrease in the plasma sodium concentration by 20 mmol/L.
Symptoms of water depletion and water excess are caused by changes in
the hydration of the cells.
Water Depletion
Causes of water depletion are given in Table 2.8.
A decreased intake of water, especially in elderly subjects or unconscious patients, is not an uncommon finding in hospital practice. When
there is a lack of ADH (neurogenic diabetes insipidus) or resistance to
the action of ADH (nephrogenic diabetes insipidus), water can be lost
in the urine causing water depletion. In osmotic diuresis, there is a
greater loss of water than sodium leading to water depletion. Sweat is

Table 2.8

Causes of water depletion

Decreased water intake

Elderly
Very young
Unconscious subjects
Increased water loss
Renal loss
Central (neurogenic) diabetes insipidus
Nephrogenic diabetes insipidus
Congenital
Acquired hypokalaemia, hypercalcaemia
Osmotic diuresis glucose
Insensible loss
Increased sweating
Hyperventilation

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Disorders of Fluid Balance

35

a hypotonic fluid, thus if there is excessive sweating, water depletion

may result. If the humidity of the external environment is low, water
can be lost without visible sweating. It is important to note that in conditions where there is increased loss of water, water depletion will not
develop unless there is a failure to increase water intake.
Symptoms of water depletion are non-specific such as confusion,
thirst and dry mouth. As the loss of water is shared between ICF and
ECF, the decrease in ECF volume is relatively small and signs of volume depletion are minimal in water depletion. If the loss of water is
non-renal, there will be increased reabsorption of water by the renal
tubules and a small amount of concentrated urine will be produced;
plasma sodium concentration will be high. As water depletion develops slowly, brain cells adapt to the high ECF osmolality by producing
osmotically active organic compounds (called osmolytes) in order to
prevent cerebral dehydration.
Water depletion is treated by the administration of water orally or
by 5% glucose intravenously. It is important to reduce the deficit
slowly if the water depletion has occurred over a period of time, in
order to prevent cerebral oedema. Furthermore, when replacing the
lost water, it is important to give additional amounts of water, sufficient to compensate for obligatory loss. The amount of water deficit
can be calculated from the increase in plasma sodium concentration.
Water Excess
The normal system can cope with a water intake of up to 20 L/day
without significant gain of total body water. Therefore, water
excess is usually observed with impaired excretion. The excess
water accumulates both in the ICF and ECF. Swelling of the brain
cells causes symptoms such as confusion, behavioural disturbances,
headache, convulsions and coma. The most important laboratory
finding is a decrease in plasma sodium concentration with normal
or low plasma urea concentration. Causes of water excess are given
in Table 2.9.
During bladder irrigation, a decrease in plasma sodium concentration is common due to the absorption of irrigation fluid. Occasionally,
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Chapter 2
Table 2.9

Causes of water excess

Increased intake
Psychogenic polydipsia very rare
Bladder irrigation
Decreased excretion
Renal failure
ADH secretion
Stress post-operative states (common)
Pulmonary disease pneumonia, tuberculosis, etc.
Neurological disease infections, vascular accidents
Ectopic secretion of ADH oat cell carcinoma
Drugs cyclophosphamide, etc.
Potentiation of ADH effects
Carbamazepine, chlorpropamide
Exogenous ADH/analogues
Oxytocin
Others
Cortisol deficiency

symptomatic hyponatraemia develops. The most common cause of

water excess in hospital practice is the secretion of ADH due to stress
or trauma. When these patients are given hypotonic fluids, i.e. 5% dextrose or a dextrose saline, hyponatraemia will develop.
Syndrome of inappropriate ADH secretion (SIADH) is a frequent
finding in hospital populations. This syndrome is described under
hyponatraemia. Cortisol deficiency due to adrenal failure or anterior
pituitary failure can lead to water retention (see under hyponatraemia). Note that hyponatraemia of Addisons disease is due to a
combination of water excess, as a result of cortisol deficiency, and
sodium depletion as a consequence of aldosterone deficiency.
The treatment of water excess is described under hyponatraemia.

Disorders of ECF Volume

Changes in volume, i.e. ECF volume, are mainly due to changes in
the amount of sodium in the body. As sodium is normally lost or
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Disorders of Fluid Balance

37

gained with water, changes in body content of sodium results in an

increase or decrease in extracellular fluid.
Volume Deficit
Extracellular fluid volume depletion is one of the commonest fluid disorders (Table 2.10). A decrease in the ECF volume will stimulate the
sympathetic system, causing tachycardia and vasoconstriction. If the
loss of fluid is gradual, then postural hypotension will be the only manifestation. The renal response to volume depletion is to increase the
reabsorption of sodium and water. As ECF volume depletion is a
strong stimulus for ADH secretion, water reabsorption will be
increased and a small amount of concentrated urine with very little
sodium will be produced. As the urea in the tubular fluid is reabsorbed
passively, a decrease in urine flow rate would cause increased reabsorption of urea and plasma urea concentration will increase. High plasma
urea and a high urea/creatinine ratio is a useful method of detecting
volume depletion. In severe volume depletion, GFR may decrease and
acute tubular necrosis may result. The clinical features of volume
depletion include weakness, apathy, postural dizziness, syncope, thirst
and muscle cramps. The patient will have reduced skin turgor, reduced

Table 2.10

Causes of volume depletion

Gastrointestinal losses
Gastric vomiting, nasogastric suction
Intestinal fistula, tube drainage, diarrhoea
Renal losses
Diuretics
Mineralocorticoid deficiency
Osmotic diuresis
Sequestration
Ileus
Peritonitis
Others
Loss via skin e.g. burns

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ocular pressure, hypotension (may be only postural) and oliguria.

Significant laboratory findings are an increase in plasma urea concentration and an increase in plasma urea/creatinine ratio. If the sodium
loss is via a non-renal route, urine sodium concentration will be very
low, typically less than 20 mmol/L and the urine osmolality will be
high. Plasma sodium concentration in patients with volume depletion
may be normal, low or high depending on the composition of the fluid
lost and on the composition of fluids administered. When the fluid loss
is isotonic, the concentration of plasma sodium will remain within normal limits. But it may decrease if hypotonic fluid is administered
(either orally or intravenously), as hypovolaemia is a powerful stimulus
for the secretion of ADH. If the fluid lost is hypotonic, the plasma
sodium concentration may be high.
Treatment of volume depletion is by infusion of isotonic (0.9%)
saline.

Volume Excess
Oedema
Oedema is defined as a palpable swelling produced by expansion of the
IF volume. It is associated with many clinical conditions such as congestive heart failure, nephrotic syndrome and cirrhosis of the liver.
There are two important steps involved in the formation of oedema: (1)
alteration in capillary haemodynamics, and (2) renal retention of sodium
and water. Initially, as a result of altered capillary haemodynamics, fluid
moves out of the vascular space into the interstitial compartment. This
results in a reduction of plasma volume and tissue perfusion, which triggers homeostatic mechanisms to increase the renal sodium reabsorption
in an attempt to return the plasma volume to normal. However, because
of the alteration in capillary haemodynamics, most of the fluid will enter
the interstitial compartment, eventually resulting in oedema. The net
effect is an expansion of the total ECF volume with plasma volume
maintained at near normal levels. It is important to recognise that in this
case, the increased sodium and water retention is an appropriate
response to the decrease in tissue perfusion produced by altered

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Disorders of Fluid Balance

39

capillary haemodynamics. Thus rapid removal of fluid, for example by

diuretic therapy, may cause diminished tissue perfusion.
Mechanism of oedema
1. Increased capillary hydrostatic pressure
Although capillary hydrostatic pressure at the arteriolar end is important in determining the movement of fluid out of the capillaries, it is
not sensitive to changes in arterial pressure due to autoregulation of
the precapillary sphincter. In contrast, the capillary pressure at the
venous end is not well regulated and changes in venous pressure can
lead to accumulation of interstitial fluid. Venous pressure can be
increased either by an increase in the volume of blood in the venous
system or when there is venous obstruction. The former is seen in
heart failure and the latter is seen in deep vein thrombosis.
2. Decreased plasma oncotic pressure
A decrease in plasma albumin concentration, as a result of loss of
albumin in the urine or due to reduced synthesis as in cirrhosis, will
cause decreased reabsorption of interstitial fluid and hence oedema.
3. Increased capillary permeability
Capillaries are normally impermeable to large molecules such as
proteins and albumin. If the capillary permeability is increased,
albumin moves out into the interstitial compartment and more
fluid is retained in the interstitial compartment, as a result of
increased oncotic pressure. In certain forms of angioneurotic
oedema (e.g. after replacement with interleukin II) and in conditions associated with adult respiratory distress syndrome, capillary
permeability is increased.
4. Lymphatic obstruction
As some of the fluid accumulated in the interstitial compartment
is normally removed by the lymphatics system, obstruction to the
lymphatic system will also result in oedema.
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Chapter 2

5. Renal sodium retention

When capillary haemodynamics are altered, increased renal reabsorption of sodium and water is the appropriate response to the
decrease in ECV. However, primary renal retention of sodium may
also cause oedema, as seen in chronic renal failure and acute
glomerular nephritis. The increased reabsorption of sodium is
probably a consequence of the decreased filtration rate.
In some situations, multiple factors are involved in the accumulation
of fluid. In hepatic diseases, for example, hypoalbuminaemia caused by
decreased albumin synthesis, splanchnic pooling and increases in sinusoidal pressure all contribute to the accumulation of fluid.
Common causes of oedema are congestive heart failure,
nephrotic syndrome and cirrhosis of the liver.
Pulmonary oedema
In diseases of the left ventricle, increased left ventricular end-diastolic
pressure and left atrial pressure are transmitted to the pulmonary
capillaries, and fluid accumulates in the pulmonary compartment.
Hypoalbuminaemia does not lead to oedema in the lungs because
alveolar capillaries are more permeable to proteins and the difference
in oncotic pressure between the capillaries and interstitial fluid
is small.

Pleural effusion and ascites

In healthy people, the amount of fluid in the pleural and peritoneal
spaces at any one time is small (about 1050 ml), but there is a continuous turnover. In the pleural cavity, 510 litres of fluid are formed
and reabsorbed daily. Accumulation of fluids in these spaces depends
on similar haemodynamic factors as those outlined above.
Fluid accumulating in these spaces is sometimes classified as
exudates or transudates. This classification is based primarily on
protein concentration: Exudate has a protein concentration greater
than 30 g/L and transudate has a protein concentration of less than
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