oxford handook of endocrinology and diabetes 3rd ed

OXFORD MEDICAL PUBLICATIONSOxford Handbook of Endocrinology and Diabetes... Oxford Handbook for the Foundation Programme 3eOxford Handbook of Acute Medicine 3e Oxford Handbook of Anaesth

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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 Centre for Diabetes, Endocrinology and

Metabolism (OCDEM), Oxford, UK

1

Great Clarendon Street, Oxford, OX2 6DP,

United Kingdom

Oxford University Press is a department of the University of Oxford

It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries

© 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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stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press,

or as expressly permitted by law, or under terms agreed with the appropriate reprographics rights organization Enquiries concerning reproduction

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and you must impose this same condition on any acquirer

Published in the United States of America by Oxford University Press

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Library of Congress Control Number: 2013945298

ISBN 978–0–19–964443–8

Printed in China by

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Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse

or misapplication of material in this work Except where otherwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breast-feeding.

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for information only Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

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 obesity … where 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 sicians interested in hormones and related diseases, and in medicine in general

phy-Philippe BouchardPresident, European Society of EndocrinologyMember of the National Academy of Medicine

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 ants that it was essential to have it in outpatients We hope that the same will be true of the second edition

consult-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 WassHelen E.Turner2009

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 vided expertise and willing collaboration with our project As always, we welcome comments which may enhance the next edition

pro-John Wass and Katharine Owen

2013

Preface

Contributors x

Contributors to the second edition xii

Symbols and Abbreviations xiii

11 Endocrinology and ageing 613

12 Endocrinology aspects of other clinical

Ramzi Ajjan

Senior Lecturer and Consultant

in Diabetes and Endocrinology,

Division of Cardiovascular and

Diabetes Research, The LIGHT

Laboratories, University of

Leeds, UK

Asif Ali

Consultant Physician (Diabetes

and Endocrinology), Department

of Medicine, Milton Keynes

Hospital, UK

Wiebke Arlt

Professor of Medicine and Head

of the Centre for Endocrinology,

Diabetes and Metabolism,

University of Birmingham, UK

Rudy Bilous

Professor of Clinical Medicine,

Academic Centre, James

Cook University Hospital,

Middlesbrough, UK

Pratik Choudhary

Senior Lecturer/Consultant,

Department of Diabetes and

Nutritional Sciences, The School

of Medicine, Kings College

London, UK

Peter Clayton

Professor of Child Health &

Paediatric Endocrinology;

Director, NIHR Greater

Manchester, Lancashire & South

Cumbria Medicines for Children

Research Network, University of

Manchester, UK

Gerard Conway

Clinical Lead in Endocrinology

and Diabetes, Department of

Endocrinology, University College

London Hospitals, UK

Ketan Dhatariya

Consultant in Diabetes, Endocrinology and General Medicine, Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK

Julie Edge

Consultant in Paediatric Diabetes, Oxford Children’s Hospital, John Radcliffe Hospital, Oxford, UK

Nick Finer

Consultant Metabolic Physician, Centre for Weight Loss, Metabolic and Endocrine Surgery, University College London Hospitals, UK

Neil Gittoes

Consultant Endocrinologist and Associate Medical Director, Queen Elizabeth Hospital, Birmingham, UK

Steve Gough

Professor of Diabetes and Consultant Physician, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Oxford, UK

Maggie Hammersley

Consultant Physician and Senior Clinical Lecturer, John Radcliffe Hospital, Oxford, UK

Niki Karavitaki

Consultant Endocrinologist, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Oxford, UK

Contributors

CONTRIBUTORS

Fredrik Karpe

Professor of Metabolic Medicine,

Honorary Consultant Physician,

Oxford Centre for Diabetes,

Endocrinology and Metabolism

(OCDEM), Churchill Hospital,

Consultant Chemical Pathologist,

Epsom and St Helier University

Hospitals NHS Trust, Surrey, UK

Helen Murphy

Senior Research Associate

Honorary Consultant, Department

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

Peter Scanlon

Consultant Ophthalmologist, Gloucestershire and Oxford Eye Units; Medical Tutor and Senior Research Fellow, Harris Manchester College, University

of Oxford; Visiting Professor

of Medical Ophthalmology, University of Bedfordshire, and Hertfordshire Postgraduate Medical School, UK

Gary Tan

Consultant Diabetologist, Oxford Centre for Diabetes, Endocrinology & Metabolism (OCDEM), Churchill Hospital, UK

Solomon Tesfaye

Professor of Diabetic Medicine, Royal Hallamshire Hospital, Sheffield, UK

Gaya Thanabalasingham

Specialist Registrar, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Oxford, UK

Mark Vanderpump

Consultant Physician and Honorary Senior Lecturer in Diabetes and Endocrinology, Royal Free Hampstead NHS Trust, UK

Contributors to the

second edition

Julian Barth

Consultant in Chemical Pathology

and Metabolic Medicine, Leeds

General Infirmary, Leeds, UK

Karin Bradley

Consultant Physician and

Endocrinologist, Bristol Royal

Infirmary and Honorary Senior

Clinical Lecturer, University of

Bristol, Bristol, UK

Emma Duncan

Consultant Endocrinologist,

Princess Alexandra Hospital

Senior Lecturer, University of

Queensland, Austalia;

Postdoctoral Research Fellow, UQ

Diamantina Institute for Cancer,

Immunology and Metabolic

Consultant Endocrinologist, Royal

Berkshire Hospital, Reading, UK

Kevin Shotliff

Consultant Physician and Diabetologist, Beta Cell Diabetes Centre, Chelsea and Westminster Hospital, London, UK

Sara Suliman

Specialist Registrar in Diabetes, Endocrinology and Metabolism, and Diabetes UK; Clinical Research Fellow, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Oxford, UK

John Wong

Consultant Chemical Pathologist, Kingston Hospital, Surrey, UK

≤ less than or equal to

≥ greater than or equal to

ACA adrenocortical adenoma

ACC adrenocortical carcinoma

ACE angiotensin-converting enzyme

ACEI angiotensin-converting enzyme inhibitor

ACR albumin:creatinine ratio

ACTH adrenocorticotrophic hormone

ADA American Diabetes Association

ADH antidiuretic hormone

ADHH autosomal dominant hypocalcaemic hypercalciuria

Symbols and

Abbreviations

aFP alpha fetoprotein

AGE advanced glycation end-product

AGHDA adult growth hormone deficiency assessmentAHC adrenal hypoplasia congenita

AI adrenal insufficiency

AIDS acquired immunodeficiency syndrome

AIH amiodarone-induced hypothyroidism

AIMAH ACTH-independent macronodular adrenal hyperplasiaAIT 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

ANCA anti-neutrophil cytoplasmic antibody

APS autoimmune polyglandular syndrome

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

BMD bone mineral density

CCF congestive cardiac failure

CEA carcinoembryonic antigen

SYMBOLS AND ABBREVIATIONS

CF cystic fibrosis

CFRD CF-related diabetes

CGM continuous glucose monitoring

cGMP cyclic guanyl monophosphate

cGy centigray

CHD coronary heart disease

CHO carbohydrate

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

CSII continuous subcutaneous insulin infusion

CSMO ‘clinically significant’ diabetic macular oedema

CSW cerebral salt wasting

DCCT Diabetes Control and Complications Trial

DCT distal convoluted tubule

DI diabetes insipidus

DIT diiodotyrosine

DKA diabetic ketoacidosis

DKD diabetic kidney disease

DSN diabetes specialist nurse

DSD disorders of sexual differentiation; disorders of sex

developmentDTC 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

EMA European Medicines Agency

ENaC epithelial sodium channel

ENETS European Neuroendocrine Tumour SocietyENSAT European Network for the Study of Adrenal TumoursENT ear, nose, and throat

EOSS Edmonton Obesity Staging System

ERT (o)estrogen replacement therapy

ESR erythrocyte sedimentation rate

ESRD end-stage renal disease

ESRF end-stage renal failure

SYMBOLS AND ABBREVIATIONS

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

GDM gestational diabetes mellitus

GDP guanosine diphosphate

GEP gastroenteropancreatic

GFR glomerular filtration rate

GGT gamma glutamyl transferase

GHD growth hormone deficiency

GHDC growth hormone day curve

GHRH growth hormone-releasing hormone

GI gastrointestinal; glycaemic index

GIFT gamete intrafallopian transfer

GIP gastric intestinal polypeptide

GTN glyceryl trinitrate

GTP guanyl triphosphate

GTT glucose tolerance test

GWAS genome-wide association studies

HbA1c glycosylated haemoglobin

hCG human chorionic gonadotrophin

HCO3– bicarbonate ion

HDL-C high-density lipoprotein cholesterolHDU high dependency unit

HFEA Human Fertilisation and Embryology Act

HH hypogonadotrophic hypogonadismHHS hyperglycaemic hyperosmolar stateHIV human immunodeficiency virus

HLA human leukocyte antigen

hMG human menopausal gonadotrophinHMG CoA 3-hydroxy-3-methylglutaryl coenzyme AHNF 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

HRT hormone replacement therapy

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

IVII intravenous insulin infusion

kcal kilocalorie

KCl potassium chloride

kDa kilodalton

MAOI monoamine oxidase inhibitor

MAPK mitogen-activated protein kinase

SYMBOLS AND ABBREVIATIONS

mOsm milliosmole

MPH mid-parental height

MRI magnetic resonance imaging

mRNA messenger ribonucleic acid

MRSA meticillin-resistant Staphylococcus aureus

MSH melanocyte-stimulating hormone

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

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

NSAID non-steroidal anti-inflammatory drug

NSC National Screening Committee

NSF National Service Framework

NVD new vessels on disc

NVE new vessels elsewhere

OA osteoarthritis

OCP oral contraceptive pill

od omne in die (once daily)

OD overdose

OGTT oral glucose tolerance test

OHA oral hypoglycaemic agent

OHSS ovarian hyperstimulation syndrome

PAI plasminogen activator inhibitor

PAK pancreas after kidney

PAL physical activity level

PAR-Q physical activity readiness questionnairePBC primary biliary cirrhosis

PCOS polycystic ovary syndrome

PDE phosphodiesterase

PDR proliferative diabetic retinopathy

PEG polyethylene glycol

PET positron emission tomography

pg picogram

PHP primary hyperparathyroidism

PID pelvic inflammatory disease

PIH pregnancy-induced hypertensionPKA protein kinase A

p.m post meridiem (after noon)

POF premature ovarian failure

POI premature ovarian insufficiency

POMC pro-opiomelanocortin

POP progesterone-only pill

PPI proton pump inhibitor

PPNAD primary pigmented nodular adrenal diseasePRA plasma renin activity

PRH postprandial reactive hypoglycaemiaPRL prolactin

PRRT peptide receptor radioligand therapy

SYMBOLS AND ABBREVIATIONS

PRTH pituitary resistance to thyroid hormone

PSA prostate-specific antigen

PTA pancreas transplant alone

PTHrP parathyroid hormone-related peptide

PTTG pituitary tumour transforming gene

PTU propylthiouracil

PUD peptic ulcer disease

PVD peripheral vascular disease

QCT quantitative computed tomography

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

SERM selective (o)estrogen receptor modulator

SGA small for gestational age

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

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

TENS transcutaneous electrical nerve stimulationTFT thyroid function test

Tg thyroglobulin

TG triglyceride

TGF transforming growth factor

TgAb thyroglobulin antibody

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 antibodiesTTR transthyretin

U unit

U&E urea and electrolytes

UFC urinary free cortisol

UKPDS United Kingdom Prospective Diabetes Study

VEGF vascular endothelial growth factor

VEGFR vascular endothelial growth factor receptor

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

WDHA watery diarrhoea, hypokalaemia, acidosis

WHI Women’s Health Initiative

WHO World Health Organization

ZE Zollinger–Ellison (syndrome)

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

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

Chapter 1

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 tracheal fascia, which anchors it to the trachea, so that the thyroid moves

pre-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 sequences of T4 and T3 are synthesized and stored as a component of thyroglobulin

• 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

• T4 from the fetal thyroid is the major thyroid hormone available to the fetus The fetal pituitary-thyroid axis is a functional unit, distinct from 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

• 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

• 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

to form the two-ringed structure T4, and MIT and DIT to form small amounts of T3 and reverse T3 (rT3)

• The thyroid is the only source of T4

• The thyroid secretes 20% of circulating T3; the remainder is generated

in extraglandular tissues by the conversion of T4 to T3 by deiodinases (largely in the liver and kidneys)

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

In the blood, T4 and T3 are almost entirely bound to plasma proteins T4 is bound in d order of affinity to thyroid-binding globulin (TBG), transthyre-tin (TTR), and albumin T3 is bound 10–20 times less avidly by TBG and not significantly by TTR Only 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

T3 accounts for its more rapid onset and offset of action Table 1.1 marizes those states associated 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)

sum-The concentration of free hormones does not necessarily vary directly with that of the total hormones, e.g while the total T4 level rises in preg-nancy, the free T4 level remains normal (b Endocrinology 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

T4 and also T3 TRH stimulates the synthesis and secretion of TSH

• T4 and T3 are bound to TBG, TTR, and albumin The remaining free hormones inhibit the synthesis and release of TRH and TSH

• T4 is converted peripherally to the metabolically active T3 or the inactive rT3

• T4 and T3 are metabolized in the liver by conjugation with glucuronate and sulphate Enzyme inducers, such as phenobarbital, carbamazepine, 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 T 4 and T 3 Free T 4 and T 3

Hepatitis A; chronic active hepatitis Active acromegaly

Acute intermittent porphyria Genetically determined

Genetically determined Drugs, e.g phenytoin (see also

Molecular action of thyroid

TRB1: liver and kidney; TRB2: pituitary and hypothalamus)

• Both T4 and T3 enter the cell via active transport mediated

by monocarboxylate transporter-8 and other proteins Three iodothyronine deiodinases (D1–3) regulate T3 availability to target cells The D1 enzyme in kidney and liver is generally considered

to be responsible for the production of the majority of circulating

T3 Although serum T3 concentrations are maintained constant by the negative feedback actions of the HPT axis, intracellular thyroid status may vary as a result of differential action of deiodinases In the hypothalamus and pituitary, 5’-deiodination of T4 by D2 results

in the generation of T3, whereas 5’-deiodination by the D3 enzyme irreversibly inactivates T4 and T3, resulting in the production of the metabolites rT3 and T2 Thus, the relative activities of D2 and D3 enzymes in T3 target cells regulate the availability of the active hormone T3 to the nucleus and ultimately determine the saturation of the nuclear TR

• 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

to T3 binding TRα and TRB receptors bind to specific DNA thyroid hormone response elements (TREs) located in the promoter regions

of T3-responsive target genes and mediate the actions of T3

• Unliganded TR (unoccupied TR, ApoTR) inhibits basal transcription

of T3 target genes by interacting preferentially with co-repressor proteins, leading to repression of gene transcription Upon T3 binding, the liganded TR undergoes conformational change and reverses the 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 For example, TRα mediates important T3 actions during heart, bone, and intestinal development and controls basal heart rate and thermoregulation in adults, whilst TRB mediates T3 action in the liver and is responsible for the regulation of the HPT axis

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.

Tests of hormone concentration

• Highly specific and sensitive chemiluminescent and radioimmunoassays are used to measure serum T4 and T3 concentrations Free hormone concentrations usually correlate better with the metabolic 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

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 levels of free T4 and free T3, non-suppressed serum TSH, and intact TSH responsiveness to TRH

• 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

TSH secretion Amiodarone (transiently;

becomes normal after

2–3 months)

Sertraline

St John’s wort (Hypericum)

Glucocorticoids, dopamine agonists, phenytoin, dopamine, octreotide, paroxetine

T4 synthesis/

release Iodide, amiodarone, interferon α,

lithium Iodide, amiodarone, interferon alfa, lithium,

sunitinib Binding proteins Oestrogen, clofibrate, heroin Glucocorticoids,

androgens, phenytoin, carbamazepine

T4 metabolism Anticonvulsants, rifampicin

T4/T3 binding in

serum Heparin Salicylates, furosemide, mefenamic acid

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.

Table 1.5 Atypical thyroid function tests1

Suppressed TSH and normal

free T4 Tthyrotoxicosis)3 toxicosis (approximately 5% of

Suppressed TSH and normal

free T4 and free T3 Subclinical hyperthyroidismRecovery from thyrotoxicosis

Excess thyroxine replacement Non-thyroidal illness Detectable TSH and elevated

free T4 and free T3 TSH-secreting pituitary tumour Thyroid hormone resistance

Heterophile antibodies, leading to spurious measurements of free T4 and free T3Thyroxine replacement therapy (including poor compliance)

Elevated free T4 and low

normal free T3, normal TSH Amiodarone

Suppressed or normal TSH

and low normal free T4 and

free T3

Non-thyroidal illness Central hypothyroidism Isolated TSH deficiency