Oxford handbook of endocrinology and diabetes - Book 1

OXFORD MEDICAL PUBLICATIONS

Oxford Handbook of

Endocrinology and
Diabetes

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Oxford Handbook of

Endocrinology
and Diabetes

Third edition

Edited by

John Wass

Professor of Endocrinology,
Oxford Centre for Diabetes,
Endocrinology and Metabolism (OCDEM),
Oxford, UK

Katharine Owen

Senior Clinical Researcher and Honorary Consultant,
Oxford Centre for Diabetes, Endocrinology and
Metabolism (OCDEM), Oxford, UK

Advisory editor

Helen Turner

Consultant in Endocrinology
Oxford Centre for Diabetes, Endocrinology and
Metabolism (OCDEM), Oxford, UK

1

3

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United Kingdom

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© Oxford University Press 2014

The moral rights of the authors have been asserted

First edition published 2002

Second edition published 2009

Third edition published 2014

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ISBN╇978–0–19–964443–8

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v

Foreword

Introduction to the Handbook of Endocrinology
and Diabetes
It is clear that endocrinology is progressing fast and moving far from its
original borders. Originally described as the study of the physiology and
diseases of the endocrine glands, classical endocrinology encompassed the
study of thyroid, hypothalamus, pituitary, adrenals, pancreas, parathyroids
and the reproductive glands. Increasingly diabetes and metabolism are rec-
ognised as overwhelming issues, which are responsible for world epidem-
ics with an enormous human and financial cost. Thus, lately it has become
obvious that the initial definition is too narrow and does not encompass
the breadth of the specialty—it needs to be redefined.

The speciality ‘endocrinology’ should be applied to every area in which
hormones act, extending to brain neurohormones, cognition, oncology,
and also bone diseases, the cardiovascular system and obesityâ•…› â•w› here
hormones and growth factors interact closely. This new science is closer
to the Hormonology that Starling described, than to Endocrinology as
defined by Laguesse at the end of the 19th century.

This immense amount of knowledge is well summarised in the third
edition of the Oxford Handbook of Endocrinology and Diabetes. Few of
us have the talent of John Wass and Katharine Owen, and Helen Turner
contributed to earlier editions. They have summarised with their col-
leagues, in an extensive though concise manner, our incredible specialty.
This specialty develops every day and continues to rule our behaviours
and diseases.

This Handbook of Endocrinology and Diabetes is a must for all phy-
sicians interested in hormones and related diseases, and in medicine in
general.

Philippe Bouchard
President, European Society of Endocrinology
Member of the National Academy of Medicine

vi

Preface to the
second€edition

The first edition of this handbook was well received and sold many copies.
We were told by a number of specialist registrars in training and consult-
ants that it was essential to have it in outpatients. We hope that the same
will be true of the second edition.

Endocrinology remains the most exciting of specialties—enormously
varied in presentation and management and with the ability to affect hugely
and beneficially the quality of life over a long period of time. Our aims with
this second edition remain the same, mainly to have a pocket handbook
which can be easily transported in which all the pieces of information one
so often needs are there as a reminder. We hope it will enable trainees
to enhance their knowledge but also the older and so-called ‘trained’ will
continue to have recourse to its pages when memory lapses occur. We
regard it too as a companion to the Oxford Textbook of Endocrinology and
Diabetes.

We are enormously indebted to our contributors who once again have
provided timely texts full of practical detail. We are also hugely grateful to
our external referees who have looked at all the chapters with great care
and attention. Both have ensured that the text is as up-to-date as possible.
As always we welcome comments for future editions and we hope this
one proves as useful as the first one.

John A.H. Wass
Helen E.Turner

2009

vii

Preface

We remain happy that this handbook has been well received both in its
first and second editions. It has been translated into Chinese, and there
is also an American version which has sold well. We want it to remain
essential for specialist registrars in training and consultants who may have
the occasional memory lapse.

Our subject remains one of the most exciting of the specialties; our aims
with this third edition remain the same—to have, within a small volume,
all the essential information that one needs to look after patients with
endocrine problems and diabetes.

It is also an accompaniment to the Oxford Textbook of Endocrinology
and Diabetes which has recently been published in its second edition
(2011).

For this edition, we have completely revamped the diabetes section,
and we hope and think that this has been made more readily accessible
and assimilable.

We are enormously indebted to our contributors who have pro-
vided expertise and willing collaboration with our project. As always, we
Âw



Contents ix

Contributors╇ x ╇╇1
Contributors to the second edition╇ xii 106
Symbols and Abbreviations╇ xiii 227
297
1 Thyroid 425
2 Pituitary 449
3 Adrenal 513
4 Reproductive endocrinology 553
5 Endocrinology in pregnancy 575
6 Calcium and bone metabolism 601
7 Paediatric endocrinology 613
8 Neuroendocrine disorders
9 Inherited endocrine syndromes and MEN 627
10 Endocrine surgery 683
11 Endocrinology and ageing 823
12 Endocrinology aspects of other clinical 847

or physiological situations
13 Diabetes
14 Lipids and hyperlipidaemia
15 Obesity

Appendix 1╇867
Appendix 2╇873
Appendix 3╇881
Index╇ 887

x

Contributors

Ramzi Ajjan Ketan Dhatariya
Senior Lecturer and Consultant Consultant in Diabetes,
in Diabetes and Endocrinology, Endocrinology and General
Division of Cardiovascular and Medicine, Elsie Bertram Diabetes
Diabetes Research, The LIGHT Centre, Norfolk and Norwich
Laboratories, University of University Hospitals NHS
Leeds,€UK Foundation Trust, Norwich, UK

Asif Ali Julie Edge
Consultant Physician (Diabetes Consultant in Paediatric Diabetes,
and Endocrinology), Department Oxford Children’s Hospital, John
of Medicine, Milton Keynes Radcliffe Hospital, Oxford, UK
Hospital, UK
Nick Finer
Wiebke Arlt Consultant Metabolic Physician,
Professor of Medicine and Head Centre for Weight Loss, Metabolic
of the Centre for Endocrinology, and Endocrine Surgery, University
Diabetes and Metabolism, College London Hospitals, UK
University of Birmingham, UK
Neil Gittoes
Rudy Bilous Consultant Endocrinologist and
Professor of Clinical Medicine, Associate Medical Director,
Academic Centre, James Queen Elizabeth Hospital,
Cook University Hospital, Birmingham, UK
Middlesbrough, UK
Steve Gough
Pratik Choudhary Professor of Diabetes
Senior Lecturer/Consultant, and Consultant Physician,
Department of Diabetes and Oxford Centre for Diabetes,
Nutritional Sciences, The School Endocrinology and Metabolism
of Medicine, Kings College (OCDEM), Churchill Hospital,
London, UK Oxford, UK

Peter Clayton Maggie Hammersley
Professor of Child Health€& Consultant Physician and Senior
Paediatric Endocrinology; Clinical Lecturer, John Radcliffe
Director, NIHR Greater Hospital, Oxford, UK
Manchester, Lancashire & South
Cumbria Medicines for Children Niki Karavitaki
Research Network, University of Consultant Endocrinologist,
Manchester, UK Oxford Centre for Diabetes,
Endocrinology and Metabolism
Gerard Conway (OCDEM), Churchill Hospital,
Clinical Lead in Endocrinology Oxford, UK
and Diabetes, Department of
Endocrinology, University College
London Hospitals, UK

Contributors xi

Fredrik Karpe Peter Scanlon
Professor of Metabolic Medicine, Consultant Ophthalmologist,
Honorary Consultant Physician, Gloucestershire and Oxford
Oxford Centre for Diabetes, Eye Units; Medical Tutor and
Endocrinology and Metabolism Senior Research Fellow, Harris
(OCDEM), Churchill Hospital, Manchester College, University
Oxford, UK of Oxford; Visiting Professor
of Medical Ophthalmology,
Kim Lambert University of Bedfordshire, and
Specialist Registrar, Wessex Hertfordshire Postgraduate
Deanery, Winchester, UK Medical School, UK

Alistair Lumb Gary Tan
Locum Consultant Physician, Consultant Diabetologist,
Buckinghamshire Healthcare NHS Oxford Centre for Diabetes,
Trust, Aylesbury, Bucks, UK Endocrinology & Metabolism
(OCDEM), Churchill Hospital, UK
Niki Meston
Consultant Chemical Pathologist, Solomon Tesfaye
Epsom and St Helier University Professor of Diabetic Medicine,
Hospitals NHS Trust, Surrey, UK Royal Hallamshire Hospital,
Sheffield, UK
Helen Murphy
Senior Research Associate Gaya Thanabalasingham
Honorary Consultant, Department Specialist Registrar, Oxford
of Clinical Biochemistry, Centre for Diabetes,
Addenbrooke’s Hospital, Endocrinology and Metabolism
Cambridge, UK (OCDEM), Churchill Hospital,
Oxford, UK
Catherine Nelson-Piercy
Consultant Obstetric Physician, Mark Vanderpump
Department of Obstetrics, Consultant Physician and
Guys and St Thomas’ Hospitals, Honorary Senior Lecturer in
London,€UK Diabetes and Endocrinology,
Royal Free Hampstead NHS
Sankalpa Neupane Trust, UK
Wolfson Diabetes and Endocrine
Clinic, Institute of Metabolic
Science, Addenbrooke’s Hospital,
Cambridge, UK

Shwe Zin Chit Pan
Wolfson Diabetes and Endocrine
Clinic, Institute of Metabolic
Science, Addenbrooke’s Hospital,
Cambridge, UK

xii

Contributors to the
second edition

Julian Barth Peter Selby
Consultant in Chemical Pathology Consultant Physician and Senior
and Metabolic Medicine, Leeds Lecturer in Medicine, Manchester
General Infirmary, Leeds, UK Royal Infirmary, Manchester, UK

Karin Bradley Kevin Shotliff
Consultant Physician and Consultant Physician and
Endocrinologist, Bristol Royal Diabetologist, Beta Cell Diabetes
Infirmary and Honorary Senior Centre, Chelsea and Westminster
Clinical Lecturer, University of Hospital, London, UK
Bristol, Bristol, UK
Sara Suliman
Emma Duncan Specialist Registrar in Diabetes,
Consultant Endocrinologist, Endocrinology and Metabolism,
Princess Alexandra Hospital and Diabetes UK; Clinical
Senior Lecturer, University of Research Fellow, Oxford Centre
Queensland, Austalia; for Diabetes, Endocrinology and
Postdoctoral Research Fellow, UQ Metabolism (OCDEM), Churchill
Diamantina Institute for Cancer, Hospital, Oxford, UK
Immunology and Metabolic
Medicine, Australia Janet Sumner
Lead Diabetes Specialist Nurse,
Pam Dyson Churchill Hospital, Oxford, UK
Research Dietician, Oxford
University, Oxford, UK Vivien Thornton-Jones
Lead Endocrine Specialist Nurse,
Mohgah Elsheikh Churchill Hospital, Oxford, UK
Consultant Endocrinologist, Royal
Berkshire Hospital, Reading, UK Helen E. Turner
Consultant Endocrinologist,
Stephen Gardner Department of Endocrinology,
Consultant Physician, Churchill Hospital, Oxford, UK
Buckinghamshire Hospitals NHS
Trust, UK John Wong
Consultant Chemical Pathologist,
John Newell-Price Kingston Hospital, Surrey, UK
Senior Lecturer and Consultant
Endocrinologist, University of
Sheffield, Royal Hallamshire
Hospital, Sheffield, UK

xiii

Symbols and
Abbreviations

b cross-reference

7 approximately

i increased

d decreased

p primary

s secondary

α alpha

β beta

γ gamma

% per cent

♀ female

♂ male

+ve positive

–ve negative

= equal to

≡ equivalent to

< less than

> more than

≤ less than or equal to

≥ greater than or equal to

°C degree Celsius

£ pound Sterling

® registered trademark

2 important

3 don’t dawdle

ACA adrenocortical adenoma

ACC adrenocortical carcinoma

ACE angiotensin-converting enzyme

ACEI angiotensin-converting enzyme inhibitor

ACR albumin:creatinine ratio

ACTH adrenocorticotrophic hormone

AD autosomal dominant

ADA American Diabetes Association

ADH antidiuretic hormone

ADHH autosomal dominant hypocalcaemic hypercalciuria

xiv Symbols and Abbreviations

aFP alpha fetoprotein

AGE advanced glycation end-product

AGHDA adult growth hormone deficiency assessment

AHC adrenal hypoplasia congenita

AI adrenal insufficiency

AIDS acquired immunodeficiency syndrome

AIH amiodarone-induced hypothyroidism

AIMAH ACTH-independent macronodular adrenal hyperplasia

AIT amiodarone-induced thyrotoxicosis

AITD autoimmune thyroid disease

alk phos alkaline phosphatase

ALL acute lymphoblastic leukaemia

ALP alkaline phosphatase

ALT alanine transaminase

a.m. ante meridiem (before noon)

AME apparent mineralocorticoid excess

AMH anti-Müllerian hormone

AMN adrenomyeloneuropathy

AMP adenosine monophosphate

AN autonomic neuropathy

ANCA anti-neutrophil cytoplasmic antibody

APS autoimmune polyglandular syndrome

AR autosomal recessive

ARB angiotensin II receptor blocker

ART assisted reproductive technique

AST aspartate transaminase

ATD antithyroid drug

ATP adenosine triphosphate

AVP arginine vasopressin

AVS adrenal vein sampling

bd bis in die (twice daily)

BMD bone mineral density

BMI body mass index

BP blood pressure

bpm beat per minute

Ca calcium

CAH congenital adrenal hyperplasia

CBG cortisol-binding globulin

CCF congestive cardiac failure

CEA carcinoembryonic antigen

Symbols and Abbreviations xv

CF cystic fibrosis

CFRD CF-related diabetes

CGM continuous glucose monitoring

cGMP cyclic guanyl monophosphate

cGy centigray

CHD coronary heart disease

CHO carbohydrate

CK creatine kinase

CKD chronic kidney disease

CLAH congenital lipoid adrenal hyperplasia

cm centimetre

CMV cytomegalovirus

CNS central nervous system

COCP combined oral contraceptive pill

COPD chronic obstructive pulmonary disease

CPA cyproterone acetate

CPK creatine phosphokinase

Cr creatinine

CRF chronic renal failure

CRH corticotrophin-releasing hormone

CRP C-reactive protein

CSF cerebrospinal fluid

CSII continuous subcutaneous insulin infusion

CSMO ‘clinically significant’ diabetic macular oedema

CSW cerebral salt wasting

CT computed tomography

CTLA4 cytotoxic T lymphocyte antigen 4

cv coefficient of variation

CV cardiovascular

CVA cerebrovascular accident

CVD cardiovascular disease

CVP central venous pressure

CXR chest X-ray

DCCT Diabetes Control and Complications Trial

DCT distal convoluted tubule

DD disc diameter

DEXA dual-energy X-ray absorptiometry

DHEA dehydroepiandrostenedione

DHEAS dehydroepiandrostenedione sulphate

DHT dihydrotestosterone

xvi Symbols and Abbreviations

DI diabetes insipidus

DIT diiodotyrosine

DKA diabetic ketoacidosis

DKD diabetic kidney disease

dL decilitre

DM diabetes mellitus

DME diabetic macular (o)edema

DN diabetic neuropathy

DNA deoxyribonucleic acid

DOC deoxycorticosterone

DR diabetic retinopathy

DRIP/TRAP vitamin D receptor interacting protein/TR-associated
protein

DRS Diabetic Retinopathy Study

DSN diabetes specialist nurse

DSD disorders of sexual differentiation; disorders of sex
development

DTC differentiated thyroid cancer

DVA Driver and Vehicle Agency

DVLA Driver and Vehicle Licensing Agency

DVT deep vein thrombosis

DXA dual-energy absorptiometry

EBRT external beam radiation therapy

ECF extracellular fluid

ECG electrocardiogram

EEG electroencephalogram

eFPGL extra-adrenal functional paraganglioma

e.g. exempli gratia (for example)

eGFR estimated glomerular filtration rate

EM electron microscopy

EMA European Medicines Agency

ENaC epithelial sodium channel

ENETS European Neuroendocrine Tumour Society

ENSAT European Network for the Study of Adrenal Tumours

ENT ear, nose, and throat

EOSS Edmonton Obesity Staging System

ER (o)estrogen receptor

ERT (o)estrogen replacement therapy

ESR erythrocyte sedimentation rate

ESRD end-stage renal disease

ESRF end-stage renal failure

Symbols and Abbreviations xvii

ETDRS Early Treatment of Diabetic Retinopathy Study

EUA examination under anaesthesia

FAI free androgen index

FAZ foveal avascular zone

FBC full blood count

FCHL familial combined hyperlipidaemia

FDA Food and Drug Administration

FDG fluorodeoxyglucose

FeSO4 ferrous sulfate
FGD familial glucocorticoid deficiency

FGFR1 fibroblast growth factor receptor 1

FH familial hypercholesterolaemia

FHH familial hypocalciuric hypercalcaemia

FIHP familial isolated hyperparathyroidism

FMTC familial medullary thyroid carcinoma

FNA fine needle aspiration

FNAC fine needle aspiration cytology

FRIII fixed-rate intravenous insulin infusion

FSH follicle-stimulating hormone

FT3 free tri-iodothyronine
FT4 free thyroxine
FTC follicular thyroid carcinoma

5FU 5-fluorouracil

g gram

GAD glutamic acid decarboxylase

GAG glycosaminoglycan

GBM glomerular basement membrane

GBq giga becquerel

GC glucocorticoid

GCK glucokinase

GCS Glasgow coma score

GDM gestational diabetes mellitus

GDP guanosine diphosphate

GEP gastroenteropancreatic

GFR glomerular filtration rate

GGT gamma glutamyl transferase

GH growth hormone

GHD growth hormone deficiency

GHDC growth hormone day curve

GHRH growth hormone-releasing hormone

xviii Symbols and Abbreviations

GI gastrointestinal; glycaemic index

GIFT gamete intrafallopian transfer

GIP gastric intestinal polypeptide

GK glycerol kinase

GLP-1 glucagon-like peptide-1

GnRH gonadotrophin-releasing hormone

GO Graves’s orbitopathy

GO-QOL Graves’s Ophthalmopathy Quality of Life

GP general practitioner

GRA glucocorticoid-remediable aldosteronism

GRTH generalized resistance to thyroid hormone

GTF glucose tolerance factor

GTN glyceryl trinitrate

GTP guanyl triphosphate

GTT glucose tolerance test

GWAS genome-wide association studies

Gy Gray

h hour

HA hypothalamic amenorrhoea

HAART highly active antiretroviral therapy

Hb haemoglobin

HbA1c glycosylated haemoglobin

hCG human chorionic gonadotrophin

HCO3– bicarbonate ion
HDL-C high-density lipoprotein cholesterol

HDU high dependency unit

HFEA Human Fertilisation and Embryology Act

hGH human growth hormone

HH hypogonadotrophic hypogonadism

HHS hyperglycaemic hyperosmolar state

HIV human immunodeficiency virus

HLA human leukocyte antigen

hMG human menopausal gonadotrophin

HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A

HNF hepatocyte nuclear factor

HNPGL head and neck paraganglioma

HP hypothalamus/pituitary

HPT hypothalamo–pituitary–thyroid

HPT-JT hyperparathyroidism-jaw tumour (syndrome)

HPV human papillomavirus

Symbols and Abbreviations xix

HRT hormone replacement therapy

HSD 11B-hydroxysteroid dehydrogenase

HSG hysterosalpingography

5-HT2B 5-hydroxytryptamine 2B

HTLV-1 human T lymphotropic virus type 1

HU Hounsfield unit

HyCoSy hysterosalpingo-contrast-sonography

Hz hertz

IADPSG International Association of the Diabetes and Pregnancy
Study Groups

ICA islet cell antibodies

ICF intracellular fluid

ICSI intracytoplasmic sperm injection

IDDM insulin-dependent diabetes mellitus

IDL intermediate density lipoprotein

i.e. id est (that is)

IFG impaired fasting glycaemia

Ig immunoglobulin

IGF insulin growth factor

IGT impaired glucose tolerance

IHD ischaemic heart disease

IHH idiopathic hypogonadotropic hypogonadism

IM intramuscular

IPSS inferior petrosal sinus sampling

IQ intelligence quotient

IRMA intraretinal microvascular abnormalities

ITT insulin tolerance test

ITU intensive treatment unit

IU international unit

IUD intrauterine contraceptive device

IUGR intrauterine growth restriction

IUI intrauterine insemination

IV intravenous

IVC inferior vena cava

IVF in vitro fertilization

IVII intravenous insulin infusion

K+ potassium ion

kcal kilocalorie

KCl potassium chloride

kDa kilodalton

xx Symbols and Abbreviations

kg kilogram

KPD ketosis-prone diabetes

L litre

LADA latent autoimmune diabetes of adulthood

LCAT lecithin:cholesterol acyltransferase

LDL low-density lipoprotein

LDL-C LDL cholesterol

LFT liver function test

LH luteinizing hormone

LOH loss of heterozygosity

Lpa lipoprotein a

LPL lipoprotein lipase

LVH left ventricular hypertrophy

m metre

MAI Mycobacterium avium intracellulare

MAOI monoamine oxidase inhibitor

MAPK mitogen-activated protein kinase

MBq mega becquerel

MC mineralocorticoid

MCR1 melanocortin 1 receptor

MDI multiple dose injection

MDT multidisciplinary team

MEN multiple endocrine neoplasia

mg milligram

Mg magnesium

MGMT O-6-methylguanine DNA methyltransferase

mGy milligray

MHC major histocompatibility complex

MI myocardial infarction

MIBG metaiodobenzylguanidine

min minute

MIS Müllerian inhibitory substance

MIT monoiodotyrosine

mIU milli international unit

MJ megajoule

mm millimetre

mmHg millimetre of mercury

MMI methimazole

mmol millimole

MODY maturity onset diabetes of the young

Symbols and Abbreviations xxi

mOsm milliosmole

MPH mid-parental height

MRI magnetic resonance imaging

mRNA messenger ribonucleic acid

MRSA meticillin-resistant Staphylococcus aureus

MSH melanocyte-stimulating hormone

MSU midstream urine

mSv microsievert

MTC medullary thyroid carcinoma

mTOR mammalian target of rapamycin

mU milliunit

Na sodium

NaCl sodium chloride

NAFLD non-alcoholic fatty liver disease

NASH non-alcoholic steatohepatitis

NaU urinary sodium

NB nota bene (take note)

NDST National Diabetes Support Team

NEC neuroendocrine carcinoma

NEN neuroendocrine neoplasia

NET neuroendocrine tumour

NF neurofibromatosis

NFA non-functioning pituitary adenoma

ng nanogram

NG nasogastric

NHS National Health Service

NICE National Institute for Health and Care Excellence

NIDDM non-insulin-dependent diabetes mellitus

NIS sodium/iodide symporter

nmol nanomole

NOGG National Osteoporosis Guideline Group

NR normal range

NSAID non-steroidal anti-inflammatory drug

NSC National Screening Committee

NSF National Service Framework

NVD new vessels on disc

NVE new vessels elsewhere

O2 oxygen
OA osteoarthritis

OCP oral contraceptive pill

xxii Symbols and Abbreviations

od omne in die (once daily)

OD overdose

OGTT oral glucose tolerance test

OHA oral hypoglycaemic agent

OHSS ovarian hyperstimulation syndrome

OR odds ratio

PAI plasminogen activator inhibitor

PAK pancreas after kidney

PAL physical activity level

PAR-Q physical activity readiness questionnaire

PBC primary biliary cirrhosis

PCOS polycystic ovary syndrome

PDE phosphodiesterase

PDR proliferative diabetic retinopathy

PE pulmonary embolism

PEG polyethylene glycol

PET positron emission tomography

pg picogram

PHP primary hyperparathyroidism

PI protease inhibitor

PID pelvic inflammatory disease

PIH pregnancy-induced hypertension

PKA protein kinase A

p.m. post meridiem (after noon)

PMC papillary microcarcinoma

pmol picomole

PNDM permanent neonatal diabetes mellitus

PNMT phenylethanolamine-N-methyltransferase

PO per os (orally)

PO4 phosphate
POF premature ovarian failure

POI premature ovarian insufficiency

POMC pro-opiomelanocortin

POP progesterone-only pill

PPI proton pump inhibitor

PPNAD primary pigmented nodular adrenal disease

PRA plasma renin activity

PRH postprandial reactive hypoglycaemia

PRL prolactin

PRRT peptide receptor radioligand therapy

Symbols and Abbreviations xxiii

PRTH pituitary resistance to thyroid hormone

PSA prostate-specific antigen

PTA pancreas transplant alone

PTH parathyroid hormone

PTHrP parathyroid hormone-related peptide

PTTG pituitary tumour transforming gene

PTU propylthiouracil

PUD peptic ulcer disease

PVD peripheral vascular disease

QCT quantitative computed tomography

qds quarter die sumendus (four times daily)

QoL quality of life

RAA renin–angiotensin–aldosterone

RAI radioactive iodine

RCAD renal cysts and diabetes (syndrome)

rhGH recombinant human growth hormone

rhTSH recombinant human thyroid-stimulating hormone

RNA ribonucleic acid

RR relative risk

RRT renal replacement therapy

rT3 reverse T3

RTH resistance to thyroid hormone

s second

SC subcutaneous

SD standard deviation

SDH succinate dehydrogenase

SERM selective (o)estrogen receptor modulator

SGA small for gestational age

SH severe hypoglycaemia

SHBG sex hormone-binding globulin

SIADH syndrome of inappropriate ADH

SLE systemic lupus erythematosus

SNP single nucleotide polymorphism

SNRI serotonin noradrenaline reuptake inhibitor

SPK simultaneous pancreas kidney

SSA somatostatin analogue

SSRI selective serotonin reuptake inhibitor

SST short Synacthen® test

SSTR somatostatin receptor

STED sight-threatening diabetic eye disease

xxiv Symbols and Abbreviations

SU sulphonylurea

T3 tri-iodothyronine
T4 thyroxine
TART testicular adrenal rest tissue

TB tuberculosis

TBG thyroid-binding globulin

TBI traumatic brain injury

TBPA T4-binding prealbumin
TC total cholesterol

TCA tricyclic antidepressant

TDD total daily dose

T1DM type 1 diabetes mellitus

T2DM type 2 diabetes mellitus

tds ter die sumendus (three times daily)

TENS transcutaneous electrical nerve stimulation

TFT thyroid function test

Tg thyroglobulin

TG triglyceride

TGF transforming growth factor

TgAb thyroglobulin antibody

TK tyrosine kinase

TKI tyrosine kinase inhibitor

TNDM transient neonatal diabetes mellitus

TNF tumour necrosis factor

TPO thyroid peroxidase

TR thyroid hormone receptor

TRE thyroid hormone response element

TRH thyrotropin-releasing hormone

TSA transsphenoidal approach

TSAb TSH-stimulating antibody

TSG tumour suppressor gene

TSH thyroid-stimulating hormone

TSH-RAB thyroid-stimulating hormone receptor antibodies

TTR transthyretin

U unit

U&E urea and electrolytes

UFC urinary free cortisol

UK United Kingdom

UKPDS United Kingdom Prospective Diabetes Study

Symbols and Abbreviations xxv

US ultrasound

USA United States of America

V volts

VA visual acuity

VEGF vascular endothelial growth factor

VEGFR vascular endothelial growth factor receptor

VHL von Hippel–Lindau

VIP vasoactive intestinal polypeptide

VLCFA very long chain fatty acid

VLDL very low density lipoprotein

VMA vanillylmandelic acid

VRIII variable-rate intravenous insulin infusion

vs versus

VTE venous thromboembolism

WBS whole body scan

WDHA watery diarrhoea, hypokalaemia, acidosis

WHI Women’s Health Initiative

WHO World Health Organization

w/v weight by volume

ZE Zollinger–Ellison (syndrome)



Chapter€1 1

Thyroid

Anatomy╇ 2
Physiology╇ 4
Molecular action of thyroid hormone╇ 6
Tests of hormone concentration╇ 8
Tests of homeostatic control╇ 10
Rare genetic disorders of thyroid hormone metabolism╇ 14
Antibody screen╇ 15
Scintiscanning╇ 16
Ultrasound (US) scanning╇ 18
Fine needle aspiration cytology (FNAC)╇ 20
Computed tomography (CT)╇ 22
Positron emission tomography (PET)╇ 23
Additional laboratory investigations╇ 24
Non-thyroidal illness╇ 24
Atypical clinical situations╇ 25
Thyrotoxicosis—aetiology╇ 26
Manifestations of hyperthyroidism╇ 28
Medical treatment╇ 30
Radioiodine treatment╇ 34
Surgery╇ 38
Thyroid crisis (storm)╇ 40
Subclinical hyperthyroidism╇ 42
Thyrotoxicosis in pregnancy╇ 44
Hyperthyroidism in children╇ 48
Secondary hyperthyroidism╇ 50
Graves’s ophthalmopathy╇ 54
Medical treatment of Graves’s ophthalmopathy╇ 58
Surgical treatment of Graves’s ophthalmopathy╇ 60
Graves’s dermopathy╇ 62
Thyroid acropachy╇ 63
Multinodular goitre and solitary adenomas╇ 64
Thyroiditis╇ 68
Chronic autoimmune (atrophic or Hashimoto’s) thyroiditis╇ 70
Other types of thyroiditis╇ 72
Hypothyroidism╇ 74
Subclinical hypothyroidism╇ 78
Treatment of hypothyroidism╇ 80
Congenital hypothyroidism╇ 84
Amiodarone and thyroid function╇ 86
Epidemiology of thyroid cancer╇ 91
Aetiology of thyroid cancer╇ 92
Papillary thyroid carcinoma╇ 96
Follicular thyroid carcinoma (FTC)╇ 99
Follow-up of papillary and FTC╇ 100
Medullary thyroid carcinoma (MTC)╇ 103
Anaplastic (undifferentiated) thyroid cancer╇ 104
Lymphoma╇ 105

2 Chapter€1╇ Thyroid

Anatomy

The thyroid gland comprises:
• A midline isthmus lying horizontally just below the cricoid cartilage.
• Two lateral lobes that extend upward over the lower half of the

thyroid cartilage.
The gland lies deep to the strap muscles of the neck, enclosed in the pre-
tracheal fascia, which anchors it to the trachea, so that the thyroid moves
up on swallowing.

Histology

• Fibrous septa divide the gland into pseudolobules.
• Pseudolobules are composed of vesicles called follicles or acini,
surrounded by a capillary network.
• The follicle walls are lined by cuboidal epithelium.
• The lumen is filled with a proteinaceous colloid, which contains the
unique protein thyroglobulin. The peptide stehqyruoegnlcoebsuolinf .T4 and T3 are
synthesized and stored as a component of

Development

• Develops from the endoderm of the floor of the pharynx with some
contribution from the lateral pharyngeal pouches.
• Descent of the midline thyroid precursor gives rise to the thyroglossal
duct, which extends from the foramen caecum near the base of the
tongue to the isthmus of the thyroid.
• During development, the posterior aspect of the thyroid becomes
associated with the parathyroid glands and the parafollicular C cells,
derived from the ultimo-branchial body (fourth pharyngeal pouch),
which become incorporated into its substance.
• The C cells are the source of calcitonin and give rise to medullary
thyroid carcinoma when they undergo malignant transformation.
• The fetal thyroid begins to concentrate and organify iodine at about
10–12 weeks’ gestation.
• Maternal TRH readily crosses the placenta; maternal TSH and T4
do€not.
• Tfe4tufrso. mThtehefefteatlaplitthuyitraoriyd-tihsytrhoeidmaaxjoisristhayfruonidcthioonraml ounneit,adviasitlianbclteftroomthe
that of the mother—active at 18–20€weeks.

Thyroid examination

Inspection
• Look at the neck from the front. If a goitre (enlarged thyroid gland of

whatever cause) is present, the patient should be asked to swallow a
mouthful of water. The thyroid moves up with swallowing.
• Assess for scars, asymmetry, or masses.
• Watch for the appearance of any nodule not visible before swallowing;
beware that, in an elderly patient with kyphosis, the thyroid may be
partially retrosternal.

Anatomy 3

Palpation (usually from behind)
• Is the thyroid gland tender to€touch?
• With the index and middle fingers, feel below the thyroid cartilage

where the isthmus of the thyroid gland lies over the trachea.
• Palpate the two lobes of the thyroid, which extend laterally behind the

sternomastoid muscle.
• Ask the patient to swallow again while you continue to palpate the

thyroid.
• Assess size, whether it is soft, firm or hard, whether it is nodular or

diffusely enlarged, and whether it moves readily on swallowing.
• Palpate along the medial edge of the sternomastoid muscle on either

side to look for a pyramidal€lobe.
• Palpate for lymph nodes in the€neck.
Percussion
Percuss the upper mediastinum for retrosternal goitre.
Auscultation
• Auscultate to identify bruits, consistent with Graves’s disease (treated

or untreated).
• Occasionally, inspiratory stridor can be heard, with a large or

retrosternal goitre causing tracheal compression (b see Pemberton’s
sign, p.€64).
Assess thyroid€status
• Observe for signs of thyroid disease—exophthalmos, proptosis,
thyroid acropachy, pretibial myxoedema, hyperactivity, restlessness, or
whether immobile.
• Take pulse; note the presence or absence of tachycardia, bradycardia,
or atrial fibrillation.
• Feel palms—whether warm and sweaty or€cold.
• Look for tremor in outstretched€hands.
• Examine eyes:€exophthalmos (forward protrusion of the eyes—
proptosis); lid retraction (sclera visible above cornea); lid lag;
conjunctival injection or oedema (chemosis); periorbital oedema; loss
of full-range movement.

4 Chapter€1╇ Thyroid

Physiology

• Biosynthesis of thyroid hormones requires iodine as substrate.
Iodine is actively transported via sodium/iodide symporters (NIS)
into follicular thyrocytes where it is organified onto tyrosyl residues
in thyroglobulin first to produce monoiodotyrosine (MIT) and then
diiodotyrosine (DIT). Thyroid peroxidase (TPO) then links two DITs
(iTtTanolmahhereefogoxuettrthhnlrmyayytsgrritnoolhoaiinteddfhdTtesiusw3ellctaaoihvrrn-eeerdtrtiinoesrasgsnenuelv2dyede0srsk%ssobitderuyonurTftecch3ctyeÂeu€is(Âr€ror)ccT.efuo€3TlT)na.44vt.,ienargnsidTo3nM; toIhTfeTarn4edtmoDaTiInT3dbteyor form small
• is generated
• deiodinases

Synthesis of the thyroid hormones can be inhibited by a variety of agents
termed goitrogens.
• Perchlorate and thiocyanate inhibit iodide transport.
• Thioureas (e.g. carbimazole and propylthiouracil) and mercaptoimidazole

inhibit the initial oxidation of iodide and coupling of iodothyronines.
• In large doses, iodine itself blocks organic binding and coupling

reactions.
• Lithium has several inhibitory effects on intrathyroidal iodine

metabolism.

bInotuhnedbinlododo, rTd4earnodf Taf3fianrietyatlmo othsytreonidti-rbeilnydbinogungdlotboulpinla(sTmBaGp)r,otrteaninsst.hTyr4eis-
tin (TTR), and albumin. OT3nilsy bound 10–20 times less avidly by TBG and
not significantly by TTR. the free or unbound hormone is available to
tissues. The metabolic state correlates more closely with the free than the
total hormone concentration in the plasma. The relatively weak binding of
Tm3aariczceosutnhtossfeosrtaittsesmaosrseocriaapteidd onset and offset of action. Table 1.1 sum-
with p alterations in the concentration of
TBG. When there is primarily an alteration in the concentration of thyroid
hormones, the concentration of TBG changes little (Table€1.2).
The concentration of free hormones does not necessarily vary directly
with that of the total hormones, neo.gr.mwahl il(ebthEentdootaclriTn4olleovgeyl rises in preg-
nancy, the free T4 level remains in pregnancy,
p. 426).
The levels of thyroid hormone in the blood are tightly controlled by
feedback mechanisms involved in the hypothalamo–pituitary–thyroid
(HPT) axis (see Fig.€1.1).
• TSH secreted by the pituitary stimulates the thyroid to secrete principally
• ThTo44 raamnnddonaTles3soairTneh3.bibToiRtuHtnhdesttisomynTutlBahtGees,sisTthTaenRds,yarnnetdlheeaasslibesuaomnfdiTns.ReTHchreeatnirodenÂm€ToSafHinTi.nSgHf.ree
•• TiTann44adciastnsicduvoelpTn€rh3vTaeat3rr.ete.eEmdnepzteyarmbipoehliieznredadullcyinetrotsh,teshuleicvhmeraesbtaypbhcoeolinncojaubllgyaartabicoittnaivlw,eciTtahr3 bogalrumtchauzereopninatee,
and phenytoin, increase the metabolic clearance of the hormones
without d the proportion of free hormone in the€blood.

Physiology 5

Table€1.1╇ Disordered thyroid hormone–protein interactions

Serum total T4 and T3 Free T4 and T3

Primary abnormality in TBG

i Concentration i Normal

d Concentration d Normal

Primary disorder of thyroid function

Hyperthyroidism i i

Hypothyroidism d d

Table€1.2╇ Circumstances associated with altered
concentration€of€TBG

i TBG d TBG

Pregnancy Androgens

Newborn state Large doses of glucocorticoids;
Cushing’s syndrome

OCP and other sources of oestrogens Chronic liver disease

Tamoxifen Severe systemic illness

Hepatitis A; chronic active hepatitis Active acromegaly

Biliary cirrhosis Nephrotic syndrome

Acute intermittent porphyria Genetically determined

Genetically determined Drugs, e.g. phenytoin (see also
Table 1.4, p.€11)

Hypothalamus

TRH Other tissues

Anterior
pituitary

TSH

I I T4 and T3 T4 and T3 + TBG TBG˙T4
TBG˙T3

Fig.€1.1╇ Regulation of thyroid function. Solid arrows indicate stimulation; broken
arrow indicates inhibitory influence. TRH, thyrotropin-releasing hormone; TSH,
thyroid-stimulating hormone; T4, thyroxine; T3, tri-iodothyronine; I, iodine; TBG,
thyroid-binding globulin.

6 Chapter€1╇ Thyroid

Molecular action of thyroid
hormone

• Tho3 rismtohneearceticveepftoorrms (oTfRtsh)yirnoitdarhgoetrmceolnl enuacnldei binds to thyroid
to initiate a range
of physiological effects, including cellular differentiation, post-natal
development, and metabolic homeostasis. The actions of thyroid
hormone are mediated by two genes (TRα, TRB), which encode
three nuclear receptor subtypes with differing tissue expression
(TRα1:€central nervous system, cardiac and skeletal muscle;
TRB1:€liver and kidney; TRB2:€pituitary and hypothalamus).
• bByotmhoTn4oacnadrbTo3xeynlatteer the cell via active transport mediated
transporter-8 and other proteins. Three
iodothyronine deiodinases (D1–3) regulate gTe3naevraailllaybciloitnystidoetraerdget
cells. The D1 enzyme in kidney and liver is
to be responsible for the production of the majority of circulating
tTh3e. Although fseeerdubmacTk3accotinocnesnotrfatthioenHs ParTe maintained constant by
negative axis, intracellular thyroid
status may vary as a result of differential action of deiodinases. In
tttDiihnrhhhor3eeeetrhmvemnheenuyoerzpgcsntyeloiaeebmntbalheTyoerarÂs3l€iTlainattitRenaomiosc.Tuttnrhis3vTeoata3fatnnearTdugns3ced,pTltewi4Ttcuuha2es.inetlTlaardsnerhyrTdaue,s3sgu5,,5ul’rt-t’el-hdiamdseetueeiaolrittoetdeihndlliaeygnintaidiaavntvteeioiattoahneilncareomtbbipfviyliriinTttoteiy4ehdbsoetuhyfcoDettDfih3osD2eanet2raunoecarzfstanyiutvmdileotesn of
• TRs belong to the nuclear hormone receptor superfamily and function
as ligand-inducible transcription factors. They are expressed in virtually
all tissues and involved in many physiological processes in response
thoorTm3 obninedrinegs.pToRnsαe and TRB receptors bind to specific DNA thyroid
elements (TREs) located in the promoter regions
• UofnTlig3-arnedspeodnTsRive(utnarogcectugpeiendesTaRn,dAmpoeTdRia)teinthhiebiatsctbioasnasl€otrfÂa€Tn3s.cription
opthrfeoTtl3eigtinaansr,gdeleetdagdTeinRngeustnobdyreerinpgtroeeerssascicotoinnngofofprgrmeefnaeterioetnnraatinlascllchyraiwpntgitieohnac.noUd-rpreoepvnreeTrss3seobsrinthdeing,
histone deacetylation associated with basal repression. Subsequent
recruitment of a large transcription factor complex known as
vitamin D receptor interacting protein/TR-associated protein (DRIP/
TRAP) leads to binding and stabilization of RNA polymerase II and
hormone-dependent activation of transcription.
• The roles of TRα and TRB have been shown to be tissue-specific.
Fboornee,xaanmdpilnet,eTsRtinαalmdeedviealtoepsmimepnot ratnadntcTo3ntarcotilos nbsasdaulrhinegarhteraartte, and
thermoregulation in adults, whilst TRB mtheedHiaPteTs€aTx3isa.ction in the liver
and is responsible for the regulation of

Molecular action of thyroid hormone 7

Abnormalities of development
• Remnants of the thyroglossal duct may be found in any position along

the course of the tract of its descent:
• In the tongue, it is referred to as ‘lingual thyroid’.
• Thyroglossal cysts may be visible as midline swellings in the€neck.
• Thyroglossal fistula develops as an opening in the middle of

the€neck.
• As thyroglossal nodules€or
• The ‘pyramidal lobe’, a structure contiguous with the thyroid

isthmus which extends upwards.
• The gland can descend too far down to reach the anterior

mediastinum.
• Congenital hypothyroidism may result from failure of the thyroid

to develop (agenesis). More commonly, however, congenital
hypothyroidism reflects enzyme defects impairing hormone synthesis.

Further reading

Williams GR, Bassett JH (2011). Deiodinases:€the balance of thyroid hormone:€local control of
thyroid hormone action:€role of type 2 deiodinase. J Endocrinol 209, 261–72.

8 Chapter€1╇ Thyroid

Tests of hormone concentration

• Highly specific and sensitive chemiluminescent and radioimmunoassays
caorencuesnetdrattoiomnseaussuuraellysecrourmreTla4teanbdetTt3ercownicthentthreatmioentsa.bForleice hormone
state than
do total hormone concentrations because they are unaffected by
changes in binding protein concentration or affinity.
• See UK guidelines for the use of thyroid function tests. Association
for Clinical Biochemistry, British Thyroid Association, British
Thyroid Foundation (M http://www.british-thyroid-association.org/
info-for-patients/Docs/TFT_guideline_final_version_July_2006.pdf).

Tests of hormone concentration 9

10 Chapter€1╇ Thyroid

Tests of homeostatic control

(See Table€1.3.)
• Serum TSH concentration is used as first line in the diagnosis of p

hypothyroidism and hyperthyroidism. The test is misleading in patients
with s thyroid dysfunction due to hypothalamic/pituitary disease
(b p. 127).
• The TRH stimulation test, which can be used to assess the functional
state of the TSH secretory mechanism, is now rarely used to diagnose
p thyroid disease since it has been superseded by sensitive TSH
assays. It is of limited use; its main use is in the differential diagnosis
of elevated TSH in the setting of elevated thyroid hormone levels and
in the differential diagnosis of resistance to thyroid hormone and a
TSH-secreting pituitary adenoma (see Box€1.1).
In interpreting results of TFTs, the effects of drugs that the patient might
be on should be borne in mind. Table 1.4 lists the influence of drugs on
TFTs. Table 1.5 sets out some examples of atypical thyroid function€tests.

Box 1.1╇ Thyroid hormone resistance (RTH) (b see also
p.€50)

• Rare syndrome characterized by reduced responsiveness to elevated
circulating TleSvHelsreosfpforenesivTe4naensds tfore€Te RTH3, .non-suppressed serum TSH,
and intact
• Clinical features, apart from goitre, are usually absent but may
include short stature, hyperactivity, attention deficits, learning
disability, and goitre.
• Associated with THB gene defects, and identification by gene
sequencing can confirm diagnosis in€85%.
• Differential diagnosis includes TSH-secreting pituitary tumour
(b p. 180).
• Most cases require no treatment. If needed, it is usually B-adrenergic
blockers to ameliorate some of the tissue effects of raised thyroid
hormone levels.

Tests of homeostatic control 11

Table€1.3╇ Thyroid hormone concentrations in various thyroid
abnormalities

Condition TSH Free T4 Free T3
p hyperthyroidism Undetectable ii i

T3 toxicosis Undetectable Normal ii
Subclinical hyperthyroidism d Normal Normal

s hyperthyroidism (TSHoma) i or normal i i

Thyroid hormone resistance i or normal i i

p hypothyroidism i d d or
normal

Subclinical hypothyroidism i Normal Normal

2° hypothyroidism d or normal d d or
normal

Table€1.4╇ Influence of drugs on thyroid function€tests

Metabolic i d
process

TSH secretion Amiodarone (transiently; Glucocorticoids,
rTe4lesaysnethesis/ becomes normal after dopamine agonists,
2–3€months) phenytoin, dopamine,
Sertraline octreotide, paroxetine
St John’s wort (Hypericum) Iodide, amiodarone,
interferon alfa, lithium,
Iodide, amiodarone, interferon α, sunitinib
lithium

Binding proteins Oestrogen, clofibrate, heroin Glucocorticoids,
androgens, phenytoin,
carbamazepine

T4 metabolism Anticonvulsants, rifampicin Salicylates, furosemide,
sTe4r/Tum3 binding in Heparin mefenamic acid

12 Chapter€1╇ Thyroid

Table€1.5╇ Atypical thyroid function€tests1

Test Possible cause

Suppressed TSH and normal tTh3yrtootxoicxoicsoissi(sa)pproximately 5% of
free T4
Suppressed TSH and normal Subclinical hyperthyroidism
free T4 and free T3 Recovery from thyrotoxicosis
Excess thyroxine replacement
Non-thyroidal illness

Detectable TSH and elevated TSH-secreting pituitary tumour
free T4 and free T3 Thyroid hormone resistance
Heterophile antibodies, leading to spurious
measurements of free T4 and free T3
Thyroxine replacement therapy (including
poor compliance)

nEolervmataeldfrfereeeTT3,4naonrdmlaolwTSH Amiodarone

Suppressed or normal TSH Non-thyroidal illness
and low normal free T4 and Central hypothyroidism
free T3 Isolated TSH deficiency

Reference

1. Gurnell M, Halsall DJ, Chatterjee VK (2011). What should be done when thyroid function tests
do not make sense? Clin Endocrinol (Oxf) 74,€673–8.

Tests of homeostatic control 13

14 Chapter€1╇ Thyroid

Rare genetic disorders of thyroid
hormone metabolism1

• An X-linked disorder of childhood onset with psychomotor
retardation, including speech and developmental delay and spastic
quadriplegia, caused by defects in the MCT8 gene encoding a
membrane transporter. Male patients have elevated FT3, low FT4, and
normal TSH levels.
• The deiodinase enzymes are part of a larger family of 25 human
proteins containing selenocysteine. A€multisystem selenoprotein
deficiency disorder has been identified, manifested by growth
retardation in childhood and male infertility, skeletal myopathy,
photosensitivity, and hearing loss in adults. Thyroid function tests show
Dra2iseddefFicTie4,nncoy.rmal/low FT3, and normal TSH levels due to functional

1Reviewed by Refetoff and Dumitrescu (2007) Syndromes of reduced sensitivity to thyroid hor-
mone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin
Endocrinol Metab 21, 277–305.

Antibody€screen 15

Antibody€screen

High titres of antithyroid peroxidase (anti-TPO) antibodies and/or antithy-
roglobulin antibodies are found in patients with autoimmune thyroid dis-
ease (Hashimoto’s thyroiditis, Graves’s disease, and sometimes euthyroid
individuals). See Table€1.6.

Screening for thyroid disease1
The following categories of patients should be screened for thyroid
disease:
• Patients with atrial fibrillation or hyperlipidaemia.
• Periodic (6-monthly) assessments in patients receiving amiodarone and

lithium.
• Annual check of thyroid function in the annual review of diabetic

patients.
• ♀ with type 1 diabetes in the first trimester of pregnancy and

post-delivery (because of the 3-fold increase in incidence of
post-partum thyroid dysfunction in such patients) (b p. 432).
• ♀ with past history of post-partum thyroiditis.
• Annual check of thyroid function in people with Down’s syndrome,
Turner’s syndrome, and autoimmune Addison’s disease, in view of the
high prevalence of hypothyroidism in such patients.
• ♀ with thyroid autoantibodies—8x risk of developing hypothyroidism
over 20€years compared to antibody€–ve controls.
• ♀ with thyroid autoantibodies and isolated elevated TSH—38x
risk of developing hypothyroidism, with 4% annual risk of overt
hypothyroidism.
• Maternal thyroid antibodies are associated with miscarriage and
preterm€birth2.

Table€1.6╇ Antithyroid antibodies and thyroid disease

Condition Anti-TPO Antithyroglobulin TSH receptor
antibody

Graves’s disease 70–80% 30–50% 70–100% (stimulating)

Autoimmune 95% 60% 10–20% (blocking)
hypothyroidism

NB TSH receptor antibodies may be stimulatory or inhibitory. Heterophile antibodies present
in patient sera may cause abnormal interference, causing abnormally low or high values of free
T4 and free T3, and can be removed with absorption€tubes.

Reference

1. Tunbridge WM, Vanderpump MP (2000). Population screening for autoimmune thyroid disease.
Endocrinol Metab Clin N Am 29, 239–53.

2. Thangaratinam S, et€al. (2011). Association between thyroid autoantibodies and miscarriage and
preterm birth:€meta-analysis of evidence. BMJ 342,€1065.

16 Chapter€1╇ Thyroid

Scintiscanning

Permits localization of sites of accumulation of radioiodine or sodium
pertechnetate (99mTc), which gives information about the activity of the
iodine trap (see Table 1.7). This is useful:
• To define areas of i or d function within the thyroid (see Table 1.8)

which occasionally helps in cases of uncertainty as to the cause of the
thyrotoxicosis.
• To distinguish between Graves’s disease and a thyroiditis (autoimmune
or viral—de Quervain’s thyroiditis).
• To detect retrosternal goitre.
• To detect ectopic thyroid tissue.
The scan may be altered€by:
• Agents which influence thyroid uptake, including intake of high-iodine
foods and supplements, such as kelp (seaweed).
• Drugs containing iodine, such as amiodarone.
• Recent use of radiographic contrast dyes can potentially interfere with
the interpretation of the€scan.

Table€1.7╇ Radioisotope€scans

123Iodine 99Technetium pertechnetate
Short
Half-life Short Maximum thyroid uptake
within 30min of administration.
Advantage Low emission of radiation Can be used in breastfeeding
Has higher energy women (discontinue feeding
photons. Hence useful for for 24h)
imaging a toxic goitre with
a substernal component Technetium is only trapped
by the thyroid without being
Disadvantage organified
Rapid scanning
Use Functional assessment of
the thyroid

Scintiscanning 17

Table€1.8╇ Radionuclide scanning (scintigram) in thyroid disease

Condition Scan appearance

Graves’s hyperthyroidism Enlarged gland
Homogeneous radionucleotide uptake

Thyroiditis (e.g. de Quervain’s) Low or absent uptake

Toxic nodule A solitary area of high uptake

Thyrotoxicosis factitia Depressed thyroid uptake

Thyroid cancer Successful 131I uptake by tumour tissue
requires an adequate level of TSH,
achieved by giving recombinant TSH
1in0jedcatiyosnboerfosrteopscpainngniTng3 replacement

18 Chapter€1╇ Thyroid

Ultrasound (US) scanning

Provides an accurate indication of thyroid size and is useful for differen-
tiating cystic nodules from solid ones but cannot be used to distinguish
between benign and malignant disease. There are several ultrasonographic
findings that are suspicious for thyroid cancer (hypoechoic, microcalcifica-
tions, irregular margins, central vascularity, incomplete halo). The predic-
tive value of these characteristics varies widely, and they can be used to
select nodules for fine needle aspiration (FNA) biopsy.
• Microcalcification within nodules favours the diagnosis of malignancy;

microcalcifications <2mm in diameter are observed in 760% of
malignant nodules but in <2% of benign lesions.
• Calcification is a prominent feature of medullary carcinoma of the
thyroid.
• It can detect whether a nodule is solitary or part of a multinodular
process.
• Sequential scanning can be employed to assess changes in size of
thyroid over€time.
NB Neither scintigraphy nor US is routinely indicated in a patient with
goitre.

Ultrasound (US) scanning 19

20 Chapter€1╇ Thyroid

Fine needle aspiration
cytology€(FNAC)

• FNAC is now considered the most accurate test for the diagnosis
of thyroid nodules. It is performed in an outpatient setting. One to
two aspirations are carried out at different sites for each nodule.
Cytologic findings are satisfactory or diagnostic in approximately 85% of
specimens and non-diagnostic in the remainder.

• In experienced hands, FNAC is an excellent diagnostic technique, as
shown in Table€1.9.

• Non-palpable nodules (discovered incidentally during other imaging
procedures) have the same risk of malignancy as palpable nodules
of similar size. US-guided FNAC can be performed for non-palpable
nodules and for nodules that are technically difficult to aspirate using
palpation methods alone, such as predominantly cystic or posteriorly
located nodules. In patients with large nodules (>4cm), US-guided
FNAC directed at several areas within the nodule may reduce the risk
of a false€–ve biopsy.

• Repeat FNAC after 3–6€months further reduces the proportion of
false€–ves.

• It is impossible to differentiate between benign and malignant follicular
neoplasm using FNAC. Therefore, surgical excision of a follicular
neoplasm is always indicated (b p. 99).

• See Table 1.10 for diagnostic categories from€FNAC.

Table€1.9╇ Diagnostic features of€FNAC

Feature Range (%) Mean value (%)
95
Accuracy 85–100 92
83
Specificity 72–100 5

Sensitivity 65–98

False€–ve 1–11

Fine needle aspiration cytology€(FNAC) 21

Table€1.10╇ Diagnostic categories from€FNAC

Category Action

Thy 1 Non-diagnostic. Repeat sampling, using US if
Inadequate necessary

Thy 2 Non-neoplastic Two samples, 3–6€months apart,
showing benign appearances are
indicated to exclude neoplasia. If
rapid growth/pressure effects/high
risk, diagnostic lobectomy may be
indicated

Thy 3 (i) Follicular lesions Lobectomy, with completion
thyroidectomy if malignant (up to
20% risk of malignancy)

(ii) Other suspicious Discussion at thyroid cancer MDT
findings

Thy 4 Suspicious of malignancy, Surgical excision for differentiated
e.g. papillary, medullary, tumour (80% risk of malignancy)
or anaplastic carcinoma/
lymphoma

Thy 5 Diagnosis of malignancy Surgical excision for differentiated
thyroid cancer (>95% risk of
malignancy). Radiotherapy/
chemotherapy for anaplastic thyroid
cancer, lymphoma/metastases

22 Chapter€1╇ Thyroid

Computed tomography€(CT)

• CT is useful in the evaluation of retrosternal and retrotracheal
extension of an enlarged thyroid.

• Compression of the trachea and displacement of the major vessels can
be identified with CT of the superior mediastinum.

• It can demonstrate the extent of intrathoracic extension of thyroid
malignancy and infiltration of adjacent structures, such as the carotid
artery, internal jugular vein, trachea, oesophagus, and regional
lymph€nodes.