Clinical Chemistry PDF

CLINICAL
CHEMISTRY
MADE EASY
For Elsevier:
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CLINICAL
CHEMISTRY
MADE EASY
Jeremy Hughes MA FRCPE PhD

Wellcome Trust Senior Research Fellow in Clinical Science and
Honorary Consultant Physician at the Royal Infirmary Edinburgh,
MRC Centre for Inflammation Research, The Queen’s Medical
Research Institute, Edinburgh, UK
Ashley Jefferson MD MRCP

Clinical Associate Professor, Division of Nephrology, University of
Washington, Seattle, USA
Foreword by
John Iredale DM FRCP FMedSci
Professor of Medicine, University of Edinburgh
Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto 2008
CHURCHILL LIVINGSTONE
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Foreword
The functions of cells are governed by the laws of chemistry and phys-
ics, and biochemical reactions underlie the fundamental processes of
life. For these reasons, it is no surprise that in many countries a high
school chemistry qualification is a prerequisite for undergraduate
admission to medical school. Medical students become exposed to
biochemistry during their early training and many joke about the
impenetrability of the subject. Indeed one classmate of mine, a witty
songwriter, penned the classic ‘Don’t cry for me biochemistry, the
truth is I never learnt you’, to be sung to the tune of ‘Don’t cry for
me Argentina’, from the then hit Lloyd Webber musical ‘Evita’. Of
course, this levity disguises the fact that medical graduates invariably
acquire a good working knowledge of biochemical process.
Having acquired a grounding in biochemistry, as clinical students
and junior doctors we are then confronted with the challenge of assim-
ilating that knowledge with the practice of medicine and exploiting it
in clinical practice. Nowhere is that assimilation more direct than the
field of clinical chemistry. However, the expanding content of under-
graduate syllabuses means that the time and opportunity to make
this synthesis is becoming eroded. Moreover, the integration of pre-
clinical biochemistry with the approach to clinical problems is not
always straightforward. For example, understanding the Henderson–
Hasselbalch equation and the principles underlying pH balance and
buffering may seem straightforward in abstract, but grouping the pat-
terns of changes in pH and accompanying alterations in the PO2 and
PCO2 in the blood gases of a breathless patient can seem daunting to
the medical student and junior doctor. The approach to clinical chem-
istry in real clinical situations requires knowledge, experience and an
integrated and clinically relevant model. It is precisely this integrated
model which Jeremy Hughes and Ashley Jefferson have brought
together in this text.
The use of appropriate clinical context throughout the book illus-
trates how clinical chemistry tests can be deployed to rapidly obtain
information critical for the management of sick patients. This area of
medicine is now of essential importance given the changes in the pro-
cess of care delivery in hospitals. Junior doctors are frequently called
to see sick patients with whom they are unfamiliar, and for whom a
rapid appraisal of clinical need and diagnosis will be required. The
Foreword
armamentarium of clinical chemistry tests is invaluable in this setting

– frequently simple investigations, such as blood gas measurements,
can rapidly provide information essential to diagnosis and manage-
ment. Far from being a setting neglected by the authors, clear and con-
cise guidance to the use and interpretation of tests in the emergency
setting is a particular strength of this volume. An additional area of
focus is the role of drugs in influencing the results of clinical chemistry
tests and as possible causes of abnormalities in routine tests under-
taken in both the community and hospital settings. With the increasing
number of elderly patients who are all too frequently exposed to poly-
pharmacy, this area also will assume a greater and greater importance
in the diagnosis and effective management of our patient population.
This concise and highly readable text provides exactly the informa-
tion that senior clinical students and junior doctors need to request,
arrange and interpret clinical chemistry tests effectively, and in so
doing enhance clinical care. It is the kind of book I wish had been
available when I was a student and should be valuable to trainees
across all specialities. There is no longer any excuse for biochemistry
and clinical chemistry to be a neglected or ‘tearful’ partner in the
curriculum.
John Iredale
Edinburgh 2007
viii
Preface
Clinicians are unable to provide adequate medical care in isolation.
They are dependent upon numerous laboratory disciplines to assist in
the management of patients with varied medical problems. Depart-
ments of Clinical Chemistry and related departments such as Micro-
biology and Clinical Immunology play a very important role in patient
care. They provide critically important information that may be either
diagnostic, as in the levels of cardiac enzymes, or facilitate the accurate
monitoring of conditions such as systemic inflammation or hepatic fail-
ure. Although many of these tests may be interpreted in isolation, it is
usually important to examine any ‘trends’ that are evident, e.g. deterio-
ration in renal function, overall control of diabetes mellitus.
It is imperative to realise that the use of simple clinical acumen and
skill is a critically important facet of patient care. It is always inadequate
to investigate a patient by simply ‘ordering a few tests’. Although there
is unquestionably a role for routine screening tests in certain patient
populations, it is useful to request and interpret pertinent investigations
in the clinical context of the individual patient. Indeed, significant
errors in clinical management may ensue if data derived from labora-
tory investigations are acted upon without an adequate clinical assess-
ment of the patient.
Junior clinical staff are typically the first point of contact for ward
staff who are concerned about the condition of inpatients during the
night or at the weekend. Often, junior doctors will be required to
assess and treat patients ‘out of hours’, despite the fact that they
may not be directly involved in their routine medical care. The key
to success in these circumstances is:
1. Get to grips with the acute problem, pertinent medical background
and current drug treatment.
2. Examine the patient briefly with particular emphasis upon the rel-
evant physiological system.
3. If the diagnosis is not apparent then make a differential diagnosis
and institute tests that will enable you to make a definitive diagno-
sis. This may include clinical chemistry, haematological, radiologi-
cal and cardiological investigations.
4. Reconsider the clinical situation when the results of investigations
become available and integrate all of the available data. It may well
be necessary to institute appropriate therapy at this point.
Preface
5. If the situation is problematical then seek the advice of a senior col-

league at an early stage.
In addition, it is not uncommon for junior medical staff to be contacted
regarding an ‘abnormal test result’ that has come back. This book has
been written with the above practical tips in mind and the integration
of clinical and laboratory data emphasised. It is our hope that this
book will help the reader develop and hone the skills necessary to deal
effectively with patients in diverse circumstances.
2008 Edinburgh, JH
Seattle, AJ
x
CHAPTER
1
Sodium and
water balance
Introduction
Abnormalities of sodium and water balance are the commonest fluid

and electrolyte abnormalities in clinical medicine. Both hyponatraemia
and hypernatraemia may have serious consequences but, as will be
outlined in this chapter, the treatment of these conditions is not with-
out risk.
It is important to recognise that sodium balance and water balance

are controlled separately. Abnormalities in sodium balance lead
to changes in the extracellular volume (volume depletion or vol-
ume overload), whereas abnormalities in water balance lead to
changes in the serum sodium concentration (hyponatraemia or
hypernatraemia).
Distribution
Some 60% of the weight of an adult male (50% in females) is water and
termed the total body water (TBW). This is distributed between the
intracellular fluid (ICF) and the extracellular fluid (ECF). The ECF is
further divided into interstitial fluid and plasma (Fig. 1.1). As water
1 Sodium and water balance
ICF (2/3 TBW) ECF (1/3 TBW)
Interstitial fluid Plasma
28 L 11 L 3L
Na+ 10 Na+ 140
K+ 150 K+ 4.5
Cl− 4 Cl− 104
HCO3− 12 HCO3− 24
PO43− 140 PO43− 1
Figure 1.1 Composition of water and electrolytes in body compartments of a 70-kg

man. Data expressed as concentrations (mmol/L). Note that sodium is the major
extracellular fluid cation and potassium the major intracellular fluid cation.
can move freely across cell membranes, the size of the ICF and ECF is
determined by the number of osmotically active particles in each of
these spaces. There are approximately twice as many osmoles in the
ICF (mostly potassium and organic phosphates) as in the ECF (mostly
sodium, the accompanying anions chloride and bicarbonate together
with albumin), and therefore two-thirds of TBW is in the ICF and
one-third is in the ECF. Sodium is maintained predominantly in the
ECF by the action of the Na–K-ATPase pump in cell membranes.
Control of sodium balance
The average daily Western diet contains 150–200 mmol of sodium which
must be excreted to avoid volume overload. The kidneys are primarily
responsible for excreting the daily sodium load. With a normal glomer-
ular filtration rate (GFR) of 180 L per day, approximately 25 000 mmol
of sodium are filtered at the glomerulus, with less than 1% of this being
excreted in the urine (approx. 150 mmol/d). The majority of filtered
sodium is reabsorbed along the nephrons, with the majority of sodium
being reabsorbed in the proximal tubule (Fig. 1.2).
Abnormalities of sodium balance lead to volume depletion or vol-
ume expansion.
Volume depletion (decreased total body sodium)

Volume depletion is sensed by arterial (carotid) and venous barore-
ceptors leading to activation of angiotensin II, aldosterone and the
2
Control of water balance
1
65–70% 5–7%
18 000 mmol 1 500 mmol
GFR 180 L/d

27 000 mmol
2–5%
sodium filtered
450 mmol
Cortex
Medulla
20–25%
6 000 mmol
Collecting
tubule
Loop of Henle
1.5 L urine containing
150 mmol sodium
Figure 1.2 Sodium reabsorption along the nephron. Large amounts of sodium
are filtered at the glomeruli daily, with the majority of filtered sodium being
reabsorbed.
sympathetic nervous system, and decreased activity of natriuretic

peptides. In this setting, the kidneys will retain filtered sodium and
typically excrete urine with a sodium concentration of less than
10 mmol/L.
Volume overload (increased total body sodium)

Conversely, in the setting of an increased sodium load (volume over-
load), excess sodium can be excreted in the urine due to an increased
GFR (pressure natriuresis), increased natriuretic peptides and inhibi-
tion of the renin–angiotensin system and aldosterone.
Control of water balance
Water balance is controlled primarily by thirst and the production of

either a dilute or concentrated urine. Urinary concentration is under
the control of antidiuretic hormone (ADH). ADH is a nine-amino-acid
peptide secreted by the posterior lobe of the pituitary gland. ADH acts
on the cells of the medullary collecting duct and stimulates the inser-
tion of aquaporin 2 water channels into the luminal membrane of the
3
epithelial cells. This allows the reabsorption of water from the tubular
lumen into the hypertonic medulla which is established by the coun-
tercurrent system (Fig. 1.3).
Abnormalities of water balance lead to hyponatraemia or
hypernatraemia.
Water excess (hyponatraemia)

In this setting thirst is inhibited, the plasma osmolality falls, and this
suppresses the release of ADH. The absence of ADH reduces the
Pituitary
Collecting tubule
H2O ADH
V2
Vasa
recta AQ2
Maximum 1200 mOsm/kg

Figure 1.3 Action of antidiuretic hormone (ADH). ADH is produced by the
hypothalamus and stored in the pituitary gland. The binding of ADH to the V2
receptors on principal cells in the medullar, collecting duct results in the insertion of
aquaporin 2 (AQ2) water channels into the luminal membrane. This allows the
reabsorption of water from the ultrafiltrate with a resultant increase in the
concentration of the urine.
4
When should I check sodium level?
1
Table 1.1 Causes of antidiuretic hormone release
Hyperosmolality Hypernatraemia
Hyperglycaemia
Decreased effective arterial blood volume Volume depletion
Severe cardiac failure
Liver failure
Stress Postoperative
Nausea
Pain
permeability of the collecting ducts to water, allowing the passage of

a dilute urine (minimum urinary osmolality 25–50 mOsm/kg). This
effectively excretes the excess water with a resultant increase in the
serum sodium level.
Water depletion (hypernatraemia)

By contrast, in setting of water depletion (hypernatraemia), the plasma
osmolality becomes raised and stimulates ADH release. This results in
the production of urine that is concentrated (maximal 1200 mOsm/kg)
and the subsequent retention of water.
It should be noted that ADH can be stimulated by factors other than
hypertonicity (Table 1.1). Volume depletion stimulates ADH synthe-
sis, and hyponatraemia is typically found in settings of volume deple-
tion or a decreased effective arterial blood volume (e.g. heart failure,
liver disease). The restoration of plasma volume takes precedence over
osmolality and ADH is stimulated in volume depletion despite the
presence of hypo-osmolality.
When should I check sodium level?
The measurement of serum sodium together with other electrolytes is

commonly performed in ‘everyday’ clinical practice, e.g. preoperative
bloods, outpatient clinics. However, there are indications for specifi-
cally checking the serum sodium. These include:
l Seriously ill patients including those who are unconscious or
obtunded
l Patients with significant cardiac, renal or liver disease
5
l Patients receiving intravenous fluids or parenteral nutrition

l Patients receiving drugs that may affect serum sodium levels
including diuretics (a very common cause of hyponatraemia)
l Patients with uncontrolled diabetes mellitus
l Patients with polyuria or polydipsia.
What do I do with the result?
In the majority of instances, an abnormal sodium level will not require

urgent action. Indeed, the over-enthusiastic treatment of hyponatraemia
or hypernatraemia may be dangerous. However, the clinician should
look for ‘trends’, as it may well be possible to adjust therapy to prevent
the development of severe hyponatraemia or hypernatraemia (e.g. fluid
restriction, a reduction in diuretic dosage or adjustment of intravenous
fluid therapy). If the sodium level is below 120 mmol/L or greater than
160 mmol/L, then active treatment should be considered.
Hyponatraemia (serum Na <135 mmol/L)
Hyponatraemia is best considered an abnormality of water balance

representing an excess of water relative to sodium. Although sodium
loss can cause hyponatraemia, this rarely happens in excess of water
loss and therefore does not cause hyponatraemia directly. Instead,
sodium loss causes ECF depletion with subsequent volume-mediated
activation of ADH leading to an impairment of electrolyte free water
(EFW) excretion.
Two factors are required to develop hyponatraemia

1. A source of electrolyte free water (usually oral or intravenous (i.v.)
fluids, rarely EFW generation from hypertonic urine). It should
be noted that the ingestion of excess free water alone (psychogenic
polydipsia) rarely causes hyponatraemia in the absence of
impaired urinary dilution.
2. An impaired ability of the kidneys to excrete dilute urine. This impaired
ability may be due to:
(a) defective ADH action (this the commonest cause; see Table 1.1)
(b) a low urine output which may result from (i) severe renal failure
e.g. GFR <10 mL/min or (ii) a markedly decreased urine solute
load. There is a minimum level to which the kidneys can dilute
the urine (50 mOsm/kg) and this may be limited by a reduction
6
1
in the daily solute load, e.g. tea and toast diet in the elderly or beer
potomania.
Learning point
Hyponatraemia is often asymptomatic. A decreased sodium
intake alone is not a common cause of hyponatraemia and persis-
tent hyponatraemia is often found in patients with defective
homeostatic mechanisms.
Assessment of the patient

1. Is this pseudohyponatraemia? This may be found in patients with
severe hypertriglyceridaemia or severe paraproteinaemia. It is very
rare and is detected by a normal serum osmolality despite
hyponatraemia.
2. Is the hyponatraemia acute (<48 h) or chronic? This is a critical ques-
tion as inappropriate treatment of hyponatraemia may be as dan-
gerous as the hyponatraemia itself.
3. (i) Acute hyponatraemia (<48 h). The main risk is acute cerebral
oedema secondary to water moving into brain cells. The treat-
ment of acute hyponatraemia may need to be aggressive.
(ii) Chronic hyponatraemia (>48 h). The main risk is overly aggressive
therapy as rapid changes in plasma sodium levels may result in
major neurological consequences (central pontine myelinolysis).
The aim of treatment is to increase the plasma sodium level slowly.
4. Does the patient exhibit any acute neurological disturbance, such
as seizures or confusion? Symptomatic hyponatraemia needs rapid
treatment, generally with hypertonic saline.
5. What is the volume status of the patient? This assessment is the key to
determining the underlying cause of the hyponatraemia and choos-
ing the appropriate therapy.
6. What is the source of the EFW? This is the primary diagnostic ques-
tion in patients with acute hyponatraemia. It is important to check
i.v. fluids, TPN or enteral feeds as well as oral fluid intake. It is not
uncommon for inappropriate prescribing of hypotonic fluids to be
a factor in the development of hyponatraemia.
7. Why are the kidneys not able to excrete the excess EFW? This is the pri-
mary diagnostic question in patients with chronic hyponatraemia.
Is it usually due to ADH secretion (see Table 1.1).
7
Laboratory tests
The laboratory tests required to assess hyponatraemia include serum
osmolality, urine osmolality and urine sodium.
1. Plasma osmolality – this should be hypotonic (<280 mOsm/kg). Iso-
tonic plasma (280–295 mOsm/kg) suggests pseudohyponatraemia,
and hypertonic plasma (>295 mOsm/kg) suggests hyperglycaemia
or rarely mannitol treatment.
2. Urine osmolality – this is typically raised (>100 mOsm/kg), confirm-
ing impaired renal excretion of EFW. Rarely the urine osmolality is
low (<100 mOsm/kg), implying excess water intake.
3. Urine sodium – a low urine sodium level (<20 mmol/L) may suggest
volume depletion which increases ADH release. It should be noted
that there is a decreased effective arterial blood volume in oedema-
tous states such as cardiac failure, liver failure and nephrotic syn-
drome. This results in both ADH release and impaired renal
perfusion with a low urine sodium concentration.
Symptoms and signs
Clinical features are typically related to the central nervous system
(CNS) and relate to both the degree of hyponatraemia and the rate of
decline. Acute hyponatraemia leads to swelling of the brain cells,
termed cerebral oedema. This may result in confusion, seizures, coma
and tonsillar herniation in severe cases. Most patients with seizures
and coma have serum sodium levels <120 mmol/L. By contrast,
patients with chronic hyponatraemia are often asymptomatic or pres-
ent with mild confusion or nausea. In these patients cerebral adaptation
has occurred and the brain cells have excreted intracellular osmoles to
limit cell swelling. In this setting, the over-rapid correction of chronic
hyponatraemia may produce profound neurological abnormalities.
Differential diagnosis of hyponatraemia

This can be determined from the algorithm Figure 1.4. It is, however,
important to note that several factors are often present in the same
patient, e.g. thiazide diuretic use in an elderly patient with poor solute
intake and mild chronic renal failure, with the latter two factors reduc-
ing the ability to dilute the urine maximally.
Hyperglycaemia
This is a common cause of hyponatraemia. Hyperglycaemia increases
the serum osmolality and results in the movement of water from the
8
1
Hyponatraemia
Serum Sosm 280–295 Sosm <280 Sosm >295

osmolality Pseudohyponatraemia Hypotonic Hypertonic
Paraproteinaemia hyponatraemia hyperglycaemia
Hypertriglyceridaemia (mannitol)
Urine Uosm <100 Uosm >100

osmolality Excess water intake Impaired urinary
Primary polydipsia dilution
Low solute intake
Renal failure ↑ADH Dysfunctional

Rare unless GFR <10 diluting sites
Interstitial renal
disease
Volume Euvolaemia Volume

depletion expansion
Urinary UNa+<10 UNa+ >20 UNa+ >20 UNa+ <10

sodium
Non-renal Renal Na+ loss SIADH Oedematous states

Na+ loss Diuretics Reset osmostat Cardiac failure
GI tract Osmotic diuresis Hypothyroidism Cirrhosis
Sweat Adrenal insufficiency Glucocorticoid Nephrotic syndrome
Salt wasting nephropathy deficiency
Renal tubular acidosis Drugs
with bicarbonaturia
Figure 1.4 Causes of hyponatraemia.
ICF to the ECF in order to restore osmotic equilibrium. The serum

sodium should fall by 3 mmol/L for every 10-mmol/L increase in blood
glucose concentration. Urea and ethanol also raise the serum osmolality
but move rapidly across cell membranes and are thus ineffective
osmoles and do not alter the serum sodium level.
9
Pseudohyponatraemia
Sodium is distributed in the aqueous phase of plasma (93% of plasma
volume), but the expressed sodium concentration is based upon the
total volume of plasma analysed. Rarely, a marked hypertriglycerid-
aemia (>10–15 mmol/L) or severe paraproteinaemia (>100 g/L) may
increase the non-aqueous phase and result in pseudohyponatraemia.
The serum osmolality is normal in this setting.
Artefactual hyponatraemia
Artefactual hyponatraemia may occur when the blood sample is taken
from a ‘drip arm’, i.e. there is an intravenous infusion of 5% dextrose
or ‘dextrose/saline’ running into the arm when the blood sample is
collected.
Iatrogenic
This is a very common cause of hyponatraemia in hospitalised
patients due to inappropriate intravenous fluids. In the postoperative
setting, there is often ADH release secondary to pain and stress, and
excess 5% dextrose may result in hyponatraemia. It should be remem-
bered that hospitalised patients often have additional sources of EFW,
including oral fluids, parenteral nutrition or ice chips.
Polydipsia
Excess water intake alone is rarely the sole cause of hyponatraemia as
normal kidneys can excrete close to 15–20 L of EFW per day. Some
psychiatric patients may drink these very large amounts. In this
setting the urine osmolality will be very low (<100 mOsm/kg). More
commonly a large water intake contributes to the hyponatraemia that
develops in the presence of impaired free water excretion, e.g. in the
presence of ADH.
Diuretics and other drugs

Thiazide diuretics commonly cause hypovolaemic hyponatraemia due
to volume depletion-mediated activation of ADH and ongoing EFW
ingestion. Loop diuretics rarely cause this effect as the blockade of
Naþ reabsorption in the loop of Henle interferes with the maintenance
of medullary hypertonicity, which impairs the action of ADH.
Other drugs associated with hyponatraemia are shown in Table 1.2.
10
1
Table 1.2 Drugs associated with hyponatraemia
Mechanism Drug
ADH analogues Vasopressin
Desmopressin (DDAVP)
Oxytocin
Stimulation of ADH release Carbamazepine
Chlorpropamide
Antidepressantsa
Antipsychotic agentsa
Vincristine/vinblastine
Narcotics
Clofibrate
Ifosfamide
Enhanced ADH renal effect NSAIDs
Chlorpropamide
Cyclophosphamide
a
Mechanism unknown for several of these agents. ADH, antidiuretic hormone; NSAIDs,
non-steroidal anti-inflammatory drugs.
Syndrome of inappropriate ADH (SIADH)
Diagnostic criteria for SIADH

1. Hyponatraemia (<135 mmol/L)
2. Decreased serum osmolality (<270 mOsm/kg)
3. Urine sodium >20 mmol/L
4. Inappropriate urine concentration (urine osmolality >100 mOsm/
kg)
5. Exclusion of renal failure and endocrine dysfunction
This is a common cause of hyponatraemia but is a diagnosis of exclu-

sion. It is a disorder of osmoregulation where hypotonicity fails ade-
quately to suppress the production of ADH. The causes of SIADH are
categorised as pulmonary, neurological (CNS) or carcinoma (Table 1.3).
SIADH is diagnosed when hyponatraemia is present with evidence
of ADH action (urine osmolality >100 mOsm/kg) and when other
11
Table 1.3 Causes of SIADH
Carcinomas Pulmonary Central nervous system

Bronchogenic Pneumonia (viral/ Encephalitis (viral/bacterial)
Gastrointestinal bacterial) Meningitis (viral/bacterial/TB/
Bladder Tuberculosis fungal)
Prostate Pulmonary abscess Brain tumours
Pancreas Aspergillosis Brain abscess
Mesothelioma Cerebral haemorrhage
causes for ADH action have been excluded (hypovolaemia, oedema-

tous states, endocrine dysfunction such as adrenal insufficiency and
hypothyroidism, renal impairment or drugs). The urine sodium con-
centration is not reduced (>20 mmol/L), but reflects the daily sodium
intake.
Management
Never treat a sodium concentration in isolation. Clinically important
consequences often depend on the rate of change of serum sodium levels
and not the absolute value.
Treatment of acute symptomatic hyponatraemia is a medical emer-
gency. Treatment of chronic asymptomatic hyponatraemia must be
cautious as over-aggressive therapy can have serious consequences.
The treatment of hyponatraemia is related to both the underlying cause
and the clinical severity. If symptoms are present (seizures, coma), this
is a medical emergency. The underlying cause of the hyponatraemia
must also be treated, e.g. pneumonia, tumour, etc.
Acute symptomatic hyponatraemia (<48 h)

Hyponatraemia complicated by symptomatic cerebral oedema should
be treated rapidly. The correction rate should be 1–2 mmol/L/h over
the first 3–4 h with a maximum correction of 12 mmol/L/24 h.
This condition typically arises in the postoperative setting in patients
who have received excessive hypotonic intravenous fluids. It may also
be seen in acute water intoxication (e.g. ecstasy use, psychogenic poly-
dipsia). The main risk is cerebral oedema with potentially devastating
neurological injury. For unclear reasons the neurological complications
12
1
appear more common in women. Treatment guidelines include water

restriction and:
1. Intravenous administration of hypertonic 3% saline (1–2 mL per kg
bodyweight per h), which may be combined with furosemide to
prevent sodium overload and increase EFW excretion.
2. If patients are severely obtunded or have seizures, the hypertonic
saline may be administered at an increased rate (4–6 mL/kg/h)
for a 2–3-h period to improve symptoms.
The goal is to raise the serum sodium level by 1–2 mmol/h over the first
3–4 h, but with a maximum increase of 12 mmol in 24 h. Vigilant monitor-
ing (at least 2-hourly) is clearly mandatory during this acute stage. The
saline used must be hypertonic to urine, otherwise the renal generation
of EFW may occur and this will exacerbate the hyponatraemia.
Volume depletion
Patients with hyponatraemia secondary to volume depletion typically
respond to isotonic normal saline, as correction of the volume deple-
tion will remove the stimulus for ADH release and permit renal excre-
tion of a maximally dilute urine. Great care must be taken as the rapid
renal excretion of the excess water may correct the serum sodium level
too quickly.
Chronic hyponatraemia (>48 h)
Over-rapid correction of serum Naþ concentration in patients with
chronic hyponatraemia can precipitate central pontine myelinolysis.
The correction rate should be less than 1 mmol/L/h, with a maximum
of 10–12 mmol/L over a 24-h period.
In patients with chronic hyponatraemia (>48 h) some cerebral adapta-
tion has occurred and these patients are at risk of a demyelinating syn-
drome associated with flaccid paraplegia, dysarthria and dysphagia
(central pontine myelinolysis) if the sodium is corrected too quickly.
Recommended therapeutic strategies include:
1. water restriction
2. increased salt intake with furosemide to promote renal EFW
excretion
3. administration of drugs to antagonise the action of ADH (e.g.
demeclocycline, conivaptan).
However, if the patient is symptomatic with seizures or a decreased
level of consciousness then the initial treatment should be more rapid
13
and aim to raise the serum sodium level by 1–2 mmol/L/h over the
first 3–4 h.
Hypernatraemia (serum Na >145 mmol/L)
This represents a decrease in water relative to sodium, and is almost

always due to a problem with water balance. Rarely, excess sodium
intake causes hypernatraemia (e.g. iatrogenic, drinking sea water)
when it is associated with a marked increase in ECF volume. It should
be noted that hypernatraemia will not develop unless there is an
impaired thirst mechanism or difficulties with access to water (hospi-
talised patients, infants and the elderly).
Symptoms and signs

Thirst is the predominant symptom of hypernatraemia. The serum
hypertonicity promotes water movement from ICF to ECF, and results
in cell shrinkage. CNS symptoms such as confusion or coma may
occur if the hypernatraemia is severe (typically approaching
160 mmol/L). Marked brain cell shrinkage increases the risk of cere-
bral haemorrhage. It should be noted that patients with diabetes insi-
pidus usually have a normal serum sodium level due to marked
polydipsia compensating for the polyuria, but the sodium level may
rise rapidly if they become unable to maintain their fluid intake, e.g.
if vomiting.
Clinical assessment
1. Is the ECF volume expanded? Check for the presence of peripheral
oedema, hypertension, cardiac failure, pulmonary oedema or a
change in the patient’s weight as this typically reflects a change
in fluid status. Hypernatraemia is typically associated with a
decreased bodyweight secondary to water loss. Although rare,
the weight is increased with an expanded ECF volume in the
setting of a significant gain of total body sodium.
2. What is the source of the water loss? Are there high insensible losses,
e.g. fever, ventilation, excess sweating. Other causes include diar-
rhoea and high urinary losses secondary to polyuria, e.g. the recov-
ery phase of acute tubular necrosis or glycosuria in poorly
controlled diabetes.
3. Why has there not been a compensatory increase in water intake? Is the
patient thirsty? A small increase in plasma tonicity should lead to
14
1
marked thirst, and the absence of thirst suggests a CNS lesion or

altered mental status.
4. Is the patient polyuric? This may be due to an osmotic diuresis (urine
osmolality 400–500 mOsm/kg) or a water diuresis (<150 mOsm/kg).
Laboratory results
The urine osmolality helps to differentiate between the three major
causes of hypernatraemia: diabetes insipidus, osmotic diuresis (usu-
ally glucose) and the inadequate replacement of non-renal EFW loss.
Serum hypertonicity stimulates ADH release such that the urine
osmolality should be markedly increased (800–1200 mOsm/kg).
A low urine osmolality suggests ADH deficiency secondary to
reduced production (central diabetes insipidus) or a diminished renal
responsiveness to ADH (nephrogenic diabetes insipidus).
Differential diagnosis
This can be determined from the algorithm in Figure 1.5.
Non-renal water loss

This typically occurs in the hospitalised patient or nursing home resi-
dent. Insensible losses (respiratory tract and sweat) are hypotonic and,
if not replaced with adequate water, will lead to hypernatraemia. Gastro-
intestinal losses (diarrhoea) are also typically hypotonic (80–200 mOsm/
kg) and may exacerbate EFW loss. Patients with diarrhoea often have a
significant sodium loss in addition to the relatively greater water loss,
and this is reflected by additional evidence of volume depletion on
examination. When faced with non-renal water loss, the normal kidneys
are able to produce a low volume of a urine with a high osmolality.
Osmotic diuresis
In this setting the urine osmolality is typically about 500 mOsm/kg
and the urine contains close to 50 mmol/L Naþ and 25–50 mmol/L
Kþ. The diagnosis should be suspected in patients with a high urine
volume and a high urine osmolality. This results in a high osmole
excretion rate (normal 600–900 mOsm per day). The most common
cause is glycosuria secondary to hyperglycaemia. Occasionally a high
urea excretion rate may cause urine water loss in excess of sodium,
and this may be present in patients who are catabolic, receiving high
protein feeding or recovering from acute renal failure.
15
Hypernatraemia
Extracellular ↑ECV ↓ECV

volume Sodium gain Water loss
Urine ↓Uvol ↑Uvol

volume ↑Uosm
Non-renal loss Polyuria

insensible, diarrhoea
Remote renal loss
remote diuretics
Urine ↑Uosm ↓Uosm (<150)

osmolality
Osmotic diuresis Water diuresis

glucose
urea
mannitol
Central diabetes Nephrogenic diabetes

insipidus insipidus
Response Responds to Poor response

to ADH ADH therapy to ADH therapy
Figure 1.5 Causes of hypernatraemia.
Diabetes insipidus
Diabetes insipidus is characterised by the inability of the kidneys to
concentrate the urine, resulting in polyuria. The patient typically has
intense thirst and polydipsia. Although hypernatraemia will develop
if water intake is insufficient, patients are often able to maintain the
serum sodium level in the normal range by drinking large amounts
of water (sometimes >10 L per day).
16
1
Diabetes insipidus is divided into

1. Central diabetes insipidus. This condition results from a deficiency of
ADH and is caused by lesions to the hypothalamus or pituitary
(Table 1.4). The onset of polyuria is often abrupt. Serum ADH
levels are low and the urine osmolality is often markedly low
(50–100 mOsm/kg).
2. Nephrogenic diabetes insipidus. This condition results from an abnor-
mal renal response to ADH (see Table 1.4). Serum ADH levels
are increased but the urine osmolality remains low (often 50–
250 mOsm/kg).
Management
There are two aspects to the management of hypernatraemia:
1. Stop any ongoing excessive loss of EFW.
2. Replace the EFW loss with hypotonic fluids (5% dextrose, oral
water, half-normal saline) at an appropriate rate.
If the patient has significant volume depletion in addition to hyperna-
traemia (osmotic diuresis, diarrhoea), this should first be corrected
Table 1.4 Causes of diabetes insipidus
Central Nephrogenic
Congenital Autosomal dominant X-linked (mutations in V2 receptor)
(mutations in Autosomal recessive (mutations in
vasopressin precursor) aquaporin 2)
Autosomal recessive
(Wolfram syndrome)
Acquired Tumours (pituitary, Chronic renal failure
metastases) Renal interstitial disease (interstitial
Postsurgery, head trauma nephritis, obstructive uropathy,
Infiltration of the pituitary polycystic kidney disease, lithium
(sarcoid, histiocytosis) therapy, sickle cell anaemia)
CNS infections Electrolyte disorders (hypokalaemia,
Idiopathic (50%) hypercalcaemia)
Drugs (lithium, amphotericin, foscarnet)
17
with normal saline. Great care must be taken with polyuric patients as
any changes in urine osmolality or urine volume can rapidly change the
serum sodium concentration, which needs frequent monitoring. The cor-
rection of hypernatraemia should not occur too rapidly as this may pre-
cipitate cerebral oedema and seizures. In general the hypernatraemia
should be corrected over more than 48 h and no faster than 1–2 mmol/h.
Non-renal EFW loss

This is the commonest situation found in hospitalised patients as
insensible losses can be large, especially if the patient is ventilated,
febrile, etc. The key to successful management is the accurate estima-
tion of all EFW losses (respiratory, sweat, gastrointestinal) and to
match these losses with the appropriate intravenous fluids. This will
prevent worsening of the hypernatraemia whilst additional EFW must
then be given to correct the hypernatraemia. The water deficit can be
calculated from the equation:
ðSerum½Na 140Þ
Water deficit ¼ Total body water
140
This may be a useful guide to therapy. Typically half of the calculated
water deficit may be replaced within the first 24 h.
Osmotic diuresis
Therapy should be directed at treating the underlying cause (e.g. insu-
lin for hyperglycaemia) in order to reduce the excess EFW losses.
There is often significant volume depletion, which should be corrected
with normal saline. Half-normal saline is usually used as a source of
EFW in hyperglycaemia to correct the hypernatraemia as 5% dextrose
may exacerbate the raised blood sugar.
Central diabetes insipidus

This responds to ADH replacement therapy, which is usually adminis-
tered as intranasal desmopressin acetate (10–20 mg once or twice per
day). The patient should reduce oral water intake while receiving this
therapy or hyponatraemia will develop.
Nephrogenic diabetes insipidus

The underlying cause should be treated e.g. hypercalcaemia or hypo-
kalaemia and any contributing drugs such lithium discontinued if
18
Assessment of polyuria
1
possible. Often, nephrogenic diabetes insipidus is due to chronic inter-

stitial renal disease, which may not be reversible. In such circum-
stances the maintenance of a high oral water intake will maintain the
serum sodium level in the normal range but at the expense of poly-
uria. Measures to decrease the polyuria include dietary changes (low
sodium intake, protein restriction) and drugs that interfere with urine
dilution such as thiazide diuretics.
Assessment of polyuria
Subjects with abnormal water balance and polyuria can maintain nor-
mal serum sodium concentrations by matching their EFW losses with
adequate water intake. These patients present with polyuria rather
than hypernatraemia. The polyuria, generally defined as more than
3 L urine per day, should be confirmed by measuring at least two
24-h urine collections. Laboratory testing should include estimation
of plasma sodium, potassium, calcium and glucose levels, and plasma
osmolality. Urine tests should include osmolality and urine electro-
lytes (sodium, potassium, chloride and urea) and testing for glycos-
uria. The polyuria should be considered to be due to a water
diuresis or a solute diuresis, although both may be present in the same
patient.
Water diuresis
In this setting, the polyuria is due to excess urine water loss (diabetes
insipidus, psychogenic polydipsia). Therefore, the 24-h osmole excre-
tion rate is normal (10 mOsm/kg/day). It can be difficult to differen-
tiate between diabetes insipidus and psychogenic polydipsia. A water
deprivation test and measurement of plasma ADH levels may need to
be performed.
Solute diuresis
In this setting, the polyuria is driven by excess solute excretion (gly-
cosuria, high sodium intake (i.v. saline, high salt diet) or, more rarely,
high urea excretion (patients who are catabolic, receiving high protein
feeds or recovering from acute renal failure). Correcting the source of
the excess solute will treat the cause of polyuria, and hypotonic fluids
will correct the hypernatraemia.
19
CHAPTER
2
Disorders of
potassium
balance
The body in steady state is in potassium balance with potassium
intake (normally 60–80 mmol/d) equal to potassium excretion (renal
excretion 50–65 mmol/d and stool 10–15 mmol/d). The normal serum
potassium concentration ranges from 3.5 to 5.0 mmol/L.
Learning point
Disturbances of plasma potassium (K) levels are commonly
encountered in clinical practice. Both hyperkalaemia and hypo-
kalaemia may be life-threatening medical emergencies.
Distribution
Some 98% of total body potassium is intracellular and this is main-

tained by the Na–K-ATPase pump (Fig. 2.1). Therefore, a significant
shift in potassium to or from the intracellular fluid (ICF) can markedly
affect the serum potassium concentration and exert profound effects
on the resting membrane potential.
2 Disorders of potassium balance
98% of total body

potassium is intracellular
+
− +
ICF − ECF
[K+] = 140 mmol/L [K+] = 4 mmol/L
+ −
− + β2 antagonists directly
2K+ stimulate
Na–K-ATPase pump
+ −
3Na+
K+ Na+
H+
−
K+ + − Insulin drives K+ into cells
+ indirectly by stimulating
Na–H antiporter
Resting membrane potential
produced by electrogenic Na–K-
ATPase and passive diffusion of K+
out of cell down concentration gradient
Figure 2.1 Potassium distribution and resting membrane potential. Some 98%
of potassium is intracellular. The resting membrane potential is produced by the
electrogenic Na–K-ATPase and passive diffusion of Kþ out of the cell down the
concentration gradient. ICF, intracellular fluid; ECF, extracellular fluid.
Example:
A 70-kg man contains 42L total body water, 14L extracellular
fluid and 28L intracellular fluid.
Total ECF potassium ¼ 14 4:0 ¼ 56 mmol
Total ICF potassium ¼ 28 140 ¼ 3920 mmol
22
When should I check potassium level?
2
Potassium excretion
The kidney is primarily responsible for potassium regulation. In

health, the kidney can lower renal excretion to 5–10 mmol per day or
increase excretion to 450 mmol per day depending upon potassium
intake.
Renal potassium excretion

Under normal circumstances, 180 L plasma are filtered per day, result-
ing in the entry of 720 mmol potassium into the lumen of the nephron.
If the serum K concentration increases to 5.0 mmol/L, then an extra
180 mmol K will be filtered. The majority of the filtered K (around
500 mmol) is reabsorbed in the proximal tubule. The control of potas-
sium secretion occurs primarily in the principal cells of the cortical
collecting duct (CCD) (Fig. 2.2). Potassium secretion is dependent on
the delivery of sodium and water to the CCD and on the action of
the hormone aldosterone. Aldosterone increases sodium reabsorption
from the lumen and promotes potassium secretion into the lumen,
restoring electrical neutrality.
Gastrointestinal potassium excretion

Although gastrointestinal loss usually accounts for 10–15 mmol K
excretion per day, this route can be increased in chronic renal failure,
when it may account for up to 50% of potassium intake.
There are myriad potential reasons for requesting estimation of a

serum potassium (K) level but the commonest and most important
indications in clinical practice include the following.
Patients with cardiac disease

Both raised (hyperkalaemia) and subnormal (hypokalaemia) serum
potassium levels may have significant effects upon cardiac conduc-
tion. It is therefore critically important to ensure that potassium levels
are maintained in the normal range in patients with myocardial infarc-
tion, cardiac dysrhythmias or receiving digoxin therapy.
23
Lumen Cortical collecting duct Blood
Na+
Cl
Na+ 2K+
Na+ reabsorption
creates luminal
3Na+
electronegativity
promoting K+ and
H+ secretion Aldo-R Aldosterone stimulates
Na–K-ATPase pumps
and inserts Na and K
−ve K+
channels in luminal
membrane
Principal cell
Cl
2K+
3Na+
K+ H+
Cl−
−
HCO3
Intercalated cell
Figure 2.2 Renal excretion of potassium. Potassium secretion is controlled in the

cortical collecting duct (CCD). Sodium reabsorption in this segment produces a
negative voltage gradient, promoting K secretion under the actions of aldosterone.
Aldo-R, aldosterone receptor.
Patients receiving drugs that may affect serum

potassium level
Drugs such as loop diuretics may lower serum potassium levels,
whereas drugs such as potassium-sparing diuretics, angiotensin
24
2
converting enzyme (ACE) inhibitors, non-steroidal anti-inflammatory

drugs (NSAIDs) may increase serum potassium levels.
Patients with diabetes mellitus

Patients who present to hospital with acute diabetic ketoacidosis often
have normal or slightly raised potassium levels as the systemic acido-
sis promotes the exit of potassium from cells into the extracellular
fluid. Treatment with insulin drives potassium back into the intracel-
lular compartment and the serum potassium level may rapidly fall
such that hypokalaemia is a real risk. These dehydrated patients typi-
cally receive large volumes of intravenous fluid and are markedly
polyuric. They therefore require very close monitoring of serum potas-
sium level (2–4-hourly) combined with judicious potassium supple-
mentation. Patients with long-standing diabetes mellitus may also
develop a type IV renal tubular acidosis, which may lead to trouble-
some hyperkalaemia. This often results in an intolerance to ACE inhi-
bitors and to renal replacement therapy being commenced slightly
earlier in diabetic patients than in patients with other causes of renal
failure.
Patients with major fluid and electrolyte fluxes

This may be seen in patients receiving large volume of intravenous
fluids, e.g. postsurgical patients with major fluid losses from drains
and wounds as well as patients receiving total parenteral nutrition.
In addition, severe diarrhoea may cause significant fluid and electro-
lyte disturbance with hypokalaemia.
Patients with renal impairment

Patients with renal functional impairment have a reduced capacity to
excrete potassium and are therefore more prone to hyperkalaemia.
A low threshold for checking serum potassium is recommended in
such patients, particularly if a potential cause for hyperkalaemia is
present.
Patients with weakness of unknown aetiology

Potassium plays an important role in neuromuscular physiology, and
paralysis and ventilatory respiratory failure may ensue from severe
hypokalaemia.
25
Usually, the potassium level does not require overt action, although
trends should be sought, i.e. if the potassium level is ‘drifting up’ then
look for a cause and deal with it. Is the patient receiving potassium
supplements? Is the patient’s renal function normal? However, any-
thing other than prompt action when potassium levels are below
3 mmol/L or greater than 6 mmol/L is perilous. The management of
these important scenarios is outlined later in this chapter.
Hypokalaemia (<3.5 mmol/L)
Hypokalaemia may result from depletion of total body potassium sec-

ondary to excessive renal or gastrointestinal losses, but may also result
from a shift of potassium into cells.
Symptoms and signs
The primary symptoms of hypokalaemia are muscle weakness

and paraesthesia. The primary risks are cardiac arrhythmias and
ventilatory failure.
Hypokalaemia results in hyperpolarisation of the cell membrane,

which impairs the ability of the cell to generate action potentials in
excitable tissues such as muscles and nerves. Mild hypokalaemia
(3–3.5 mmol/L) is often asymptomatic. Moderate hypokalaemia
(2.5–3.0 mmol/L) may result in muscle weakness, fatigue and paraes-
thesia as well as ileus and constipation, because the smooth muscle of
the gastrointestinal tract may be affected. In rare instances, severe
hypokalaemia may precipitate rhabdomyolysis. Hypokalaemia may
also interfere with the ability of the kidney to concentrate the urine,
thereby resulting in nephrogenic diabetes insipidus with polyuria
and polydipsia.
In patients with cardiac disease, hypokalaemia is associated with a
greatly increased risk of ventricular arrhythmias. Although ECG
changes (flattened T waves, inverted T waves, U waves) are typically
present when the serum potassium level is less than 3.0 mmol/L,
these changes do not correlate well with the risk of ventricular
26
2
arrhythmias (Fig. 2.3). Severe hypokalaemia (< 2.5 mmol/L) can lead
to weakness of respiratory muscles and ventilatory failure.
Differential diagnosis
Hypokalaemia may be considered to be due to insufficient potassium
intake, a shift of potassium from the extracellular fluid to the intracel-
lular compartment or excessive potassium excretion from the gut or
kidneys.
Artefactual
This may occur if the blood was drawn from near the site of an intra-
venous infusion of fluid that does not contain potassium. In cases of
doubt, take another sample to confirm or refute the diagnosis.
Low potassium intake

This may be due to insufficient potassium in the diet or intravenous
fluids (e.g. postsurgery). It should be noted that, as the fall in potas-
sium intake induces increased renal conservation of potassium,
a low potassium intake alone does not cause hypokalaemia.
Shift of potassium into the intracellular compartment

Factors stimulating a shift of potassium into cells include insulin,
b2 agonists such as salbutamol, catecholamines or an alkalosis. Hypo-
kalaemia may therefore occur in patients receiving treatment for diabe-
tes mellitus or asthma. It should also be noted that concurrent
hypophosphataemia is suggestive of an intracellular shift of potassium.
Gastrointestinal losses
Gastrointestinal losses such as vomiting, nasogastric aspiration or
diarrhoea are a common cause of hypokalaemia. Interestingly, the
potassium concentration of gastric juice is only 10 mmol/L, but the
vomiting is often associated with extracellular volume contraction.
This stimulates aldosterone release and, combined with the increased
delivery of sodium bicarbonate to the distal nephron, results in renal
potassium wasting. The potassium concentration in diarrhoea is often
30–35 mmol/L, and the hypokalaemia that may result is associated
with a non-anion gap metabolic acidosis. Other causes of gastrointes-
tinal potassium loss include villous adenomas, fistulae, laxative abuse
and ureterosigmoidostomy.
27
Hypokalaemia
Shift Acidosis Alkalosis

• Insulin • Renal tubular
• Catecholamines acidosis
• Periodic paralysis • Diarrhoea
• Thyrotoxic • Laxative abuse
periodic paralysis • Villous adenoma ↓ ECV ↑⁄↔ ECV
• Ureterosigmoidostomy
• Carbonic anhydrase
Check renin and
inhibitor
aldosterone levels
Low urine Cl− High urine Cl−

• Vomiting • Diuretics
• Remote • Bartter’s
diuretic use • Gitelman’s
• Cystic fibrosis • Gentamicin
• HypoMg
↑ Aldo ↑ Aldo ↓ Aldo

↑ Renin ↓ Renin ↓ Renin
• Renal artery stenosis • Primary • Liddle’s (amphotericin)

• Renin tumour hyperaldosteronism • Apparent mineralocorticoid
• Malignant hypertension (BAH, adenoma) excess (liquorice)
• Glucocorticoid remediable • Hypomagnesaemia
hyperaldosteronism • Cushing’s
(fludrocortisone) • (17α or 11β
hydroxylase deficiency)
Figure 2.3 Differential diagnosis of hypokalaemia. Aldo, aldosterone;

BAH, bilateral adrenal hyperplasia; ECV, extracellular fluid volume;
hypoMg, hypomagnesaemia.
28
2
Renal losses
Diuretics are the most common cause of hypokalaemia. They inhibit
sodium reabsorption resulting in extracellular volume contraction
with stimulation of aldosterone release, and increase the delivery of
sodium and chloride to the CCD. Bartter’s and Gitelman’s syndromes
are rare genetic conditions in which mutations in genes encoding
sodium transporters in the loop of Henle and distal tubule respec-
tively simulate chronic diuretic use.
Drugs associated with hypokalaemia:

Diuretics, gentamicin, amphotericin, carbenoxolone, laxatives,
acetazolamide, fludrocortisone
Hyperaldosteronism secondary to a decreased extracellular volume

promotes renal potassium loss. In primary hyperaldosteronism there
is autonomous aldosterone production from an adrenal adenoma or
bilateral adrenal hyperplasia resulting in expansion of extracellular
volume and an increased delivery of sodium and chloride to the
CCD. The sodium and water retention results in hypertension with a
characteristic hypokalaemic metabolic alkalosis. Other causes of
excess mineralocorticoid activity include Cushing’s syndrome and
exogenous corticosteroids or fludrocortisone.
Although renal diseases that result in renal failure are typically
associated with hyperkalaemia due to a decreased glomerular filtra-
tion rate, some renal disorders are associated with hypokalaemia.
For example, renal tubular acidosis (RTA) results in increased urinary
potassium loss as well as causing a chronic systemic acidosis. The
increased urinary potassium loss results from distal potassium secre-
tion secondary to either increased sodium delivery to the distal tubule
(proximal RTA) or defective distal hydrogen ion excretion (distal
RTA).
Special situations
Heart disease
In patients with cardiac disease, e.g. postmyocardial infarction and
cardiac failure (particularly if taking digoxin), hypokalaemia may
induce ventricular arrhythmias and the serum potassium level should
be maintained at the high end of normal.
29
Liver failure
Hypokalaemia results in increased production of ammonia and can
exacerbate hepatic encephalopathy.
Management
Assessment
The presence of paralysis or arrhythmias indicates an emergency situa-
tion. Assess the cardiovascular status (pulse rate, rhythm, lying and
standing blood pressure, jugular venous pressure, presence of oedema)
and look for evidence of arrhythmias (check ECG) and hypo/hypervo-
laemia. Is the patient diabetic or asthmatic? Carefully scrutinise the
fluid balance charts – is the patient oliguric and in renal failure? Exam-
ine the drug chart for drugs that can affect potassium levels, e.g. insu-
lin, diuretics, steroids, gentamicin. Does the patient have an abnormal
venous bicarbonate level indicating a metabolic acidosis or alkalosis?
Consider the degree of potassium deficit and ongoing potassium losses
from gastrointestinal tract or kidneys. Check the serum magnesium
level in complicated patients or in those with severe hypokalaemia, as
hypokalaemia will not respond to replacement therapy if the patient
is hypomagnesaemic.
Emergency treatment
l If hypokalaemia is severe (<2.5 mmol/L) it may be associated with
muscle weakness leading to ventilatory failure or cardiac arrhyth-
mias. Intravenous replacement is appropriate in this setting.
l Potassium chloride should be diluted in normal saline to a con-
centration of 40–60 mmol/L. Note that dextrose solutions
may stimulate insulin and shift potassium into cells and should
not be used. Rarely 10–20 mmol potassium chloride (KCl) may
be infused in 100 mL saline over 30 min in extreme situations.
Never give ampoules of KCl directly without diluting. Potas-
sium-containing intravenous solutions can be very irritant to
peripheral veins and it may be preferable to give these through a
central line.
l The initial rate of potassium replacement may be as high as
20–40 mmol/h, but this should be done only with continuous
ECG monitoring. The replacement rate should be reduced to
30
Hyperkalaemia
2
10 mmol/h when the patient is out of immediate danger. The

serum potassium must be checked regularly (initially at least
hourly) during emergency treatment.
Non-urgent treatment
l Any underlying conditions such as renal failure should be treated
and causative drugs discontinued.
l Oral potassium replacement is the safest route for potassium
replacement in most situations, although potassium supplements
may cause gastrointestinal upset. Typical replacement in the short
term may be 60–120 mmol potassium chloride per day in three or
four divided doses. Attention should be paid to ongoing potassium
losses, and treatment should be guided by serum potassium mea-
surements.
Hyperkalaemia
Hyperkalaemia is often asymptomatic, but the primary risk is of

cardiac arrhythmias and sudden death.
Symptoms and signs

Hyperkalaemia reduces the polarisation of the cell membrane so that
it falls closer to the threshold for depolarisation, thereby making cells
more excitable. Clinical symptoms are uncommon, although some
patients may experience paraesthesia, cramps, severe muscle weak-
ness or even paralysis.
The main danger is cardiac arrhythmia, particularly bradyarrhyth-
mias or sudden death. The risk is related to the degree of hyperkalae-
mia (>6.0 mmol/L), the rate of rise of the serum potassium level and
the degree of acidosis or hypoxia. ECG changes including tall peaked
T waves are typically present, but more worrisome changes include
bradycardia, prolongation of the PR interval, loss of P waves, broaden-
ing of the QRS complex and the development of a ‘sine wave’ pattern
(Fig. 2.4).
31
T wave
P wave
QRS
Normal ECG Peaked T waves
Tall tented
Wide QRS T wave
Prolonged PR
interval
Prolonged PR interval Widening QRS complex

Figure 2.4 ECG changes of hyperkalaemia.
Special situations
Diabetic ketoacidosis
Hyperkalaemia may occur at presentation due to a shift of potas-
sium out of cells (due to insulin lack and hyperglycaemia). How-
ever, total body potassium is depleted due to prior urinary loss of
K (osmotic diuresis and loss with keto-anions) and serum potas-
sium levels can fall precipitously when insulin and IV fluids are
commenced.
32
Hyperkalaemia
2
Differential diagnosis (Fig. 2.5)
The most common causes of hyperkalaemia are

l Acute or chronic renal impairment with consequent reduced
potassium excretion
l Drug related
l Acute shifts of potassium out of cells into the extracellular fluid.
Hyperkalaemia
Shift • Renal failure Decreased ↓ Distal Na+ and

• Insulin lack aldosterone H2O delivery
• Hyperglycaemia action • Volume depletion
• Acidosis • Heart failure
• β-blockers
• Digoxin
• Cell injury/catabolism
• (Pseudohyperkalaemia)
Aldosterone Aldosterone
deficiency resistance
Primary Hyporeninaemic • Drugs (K-sparing diuretics,

• Adrenal disease hypoaldosteronism trimethoprim, pentamidine)
• Congenital adrenal • Diabetic nephropathy • Tubulointerstitial disease
hyperplasia • Renal disease • Rare genetic abnormalities
• Aldosterone • NSAIDs
synthase deficiency • Ciclosporin
• Heparin • Obstruction
• (ACEI/ARB)
Figure 2.5 Differential diagnosis of hyperkalaemia. ACEI, angiotensin-

converting enzyme inhibitors; ARB, angiotensin II receptor blockers;
NSAIDs, non-steroidal anti-inflammatory drugs.
33
Artefactual and pseudohyperkalaemia

This may occur if the venesection was traumatic or there was a long
delay (>3 h) between venesection and separation of the plasma, as
potassium may leak slowly from cells. Consider pseudohyperkalaemia
in situations where there is a marked leukocytosis (>11 106/mL)
or thrombocytosis (>400 106/mL). In this case the serum K concentra-
tion will be raised but the plasma K level will be normal.
High potassium intake

Increased potassium intake per se is not a cause of hyperkalaemia as
the kidneys can excrete a large potassium load. A high potassium
intake, however, may be a significant contributing factor especially
in patients with impaired renal function. High intake may be dietary
(fruits, certain vegetables) or iatrogenic (secondary to excessive K
replacement).
Shift of potassium from the intracellular compartment

Factors promoting a shift of potassium out of cells include hypergly-
caemia, a lack of insulin, b2 antagonists and acidosis. Note that the
combination of hyperphosphataemia and hyperkalaemia is found in
conditions associated with cell damage such as rhabdomyolysis,
severe burns, tumour lysis syndrome or following severe blood trans-
fusion reactions.
Reduced renal potassium excretion

This is most commonly due to renal failure or to drugs that interfere
with potassium excretion.
Drugs associated with hyperkalaemia

ACE inhibitors, angiotensin II receptor blockers, potassium-
sparing diuretics, NSAIDs, digoxin, b2 antagonists, ciclosporin.
Renal potassium excretion requires an adequate glomerular filtra-

tion rate, delivery of sodium to the distal nephron and the action of
aldosterone (see Fig. 2.2).
l A decreased glomerular filtration rate is found in acute and chronic
renal failure.
34
Hyperkalaemia
2
l Reduced sodium delivery to the distal nephron may be seen with

severe volume depletion or heart failure – the urine sodium con-
centration is low (<20 mmol/L).
l Impaired aldosterone action may be due to adrenal disease (e.g.
Addison’s disease, hyporeninaemic hypoaldosteronism) or aldoste-
rone resistance (e.g. potassium-sparing diuretics, tubulointerstitial
disease, obstructive nephropathy). It should be noted that diabetic
patients with diabetic nephropathy may develop hyporeninaemic
hypoaldosteronism and troublesome hyperkalaemia at an earlier
stage than non-diabetic patients with chronic renal impairment,
often necessitating the institution of renal replacement therapy at
an earlier stage.
Management
Assessment
If the serum potassium is >6.5 mmol/L then emergency treatment is
merited. Check the ECG trace for signs of cardiac instability and pro-
ceed to emergency treatment if ECG changes are present. Assess the
patient’s cardiovascular status (pulse rate and rhythm, lying and sit-
ting/standing blood pressure, jugular venous pressure, presence of
oedema) for evidence of arrhythmias and hypo/hypervolaemia. Is
the patient diabetic? What is the blood glucose level? Is the patient
hypoxic or acidotic? Check the urine output and the drug chart care-
fully for drugs that may be implicated in raising the potassium level.
Emergency treatment (Table 2.1)

If ECG reveals changes of hyperkalaemia, continue ECG monitoring
and obtain intravenous access.
1. Give intravenous calcium gluconate (10%, 10 mL administered
over 5 min) to antagonise the effects of hyperkalaemia on the heart
and stabilise the myocardium. This drug is short acting and may
need to be repeated.
2. Shift potassium into cells by giving insulin and dextrose (6 units
fast-acting insulin and 50 mL 50% dextrose) over 10 min. Com-
mence an insulin and dextrose infusion (6 units fast-acting insulin,
50 mL 50% dextrose in 500 mL 5% dextrose) with monitoring of
blood glucose levels. If the patient is acidotic and not in pulmonary
oedema, consider giving sodium bicarbonate (500 mL 1.4% NaHCO3
35
2
36
Disorders of potassium balance

Table 2.1 Emergency therapy of hyperkalaemia
Therapy Dose Mechanism of Onset Duration of Risks

action action
Calcium 10 mL of 10% Stabilises 1 min 10–20 min Vein irritation
gluconate myocardium
Insulin and 50 mL 50% þ 6 units Shifts Kþ into cells 20–30 2h Hypoglycaemia
dextrose insulin min
Sodium 500 mL of 1.4% Shifts Kþ into cells 2–4 h Up to 24 h Volume
bicarbonate overload
Salbutamol 20 mg in 4 mL saline Shifts Kþ into cells 15–30 2h Tachycardia
nebulised min
Calcium 15 g t.i.d. (with 30 mL Binds Kþ in bowel 2–4 h Removes Kþ Intestinal
resonium lactulose) obstruction
Haemodialysis – Removes Kþ 30 min Removes Kþ
Hyperkalaemia
2
over 1–2 h). Note that 8.4% NaHCO3 is hypertonic and should not be
given peripherally. If central venous access is available, consider
giving aliquots of 25–50 mL 8.4% NaHCO3 but monitor carefully
for volume overload. b2 agonists such as salbutamol will also shift
potassium into cells, but may exacerbate cardiac instability and are
usually used in children.
3. Increase potassium elimination by giving cation exchange resin
(15 g calcium resonium with 30 mL lactulose three times per day).
This is a slow-acting treatment and not appropriate in an emer-
gency setting.
4. Dialysis may be required in patients with renal failure and refrac-
tory hyperkalaemia.
Non-urgent treatment
Any underlying causes should be treated, offending drugs discontin-
ued and a low potassium diet considered. Long-term therapy with cat-
ion exchange resins should be avoided as there is a risk of forming
concretions in the bowel. Increased renal potassium elimination may
be achieved by volume expansion with normal saline and judicious
use of loop diuretics to improve the distal delivery of sodium and water.
Fludrocortisone may be useful in the setting of hypoaldosteronism.
37
CHAPTER
3
Assessment of
renal function and
urinary protein
excretion
Introduction
The assessment of renal function is important in both inpatient

and outpatient settings. Renal function is generally assessed by
measuring the serum creatinine and urea levels, or calculating
the glomerular filtration rate (GFR) (or creatinine clearance). Acute
renal failure occurs when renal function deteriorates over a
short period of time (days to weeks) and is common in patients
in intensive care units as a complication of conditions such as
septic shock, pancreatitis, etc. Chronic renal failure is irreversi-
ble renal impairment that commonly occurs in patients with
medical conditions such as diabetes, ischaemic heart disease and
long-standing hypertension, and must be taken into account in
their clinical management. It is important to note that, in condi-
tions that are limited to the kidneys, the only clinical evidence of
disease may be the presence of haematuria, proteinuria and/or
3 Assessment of renal function and urinary protein excretion
renal impairment. Therefore the pertinent investigations covered

in this chapter will include:
l Measurement of serum creatinine and urea levels, and creatinine
clearance
l Dipstick urinalysis for blood and protein
l Urinary protein excretion and estimation.
Learning point
Many seriously ill, hospitalised patients develop a degree of renal
failure and the early detection of impaired renal function facili-
tates the initiation of relevant clinical investigations, appropriate
management of fluid and drug therapy, and may prevent a
requirement for dialysis.
The incidence of renal failure is increasing inexorably, with the

elderly population being particularly affected. These individuals
exhibit a range of conditions including renovascular disease and
prostatic obstruction, as well as diabetic nephropathy or acute
glomerulonephritis.
It is pertinent to consider the normal function of the kidneys as this
provides insights into what may become deranged in disease. In
health the kidneys are responsible for maintaining salt and water,
potassium, phosphate and acid–base homeostasis as well as produc-
ing the hormones 1,25-dihydroxycholecalciferol (active vitamin D)
and erythropoietin, which stimulates the production of erythrocytes.
It is therefore predictable that patients with failing kidneys may
exhibit salt and water retention (hypertension, oedema), hyperkalae-
mia, hyperphosphataemia, a metabolic acidosis (low venous bicarbon-
ate), a raised parathyroid hormone level, hypocalcaemia and anaemia,
as well as increased levels of urea and creatinine.
Assessment of renal function
Serum creatinine
Creatinine is a nitrogenous waste product produced from creatine in
muscle and is excreted by the kidneys. The majority of creatinine is
excreted by glomerular filtration, but a small portion (10%) is secreted
40
3
into the proximal tubular lumen. The normal serum concentration of

creatinine varies considerably between individuals (60–120 mmol/L),
depending on muscle mass, and can be used to estimate renal function.
Serum creatinine levels may be increased in

l Impaired renal function (renal failure). This is the most common
cause.
l Individuals with a large muscle mass, e.g. body builders
l Individuals taking certain drugs, such as trimethoprim or cimeti-
dine, as these can interfere with the renal tubular handling of
creatinine.
The serum creatinine may be low in

l Patients with a low muscle mass (malnourished, wasting and
debilitating diseases, or frail elderly individuals)
l Pregnant women (as a result of the increased GFR).
It must be emphasised that the serum creatinine level per se (normal
range 60–120 mmol/L) is not an accurate measure of renal function,
as the serum creatinine level does not become raised until more than
50% of renal function has been lost. It is therefore an insensitive
marker of the early stages of renal impairment as large changes in
1200
1100
1000
Plasma creatinine (μmol/L)
900
800 Small change in creatinine
clearance results in significant
700
change in plasma creatinine
600 Large change in creatinine
500 clearance results in small
400 change in plasma creatinine
300
200
100
0
10 30 50 80
Creatinine clearance (mL/min)
Figure 3.1 Relationship between plasma creatinine and creatinine clearance.
41
GFR result in small changes in serum creatinine concentration

(Fig. 3.1). The serum creatinine level may, however, be used to track
the progression of established acute or chronic renal failure. In partic-
ular, a graphical plot of 1/plasma creatinine against time (a reciprocal
creatinine plot) approximates to a straight line and the line may be
extrapolated to intersect the x-axis (time) and provide an estimate of
when the patient will reach end-stage renal disease if the rate of dete-
rioration in renal function remains constant (Fig. 3.2). The slope of the
reciprocal creatinine plot is very important: if the slope increases, this
indicates that the rate of loss of renal function has accelerated and the
patient will require dialysis earlier. Conversely, if the slope diminishes
then this indicates a diminution in the rate of progression of renal fail-
ure. Figure 3.2 depicts the reciprocal creatinine plot of a patient with
hypertensive renal disease who has progressive renal impairment.
An increased rate of deterioration was secondary to a period of uncon-
trolled severe hypertension, although eventually the hypertension was
controlled by a change in treatment. Comparison of the extrapolated
lines demonstrates that the regaining of blood pressure control will
have a major impact upon the eventual timing of the requirement
for dialysis.
100
Good BP control
120
130
Serum creatinine (μmol/L)
140
150 Uncontrolled
160 hypertension
170 Increased antihypertensive treatment
180
190 and stabilisation of progression
220
240
260
300
350
400
500
600 Dialysis
800 required 4 years
1300
Time (years/months)
Figure 3.2 The reciprocal creatinine plot.
42
3
Serum urea
Serum urea is of much less value than the serum creatinine level in the
assessment of renal function as the urea level is determined by many
variables other than renal function. Urea is a product of protein
metabolism and is generated in the liver following the deamination
of amino acids. Urea is excreted by the kidneys, undergoing glomeru-
lar filtration, but approximately 50% is then reabsorbed. The normal
urea concentration is 2.5–6.6 mmol/L, but is highly dependent on pro-
tein intake and volume status.
The serum urea concentration may be raised in

l Impaired renal function (renal failure)
l Volume depletion (increases renal reabsorption of urea)
l High protein diet
l Upper gastrointestinal bleed (protein load and hypovolaemia)
l Catabolic states (sepsis, steroid therapy).
The serum urea concentration may be decreased in

l Reduced protein intake (starvation, anorexia)
l Malabsorption
l Liver disease (unable to generate urea).
Of note, a disproportionate rise in the level of urea or creatinine in

acute renal failure may give a clue to the underlying disorder. Serum
creatinine levels may be increased when urea levels are relatively nor-
mal owing to decreased protein intake. Acute muscle injury (rhabdo-
myolysis) may cause acute renal failure (see Chapter 9), and in this
setting the serum creatinine concentration may be disporportionately
raised (muscle injury). By contrast, a disproportionate increase in the
serum urea level may suggest volume depletion (secondary to
increased urea reabsorption).
Glomerular filtration rate and creatinine clearance

Approximately 180 L of plasma water are filtered per day as blood
passes through the microvascular networks of the two to three million
glomeruli that are present in normal kidneys. This glomerular filtration
rate (GFR) depends upon the number of functioning glomeruli, the intra-
glomerular hydrostatic pressure, and the nature and surface area of glo-
merular filtration surface. Disease may affect any or all of these variables.
43
The normal GFR is approximately 100 mL per min per 1.73 m2 body sur-
face area, although the normal range is wide and varies with age
(Table 3.1). The GFR may be measured by various clearance techniques.
The clearance of any substance can be calculated by the equation:
C ¼ ðU VÞ=P
where U is the urine concentration of the substance, V is the urine flow

rate and P is the plasma concentration. When the substance is freely fil-
tered at the glomerulus and is neither reabsorbed nor secreted by the
tubules, the clearance of that substance is equal to the GFR. Inulin,
iohexol, 51Cr-EDTA or 99Tc-DTPA may be used accurately to measure
GFR by this methodology, but this requires the intravenous administra-
tion of the chosen filtration marker and is not performed routinely.
The clearance of creatinine over a 24-h period may be calculated
using a 24-h urine collection (urine volume and creatinine concentra-
tion) and a serum creatinine measurement. The 24-h creatinine clear-
ance is used in clinical practice to give a useful, albeit approximate,
measure of the GFR. Creatinine is freely filtered at the glomerulus but
is also secreted by the tubules to a limited extent (10%), and thus
the creatinine clearance overestimates the GFR, particularly in the
setting of advanced renal impairment where secretion of creatinine
constitutes a larger proportion of creatinine excretion. Another factor
that limits the exactness of the creatinine clearance is the potential inac-
curacy of any timed urine collection, which can vary by 20–30%.
Table 3.1 Normal GFR at different ages
Age (years) GFR (mL per min per1.73 m2)

20–30 116
30–40 107
40–50 99
50–60 93
60–70 85
70þ 75
44
3
Table 3.2 Stages of chronic kidney disease
Stage GFR (mL/min) Level of renal Comments

function
1 >90 Normal renal Requires the presence of
function proteinuria, microscopic
haematuria or abnormal renal
structure, e.g. genetic disease
or evidence of renal injury or
scarring
2 60–89 Mild renal Requires the presence of
impairment proteinuria, microscopic
haematuria or abnormal renal
structure, e.g. genetic disease
or evidence of renal injury or
scarring
3 30–59 Moderate renal
impairment
4 15–29 Severe renal Consider active planning for
impairment end-stage renal disease
5 <15 Approaching or at Consider renal replacement
end-stage renal therapy (haemodialysis or
failure peritoneal dialysis), renal
transplantation or
conservative management
Stages of chronic kidney disease

The GFR is used to categorise the stage of chronic kidney disease
(CKD), as indicated in Table 3.2. Note that the presence of proteinuria,
haematuria, genetic renal disease (e.g. polycystic renal disease) or evi-
dence of renal injury on a renal biopsy results in individuals being
classified as having stage 1 CKD even if the GFR is completely normal.
Equations to estimate glomerular filtration rate

As indicated above, the creatinine clearance is commonly measured
by using a 24-h urine collection, but this does introduce the potential
for error in terms of the completeness of the collection. An alternative
and more convenient method is to employ various formulae devised
to calculate the creatinine clearance using parameters such as serum
45
creatinine level, sex, age and weight of the patient. An example is the
Cockcroft and Gault formula:
K ð140 AgeÞ Bodyweight

GFR ¼
Serum creatinine ðmmol=LÞ
where K is a constant that varies with sex: 1.23 for males and 1.04 for
females. The constant K is used as females have a relatively lower
muscle mass. The Cockcroft and Gault formula overestimates the
GFR if the patient is obese.
An alternative formula for calculating GFR from the serum creatinine
is the Modification of Diet in Renal Disease (MDRD) formula, which
does not use the patient’s weight for the calculation of GFR. The for-
mula uses the serum levels of urea, creatinine and albumin together
with age and various correction coefficients for sex and race. There
are limitations to the use of the MDRD formula and it has not been vali-
dated in elderly patients, pregnant women, children or patients with
marked hypoalbuminaemia. Despite these caveats, it is of use in adult
medicine and some laboratories are including the value for the ‘esti-
mated GFR’ (eGFR) derived from the MDRD formula on clinical chem-
istry reports. An MDRD GFR calculator can be accessed online at
http://www.kidney.org/professionals/KDOQI/gfr_calculator.cfm.
The inaccuracy of using the serum creatinine level in isolation as an
indicator of renal function is demonstrated by calculating the esti-
mated creatinine clearance using such equations. Using the Cockcroft
and Gault formula, the estimated GFR of a 55-year-old man weighing
100 kg with a serum creatinine level of 230 mmol/L is 46 mL/min
(stage 3 CKD). In contrast, a 55-year-old woman weighing 44 kg with
a serum creatinine level of 230 mmol/L has an estimated GFR of
16 mL/min (stage 4 CKD, and very near to stage 5). This very marked
difference in renal function would have a major impact on patient
management and results from the fact that the serum creatinine level
is related to muscle mass. There are numerous examples of malnour-
ished small older women with significant renal impairment but a
serum creatinine level that is not far outside the ‘normal range’.
Other examples using the MDRD formula are shown in Table 3.3. Of
note, although renal function does deteriorate slightly with age, the
serum creatinine concentration of elderly individuals should still be
in the normal range. Thus, a raised serum creatinine level in an elderly
individual is abnormal and merits further investigation.
46
3
Learning point
The serum creatinine concentration is of limited value on its own
and must be considered in conjunction with the age and muscle
mass of the patient. It may be used:
l to generate an estimated GFR using various formulae
l to track the individual progress of a patient over time using a
reciprocal creatinine plot.
Table 3.3 Examples of GFR estimated from serum

creatinine
Age Sex Race Serum creatinine eGFRa (mL per min

(years) (mol/L) per1.73 m2)
25 M Black 140 69
25 M Caucasian 140 57
25 F Caucasian 140 42
60 M Caucasian 140 48
60 F Black 140 43
60 F Caucasian 140 35
a
Glomerular filtration rate estimated by the Modification of Diet in Renal Disease (MDRD)
Study equation.
Regulation of renal blood flow and the glomerular

filtration rate
Renal autoregulation acts to maintain renal blood flow at a constant
level despite fluctuations in the mean systemic arterial pressure. For
example, the glomerulus is protected from the effects of systemic blood
pressure due to reflex vasoconstriction of the afferent arteriole supply-
ing the glomerulus. Afferent arteriolar vasoconstriction is also induced
if there is increased delivery of sodium chloride to the macula densa at
the end of the loop of Henle (as would happen as a result of an increase
in systemic blood pressure, renal blood flow or GFR). There are also
mechanisms to maintain the GFR in the face of diminished renal perfu-
sion as may occur in hypovolaemic patients. Reduced renal perfusion
results in prostaglandin-mediated dilatation of the afferent arteriole
and angiotensin II-mediated vasoconstriction of the efferent arteriole
47
exiting the glomerulus. This maintains intraglomerular hydrostatic fil-

tration pressure and preserves the GFR (Fig. 3.3). Despite these protec-
tive mechanisms, the GFR will eventually fall in conditions associated
with a prolonged or severe reduction in renal perfusion.
PGE2 Angiotensin II
Afferent arteriole Efferent arteriole
a Glomerular filtration b Maintained glomerular filtration
PGE2 Angiotensin II
NSAID ACEI
c ↓↓ Glomerular filtration
Figure 3.3 Glomerular filtration during (a) normal renal perfusion and
(b) reduced renal perfusion. GFR is maintained by prostaglandin (PG)-mediated
dilatation of the afferent arteriole, and angiotensin II-mediated vasoconstriction of
the efferent arteriole. (c) Reduced filtration during reduced renal perfusion due to
NSAID or ACE inhibitor (ACEI) treatment antagonising autoregulation.
48
Assessment of proteinuria
3
An important clinical point is that many patients are treated with

angiotensin-converting enzyme (ACE) inhibitors and non-steroidal
anti-inflammatory drugs (NSAIDs), both of which are potentially dan-
gerous in the setting of reduced renal perfusion. ACE inhibitor-
mediated inhibition of efferent arteriolar vasoconstriction lowers the
intraglomerular pressure and reduces nephron hyperfiltration. This
may be beneficial in CKD as the decreased glomerular pressure will
reduce proteinuria, which is a well documented risk factor for progres-
sion of renal disease. However, in the context of reduced renal perfusion
(e.g. renal artery stenosis, hypovolaemia, severe heart failure), the
reduction in the capacity of the kidney to maintain the GFR puts patients
at an increased risk of developing acute renal failure. NSAIDs may also
lead to acute renal failure in these settings by inhibiting the autoregula-
tory dilatation of the afferent arteriole by prostaglandins.
Learning point
Treatment with ACE inhibitors or NSAIDs reduces the capacity of
the kidney to maintain the GFR during episodes of renal hypoper-
fusion, putting the patient at risk of acute renal failure.
Both protein size and charge dictate whether proteins are filtered at
the glomerulus under normal circumstances, with anionic proteins
being filtered to a lesser extent than cationic proteins. Low molecular
weight proteins are filtered in normal circumstances but are actively
reabsorbed by proximal renal tubular cells. Thus, although 4–5 g pro-
tein is filtered per day, the normal urinary protein excretion is less
than 300 mg per 24 h. Glomerular diseases damage the glomerular fil-
tration barrier resulting in large amounts of urinary protein (predom-
inantly albumin) excretion. By contrast, tubular injury impairs the
reabsorption of low molecular weight proteins.
Classification of proteinuria
Microalbuminuria
This comprises an increased level of urinary albumin excretion that is
insufficient to be positive on a urinary dipstick (a positive urinary
49
dipstick analysis for protein is called ‘macroalbuminuria’). Microalbu-

minuria is defined as the excretion of 30–300 mg albumin per 24 h that
has been confirmed on at least two occasions over a 3-month period
(Table 3.4). Microalbuminuria may be determined by analysing:
l A 24-h urine collection: an albumin excretion of 30–300 mg/day
represents microalbuminuria.
l A timed urine collection (e.g. overnight): an albumin excretion rate
of 20–200 mg/min represents microalbuminuria.
l A spot urine sample (e.g. early morning urine), when the level of
albumin is expressed with reference to the amount of creatinine in
order to control for variation in urine concentration. An ‘albumin
to creatinine ratio’ (or ACR) of 30–300 mg/g creatinine (3–30 mg/
mmol creatinine) represents microalbuminuria. Normal ACR values
vary with sex, and this needs to be taken into account: normal ACR is
<2.5 mg/mmol creatinine in males and <3.5 mg/mmol creatinine in
females.
Patients with type 1 or 2 diabetes and microalbuminuria are at high
risk of developing overt diabetic nephropathy and such patients merit
aggressive blood pressure control with ACE inhibitors as well as tight
glycaemic control and correction of dyslipidaemia. Microalbuminuria
may also be found in patients with hypertension and cardiovascular
disease, and is an independent risk factor for cardiovascular mortality.
Table 3.4 Urinary albumin excretion
Normal Microalbuminuria Macroalbuminuria

Albumin excretion <30 mg/day 30–300 mg/day >300 mg/day
rate using a
24-h urine
collection
Albumin excretion <20 mg/min 20–200 mg/min >200 mg/min
rate using a
timed urine
collection
Albumin <30 mg/g 30–300 mg/g >300 mg/g
creatinine ratio creatinine or creatinine or creatinine or
using a spot <3 mg/mmol 3–30 mg/mmol >30 mg/mmol
urine sample creatinine creatinine creatinine
50
3
Benign proteinuria
This is typically transient and secondary to physical activity or fever.
Some patients exhibit orthostatic proteinuria that is dependent upon
posture (see below).
Glomerular proteinuria
This is secondary to abnormal permeability of the glomerular filtration
barrier. It may be due to structural damage, e.g. immune complex
deposition in membranous nephropathy, or alteration of the cationic
charge of the glomerular basement membrane, as this facilitates
glomerular filtration of albumin, e.g. minimal change disease. Severe
glomerular proteinuria may cause the nephrotic syndrome – a triad of
heavy proteinuria (>3.5 g/day), hypoalbuminaemia and peripheral
oedema.
Tubular proteinuria
This is secondary to reduced reabsorption of low molecular proteins
such as b2-microglobulin. Tubular proteinuria is found in conditions
such as renal tubular acidosis, interstitial nephritis and acute tubular
necrosis, and is usually less than 2 g/day. Tubular proteinuria never
causes the nephrotic syndrome.
Overflow proteinuria
This is secondary to raised serum levels of proteins, such that the fil-
tered load simply exceeds the capacity of the tubules to reabsorb
them. For example, patients with myeloma may exhibit high circulat-
ing levels of light chains that are secreted by the clonal population of
B cells and this gives rise to light chains in the urine (Bence Jones pro-
tein). Similarly, myoglobin or amylase may be evident in the urine of
patients with rhabdomyolysis or pancreatitis respectively.
When should I consider performing dipstick urinalysis?

Ideally, all patients should have the urine checked for the presence of
microscopic haematuria and protein. It is important to note that renal
inflammation is typically ‘silent’ in most renal pathologies, including
the ‘renal limited’ forms of diseases such as vasculitis. In these circum-
stances, the only sign of ongoing severe renal disease may be dipstick
haematuria and proteinuria. Dipstick urinalysis detects mainly urinary
albumin as it is less sensitive to immunoglobulins and other urinary
51
proteins. The dipstick results are graded from negative to 4þ and the
values approximate to the urinary protein concentration as follows:
<10 mg/dL, negative; 10–20 mg/dL, trace; 30 mg/dL, 1þ;
100 mg/dL, 2þ; 300 mg/dL, 3þ; 1000 mg/dL, 4þ. Dipstick uri-
nalysis should be performed in:
l Patients with diabetes mellitus as they are at risk of developing
diabetic nephropathy.
l Patients with peripheral oedema or hypoalbuminaemia as they
may have the nephrotic syndrome.
l Patients with known renal disease under follow-up as it may be a
useful indicator of disease progression, remission or relapse, e.g.
patients with minimal change disease.
l Patients with renal impairment as it can inform the differential
diagnosis. For example, a middle-aged patient with renal
impairment but no haematuria or proteinuria would be extremely
unlikely to have active glomerulonephritis, and conditions such
as renovascular disease or interstitial renal disease would need to
be considered.
l Patients with immunological conditions such as systemic lupus
erythematosus (SLE) as the onset of haematuria or proteinuria
may be the first sign of renal involvement. Indeed, such patients
may have significant renal disease that requires aggressive treat-
ment despite having a completely normal plasma creatinine level.
Note that Bence Jones protein is not detected by urine dipstick analy-
sis and requires specific immunoelectrophoresis of the urine. In addi-
tion, patients with a negative finding on dipstick urinalysis may still
merit testing for microalbuminuria, for example patients with type 1
diabetes (after 5 years of disease), patients with newly diagnosed type
2 diabetes, or patients with cardiovascular disease or hypertension.

Quantify the amount of proteinuria
All patients with persistent proteinuria on dipstick urinalysis require
accurate quantification of protein excretion. This can be performed
using a 24-h urine collection, but such collections may be inaccurate
as patients may not collect all of the urine passed! Measurement of
the urinary albumin/creatinine ratio on a spot urine sample is a useful
and convenient method of determining the level of protein excretion.
The correction for urine creatinine attempts to take into account the
52
3
Table 3.5 Conversion of protein/creatinine ratio to

24-h urinary protein excretion
Protein excretion (g/24 h) Protein/creatinine ratio (mg/mmol

creatinine)
<0.3 <30
1 100
3.5 (nephrotic range 350
proteinuria)
10 1000
variation in urine concentration that occurs during the day. Table 3.5
shows the approximate conversions for a 70-kg man, although it should
be noted that the muscle mass of the patient and the rate of creatinine
production, and hence of excretion, will affect the values obtained.
Therefore, individuals with a higher creatinine production will have a
lower protein/creatinine ratio for a particular level of proteinuria. Ide-
ally the spot urine should be taken at approximately the same time of
day as there is a diurnal variation in protein excretion (reduced at night),
whereas the urinary excretion of creatinine is relatively constant.
Patients with heavy proteinuria require measurement of the serum
albumin concentration as they may be nephrotic. The presence of pro-
teinuria greater than 1 g per 24 h, microscopic haematuria, impaired
renal function, hypertension, or a suggestive clinical or family history
increases the likelihood of significant underlying renal pathology;
such patients need full investigation. Patients with significant protein-
uria benefit from rigorous blood pressure control if hypertensive and
treatment with ACE inhibitors (even if normotensive) as these drugs
lower the intraglomerular hydrostatic pressure and reduce protein-
uria. Nephrotic patients typically have markedly raised cholesterol
levels, and cholesterol-lowering treatment such as statin therapy is
indicated. Nephrotic patients are also hypercoagulable and should
receive prophylaxis for deep vein thrombosis.
Isolated proteinuria
If proteinuria is present only after strenuous exercise or urinary tract
infection, or during febrile illnesses, it is likely to be unimportant.
Young patients with dipstick proteinuria, however, do require the
53
exclusion of benign orthostatic proteinuria. This condition is charac-

terised by the absence of proteinuria following a period of recum-
bency: a fresh morning urine sample is negative for protein, with
proteinuria becoming detectable later during the day. If patients are
collecting a 24-h urine specimen then it is useful to perform a ‘split’
collection and analyse the early morning urine separately. The long-
term prognosis for this condition is very good.
Microscopic haematuria in the absence of proteinuria

Several urine specimens should be analysed in order to ensure that the
haematuria is not a transient finding, and urinary tract infection
should be excluded. Other potentially confounding factors include
menstruation, exercise-induced haematuria (marathon runners!) and
the ingestion of various food colourings. Malignancy of the urinary
tract and renal stones should be considered in patients over 40 years
of age. Relevant investigations include renal ultrasonography and a
kidney, ureter and bladder (KUB) X-ray, as well as possible referral
to the urologist for a cystoscopy. The presence of a family history of
renal disease, hypertension or impaired renal function would merit
referral to a nephrologist for a full assessment, to exclude intrinsic
renal disease.
When should I check renal function?

The measurement of serum urea, creatinine and electrolytes is com-
mon, and often performed as a ‘routine test’ before surgery. However,
it should be considered in many patients, including:
l All patients with microscopic haematuria and/or proteinuria
l All renal transplant patients
l Any seriously ill patient
l Patients with previously documented renal disease as renal func-
tion may deteriorate further in the context of an acute illness
(‘acute on chronic’ renal failure)
l Patients receiving potentially nephrotoxic drugs, e.g. aminoglyco-
sides, NSAIDs
l Patients who are oliguric (urine output <400 mL/day)
l Patients commenced on an ACE inhibitor, as initiation of this treat-
ment may result in a deterioration of renal function and/or hyper-
kalaemia. These complications are more common in patients with
diabetes, vascular disease or pre-existing renal impairment as such
patients may have occult renovascular disease. Serum urea,
54
3
creatinine and electrolytes should be checked before ACE inhibitor

treatment and at 4 days (moderate–high risk patients) or 7 days
(low risk patients) after commencing the ACE inhibitor. A repeat
blood test should be performed at 10 days in moderate–high risk
patients and after changes in the dose of ACE inhibitors or diure-
tics. Note that similar adverse effects may occur with angiotensin
receptor blockers. A rise of up to 20% in the serum creatinine level
after starting treatment with an ACE inhibitor may be tolerated,
but underlying renovascular disease should be considered if the
increase is more marked. The ACE inhibitor should be discontin-
ued if the serum potassium level becomes significantly increased.

If the result indicates renal impairment then previous laboratory data
are invaluable, even if they have to be obtained from another hospital
or the general practitioner. This may indicate whether the renal
impairment is acute or chronic, as well as giving an indication of the
rate of deterioration. If a number of values for plasma creatinine con-
centration are available, a reciprocal creatinine plot may be generated;
if the slope is steep, this may reinforce the severity of the situation. In
addition, patients with a serum creatinine level that is rising ‘through
the normal range’ need a careful assessment as this is also an omen
that all is not well.
Patients who develop renal impairment require a thorough and
careful clinical assessment as well as scrutiny of the drug chart. Have
they received nephrotoxic drugs, such as aminoglycosides (?recent
drug levels), NSAIDs or ACE inhibitors? Have they undergone a
radiological procedure involving the administration of contrast
medium? Important physical signs include evidence of generalised
vascular disease with reduced or absent peripheral pulses, bruits,
etc. (underlying renovascular disease), skin rashes (allergic interstitial
nephritis, vasculitis, endocarditis), fever (sepsis), or a palpable bladder
(prostatic obstruction) or kidneys (polycystic kidney disease).
Most acute renal failure that occurs in a hospital setting is secondary
to acute tubular necrosis, which may result from severe sepsis, hypoten-
sion or renal toxins. In all such patients, a careful assessment of fluid sta-
tus is critical as the patient may be clinically hypovolaemic (low jugular
venous pressure [JVP], postural hypotension, weight loss) and have
developed pre-renal uraemia. Potential causes include excessive admin-
istration of diuretics, insufficient intravenous fluid replacement, and
55
excessive gastrointestinal (vomiting, diarrhoea) or renal (polyuria sec-

ondary to uncontrolled diabetes mellitus or diabetes insipidus) losses.
It should be remembered that patients with established chronic renal
impairment exhibit a defective capacity to concentrate their urine and
are therefore more prone to the development of ‘acute on chronic’ renal
failure. If detected at an early stage ‘pre-renal’ uraemia is readily reme-
diable by the administration of intravenous fluids, with appropriate
monitoring of urine output and blood pressure. Renal function may,
however, deteriorate further if pre-renal uraemia is undetected or trea-
ted inappropriately, e.g. administration of furosemide to an oliguric
patient who is dehydrated.
In contrast, some patients with acute or chronic renal impairment
may be salt and water overloaded (raised JVP, hypertension, periph-
eral oedema, basal pulmonary crepitations), such that further adminis-
tration of fluids may be dangerous and provoke acute pulmonary
oedema. The levels of serum potassium must be monitored closely
and drugs that may cause hyperkalaemia discontinued (potassium
supplements, potassium-sparing diuretics, etc.).
Differential diagnosis of renal failure
There are myriad causes of renal failure, classically categorised as pre-

renal, renal or post-renal. Renal ultrasonography is essential to success-
ful management and provides very important information. If the
kidneys are normal in size and non-obstructed, the patient has acute
renal failure. The presence of small atrophic kidneys or large cystic
kidneys indicates an element of chronic renal impairment. Asymmetry
in renal size suggests unilateral congenital dysplasia, renal scarring sec-
ondary to reflux nephropathy, or renovascular disease with unilateral
ischaemic renal atrophy. However, it is important to note that patients
with pre-existing chronic renal failure may develop acute-on-chronic
renal failure for any of the reasons outlined previously, and this is
potentially reversible if diagnosed and treated appropriately.
Pre-renal causes
l Hypovolaemia, e.g. acute blood loss, third space sequestration of
fluid (bowel obstruction), hypotension (systemic sepsis, myocar-
dial infarction)
l Reduction in renal blood flow (e.g. renovascular disease).
56
Management
3
Renal causes
Glomerular disease
The differential diagnosis is wide but includes diabetic nephropathy,
forms of glomerulonephritis (IgA nephropathy, membranous nephro-
pathy, focal segmental glomerulosclerosis); lupus nephritis, antineutro-
phil cytoplasmic antibody (ANCA)-positive vasculitis, haemolytic
uraemic syndrome.
Tubulointerstitial disease
Acute tubular necrosis is the commonest cause of acute renal failure in
hospitalised patients and may be multifactorial in aetiology, for exam-
ple sepsis, severe hypotension or nephrotoxic drugs (aminoglycosides,
NSAIDs). Drug-induced interstitial nephritis may be a complication of
myriad drugs including antibiotics and diuretics. Patients with adult
polycystic kidney disease have a characteristic appearance on renal
ultrasonography. Sarcoidosis may be associated with hypercalcaemia
and a raised level of ACE. Patients with analgesic nephropathy typi-
cally exhibit small smooth kidneys and have a history of prolonged
analgesic intake for arthritis, headaches, etc.
Post-renal causes
There are numerous causes of obstructive nephropathy including
prostatic hypertrophy, pelvic malignancy (e.g. cervical carcinoma),
retroperitoneal disease (fibrosis, tumour infiltration), transitional cell
carcinoma of the ureter, or renal calculi in a single functional kidney.
In addition, myeloma may cause acute intra-renal obstruction of
nephrons as a result of the intratubular precipitation of filtered light
chains (‘myeloma kidney’).
Management
The aims of management for all patients with acute or chronic renal
failure include:
l Actively treat any readily reversible component, e.g. intravenous
fluids in patients with pre-renal uraemia, stop nephrotoxic drugs,
commence immunosuppression for acute lupus nephritis.
l Minimise the rate of subsequent progression of renal failure, e.g.
tight diabetic and blood pressure control, reduce proteinuria with
ACE inhibitor treatment.
57
l Treat and prevent complications, e.g. oral sodium bicarbonate for a

metabolic acidosis, vitamin D derivatives for secondary hyperpara-
thyroidism and the prevention of renal bone disease, oral phos-
phate binders for hyperphosphataemia.
l Modify cardiovascular risk (smoking, lipids) as patients with renal
disease exhibit a much higher cardiovascular mortality. This is
particularly marked in young patients (<30 years old) who have
a 100-fold increase in cardiovascular mortality compared with
age-matched controls.
l Make a definitive diagnosis if possible, as treatment may be avail-
able and some diseases may recur following renal transplantation,
e.g. focal segmental glomerulosclerosis.
l Ensure a smooth transition to renal replacement therapy if and
when indicated.
Learning point
When managing patients with renal failure, liaise with senior col-
leagues at an early stage to ensure optimal early management and
prevent potentially serious complications.
Fluid balance
Patients with significant renal impairment have diminished homeo-
static mechanisms regarding salt and water balance, and therefore
fluid replacement therapy must be appropriate (not too much and
not too little). Close monitoring of serum electrolytes is required dur-
ing such intravenous treatment in order to avoid electrolyte disorders
such as hyponatraemia. In general the administration of potassium is
avoided as few patients with renal impairment become significantly
hypokalaemic, but hyperkalemia is a real risk. In severely ill patients
the monitoring of central venous pressure may be a useful guide to
fluid treatment.
Renal biopsy
If a patient develops renal failure in the context of unobstructed, nor-
mally sized kidneys and the cause is not apparent, a renal biopsy
should be considered and the patient discussed with the nephrology
team. Such patients also undergo extensive immunological tests
as these may be informative, e.g. complement levels, antinuclear
58
Management
3
antibody, ANCA, antiglomerular basement antibody levels, serum

IgG electrophoresis, urinary Bence Jones protein, etc. (see Chapter 10).
Renal replacement therapy

Dialysis is indicated for:
l Hyperkalaemia unresponsive to conventional medical manage-
ment (see Chapter 2)
l Severe uraemia with a low GFR, especially if the patient has severe
nausea, is obtunded or develops uraemic pericarditis
l Severe fluid overload in oliguric patients with severe renal failure
who are unresponsive to diuretic therapy.
Current practice is to initiate haemodialysis earlier rather than later in
patients in whom it is apparent that the renal failure is irreversible or
will require time to respond to treatment. The adjustment of fluid sta-
tus by dialysis allows appropriate nutritional support and the admin-
istration of drugs, blood products, etc. Peritoneal dialysis is not
commonly used for patients with acute renal failure but is a useful
modality for chronic renal replacement therapy.
59
CHAPTER
4
Metabolic acid–
base disorders
Introduction
Disorders of acid–base balance are commonly encountered in acutely

unwell or complicated medical and surgical patients but the interpre-
tation of acid–base data must be placed in the context of the clinical
situation in order to be used to maximal effectiveness. In addition,
an understanding of some key physiological principles is required.
Acid–base homeostasis
The plasma concentration of hydrogen ion (Hþ) is very low

(40 nmol/L) and is maintained within a very narrow range by:
1. buffering, with excretion of CO2 by lungs
2. excretion of Hþ by the kidneys.
pH
The pH of a solution is equal to the negative logarithm of the hydro-
gen ion concentration:
pH ¼ log½Hþ
4 Metabolic acid–base disorders
The pH of extracellular fluid (ECF) is maintained within a narrow

range (close to 7.4) which equates to a [Hþ] of 40 nmol/L. These tiny
concentrations of Hþ can be contrasted to the millimolar concentra-
tions of Naþ in the ECF (one million times greater) and to the daily
load of Hþ (1 mmol/kg) that must be excreted. Venous pH is 0.05 less
than arterial pH owing to the generation of carbon dioxide in the tis-
sues before removal by the lungs. In addition, the intracellular pH is
lower than extracellular pH and varies between tissues (e.g. skeletal
muscle 7.06, proximal convoluted tubule 7.13). It is important to
note at the outset that nanomolar changes in [Hþ] will generate biolog-
ically significant changes in pH. For example, a change in [Hþ] from
40 to 25 nmol/L will result in a large change in pH from 7.4 to 7.6.
The Henderson–Hasselbalch equation

pH is determined by the ratio of HCO3 to the partial pressure of car-
bon dioxide (PCO2) as given by Henderson–Hasselbalch equation:
pH ¼ pKa þ log½base=½acid
or
pH ¼ 6:1 þ log½HCO3 =½H2 CO3

The H2CO3 concentration can be derived from the arterial PCO2 by
multiplying by the solubility constant for CO2 in plasma (0.03 in
mmHg):
pH ¼ 6:1 þ log½HCO3 =½0:03 P CO2

In the normal state, the kidneys maintain the [HCO3] at 24 mmol/L
and the lungs maintain the PCO2 at about 40 mmHg (5.3 kPa).
Where does the acid load come from?

On a normal diet, the metabolism of fats and carbohydrate generates
15000mmol CO2 per day, which is excreted by respiration. The metab-
olism of proteins results in the generation of non-carbonic acids from
sulphur-containing amino acids (methionine and cysteine generate
H2SO4) or non-sulphur-containing amino acids (lysine and arginine
generate HCl). In addition, the metabolism of organophosphates yields
small amounts of H3PO4 and there is a small daily production of acid
62
Buffers
4
from cellular metabolism (lactic acid, pyruvic acid, acetic acid). There is
also some daily production of alkali from amino acids (glutamate,
aspartate) as well as organic anions (acetate, citrate). Vegetarian diets
contain higher levels of alkali-containing foods.
A normal diet generates 1 mmol/kg Hþ per day as non-volatile

acids, resulting in a net daily acid load of 50–100 mmol Hþ
(1 mmol/kg). These non-volatile acids cannot be excreted by res-
piration and must be excreted by the kidneys.
How does the body deal with the daily acid load?
The daily acid load and maintenance of the extracellular pH close to
7.4 is achieved by three key processes:
1. buffering free Hþ ions
2. alveolar ventilation, which removes CO2
3. Hþ excretion by the kidneys.
Buffers
A buffer is a substance (usually a weak acid or its base) that is able to

release or take up Hþ and is thus able to minimise any changes in
Hþ concentration. Buffers are present in both the extracellular (ECF)
and intracellular (ICF) fluid compartments. It should be noted that
buffers minimise changes in pH but do not remove acid from the body.
ECF buffers
HCO3 is the most important buffer in the ECF. Minor additional buf-
fers include plasma proteins and inorganic phosphates. HCO3 buffers
Hþ to generate water and CO2 that is excreted by alveolar ventilation:
Hþ þ HCO3 $ H2 CO3 $ H2 O þ CO2
As the level of HCO3 falls, the buffering capacity of the ECF falls and
the defence against overwhelming acidosis is diminished. Renal excre-
tion of Hþ must occur in order to replenish HCO3 buffer.
63
ICF buffers
These comprise various intracellular proteins (imidazole group on histi-
dines), haemoglobin in erythrocytes, HCO3 and phosphates (Table 4.1).
Buffering of Hþ in bone by calcium carbonate and calcium phosphates
can lead to bone demineralisation. The greater availability of intracellu-
lar buffers leads to a more efficient maintenance of intracellular pH.
The majority of Hþ is buffered initially by bicarbonate in the

extracellular fluid. Other buffers are recruited as the acid load
increases.
Respiratory control of pH
From the Henderson–Hasselbalch equation we can see that the pH is

determined by the PCO2 and the HCO3. The PCO2 is controlled by
respiratory ventilation and is maintained close to 40 mmHg in the nor-
mal resting state. Around 15 000 mmol CO2 are generated each day
from fat and carbohydrate metabolism. The accumulation of CO2 with
the resultant formation of H2CO3 is prevented by alveolar ventilation.
The increased [Hþ] is sensed by medullary chemoreceptors, which sig-
nal to the brainstem respiratory centres to increase ventilation.
Hypoventilation therefore results in an accumulation of CO2, the
formation of H2CO3, and a respiratory acidosis. Conversely, hyper-
ventilation leads to an excessive removal of CO2 (‘blowing off CO2’)
and a respiratory alkalosis (see Respiratory acid–base disorders in
Chapter 5).
Table 4.1 Distribution of buffers in a 70-kg man,

assuming a total body water of 42 L, [HCO3]ECF of
24 mmol/L and [HCO3]ICF of 12 mmol/L
Buffers (mmol)
Location HCO3 Protein Phosphate Other

ECF 336 <10 <15 0
ICF 336 400 <50 Minor
64
When should I check acid–base balance?
4
Renal regulation of pH
The kidneys perform two key functions

1. excretion of acid (mostly as NH4Cl)
2. regeneration of HCO3.
CO2 is generated when an acid load is buffered by HCO3 and is

excreted by alveolar ventilation. Unless the HCO3 is regenerated by
the kidneys, the HCO3 levels will fall and the buffering capacity of
the ECF will diminish. This is achieved by:
l Reclamation of all filtered HCO3 to avoid simply excreting buffer
(Fig. 4.1). This occurs primarily in the proximal tubule and is
dependent on brush border carbonic anhydrase, apical Naþ–Hþ
antiporter and basolateral Naþ–3HCO3 co-transporter. This pro-
cess is driven by the basolateral Naþ–Kþ-ATPase.
l Excretion of Hþ with the resultant generation of HCO3 (Fig. 4.2). In a
70-kg man, the daily acid load of 70 mmol Hþ is excreted as 40 mmol
NaH2PO4 and 30 mmol NH4Cl. The amount of NaH2PO4 is fixed
and, to excrete a greater acid load, extra NH4þ (ammonium) can
be generated and excreted with the resultant generation of more
HCO3.
The assessment of acid–base should be considered in:

l Any seriously ill patient, e.g. multiorgan failure, severe pancreatitis
l Patients with respiratory disease and/or respiratory failure
l Patients with uncontrolled diabetes mellitus
l Patients who have, or are suspected of having, ingested drugs or
poisons such as ethylene glycol (antifreeze) that can affect acid–
base balance.
65
3Na+ Na+ 3HCO3−
NBC-1
2K+ HCO3−
CA-II H2O
+
CO2
Na+ H+
NHE-3 CA-IV
− H+
Filtered HCO3 −
(4300 mmol/24 h) HCO3 H2CO3
Figure 4.1 Reclamation of filtered HCO3. With a daily glomerular filtration

rate of 180 L, approximately 4300 mmol (180 24) of HCO3 must be
reabsorbed. Some 90% of HCO3 reabsorption occurs in the proximal convoluted
tubule where it is coupled to Naþ reabsorption. Naþ is reabsorbed by a sodium
hydrogen exchanger (NHE-3) on the apical membrane, driven by a basolateral
Na–K-ATPase. The secreted Hþ combines with luminal HCO3 in setting of the
brush border carbonic anhydrase enzyme (CA-II), producing H2O and CO2,
which diffuses into the proximal tubular cell. Recombination of intracellular CO2
with H2O (catalysed by a different carbonic anhydrase enzyme) produces
HCO3, which leaves the cell by a basolateral Naþ–3HCO3 co-transporter and
enters the circulation. A failure of proximal tubular reabsorption of HCO3 results
in a proximal renal tubular acidosis. NBC-1, Naþ–HCO3 co-transporter
66
4
Proximal tubular
epithelial cell
Glutamine
NH4+
Intercalated
NH3 H+ cell
Cortex
H+
Medula
NH3
a NH4+ ~40 mmol/day

Figure 4.2 (a) Excretion of NH4Cl. Hþ is secreted by the kidney, mostly buffered
by ammonia (NH3). Ammonium (NH4þ) is generated in proximal tubular cells from
glutamate and secreted by the Naþ–Hþ exchanger (NHE-3) into the tubular lumen.
The NH4þ is reabsorbed by the Naþ–Kþ–2Cl co-transporter (NH4þ replaces Kþ) in
the ascending loop of Henle and dissociates into NH3 and Hþ; this Hþ is used to
reabsorb further HCO3. NH3 diffuses from the renal medulla into the lumen of the
cortical collecting duct, where it buffers Hþ and is excreted as NH4Cl.
(Continued)
67
Na+ 2K+
Na+ reabsorption
creates luminal 3Na+
electronegativity
promoting K+ and
H+ secretion Aldo-R
K+
Principal cell
K+ 2K+
NH3
H+ 3Na+
CO2
NH3 + H2O
H+-ATPase
CA Cl–
H+
H+ HCO3 –
AE1
HCO3–
NH4+
α Intercalated cell
b
Figure 4.2 cont’d (b) Reabsorption of Naþ (promoted by aldosterone) in the
principal cells of the cortical collecting duct imparts a negative charge to the
tubular lumen, facilitating the secretion of Hþ by the Hþ-ATPase of intercalated
cells (secretion of Kþ is also promoted). Aldo-R, aldosterone receptor; AE1, anion
exchanger 1; CA, carbonic anhydrase. See also Figure 2.2.
Seven steps to the clinical assessment of acid–base status
See Figure 4.3.
Step 1: What is the pH (normal 7.35–7.45)

pH <7.35 implies acidaemia
68
4
Check pH
Low (<7.35) Normal High (>7.45)
Acidaemia No disorder or Alkalaemia

mixed acid–base disorder
Low HCO3− High PCO2 High HCO3− Low PCO2
Metabolic Respiratory Metabolic Respiratory

acidosis acidosis alkalosis alkalosis
Figure 4.3 Initial assessment of acid–base status. Note that PO2 has no direct
effect on acid–base analysis.
pH >7.45 implies alkalaemia

pH in the normal range implies either no acid–base disturbance or a com-
plex disorder where acidosis and alkalosis exactly cancel each other out.
Step 2: Check the serum bicarbonate (HCO3) (normal

22–30mmol/L)
HCO3 <22 implies metabolic acidosis
HCO3 >30 implies metabolic alkalosis
Step 3: Check the arterial PCO2 (normal 35–45mmHg

[4.5–6.0kPa])
PCO2 >40 mmHg implies respiratory acidosis
PCO2 <40 mmHg implies respiratory alkalosis
Step 4: Assess the compensatory responses

In order to maintain the pH within the narrow physiological range,
the kidneys try to compensate for respiratory acid–base disorders
and the lungs try to compensate for metabolic disorders. For example,
in the setting of a metabolic acidosis (low pH, low HCO3), alveolar
ventilation increases, creating a respiratory alkalosis (low PCO2) in
order to return the pH towards the normal range. Similarly, in the
69
setting of a respiratory acidosis (low pH, high PCO2), the kidneys

excrete increased amounts of Hþ and create a metabolic alkalosis (high
HCO3) in order to return the pH toward the normal range.
Respiratory or metabolic compensation never over-corrects the

pH. If the pH is acidaemic (pH <7.4), an acidosis is the primary
acid–base disorder, and if the pH is alkalaemic (pH >7.4) then
an alkalosis is the primary acid–base disorder.
The degree of compensation can be determined from the equations

in Box 4.1. A mixed respiratory metabolic acid–base disorder may be
present if the change in PCO2 is inappropriate for the change in
HCO3 (or vice versa). For example, in a metabolic acidosis with a
serum [HCO3] of 16, you would expect the PCO2 to drop by
8 mmHg (1.2kPa) (see Box 4.1). If the actual PCO2 has dropped by
20mmHg, this implies the presence of an additional respiratory alka-
losis, i.e. a metabolic acidosis and respiratory alkalosis, as can occur
in aspirin intoxication.
Box 4.1 Renal respiratory compensations
Metabolic acidosis
For every 1-mmol/L drop in [HCO3], expect PCO2 to be reduced by 1mmHg,
from 40mmHg (0.15kPa from 5.3kPa).
Metabolic alkalosis
For every 1-mmol/L rise in [HCO3], expect PCO2 to be increased by 0.6mmHg.
Respiratory acidosis
Acute: Expect a 1-mmol/L increase in [HCO3] per 10-mmHg rise in PCO2.
Chronic: Expect a 3.5-mmol/L increase in [HCO3] per 10-mmHg rise in PCO2.
Respiratory alkalosis
Acute: Expect a 2-mmol/L decrease in [HCO3] per 10-mmHg fall in PCO2.
Chronic: Expect a 4-mmol/L decrease in [HCO3] per 10-mmHg fall in PCO2.
Step 5: Assess the anion gap

The anion gap is the calculated difference between cations and anions in
the blood, and is roughly equal to the negative charge contributed by
70
4
proteins (Fig. 4.4). The anion gap (AG) can be calculated from the
equation:
þ
AG ¼ ðNa þ Kþ Þ ðCl þ HCO3 Þ
which is roughly equal to 16. However, the concentration of Kþ does not

vary much (4 mmol/L), and for convenience the equation becomes:
þ
AG ¼ Na ðCl þ HCO3 Þ ¼ 12
Cations Anions
(mmol/L) (mmol/L)
Chloride
104
Sodium
140
Bicarbonate
24
Proteins
Potassium 16 (mEq/L)
4.5
Calcium Phosphate ~1.2

2.5
Magnesium ~1 Sulphate ~1
Others (Fe, Se, Others (organic
Zn, etc.) ~2 anions, etc.) ~2–4
Figure 4.4 Cations and anions found in serum. Note that the numbers of each
are identical. Hþ is not illustrated as its concentration is in nanomoles, one million
times less than the millimolar concentrations depicted. Subtracting the measured
anions from the measured cations gives the anion gap, which is roughly equal to
the multivalent charge on albumin. As the ions in the shaded area approximately
cancel each other out, the anion gap can be calculated from the equation AG ¼
(Naþ þ Kþ) (Cl þ HCO3). This is often simplified by removing the Kþ, as it is
the change in the anion gap and not the absolute value that is clinically useful.
71
Note that the normal value for the anion gap is dependent upon
the serum protein concentration and approximates to 0.3 [albumin]
(g/L). In a person with a hypoalbuminaemic condition such as the
nephrotic syndrome, with a serum albumin concentration of 30 g/L,
the expected anion gap would be 9. Although rare, cationic proteins, as
may be found in patients with myeloma, can result in a falsely increased
value for the anion gap.
Causes of a low anion gap

1. hypoalbuminaemia
2. positively charged paraproteinaemia (myeloma)
3. rarely, addition of halides to the serum
The anion gap is calculated for two main reasons.

1. To help determine the aetiology of a metabolic acidosis
2. To determine whether a complex metabolic disorder is present. For
example, a diabetic patient with a metabolic ketoacidosis may have
a simultaneous metabolic alkalosis secondary to severe vomiting.
Step 6: Assess the (change in serum anion gap/change in

HCO3) (the ‘delta/delta’)
If HCO3 were the only buffer there would be a 1:1 relationship
between the increase in anion gap and the fall in serum [HCO3] in
a raised anion gap metabolic acidosis. Certainly, with mild degrees
of acidosis this is the case, but as the acid load increases the Hþ is buff-
ered by other buffers (predominantly intracellular) and the change in
anion gap is usually greater than the change in HCO3.
However, if the delta/delta ratio is much greater than expected (i.e.
>1.5:1), this suggests the simultaneous presence of an underlying met-
abolic alkalosis (which raises the [HCO3]) and a raised anion gap
metabolic acidosis (e.g. vomiting in patient with diabetic ketoacidosis).
Rarely a patient may have a normal [HCO3] and the only clue to the
presence of a metabolic acidosis is the raised anion gap value.
Similarly, if the delta/delta ratio is much less than expected (i.e. <1 : 1),
this implies the presence of a normal anion gap acidosis in addition to the
raised anion gap metabolic acidosis (e.g. a patient with renal tubular aci-
dosis who develops a lactic acidosis).
72
Metabolic acidosis
4
Step 7: Identify underlying cause of acid–base disturbance

Once the type of acid–base disorder has been identified it is important to
establish the underlying cause of the disorder. This requires a careful
history, examination, and a variety of biochemical tests. The cause
may be obvious if a patient presents with an acute abdomen and has a
grossly raised serum amylase level. However, it may be a careful drug
history that provides the diagnosis in an elderly diabetic patient with
renal impairment who has been commenced on metformin and has
developed a lactic acidosis as a complication of this treatment.
Metabolic acidosis
As [Hþ] is determined by the ratio of PCO2 to HCO3, the appropriate

respiratory response to a metabolic acidosis (#HCO3) is to hyperven-
tilate (‘blow-off CO2’). The PCO2 falls by 1mmHg per 1mmol drop in
HCO3. Patients with a severe metabolic acidosis exhibit a marked
increase in ventilation due to both an increased respiratory rate and
an increased depth of respiration, and this is described as Kussmaul
respiration. The failure to lower PCO2 by 1mmol per mmol drop in
HCO3 implies the presence of a simultaneous respiratory acidosis,
i.e. a mixed acid–base disturbance.
A metabolic acidosis is usually present if the serum [HCO3] is

less than 22 mmol/L. Rarely, this may be a compensatory
response to a chronic respiratory alkalosis (e.g. pregnancy), in
which case the pH will be >7.4.
Causes of metabolic acidosis (Fig. 4.5)
A metabolic acidosis can be caused by:

1. a gain of acid, or
2. a loss of HCO3.
Calculation of the anion gap aids in establishing the cause of the
metabolic acidosis.
Why does a lactic acidosis cause a raised anion gap, whereas diarrhoea
causes a normal anion gap acidosis? Consider adding 5 mmol/L lactic
acid to the body. This will be buffered primarily by NaHCO3, resulting
73
Metabolic acidosis
Raised anion gap Normal anion gap

(Na+ − (Cl– + HCO3–) > 12) (Hyperchloraemic metabolic acidosis)
1. Lactic acidosis 1. Gastrointestinal HCO3– loss
2. Ketoacidosis 2. Renal tubular acidosis
3. Renal failure
4. Poisoning
Figure 4.5 Causes of a metabolic acidosis.
in roughly 5 mmol/L sodium lactate and 5 mmol/L H2CO3. The H2CO3

dissociates to H2O and CO2, which is removed by ventilation. The result is
a lowering of the [HCO3] by 5 mmol, the presence of 5 mmol of unmea-
sured anions (lactate), with no changes in [Naþ] or [Cl]. From the anion
gap equation (AG ¼ Naþ [Cl þ HCO3]), the anion gap now becomes
17 (raised by 5mmol, i.e. a raised anion gap). In contrast, diarrhoea results
in the loss of NaHCO3 from the gastrointestinal tract. NaCl will be reab-
sorbed more avidly to maintain extracellular volume, resulting in an
increase in serum [Cl]. This increase in serum [Cl] compensates for
the fall in HCO3, such that the sum of [Cl þ HCO3] remains constant.
Thus severe diarrhoea results in a hyperchloraemic normal anion gap
metabolic acidosis as there is no increase in any unmeasured anions.
How serious is the metabolic acidosis?

This is dependent on a number of factors, including volume status, rate of
generation of acid, presence of hypoxia, degree of respiratory compensa-
tion and any associated potassium disorders. In general, a metabolic aci-
dosis is becoming extremely dangerous when the pH is <7.2 and/or the
serum [HCO3] is in single figures (<10). The consequence may be
depressed myocardial contractility and impaired enzyme function.
The treatment of a metabolic acidosis should be aimed at stopping the
production of Hþ, e.g. insulin treatment in ketoacidosis or oxygen ther-
apy in a patient with a lactic acidosis. In addition, serious threats asso-
ciated with acidosis must be treated, e.g. haemodialysis in cases of
ethylene glycol poisoning. In addition, dangerous potassium abnormal-
ities can be associated with a metabolic acidosis and these need careful
management. For example, hypokalaemia in a patient with a renal tubu-
lar acidosis can be exacerbated by treatment of the acidosis.
74
Lactic acidosis
4
Lactic acidosis
Cellular metabolism requires adenosine triphosphate (ATP) for

energy, much of which is produced from carbohydrate metabolism.
One mole of glucose can be metabolised by glycolysis, the Krebs cycle
and oxidative phosphorylation to produce 36–38moles of ATP. In the
absence of oxygen as an electron receptor, glucose metabolism would
stop as nicotine adenine dinucleotide (NADþ; a co-factor for glycoly-
sis) is converted to NADH. In humans this does not happen as the
NADH can be recycled by the conversion of pyruvate to lactic acid
by lactate dehydrogenase, thereby regenerating a supply of NADþ
for glycolysis (Fig. 4.6).
ADP
Glucose Glycolysis ATP
NAD
NADH
Lactate dehydrogenase
Pyruvate Lactate
NADH NAD
Acetyl-CoA
Tricarboxylic acid ADP

(Krebs) cycle ATP
NADH, FADH2
Electron transport chain ADP

‘Oxidative phosphorylation’ ATP
O2 H2O
Figure 4.6 Energy production from the metabolism of carbohydrate. In the

absence of oxygen, NAD is regenerated by the conversion of pyruvate to lactate,
generating a lactic acidosis.
75
The lactic acid is buffered by serum bicarbonate with the generation

of lactate (hence the positive anion gap in lactic acidosis). Normal
serum lactate levels are 1–1.5 mmol/L and a lactic acidosis is present
if levels are greater than 4–5 mmol/L in an acidaemic patient
(Table 4.2). The lactate can subsequently be metabolised by the liver
back to pyruvate, and thence to H2O and CO2.
Type A lactic acidosis

Clinically any condition that impairs the delivery of oxygen to the tis-
sues will result in the anaerobic metabolism of glucose by glycolysis
with the increased formation of lactic acid. This is most often seen in
ill patients with hypotension due to sepsis, hypovolaemia or cardio-
genic shock. Other causes include prolonged epileptic seizures and
carbon monoxide poisoning.
An acute lactic acidosis is commonly seen during marked physical
exertion (‘the burn’) when enhanced energy requirements temporarily
outstrip oxygen delivery. An Olympic sprinter can temporarily get
their venous pH to 6.8 with lactate levels greater than 20 mmol/L.
However, this is rapidly reversed as the oxygen debt is quickly
replaced. However, a critically ill patient in the intensive care unit
with sepsis syndrome is likely to have problems with gas exchange
and oxygen delivery to tissues from hypotension that are not readily
Table 4.2 Causes of a lactic acidosis
Type A Anaerobic metabolism due to tissue hypoxia

Shock (hypovolaemic, septic, cardiogenic, anaphylactic)
Lung problem (severe hypoxaemia <25–30 mmHg)
Haemoglobin problem (carbon monoxide poisoning)
Increased oxygen requirement (seizures, sprinting)
Type B Impaired lactic acid metabolism without hypoxia
Liver problems with impaired lactate clearance (hepatotoxins,
inborn errors, ethanol, tryptophan)
Mitochondrial disorders ! impaired oxidative phosphorylation !
increased glycolysis (cyanide, mitochondrial diseases, HIV
drugs)
Impaired pyruvate dehydrogenase (thiamine, inborn errors)
D-Lactic Bacterial overgrowth in bowel
acidosis
76
Ketoacidosis
4
reversed even with inotropic support, and is therefore likely to have a

persistent metabolic acidosis.
Type B lactic acidosis

A second type of lactic acidosis occurs in patients with abnormal lac-
tate metabolism in the setting of adequate tissue oxygen delivery. This
setting is much less common and is usually due to the effect of a drug
such as metformin or HIV medications, to inborn errors of metabolism
or to mitochondrial dysfunction. It is important to note that metformin
is a widely used hypoglycaemic agent which may cause a type B lactic
acidosis. This occurs more commonly in those with renal impairment,
and this agent should be discontinued when the serum creatinine level
climbs above 150 mmol/L or before interventions that may compro-
mise renal function, e.g. intravenous contrast studies.
D-Lactic acidosis
The conditions above refer to the accumulation of the physiological
L-form of lactic acid. Rarely in sick patients with bacterial over-
growth in the bowel, gut organisms can produce the isomer D-lactic
acid, which cannot be metabolised by the enzyme lactate dehydro-
genase as this enzyme only recognizes the L-form. The resulting D-
lactic acidosis is important to consider when the cause of a raised
anion gap metabolic acidosis is unclear, as D-lactate is not measured
by standard assays for lactic acid.
Treatment of lactic acidosis

This is directed at the underlying cause of the lactic acidosis with the
aim of increasing tissue oxygenation. Measures to correct shock are
the principal intervention. Oxygen therapy may be required in cases
of systemic hypoxia. The use of bicarbonate therapy to replace buffer
and improve the pH is a controversial issue as it may have deleterious
effects. However, NaHCO3 could be considered when the patient is
very acidotic, e.g. pH <7.1 or [HCO3] less than 8mmol/L.
Ketoacidosis
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) occurs in patients with type 1 diabetes
mellitus who have absent or very low levels of insulin. Insulin is
required to allow the movement of glucose into most cells (excluding
77
brain and liver) via specific glucose transporters such as GLUT1. This
permits glucose metabolism and the production of ATP. In the setting
of insulin lack, the serum levels of glucose increase and an alternative
source of energy (free fatty acids) is required.
The raised serum glucose concentration raises the serum osmolality,
with a resultant shift of water from within cells to the extracellular com-
partment. An osmotic diuresis occurs with loss of significant amounts
of water (3–6 L), sodium (600 mmol) and potassium (200 mmol).
The hyperglycaemia is exacerbated by the pre-renal uraemia induced
by the osmotic diuresis, as this impairs urinary glucose excretion.
The lack of insulin activates lipolysis in adipocytes with the release
of large amounts of free fatty acids (FFAs). The FFAs enter mitochon-
dria where they are oxidised to acetyl-coenzyme A (CoA), which
enters the Krebs cycle to produce ATP. When large amounts of
acetyl-CoA are produced, they are converted in the liver to ketoacids.
These ketoacids can be used as a source of energy, predominantly in
the brain and kidneys.
The resultant accumulation of ketoacids (acetoacetic acid and b-hydro-
xybutyric acid) generates a raised anion gap metabolic acidosis. The vol-
ume depletion that accompanies diabetic ketoacidosis may cause
sufficient tissue underperfusion to result in a simultaneous lactic acidosis.
Although the presence of ketoacids in the urine can be detected by dip-
sticks, it should be recognised that many dipstick tests for ketoacids do
not detect b-hydroxybutyrate, which may be the predominant ketone
body. As indicated previously, the degree of increase of the anion gap
may be less than expected from the serum [HCO3] (see Step 6, assess-
ment of ‘delta/delta’). This may be due to urinary excretion of ketoacids
or a concomitant metabolic alkalosis from associated vomiting.
Treatment of diabetic ketoacidosis

Patients with DKA typically present with a decreased level of con-
sciousness, Kussmaul breathing, hyperglycaemia and a severe meta-
bolic acidosis (arterial pH may be less than 7.0). Treatment with
intravenous fluids, insulin (typical loading dose of 20units, then 8–
10units/h intravenously) and potassium replacement will permit cor-
rection of the various metabolic abnormalities. Phosphate replacement
may also be required. Insulin therapy will allow the metabolism of
keto-anions to bicarbonate, which will replenish the buffer. It should
be noted that, although a marked acidosis may be present in patients
with DKA, the generation of acid from ketogenesis is slow and the
rapid correction of the pH with bicarbonate is rarely required and
may even be detrimental.
78
Poisoning
4
Alcoholic ketoacidosis
Rarely ketoacidosis can occur in patients who are not diabetic. A mild
ketosis occurs in starvation. In patients who abuse alcohol, a ketoaci-
dosis may develop – usually in those who have been vomiting and
are volume depleted. The insulin deficiency in this setting may be
due to intense sympathetic stimulation. Treatment with intravenous
fluids alone will reverse the ketoacidosis (dextrose to stimulate insulin
release, and saline to replace any volume deficit).
Renal failure
As the number of functioning nephrons decreases, the ability of the

kidneys to excrete acid falls. The accumulation of anions such as sul-
phate, phosphate, urate and hippurate in this setting results in a raised
anion gap. The acidosis of renal failure is not usually severe, and typi-
cally becomes apparent only when the glomerular filtration rate is
< 25 mL/min, unless there is a significant normal anion gap acidosis
from interstitial diseases such as renal tubular acidosis. The chronic
acidosis associated with chronic renal disease, although often mild,
is usually treated with oral sodium bicarbonate as it may lead to bone
demineralisation and skeletal muscle wasting, and may promote
progression of the underlying renal disease.
Poisoning
Acute poisoning should be considered in patients with a raised

anion gap metabolic acidosis and an increased plasma osmolal gap.
Methanol and ethylene glycol

These potentially fatal alcohols are occasionally taken for their intoxi-
cating effects or in a suicide attempt. Metabolism of these compounds
by alcohol dehydrogenase produces formic acid (from methanol) or
glycolic and oxalic acids (from ethylene glycol), which are responsible
for the raised anion gap metabolic acidosis. Clinically, the early signs
of intoxication are drunkenness, progressing to coma, nausea, blind-
ness (methanol), oxalate crystalluria and acute renal failure (ethylene
glycol), and a raised anion gap metabolic acidosis, which may be
severe. Emergency treatment includes inhibiting the metabolism of
these alcohols with ethanol, or fomepizole, as this will limit the
generation of the toxic metabolites together with haemodialysis.
79
Osmolal gap
A clue to the presence of these toxins may be made by determining
the osmolal gap. This is the difference between the measured plasma
osmolality and the calculated osmolality:
2 ½Na þ ½glucose þ ½urea
The normal value is <10 mOsm, and a high osmolal gap implies the pres-
ence of unmeasured osmoles such as alcohol, methanol, ethylene glycol
or ketones. An osmolal gap >25 in the setting of a raised anion gap meta-
bolic acidosis is highly suggestive of methanol or ethylene glycol poisoning.
Aspirin
Aspirin intoxication can lead to complex acid–base disturbances. It
characteristically results in a respiratory alkalosis from direct stimula-
tion of the respiratory centre, and a mildly raised anion gap metabolic
acidosis primarily due to the accumulation of organic acids, lactic acid
and ketoacids (not salicylic acid!). Emergency treatment may include
alkali therapy and haemodialysis.
Hyperchloraemic metabolic acidosis
This can generally be regarded as a normal anion gap metabolic

acidosis and may be due to gastrointestinal bicarbonate loss or
renal tubular acidosis.
Clinical assessment of a hyperchloraemic metabolic

acidosis
Once a normal anion gap acidosis has been diagnosed by following
steps 1–5 above, it is necessary to try to determine the underlying
cause (Fig. 4.7). It is usually relatively straightforward to differentiate
between gastrointestinal loss of bicarbonate and renal tubular acidosis
from the history of gastrointestinal symptoms. It is, however, more
difficult to determine the type of renal tubular acidosis (RTA).
The urine anion gap (UAG)

This is calculated as an estimate of urine ammonium excretion and is
derived from the formula:
UAG ¼ UNa þ UK UCl
80
Hyperchloraemic metabolic acidosis
4
Hyperchloraemic
metabolic acidosis
Check urine anion gap

(Na + K) – Cl
(Na + K) < Cl (Na + K) > Cl

(appropriate) (impaired NH4+ excretion)
Check serum potassium
GI bicarbonate loss Hyperkalaemia Hypokalaemia

(diarrhoea)
Type IV RTA Check urine pH

(aldosterone problem)
pH <5.5 pH >6
Proximal NH3 (buffer) Distal RTA

RTA defect
Liver disease
FEHCO3>15%
TPN
Figure 4.7 Assessment of a hyperchloraemic metabolic acidosis.
The normal value is negative, ranging between 20 and 50 mmol/L,
reflecting urine NH4þ excretion with Cl. In states of metabolic acidosis,
the NH4Cl excretion should increase and the urine anion gap should
become progressively more negative (from 75 to 100 mmol/L),
reflecting increased excretion of the NH4þ cation. However, in RTA
there is a failure of ammonium excretion and the UAG has a positive
value. This allows differentiation between gastrointestinal HCO3 loss
and RTA in situations where the history is unreliable. It should be noted
that the urine pH may be high in patients with diarrhoea owing to
81
hypokalaemia-induced increased generation of NH3 and excess buffer-

ing of free urinary hydrogen ions.
Gastrointestinal HCO3 Loss
Intestinal secretions below the stomach contain a total base concentra-

tion of 60 mmol/L. Diarrhoea can therefore lead to a significant loss
of base and a metabolic acidosis. There is no change in the anion gap
as unmeasured anions are not added to the serum in these circum-
stances and there is a concomitant rise in the serum [Cl].
As the kidneys can compensate for a metabolic acidosis, the acidosis
is rarely marked in this setting unless there is concomitant renal
impairment, possibly due to volume depletion. The diminished distal
delivery of sodium to the cortical collecting duct (CCD) may also
result in impaired renal excretion of potassium and hydrogen ions.
Ureteral diversion into bowel may also generate a normal anion gap
metabolic acidosis from HCO3/Cl exchange and gut reabsorption
of NH4Cl.
Renal tubular acidosis
This is due either to the inability to reabsorb filtered bicarbonate

(proximal RTA) or to impaired excretion of ammonium chloride
(distal RTA).
Proximal RTA
The normal serum concentration of HCO3 is 24 mmol/L and the daily
glomerular filtration volume is 180 L. This implies that approximately
4300 mmol of HCO3 must be reabsorbed by the tubules to prevent loss
of buffer in the urine. Some 90% of HCO3 reabsorption occurs in the
proximal tubule (see Fig. 4.1). Failure to reabsorb HCO3 can result in
HCO3 wasting and a normal anion gap metabolic acidosis (Table 4.3).
There may also be an impairment of proximal ammoniagenesis in this
condition, resulting in a more positive urine anion gap. Proximal RTA
may be isolated but usually occurs in the setting of other evidence of
proximal tubular dysfunction such as glucosuria, aminoaciduria and
phosphate wasting, and is termed Fanconi’s syndrome. The commonest
cause of proximal RTA in adults is multiple myeloma.
82
4
Table 4.3 Causes of RTA in adults
Proximal RTA
Dysproteinaemias Multiple myeloma, light chain deposition disease,
amyloidosis
Toxins Heavy metals (lead, mercury, cadmium)
Genetic disorders Wilson’s disease, cystinosis, galactosaemia, hereditary
fructose intolerance, Lowe’s syndrome, tyrosinaemia
Other Hyperparathyroidism (hypocalcemia, Vitamin D deficiency),
acetazolamide (CAII deficiency), paroxysmal nocturnal
haemoglobinuria
Distal RTA
Autoimmune Sjögren’s syndrome, rheumatoid arthritis, SLE, primary
disorders biliary cirrhosis
Nephrocalcinosis Idiopathic hypercalciuria and myriad causes of
hypercalcaemia
Drugs Amphotericin B, ifosfamide, lithium
Interstitial disease Sickle cell, obstructive uropathy, medullary sponge kidney,
renal transplantation
Other Cirrhosis, myeloma, genetic syndromes (Ehlers–Danlos
syndrome, Marfan’s syndrome)
In clinical practice, the serum [HCO3] is reset to a new level at

which compensatory renal mechanisms are able fully to reabsorb
and prevent further loss of HCO3 in the urine, i.e. a lowered tubular
threshold for HCO3 reabsorption. When this is reached, all the fil-
tered HCO3 can be reabsorbed and the urine pH becomes appropri-
ately acidic (urine pH <5.5). The typical serum [HCO3] in proximal
RTA is 16–18 mmol/L. It is, however, difficult to correct the acidosis
as raising the serum [HCO3] leads to an increase of filtered HCO3
and wasting of HCO3 in the urine. The specific diagnosis of proximal
RTA requires the finding of a high urine pH (>7.5) and a high
fractional excretion of HCO3 (>15%) during HCO3 infusion.
Distal RTA
Hydrogen ions are excreted by the kidney predominantly as ammo-
nium chloride (NH4Cl) and sodium dihydrogen phosphate (NaH2PO4).
The amount of NaH2PO4 is relatively fixed and increased acid loads are
excreted predominantly as NH4Cl. As described in Figure 4.2, excretion
83
of NH4Cl requires the generation of ammonium from glutamine in the

proximal tubule, the medullary recycling of ammonia, the generation
of a negative intratubule potential in the CCD, and the secretion of
hydrogen ion by the apical Hþ-ATPase. Abnormalities in any of these
areas can result in a distal RTA (Table 4.4). The commonest cause in
adults is Sjögren’s syndrome, in which there is reduced expression of
Hþ-ATPase in the intercalated cells of the CCD.
A more pronounced metabolic acidosis can develop in distal RTA
and the serum [HCO3] may fall to less than 10 mmol/L with a urine
pH that is always greater than 5.3. However, treatment of the acidosis
requires less bicarbonate therapy as the maximum required will be
only that necessary to supply sufficient buffer to balance the daily
net acid load (1 mmol/kg daily). Associated features of distal RTA
include hypokalaemia, nephrocalcinosis due to hypercalciuria (bone
demineralisation), and hypocitraturia. It is important to note that cor-
rection of hypokalaemia should be performed before correction of the
acidosis, as correction of the pH will drive potassium into cells and
can exacerbate hypokalaemia.
Type IV renal tubular acidosis

Type IV RTA is due to impaired aldosterone secretion or aldosterone
resistance, and results in a mild normal anion gap metabolic acidosis
in the setting of hyperkalaemia.
Impaired aldosterone action results in impaired Naþ reabsorption
in the CCD and diminished generation of the negative intraluminal
potential. This results in failure of Hþ secretion by the intercalated
cells in the CCD. There is also a failure of Kþ secretion by the princi-
pal cells in the CCD. The hyperkalaemia generates an intracellular
acidosis in proximal tubular epithelial cells, and this impairs ammo-
nium generation. The commonest cause of a type IV RTA is the
hyporeninaemic hypoaldosteronism that can be found seen in
patients with diabetes mellitus. Type IV RTA is usually associated
with renal impairment (see Table 4.4). Indeed, patients with
advanced diabetic nephropathy develop hyperkalaemia more readily
when treated with angiotensin-converting enzyme inhibitors, and
may need to start dialysis slightly earlier than non-diabetic patients
because of troublesome hyperkalaemia. In patients with type IV
RTA the urine pH can often be appropriately lowered to less than
5.3, but the UAG is inappropriately low due to impaired
ammoniagenesis.
84
Table 4.4 Hyperchloraemic (normal anion gap) metabolic acidosis
Diarrhoea Proximal RTA Distal RTA Type IV RTA

Serum [HCO3] Usually >17 12–20 May be <10 >17
(mmol/L)
Serum [K] (mmol/L) Low/normal Low Low High
Urinary pH Low (rarely high due to <5.5 (in established >6 Variable
"NH3 secondary to proximal RTA)
hypokalaemia)
Urine anion gap Increased Normal/low (can Low (impaired Low (impaired
[(Na þ K) Cl] appropriately increase if NH4Cl excretion) ammoniagenesis)

(Na þ K Cl) additional acid load) (Na þK > Cl) (Na þK > Cl)
85
4
Metabolic alkalosis
A metabolic alkalosis is present if the serum [HCO3] is greater

than 30 mmol/L. Rarely this may be a compensatory response to
a chronic respiratory acidosis (e.g. chronic respiratory pulmonary
disease), in which case the pH will be less than 7.4. A metabolic
alkalosis is usually associated with hypokalaemia.
Metabolic alkalosis tends to be a less critical disorder than metabolic aci-

dosis as the generation of alkalosis is usually slow and the kidneys can
readily excrete excess HCO3. An impairment of renal excretion is
almost always required before a significant metabolic alkalosis can
develop. It is important to note that the ability of the proximal tubule
to reabsorb HCO3 is increased in chronic metabolic alkalosis, and this
maintains the alkalosis. This seemingly paradoxical response prevents
further loss of Naþ and HCO3 to maintain the extracellular volume.
The lungs compensate for a metabolic alkalosis by hypoventilation,
which retains CO2 and lowers the pH toward the normal range. The
PCO2 should drop by 0.6 mmHg per 1-mmol increase in HCO3
(see Box 4.1). Hypokalaemia is almost universally associated with a
metabolic alkalosis, and both have similar causes (see Chapter 2). In
general, the addition of alkali by itself does not cause a metabolic
alkalosis in normal circumstances as the excess base is simply excreted
in the urine. However, in the setting of renal impairment the addition
of alkali may cause a metabolic alkalosis, as is seen in patients with
dyspepsia who develop the milk alkali syndrome.
Causes of metabolic alkalosis (Fig. 4.8)
Assessment of the volume status is critical to determining the

cause of a metabolic alkalosis. The vast majority of metabolic alka-
loses are due to vomiting or diuretic use.
The causes of metabolic alkalosis are usually divided into those with a
decreased effective arterial blood volume (EABV) and those with an
increased EABV. The volume status of the patient is assessed by physical
86
Metabolic alkalosis
4
Metabolic
alkalosis
Assess volume
status
↓ ECV ↑⁄↔ ECV
Low urine Cl− High urine Cl− Check renin and

• Vomiting • Diuretics aldosterone levels
• Remote diuretic use • Bartter’s syndrome
• Cystic fibrosis • Gitelman’s syndrome
• Gentamicin
• Hypomagnesaemia
↑ Aldo ↑ Aldo ↓ Aldo

↑ Renin ↓ Renin ↓ Renin
• Renal artery stenosis • Primary hyperaldosteronism • Liddle’s syndrome

• Renin tumour (bilateral adrenal hyperplasia, • Liquorice abuse
• Malignant hypertension adenoma) • Cushing’s syndrome
• Glucocorticoid remediable
hyperaldosteronism
Figure 4.8 Causes of a metabolic alkalosis. Aldo, aldosterone.
examination including the pulse rate, blood pressure, postural changes

in blood pressure, presence of oedema, jugular venous pressure, heart
sounds, pulmonary crackles, presence of cold peripheries, etc.
Urine electrolytes in metabolic alkalosis

If the kidneys are functioning appropriately, the normal response to a
decreased EABV is to retain Naþ, and the urine [Naþ] is typically low
87
(<20 mmol/L) (Table 4.5). However, in a metabolic alkalosis there

may be an obligate loss of Naþ with HCO3 in the urine, and in this
setting a more accurate assessment of volume status can be deter-
mined from a low urine chloride (<20 mmol/L).
Specific causes of metabolic alkalosis

Vomiting
The concentration of HCl in gastric juice is 125 mmol/L, and several
litres may be lost per day with vomiting or nasogastric suction. The
associated volume depletion from NaHCO3 loss in the urine leads to
an inability of the kidneys to excrete the excess HCO3. In this setting,
the urine pH is usually high (>6.0). Note the urine Naþ may not be as
low as predicted in the setting of volume depletion owing to obligate
urine loss of Naþ with HCO3. Treatment with normal saline and KCl
will expand the extracellular fluid volume and allow the kidneys to
excrete the excess HCO3, thereby correcting the alkalosis.
Diuretics
Diuretic use causes volume depletion due to increased urinary losses
of NaCl, and therefore result in secondary hyperaldosteronism. The
increased aldosterone concentration, along with the increased delivery
of Naþ to the CCD, results in enhanced reabsorption of Naþ at this site
leading to increased excretion of Kþ and Hþ. The hypokalaemia
Table 4.5 Urinary electrolytes in metabolic alkalosis
Urinary electrolytes (mmol/L)
Usodium Upotassium Uchloride UpH

Diuretics (recent) >20 High (>20) >20 <6.0
Diuretics (remote) <20 Low (<20) <20 <5.5
Vomiting (recent) >20 High (>20) <20 >7.0
Vomiting (remote) <20 Low (<20) <20 <5.5
Bartter’s syndrome >20 High (>20) >20 6–6.5
Primary hyperaldosteronisma >20 High (>20) >20 Variable
a
Extracellular fluid volume is expanded in this condition.
88
Metabolic alkalosis
4
promotes proximal tubule ammoniagenesis, and a metabolic alkalosis

results from the excretion of extra NH4þ. Treatment with NaCl and
KCl will allow the kidneys to excrete the excess HCO3.
Other causes of renal salt wasting include interstitial renal disease,
an osmotic diuresis or, rarely, Bartter’s and Gitelman’s syndromes.
Primary hyperaldosteronism
This is also known as Conn’s syndrome and is due to either bilateral
adrenal hyperplasia or an adrenal tumour (usually an adenoma) pro-
ducing aldosterone. It typically presents with hypertension with hypo-
kalaemia and a mild metabolic alkalosis. It is a much more common
cause of hypertension than is usually appreciated. The mechanism of
metabolic alkalosis is similar to that for diuretic use, except the
increased distal delivery of Naþ is due to the volume-expanded state
in the setting of aldosterone action. Hypokalaemia is similarly impor-
tant in augmenting proximal tubule ammoniagenesis.
A good screening test for primary aldosteronism is the aldosterone/
renin ratio, which will be high because of a raised aldosterone level
and low renin concentration. Treatment consists of antagonism of
the aldosterone effects with spironolactone or eplerenone for bilateral
adrenal hyperplasia, and surgery if indicated for an aldosterone-
secreting adrenal adenoma.
89
CHAPTER
5
Arterial blood
gas analysis
Normal values
See Table 5.1.
Table 5.1 Normal median (range) values for arterial

blood gases
Arterial partial pressure of oxygen (PaO2) 95 (85–100) mmHg

12.5 (11.0–13.2) kPa
Arterial partial pressure of carbon dioxide 40 (35–45) mmHg
(PaCO2) 5.3 (4.5–6.0) kPa
Standard bicarbonatea 24 (22–28) mmol/L
a
Calculated value indicating what the [HCO3] would be at a standard PCO2 of 40 mmHg
(5.3 kPa). The total CO2 (TCO2) measured on a serum sample represents the [HCO3] plus
the concentrations of dissolved CO2 and H2CO3. It is usually 1–2 mmol/L higher than the
[HCO3] value on arterial blood gas analysis.
5 Arterial blood gas analysis
Respiratory physiology
Oxygen
Oxygen is required for the production of energy (adenosine

triphosphate; ATP) during oxidative metabolism.
Ambient air contains 21% oxygen and the partial pressure of inspired
air (PiO2) at sea-level is 150 mmHg (20 kPa). Gas exchange occurs at
the alveolar surface, where the alveolar air is separated from the blood
in the pulmonary capillary by a thin layer of capillary endothelial
cells, a basement membrane and alveolar epithelial cells lined by sur-
factant (Fig. 5.1).
Oxygen transport
Oxygen is transported bound to haemoglobin in red cells. Four mole-
cules of O2 bind per molecule of haemoglobin. The affinity of O2 for
haemoglobin can be reduced by increased levels of 2,3-diphosphogly-
cerate (2,3-DPG), an increase in [Hþ], increased partial pressure of car-
bon dioxide (PCO2) and increased temperature. During exercise, the
increased [Hþ] from lactic acidosis, the increased PCO2 and the raised
temperature all lower the affinity of O2 for haemoglobin and facilitate
O2 delivery to tissues. 2,3-DPG production is slower, but enhances O2
tissue delivery in settings such as high altitude and anaemia.
Carbon dioxide
CO2 is the end-product of oxidative metabolism of carbohydrates

and fats, and is excreted by alveolar ventilation.
CO2 production
Typically 15 000 mmol CO2 are produced daily from the metabolism
of carbohydrates and fat (10 mmol/min). During vigorous exercise
this can increase to 160 mmol/min.
The CO2 produced diffuses from cells into red blood cells. Red cell
carbonic anhydrase converts this to Hþ and HCO3. The HCO3 is
92
Respiratory function
5
Inspired air Expired air

PiO2 = 150 mmHg (20 kPa) PiO2 = 116 mmHg (15 kPa)
PiCO2 = 0.2 mmHg PiCO2 = 26 mmHg (3.4 kPa)
Alveoli
Pulmonary artery Pulmonary vein

PvO2 = 40 mmHg (5.3 kPa) PaO2 = 95 mmHg (12.5 kPa)
PvCO2 = 46 mmHg (6 kPa) PaCO2 = 40 mmHg (5.3 kPa)
Venous circulation Arterial circulation

PvO2 = 40 mmHg (5.3 kPa) PaO2 = 95 mmHg (12.5 kPa)
PvCO2 = 46 mmHg (6 kPa) PaCO2 = 40 mmHg (5.3 kPa)
Peripheral tissues
P O2 <40 mmHg (5.3 kPa)
PCO2 ≥46 mmHg (6 kPa)
Figure 5.1 Gas transport in the pulmonary and systemic circulation. Note that
the oxygenated blood in the pulmonary vein is the same as arterial blood in
the systemic circulation.
transported into plasma in exchange for chloride (chloride shift) and

the Hþ is buffered by haemoglobin. At the lung this process is
reversed; CO2 is released and excreted by alveolar ventilation.
Respiratory function
Control of ventilation
The normal alveolar ventilation is 5 L/min and is controlled by respi-
ratory centres in the brainstem (medulla and pons). Sensory input
93
from receptors for CO2, Hþ and O2 modify the standard ventilatory

response:
l Central chemoreceptors (ventral surface medulla) stimulate venti-
lation in response to an increased PCO2 or decreased pH of the
cerebrospinal fluid.
l Peripheral chemoreceptors in the carotid body (type 1 glomus
cells) are responsible for the ventilatory response to low arterial
partial pressure of oxygen (PaO2).
l Pulmonary mechanoreceptors respond to local mechanical and
chemical stimuli, and may control ventilatory rate.
Lung perfusion
This is equal to the cardiac output (heart rate stroke volume of right
ventricle) and is 5 L/min in an average resting human adult. Oxygen
receptors in the pulmonary vasculature may initiate vasoconstriction
in response to hypoxia, leading to changes in lung perfusion and
ventilation/perfusion (V/Q) matching.
Areas of ventilated lung may be underperfused by a reduction in car-
diac output or by regional decreases in perfusion (e.g. pulmonary
embolism) leading to hypoxia from V/Q mismatch. By contrast, areas
of unventilated lung may be perfused wastefully, resulting in shunting.
Diffusion
Oxygen diffuses from the alveolar air across the alveolar epithelium
(covered by surfactant), basement membrane and pulmonary capillary
endothelium, and is taken up by haemoglobin. Diffuse lung fibrosis
may impair oxygen diffusion. Gas exchange may be assessed by the
carbon monoxide transfer factor (TLCO2)
Assessment of oxygenation
Clinical assessment
A full clinical examination should be performed with particular
emphasis on cardiac and respiratory systems. Cyanosis does not occur
until there is 5 g/L deoxyhaemoglobin or an arterial oxygen saturation
(SaO2) of less than 67%. Cyanosis is affected by skin colour, pigmenta-
tion and haematocrit. Ventilation should be assessed by examining
rate and depth of respiration.
94
Assessment of oxygenation
5
Arterial partial pressure of oxygen (P aO2)

This is measured on arterial blood gas analysis. Normal values on
room air are 83–100 mmHg (11–13.2 kPa). Analysis of PaO2 will iden-
tify hypoxaemia, but will not identify the cause, which must be deter-
mined from assessment of PaCO2, the alveolar-arterial gradient and
other investigations.
Arterial oxygen saturation (SaO2)
SaO2 assesses oxygenation but not respiratory ventilation. Because

of the shape of the oxygen dissociation curve, a small drop in
SaO2 represents a large drop in PaO2.
This is measured by a pulse oximeter, and in many places has become

part of the standard nursing observations.
There are two main pitfalls:

1. SaO2 gives no information about respiratory ventilation. A low
SaO2 demonstrates hypoxia, but does not determine whether the
cause is hypoventilation (e.g. opioids) or another effect. An assess-
ment of ventilation, ideally by arterial blood gas analysis, should
be performed in this setting.
2. A large fall in PaO2 may cause only a small fall in SaO2 owing to
the shape of the oxygen dissociation curve. It is important to recog-
nise that SaO2 values of 93–95% may reflect a substantial fall in
PaO2 (Fig. 5.2).
Alveolar-arterial oxygen gradient (AA gradient)

This calculation is used in the assessment of hypoxia to determine the
contribution of hypoventilation to the decrease in PO2. It can be fol-
lowed serially to determine whether a condition is improving or
worsening:
AA gradient ¼ 150 mmHg ½ð1:25 PaCO2 Þ þ PaO2
AA gradient ¼ 20 kPa ½ð1:25 PaCO2 Þ þ PaO2
95
100
Oxygen saturation of haemoglobin (%) 90
80
70
60
50
40
30
20
10
0
0 20 40 60 80 100
PO2 (mmHg)
Figure 5.2 Oxygen dissociation curve. Note that the curve is relatively flat down
to a PaO2 of 60 mmHg (8 kPa) and that relatively large changes in PaO2 can
occur without major changes in SaO2.
Normal values for the AA gradient are 5–10 mmHg (1–1.5 kPa). Hypo-
ventilation will lower the arterial PO2 but will not increase the AA
gradient. By contrast, any impairment of diffusion, V/Q mismatch
or shunting will lead to an increased AA gradient.
Notes:
1. The AA gradient can be calculated only when the PO2 of
inspired air is known precisely (i.e. at room air or on a mechan-
ical ventilator (when PaO2 becomes the FiO2 [inspired oxygen
fraction] 713 mmHg).
2. The normal AA gradient increases with age and with increas-
ing FiO2.
Assessment of tissue hypoxia

Although we are measuring the degree of oxygenation of the blood
and the adequacy of ventilation using arterial blood gas analysis,
96
Respiratory failure
5
it should be appreciated that these are surrogate values and that what
we are most interested in is the adequacy of tissue oxygenation.
Tissue hypoxia is often assessed in ill patients in the intensive care
setting. This is done clinically by looking for evidence of organ dys-
function (e.g. hypotension, cold peripheries, adult respiratory distress
syndrome [ARDS], acute renal failure, mental obtundation). Other
methods include looking for the products of anaerobic metabolism
(e.g. serum lactate), assessing the mixed venous oxygen saturation
(SvO2), measuring the ratio of oxygen delivery to oxygen consumption
(DO2/VO2 ratio) or, rarely, gastric tonometry.
Assessment of ventilation
Examination of the PaCO2 allows an assessment of alveolar

ventilation.
This can be assessed clinically by observing the rate and depth of res-
piration, although this is inaccurate. Alveolar ventilation is best
assessed by measuring the PaCO2. The normal PaCO2 at rest is
40 mmHg (5.3 kPa).
l Increased ventilation will lower the PaCO2 and lead to a respira-
tory alkalosis.
l Decreased ventilation will raise the PaCO2 and lead to a respira-
tory acidosis.
Respiratory failure
This is a term used to describe hypoxaemia when PaO2 is <60 mmHg

(8.0 kPa), and is divided into two types:
l Type I respiratory failure is hypoxaemia in the absence of hyper-
capnia (due to diffusion impairment, shunting or V/Q mismatch
(e.g. pulmonary oedema, lung fibrosis, pulmonary embolism,
asthma).
l Type II respiratory failure is hypoxaemia in the setting of hyper-
capnia indicating hypoventilation (e.g. chronic obstructive pulmo-
nary disease [COPD], opioid overdose).
97
Treatment of hypoxaemia
The underlying cause of hypoxia should be determined and treated

(e.g. naloxone treatment for opioid overdose).
Oxygen therapy
Oxygen therapy should be initially prescribed by mask and titrated
upwards to achieve SaO2 >95% (Table 5.2). It should be noted that
with most masks the maximum FiO2 may reach only 35–40%. In order
to increase FiO2 further, ‘tusks’ or a rebreathing bag may be added to
the mask. If oxygenation is still insufficient, consideration should be
given to continuous positive airway pressure (CPAP) or mechanical
ventilation.
Use of oxygen in patients with chronic respiratory acidosis

In a subset of patients with chronic hypoxia and hypercapnia, oxygen
therapy may worsen hypercapnia. The pathophysiology is unclear,
but factors include diminished hypoxic ventilatory drive, worsening
of V/Q mismatching and decreased affinity of haemoglobin for CO2.
Concern over this feature has led to the inappropriate withholding
Table 5.2 Maximum oxygen delivery by nasal

cannulae and maska
Oxygen flow rate (L/min) % O2 delivered

Nasal cannulae 1 24
2 28
3 32
4 36
5 40
6 (max) 44
Basic oxygen mask 5–6 40
6–7 50
7–8 (max) 60
Mask with reservoir bag 5–8 L 80–85
(one-way valve on reservoir)
a
Patients with a high minute ventilation usually entrain large amounts of room air and
markedly dilute the actual concentration of O2 inspired.
98
Respiratory acid–base disorders
5
of oxygen from some patients and potential complications from

hypoxaemia. In these patients oxygen therapy should be prescribed
to maintain a PaO2 of 60–70 mmHg (8–9 kPa; SaO2 >90%) and the
PaCO2 followed. Problems with respiratory acidosis are unlikely
unless the PaCO2 climbs above 80–85 mmHg (10 kPa).
Respiratory acid base disorders are due to abnormalities of pul-

monary ventilation. Hypoventilation leads to a respiratory acido-
sis and hyperventilation leads to a respiratory alkalosis.
Assessment of respiratory acid–base status

Determination of the acid–base status should be performed according
to the seven steps outlined in Chapter 4.
Seven steps for assessing acid–base status

1. Assess the pH.
2. Check the serum HCO3 level.
3. Check the arterial PCO2.
4. Assess the compensatory responses.
5. Calculate the serum anion gap.
6. Calculate the delta/delta.
7. Identify the underlying causes.
An arterial blood gas will give the values for pH, arterial PCO2 and
bicarbonate. Similar information can be gained from a venous blood
gas, although PCO2 is typically a little higher (46 mmHg [6 kPa])
and the venous pH is 7.35. Of course, the PO2 will be much lower
(40 mmHg [5.3 kPa]).
Initial assessment of acid–base status (steps 1–3) is shown in
Figure 5.3. Although the PCO2 will allow assessment of alveolar ven-
tilation, it is still necessary to complete all seven steps to interpret the
results fully and to avoid missing a complex acid–base disorder (see
Chapter 4).
99
Check pH
Low (<7.35) Normal High (>7.35)
Acidaemia No disorder or Alkalaemia

mixed acid–base disorder
Low HCO3 High PCO2 High HCO3 Low PCO2
Metabolic Respiratory Metabolic Respiratory

acidosis acidosis alkalosis alkalosis
Figure 5.3 Initial assessment of respiratory acid–base disorder.
Is a respiratory acid–base disorder present?

The normal arterial PCO2 is 40 mmHg (5.3 kPa). A normal PaCO2 with
a normal pH (7.4) indicates that there is no respiratory acid–base dis-
order present.
l An arterial PCO2 <40 mmHg with pH >7.4 implies a respiratory
alkalosis.
l An arterial PCO2 >40 mmHg, with pH <7.4 implies a respiratory
alkalosis.
Is this merely respiratory compensation for

a metabolic disorder?
In metabolic acid–base disorders, the change in pH will either stimu-
late or inhibit respiration in an attempt to return the pH toward nor-
mal (7.4). The expected change in PCO2 for metabolic disorders is
shown in Box 5.1.
With a metabolic acidosis, pulmonary hyperventilation would be
expected to ‘blow off’ CO2; this will partially correct the pH. In this
setting the arterial PCO2 will be low (this is considered normal respi-
ratory compensation or an appropriate respiratory alkalosis).
However, if the degree of hyperventilation is greater than expected,
there may be an additional respiratory alkalosis in excess of the
100
5
Table 5.3 Examples of arterial blood gases in different

conditions
PaO2 PaCO2 Serum pH AA

(mmHg) (mmHg) [HCO3] gradient
(mmol/L) (mmHg)
Normal 100 40 24 7.4 10
Opioid overdose 70 75 24 7.13 10
(acute respiratory
acidosis)
COPD (chronic 60 75 35 7.29 25a
respiratory acidosis)
Anxiety (acute 110 25 24 7.6 10
respiratory alkalosis)
Pulmonary fibrosis 50 30 20 7.45 75
(chronic respiratory
alkalosis)
Oxygen maskb 135 40 24 7.4 ?
Note the more extreme changes in pH in the acute respiratory disorders due to lack of renal
compensation.
a
V/Q mismatch is often present in COPD (in addition to pure hypoventilation), leading to
a raised AA gradient.
b
Note that PO2 þ PCO2 > 150 mmHg (room air inspired PO2) implies the patient is receiving
supplemental oxygen; in this setting the AA gradient cannot be calculated.
expected compensatory response (as seen in salicylate intoxication).

By contrast, if the expected fall is less than expected, a respiratory aci-
dosis is present (e.g. impaired ventilation secondary to narcotics).
Example:
Arterial blood gases reveal pH 7.35, HCO3 14 mmol/L and PCO2
26 mmHg.
The low pH and low HCO3 tell us that the primary disorder is a
metabolic acidosis. The PCO2 is low, however, as we would
expect the PCO2 to drop by only 1–1.2 mmHg (from 40 mmHg)
for each 1-mmol/L drop in HCO3. This suggests that hyperventila-
tion in excess of the normal compensatory mechanisms is present.
101
Box 5.1 Respiratory–renal compensation
Metabolic acidosis
For every 1-mmol/L drop in [HCO3], expect P CO2 to be reduced by 1 mmHg
(0.15 kPa) from normal.
Metabolic alkalosis
For every 1-mmol/L rise in [HCO3], expect P CO2 to be increased by 0.6 mmHg
(0.8 kPa) from normal.
Acute: Expect a 1-mmol/L increase in [HCO3] per 10-mmHg (1.5-kPa) rise in
P CO2.
Chronic (>5 days): Expect a 3.5-mmol/L increase in [HCO3] per 10-mmHg (1.5-kPa)
rise in P CO2.
Acute: Expect a 2-mmol/L decrease in [HCO3] per 10-mmHg (1.5-kPa) fall in P CO2.
Chronic (>3 days): Expect a 4-mmol/L decrease in [HCO3] per 10-mmHg (1.5-kPa)
fall in P CO2.
Renal compensation for a respiratory disorder

In a similar manner to respiratory compensation, the kidneys will try
to correct the pH toward normal if there is a respiratory acid–base dis-
order. This compensation is less efficient than the lungs and takes sev-
eral days for the maximal change in HCO3.
With a respiratory acidosis the kidneys will increase ammonium
(NH4þ) excretion to raise serum HCO3 concentration, and with a
respiratory alkalosis the kidneys will decrease HCO3 reabsorption
to decrease the serum HCO3 level.
The degree to which the HCO3 level should change with respira-
tory acid–base disorders is shown in Box 5.1.
A respiratory acidosis is due to CO2 retention as a result of

hypoventilation.
102
5
Carbonic acid (H2CO3) cannot be buffered by bicarbonate and the

serum HCO3 level does not fall with a respiratory acidosis. By con-
trast, the HCO3 concentration rises as the kidney compensates for
the respiratory acidosis by increasing ammonium (NH4þ) excretion.
The expected increase is given in Box 5.1.
Example:
Arterial blood gases reveal pH 7.2, HCO3 16 mmol/L, PCO2
40 mmHg.
The low pH and low HCO3 tell us that the primary disorder is a
metabolic acidosis. The expected PCO2 would be 32 mmHg (see
Box 5.1); however, the PCO2 is higher than expected at 40 mmHg,
implying a problem with ventilation. A respiratory acidosis can
therefore be present with a normal PCO2.
Clinical features
Acute respiratory acidosis is usually associated with a decreased
respiratory rate and often with a decreased level of consciousness.
When severe, it may be associated with hypotension.
Chronic respiratory acidosis is often dominated by the associated
features of hypoxaemia. Hypercapnia may lead to peripheral vasodila-
tation with bounding pulse and headache, tachycardia, papilloedema
and flapping tremor.
Causes of respiratory acidosis

See Table 5.4.
l The commonest cause of acute respiratory acidosis is central

respiratory depression due to drugs (especially opioids), and
should be considered in any patient with a reduced respiratory
rate.
l Chronic obstructive pulmonary disease is the commonest
cause of chronic respiratory acidosis.
103
Note that the change in serum HCO3 may help to differentiate between
an acute condition (e.g. drug overdose) and a chronic condition where
maximal renal compensation should have occurred (e.g. COPD).
Acute versus chronic respiratory acidosis

In acute respiratory acid–base disorders there has not been time for
renal compensation to vary NH4þ excretion, and changes in arterial
Table 5.4 Causes of respiratory acidosis
Central causes Central sleep apnoea, cerebral injury or hypoxia,

brainstem herniation, status epilepticus, primary
hypoventilation
Drugs Opioids, sedatives, psychotropics, muscle relaxants
Upper airway obstruction Laryngeal oedema or bronchospasm
Lung problems Chronic obstructive pulmonary disease (COPD)
Neuromuscular problems Myasthenia gravis, myotonic dystrophy, trauma
pH may be marked. By contrast, chronic respiratory acidosis is toler-

ated much better due to renal ammonium excretion raising the serum
[HCO3]. Maximum renal compensation probably occurs by 5–6 days.
Example:
Consider an acute respiratory acidosis in which the PCO2 rises
from 40 to 80 mmHg in a short period. There will be little time
for the kidneys to increase ammonium excretion and, from the
Henderson–Hasselbalch equation, the pH will go from 7.4 to 6.1
þ log(24/0.03 80) ¼ 7.1. However, in chronic acidosis the
kidneys would be expected to raise the serum [HCO3] by
3.5 mmol per 10-mmHg rise in PCO2. The new [HCO3] would be
38 mmol/L and the new pH (6.1 þ log[38/0.03 80]) ¼ 7.3.
Treatment of respiratory acidosis

Treatment is aimed at the underlying aetiology of the hypoventilation.
Acute respiratory centre depression by opioids may be reversed with
naloxone. Upper airways should be cleared or a tracheostomy may be
104
5
required. Patients with COPD may require bronchodilators and ster-

oids. If the hypoventilation does not respond to these measures,
mechanical ventilation may be required.
This is a common abnormality due to hyperventilation (‘blowing off’

CO2). The significance of this acid–base disorder usually relates to
the underlying aetiology.
The kidney compensates for a respiratory alkalosis by increasing
urine bicarbonate excretion, creating a compensatory metabolic acido-
sis. This process occurs rapidly and is usually complete within 48 h.
The expected change in serum [HCO3] is given in Box 5.1.
Clinical features
Hyperventilation may be clinically apparent (tachypnoea, Kussmaul
respiration). Symptomatically patients may complain of muscle
cramps, tingling and paraesthesias. This is due to the alkalosis (low
serum [Hþ]), which promotes increased binding of calcium to pro-
teins, resulting in a decrease in ionised calcium concentration.
Table 5.5 Causes of respiratory alkalosis
Hypoxia Lung disease, heart failure, altitude, anaemia

Pulmonary receptor stimulation Lung disease (e.g. pneumonia, pulmonary
embolism, pulmonary oedema)
Drugs Aspirin, theophylline, catecholamines
CNS disorders Subarachnoid haemorrhage, cerebral injury
Miscellaneous Anxiety, pregnancy, sepsis, cirrhosis, pain
Causes of respiratory alkalosis

Respiratory alkalosis may be due to stimulation of peripheral chemore-
ceptors by hypoxia or hypotension, to stimulation of central chemorecep-
tors by a fall in pH, or to intrinsic pulmonary disease affecting pulmonary
receptors (Table 5.5).
Treatment of respiratory alkalosis

Treatment is aimed at the underlying cause of the disorder. Rebreath-
ing of expired air is rarely required.
105
CHAPTER
6
Calcium,
phosphate and
magnesium
metabolism
Calcium homeostasis
Although calcium levels are measured in the blood, 99% of total body
calcium is contained within the mineral content of bones. Serum
calcium levels are determined by the balance of calcium entering the
blood (following absorption from the gut or resorption from bones)
and that leaving the blood (by renal excretion or being utilised during
bone mineralisation). During periods of active growth, such as in
childhood, there is a net positive balance of calcium. In normal adults
the serum calcium levels are generally constant with net calcium input
matching output, although elderly patients and postmenopausal
women may develop a negative calcium balance.
Extracellular calcium exists in the blood as three forms:
l 45% of total calcium is ionised calcium (the most important
physiologically)
l 45% is bound to plasma proteins (principally albumin)
l 10% forms complexes with other molecules (e.g. citrate).
6 Calcium, phosphate and magnesium metabolism
Free ionised calcium is critical in a number of important physiological

processes, including nerve conduction, muscle contraction and activa-
tion of clotting factors.
Intracellular calcium levels (0.001 mmol/L) are markedly lower
than extracellular calcium levels (2.2–2.6 mmol/L), so that a large con-
centration gradient is constantly maintained across the cell membrane.
Calcium plays a critical role in many intracellular processes such as
cell signalling, contraction, activation and secretory activity. An
increase in intracellular calcium concentration may result from the
entry of calcium from the extracellular fluid via calcium channels in
the plasma membrane, or via release from intracellular calcium stores
(mitochondria, sarcoplasmic reticulum).
Regulation of calcium homeostasis

The free ionised calcium level is controlled predominantly by the
actions of parathyroid hormone (PTH) and 1,25-dihydroxycholecalci-
ferol (1,25-DHCC, or calcitriol) (Fig. 6.1), with other factors such as cal-
citonin, oestrogens and glucocorticoids playing a minor role.
Parathyroid hormone
PTH is secreted by the parathyroid glands. PTH secretion is regulated
by the interaction between free ionised calcium and the cell surface
calcium-sensing receptors (CaRG) of parathyroid gland cells. PTH
secretion is inhibited by hypercalcaemia and stimulated by hypocal-
caemia. PTH acts to:
1. increase calcium release from bones by promoting osteoclastic
bone resorption
2. stimulate 1a-hydroxylation of vitamin D in the kidney, leading to
increased gut absorption of calcium (and phosphate)
3. increase renal tubular calcium reabsorption (and inhibit renal
phosphate reabsorption).
Vitamin D
1,25-DHCC is the most active metabolite of vitamin D. Vitamins D2 and
D3 are present in the diet (e.g. fish oil, plants) and are generated in the skin
by the action of ultraviolet light (Fig. 6.2). Conversion to 25-hydroxy-
cholecalciferol by the 25-hydroxylase enzyme occurs in the liver, and
this is further converted to 1,25-DHCC by the 1a-hydroxylase enzyme
in the kidney (see Fig. 6.2). 1,25-DHCC increases calcium absorption
108
Calcium homeostasis
6
Parathyroid
glands
PTH
–ve
+ve ↑ Bone resorption
+ve
Ca2+
Ca2+
+ve
1,25-(OH) Vit D3
+ve
↑ Small bowel absorption
of calcium and phosphate
Bone
mineralisation
↓ Urinary calcium excretion
↑ Urinary PO4 excretion
Figure 6.1 Calcium homeostasis. In settings of low serum calcium concentration,
PTH is stimulated, resulting in increased calcium release from bone and
decreased renal calcium excretion. PTH also stimulates 1a-hydroxylase activity
with increased production of 1,25-dihydroxycholecalciferol, which acts to
increase gut absorption.
in the intestine by inducing the synthesis of the calcium binding protein,

calbindin D9k, in the gut. The kidney also contains a 24-hydroxlase
that produces the vitamin D metabolite 24,25-DHCC, which has a less
clear function.
Calcitonin
Calcitonin is produced by the parafollicular cells of the thyroid gland.
Although calcitonin can reduce serum calcium levels by inhibiting
calcium release from bone and renal calcium reabsorption, it has a
109
+ Sunlight Endogenous
Diet
precursors in skin
Vitamin D
25-hydroxylase
25-(OH) vitamin D
1α-hydroxylase
1,25-dihydroxycholecalciferol
(calcitriol)
Figure 6.2 Vitamin D metabolism. Vitamin D produced in the skin is 25-

hydroxylated in the liver, then 1a-hydroxylated in the kidney to 1,25-dihydroxy-
vitamin D (the most active form of vitamin D).
limited action. A chronic increase or deficiency of calcitonin appears to

have no clinically relevant effects upon calcium homeostasis or bone
mineralisation. Calcitonin levels are, however, useful as a tumour
marker in patients with medullary carcinoma of the thyroid.
Assessment of serum calcium levels

Although the total serum calcium level is measured in the blood (nor-
mal range 2.1–2.6 mmol/L), it is the ionised fraction that is important
physiologically. There are two settings where the total calcium level
may not accurately reflect the ionised calcium concentration.
110
Calcium homeostasis
6
1. Protein binding
As albumin is the major calcium binding protein in the blood, total
calcium levels can be markedly affected by a change in the albumin
concentration. Low serum albumin levels will lead to a low total
serum calcium level, but the ionised calcium level may still be in the
normal range. As a result, the total serum calcium concentration must
be ‘corrected’ for the albumin concentration. In general, the serum cal-
cium falls by 0.02 mmol/L for each 1 g/L fall in serum albumin con-
centration. A formula commonly used to correct for variation in
plasma albumin is:
Corrected ½calcium ¼ Measured ½calcium þ 0:02 ð40 ½albuminÞ
Rarely an abnormal monoclonal protein in myeloma will bind calcium

and give a raised total, but normal ionised, calcium level.
2. Acid–base status
The level of ionised calcium is affected by the blood pH. Acidosis
reduces the ability of albumin to bind calcium, thus resulting in an
increase in ionised calcium. An alkalosis induces the opposite effect
with a resultant fall in ionised calcium levels. This may be clinically
evident in patients who hyperventilate and develop an acute respira-
tory alkalosis. They may complain of circumoral paraesthesia and
may even develop tetany as a result of the acute reduction in ionised
calcium. Similarly, in patients who are acidotic, rapid correction of
pH with sodium bicarbonate or dialysis may acutely lower the ionised
calcium fraction.
When should I consider checking a patient’s calcium level?

Consider in patients with:
l neurological symptoms (confusion, irritability, tetany or seizures)
l renal calculi or evidence of abnormal calcification
l suspected or confirmed malignant disease
l polyuria and polydipsia
l drug treatment that can induce hypercalcaemia (e.g. vitamin D
derivatives, calcium-containing phosphate binders, thiazide
diuretics)
l acute or chronic renal failure
111
l conditions such as sarcoidosis, thyrotoxicosis that may be compli-

cated by hypercalcaemia
l bone disease (such as rickets or osteomalacia)
l suspected pancreatitis or rhabdomyolysis (both may result in
hypocalcaemia).
Hypercalcaemia
Hypercalcaemia should be confirmed with a repeat sample, preferably
taken without the use of a tourniquet. Hypercalcaemia is often asymp-
tomatic until levels reach >3 mmol/L. Indeed, many patients with pri-
mary hyperparathyroidism are detected incidentally following a
‘routine’ blood test when they are found to have moderate hypercal-
caemia. The symptoms of hypercalcaemia depend upon both the abso-
lute levels and the rate of increase. Marked hypercalcaemia can
produce a variety of locomotor, gastrointestinal, renal and even psy-
chiatric symptoms (‘bones, stones and abdominal groans’). The com-
monest causes of hypercalcaemia are hyperparathyroidism and
malignant disease (Table 6.1).
Symptoms of hypercalcaemia
l Anorexia, nausea, vomiting, constipation
l Volume depletion
l Polyuria and polydipsia (secondary to antidiuretic hormone
antagonism)
l Fatigue
l Mental changes including confusion, depression and psychosis
l Renal stones and nephrocalcinosis
l Pancreatitis
Hyperparathyroidism
Most modern PTH immunoassays measure intact PTH molecules
(PTH1–84). Therefore, the PTH-like proteins (PTHRP) produced by
some malignant tumours may not be detected using these methods.
Primary hyperparathyroidism
Primary hyperparathyroidism accounts for 10–20% of patients with
hypercalcaemia and is usually secondary to a solitary adenoma
112
Calcium homeostasis
6
Table 6.1 Causes of hypercalcaemia
Hyperparathyroidism Primary (mostly single adenoma)

Tertiary (usually secondary to chronic kidney disease)
Malignancy Solid tumours (may result from metastatic bony invasion,
osteoclast activation or release of PTH-related protein)
Multiple myeloma
Granulomatous Sarcoid, tuberculosis, leprosy, others
disorders
Drugs Calcium supplements, vitamin D, thiazide diuretics,
lithium, theophylline, vitamin A excess
Endocrine Hyperthyroidism, acromegaly, phaeochromocytoma,
multiple endocrine neoplasia (MEN) syndromes,
Addison’s disease
Other Prolonged immobility, familial hypocalciuric
hypercalcaemia
(80%), diffuse hyperplasia of all four glands (15%) and rarely the
result of carcinoma. The typical clinical picture includes a raised
PTH level in the context of hypercalcaemia (note: the PTH level should
be suppressed in these circumstances!). A reduced phosphate level
secondary to increased renal phosphate excretion and a raised bony
alkaline phosphatase level reflecting increased bone turnover may also
be found. In severe cases renal function may be impaired, and radiog-
raphy may reveal bony changes such as subperiosteal erosion of the
phalanges or a ‘pepper-pot skull’.
Secondary and tertiary hyperparathyroidism

Patients with chronic renal failure may develop secondary hyperpara-
thyroidism. This reflects an appropriate physiological response to the
persistent hyperphosphataemia and hypocalcaemia that accompanies
chronic renal failure. Treatment is aimed at reducing plasma phos-
phate levels with dietary phosphate restriction and phosphate binders
(such as calcium acetate, calcium carbonate or sevelamer). These are
taken with food and bind phosphate in the gut, preventing phosphate
absorption. In addition, treatment with 1a-calcidol or calcitriol will
restore 1,25-DHCC levels, promote calcium absorption from the gut
and directly inhibit PTH secretion. Patients are monitored by regular
checks of calcium, phosphate and PTH levels. However, if secondary
113
hyperparathyroidism is not adequately controlled, patients may

develop tertiary hyperparathyroidism characterised by autonomous
PTH secretion. Such patients may require surgical intervention.
Hypercalcaemia and malignancy

This is typically due to increased bone resorption from osteolytic
metastases (commonly breast and lung cancer) or from tumour secre-
tion of a peptide with PTH activity, called PTH-related protein
(PTHrP). Hypercalcaemia is often prominent in multiple myeloma
(partly due to the production of osteoclast activating factors), and
hypercalcaemia in lymphoma may be secondary to tumour secretion
of calcitriol. Of note, by the time hypercalcaemia develops, the tumour
is typically advanced and readily apparent.
Granulomatous disorders
Hypercalcaemia may be found in sarcoidosis, and less commonly other
granulomatous diseases (e.g. tuberculosis, leprosy). Macrophages in
granulomas contain 1a-hydroxylase and can produce 1,25-DHCC.
The hypercalcaemia is usually readily corrected with glucocorticoids.
What to do if the plasma calcium level is raised

l Consider the clinical history – any evidence of overt or occult
malignancy?
l Carefully review the drug history – is the patient taking vitamin D
derivatives or calcium supplements?
l Other investigations required may include:
– PTH, serum phosphate
– Biochemical/haematology screen may provide clinical clues, e.g.
deranged liver function test results
– Immunoglobulins and serum electrophoresis, Bence Jones protein
(exclude myeloma)
– Tumour workup (chest radiography, faecal occult blood
colonoscopy, mammography, etc.)
l Institute treatment (see box).
Treatment of hypercalcaemia
Mild hypercalcaemia may not require treatment other than oral hydration
and treatment of the underlying cause. Any contributing medications
114
Calcium homeostasis
6
(e.g. calcium supplements, vitamin D, thiazide diuretics) should be

stopped. More severe hypercalcaemia increases urinary excretion of
sodium and water causing volume depletion and decreased urinary cal-
cium excretion. The first goal of treatment is to replete the extracellular
volume with normal saline, which often takes 3–4 L. Loop diuretics will
also enhance urinary calcium excretion, but should be used only once
the patient has been volume expanded. Adjunctive therapy includes the
administration of bisphosphonates, glucocorticoids or calcitonin.
Bisphosphonates impair osteoclastic function and inhibit bone
resorption. They are typically given intravenously (e.g. disodium pal-
midronate 60 mg over 2 h), but if hypercalcaemia is less severe they
may be given orally (e.g. alendronic acid 10 mg daily). The hypocal-
caemic effect of bisphosphonates typically takes several days. If a
more rapid response is required, salmon calcitonin may be used
(100–400 units every 6–8 h, subcutaneously). Glucocorticoids (e.g.
prednisolone 20–40 mg daily) may be effective for hypercalcaemia
associated with granulomatous disorders. Haemodialysis can be con-
sidered if other therapies have failed or the serum calcium concentra-
tion is markedly raised (4.5–5 mmol/L).
Treatment of hypercalcaemia
l Ensure adequate hydration with intravenous normal saline.
l Intravenous furosemide given to a well hydrated patient pro-
motes urinary calcium loss.
l Bisphosphonates are very effective in malignant disease.
l Steroids may be effective in cases characterised by excess 1,25-
DHCC (e.g. sarcoidosis).
l Definitive treatment of the underlying disorder should be
planned, e.g. chemotherapy for malignant disease, surgery
for severe hyperparathyroidism.
l Other less commonly used treatments include calcitonin, pros-
taglandin inhibitors (non-steroidal anti-inflammatory drugs),
beta-blockers (in thyrotoxicosis), haemodialysis.
Hypocalcaemia
The causes of hypocalcaemia are shown in Table 6.2. Some patients
with so-called ‘hypocalcaemia’ may simply have a reduced plasma
protein level, e.g. hypoalbuminaemic patients with severe nephrotic
115
syndrome. Such patients have a normal corrected and ionised calcium

level. True hypocalcaemia is commonly due to inadequate levels of
active vitamin D. Causes include nutritional deficiency, although this
is less common following the addition of vitamin D to foods such as
margarine. Malabsorption of vitamin D from the gut may occur in var-
ious conditions such as coeliac disease, pancreatic disease or following
surgical resection. Renal failure leads to reduced 1,25-DHCC levels as
a result of diminished renal 1a-hydroxylase enzyme activity, and liver
disease may impair 25-hydroxylation.
Symptoms and complications of hypocalcaemia

l Paraesthesia, e.g. around mouth, fingers
l Muscle cramps
l Increased neuromuscular irritability including tetany – check
clinically for Chvostek’s sign and Trousseau’s sign
l Seizures
l ECG changes – bradycardia, prolonged QT interval
l Calcification of basal ganglia
Table 6.2 Causes of hypocalcaemia
Pseudohypocalcaemia Secondary to hypoalbuminaemia (normal ionised

calcium)
Vitamin D deficiency See Table 6.3
Decreased PTH action Autoimmune hypoparathyroidism
Postparathyroid surgery (‘hungry bone’ syndrome)
Hypomagnesaemia
Pseudohypoparathyroidism (tissue resistance to actions
of PTH)
Acute tissue Acute pancreatitis
deposition of Rhabdomyolysis
calcium
Renal losses Nephrotic syndrome (loss of vitamin D binding protein)
Fanconi syndrome
Other Critical illness/sepsis; multiple blood transfusions (citrate
binds calcium and reduces ionised calcium levels)
116
Calcium homeostasis
6
Rickets and osteomalacia

These conditions may develop in patients with vitamin D deficiency
or abnormal vitamin D metabolism (Table 6.3). Adults develop osteo-
malacia, whereas children develop rickets with its characteristic bony
deformities. Patients complain of localised bone pain and tenderness,
and may exhibit a proximal myopathy. The biomineralisation of bone
is defective and a bone biopsy demonstrates non-mineralised osteoid
tissue. Radiography may demonstrate ‘pseudo-fractures’ or Looser’s
zones. Disease may also result from genetic deficiency of 1a-hydroxy-
lase or end-organ resistance to the actions of 1,25-DHCC. Clinically
similar disease with rickets may result from defective tubular reab-
sorption of phosphate. In this condition, called hypophosphataemic
vitamin D-resistant rickets, there is a low serum phosphate level,
marked phosphaturia and no myopathy.
Hypoparathyroidism
This is rare and is characterised by hypocalcaemia, hyperphosphatae-
mia and normal renal function (note that hypocalcaemia and hyper-
phosphataemia are common in chronic renal failure). The serum PTH
concentration is very low or undetectable. Causes include previous
parathyroid or thyroid surgery (inadvertent removal of the parathyroid
glands), autoimmune disease and infiltrative disorders. The condition
Table 6.3 Causes of vitamin D deficiency
Low vitamin D intake Low dietary intake (fat-soluble vitamin)

Low sunlight exposure
Malabsorption Coeliac disease
Chronic pancreatitis
Biliary cirrhosis
Intestinal bypass, postgastrectomy
Abnormal metabolism Renal disease (reduced 1a-hydroxylase level)
Liver disease (reduced 25-hydroxylase level)
Vitamin D-dependent rickets (25-hydroxylase
deficiency)
Anticonvulsant therapy
Renal losses of vitamin D Nephrotic syndrome (loss of vitamin D binding protein)
Fanconi syndrome
117
of pseudohypoparathyroidism is the result of end-organ insensitivity to

the action of PTH, and patients exhibit raised PTH levels.
Miscellaneous conditions
Paget’s disease is common in the elderly. Localised areas of the skeleton
exhibit increased bone turnover resulting in an increased alkaline phos-
phatase level, which may be very high. Indeed, Paget’s disease is often
the cause of an isolated increase in alkaline phosphatase concentration
in elderly individuals. Plasma calcium and phosphate levels are usually
normal, although patients may become hypercalcaemic during a period
of prolonged immobilisation. Osteoporosis is a common bone disorder
characterised by a reduced bone mass and an increased fracture risk.
Routine biochemical tests show normal calcium and phosphate levels
in this condition.
Treatment of hypocalcaemia
Hypocalcaemia is often asymptomatic and can be treated with
increased oral calcium intake and supplemental vitamin D. Any
underlying cause should be treated. Symptomatic hypocalcaemia (par-
aesthesia, tetany, seizures, bradyarrhythmias) requires urgent therapy.
Intravenous calcium (e.g. 10 mL 10% calcium gluconate over 10 min,
followed by slow IV infusion) should be given until the serum calcium
level can be maintained by oral calcium and vitamin D supplements.
Patients receiving chronic calcium replacement (e.g. in hypoparathy-
roidism) must be monitored carefully to avoid hypercalciuria, as this
can lead to renal stones and nephrocalcinosis.
Caution
Great care must be taken to ensure that intravenous calcium solu-
tions are administered correctly as severe skin necrosis may result
if the solution leaks into the tissues.
Phosphate homeostasis
Phosphate is a predominantly intracellular molecule and is found in

most foods, but especially dairy produce and animal protein. It plays
a key role in cellular energy metabolism (adenosine triphosphate;
ATP) and enzyme reactions (e.g. kinases, phosphatases), and is a com-
ponent of bone (hydroxyapatite). Phosphate levels are controlled by
parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23),
118
Phosphate homeostasis
6
vitamin D and renal excretion. Normal serum phosphate levels range

from to 0.85–1.45 mmol/L.
When should I consider checking a patient’s

phosphate level?
l renal impairment
l renal tubular disease, e.g. Fanconi’s syndrome
l hypoparathyroidism or hyperparathyroidism
l bone disease such as rickets, etc., as this may be secondary to
defects in phosphate metabolism
l muscle weakness.
Hyperphosphataemia
Hyperphosphataemia (Table 6.4) is most commonly a problem in kid-
ney disease where decreased glomerular filtration of phosphate
occurs. The increased serum phosphate levels may stimulate PTH pro-
duction by the parathyroid glands (leading to secondary hyperpara-
thyroidism and renal bone disease), or may precipitate with calcium
in blood vessels and heart valves. Alternatively, cell lysis with release
of intracellular contents may lead to acute hyperphosphataemia; in
this condition calcium may be bound, leading to an acute drop in
the ionised calcium level and seizures.
Renal bone disease

The commonest cause of hyperphosphataemia is renal impairment.
As the glomerular filtration rate falls, the serum phosphate level starts
to rise. PTH is stimulated by the rising phosphate concentration, and
Table 6.4 Causes of hyperphosphataemia
Increased absorption Vitamin D excess

Phosphate enemas
Cell lysis Rhabdomyolysis
Chemotherapy for malignancy
Decreased excretion Renal impairment
Hypoparathyroidism
119
also by low calcium levels and the impaired activation of vitamin D.

Renal bone disease is the combination of secondary hyperparathyroid-
ism (increased bone turnover) and low vitamin D levels (osteomalacia).
Treatment is aimed at lowering phosphate levels (oral phosphate bin-
ders) and replacing activated vitamin D (calcitriol) to lower PTH levels.
Note that the raised phosphate levels in combination with high calcium
levels (from vitamin D therapy and calcium-containing phosphate bin-
ders) may lead to metastatic calcification in blood vessels and cardiac
valves. Calcification in small dermal arterioles leads to an ulcerating
skin condition called uraemic calcific arteriolopathy, which is often fatal.
Hypophosphataemia
This is often asymptomatic, but in the longer term osteomalacia (in
children, rickets) or renal stones secondary to hypercalciuria may
develop. At lower levels (serum phosphate <0.4 mmol/L), patients
may develop acute symptoms of rhabdomyolysis, muscle weakness
(hypoventilation, heart failure) and CNS symptoms (seizure, encepha-
lopathy). See Table 6.5.
Hypophosphataemia in the alcoholic patient

There are multiple reasons for hypophosphataemia in the alcoholic
patient who is admitted to hospital. Underlying malnutrition and vita-
min D deficiency are compounded by increased urinary phosphate
losses from secondary hyperparathyroidism (secondary to vitamin D
deficiency) and the toxic effects of alcohol on proximal tubular cells.
After admission, a refeeding syndrome may occur, where phosphate
is driven into cells by higher insulin levels, glucose phosphorylation
and synthesis of new proteins.
Treatment of hypophosphataemia
Acute hypophosphataemia with symptoms requires intravenous
phosphate replacement, but this is relatively uncommon. Intravenous
phosphate (typically given as potassium phosphate 9 mmol over 12 h)
may cause hypocalcaemia or metastatic calcification, and plasma con-
centrations of calcium and phosphate need to be monitored closely. In
most cases, oral phosphate replacement (e.g. Phosphate-Sandoz, 2–6
tablets per day) is sufficient, although diarrhoea is a common side
effect.
120
Magnesium homeostasis
6
Table 6.5 Causes of hypophosphataemia
Decreased absorption Malnutrition

Phosphate binders (e.g. antacids)
Chronic diarrhoea
Vitamin D deficiency (may be secondary to drugs that
are P450 enzyme inducers)
Intracellular shift Glucose phosphorylation (insulin therapy, refeeding
syndrome)
Increased urinary losses Hyperparathyroidism
Fanconi syndrome
Oncogenic osteomalacia
Following kidney transplant
Hypophosphataemic rickets
Hereditary hypophosphataemia and hypercalciuria
(HHRH)
Magnesium is an important and abundant intracellular cation that is

involved in many enzymatic reactions. It is contained predominantly
within bone and within cells. The plasma magnesium level is closely
regulated and, although the exact nature of the homeostatic mechan-
isms is unclear, regulation of gastrointestinal absorption and renal
excretion is important. Unusually for most cations, after glomerular
filtration the major site of tubular reabsorption is in the thick ascend-
ing limb of the loop of Henle and not the proximal tubule. Although
plasma magnesium levels are often poor indicators of total body mag-
nesium reserves, the normal range is 0.7–1.1 mmol/L.
When should I consider checking a patient’s

magnesium level?
l resistant hypokalaemia
l cardiac arrhythmias
l pregnant women with pre-eclampsia.
121
Hypomagnesaemia
Hypomagnesaemia is often accompanied by hypokalaemia or hypo-
calcaemia; the symptoms such as muscular weakness, neurological
symptoms (tetany, seizures) and cardiac dysrhythmias are similar. Hypo-
magnesaemia should be suspected when patients with these conditions
fail to respond appropriately to replacement therapy with potassium
or calcium. Causes of hypomagnesaemia are listed in Table 6.6. Measure-
ment of urinary magnesium excretion should be performed as this will
distinguish between renal and gastrointestinal losses.
Treatment of hypomagnesaemia
Treatment consists of replacement therapy. Oral therapy (e.g. magne-
sium glycerophosphate) may result in diarrhoea, and in some condi-
tions, such as short bowel syndromes, systemic therapy is required
(e.g. intravenous magnesium sulfate).
Hypermagnesaemia
This is an uncommon finding and usually occurs in the context of
severe renal failure in a patient taking magnesium supplements (e.g.
magnesium-containing laxatives or antacids). Symptoms include gas-
trointestinal disturbance, muscle weakness (may cause respiratory
failure) and bradyarrhythmias (ECG may show a prolonged PR inter-
val, wide QRS and long QT interval).
Table 6.6 Causes of hypomagnesaemia
Increased urinary losses Diuretics (loop and thiazide diuretics)

Renal tubular injury (following acute
tubular necrosis or kidney transplant)
Other drugs (aminoglycosides, cisplatin,
amphotericin, tacrolimus, alcohol)
Volume expansion (hyperaldosteronism)
Gitelman’s syndrome
Familial hypomagnesaemia
Increased gastrointestinal losses Diarrhoea
Laxatives
122
6
Treatment
Magnesium is a physiological calcium channel blocker, and calcium
can reverse this antagonistic action. Intravenous calcium is especially
effective for hypotension, dysrhythmias and respiratory distress. Nor-
mal saline will expand the extracellular volume and enhance renal
elimination.
123
CHAPTER
7
Liver function
tests
Introduction
The term liver function tests (LFTs) refers to a panel of biochemical

tests that are often deranged in patients with various forms of liver
dysfunction and disease (Table 7.1). The liver may be adversely
affected in many diseases, and measuring and monitoring liver func-
tion has great clinical utility. It should be recognised that measuring
the circulating levels of liver enzymes does not evaluate hepatic syn-
thetic function; this is more appropriately assessed by serum albumin
and prothrombin time. The liver performs a number of vital and
varied functions including:
l Synthesis – the majority of circulating plasma proteins including
albumin, coagulation factors and complement components, are
synthesised by the liver.
l Metabolism – the liver metabolises carbohydrates (gluconeogenesis
and the synthesis and breakdown of glycogen), lipids (fatty acid
synthesis, cholesterol synthesis, lipoprotein synthesis, ketogenesis),
proteins (conversion of amino acids to ammonia [NH3] and urea)
and hormones (25-hydroxylation of vitamin D as well as metabo-
lism of steroid hormones and polypeptide hormones).
l Excretion – the liver excretes bile salts and bilirubin, together with
many drugs.
7 Liver function tests
Table 7.1 Typical liver function test panel
Test Normal value (individual labs may vary)

Bilirubin 5–18 mmol/L
Alkaline phosphatase 35–120 iu/L
g-Glutamyltransferase (GGT) 12–58 iu/L
Aspartate aminotransferase (AST) 5–40 iu/L
Alanine aminotransferase (ALT) 10–60 iu/L
Albumin 35–45 g/L
l Storage – the liver stores proteins (allowing complex proteins to be

rapidly produced if required), glycogen, fat-soluble vitamins (A, D,
K) and vitamin B12.
l Immunological – the Kupffer cells within the liver may remove cir-
culating immune complexes, present antigen, etc.
The liver is therefore a key organ and often requires careful biochemi-
cal assessment.
Anatomy and physiology
The liver is the largest internal organ in the body and is divided into
thousands of functional units called lobules (Fig. 7.1). Each lobule con-
sists of cords of hepatocytes that surround vascular channels called
sinusoids. The sinusoids are lined by highly specialised cells of the
reticuloendothelial system called Kupffer cells.
The liver receives one-third of its blood supply from the systemic
circulation, and the remainder is derived from the portal system.
Branches of the hepatic artery and portal vein reach the periphery of
a lobule through special tracts called portal triads. Blood percolates
to the lobule centre through the sinusoids and drains via a small cen-
tral vein. Sinusoidal blood is therefore a mixture of arterial and portal
blood, and the low PO2 of sinusoidal blood renders the liver suscepti-
ble to hypoxic injury in conditions such as cardiovascular shock.
Hepatocytes produce 1–1.5 L bile per day. Bile is secreted into the
biliary canaliculi, which join to form ductules and ultimately the extra-
hepatic ducts that drain bile to the gallbladder for storage. Bile
secreted into the small bowel acts to emulsify lipids into small
particles and facilitates the digestive action of the enzyme lipase.
126
7
Bile canaliculus
Hepatocytes
Bile duct
(Takes bile
to gall bladder) Central vein
Portal vein
branch
(Brings blood
from gut)
Arteriole branch of
hepatic artery
(Brings oxygenated blood) Sinusoids
Figure 7.1 Hepatic lobule.
Thus, bile enhances the breakdown and absorption of fat-soluble

nutrients.
Bilirubin metabolism
Bilirubin is a degradation product of haem. Some 80% of haem is
derived from haemoglobin and 20% is derived from other haem-
containing proteins such as myoglobin and cytochromes. Approxi-
mately 300 mg bilirubin is produced per day, although the liver
can metabolise and excrete ten times this amount. The excretion of
bilirubin can be considered in four steps (Fig. 7.2):
1. Production of bilirubin – Haemoglobin released from red cells is
bound to haptoglobin in the circulation and this complex is
removed by cells of the reticuloendothelial system located princi-
pally in the spleen. The haem ring is cleaved to produce the tetra-
pyrrole bilirubin and this unconjugated (hydrophobic) form
circulates in the plasma bound to albumin.
2. Conjugation and secretion of bilirubin – In the liver the bilirubin is
detached from albumin by hepatocytes and transported to the
127
Haemoglobin
Globin Haem
Bilirubin (unconjugated)
Bilirubin Iron
bound to albumin
Spleen,
Bilirubin reticuloendothelial cells
Bilirubin diglucuronide
(conjugated)
Bilirubin
(conjugated) Small intestine
Urobilinogen Urobilinogen
(enterohepatic
circulation) Urobilinogen
and Large intestine
stercobilin
Urobilinogen
Figure 7.2 Bilirubin excretion and the enterohepatic circulation.
smooth endoplasmic reticulum. The bilirubin is then conjugated

with glucuronic acid to form water-soluble conjugated bilirubin
(bilirubin diglucuronide), which is secreted into the biliary canali-
culi for excretion in the bile.
3. Intestinal metabolism of bilirubin – Bilirubin is degraded by bacteria
within the colon and urobilinogen is generated. This is then con-
verted to urobilin or the pigmented stercobilin, which imparts a
dark brown colour to faeces.
4. Enterohepatic circulation – Some of the water-soluble urobilinogen is
reabsorbed from the colon into the portal blood and returned to the
liver for biliary excretion. However, small amounts of water-
soluble urobilinogen do reach the systemic circulation and are
excreted in the urine.
128
7
Direct and indirect bilirubin

In normal individuals 95% of circulating bilirubin is unconjugated and
bound to albumin. The systemic circulation contains only very small
amounts of conjugated bilirubin as a result of minor leakage from
hepatocytes. Conjugated bilirubin is described as ‘direct reacting’
because of its water solubility. Unconjugated or ‘indirect’ bilirubin
must be solubilised in alcohol or other agents before being assayed
in common tests. The total and direct bilirubin is typically measured
and the difference between the two values used to calculate the level
of indirect bilirubin.
Bile salts
Bile salts comprise 70–90% of bile and are synthesised by hepatocytes
from cholesterol conjugated to glycine or taurine. The commonest bile
salts are cholic acid and chenodeoxycholic acid. They act to solubilise
cholesterol and prevent gallstone formation, and emulsify fats in the
intestine in order to facilitate the digestion and reabsorption of fat. Bile
salts are normally reabsorbed in the colon by the enterohepatic circu-
lation and recycled to the liver. Bile salts are a sensitive indicator of
structural liver disease but are not measured routinely. Bile salts accu-
mulate in blood in biliary obstruction and are responsible for the
intense itching complained of by patients.
Alkaline phosphatase (ALP)

This enzyme is predominantly found in liver (biliary tract and liver
epithelial cells) and bone (osteoblasts), but may also be found in gran-
ulocytes, intestinal epithelial cells and renal proximal tubular cells.
Circulating ALP is derived predominantly from liver, bone and intes-
tine (10–20%) and has a half-life of approximately 7days. Therefore,
raised ALP levels may also be found in non-hepatic conditions such
as bone disease (Paget’s disease, bony metastases), late pregnancy
(placental ALP) and some intestinal disorders. ALP levels may be
raised 2–3-fold in rapidly growing adolescents, and may be increased
slightly (1.5-fold) in older adults. In obstructive liver disease, damage
to biliary duct epithelial cells results in the release of ALP, which then
leaks into the circulation.
g-Glutamyltransferase (GGT)
This enzyme is found predominantly in hepatocytes and biliary epi-
thelium, but also at lower levels in kidney, pancreas, liver, spleen,
129
heart, brain and seminal vesicles. It may increase in biliary obstruction

but may also be induced by alcohol and drugs such as phenytoin.
Aminotransferases
Alanine aminotransferase (ALT) is a cytoplasmic enzyme that is rela-
tively liver specific. ALT has a half-life of 37–57 h and the level tends
to become raised at an early stage in hepatic injury.
Aspartate aminotransferase (AST) is a cytoplasmic and mitochon-
drial enzyme in hepatocytes, but is less liver specific as it is also found
in cardiac muscle, skeletal muscle kidney and brain tissue. It has a
shorter half-life (12–22 h), but levels may be raised to a greater degree
in chronic conditions.
When should I consider checking a patient’s liver function?
LFTs are now performed routinely in many patients, but there are still
a number of specific indications including:
l jaundice
l suspected neoplasm (?metastases)
l excess ethanol ingestion
l suicidal overdoses (?paracetamol)
l sepsis and very ill patients (?shock liver)
l acute abdominal pain (?gallstones)
l viral illnesses
l diabetes (fatty infiltration)
l a coagulation disorder.
The detection of minor abnormalities in liver function is a common
finding with the widespread use of multi-channel analysers. Abnor-
mal LFT results can be broadly classified according to the pattern of
enzyme abnormalities into:
l an isolated abnormality, such as an increased level of bilirubin or
ALP alone
l obstructive LFT findings, characterised predominantly by a rise in
ALP and GGT levels
l hepatocellular injury, characterised predominantly by a rise in AST
and ALT levels.
Increased serum bilirubin concentration may occur in conditions
resulting in an obstructive pattern of LFTs as well as in hepatocellular
130
7
injury, and is thus less specific. Indeed, a clear distinction between

cholestatic disease and hepatocellular injury is not always possible
as they may coexist. For example, acute hepatitis often has a marked
cholestatic element at later stages.
In most patients with abnormal LFT results a diagnosis can be obtained
non-invasively. A liver biopsy may be required in patients with an
unclear diagnosis, and the commonest findings include alcoholic
liver disease, steatosis or steatohepatitis.

For the sake of simplicity, this will be broken down into sections
depending upon the primary pattern of the LFT result, categorised as:
l Jaundice pattern with significant increase in bilirubin concentration
alone
l Obstructive pattern with raised ALP and GGT levels
l Hepatocellular pattern with increased ALT and AST levels.
Jaundice (with increased levels of bilirubin alone)
Mild jaundice will pass unnoticed as jaundice is clinically detect-

able only when the serum bilirubin level is greater than
50 mmol/L.
See Figure 7.3 for a breakdown of the causes of jaundice.
Haemolysis
Increased release of haemoglobin from cells undergoing haemolysis
generates large amounts of bilirubin. If liver function is normal, the rise
in serum bilirubin concentration will be largely unconjugated (bound
to serum albumin) as the liver is able to excrete large amounts of conju-
gated bilirubin. The increased amounts of conjugated bilirubin in the
gut produce increased urobilinogen, which may be absorbed via the
enterohepatic circulation and increase urinary urobilinogen levels.
Haemolysis may be detected by the combined measurement of haemo-
globin, the reticulocyte count and haptoglobin levels, coupled with
scrutiny of the blood film. The level of serum bilirubin is rarely greater
than 70 mmol/L in haemolytic conditions.
131
Causes of jaundice
Normal LFTs Abnormal LFTs
Indirect Direct Cholestatic Hepatocellular

hyperbilirubinaemia hyperbilirubinaemia • mainly ↑ alkaline • mainly ↑
(unconjugated) phosphatase transaminases
Haemolysis see table 7.2 for see table 7.4 for

Dyserythropoiesis causes of causes of
Gilbert’s syndrome cholestatic hepatocellular
Drugs (rifampicin, liver disease liver disease
radiocontrast media,
contraceptive pill)
Inherited disorders Acquired disorders

(Dubin-Johnson, • neonatal
Rotor syndromes) • maternal milk
• Wilson’s disease
• hyperthyroidism
• chronic hepatitis
Figure 7.3 Causes of jaundice.
Gilbert’s syndrome
This is a common inherited condition occurring in approximately 5% of
the population, more commonly in males. Bilirubin is conjugated with
glucuronic acid by UDP–glucuronosyltransferase, a family of enzymes
derived from multiple splice variants of a single gene. A common poly-
morphism in the promoter sequence of this gene impairs the rate of tran-
scription. Individuals with impaired enzyme levels or function have
a persistent mild unconjugated hyperbilirubinaemia (<80 mmol/L) with
otherwise normal LFTs. Patients are clinically unaffected, although they
may become noticeably jaundiced at times of illness or fasting.
132
7
Obstructive pattern of LFTs with raised ALP and GGT levels

The conjugation of bilirubin may be normal in this setting, but the
excretion of bile into the gut is hindered. Conjugated bilirubin levels
rise in the plasma, and the water-soluble conjugated bilirubin may
be found in the urine imparting a dark yellow colour. The absence
of urobilinogen and hence stercobilinogen in the gut results in pale
coloured faeces.
Levels of ALP and GGT are typically raised in hepatic and biliary
obstruction. To confirm whether the ALP is of hepatic origin it is pos-
sible to measure tissue specific isoenzymes, but this is rarely per-
formed because the associated increase in GGT concentration is
sufficient corroborative evidence of a hepatic source for the ALP.
It should be noted that low ALP values may be seen in hypothyroid-
ism, pernicious anaemia, zinc deficiency, congenital hypophosphatae-
mia and fulminant Wilson’s disease complicated by haemolysis.
Raised levels of GGT are less specific than ALP, as increased levels
may be found in pancreatic disease, myocardial infarction, renal fail-
ure and chronic obstructive pulmonary disease. An isolated increase
in GGT concentration with otherwise normal LFT findings should
not lead to exhaustive testing for liver disease (see below).
Learning points
l Bilirubin in the urine suggests hepatobiliary disease as it is
only water-soluble conjugated bilirubin that can be excreted
in the urine.
l Cholestasis is suggested by raised alkaline phosphatase (ALP)
and g-glutamyltransferase (GGT) levels.
l Cholestasis may be present in the absence of jaundice.
l The combination of ALP and GGT measurement provides a
sensitive marker of liver metastases that rivals radiological
imaging.
l A low serum albumin level suggests a chronic process owing
to its long half-life (20 days), whereas a normal albumin con-
centration implies an acute process (e.g. acute hepatitis,
gallstones).
There are many causes of obstructive LFTs that may be divided into
causes of extrahepatic and intrahepatic cholestasis (Table 7.2).
133
Table 7.2 Causes of cholestatic liver disease
Extrahepatic cholestasis
Cholelithiasis
Malignancy (carcinoma of head of the pancreas or ampulla,
cholangiocarcinoma), portal lymphadenopathy
Primary sclerosing cholangitis
Miscellaneous – AIDS cholangiopathy (cytomegalovirus [CMV], cryptosporidium,
human immunodeficiency virus [HIV]), chronic pancreatitis, biliary stricture,
parasitic infection (ascariasis, liver fluke).
Intrahepatic cholestasis
Alcoholic hepatitis
Primary biliary cirrhosis
Non-alcoholic steatohepatitis
Drugs – myriad! (Table 7.3)
Secondary to hepatocellular injury, e.g. viral hepatitis and secondary tissue oedema
Sepsis
Infiltrative disease – amyloid, lymphoma, sarcoid, tuberculosis
Miscellaneous conditions – total parenteral nutrition, cholestasis of pregnancy,
postoperative cholestasis, vanishing bile duct syndrome, various rare syndromes
(Dubin–Johnson, Rotor), paraneoplastic syndrome (Stauffer’s syndrome), Caroli’s
disease, thyrotoxicosis, protoporphyria.
Table 7.3 Drugs and liver disease
Predominantly hepatocellular injury Predominantly cholestatic injury

Paracetamol, salicylates, tetracyclines, Androgens, phenothiazines
azathioprine, methotrexate, ferrous (chlorpromazine, haloperidol),
sulphate, antituberculous agents hypoglycaemic agents
(isoniazid, rifampicin), amiodarone, (chlorpropamide, tolbutamide),
halothane, methyldopa, dantrolene, antibiotics (nitrofurantoin,
anticonvulsants (sodium valproate, erythromycin, co-trimoxazole,
phenytoin), NSAIDs, ketoconazole, penicillins), phenytoin, imipramine,
beta-blockers, tacrine, sulindac, cimetidine, oestrogens,
propylthiouracil immunosuppressive agents
(ciclosporin, azathioprine),
hydralazine, captopril, carbimazole
134
7
Alcohol and GGT

The synthesis of GGT is induced by alcohol as well as drugs such as
phenytoin, barbiturates and rifampicin. Levels take 3 – 6 weeks to
return to normal following cessation of alcohol intake, and levels of this
enzyme are used to monitor patients in alcohol abuse programmes.
Patterns of enzyme rises

In liver disease, levels of ALP and GGT are usually increased together
in roughly equal amounts. Variations to this pattern may provide
clues to particular diagnoses:
l Raised ALP with normal GGT levels – this suggests a non-hepatic
cause of the increased ALP concentration, e.g. bone disease, intesti-
nal disease, pregnancy, adolescence.
l Isolated increase in GGT level – this suggests excess alcohol con-
sumption or other liver enzyme inducers, e.g. rifampicin, pheny-
toin and barbiturates. A raised GGT level may also be found in
pancreatic disease, myocardial infarction and renal failure.
The degree of increase of these markers may also provide diagnostic
clues:
l A marked increase in ALP concentration (up to 10–20 times nor-
mal) is suggestive of primary biliary cirrhosis or extrahepatic bili-
ary obstruction with malignant obstruction, typically causing
higher bilirubin levels than obstruction secondary to gallstones.
l A marked increase in both ALP and GGT levels with a dispropor-
tionate rise in GGT concentration suggests drug-induced cholesta-
sis, with resultant induction of GGT synthesis.
l Hepatocellular injury may not affect solely ALT and AST, but may
also increase ALP and GGT levels 2–3-fold.
l Fluctuating levels may suggest the presence of intermittent
obstruction, as may occur in patients with gallstones.
See Figure 7.4 for initial investigation of cholestatic LFTs.
Learning points
l Raised levels of aminotransferases (AST and ALT) suggest
hepatocellular injury.
l The degree of increase in the concentration of aminotrans-
ferases does not correlate with the degree hepatocellular injury
on biopsy, but may be used to follow the course of disease.
135
Investigation of cholestatic LFTs
History and examination

Exclude drug causes
Abdominal ultrasound
Anti-mitochondrial antibody (AMA)
Duct dilatation AMA positive No duct dilatation

(suggests PBC) see table 7.2 for
causes of
cholestatic liver disease
ERCP Liver biopsy Observe ERCP or

(if mild) liver biopsy
Figure 7.4 Investigation of cholestatic liver function test results. ERCP,

endoscopic retrograde cholangiopancreatography.
Hepatocellular pattern with increased ALT and AST levels

The liver has a large functional reserve and minor injury may not be
reflected by changes in LFT results. Moderate injury may result in raised
levels of transaminases, with cholestatic changes and jaundice appear-
ing as the hepatocellular injury worsens. Abnormalities in the synthetic
function of the liver are evident in cases of marked hepatocellular injury.
Patterns of raised aminotransferase levels
The degree of increase in the levels of aminotransferases may provide
diagnostic clues:
1. Marked increase (up to 20 times normal) – this suggests conditions
such as acute viral hepatitis, shock liver (ischaemic hepatitis) or
acute drug/toxin hepatotoxicity such as paracetamol poisoning.
Less common causes include acute Budd–Chiari syndrome, veno-
occlusive disease, the HELLP syndrome (haemolytic anaemia, ele-
vated liver enzymes and low platelet count) or acute fatty liver of
136
7
pregnancy, hepatic infarction and acute exacerbation of autoim-

mune chronic active hepatitis. It is important to note that a sudden
fall in AST and ALT levels in the absence of clinical improvement
is an ominous sign as it implies exhaustion of viable hepatocytes.
2. Moderately raised levels (3–10 times normal) – this may be seen with
infectious mononucleosis, chronic hepatitis, extrahepatic obstruc-
tion, Reye’s syndrome, myocardial infarction, etc.
3. Mildly raised levels (1–3 times normal) – may be found in pancreati-
tis, alcoholic fatty liver, granulomatous/neoplastic hepatic infiltra-
tion, primary biliary cirrhosis, etc.
Note
Normal aminotransferase levels are often found in patients with
chronic hepatitis C infection.
The AST : ALT ratio

Usually the AST and ALT levels are raised to a similar degree, with a
ratio of approximately 0.8 (see Figure 7.5 for investigation). In some
conditions the AST concentration is increased to a greater degree,
resulting in a high ratio. This may occur in:
1. Alcoholic hepatitis – a ratio >2 is suggestive of alcoholic hepatitis
but it may be as high as 5. Note that the sources of AST may be
partly extrahepatic, e.g. seizures and rhabdomyolysis that result
in release of AST from muscle tissue.
2. Hepatitis C with cirrhosis.
3. Non-alcoholic steatohepatitis.
4. Liver metastases – the AST rise may be marked compared with the
ALT rise.
5. Non-hepatic disease, e.g. muscle disorders, myocardial infarction,
thyroid disorders, coeliac disease, false-positive increase in AST
concentration with erythromycin treatment.
By contrast, a low AST : ALT ratio may be seen with:
1. Acute inflammation – ALT is a more sensitive and early marker of
hepatocellular injury, e.g. post-transfusion hepatitis, occupational
toxic exposure.
2. Cholestasis – extrahepatic obstruction is an acute process resulting
in a greater rise in ALT concentration. The reverse may be present
with intrahepatic obstruction.
137
Investigation of raised aminotransferases
History and examination
Hepatitis serology Consider non-hepatic causes

Serum iron studies • Creatinine kinase and aldolase
• Thyroid function tests
• Coeliac disease
Consider less common hepatic causes
• Autoimmune hepatitis (autoantibody screen)
• Wilson’s disease (serum caeruloplasmin)
• α-1-Antitrypsin deficiency
see table 7.4 for causes of hepatocellular
liver disease
Liver biopsy
• Consider if aminotransferases
persistently >2x normal
Figure 7.5 Investigation of raised levels of aminotransferases.
Postoperative jaundice
This is a common finding and is typically multifactorial with aetiologi-
cal factors including (Table 7.4):
l increased erythrocyte breakdown (haematoma, transfusion of
stored blood)
l possible hepatocellular damage resulting from drugs, anaesthetic
agents, hypotensive shock, etc.
l intrahepatic cholestasis, e.g. sepsis, hypotension, total parenteral
nutrition
l surgical injury to bile ducts should also be considered.
Assessment of hepatic synthetic function
The serum albumin and prothrombin time are used to assess hepatic
synthetic function and the severity of the liver injury. Very severe liver
138
7
Table 7.4 Causes of hepatocellular injury
Group of causes Specific

Viral Hepatitis viruses (HAV, HBV, HCV), herpes viruses,
haemorrhagic viruses (yellow fever, Ebola, Marburg,
Lassa), adenoviruses, enteroviruses
Drugs See Table 7.3
Alcohol and Chlorinated hydrocarbons (carbon tetrachloride; chloroform),
toxins amanita phylloides (mushroom poisoning), aflatoxin B1,
arsenic, phosphorus
Immunological Autoimmune hepatitis, non-alcoholic steatohepatitis
Specific liver Wilson’s disease, haemochromatosis, a1-antitrypsin
conditions deficiency, porphyrias, liver infiltration (amyloid,
lymphoma, sarcoid)
Neoplasms Metastatic liver disease, hepatocellular carcinoma, lymphoma
Vascular Congestive heart failure, shock liver, tricuspid incompetence,
constrictive pericarditis, Budd–Chiari syndrome, veno-
occlusive disease
Other infections Bacterial – tuberculosis, leptospirosis, syphilis, pyogenic
abscess, brucella, rickettsia
Fungal – candida, blastomyces, coccidioides, histoplasma,
cryptococcus
Parasitic – helminths (ascaris, fasciola, clonorchis,
schistosomiasis, echinococcus), protozoa (amoebiasis,
plasmodia, babesiosis, toxoplasmosis, leishmaniasis)
injury may be associated with a low serum urea concentration as a

result of failure of urea production together with hypoglycaemia.
Albumin
The liver synthesises 12–15 g albumin each day. The serum half-life of
albumin is 17–20 days and it therefore takes about 3 weeks of liver
injury before the serum albumin levels fall. Pre-albumin (transthyre-
tin) has a half-life of 2 days and offers a more accurate assessment of
hepatic synthetic function in patients with acute liver injury. It is
important to be aware that hypoalbuminaemia is non-specific and
may also be seen in patients with malnutrition, protein-losing entero-
pathy or nephrotic syndrome.
139
Coagulation factors
The liver is responsible for the production of many coagulation fac-
tors. Four of these factors (prothrombin and factors VII, IX and X)
are dependent on vitamin K for that post-translational modification
of the proteins that is required for their functional activity.
The coagulopathy associated with liver disease may be due to:
1. hepatocellular dysfunction
2. vitamin K deficiency, as cholestasis results in impaired absorption
of fat-soluble vitamins including vitamin K.
Vitamin K treatment will thus help to distinguish between these pos-
sibilities and will almost always rapidly correct the coagulation abnor-
mality secondary to extrahepatic jaundice (<12 h). It should be noted
that cholestasis may occur in association with hepatocellular dysfunc-
tion and treatment with vitamin K may be partly effective in this
setting.
Factor VII has the shortest half-life of the coagulation factors. As a
result, the prothrombin time (PT) becomes prolonged at an early stage,
and PT is the most sensitive measure of coagulation in liver dysfunc-
tion. PT >5 s above normal should raise concern of a fulminant course
in acute viral or toxic hepatitis. PT >100s is an indication for liver
transplantation.
Patients with chronic liver disease exhibit prolongation of both the
PT (factors II, VII, X) and the activated partial thromboplastin time
(factors II, IX, X). The levels of fibrinogen and factor V fall at a late
stage in severe liver failure and abnormalities of other factors are usu-
ally responsible for the coagulation defects.
In clinical practice, coagulation abnormalities due to hepatocellular
injury may not require correction as the raised PT is often not clinically
serious and may be a useful parameter to monitor disease severity. The
PT is one of the parameters employed in the Child–Pugh classification of
the severity of liver disease (Table 7.5). Treatment with vitamin K and
fresh frozen plasma should be considered when there is active bleeding
(usually gastrointestinal) or before invasive procedures.
Urea and ammonia
The nitrogenous products of protein metabolism are converted in the
liver to ammonia and then to urea in the urea cycle. In severe liver dis-
ease this pathway breaks down and serum levels of urea may fall.
Some 90% of liver function must be lost before urea production is
impaired. Ammonia is generated in the gut by bacteria and is a potent
140
Table 7.5 Child–Pugh classification of severity of liver disease. The patient is scored
from 1 to 3 for each of the five categories
Points assigned
1 2 3

Bilirubin (mmol/L) <28 28–51 >51
Albumin (g/L) >35 28–35 <28
Prothrombin time (seconds 1–3 4–6 >6
> control)
Ascites Absent Slight Moderate
Encephalopathy None Grade 1–2 Grade 3–4
Child–Pugh grade A (well compensated) B (significant functional C (decompensated)

compromise)
Score 5–6 7–9 10–15
1-year survival (%) 100 80 45
2-year survival (%) 85 60 35
141
7
neurotoxin. In liver disease, the serum levels of ammonia may rise due
to inadequate hepatic conversion to urea. This may also be due to
shunting of portal blood away from hepatocytes. Raised ammonia
levels have been associated with hepatic encephalopathy in severe
liver disease.
Glucose
During fasting, the liver plays an important role in maintaining blood
sugar levels by glycogenolysis (breakdown of stored glycogen) or glu-
coneogenesis (generation of glucose from amino acids or free fatty
acids). This protective mechanism may be impaired in severe liver
dysfunction, such as during fulminant acute liver necrosis, thereby
resulting in hypoglycaemia. Patients may require regular monitoring
of blood sugar levels.
Clinical assessment
The underlying cause of the abnormal LFT results, as well as the

severity of liver dysfunction, may be suggested by the pattern of the
abnormalities (Table 7.6) and by taking a full history and performing
a thorough physical examination. Specific features to look for include
the following.
Clinical history
l Presence of jaundice, change in stool or urine colour, itch (obstruc-
tive jaundice)
l Abdominal pain, fever, rigors, jaundice (gallstones, ascending
cholangitis)
l Arthralgias, myalgia, anorexia, rash (drugs, hepatitis)
l Alcohol consumption
l Exposure to drugs, medications and herbal remedies
l Disorientation, memory loss (encephalopathy)
l Easy bruising, bleeding, black stools (coagulopathy, bleeding oeso-
phageal or gastric varices)
l Previous history of injections, blood transfusions, intravenous drug
use and tattoos together with sexual history (risk factors for
hepatitis)
l Occupational history, e.g. exposure to industrial toxins, farming
(hydatid disease), sewage workers (leptospirosis), healthcare work-
ers (hepatitis)
142
Table 7.6 Patterns of abnormal liver function tests
Gilbert’s/ Acute Chronic Cirrhosis Cholestasis Malignancy

haemolysis hepatitis hepatitis
Bilirubin " N or "" N or " N or " " or """ N
ALP N N or " N N or "" """ ""
GGT N N or " N N or "" """ ""
Aminotransferases N """ " N or " N or " N or "
Albumin N N N or # N or # N N or #
Immunoglobulinsa N N " " N N
Prothrombin time N N or " N or " N or " N or "b N
N, normal.
Clinical assessment
a
IgA levels increased in cirrhosis; IgG levels increased in autoimmune hepatitis.
b
May correct with vitamin K.
143
7
l Other – travel history, contaminated food, history of previous gall-

stones, abdominal surgery, family history of liver disease.
Examination
l Degree of jaundice
l Clinical stigmata of chronic liver disease
l General (spider naevi, hepatomegaly, parotid enlargement, muscle
wasting)
l Hands (finger clubbing, leuconychia, Dupuytren’s contracture)
l Disturbed endocrine function (gynaecomastia, impotence, decreased
body hair, testicular atrophy, palmar erythema)
l Portal hypertension (splenomegaly, ascites, peripheral oedema,
caput medusa, rectal varices)
l Liver failure (hepatic fetor, encephalopathy, flapping tremor)
l Cardiovascular system – raised jugular venous pressure (conges-
tive cardiac failure with hepatic congestion, tricuspid incompe-
tence, constrictive pericarditis)
l Presence of lymphadenopathy (neoplasm, lymphoma), Kayser–
Fleischer ring (Wilson’s disease), hyperpigmentation (haemochro-
matosis, primary biliary cirrhosis) or xanthomata (primary biliary
cirrhosis).
Special tests
Hepatitis serology in liver disease
Acute hepatitis is usually secondary to hepatitis viruses (A–E)
(Table 7.7), but other systemic viral infections (Epstein–Barr virus,
CMV, HIV) or toxins (alcohol, paracetamol, carbon tetrachloride, fun-
gal toxins) may produce a similar clinical picture. Transaminase levels
may be greatly increased.
Initial screening hepatitis serology consists of testing for hepatitis B
surface antigen (HBsAg) and antihepatitis C antibody. A higher index
of suspicion or positivity on initial screening tests prompts further
testing.
Hepatitis A (HAV)
This infection is spread by the faeco-oral route and is more common in
children and those living in poor sanitary conditions. Clinically, an
incubation period of 2–6 weeks is followed by malaise, nausea and
anorexia. An icteric illness follows that rarely lasts longer than
6 weeks. Fulminant hepatitis occurs in less than 0.3% of cases. Chronic
144
Table 7.7 Clinical features of hepatitis viruses
Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E

Route of infection Faeco-oral Parenteral Parenteral Parenteral Faeco-oral
Incubation period 2–6 weeks 2–6 months 2–52 weeks 3–13 weeks 3–6 weeks
Onset Abrupt Insidious Insidious Abrupt Abrupt
Chronic carriage No Yes Yes – No
Acute mortality rate <0.3% 1–4% <1% 30% 1–2% (pregnant women 20%)
Progression to end-stage liver No Rare 25% – No
disease
Clinical assessment
145
7
hepatitis or progression to cirrhosis does not occur. The diagnosis is

confirmed by the presence of IgM anti-HAV antibodies or increasing
titres of IgG anti-HAV antibodies.
Hepatitis B infection
This virus is acquired parenterally, most commonly by transfusion,
needle-sharing or sex. After a 2–6-month incubation period, an acute ill-
ness develops in about 50% of infected adults, with fulminant hepatitis
occurring in about 1% of cases. Patients may develop chronic hepatitis
or an asymptomatic chronic carrier state (HBsAg positive, but HBV
e antigen [HBeAg] and HBV DNA negative). Levels of transaminases
are typically normal in the carrier state. HBV infection is assessed by
measuring HBsAg, HBV core antigen (HBcAg) and HbeAg, together
with their corresponding antibodies (Table 7.8).
Hepatitis C infection
This virus is acquired parenterally, often through intravenous drug use
or therapeutic blood products. The acute infection is usually mild and
subclinical. However, only 10–15% of infected individuals eradicate
Table 7.8 Serological markers of hepatitis B infection
Marker Time of Clinical implication

appearance
after infection
HBsAg 4–12 weeks Earliest indicator of acute infection.
Persistence >6 months indicates
chronic infection
HBeAg 4–12 weeks Indicates viral replication and
associated with high infectivity
HBcAg – Not detectable in serum
Anti-HBs antibody 4–10 months Indicates previous infection and
immunity to further HBV infection
Anti-HBe antibody 8–16 weeks Indicates resolution of acute infection
Anti-HBc IgM 6–14 weeks Indicates acute infection with HBsAg
antibody
HBV DNA 4–12 weeks Used to assess viral replication and
suitability for antiviral treatment
146
Clinical assessment
7
the virus and chronic infection is the typical course. Over 10–20 years,
cirrhosis and later hepatocellular carcinoma commonly develop.
The presence of HCV antibody demonstrates exposure to the virus
(appears 12–16 weeks after infection), and viraemia (HCV RNA) may
be detected by the polymerase chain reaction (PCR).
Autoantibody screen in liver disease

A polyclonal increase in immunoglobulin levels is common in many
types of liver disease, particularly raised IgA levels (detected by
performing plasma protein immunoelectrophoresis and measuring
serum immunoglobulins). IgG levels are markedly increased in
chronic hepatitis, and IgM levels are raised in primary biliary cirrho-
sis. Specific autoantibodies may be associated with a number of
hepatic diseases.
Autoimmune hepatitis
This condition occurs more commonly in young women and has a
variable presentation ranging from chronic abnormalities on LFTs to
severe acute hepatitis and cirrhosis. Extrahepatic manifestations may
be prominent, including haemolytic anaemia, thrombocytopenia, thy-
roiditis, colitis and type 1 diabetes mellitus. Antinuclear antibodies
(ANAs) are positive in autoimmune hepatitis, although non-specific,
with anti-double-stranded DNA antibodies typically being absent.
More specific autoantibodies include anti-smooth muscle antibodies
(SMAs) and anti-liver and kidney microsomal antibodies. It should
be noted that approximately 5% of patients with chronic hepatitis C
infection have a positive ANA result, and anti-SMA and anti-liver
and kidney microsomal antibodies have also been described.
Primary biliary cirrhosis (PBC)

A positive anti-mitochondrial antibody is highly specific for PBC, with
the disease typically presenting as cholestatic liver disease. PBC pre-
dominantly affects women; clinical features include itch, hyperpig-
mentation and hepatomegaly. PBC may also be associated with other
autoimmune diseases.
Other circulating antibodies such as antineutrophil cytoplasmic
antibodies (ANCAs) may be found in chronic liver diseases such as
primary sclerosing cholangitis and autoimmune hepatitis.
147
a1-Antitrypsin (a1-AT)
This glycoprotein is an antiprotease that inhibits the action of several
proteases, including trypsin and plasmin, and thereby acts to prevent
excessive tissue destruction and scarring. Allelic variants of the gene
are common and may result in low serum a1-AT concentrations.
Affected individuals are predisposed to the development of early-
onset emphysema and liver injury with cirrhosis. The variant a1-AT
accumulates in hepatocytes and is detectable on liver biopsy. The con-
dition is suggested by the absence of the a1 peak on plasma protein
electrophoresis and is confirmed by measuring serum a1-AT levels
and determining the a1-AT phenotype.
Serum caeruloplasmin
Low levels of the copper transport protein caeruloplasmin (<20 mg/
dL) are suggestive of Wilson’s disease. This is an autosomal recessive
condition resulting from mutations in the P-type ATPase that inhibits
the cellular export of copper. This results in the intracellular accumu-
lation of copper in certain tissues, particularly liver and brain. Clini-
cally patients often present at a young age with liver disease
secondary to hepatocellular injury or cirrhosis, or with neuropsychia-
tric disorders. Corneal deposits of copper may produce the character-
istic Kayser–Fleischer rings on slit-lamp examination. Confirmatory
investigations include a high 24-h urinary copper excretion (usually
>100 mg/d, normal <30 mg/d) and evidence of copper accumulation
on liver biopsy. Note that about 10% of patients with Wilson’s disease
have normal serum caeruloplasmin levels.
Serum iron studies

Raised serum iron levels are suggestive of haemochromatosis. This is a
common autosomal dominant condition resulting from mutations in
the HFE gene and causing increased iron absorption from the gastro-
intestinal tract and subsequent iron overload. The iron is deposited
in tissues, particularly liver, heart and pancreas. Clinical features
include liver disease (hepatomegaly, abnormal LFT results, cirrhosis,
hepatocellular carcinoma), diabetes mellitus, skin pigmentation
(‘bronze diabetes’), arthropathy and cardiomyopathy. The diagnosis
of haemochromatosis is supported by iron studies revealing an
increased transferrin saturation (>45%) and a raised serum ferritin
level (>400 ng/mL in men and >300 ng/mL in women). The definitive
investigation is a liver biopsy that demonstrates parenchymal iron
148
Clinical assessment
7
deposition by Prussian blue staining. In some centres genetic testing

for the common C282Y and H63D mutations may be available.
a-Fetoprotein (AFP)
Levels of this serum tumour marker are raised in patients with hepa-
tocellular carcinoma and may be measured in those at risk of develop-
ing this tumour, e.g. patients with established cirrhosis. The level of
AFP correlates with tumour size and may reach levels >10 000 ng/
mL (normal <30 ng/mL) in patients with large undifferentiated
tumours. However, it should be noted that a mild increase in AFP
(500 ng/mL) may be found in patients with cirrhosis or hepatitis in
the absence of malignant disease. In addition, AFP levels may also
be increased in some testicular tumours and AFP is used as a maternal
marker for fetal neural tube defects.
Other tumour markers

The level of carcinoembryonic antigen (CEA) may be measured in
patients with cholestatic abnormalities on liver function testing. It is
usually normal in those with benign biliary strictures, but may be
raised (3-fold) in patients with primary sclerosing cholangitis or cho-
langiocarcinoma (5-fold). CA19-9 concentration may be increased in
ductal pancreatic carcinoma.
149
CHAPTER
8
Lipid disorders
Introduction
The two main lipids in the blood are cholesterol and triglycerides.
They are hydrophobic and circulate in plasma bound to apoproteins
in complexes known as lipoproteins. Cholesterol is essential for the
formation of cell membranes, steroid hormone production and bile
acid formation. Triglycerides are important in energy utilisation.
Hypercholesterolaemia is a major risk factor for coronary artery dis-
ease. Cholesterol lowering in patients with known cardiovascular
disease (secondary prevention) leads to a decreased mortality across
population groups. The data in patients without known cardiovascu-
lar disease (primary prevention) is less clear, but in those at high risk
(patients with diabetes or multiple risk factors) lipid lowering is
recommended.
Classification of lipoproteins
Lipoproteins consist of a core of hydrophobic lipid (triglyceride and
cholesterol esters) surrounded by hydrophilic phospholipids and
non-esterified cholesterol. Apolipoproteins are found on the surface
and play key roles in regulating lipoprotein metabolism.
Lipoproteins are classified into five major types depending on their
density (Table 8.1).
Exogenous (dietary) pathway

Cholesterol and fatty acids are absorbed from the small bowel. Within
the cells of the intestinal mucosa, fatty acids combine with glycerol to
8 Lipid disorders
Table 8.1 Classification of lipoproteins
Percentage lipid
concentrationa
Sizeb Triglyceride Cholesterol Major

(nm) apolipoprotein
Chylomicron >200 80–95% 2–7% B-48
VLDL 30–140 55–80% 5–15% B-100
IDL 23–27 20–50% 20–40% B-100
LDL 19–22 5–10% 40–50% B-100
HDL 7–13 5–10% 15–25% A-I
a
Remaining percentage consists of apolipoprotein. VLDL, very low density lipoprotein; IDL,
intermediate density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein.
b
Size is variable, and small dense LDL particles may be more atherogenic.
form triglycerides, and cholesterol is esterified. These lipids are bun-

dled with apolipoproteins to form chylomicrons, which enter the cir-
culation (Fig. 8.1).
Lipoprotein lipase in the capillaries of peripheral tissues hydrolyses
core triglycerides, releasing free fatty acids to be used as an energy
source or stored in adipose tissue. The end-product of metabolism is
the chylomicron remnant, which is taken up by the liver.
Endogenous pathway
This pathway conveys lipids from the liver to peripheral tissues or in
the reverse direction (reverse cholesterol transport) (Figs. 8.2 & 8.3).
Very low density lipoprotein (VLDL) is synthesised by the liver and
enters the circulation. VLDL is hydrolysed by lipoprotein lipase (in the
capillaries of fat and muscle tissue), depleting triglyceride and leading
to the generation of intermediate density lipoprotein (IDL). The IDL is
either cleared from circulation by the low density lipoprotein (LDL)
receptor or remodelled by hepatic lipase to form LDL. LDL may be
taken up by the liver (LDL receptor), where it is converted to bile acids
and secreted into intestinal lumen, or may be transported to non-
hepatic tissues, incorporated into cell membranes, steroid hormone
production or stored as cholesterol esters. Defects in the LDL receptor
lead to familial hypercholesterolaemia.
152
Introduction
8
Small bowel
Fatty acids Nascent

Free Chylomicron
chylomicron
cholesterol
Muscle/fat
ApoE FA
ApoC LPL
HDL2 Chylomicron
ApoE
ApoC
Liver
Chylomicron
remnant
LRP
Figure 8.1 Exogenous (dietary) pathway. Absorption of free fatty acids and free
cholesterol from the small bowel with delivery of fatty acids (FA) to peripheral
tissues and uptake of the chylomicron remnants by the liver. Apo, apolipoprotein;
LPL, lipoprotein lipase; LRP, LDL receptor-related protein.
De novo cholesterol synthesis

This occurs within cells via hydroxymethylglutaryl-coenzyme A
(HMG-CoA) reductase. Statins decrease the activity of this enzyme,
resulting in a fall in intracellular cholesterol levels, increasing LDL
receptor expression, and thus lowering serum LDL levels.
Reverse cholesterol transport

High density lipoprotein (HDL) is formed in the liver and in intestinal
cells from phospholipid and apolipoproteins, and procures further
surface components (apolipoproteins, cholesterol and phospholipid)
from chylomicron remnants and IDL (Fig. 8.3).
HDL can remove free cholesterol from intracellular sources, such as
atherogenic foam cells, (reverse cholesterol transport), accounting for
its antiatherogenic effect. Other effects may be maintenance of endo-
thelial function and of low blood viscosity via red cell deformity.
There is an inverse relationship between plasma HDL cholesterol
levels and cardiovascular risk. HDL levels lower than 1 mmol/L
153
8 Lipid disorders
Nascent
VLDL
Liver VLDL
VLDLr
LRP ApoE FA
LDLr ApoC LPL
HDL2 IDL
ApoE
ApoC
Muscle/fat
LDL IDL
Hepatic
lipase
Peripheral tissues/
arterial wall
Figure 8.2 Endogenous pathway. Trafficking of lipids from the liver to peripheral
tissues and the production of LDL. VLDL is produced by hepatocytes and released
into the circulation where it matures and undergoes lipolysis of the triglyceride
component by lipoprotein lipase (LPL) in capillaries perfusing muscle and fat to
form IDL. Further lipolysis by hepatic lipase leads to the formation of LDL, which is
removed by the liver via the LDL receptor (LDLr) or may be taken up by peripheral
tissues, promoting atherosclerosis and tissue injury. FA, fatty acids.
increase the risk of coronary artery disease (CAD) by about 20%. In

contrast, HDL levels greater than 1.9 mmol/L are associated with a
longer lifespan.
Hyperlipidaemia and atherosclerosis
Atherosclerotic plaques in the arterial walls of patients contain large

amounts of cholesterol. Circulating LDL that is not taken up by LDL
receptors may be taken up by macrophages via scavenger receptors
(CD36). Accumulation of excess cholesterol in these cells produces foam
cells, which contribute to the atherosclerotic plaque. Oxidised LDL is
more atherogenic and is taken up preferentially by macrophages.
154
8
IDL
TG CETP Lipid-laden
PL and FC macrophage
CE
Nascent
CE HDL2
HDL
LCAT
SR-B1 ABCA1
Hepatic HDL receptor (ATP-binding cassette
transporter type 1)
Figure 8.3 HDL metabolism: reverse cholesterol transport. This mechanism
transports surplus lipids from peripheral tissues (including atherogenic foam cells)
back to the liver. Promotion of this pathway by new therapeutic agents could
potentially reduce atherosclerosis. ABCA1, ATP-binding cassette transporter type
1; CE, cholesterol ester; CETP, cholesterol ester transfer protein; FC, free
cholesterol; LCAT, lecithin cholesterol acyltransferase; PL, phospholipid; SR-B1,
scavenger receptor class B type 1; TG, triglycerides.
Measurement of the lipid panel
The level of LDL cholesterol (‘bad cholesterol’) correlates with the

risk of coronary artery disease, whereas HDL cholesterol (‘good
cholesterol’) is protective against coronary artery disease.
Who should be checked?

l Any patient with cardiovascular disease (coronary artery disease,
stroke, peripheral vascular disease)
l All patients with diabetes mellitus
l Other patients at high risk for hyperlipidaemia (thyroid disease,
liver disease, renal disease)
l Cardiovascular risk assessment – it is recommended that all indivi-
duals over 40 years old should undergo a cardiovascular risk
assessment.
How should a lipid panel be measured?

l 12-h fast (meal or acute alcohol can increase the triglyceride level).
155
8 Lipid disorders
l Wait for 3 months postmyocardial infarction (but can be measured

accurately within the first 24 h after myocardial infarction).
l Note that the LDL concentration is a calculated level and may be
inaccurate when the triglyceride (TG) level is >5 mmol/L.
l Measurement of the ratio of total cholesterol to HDL is often used
to assess the significance of a raised total cholesterol (TC). As HDL
is protective, a low ratio is beneficial.
l If the cholesterol level is raised, the patient should be assessed fur-
ther for secondary causes (diabetes, renal disease, proteinuria, liver
disease, alcohol intake, hypothyroidism).
Non-HDL cholesterol
In patients with raised TG levels (>5 mmol/L), calculated LDL levels
are inaccurate, and some use non-HDL cholesterol levels (TC
HDL). The target for non-HDL cholesterol in individuals at high risk
for cardiovascular disease is <3 mmol/L.
Hypercholesterolaemia
Data from large epidemiological studies have shown that about 50% of
the adult industrialised population have a total cholesterol level
>5 mmol/L and about 20% have a TC level >6 mmol/L.
Note: Total cholesterol levels do not differentiate between the
amounts of cholesterol carried by LDL and HDL. Women often have
higher HDL levels, and for a given TC level may be at lower risk for
CAD. It is therefore important to consider the whole lipid panel and
not merely the total cholesterol.
Example:
Patient A: TC 7.1, LDL 3.5, HDL 2.8, TG 1.7 mmol/L
Patient B: TC 7.1, LDL 5.4, HDL 0.6, TG 2.3 mmol/L
Although TC is the same for both patients (7.1 mmol/L), patient B
has a much higher risk of CAD because the LDL level is markedly
increased and the HDL level is low (high TC:HDL cholesterol
ratio).
Familial hypercholesterolaemia
Patients with markedly raised LDL levels (>5 mmol/L) often have
genetic forms of hypercholesterolaemia and require early detection
156
8
and family screening (Table 8.2). Familial hypercholesterolaemia occurs

in 5–10% of individuals who develop CAD before the age of 55 years.
LDL receptor mutations

This common condition is due to mutations in the gene encoding the
LDL receptor. Homozygous patients are rare, but have extremely high
levels of LDL (8-fold greater than normal) and present with athero-
sclerotic disease in childhood. Heterozygotes have LDL concentrations
twice normal (total cholesterol usually >9 mmol/L) and develop pre-
mature CAD in their thirties and forties. Patients may have tendon
xanthomas, tuberous xanthomas or xanthelasma. A similar phenotype
may be caused by mutations in apolipoprotein (Apo) B-100.
LCAT deficiency
Lecithin cholesterol acyltransferase is important in reverse cholesterol
transport. Deficiency is an autosomal recessive disease with corneal
clouding, target cell haemolytic anaemia and proteinuric renal failure.
The lipid panel shows increased TC and TG levels, with a decreased
HDL concentration.
Combined hypercholesterolaemia and

hypertriglyceridaemia
Familial combined hyperlipidaemia
This is the most common form of dyslipidaemia, accounting for 1 in
300 of the adult population. It appears to be autosomal dominant,
although expression is variable.
Dysbetalipoproteinaemia
ApoE mediates the uptake of lipoproteins by the LDL receptor and the
LDL receptor-associated protein (LRP). There are three major ApoE
Table 8.2 Causes of hypercholesterolaemia
Primary lipid disorders Type II familial hypercholesterolaemia

Type I, IV, V hyperlipoproteinaemia
Secondary causes Cholestasis/liver disease, nephrotic syndrome/
proteinuria, hypothyroidism, pregnancy,
drugs (progestogen, ciclosporin, thiazides)
157
8 Lipid disorders
alleles (E2, E3, E4). ApoE2 has a lower affinity for the LDL receptor,
and homozygotes for this variant may have severe hyperlipidaemia.
Tuberous xanthomas and striae palmaris (cholesterol deposits in pal-
mar creases) may be present. Note that 1% of the population is homo-
zygous for ApoE2, mostly with normal lipid levels, so a second factor
is required.
Hypercholesterolaemia in certain conditions

Diabetes mellitus
Hyperlipidaemia is usually not a prominent feature of type 1 diabetes
as long as blood sugar control is adequate. In type 2 diabetes, the typ-
ical pattern is of hypertriglyceridaemia with low HDL levels. This
lipid pattern is partly due to the associated obesity and insulin resis-
tance. The term ‘metabolic syndrome’ has been applied to the constel-
lation of features of central obesity, dyslipidaemia, hypertension, gout
and type 2 diabetes. Patients with diabetes are at a greatly increased
risk of CAD, and the target levels for TC and LDL cholesterol are
the same as for those with established CAD (LDL <2 mmol/L).
Renal disease
Chronic kidney disease and haemodialysis are typically associated
with hypertriglyceridaemia and low HDL cholesterol. Proteinuria
and nephrotic syndrome may be associated with profound hypercho-
lesterolaemia secondary to increased lipoprotein production by the
liver. Renal transplant patients commonly have hypercholesterolae-
mia, as least partly secondary to the immunosuppressive medications
(calcineurin inhibitors, steroids). Note that patients undergoing hae-
modialysis, despite being at very high cardiovascular risk, tend to
have low levels of LDL.
Liver disease
Cholestatic liver disease typically causes hypercholesterolaemia. By
contrast, acute liver injury may be associated with low cholesterol
levels.
Cardiovascular risk assessment

Guidelines for cardiovascular risk assessment and treatment have
been published recently by the Joint British Societies (Heart 2005; 91
(Suppl 5):V1–V52).
158
8
When considering lipid-lowering therapy a comprehensive cardio-

vascular risk assessment should be performed (Table 8.3). It is recom-
mended that all individuals over the age of 40 years undergo
cardiovascular disease risk assessment in primary care. All patients
with diabetes aged over 40 years are considered to be at high risk.
A patient’s 10-year risk of developing cardiovascular disease can be
estimated using the Joint British Societies’ cardiovascular risk predic-
tion charts. Copies of these charts may be found at the back of the Brit-
ish National Formulary (BNF). If concomitant hypertriglyceridaemia
(>1.7 mmol/L) is present, the risk should be multiplied by 1.3.
Clinical management of hypercholesterolaemia
Lipid targets in high-risk patients (Joint British Societies

[JBS2])
Total cholesterol (TC) <4 mmol/L and
LDL cholesterol (LDL) <2 mmol/L
or
25% reduction in TC level and 30% reduction in LDL
concentrationa
a
whichever is lower.
Table 8.3 Risk factors for cardiovascular disease
Non-modifiable risk factors Modifiable risk factors

Age Smoking
Male sex Dyslipidaemia
Family history of cardiovascular disease (hypercholesterolaemia, low HDL,
hypertriglyceridaemia)
Hypertension
Diabetes mellitus
Kidney disease and albuminuria
Obesity
Physical inactivity
Stress
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8 Lipid disorders
The treatment of hypercholesterolaemia should not be considered in

isolation, but rather in the context of overall management of cardio-
vascular risk (Fig. 8.4). Other measures include smoking cessation,
blood pressure control and blood sugar control. Exercise and weight
loss should also be implemented. Aspirin should be given if the car-
diovascular risk is high enough to consider intervention.
Diet
Dietary therapy typically lowers LDL cholesterol by only 5–10%,
although some patients have a more marked response, and it is often
appropriate to begin therapy with a low cholesterol diet. A weight loss
strategy is also important in many patients. In patients with a marked
increase in LDL cholesterol or established cardiovascular disease,
drug therapy is likely to be required to achieve targets.
Lipid profile (TC, LDL, HDL, TG)

and cardiovascular risk assessment
Exclude secondary causes

Raised LDL or (Liver function, thyroid function,
total cholesterol renal function, blood sugar)
Consider genetic causes
Primary prevention Primary prevention Secondary prevention

Total CVD risk < 20% Total CVD risk ≥ 20% or diabetes
Lifestyle advice Lifestyle advice Lifestyle advice

Repeat cardiovascular Treat to target: Treat to target:
risk assessment Total cholesterol < 4 mmol/L Total cholesterol < 4 mmol/L
within 5 years and and
LDL cholesterol < 2 mmol/L LDL cholesterol < 2 mmol/L
Figure 8.4 Assessment of hypercholesterolaemia. Cardiovascular risk is

assessed by the Joint British Societies’ cardiovascular disease risk chart (Heart
2005; 91(Suppl 5):V1–V52).
160
8
Lipid-lowering (statin) treatment?

Treatment decisions should be based upon the patient’s LDL choles-
terol level and their cardiovascular risk assessment (including HDL
level). In general, lowering LDL cholesterol by 1 mmol/L reduces
the risk of cardiovascular disease by 25–30%.
It is recommended that lipid-lowering (statin) treatment (and other
cardiovascular disease protective therapies) be given to:
1. All patients with established cardiovascular disease (secondary
prevention)
2. Patients with diabetes mellitus (type 1 or type 2)
– All those aged >40 years
– Those with an additional risk factor (retinopathy, nephropathy or
microalbuminuria, HbA1c >9%, hypertension, TC >6 mmol/L, pos-
itive family history of premature CVD, metabolic syndrome)
3. Individuals with total CVD risk >20% over 10 years
4. Individuals with a TC : HDL cholesterol ratio
6.0.
Target of lipid-lowering therapy in high risk patients

The goal of lipid-lowering therapy is to reduce TC levels to <4 mmol/L
and LDL cholesterol to <2 mmol/L. In those with hypertrigyceridae-
mia, in whom LDL levels cannot be calculated, the goal is a non-HDL
cholesterol level of <3 mmol/L.
Importantly, patients at highest risk for coronary artery disease

or those with established disease may be started on statin ther-
apy irrespective of the cholesterol level.
Hypertriglyceridaemia
Triglyceride accounts for 95% of stored fat, but circulates predomi-
nantly as VLDL (80%) and LDL (15%). Patients with marked hypertri-
glyceridaemia are at risk for pancreatitis. Recent studies also suggest
that raised TG levels are an independent risk factor for cardiovascular
disease.
Causes of hypertriglyceridaemia
See Table 8.4.
161
8 Lipid disorders
Table 8.4 Causes of hypertriglyceridaemia
Primary lipid abnormalities Hyperlipoproteinaemia (I, IIb, III, IV, V) (familial

(genetic disorders) combined hyperlipidaemia, familial
hypertriglyceridaemia, familial
dysbetalipoproteinaemia)
Secondary causes Metabolic syndrome, alcoholism, type 2 diabetes,
chronic kidney disease, pregnancy, stress/
sepsis, drugs (oestrogen, beta-blockers,
thiazides, steroids, sirolimus, protease inhibitors)
Lipoprotein lipase deficiency

Mutations in the gene encoding lipoprotein lipase (LPL), the enzyme
that enables peripheral tissues to take up TG from chylomicrons and
VLDL, lead to massive accumulation of chylomicrons. These patients
have marked hypertriglyceridaemia and present with recurrent pan-
creatitis, lipaemia retinalis, eruptive xanthomas and hepatosplenome-
galy at a young age. ApoC-II deficiency is a rare autosomal recessive
disorder that causes a functional LPL deficiency.
Metabolic syndrome
Increased TG levels are an important feature of the metabolic syn-
drome, found in a subgroup of patients with a greatly increased risk
of coronary heart disease. Features of this syndrome include central
obesity, dyslipidaemia (TG >1.7 mmol/L, HDL <1 mmol/L [men] or
<1.3 mmol/L [women]), hypertension (blood pressure >130/
85 mmHg) and glucose intolerance.
Clinical management of hypertriglyceridaemia

Individuals with a TG level >1.7 mmol/L should be investigated for
secondary causes. The primary therapy for hypertriglyceridaemia is
dietary. Additional measures include weight loss, exercise, avoiding
alcohol, improving blood sugar control in patients with diabetes, and
increasing omega-3 fatty acid intake by increasing fish consumption
(Fig. 8.5).
In patients with TG levels >6 mmol/L, the immediate risk is of acute
pancreatitis and urgent therapy is required. In other patients with
lesser degrees of hypertriglyceridaemia, the primary concern is of
162
8
Lipid profile (TC, LDL, HDL, TG)

and cardiovascular risk assessment
Assess secondary causes

Raised TG Obesity, alcohol, drugs, diabetes
Check eruptive xanthomatas
TG 1.7–6 mmol/L TG 1.7–6 mmol/L TG > 6 mmol/L

No CVD With CVD
*General Rx *General Rx *General Rx

+ Drug therapy + Drug therapy
(fibrate, niacin or statin) (fibrate, niacin or statin)
Achieve targets for
total cholesterol
and LDL cholesterol
Figure 8.5 Management of hypertriglyceridaemia. *General Rx ¼ diet,

exercise, weight loss, reduce alcohol, control diabetes, increase omega-3 fatty
acid intake through fish consumption. CVD, cardiovascular disease.
cardiovascular risk, and drug therapy (using fibrates, niacin or statins)

should be considered in those with other risk factors.
Lipid-lowering drugs
HMG-CoA reductase inhibitors (statins)
These agents inhibit the rate-limiting step in the endogenous pathway of
cholesterol synthesis and lead to an increased cellular expression of LDL
receptors, removing increased amounts of cholesterol from the circula-
tion (Table 8.5). They typically reduce LDL cholesterol by 30–40%.
Examples of these medications include atorvastatin, simvastatin and
pravastatin.
Adverse effects include myositis and abnormal liver function test
results, and these should be assessed before starting these agents
and if the patient subsequently develops symptoms. The risk of
163
8 Lipid disorders
Table 8.5 Effect of drug therapy on lipoprotein levels
LDL HDL TG
Statins 25 to 40% þ5 to 10% # to ##
Fibrates 10 to 15% þ15 to 20% ##
Niacin 15 to 25% þ25 to 35% ##
Cholestyramine 15 to 25% – –
Ezetimibe 15 to 20% – –
myositis may be higher in patients concurrently taking fibrates or nia-

cin, or in transplant patients taking calcineurin inhibitors.
Fibrate derivatives
These drugs raise HDL cholesterol and lower TG levels. They are typ-
ically used for combined hypertriglyceridaemia and hypercholesterol-
aemia. Examples include gemfibrozil and fenofibrate. Adverse effects
of fibrates include cholelithiasis, hepatitis and myositis.
Bile acid binding resins

These agents (cholestyramine, colestipol) act by binding bile acids in
the gut and interrupting the enterohepatic circulation. This causes
the liver to increase bile acid production, using more cholesterol.
These agents decrease LDL levels by 15–25% with no effect on HDL,
and may increase the TG concentration. They should not be used in
patients with significant hypertriglyceridaemia.
The use of bile acid binding resins may be complicated by gastroin-
testinal symptoms (constipation, flatulence), and they may interfere
with the absorption of drugs or fat-soluble vitamins.
Ezetimibe
This is a new lipid-lowering agent that blocks the intestinal absorption
of cholesterol. It reduces LDL levels by 15–20% as monotherapy, but
can enhance LDL reduction on those already taking a statin.
Nicotinic acid
This drug raises HDL cholesterol and lowers TG levels. Intolerance is
common and only about 50% of patients can tolerate a full dose. The
164
Hypocholesterolaemia
8
main complaint is prostaglandin-mediated flushing or pruritus. Other

side effects include exacerbation of gout, peptic ulcer disease and glu-
cose intolerance.
Omega-3 fatty acids

These may be used to lower TG levels and prevent coronary heart
disease.
Hypocholesterolaemia
Some patients may present with abnormally low levels of total choles-
terol (<2.6 mmol/L). This usually reflects malnutrition or underlying
chronic disease (Table 8.6). Occasionally, rare primary disorders of
lipid metabolism may produce this phenotype.
Table 8.6 Causes of hypocholesterolaemia
Primary lipid Hypo-a-lipoproteinaemia, hypo-b-lipoproteinaemia,

abnormalities Tangier disease, lecithin cholesterol acyltransferase
(LCAT) deficiency
Secondary causes Severe liver disease, malnutrion/malabsorption,
hyperthyroidism, acute illness, myeloproliferative
disorders, chronic anaemia
165
CHAPTER
9
Markers of cardiac
and muscle injury
and disease
Introduction
The measurement of a variety of intracellular enzymes and structural

proteins in plasma can indicate the presence of severe cellular damage
or necrosis. Such tests are particularly useful in patients with sus-
pected cardiac or muscle disease. For example, the ischaemic necrosis
of cardiac myocytes occurring during myocardial infarction (MI)
results in the release of intracellular proteins and enzymes into the cir-
culation. As a result, detection of these usually sequestered molecules
provides information regarding both the presence and the extent of
muscle damage.
Creatine kinase
Creatine kinase (CK) consists of dimers of M and B chains, and there-
fore there are three potential isoenzymes (MM, MB and BB). CK is a
cytosolic enzyme that facilitates the mitochondrial transfer of high-
energy phosphates from the cytoplasm. It is widely distributed in
tissues but is found predominantly in muscle. Skeletal muscle contains
approximately 99% CK-MM and about 1% CK-MB. However, during
9 Markers of cardiac and muscle injury and disease
muscle fibre regeneration following skeletal muscle injury, the amount

of CK-MB may increase. Cardiac myocytes contain 20–30% CK-MB,
with the remainder being CK-MM. The CK-BB isoform is found
in other organs such as the brain, and is not routinely measured.
Under normal circumstances, CK-MM accounts for more than 95%
of circulating CK.
Creatine kinase levels
Although individual laboratory assays vary, the normal level of total CK
is 55–170 U/L (males) and 30–135 U/L (females), although indivi-
duals with large muscles may have higher levels. The relative specificity
of the CK-MB isoform for myocardial tissue has proved useful in the
investigation of patients with suspected cardiac disease. In order to con-
firm a diagnosis of acute MI, a 2-fold increase is typically required with
an increase in the CK-MB fraction (normal CK-MB level 0–5 ng/mL; acute
MI >9 ng/mL). Alternative measurements include determining the ratio
of CK-MB to total CK, with a ratio >2.5 suggesting a cardiac source.
CK levels usually increase by 4–6 h following a MI, peak at 18–24 h
and fall to normal by 36–48 h (Fig. 9.1 & Table 9.1). Serial testing of car-
diac enzymes is usually performed to ensure that raised levels are not
CK
Plasma level (arbitrary units)
Troponin
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (days)
Figure 9.1 Time course of cardiac enzymes/proteins following myocardial
infarction. CK, creatine kinase.
168
Creatine kinase
9
Table 9.1 Markers of myocardial infarction
Test Onset Peak Duration

CK (total and MB) 3–12 h 18–24 h 36–48 h
Troponins 3–12 h 18–24 h Up to 10 days
LDH 6–12 h 24–48 h 6–8 days
Myoglobin 1–4 h 6–7 h 24 h
missed and to guide prognosis. Most cases of acute MI will demonstrate

raised levels of CK by 12 h. However, it should be noted that this marker
is not as sensitive as cardiac troponins (see below), and a ‘small MI’ with
limited myocardial injury (a ‘microinfarct’) may not be detected using
measurement of CK alone. CK levels are not raised during an episode
of angina or pericarditis. It is important to note that an increased CK-
MB level may occur in muscle injury with regenerating fibres (e.g. mar-
athon runners, extensive rhabdomyolysis or myositis). However, in
these settings the typical acute rise and fall in CK-MB levels is absent.
A cardiac cause for a raised CK level is suggested by:

l Clinical history of chest pain, etc.
l Typical time course (rapid rise within 4–6 h and fall to normal
by 36–48 h)
l Raised CK-MB level (>9 ng/mL)
l Increased ratio of CK-MB : total CK (>2.5).
An acute MI should not be diagnosed on a single blood sample for
cardiac markers. The rise and fall of levels in the appropriate
timescale is also required.
Clinical use of creatine kinase in cardiac disease

1. Diagnosis of acute MI.
2. Assessment of prognosis following acute MI, as the total quantity of
CK released (the area under the curve) correlates with infarct size.
3. Assessment of coronary artery reperfusion. The peak level of CK
reflects the kinetics of washout from the injured myocardium and
is less strongly correlated with infarct size. Thus, successful reperfu-
sion following an angioplasty or thrombolysis leads to an increased
169
early peak level of CK-MB with a shorter duration due to ‘washout’

of the enzyme from the affected region of myocardium.
4. Diagnosis of an additional MI or extension of the original infarct.
The short duration of raised CK-MB levels (36–48 h) does not per-
mit the late diagnosis of an acute MI if the patient presents several
days after chest pain. However, it does mean that CK-MB levels
can be used to detect an additional MI or extension of the original
infarct. These events may not be detected using troponin levels,
which remain increased for a prolonged period after MI.
Non-cardiac causes of raised CK levels

l Skeletal muscle injury – myopathies, myositis, muscular dys-
trophies, muscle injury, surgery, convulsions, intramuscular
injections
l Brain injury (stroke)
l Hypothyroidism
Cardiac troponins
Troponins are structural proteins present within cardiac myocytes.

They are involved in the interaction between the contractile proteins
actin and myosin, although there is also a cytosolic pool. The two main
troponins are cardiac troponin I (cTnI) and cardiac troponin T (cTnT).
A MI is associated with an early rise in troponins due to release from
the cytoplasmic pool, and a later sustained rise secondary to breakdown
of structural actin and myosin filaments. Troponins are not released
during purely ischaemic episodes with no cardiac muscle damage.
Troponin I is specific to cardiac myocytes, whereas troponin T is
expressed to a minor degree in skeletal muscle. However, both tropo-
nins are considered relatively specific for myocardial injury. Cardiac
troponin levels begin to rise 4–6 h post-MI with a time course similar
to that of CK-MB, but a blood sample taken 12 h after the clinical event
is required to detect increases in all patients (also true for CK-MB).
The levels of cardiac troponins remain raised for up to 10 days after
a MI. This is useful as it facilitates a diagnosis of MI to be made when
patients present to hospital or their GP several days after an episode of
severe chest pain when the CK-MB levels are normal, as they return to
baseline by 36–48 h. However, subsequent rises in CK-MB may permit
the diagnosis of infarct extension or an additional MI.
170
Cardiac troponins
9
Cardiac troponin levels

Cardiac troponins are normally not detected in blood. The normal level
for cTnT is <0.01 mg/mL, and any significant increase represents myo-
cardial injury. The European Society of Cardiology/American College
of Cardiology cutoff for acute MI is 0.03 mg/mL. In general, the levels
of cardiac troponins reflect infarct size and correlate with prognosis.
There are multiple assays for cTnI that recognise different com-
plexes of serum troponin I, and local reference ranges should be
sought for this measurement. In general, levels >1.5 ng/mL suggest
significant myocardial injury.
Note:
l Although cardiac troponins are specific for myocardial injury,
increased levels may occur in acute pulmonary embolism (due
to acute right ventricular strain) and myocarditis (CK-MB
levels are often normal in myocarditis).
l A false-positive increase in cardiac troponin levels may occur
in chronic renal failure (CRF). Some 10–15% of patients with
CRF exhibit mildly raised levels of troponin T and 5% have
increased levels of troponin I. The aetiology is unclear.
l Heparin in plasma samples can bind cTnT, reducing levels by
15–30%. Therefore, troponins should be measured in serum
samples.
Clinical use of cardiac troponin levels

1. Diagnosis of acute MI. Raised levels are sensitive markers of myocar-
dial injury and are especially useful in settings where CK-MB
levels may be increased from non-cardiac tissue, e.g. in patients
with concurrent skeletal muscle injury or following surgery.
2. Prognosis of acute MI. The extent of increase correlates with infarct
size and subsequent patient prognosis.
3. Late diagnosis of acute MI. The level of cardiac troponins remains
increased for up to 10 days after MI, thereby permitting a late
diagnosis.
4. Exclusion of acute MI in patients with chest pain. Cardiac troponins are
very sensitive markers of myocardial injury and normal levels at 12 h
post chest pain may be used to exclude MI. This is especially
171
important in the assessment of patients presenting to the emergency

department with chest pain.
5. Diagnosis of ‘microinfarction’. Troponins are more sensitive than CK-
MB, and the term microinfarction has been applied to low-level
increases in troponin levels with negative CK-MB levels. These
patients would previously have been classified as having unstable
angina, but the group with raised cardiac troponin levels has been
shown to have a worse prognosis.
When should I check cardiac enzymes and troponin levels?
These should be checked in:
l Patients with an acute coronary syndrome, e.g. unstable angina, MI
with ECG changes
l Patients with a history suggestive of prolonged myocardial ischae-
mia but in whom the diagnosis of an acute coronary syndrome is
unclear
l Following surgical coronary revascularisation or percutaneous
interventions
l Consider in patients who become suddenly unwell, e.g. develop
hypotension or dyspnoea. Remember that elderly patients, espe-
cially diabetic individuals, may have a ‘silent’ MI without any
chest pain and that MI may complicate other conditions such as
sepsis or surgery.
Assessment of acute MI
Any patient presenting with chest pain requires:
l a thorough history and examination
l electrocardiography
l cardiac markers (troponins and CK-MB) to assess myocardial
injury – therapy should not be withheld pending these levels.
Definition of acute MI
An acute MI is diagnosed by the combination of a typical rise and fall
of markers of myocardial necrosis (troponins or CK-MB) in association
with one of the following:
1. Symptoms of myocardial ischaemia
2. Development of pathological Q waves on ECG
3. ECG changes typical of myocardial ischaemia (ST segment eleva-
tion or depression)
4. Coronary artery intervention (e.g. angioplasty).
172
Additional tests in acute myocardial infarction
9
Previously CK (particularly the CK-MB fraction) was used, but the

more specific cardiac troponins have become the ‘gold standard’.
Note:
l No single marker can successfully identify or exclude acute MI
within the first 6 h.
l A negative cardiac troponin test at 12 h excludes an acute MI
in a patient presenting with chest pain.
Other markers of myocardial injury
Lactate dehydrogenase (LDH)

LDH has five different isoenzymes (LDH1–5). Although LDH5 predo-
minates in skeletal muscle (and liver), and LDH1 and LDH2 predomi-
nate in the heart, analysis of isoenzymes is rarely performed in clinical
practice. LDH is a non-specific marker of tissue injury as its concentra-
tion is raised in myocardial injury, malignancy, liver disease, lung dis-
ease, kidney disease and haemolysis. Indeed, LDH levels are
monitored serially in patients with ongoing haemolysis, e.g. haemolytic
uraemic syndrome. LDH levels remain increased for 5 days post-MI and
were previously useful in the diagnosis of acute MI after CK levels had
returned to normal. This has been superseded by the measurement of
cardiac troponins.
Aspartate aminotransferase (AST) and myoglobin

AST is also non-specific and its concentration is raised in skeletal mus-
cle disease, haemolysis and liver disease. Myoglobin is a small protein
that is rapidly released from damaged tissue, and could potentially be
used as an early marker of acute MI. However, it is not measured rou-
tinely as it is non-specific for cardiac muscle and is raised in all forms
of muscle injury.
Additional tests in acute myocardial infarction
Haematological tests
Acute MI is often associated with a leucocytosis (typically 12–15
103/mm3) and a raised erythrocyte sedimentation rate (ESR) and
C-reactive protein (CRP) level, which begins by day 2–3 and can last
173
for several weeks. In patients who develop a prolonged increase of the

ESR and CRP level associated with chest discomfort, a diagnosis of
Dressler’s syndrome is suggested.
Lipid panel
The levels of total cholesterol and high density lipoprotein (HDL)
remain close to baseline for 24–48 h, but then rapidly fall. In view of
the important role of lipid-lowering agents in secondary prevention,
a lipid panel should be checked within the first 48 h or after 8 weeks
when the levels are once again close to baseline.
Disorders of skeletal muscle
Patients with a wide range of disorders may present with muscle

weakness or myalgia, and require careful investigation. The muscle
enzymes measured in clinical practice include creatine kinase (CK),
lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspar-
tate aminotransferase (AST) and aldolase.
Creatine kinase
This is present in the highest concentrations in the serum and is the most
sensitive marker of muscle injury (see above). Normal skeletal muscle
contains approximately 99% of the CK-MM isoform, but injured muscle
undergoing regeneration, as in inflammatory myopathies or after
extreme exertion, may have an increased content of the CK-MB isoform
and this can occasionally lead to confusion with myocardial injury.
However, measurement of cardiac troponin levels will resolve this issue.
Creatine kinase levels in muscle disorders

Normal serum CK levels are less than 170 U/L but can be markedly
increased in muscle injury or disease (Table 9.2). Very high levels
may be seen with rhabdomyolysis, acute myositis (polymyositis, der-
matomyositis, etc.) and Duchenne muscular dystrophy early in the
course of the disease (CK levels fall later as muscle loss ensues).
Rhabdomyolysis
This refers to acute muscle necrosis and may be seen in trauma/crush
injuries, compartment syndromes and muscle ischaemia, or following
fits or electrocution, but any severe acute muscle injury may cause this
syndrome. Rhabdomyolysis may result in acute renal failure secondary
174
9
Table 9.2 CK levels in muscle disorders
Creatine kinase level Muscle disorder

Markedly increased (CK > Rhabdomyolysis
10 000 U/L) Myositis: polymyositis, dermatomyositis
Muscular dystrophy, e.g. Duchenne muscular
dystrophy, Becker muscular dystrophy
Malignant hyperthermia
Moderately increased (CK Muscle injury/surgery
1000–10 000 U/L) Acute myositis (inclusion body myositis, infection,
cocaine abuse, adverse effect of statin)
Other muscular dystrophies
Mildly increased (CK <500– Myotonic dystrophy
1000 U/L) Female carriers of Duchenne muscular
dystrophy
Congenital myopathies
Hypothyroid myopathy
Intramuscular injections (for 48 h)
Normal levels Myasthenia gravis
Thyrotoxic myopathy
Steroid myopathy
Neurogenic causes of muscular atrophy, e.g.
poliomyelitis, motor neurone disease
to myoglobin-mediated tubular toxicity, although an additional insult

such as hypotension or sepsis may also be required. There is anecdotal
evidence for the beneficial effect of urinary alkalinisation by the admin-
istration of sodium bicarbonate in patients with renal impairment. Typ-
ically, very high serum CK levels (>15 000 U/L) are found. In addition,
patients often exhibit:
l Marked hyperkalaemia and hyperphosphataemia – potassium and
phosphate are released from the damaged muscle.
l Hypocalcaemia – it is thought that the calcium precipitates in dam-
aged muscle. No treatment is required and 25% of patients develop
mild hypercalcaemia in the recovery phase.
l An increase in creatinine concentration that is out of proportion to
the urea, as creatinine is derived from muscle.
175
Other muscle enzymes

Lactate dehydrogenase
This enzyme catalyses the last step of glycolysis, the conversion of lac-
tic acid to pyruvic acid. LDH is present in nearly every tissue and,
although it is a marker of cell necrosis, the lack of specificity limits
its diagnostic utility.
Aminotransferases
These enzymes catalyse the conversion of alanine (alanine amino-
transferase, ALT) and aspartate (aspartate aminotransferase, AST) to
a-ketoglutarate, providing a source of nitrogen for the urea cycle.
Their levels may be raised in a wide number of conditions, especially
hepatic, skeletal muscle and myocardial diseases as well as haemoly-
sis (aminotransferases are discussed further in Chapter 7).
Aldolase
This is a glycolytic pathway enzyme found in all tissues, but predom-
inantly in skeletal muscle, liver and brain. Aldolase levels are often
raised in muscle disorders, and rarely may be increased in myositis
when CK levels are normal.
Special tests associated with muscle disease

When muscle disorders are suspected from increased muscle enzyme
levels, further testing may be useful.
Autoimmune screen
This may help to identify autoimmune disease associated with muscle
disease, e.g. systemic lupus erythematosus (SLE), polymyositis, der-
matomyositis or rheumatoid arthritis. General screening tests should
include antinuclear antibody and rheumatoid factor. If polymyositis
or dermatomyositis is considered, further testing for antibodies such
as anti-Jo-1, anti-nRNP, anti-Scl-70, anti-Sm, anti-La and anti-ENA
should be considered.
Anti-acetylcholine receptor antibody

This autoantibody is present in approximately 80% of patients with
myasthenia gravis and is virtually diagnostic of the disease. Note,
however, that 20% of patients with myasthenia gravis will have a neg-
ative result.
176
9
Thyroid function tests

Both hypothyroidism and hyperthyroidism may be associated with
muscle disease and should be excluded. Note: Other endocrine disor-
ders may also present with muscle weakness, e.g. adrenal insuffi-
ciency, diabetes, acromegaly.
Serum electrolytes (calcium, potassium and phosphate)

Muscle weakness may be associated with hypercalcaemia and, in
particular, with hyperparathyroidism. Vitamin D deficiency leads
to osteomalacia and a proximal myopathy. An acute myopathy,
even rhabdomyolysis, may result from either hypokalaemia or
hypophosphataemia.
Genetic testing
Genetic tests are available for some of the congenital myopathies and
dystrophies, such as Duchenne muscular dystrophy; this may permit
more accurate genetic counselling.
177
CHAPTER
10
Immunological
investigations
Introduction
Immunological disease is not uncommon (Box 10.1) and is responsible

for considerable morbidity and mortality. The immune system com-
prises the innate and adaptive immune system and has evolved to
protect the host from various pathogens including bacteria, viruses,
protozoa, fungi, helminths, etc. The innate immune system comprises
neutrophils, monocytes, macrophages, complement, etc. Although the
innate immune system may combat infection, it is complemented by
the more highly evolved adaptive immune system. This comprises
dendritic cells that process pathogen-derived antigens and present
them to T cells in association with major histocompatibility complex
(MHC) class II molecules. This initiates the immune response charac-
terised by clonal T-cell proliferation and activation, as well as the mat-
uration of B cells into antibody-producing plasma cells. Importantly,
the adaptive immune system is characterised by ‘immunological
memory’ such that a robust immune response can be generated more
effectively following repeat exposure to the same pathogen, a feature
exploited in vaccination programmes (Fig. 10.1).
A key requirement of an effective immune system is the ability to
discern ‘self antigens’ from ‘non-self antigens’, as would be found on
pathogens. Autoimmune disease is the result of a breakdown in this
tolerance (Fig. 10.2), although the underlying mechanisms remain
10 Immunological investigations
Box 10.1 Autoimmune conditions characterised

by autoantibody generation
Various connective tissue disorders including:

– systemic lupus erythematosus (SLE)
– rheumatoid arthritis
– scleroderma
– dermatomyositis
– Sjögren’s syndrome
ANCA-positive vasculitides including:
– Wegener’s granulomatosis
– microscopic polyarteritis
– Churg–Strauss syndrome
Anti-glomerular basement membrane (GBM) antibody disease
Coeliac disease (gluten enteropathy)
Primary biliary cirrhosis and autoimmune hepatitis
Myasthenia gravis
Idiopathic thrombocytopenic purpura (ITP) and haemolytic anaemia
Thyrotoxicosis or hypothyroidism
Addison’s disease
unclear in many instances. Autoimmunity may be organ specific, as in

autoimmune thyroid disease, or non-organ specific, when it is directed
at self antigens that are not restricted to particular organs (Table 10.1).
For example, some of the autoantibodies generated in systemic lupus
erythematosus (SLE) bind DNA, histones, etc., and these antigens may
be found in any injured tissue. Some autoantibodies are directly
involved in disease pathogenesis. For example, the anti-neutrophil cyto-
plasmic antigen autoantibody (ANCA) is undoubtedly involved in
small vessel vasculitides, whereas the deposition of anti-glomerular
basement membrane (GBM) antibody in the kidney is responsible for
Goodpasture’s disease. In contrast, the role of other autoantibodies such
as rheumatoid factor or anti-nuclear antibodies (ANAs) in the disease
process is much less clear. Despite these caveats, laboratory investiga-
tions play an important role in the diagnosis of many conditions and
in the monitoring of treatment. Immunologically based tests are also
useful in non-autoimmune diseases affecting the haematopoietic or
reticuloendothelial system, such as myeloma that is characterised by
the production of a monoclonal paraprotein or excessive light chains.
180
Introduction
10
Pathogen, e.g.
bacterium or virus
Innate immune system Adaptive immune system

Neutrophils, macrophages Dendritic cells, T cells, B cells
Multi-step immune response: dendritic cell
processing and presentation of pathogen-
derived antigen to T cells, T-cell activation
(helper and cytoxic T cells), B-cell
maturation to plasma cells and development
of immunological ‘memory’
Neutrophil Complement B cells T cells

recruitment and activation
macrophage activation
Helper Memory
T cells T cells
Opsonisation,
killing and injestion Plasma
of pathogen cells
Antibody
production
Macrophage
activation
Clearance of infection
Destruction of infected Cytoxic and
and healing of tissue injury
cells and tissue, and activated
with restoration
clearance of cell debris T cells
of normal function
Figure 10.1 The innate and adaptive immune systems combine to detect and
eliminate pathogenic organisms effectively.
181
Self antigen
Breakdown of self-tolerance
Autoantigen
Adaptive immune system

Dendritic cells, T cells, B cells
Multi-step autoimmune response: dendritic cell processing
and presentation of autoantigen to T cells, T-cell activation,
generation of helper and cytotoxic T cells and B-cell
maturation to antibody-generating plasma cells
Autoantibody deposition in tissue

(anti-GBM Ab) or on cells (ANCA)
expressing the autoantigen
Complement activation
and tissue damage
Neutrophil Macrophage Activated cytotoxic

recruitment activation T cells
Cell or tissue injury and loss of function, e.g.

glomerulonephritis, hepatitis, arthritis, thyroiditis
Figure 10.2 In the absence of tolerance to self antigens, the innate and adaptive
immune systems may result in serious injury to and dysfunction of host tissues and
organs.
182
Introduction
10
Table 10.1 Autoantibodies and related conditions

Autoantibody Associated conditions
Rheumatoid factor (0–20 IU/mL) Present in about 80% of patients with
rheumatoid arthritis
Antinuclear antibody (ANA) SLE, though may be found in other
conditions
Anti-double-stranded DNA antibodies SLE
(performed if ANA positive)
Anti-extractable nuclear antigen (ENA)
– there are several antibodies in this
category:
Anti-Ro SLE, Sjögren’s syndrome, systemic
sclerosis
Anti-La Sjögren’s syndrome, SLE
Anti-Sm SLE
Anti-nRNP (nuclear Mixed connective tissue disease
ribonucleoproteins)
Anti-Scl-70 (topoisomerase 1) Systemic sclerosis
Anti-centromere Systemic sclerosis
Anti-Jo-1 Dermatomyositis
Anti-neutrophil cytoplasmic antibody Associated with small vessel vasculitides
(ANCA) such as Wegener’s granulomatosis
(PR3 ANCA) and microscopic
polyarteritis (MPO ANCA)
Anti-glomerular basement membrane Goodpasture’s syndrome
antibody
Thyrotropin receptor antibodies (may Graves’ disease (hyperthyroidism)
be stimulatory or inhibitory)
Anti-thyroglobulin and anti-thyroid Hashimoto’s thyroiditis
peroxidase antibodies
Anti-gliadin antibody Coeliac disease
Anti-endomysial antibody
Anti-smooth muscle antibodies Primary biliary cirrhosis and
autoimmune hepatitis
Anti-mitochondrial antibodies
Antibodies to the acetylcholine receptor Myasthenia gravis
Anti-cardiolipin antibodies Primary phospholipid syndrome, SLE
Anti-glutamic acid decarboxylase May be found in patients with type 1
(GAD) antibody diabetes mellitus
Anti-islet cell antibody
Anti-insulin antibody
183
Autoantibodies
Circulating autoantibodies may be detected by immunofluorescence

techniques using tissues or cells containing the target antigen. How-
ever, autoantibodies may also be detected by enzyme-linked immuno-
sorbent assays (ELISAs) that use recombinant or purified antigens, if
these are known. ANCAs may be divided into either proteinase 3
(PR3) ANCA or myeloperoxidase (MPO) ANCA, and separate ANCA
ELISAs have been developed that use purified PR3 or MPO in order to
detect autoantibodies that bind to particular neutrophil autoantigens.
This is clinically helpful as the PR3 ANCA is characteristically present
in Wegener’s granulomatosis, whereas the MPO ANCA is typically
found in microscopic polyarteritis and Churg–Strauss syndrome.
Other techniques include immunodiffusion and particle agglutination
(e.g. rheumatoid factor). Laboratories may offer several techniques for
assessing individual autoantibodies such as ANCA (ELISA and
immunofluorescence), and maximal diagnostic specificity is obtained
by employing both techniques. In addition, the introduction of ELISA
technology has also been informative as some patients exhibit ANCAs
of unusual specificities. For example, occasional patients with inflam-
matory bowel disease or suppurative pulmonary disease such as bron-
chiectasis may develop antibodies directed against additional
neutrophil antigens such as lactoferrin or elastase. These autoanti-
bodies give a positive result in an immunfluoresence ANCA assay
but are negative in specific PR3 or MPO ELISAs.
Rheumatoid factor is an IgM autoantibody directed at the Fc portion of
immunoglobulin molecules and may thus form an immune complex with
normal circulating immunoglobulin molecules. High titres of rheumatoid
factor are found in approximately 80% of patients with rheumatoid
arthritis, but patients may be negative early in the disease. A positive
rheumatoid factor must be interpreted in the clinical context as it may
be present in healthy elderly individuals and in patients with other con-
nective tissue disorders such as Sjögren’s syndrome and viral/bacterial
infections. It is, however, of little use in monitoring the disease.
The measurement of anti-nuclear antibodies (ANAs) is a commonly
used screening test for SLE. The ANA is also known as an anti-nuclear
factor (ANF). Although a strongly positive ANA result is suggestive of
SLE, this is also found in connective tissue diseases such as Sjögren’s
syndrome, rheumatoid arthritis, dermatomyositis, scleroderma, etc.
Normal healthy individuals may also have a positive ANA finding.
184
Immunoglobulins and light chains
10
If a patient has a significantly positive ANA, they should undergo

testing for anti-double-stranded DNA antibodies, levels of which are
typically raised in active SLE. Extractable nuclear antigens (ENAs)
refer to antigens that are soluble in saline, and anti-ENA antibodies
may be found in various conditions including SLE, Sjögren’s syn-
drome, systemic sclerosis, CREST syndrome, mixed connective tissue
disease and dermatomyositis (see Box 10.1).
Erythrocyte sedimentation rate (ESR)
A raised ESR is rather non-specific and this test is becoming performed

less often. An increased ESR often reflects an acute-phase response such
as a polyclonal increase in g-globulins. The ESR is also raised in haema-
tological conditions such as myeloma and Waldenström’s macroglobu-
linaemia, as well as in connective tissue diseases such as temporal
arteritis, polymyalgia rheumatica, etc.
C-reactive protein (CRP)
CRP is an acute-phase protein synthesised in the liver, and the produc-

tion and release of CRP may be markedly increased in any condition
associated with inflammation, e.g. infection, tissue injury, myocardial
infarction. It is a sensitive indicator of sepsis and may be used to monitor
the effectiveness of antibiotic therapy in acute infectious illnesses such
as pneumonia, as well as infections requiring prolonged treatment such
as infective endocarditis and osteomyelitis. CRP is also useful in the
assessment and monitoring of immunological conditions such as rheu-
matoid arthritis, vasculitis, etc., and tends to reflect disease activity in
the absence of infection.
Immunoglobulins and light chains
Measurement of serum immunoglobulins and immunoelectrophoresis

is often performed in patients in whom a diagnosis of myeloma is sus-
pected (Table 10.2). Patients with myeloma may exhibit a monoclonal
paraprotein that represents the immunoglobulin generated by a malig-
nant clone of plasma cells – the monoclonal nature of this immuno-
globulin is proven by the demonstration of a single kappa (k) or
lambda (l) specificity. A malignant paraprotein may be associated
with an immune paresis characterised by diminished levels of the
185
Table 10.2 Common immunological screening

investigations (note that units and normal ranges
will vary between laboratories)
Investigation Associated conditions

Complement assays: Reduced complement activity and components
Total haemolytic may be found in conditions associated with
complement increased complement turnover, e.g. active SLE,
(392–1019 U/mL) chronic infections such as endocarditis, etc.
C3 (0.73–1.4 U/mL) Patients may also exhibit isolated deficiencies in
C4 (0.12–0.3 U/mL) complement components
Immunoglobulin levels Low levels of immunoglobulin may be found in
patients with congenital or acquired
immunoglobulin deficiencies as well as in
patients with severe nephrotic syndrome.
Immunoelectrophoresis can determine whether
an increased immunoglobulin level is secondary
to a polyclonal or monoclonal increase in
immunoglobulins
IgG (6–15 g/L) A polyclonal increase in IgG levels may be found in
patients with acute or chronic inflammation or
infection. A monoclonal increase in IgG may be
seen in patients with myeloma (may be associated
with an immune paresis) and benign monoclonal
gammopathy (normal bone marrow examination)
IgM (0.35–0.9 g/L) Increased in Waldenström’s macroglobulinaemia
(secondary to clonal proliferation of IgM-
secreting plasma cells)
IgA (0.8–4.5 g/L) May be increased in IgA nephropathy or liver
disease
other immunoglobulins. The presence of free light chains in the urine

or blood is also determined as part of a myeloma screen. It should be
noted that some patients with myeloma do not have a circulating
paraprotein, but do show an excess of circulating or urinary light
chains. Therefore both tests should be performed. A bone marrow
examination is required to confirm a diagnosis of myeloma. Lastly,
there are rare congenital conditions characterised by reduced levels
of immunoglobulin production, e.g. Bruton’s agammaglobulinaemia.
186
When should I consider performing immunological tests?
10
Complement
The complement system is composed of a large family of proteins and

is an integral part of the innate immune system. There are three path-
ways within the complement system: the classical pathway, the alter-
native pathway and the mannose-binding lectin pathway. Activation
of all three pathways results in the activation of a C3 convertase that
converts C3 to C3b, which is deposited on the surface of microbes or
cells. Further deposition of complement components results in the
final assembly of the C5b-9 ‘membrane attack complex’. This complex
forms a pore on the surface and results in cell lysis. Complement may
be activated directly by microbes as well as immune complexes found
in conditions such as SLE, cryoglobulinaemia and post-infectious glo-
merulonephritis. Such conditions may exhibit diminished complement
levels when the disease is active and repeated measurement of com-
plement levels is useful to monitor disease activity in SLE, etc. Excess
complement consumption may also be found in chronic infections
associated with immune complex formation, such as infective endo-
carditis. Patients may exhibit a genetic deficiency of complement com-
ponents and it is interesting to note that patients with C3 deficiency
have an increased incidence of SLE.
When should I consider performing immunological tests?
Consider performing immunological assays in:

1. All patients with symptoms affecting multiple systems. For example,
young women with joint symptoms, a skin rash and haematuria/pro-
teinuria may well have SLE, and measurement of ANA, anti-double-
stranded DNA antibodies and complement is indicated. In addition,
an ANCA assay should be considered in an elderly patient with hae-
moptysis, weight loss and a mass lesion on chest radiography, as
Wegener’s granulomatosis is part of the differential diagnosis.
2. All patients with an abnormal urinalysis and/or renal failure
should undergo a comprehensive immunological assessment. Mye-
loma should be actively excluded in patients over the age of 40
years with renal impairment. Some assays such as those for ANCA
or anti-GBM antibody will provide diagnostic information in
patients with renal dysfunction.
3. Patients with symptoms suggesting immunodeficiency such as
recurrent infections should be screened for an immunoglobulin or
187
complement deficiency. Patients with hypercalcaemia, anaemia,

etc. should be screened for myeloma.
4. Patients with diseases affecting individual organs should be
screened for the appropriate autoantibodies. For example, patients
with liver disease should be screened for anti-smooth muscle, anti-
mitochondrial and anti-microsomal antibodies, as these may be
found in patients with primary biliary cirrhosis and autoimmune
hepatitis. Testing for antibodies to the acetylcholine receptor
should be considered in patients with muscular weakness sugges-
tive of myasthenia gravis.
Immunological tests are often used as screening tests in patients who

are suspected of having an autoimmune or haematological condition.
Negative investigations may allow the patient to be reassured. In con-
trast, positive test results reinforce the concern of significant underly-
ing immunopathology. They may aid the diagnosis as in patients with
vitamin B12 deficiency with positive autoantibodies to intrinsic factor.
Positive tests may lead to further investigations that may be more
specialised or invasive. For example, examination of the bone marrow
may be required in patients in whom a monoclonal paraprotein or free
urinary light chains were detected. Similarly, patients with evidence of
renal dysfunction and a positive ANCA or active ‘lupus serology’
(positive ANA, raised titres of anti-double-stranded antibodies and
hypocomplementaemia) require a renal biopsy to assess the level of
renal inflammation, as this facilitates the formulation of a treatment
strategy.
Immunological tests are also helpful in monitoring patients and
tracking their response to treatment. Determination of CRP levels is
very useful in patients with serious infection such as endocarditis or
osteomyelitis, and a falling CRP concentration suggests effective
anti-microbial treatment. Conversely, a failure of the CRP level to fall
or an increasing CRP level would raise concerns about the efficacy of
the antibiotic therapy (?antibiotic resistance) or the development of
an abscess requiring radiological or surgical drainage. Paraprotein
levels indicate the tumour burden in patients with myeloma, and
should fall with treatment. Titres of ANCA and anti-GBM antibody
are measured serially in patients with glomerulonephritis. A persis-
tently positive ANCA indicates a higher potential for disease relapse,
and also increases the risk of recurrent disease if a patient who has
188
10
received a kidney transplant. In addition, the development of a posi-

tive ANCA in a previously ANCA-negative patient in clinical remis-
sion may herald a disease relapse; such patients require a careful
assessment including analysis of urine by dipstick and microscopy,
and investigation of renal function and CRP.
189
INDEX
Note: Page numbers in italics denote figures and tables
A Alanine aminotransferase (ALT),

Acid–base homeostasis, 61–3 130
assessment, 68–73, 69, 99, AST : ALT ratio, 137
99–101, 100, 101 Albumin
anion gap, 70–2 liver function tests, 139
arterial PCO2, 69 urinary excretion, 50
calcium levels and, 111 Alcoholic ketoacidosis, 79
compensatory responses, Alcoholic liver disease, 135
69–70, 100, 102 Aldolase, 176
pH, 65–6 Aldosterone, 23, 28, 29
serum bicarbonate, 69 renal tubular acidosis, type IV,
buffers, 63–4, 64 84
metabolic disorders Alkaline phosphatase (ALP), 129
see Metabolic acid–base raised levels
disorders hepatocellular disease,
pH see pH 136–8
respiratory disorders obstructive disease, 133–5
see Respiratory acid–base Alkalosis, 70
disorders metabolic see Metabolic
see also Acidosis; Alkalosis alkalosis
Acid load, 62–3 respiratory see Respiratory
Acidosis, 70 alkalosis
metabolic see Metabolic Alpha-fetoprotein (AFP), 149
acidosis Alveolar-arterial oxygen gradient
poisoning, 79–80 (AA gradient), 95–6
respiratory see Respiratory Aminotransferases, 130, 138, 176
acidosis hepatocellular injury and,
Adaptive immune system, 181 136–8
Index
Aminotransferases (Continued ) acid–base status, 69, 99,

obstructive hepatic injury and, 99–101, 100, 101
133–5 normal values, 91
see also specific enzymes oxygenation assessment, 94–7
Ammonia, liver function tests, pitfalls, 95
140–2 respiratory failure, 97
Ammonium chloride, excretion, values in different conditions,
67 101
Angiotensin-converting enzyme ventilation assessment, 97
(ACE) inhibitors, renal see also specific measures
function, 49, 54–5 Arterial oxygen saturation
Anion gap, 71 (SaO2), 95
assessment, 70–2 Arterial partial pressure of
normal value, 72 oxygen (PaO2), 95
causes of low anion gap, 72 ventilation assessment, 97
delta/delta ratio, 72 Aspartate aminotransferase
Anti-acetylcholine receptor (AST), 130
antibody, skeletal muscle AST : ALT ratio, 137
disorders, 176 myocardial injury, 173
Antidiuretic hormone (ADH), raised levels, hepatocellular
3–5 injury, 136–8
actions, 4 Aspirin, acid–base disturbance,
water depletion, 5 80
water excess, 4–5 Atherosclerosis, hyperlipidaemia
see also Hypernatraemia; and, 154–65
Hyponatraemia see also Hypercholesterolaemia
causes of release, 5 Autoantibodies, 184–5
Anti-glomerular basement conditions associated, 183
membrane (GBM) antibody, generation, 180–1
180 screening for
Anti-neutrophil cytoplasmic anti-acetylcholine receptor
antigen autoantibody antibody, 176
(ANCA), 180 autoimmune hepatitis, 147
Anti-nuclear antibodies (ANA), primary biliary
184–5 cirrhosis, 147
a1-Antitrypsin (a1-AT), 148 skeletal muscle disorders,
Arrhythmia, hyperkalaemia and, 176
31, 32 see also specific types
Arterial blood gas analysis, Autoimmune hepatitis,
91–105 autoantibody screen(s), 147
192
Index
Autoimmunity Calcium homeostasis, 107–18, 109

autoantibody generation, 180, regulation, 108–12
180–1, 182 calcitonin, 109–10
liver disease, 147 parathyroid hormone, 108
see also Autoantibodies; specific vitamin D role, 108–9
conditions see also specific mechanisms
Calcium, serum levels, 107–8
B assessment, 110–12
Bicarbonate (HCO3), 63 acid–base status, 111
filtering of, 66 protein binding, 111
gastrointestinal loss, 82 at risk patients, 111–12
serum levels, 69, 82 decreased see Hypocalcaemia
Bile acid binding resins, raised see Hypercalcaemia
hypertriglyceridaemia, 164 skeletal muscle disorders, 177
Bile salts, 129 Cancer
Bilirubin metabolism, 127–9 hypercalcaemia, 114
conjugation, 127–8 liver function tests, 149
direct vs. indirect, 129 Carbohydrate metabolism, lactic
enterohepatic circulation, 128 acidosis, 75, 75
excretion, 128 Carbon dioxide production, 92–3
intestinal, 128 Carbonic acid, respiratory
production, 127 acidosis, 103
secretion, 127–8 Carcinoembryonic antigen
Blood gas analysis see Arterial (CEA), 149
blood gas analysis Cardiac disease/injury markers,
Buffers, acid–base homeostasis, 167–77
63–4 aspartate aminotransferase,
assessment, 69 173
distribution, 64 cardiac troponins see Cardiac
loss, 82 troponins
creatine kinase see Creatine
C kinase (CK)
Caeruloplasmin, 148 lactate dehydrogenase, 173
Calcitonin, 109–10 myoglobin, 173
Calcium potassium levels, 23, 29
extracellular, forms, 107 arrhythmia/ECG changes,
homeostasis see Calcium 31, 32
homeostasis Cardiac troponins, 170–3
intracellular, 108 clinical use of, 171–2
serum levels see Calcium, indications for test, 172
serum levels serum levels, 171
193
Index
Cardiovascular risk assessment, decreased levels, causes, 41–2

158–9 increased levels, causes, 41
disease risk factors, 159, 160 renal function, 40–2, 42
Central diabetes insipidus, 17, 17
management, 18 D
Child–Pugh classification, liver Delta/delta ratio, anion gap
disease, 141 assessment, 72
Cholestasis, 133, 136 Diabetes insipidus
extrahepatic, 134 associated with
intrahepatic, 134 hypernatraemia, 16–17
Cholesterol, 151 causes, 17
de novo synthesis, 153 central vs. nephrogenic, 17
excess management, 18–19
see Hypercholesterolaemia Diabetes mellitus
non-HDL, 156 hypercholesterolaemia and,
reverse transport, 153–4, 155 158
Coagulation factors, liver ketoacidosis see Diabetic
function tests, 140 ketoacidosis (DKA)
Cockcroft and Gault formula, potassium levels, 25
GFR calculation, 46 proteinuria, 50
Compensatory responses, Diabetic ketoacidosis (DKA),
acid–base 77–8
kidneys, 69–70 hyperkalaemia and, 25, 32
respiratory, 100–1 treatment, 78
Complement, 187 Diabetic nephropathy,
Conn’s syndrome, 89 proteinuria, 50
C-reactive protein (CRP), 185 Dialysis, renal failure, 59
serum levels, 188 Diet
Creatine kinase (CK), 167–70 lipid disorders, 160
clinical use of, 169–70 modification in renal disease,
serum levels, 168–9 46
raised, cardiac causes, 169 potassium intake, 21, 27, 34
raised, non-cardiac causes, sodium intake, 2
170 Diffusion, respiratory function,
skeletal muscle disorders, 94
174, 175 Dipstick analysis, proteinuria, 50,
Creatinine/protein ratio, 53 51–2
Creatinine, serum levels Diuretics
clearance relationship, 41, 43–4 hypercalcaemia, 115
see also Glomerular filtration hypokalaemia, 24, 29
rate (GFR) hyponatraemia, 10, 11, 13
194
Index
metabolic alkalosis induction, Ezetimibe, hypertriglyceridaemia

88–9 treatment, 164
Drug(s)
disease-causing/related F
see Drug-related Factor VII, 140
conditions Familial combined
lipid-lowering, 161, 163–4 hyperlipidaemia, 157–8
renal disease and, 49 Familial hypercholesterolaemia,
see also specific drugs/drug types 156–7
Drug-related conditions Fibrate derivatives,
hyponatraemia, 10–11, 11 hypertriglyceridaemia
liver disease, 134 treatment, 164
potassium balance, 24–5 Fluid therapy
hyperkalaemia, 34 potassium levels and, 25
hypokalaemia, 29 renal failure management, 58
Dysbetalipoproteinaemia, 157–8
G
E g-Glutamyltransferase (GGT),
Electrocardiogram (ECG), 129–30
hyperkalaemia, 32 alcohol and, 135
Electrolyte(s) raised levels, 133–5
flux, potassium levels and, 25 Gas transport, 92, 93
human body composition, 2 see also specific blood gases
urinary, metabolic alkalosis Gastrointestinal loss
and, 87–8 bicarbonate, 82
urine, metabolic alkalosis and, potassium, 23, 27
87–8, 88 Genetic testing, skeletal muscle
see also specific electrolytes disorders, 177
Electrolyte free water (EFW) Gilbert’s syndrome, 132
hyponatraemia, 6, 7, 8 Glomerular disease, renal failure,
non-renal loss, management, 18 57
Enterohepatic circulation, 128, 128 Glomerular filtration rate (GFR)
Erythrocyte sedimentation rate equations, 44, 45–7
(ESR), 185 examples, 47
Ethylene glycol, acid–base normal vs. reduced perfusion,
disturbance, 79 48
Extracellular fluid (ECF) related to age, 44
buffers, 63 renal blood flow regulation,
hypernatraemia assessment, 14 47–9
pH, 62 serum creatinine levels, 41–2,
sodium and water balance, 1–2 43–4
195
Index
Glomerular proteinuria, 51 reverse cholesterol transport,

Glucose, liver function, 142 153, 155
Granulomatous disorders, Human body
hypercalcaemia, 114 electrolyte composition, 2
water composition, 2
H 3-hydroxy–3-methyl-glutaryl-
Haematuria, microscopic, 54 CoA (HMG-CoA) reductase
Haematological tests, myocardial inhibitors (statins), 161,
infarction (MI), 173–4 163–4
Haemolysis, liver function tests, Hyperaldosteronism
131 hypokalaemia, 29
Heart see all entries beginning primary, metabolic alkalosis,
cardio-/cardiac 89
Heart attack see Myocardial Hypercalcaemia, 112
infarction (MI) causes/aetiology, 113
Henderson–Hasselbalch granulomatous disorders,
equation, 62 114
Hepatic lobule, 127 hyperparathyroidism,
Hepatic synthetic function, 112–14
assessment, 138–42 malignancy, 114
Hepatitis implications, 114
autoimmune, autoantibody symptoms, 112
screening, 147 treatment, 114–15
clinical features, 145 Hyperchloraemic metabolic
serology, 144–7 acidosis, 80–2, 85
see also specific infections clinical assessment, 80, 81
Hepatitis A (HAV), 144–6 urine anion gap, 80–1
clinical features, 145 Hypercholesterolaemia, 151,
Hepatitis B (HBV), 146 156–7
clinical features, 145 assessment, 160
serological markers, 146 causes/aetiology, 157
Hepatitis C (HCV), 146–7 diabetes mellitus and, 158
clinical features, 145 familial, 156–7, 157–8
Hepatitis D (HDV) liver disease and, 158
clinical features, 145 renal disease and, 158
Hepatitis E (HEV) clinical management, 159–60
clinical features, 145 dietary, 160
Hepatocellular injury, causes, drug-treatment, 161
139 lipid targets, 159
High density lipoprotein (HDL), Hyperglycaemia, associated with
152 hyponatraemia, 8–9
196
Index
Hyperkalaemia, 31–7 diagnosis/differential

causes/aetiology, 33 diagnosis, 15–17, 16
artefactual, 34 laboratory results, 15
diabetic ketoacidosis, 25, 32 management, 17–19
drug-related, 34 diabetes insipidus, 18–19
high potassium intake, 34 non-renal EFW loss, 18
potassium shifts, 34 osmotic diuresis, 18
reduced renal excretion, symptoms/signs, 14
34–5 Hyperparathyroidism, 112–14
diagnosis/differential primary, 112–13
diagnosis, 33, 33–5 secondary, 113–14
management, 35–7 tertiary, 113–14
emergency treatment, 35–7, Hyperphosphataemia, 119
36 causes/aetiology, 119
non-urgent treatment, 37 renal bone disease, 119–20
patient assessment, 35 Hypertriglyceridaemia, 157–8,
symptoms/signs, 31–2 161–5
cardiac arrhythmias/ECG causes/aetiology, 161–2, 162
changes, 31, 32 lipoprotein lipase deficiency,
Hyperlipidaemia 162
atherosclerosis and, 154–65 metabolic syndrome, 162
cardiovascular risk clinical management, 162–5,
assessment, 158–9 163
risk factors, 159 drug treatment, 163–4
familial Hypocalcaemia, 115–16
cholesterolaemia, 156–7 causes/aetiology, 115–16, 116
combined hyperlipidaemia, hypoparathyroidism, 117–18
157–8 osteoporosis, 118
hypercholesterolaemia Paget’s disease, 118
see Hypercholesterolaemia rickets/osteomalacia, 117,
hypertriglyceridaemia 117
see Hypertriglyceridaemia symptoms/complications, 116
Hypermagnesaemia, 122 treatment, 118
treatment, 123 Hypocholesterolaemia, 165
Hypernatraemia, 5, 14–19 causes, 165
ADH and, 5 Hypokalaemia, 26–31
causes/aetiology, 15–17, 16 causes/aetiology
diabetes insipidus, 16–17, 17 artefactual, 27
non-renal water loss, 15 cardiac disease, 23, 29
osmotic diuresis, 15 drug-related, 24–5, 29
clinical assessment, 14–15 gastrointestinal loss, 27
197
Index
Hypokalaemia (Continued ) alcoholism, 120

low potassium intake, 27 treatment, 120
potassium shifts, 27 Hypoventilation, 64
renal loss, 29 Hypoxaemia, treatment, 98–9
diagnosis/differential
diagnosis, 27–9, 28 I
management, 30–1 Immune system, 179, 181
emergency treatment, 30 Immunoglobulin(s), 185–6
non-urgent treatment, 31 Immunological investigations,
patient assessment, 30 179–89
symptoms/signs, 26–7 autoimmune disease
Hypomagnesaemia, 122, 122 see Autoantibodies
Hyponatraemia, 4–5, 6–14 common screens, 186
acute, 7 indications for, 187–8
symptomatic, 12–13 Innate immune system, 181
treatment guidelines, 13 Insulin, 77–8
ADH and, 4–5 Intracellular fluid (ICF)
asymptomatic, 9 buffers, 64
causes/aetiology, 8–11, 9 potassium levels, 21
artefactual, 10 sodium and water
drug-related, 10–11, 11 balance, 1–2
hyperglycaemia, 8–9 Iron, serum levels, 148–9
iatrogenic, 10
polydipsia, 10 J
SIADH, 11–12, 12 Jaundice
chronic, 7, 13 causes/aetiology, 132
diagnosis/differential Gilbert’s syndrome, 132
diagnosis, 8–11, 9 haemolysis, 131
SIADH, 11, 11–12 liver function tests, 131–2
laboratory tests, 8, 9 postoperative, 138
management, 12–14
acute symptomatic, 12–13 K
chronic, 13 Ketoacidosis
therapeutic strategies, 13–14 alcoholic, 79
volume depletion, 13 diabetic see Diabetic
patient assessment, 7 ketoacidosis (DKA)
risk factors, 6–7 Kidney(s)
symptoms/signs, 8 assessment see Renal function,
Hypoparathyroidism, 117–18 assessment
Hypophosphataemia, 120 compensatory responses,
causes/aetiology, 121 69–70
198
Index
respiratory conditions, 70, exogenous pathway, 151–2,

102 153
disease see Renal disease reverse cholesterol transport,
function, 40 153–4, 155
pH regulation, 65 see also specific fats/lipids
potassium excretion, 23, 24, Lipoprotein(s)
29, 34 classification, 151, 152
sodium reabsorption, 2, 3, 68 drug therapy effects, 164
hyponatraemia and, 7 see also specific types
see also entries beginning Lipoprotein lipase deficiency,
nephro-/renal 162
Kupffer cells, 126 Liver
anatomy/physiology, 126–30,
L 127
Lactate dehydrogenase (LDH), alkaline phosphatase, 129
173, 176 aminotransferases, 130
Lactic acidosis, 75–7 bile salts, 129
anion gap, 73–4 bilirubin metabolism
carbohydrate metabolism, see Bilirubin metabolism
75, 75 gglutamyltransferase,
causes, 76 129–30
D-lactic acidosis, 77 disease see Liver disease
treatment, 77 function, 125
type A, 76–7 assessment see Liver
type B, 77 function tests
Lecithin cholesterol excretion, 125
acyltransferase (LCAT) immunological function, 126
deficiency, 157 metabolism, 125
Lipid disorders, 151–65 storage, 126
diet, 160 synthesis, 125
lipid panel measurement, see also entries beginning hepato-/
155–6 hepatic
acute MI and, 174 Liver disease
criteria, 155–6 alcoholic, 135
indications for, 155, 174 autoimmune, 147
treatment, 161 Child–Pugh classification, 141
see also Hypercholesterolaemia clinical assessment, 142–9
Lipid-lowering drugs, 161, 163–4 clinical history, 142–3
Lipid metabolism/transport patient examination, 144
de novo synthesis, 153 diagnostic clues, 135
endogenous pathway, 152, 154 drug-related, 134
199
Index
Liver disease (Continued ) Low density lipoprotein (LDL),

enzyme patterns, 135 152, 152
hepatitis, 144–7, 145, 146 lowering treatment, 161
hepatocellular injury aetiology, receptor, 152, 154
139 mutations, 157
hypercholesterolaemia and, Lung perfusion, 94
158
jaundice, 131–2 M
see also specific conditions Magnesium
Liver failure, potassium levels, homeostasis, 121–3
30 hypermagnesaemia, 122–3
Liver function tests, 125–49, 126, hypomagnesaemia, 122, 122
138 serum levels, indications for
abnormal, patterns, 143 assessment, 121
clinical assessment see Liver Malignancy
disease hypercalcaemia, 114
definition, 125 liver function tests, 149
hepatocellular patterns, 136–8 Membrane potential, potassium
causes, 139 ions, 22
indications for, 130–1 Metabolic acid–base disorders,
jaundice, 131–2 61–89
obstructive patterns, 133–5, 136 acidosis see Metabolic acidosis
alcoholic, 135 alkalosis see Metabolic
extrahepatic cholestasis, 134 alkalosis
intrahepatic cholestasis, 134 underlying causes, 73
special tests see also specific disorders/causes
a-fetoprotein (AFP), 149 Metabolic acidosis, 72–4
a1-antitrypsin (a1-AT), 148 causes/aetiology, 73–4, 74
autoantibody screening, 147 HCO3 loss, 82
hepatitis serology, 144–7, 146 hyperchloraemic
serum caeruloplasmin, 148 see Hyperchloraemic
serum iron, 148–9 metabolic acidosis
tumour markers, 149 lactic acidosis see Lactic
synthetic function assessment, acidosis
138–42 poisoning-related, 79–80
albumin levels, 139 renal failure, 79
coagulation factors, 140 renal tubular see Renal
glucose levels, 142 tubular acidosis
urea/ammonia levels, 140, definition, 73
142 implications, 74
see also specific enzymes treatment, 74
200
Index
Metabolic alkalosis, 86–90 Neuromuscular disorders,

causes/aetiology, 86–90, 87 potassium levels, 25, 177
diuretics, 88–9 Nicotinic acid,
primary hypertriglyceridaemia
hyperaldosteronism, 89 treatment, 164–5
vomiting, 88 Non-renal water loss,
definition, 86 associated with
patient assessment, 86–7 hypernatraemia, 15
urine electrolytes, 87–8, 88 Non-steroidal anti-inflammatory
Metabolism, acid load, 62–3 drugs (NSAIDs), renal
Methanol, acid–base disturbance, function, 49
79
Microalbuminuria, 49–50 O
Microscopic haematuria, 54 Omega–3 fatty acids, 165
Modification of Diet in Renal Osmolal gap, 80
Disease (MDRD) GFR Osmotic diuresis
formula, 46 associated with
Muscle disease/injury hypernatraemia, 15
see Skeletal muscle management, 18
disorders, markers Osteomalacia, 117
Myeloma, diagnosis, 185–6 Osteoporosis, 118
Myocardial infarction (MI) Overflow proteinuria, 51
assessment of, 172 Oxygenation, assessment, 94–7
definition, 172–3 clinical, 94–6
haematological tests, 173–4 Oxygen dissociation curve, 96
markers, 169 Oxygen therapy, 98, 98
time course of cardiac Oxygen transport, 92
enzymes, 168
troponins see Cardiac P
troponins Paget’s disease, 118
Myoglobin, myocardial injury, Parathyroid hormone (PTH), 108
173 PCO2, 69
pH, 61–2
N assessment, 65–6
Na–K-ATPase pump, 21 definition, 61
Nasal cannulae/mask, oxygen renal regulation of, 65
therapy, 98 respiratory control of, 64
Nephrogenic diabetes insipidus, Phosphate
17, 17 excess
management, 18–19 see Hyperphosphataemia
Nephropathy, diabetic, 50 homeostasis, 118–21
201
Index
Phosphate (Continued ) skeletal muscle disorders,

reduced 25, 177
see Hypophosphataemia Pre-renal renal failure, 56
serum level assessment, 119 Primary biliary cirrhosis (PBC),
indications for, 119 autoantibody screen(s), 147
Plasma osmolality, Protein/creatinine ratio, 53
hyponatraemia, 8, 9 Proteinuria
Poisoning, metabolic acidosis, assessment, 49–56
79–80 clinical, 55
Polydipsia, 10 indications for, 51–2
Polyuria quantification, 52–3, 53
assessment, 19 classification, 49–51
hypernatraemia, 15 management, 52–4
solute diuresis, 19 asymptomatic patients, 53–4
water diuresis, 19 microscopic haematuria, 54
Post-renal renal failure, 57 see also specific proteins
Potassium Prothrombin, 140
balance disorders, 21–37 Pseudohyperkalaemia, 34
cardiac disease and, 23, 29, Pseudohyponatraemia, 7, 10
31, 32
drugs and, 24–5, 29, 34 R
see also Hyperkalaemia; Reciprocal creatinine plot, 42, 55
Hypokalaemia; specific Renal autoregulation, 47
disorders Renal blood flow regulation,
body distribution, 21–2, 22 glomerular filtration rate
depleted see Hypokalaemia (GFR), 47–9
dietary intake, 21 Renal bone disease, 119–20
high intake, 34 Renal disease
low intake, 27 chronic, stages, 45, 45
excess see Hyperkalaemia drugs and, 49
excretion, 23 GFR and see Glomerular
gastrointestinal, 23, 27 filtration rate (GFR)
increased, 27 hypercholesterolaemia and, 158
reduced, 34 kidney failure see Renal failure
renal, 23, 24, 29, 34 potassium balance and, 25
intracellular shifts, 27, 34 Renal failure, 39
membrane potential, 22 acidosis associated, 79
serum levels acute, 39
actions/management, 26 chronic, 39
indications for assessment, diagnosis/differential
23–5 diagnosis, 56–9
202
Index
post-renal causes, 57 treatment, 104–5

pre-renal causes, 56 Respiratory alkalosis, 105
renal causes, 57 causes, 105, 105
incidence, 40 clinical features, 105
management, 57–9 treatment, 105
fluid balance, 58 Respiratory compensation, 100–1
renal biopsy, 58–9 Respiratory failure, 97
renal replacement therapy, 59 Respiratory function, 93–4
Renal function, assessment, 39–59 Respiratory physiology, 92–3
actions following, 55–6 carbon dioxide, 92
GFR see Glomerular filtration production, 92–3
rate (GFR) gas transport, 92, 93
importance, 39–40 oxygen, 92
indications for, 54–5 Reverse cholesterol transport,
serum creatinine, 40–2, 42 153–4
serum urea, 43 Rhabdomyolysis, 174–5
urinary proteins Rheumatoid factor, 184
see Proteinuria Rickets, 117, 117
see also Renal failure
Renal potassium excretion, 23, S
24, 29 Self antigen(s), intolerance
Renal replacement therapy, 59 of, 182
Renal respiratory compensations, see also Autoantibodies
70, 102 Serum levels see specific markers
Renal tubular acidosis, 82–4 Skeletal muscle disorders,
causes in adults, 83 markers, 174–7
distal, 83–4 autoimmune screens, 176
proximal, 82–3 genetic tests, 177
type IV, 84 muscle enzymes, 176
Respiratory acid–base disorders, creatine kinase see Creatinine
99–105 kinase (CK)
acidosis see Respiratory acidosis see also specific enzymes
alkalosis see Respiratory serum electrolytes, 177
alkalosis thyroid function test, 177
assessment, 99–103, 100 Sodium
Respiratory acidosis, 102–5 balance, 1–19
acute vs. chronic, 104 control, 2–3
causes/aetiology, 102, 103–4, reabsorption, 2, 3, 68
104 volume depletion, 2–3
clinical features, 103 volume overload, 3
oxygen therapy, 98–9 see also Kidney(s)
203
Index
Sodium (Continued ) Urinary protein excretion

body distribution, 1–2 see Proteinuria
depletion see Hyponatraemia Urinary sodium, hyponatraemia,
dietary levels, 2 8, 9
excess see Hypernatraemia Urine anion gap (UAG),
serum levels, indications for acid–base homeostasis, 80–1
assessment, 5–6 Urine osmolality,
urinary levels, 8, 9 hyponatraemia, 8, 9
Sodium–potassium ATPase
pump, 21 V
Solute diuresis, polyuria Ventilation
assessment, 19 assessment, respiratory
Statins, 161, 163–4 function, 97
Syndrome of inappropriate control, 93–4
antidiuretic hormone Very low density lipoprotein
(SIADH), 11–12 (VLDL), 152, 152
causes, 12 Vitamin B12 deficiency, 188
diagnostic criteria, 11 Vitamin D
management, 12 calcium homeostasis, 108–9
deficiency, 117, 117
T metabolism, 110
Thyroid function test, 177 Vitamin K, liver disease
Tissue hypoxia assessment, 96–7 treatment, 140
Total body water (TBW), 1 Vomiting, metabolic alkalosis, 88
Triglycerides, 151
Troponin(s), cardiac see Cardiac W
troponins Water balance, 1–19
Tubular proteinuria, 51 body distribution, 1–2
Tubulointerstitial disease, renal control, 3–5
failure, 57 ADH see Antidiuretic
Tumour markers, liver function hormone (ADH)
tests, 149 depletion, 5
see also Hypernatraemia
U excess, 4–5
Urea see also Hyponatraemia
liver function tests, 140, 142 polyuria, 15, 19
renal function tests, 43 potassium levels and, 25
Urinalysis see also Fluid therapy
dipstick, 50, 51–2 Water diuresis, polyuria
see also Proteinuria assessment, 19
Urinary electrolytes, metabolic
alkalosis, 87–8, 88
204

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CLINICAL

Commissioning Editor: Timothy Horne

Jeremy Hughes MA FRCPE PhD

Ashley Jefferson MD MRCP

# 2008, Elsevier Limited. All rights reserved.

First published 2008

British Library Cataloguing in Publication Data

Library of Congress Cataloging in Publication Data

armamentarium of clinical chemistry tests is invaluable in this setting

5. If the situation is problematical then seek the advice of a senior col-

Abnormalities of sodium and water balance are the commonest fluid

It is important to recognise that sodium balance and water balance

ICF (2/3 TBW) ECF (1/3 TBW)

Interstitial fluid Plasma

Figure 1.1 Composition of water and electrolytes in body compartments of a 70-kg

Control of sodium balance

Volume depletion (decreased total body sodium)

GFR 180 L/d

sympathetic nervous system, and decreased activity of natriuretic

Volume overload (increased total body sodium)

Control of water balance

Water balance is controlled primarily by thirst and the production of

Water excess (hyponatraemia)

Maximum 1200 mOsm/kg

Table 1.1 Causes of antidiuretic hormone release

permeability of the collecting ducts to water, allowing the passage of

Water depletion (hypernatraemia)

When should I check sodium level?

The measurement of serum sodium together with other electrolytes is

l Patients receiving intravenous fluids or parenteral nutrition

What do I do with the result?

In the majority of instances, an abnormal sodium level will not require

Hyponatraemia (serum Na <135 mmol/L)

Hyponatraemia is best considered an abnormality of water balance

Two factors are required to develop hyponatraemia

Assessment of the patient

Differential diagnosis of hyponatraemia

Serum Sosm 280–295 Sosm <280 Sosm >295

Urine Uosm <100 Uosm >100

Renal failure ↑ADH Dysfunctional

Volume Euvolaemia Volume

Urinary UNa+<10 UNa+ >20 UNa+ >20 UNa+ <10

Non-renal Renal Na+ loss SIADH Oedematous states

Figure 1.4 Causes of hyponatraemia.

ICF to the ECF in order to restore osmotic equilibrium. The serum

Diuretics and other drugs

Table 1.2 Drugs associated with hyponatraemia

Syndrome of inappropriate ADH (SIADH)

Diagnostic criteria for SIADH

This is a common cause of hyponatraemia but is a diagnosis of exclu-

Table 1.3 Causes of SIADH

Carcinomas Pulmonary Central nervous system

causes for ADH action have been excluded (hypovolaemia, oedema-

Acute symptomatic hyponatraemia (<48 h)

appear more common in women. Treatment guidelines include water

Hypernatraemia (serum Na >145 mmol/L)

This represents a decrease in water relative to sodium, and is almost

Symptoms and signs

marked thirst, and the absence of thirst suggests a CNS lesion or