Contents

Preface

List of abbreviations

Chapter 1 Requesting and interpreting tests

Introduction

Collection of specimens

The use of clinical biochemistry tests

Point of care testing (POCT) (Table 1.5)

Interpretation of clinical biochemistry tests

Audit in clinical biochemistry

Chapter 2 Disturbances of water, sodium and potassium balance

Water and sodium balance

Abnormalities of plasma potassium concentration

Other investigations in disordered K⁺ metabolism

Fluid and electrolyte balance in surgical patients

Intravenous fluid administration

Chapter 3 Acid–base balance and oxygen transport

Transport of carbon dioxide

Renalm echanisms for HCO₃– reabsorption and H⁺ excretion

Buffering of hydrogenions

Investigating acid–base balance

Disturbances of acid–base status

Interpretation of results of acid–base assessment

Other investigations in acid–base assessment

Treatment of acid–base disturbances

Oxygen transport

Indications for full blood acid–base and oxygen measurements

Respiratory insufficiency

Oxygen therapy

Chapter 4 Renal disease

Tests of glomerular function

Tests of tubular function

Renal handling of sodium and potassium

Renal failure

Proteinuria

Renal stones

Chapter 5 Disorders of calcium, phosphate and magnesium metabolism

Calcium homeostasis

Hypercalcaemia

Hypocalcaemia

Metabolic bone disease

Phosphate metabolism

Magnesium metabolism

Chapter 6 Diabetes mellitus and hypoglycaemia

Glucose homeostasis

Diabetes mellitus

Hypoglycaemia

Chapter 7 Disorders of the hypothalamus and pituitary

The hypothalamus

Anterior pituitary hormones

Anterior pituitary disease and its investigation

Posterior pituitary hormones

Chapter 8 Abnormalities of thyroid function

Thyroid hormone synthesis, action and metabolism

Investigations to determine thyroid status

Interpreting results of thyroid function tests

Miscellaneous chemical tests and thyroid disease

Chapter 9 Disorders of the adrenal cortex and medulla

Regulation of adrenal steroid hormone synthesis and secretion

Investigation of suspected adrenocortical hyperfunction

Investigation of suspected adrenocortical hypofunction

Hyperaldosteronism and hypertension

Inherited adrenocortical enzyme defects

Phaeochromocytoma

Chapter 10 Investigation of gonadal function, infertility, menstrual irregularities and hirsutism

Male gonadal function

Investigation of infertility and male hypogonadism

Female gonadal function

Chapter 11 Pregnancy and antenatal screening

The foetoplacental unit

Effect of pregnancy on biochemical tests

Complications in pregnancy

Pre-natal diagnosis of foetal abnormalities

Chapter 12 Cardiovascular disorders

The diagnosis of myocardial infarction

The diagnosis of heart failure

The diagnosis of thromboembolic disease

Cardiovascular risk factors

Metabolism of plasma lipoproteins

Investigation of plasma lipid abnormalities

Other biochemical cardiovascular risk factors or markers

Calculation of cardiovascular risk and its treatment by lipid lowering

Chapter 13 Liver disease

Structure of the liver

Liver function tests

The place of chemical tests in the diagnosis of liver disease

Chapter 14 Gastrointestinal tract disease

Stomach

Small intestine and colon

The investigation of malabsorption and diarrhoea

Chapter 15 Nutrition

Introduction

Principal dietary constituents

Assessment of nutritional status

Nutritional support

Chapter 16 Trauma, inflammation, immunity and malignancy

Changes in plasma proteins in trauma, infection and inflammation – ‘the acute-phase response’

The immunoglobulins and disease

Malignancy and tumour markers

Chapter 17 Disorders of iron and porphyrin metabolism

Iron metabolism

Porphyrin metabolism

Abnormal derivatives of haemoglobin

Chapter 18 Uric acid, gout and purine metabolism

Purine metabolism and uric acid

Serum urate

Hyperuricaemia (Table 18.1)

Hypouricaemia

Chapter 19 Central nervous system and cerebrospinal fluid

CSF composition

Examination of CSF

Chapter 20 Therapeutic drug monitoring and chemical toxicology

Therapeutic drug monitoring

Chemical toxicology

Industrial and occupational hazards

Chapter 21 Clinical biochemistry in paediatrics and geriatrics

Paediatrics

Inherited metabolic disorders

Geriatrics

Self-assessment MCQs

Answers to MCQs

Appendix: Reference ranges – SI units and ‘conventional’ units

Index

This edition first published 2010, © 2010 by Geoffrey Beckett, Simon Walker, Peter Rae, Peter Ashby Previous editions 1975, 1980, 1984, 1988, 1993, 1998, 2005

Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing programme has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell.

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Library of Congress Cataloging-in-Publication Data

Lecture notes. Clinical biochemistry. – 8th ed. / edited by Geoffrey

Beckett … [et al.].

p. ; cm.

Includes bibliographical references and index.

ISBN 978-1-4051-9305-4 (pbk. : alk. paper)

1. Clinical chemistry. 2. Clinical biochemistry. I. Beckett, G. J. [DNLM: 1. Biochemistry. 2. Clinical Chemistry Tests. 3. Clinical Laboratory Techniques. 4. Pathology, Clinical–methods. QU 4 L4705 2010]

RB40.L4 2010

616.07′56–dc22

2009031374

A catalogue record for this book is available from the British Library.

1   2010

Preface

This is the eighth edition of the book first conceived by Professor Gordon Whitby, Dr Alistair Smith and Professor Iain Percy-Robb in 1975. As with the first edition, the book has been written primarily for medical students and junior doctors. The changes that have been introduced into the undergraduate medical teaching curriculum, including systems-based medicine, means that the book is now of relevance to each of the years of the course. In addition, we believe that the book is of value to specialist registrars, clinical scientists and biomedical scientists who are studying for higher qualifications to pursue a career in clinical biochemistry and metabolic medicine.

As with previous editions, the book has been modified in response to a number of suggestions made by a group of students commissioned by Wiley to review the previous edition. In response to their comments, Wiley have introduced a further colour into this edition and improved the format of the text and tables to make the content clearer. The order of the chapters has also been revised to allow all endocrine chapters to run consecutively. On our part, we have reviewed and updated all chapters to reflect current clinical practice and national guidelines, and we have included additional case studies since these have proved to be a very popular component of the book. It is interesting to note how lack of funding can prevent a useful test being introduced into clinical practice. In the 7th edition we were predicting that brain natriuretic peptide (BNP) measurements would play a pivotal role in the diagnosis of suspected heart failure in primary care. In the event, the introduction of BNP measurement into primary care in the UK has been slow due to lack of availability of adequate funding.

We have retained the objectives that have characterised the book throughout each of its previous editions. As a consequence, the reader should gain a knowledge and understanding of the value, limitations and interpretation of the many biochemical tests that are in common use in modern medicine. In addition we hope that this book will allow the reader to answer the questions first raised in Asher’s Catechism published in the British Medical Journal in 1954 under the title ‘Straight and Crooked Thinking in Medicine’, namely:

Why do I request this test?

What will I look for in the result?

If I find what I am looking for, will it affect my diagnosis?

How will this investigation affect my management of the patient?

We would like to thank Dr Jean Kirk for her help with the paediatric biochemistry section; Dr Allan Deacon for his views regarding the investigation of porphyria; and Dr Gordon Brydon for helpful comments concerning tests of gastrointestinal function. We also wish to thank the staff at Wiley for their continued interest and support towards this title since its conception in 1975, and for this edition particularly Laura Murphy and Ben Townsend.

Geoff Beckett
Simon Walker
Peter Rae
Peter Ashby

List of abbreviations

ABP androgen-binding protein

A&E Accident and (&) Emergency

ACE angiotensin-converting enzyme

ACTH adrenocorticotrophic hormone

ADH antidiuretic hormone

AFP α-fetoprotein

AI angiotensin I

AII angiotensin II

AIP acute intermittent porphyria

ALA aminolaevulinic acid

ALP alkaline phosphatase

ALT alanine aminotransferase

AMP adenosine 5-monophosphate

ANP atrial natriuretic peptide

API α₁-protease inhibitor

AST aspartate aminotransferase

ATP adenosine triphosphate

ATPase adenosine triphosphatase

BChE butylcholinesterase

BMI body mass index

BMR basal metabolic rate

BNP B-type natriuretic peptide

CAH congenital adrenal hyperplasia

cAMP cyclic adenosine monophosphate

CBG cortisol-binding globulin

CCK-PZ cholecystokinin-pancreozymin

CDT carbohydrate-deficient transferrin

CEA carcinoembryoinic antigen

ChE cholinesterase

CK creatine kinase

CKD chronic kidney disease

CNS central nervous system

CoA coenzyme A

COC combined oral contraceptive

COHb carboxyhaemoglobin

CRH corticotrophin-releasing hormone

CRP C-reactive protein

CSF cerebrospinal fluid

CT computed tomography

DDAVP 1-deamino, 8-D-arginine vasopressin

DHEA dehydroepiandrosterone

DHEAS dehydroepiandrosterone sulphate

DHCC dihydrocholecalciferol

DHT dihydrotestosterone

DIT di-iodotyrosine

DKA diabetic ketoacidosis

DPP-4 dipeptidyl peptidase-4

DVT deep venous thrombosis

ECF extracellular fluid

ECG electrocardiogram/electrocardiography

EDTA ethylenediamine tetraacetic acid

eGFR estimated glomerular filtration rate

ERCP endoscopic retrograde cholangiopancreatography

ESR erythrocyte sedimentation rate

FAD flavin–adenine dinucleotide

FAI free androgen index

FBHH familial benign hypocalciuric hypercalcaemia

FOB faecal occult blood

FSH follicle-stimulating hormone

FT3 free tri-iodothyronine

FT4 free thyroxine

GAD glutamic acid decarboxylase

Gal-1-PUT galactose-1-phosphate uridylyl-transferase

GC–MS gas chromatography–mass spectrometry

GFR glomerular filtration rate

GGT γ-glutamyltransferase

GH growth hormone

GHD growth hormone deficiency

GHRH growth hormone-releasing hormone

GI gastrointestinal

GIP glucose-dependent insulinotrophic peptide

GLP-1 glucagon-like polypeptide-1

GnRH gonadotrophin-releasing hormone

GP general practitioner

GSA glucocorticoid-suppressible hyperaldosteronism

GTT glucose tolerance test

Hb haemoglobin

HC hereditary coproporphyria

HCC hydroxycholecalciferol

hCG human chorionic gonadotrophin

HDL high-density lipoprotein

HDU high dependency unit

HGPRT hypoxanthine-guanine phosphoribosyltransferase

5-HIAA 5-hydroxyindoleacetic acid

HIV human immunodeficiency virus

HLA human leucocyte antigen

HMG-CoA β-hydroxy-β-methylglutaryl-coenzyme A

HNF hepatic nuclear factor

HPA hypothalamic–pituitary–adrenal

HPLC high-performance liquid chromatography

HRT hormone replacement therapy

hsCRP high sensitive C-reactive protein

5-HT 5-hydroxytryptamine

5-HTP 5-hydroxytryptophan

ICF intracellular fluid

ICU intensive care unit

IDL intermediate-density lipoprotein

IFCC International Federation for Clinical Chemistry

IFG impaired fasting glycaemia

Ig immunoglobulin

IGF insulin-like growth factor

IGFBP insulin-like growth factor-binding protein

IGT impaired glucose tolerance

IM intramuscular

INR international normalised ratio

IV intravenous

LCAT lecithin cholesterol acyltransferase

LDH lactate dehydrogenase

LDL low-density lipoprotein

LH luteinising hormone

LHRH luteinising hormone-releasing hormone

Lp (a) lipoprotein (a)

LSD lysergic acid diethylamide

MCAD medium chain acyl-CoA dehydrogenase

MCV mean cell volume

MDRD Modification of Diet in Renal Disease

MEGX monoethylglycinexylidide

MEN multiple endocrine neoplasia

MGUS monoclonal gammopathy of unknown significance

MIH Mullerian inhibitory hormone

MIT mono-iodotyrosine

MODY maturity onset diabetes of the young

MOM multiples of the median

MRI magnetic resonance imaging

MSAFP maternal serum α-fetoprotein

NAD nicotinamide–adenine dinucleotide

NADP NAD phosphate

NAFLD non-alcoholic fatty liver disase

NASH non-alcoholic steatohepatitis

NICE National Institute for Health and Clinical Excellence

NTD neural tube defect

NTI non-thyroidal illness

OGTT oral glucose tolerance test

PAPP-A pregnancy-associated plasma protein A

PBG porphobilinogen

PCOS polycystic ovarian syndrome

PCT porphyria cutanea tarda

PE pulmonary embolism

PEM protein-energy malnutrition

PKU phenylketonuria

POCT point of care testing

POP progestogen-only pill

PP pyridoxal phosphate

PRA plasma renin activity

PRPP 5-phosphoribosyl-1-pyrophosphate

PSA prostate-specific antigen

PT prothrombin time

PTC percutaneous transhepatic cholangiography

PTH parathyroid hormone

PTHrP PTH-related protein

RDA recommended dietary allowance

RF rheumatoid factor

ROC receiver operating characteristic

SAH subarachnoid haemorrhage

SD standard deviation

SHBG sex hormone-binding globulin

SI Systéme International

SIADH inappropriate secretion of ADH

SUR sulphonylurea receptor

T3 tri-iodothyronine

T4 thyroxine

TBG thyroxine-binding globulin

TDM therapeutic drug monitoring

TIBC total iron-binding capacity

TPMT thiopurine methyltransferase

TPN total parenteral nutrition

TPOAb thyroid peroxidase antibody

TPP thiamin pyrophosphate

TRAb thyrotrophin receptor antibody

TRH thyrotrophin-releasing hormone

TSH thyroid-stimulating hormone

TSI thyroid-stimulating immunoglobulin

tTG tissue transglutaminase

U&Es urea and electrolytes

UFC urinary free cortisol

VIP vasoactive intestinal peptide

VLDL very low density lipoprotein

VMA vanillylmandelic acid

VP variegate porphyria

WHO World Health Organization

Chapter 1

Requesting and interpreting tests

Introduction

Biochemical tests are crucial to many areas of modern medicine. Most biochemical tests are carried out on blood using plasma or serum, but urine, cerebrospinal fluid (CSF), faeces, kidney stones, pleural fluid, etc. are sometimes required. Plasma is obtained by taking whole blood into an anti-coagulant and represents the aqueous supernatant obtained when all the cellular elements have been separated by centrifugation. Serum is the corresponing aqueous phase when blood is allowed to clot. For many (but not all) biochemical tests on blood, it makes little difference whether plasma or serum is used and the terms are often used interchangeably.

There are many hundreds of tests available in clinical biochemistry that include many specialist tests. However, a core of common tests makes up the majority of test requesting in clinical biochemistry. These core tests will be offered by almost all clinical biochemistry laboratories and will be available 24h daily for more urgent situations. It is also sometimes appropriate to bring tests together in profiles, especially where a group of tests can provide better understanding of a problem than a single test (e.g. the liver function test profile). Many of the other more specialist tests are restricted to larger laboratories or, in some cases, to a very small number of centres offering a regional or national service.

In dealing with the large number of routine test requests, the modern clinical biochemistry laboratory depends heavily on automated instrumentation. This is most often linked to a laboratory computing system which assigns test requests to electronic patient files, maintains a cumulative patient record and regulates the printing of reports. Increasingly, test requests can be electronically booked at the ward, clinic or even general practitioner (GP) surgery via a terminal linked to the main laboratory computer. Equally, the test results can be displayed on computer screens at distant locations, even negating the need for issuing printed reports.

In this first chapter, we set out some of the principles of requesting tests and of the interpretation of results. The effects of analytical errors and of physiological factors, as well as of disease, on test results are stressed. Biochemical testing in differential diagnosis and in screening is discussed.

Collection of specimens

Test requests require unambiguous identification of the patient (patient’s name, sex, date of birth and, increasingly, a unique patient identification number), together with the location, the name of the requesting doctor and the date and time of sampling. Each test request must specify which analyses are requested and provide details of the nature of the specimen itself and relevant clinical diagnostic information. Traditionally, this information is provided through the request form with appropriate parallel labelling of the specimen itself. Increasingly, this information is provided electronically so that only the sample itself need be sent to the laboratory with its own unique identifier (e.g. a bar code which links it to the electronic request).

Because of the large number of samples which are processed by most clinical biochemistry laboratories, every step needs to be taken to avoid errors. Regrettably, errors do rarely occur and can be dividied according to the error source:

Pre-analytical. For example, assigning a specimen to the wrong patient at the ward end or taking a sample at the wrong time (e.g. digoxin level is requested on a sample shortly after digoxin has been administered (pp. 279)) or mislabelling of an aliqout of serum taken at specimen reception. Most errors fall into this category (see Table 1.1).

Analytical. For example, a small sample volume may lead to a pipetting error where insufficient sample is used for the assay. Again, developments in automated sample detection and pipetting mean these problems are very unusual.

Post-analytical. These are increasingly rare because of electronic download of results from the analyser but might include transcription errors when entering results into the lab computer manually.

On the scale of the requesting of biochemical tests, errors are fortunately rare. However, occasional blunders do arise and, if very unexpected results are obtained, it is incumbent on the requesting doctor to contact the laboratory immediately to look into the possibility that a blunder may have occurred.

Table 1.1 Some more common causes of pre-analytical errors arising from use of the laboratory

Error
Consequence

Crossover of
  addressograph labels
  between patients
This can lead to two patients each with the other’s set of results.
Where the patient is assigned a completely wrong set of results, it is important to
  investigate the problem in case there is a second patient with a corresponding
  wrong set of results.

Timing error
There are many examples where timing is important but not considered. Sending in a
  blood sample too early after the administration of a drug can lead to misleadingly
  high values in therapeutic monitoring. Interpretation of some tests (e.g. cortisol) is
  critically dependent on the time of day when the blood was sampled.

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