Oxford Handbook of Endocrinology & Diabetes 4th ed 2022 PDF

THE INDISPENSABLE RESOURCE FOR CLINICAL EXCELLENCE OXFORD HANDBOOK OF ENDOCRINOLOGY AND DIABETES EDITED BY Katharine Owen | Helen Turner John Wass A unique pocket reference, ideal for the specialist trainee, foundation doctors, and consultants Provides practical guidance on investigations a...

THE INDISPENSABLE RESOURCE FOR CLINICAL EXCELLENCE OXFORD HANDBOOK OF ENDOCRINOLOGY AND DIABETES EDITED BY Katharine Owen | Helen Turner John Wass A unique pocket reference, ideal for the specialist trainee, foundation doctors, and consultants Provides practical guidance on investigations and management of both common and rare conditions in a concise format Features new chapters transition in endocrinology and diabetes, practical nursing considerations, and genetics Contains appendices on COVID - 19 and medicolegal considerations OXFORD HANDBOOK OF Endocrinology and Diabetes Published and forthcoming Oxford Medical Handbooks Oxford Handbook for the Foundation Programme 5e Oxford Handbook of Acute Medicine 4e Oxford Handbook of Anaesthesia 5e Oxford Handbook of Cardiology 2e Oxford Handbook of Clinical and Healthcare Research Oxford Handbook of Clinical and Laboratory Investigation 4e Oxford Handbook of Clinical Dentistry 7e Oxford Handbook of Clinical Diagnosis 3e Oxford Handbook of Clinical Examination and Practical Skills 2e Oxford Handbook of Clinical Haematology 4e Oxford Handbook of Clinical Immunology and Allergy 4e Oxford Handbook of Clinical Medicine – Mini Edition 10e Oxford Handbook of Clinical Medicine 10e Oxford Handbook of Clinical Pathology 2e Oxford Handbook of Clinical Pharmacy 3e Oxford Handbook of Clinical Specialties 11e Oxford Handbook of Clinical Surgery 4e Oxford Handbook of Complementary Medicine Oxford Handbook of Critical Care 3e Oxford Handbook of Dental Patient Care Oxford Handbook of Dialysis 4e Oxford Handbook of Emergency Medicine 5e Oxford Handbook of Endocrinology and Diabetes 4e Oxford Handbook of ENT and Head and Neck Surgery 3e Oxford Handbook of Epidemiology for Clinicians Oxford Handbook of Expedition and Wilderness Medicine 2e Oxford Handbook of Forensic Medicine Oxford Handbook of Gastroenterology & Hepatology 3e Oxford Handbook of General Practice 5e Oxford Handbook of Genetics Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health 3e Oxford Handbook of Geriatric Medicine 3e Oxford Handbook of Infectious Diseases and Microbiology 2e Oxford Handbook of Integrated Dental Biosciences 2e Oxford Handbook of Humanitarian Medicine Oxford Handbook of Key Clinical Evidence 2e Oxford Handbook of Medical Dermatology 2e Oxford Handbook of Medical Imaging Oxford Handbook of Medical Sciences 3e Oxford Handbook for Medical School Oxford Handbook of Medical Statistics 2e Oxford Handbook of Neonatology 2e Oxford Handbook of Nephrology and Hypertension 2e Oxford Handbook of Neurology 2e Oxford Handbook of Nutrition and Dietetics 3e Oxford Handbook of Obstetrics and Gynaecology 3e Oxford Handbook of Occupational Health 2e Oxford Handbook of Oncology 4e Oxford Handbook of Operative Surgery 3e Oxford Handbook of Ophthalmology 4e Oxford Handbook of Oral and Maxillofacial Surgery 2e Oxford Handbook of Orthopaedics and Trauma Oxford Handbook of Paediatrics 3e Oxford Handbook of Pain Management Oxford Handbook of Palliative Care 3e Oxford Handbook of Practical Drug Therapy 2e Oxford Handbook of Pre-Hospital Care 2e Oxford Handbook of Psychiatry 4e Oxford Handbook of Public Health Practice 4e Oxford Handbook of Rehabilitation Medicine 3e Oxford Handbook of Respiratory Medicine 4e Oxford Handbook of Rheumatology 4e Oxford Handbook of Sport and Exercise Medicine 2e Oxford Handbook of Tropical Medicine 5e Oxford Handbook of Urology 4e OXFORD HANDBOOK OF Endocrinology and Diabetes FOURTH EDITION EDITED BY Katharine Owen Associate Professor of Diabetes and Honorary Consultant Physician, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK Helen Turner Consultant in Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK John Wass Professor of Endocrinology, University of Oxford, Oxford, UK 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 2022 The moral rights of the authors have been asserted First Edition published in 2002 Second Edition published in 2009 Third Edition published in 2014 Fourth Edition published in 2022 Impression: 1 All rights reserved. No part of this publication may be reproduced, 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, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2021944933 ISBN 978–0–19–885189–9 eISBN 978–0–19–259438–9 DOI: 10.1093/med/9780198851899.001.0001 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 Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.  Foreword For someone who loves endocrinology, it is a great pleasure to read and use the Oxford Handbook in day-to-day clinical practice. The editors have tried to make an accessible, succinct, comprehensive, and up-to-date text, laid out to be readable and readily assimilable. It aims to cover all endocrine and diabetes occasions, common and less common, dealing with the background science, guidelines on investigation, and advice on treatment. It is written by internationally highly acknowledged experts for trainees, consultants who may have the occasional memory lapse, nurses, and those in primary care with whom we are increasingly sharing joined-up management. This Handbook is special, as it presents a global appreciation of endocrinology, describing clinical pathways and medications which are primarily based on, and used in, the European experience, while where possible also medical therapy in countries with limited medical resources is addressed. It is remarkable how much has changed since the first publication in 2002, as well as since the third edition in 2014. New genetic and metabolic mechanisms of disease, new and improved imaging techniques, new drugs, and complications thereof, and thus new management, are all covered in this new edition. In doing this, the editors have sought to include many of the recent guidelines which summarize new evidence in the significantly updated references that are given. In the new edition, topic sections have been included on transitional endocrinology and diabetes, and newly recognized conditions such as IgG4 disease. The sections on fertility and transgender issues have been extensively updated to encompass new developments. There is also a new chapter on medicolegal issues engendered by some of the complaints within our specialty. This includes governance issues such as consent, duty of confidentiality, and safe driving advice. The nursing section has also been expanded to include more practical advice about travel, fasting, updated glucocorticoid advice, and psychological challenges which face our patients. There is also a discussion on nurse-led clinics which are an important newer addition to our specialty and which can not only increase the quality of care given to our patients, but also increase throughput, in a specialty where outpatient numbers are going up over and above those in general medicine. The diabetes section has also been carefully reviewed to encompass changes in technology (continuous glucose monitoring/glucose monitoring/closed-loop), new treatments, including immunotherapy for type 1 diabetes and an update on new treatments in type 2 diabetes, and their link to cardiovascular outcomes. The section on genetics has been updated with guidance on screening, as well as a practical overview of genetic screening for the non-geneticist. In both the endocrinology and diabetes sections, advice has been included on difficult clinical decisions, tricky issues, and clinical pearls in the relevant sections. Lastly, a publication from 2021 would not be complete without a COVID-19 section, which has been added in the form of website links. The Editors have to be congratulated in providing a beautiful and most readable new edition of this now classic, internationally highly rated handbook. This ‘Herculean’ task has resulted in a handbook that presents a science and knowledge base for this specialty which greatly helps to maintain high standards of care of our patients. Steven WJ Lamberts Erasmus University Rotterdam Professor of Medicine Past President of the European Society for Endocrinology  Preface Endocrinology and diabetes remain among the most fascinating of specialties with a very broad range of causation, presentation, and management. We have the ability in our specialty to radically change the quality and quantity of life, often within a few days of starting treatment. Editing the Oxford Handbook has been huge fun and challenging. We have tried to make an accessible, succinct, comprehensive, and up-to-date text, laid out to be readable and readily assimilable. It aims to cover all endocrine and diabetes occasions, common and less common, dealing with the background science, guidelines on investigation, and advice on treatment. It is written by experts for trainees, consultants who may have the occasional memory lapse, nurses, and those in primary care with whom we are increasingly sharing joined-up management. It is remarkable how much has changed since the last edition. New genetic and metabolic mechanisms of disease, new and improved imaging techniques, new drugs, and complications thereof, and thus new management, are all covered in this edition. In doing this, we have sought to include many of the recent guidelines which summarize new evidence in the significantly updated references that are given. In the new topics, we have included sections on transitional endocrinology and diabetes, newly recognized conditions such as IgG4 disease. The sections on fertility and transgender issues have been extensively updated to encompass new developments. There is also a new chapter on medicolegal issues engendered by some of the complaints within our specialty. This includes governance issues such as consent, duty of confidentiality, and safe driving advice. The nursing section has also been expanded to include more practical advice about travel, fasting, updated glucocorticoid advice, and psychological challenges which face our patients. There is also a discussion on nurse-led clinics which are an important newer edition to our specialty and which not only can increase the quality of care given to our patients, but also can increase throughput, in a specialty where outpatient numbers are going up over and above those in general medicine. The diabetes section has also been carefully reviewed to encompass changes in technology (continuous glucose monitoring/glucose monitoring/closed-loop), new treatments including immunotherapy for type 1 diabetes and an update on new treatments for type 2 diabetes, and their link to cardiovascular outcomes. The section on genetics has been updated with guidance on screening, as well as a practical overview of genetic screening for the non-geneticist. In both sections, we have included advice on difficult clinical decisions, tricky issues, and clinical pearls in the relevant sections. Lastly, a publication from 2021 would not be complete without a COVID-19 section, which we have added in the form of website links. We are very indebted to our excellent authors who have worked diligently to keep the publication on track. We hope that this publication will help to improve the science and knowledge base in our specialty in order to maintain high standards of care for our patients. JW, KO, HT February 2021  Contents Contributors Symbols and abbreviations 1 Thyroid Mark Vanderpump 2 Pituitary Niki Karavitaki, Chris Thompson, and Iona Galloway 3 Adrenal Jeremy Tomlinson 4 Reproductive endocrinology Waljit Dhillo, Melanie Davies, Channa Jayasena, and Leighton Seal 5 Endocrinology in pregnancy Catherine Williamson and Rebecca Scott 6 Calcium and bone metabolism Neil Gittoes and Richard Eastell 7 Paediatric endocrinology Ken Ong and Emile Hendriks 8 Transitional endocrinology Helena Gleeson 9 Neuroendocrine disorders Karin Bradley 10 Inherited endocrine syndromes and MEN Paul Newey 11 Endocrinology and ageing  Antonia Brooke and Andrew McGovern 12 Endocrinology aspects of other clinical or physiological situations Antonia Brooke, Kagabo Hirwa, Claire Higham, and Alex Lewis 13 Genetic testing in endocrinology Márta Korbonits and Paul Newey 14 Practical and nursing aspects of endocrine conditions Anne Marland and Mike Tadman 15 Diabetes Gaya Thanabalasingham, Alistair Lumb, Helen Murphy, Peter Scanlon, Jodie Buckingham, Solomon Tesfaye, Ana Pokrajac, Pratik Choudhary, Patrick Divilly, Ketan Dhatariya, Ramzi Ajjan, Rachel Besser, and Katharine Owen 16 Lipids and hyperlipidaemia Fredrik Karpe 17 Obesity John Wilding 18 Pitfalls in laboratory endocrinology Peter Trainer and Phillip Monaghan Appendix 1: Medicolegal considerations Appendix 2: COVID-19 resources Appendix 3: Reference intervals Index  Contributors Ali Abbara NIHR Clinician Scientist/Clinical Senior Lecturer, Imperial College London at Hammersmith Campus, London, UK Ramzi Ajjan Professor of Metabolic Medicine, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds and Leeds Teaching Hospitals Trust, Leeds, UK Rachel Besser Consultant in Paediatric Endocrinology, Oxford Children’s Hospital, John Radcliffe; Oxford University Hospitals NHS Foundation Trust, Oxford, UK Karin Bradley Consultant Endocrinologist, University Hospitals Bristol NHS Foundation Trust, Bristol, UK Antonia Brooke Clinical Lead Endocrine, Diabetes, and Metabolic Medicine, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK Jodie Buckingham Lead Podiatrist, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Oxford University Hospitals Foundation Trust, Oxford, UK Pratik Choudhary Professor of Diabetes, Leicester Diabetes Centre, University of Leicester, Leicester, UK Melanie Davies Consultant Gynaecologist, Reproductive Medicine Unit, University College London Hospitals, London, UK Ketan Dhatariya Consultant, Diabetes and Endocrinology/Honorary Professor, Norfolk and Norwich University Hospitals, and Norwich Medical School, University of East Anglia, Norwich, UK Waljit Dhillo Professor of Endocrinology and Metabolism, Imperial College London at Hammersmith Campus, London, UK Patrick Divilly Diabetes Clinical Research Fellow, Diabetes Research Group, Weston Education Centre, London, UK Richard Eastell Professor of Bone Metabolism, University of Sheffield, Northern General Hospital, Sheffield, UK Iona Galloway Endocrine Fellow, Beaumont Hospital/RCSI Medical School, Dublin, Ireland Neil Gittoes Consultant and Honorary Professor of Endocrinology, Queen Elizabeth Hospital and University of Birmingham, Birmingham, UK Helena Gleeson Consultant Endocrinologist, Queen Elizabeth Hospital, Birmingham, UK Emile Hendriks University Lecturer and Honorary Consultant in Paediatric Endocrinology, University of Cambridge, Cambridge, UK Claire Higham Consultant Endocrinologist, Christie Hospital NHS Foundation Trust, Manchester, UK Kagabo Hirwa Specialist Trainee Registrar, Diabetes and Endocrinology, University Hospitals Plymouth NHS Trust, Plymouth, UK Channa Jayasena Reader in Reproductive Endocrinology, Imperial College London Faculty of Medicine, Hammersmith Hospital, London, UK Niki Karavitaki Senior Clinical Lecturer in Endocrinology and Honorary Consultant Endocrinologist, Institute of Metabolism and Systems Research, University of Birmingham and Queen Elizabeth Hospital, Birmingham, UK Fredrik Karpe Professor of Metabolic Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, UK Márta Korbonits Professor of Endocrinology and Metabolism, Barts and the London School of Medicine, Queen Mary University of London, London, UK Alex Lewis Specialist Registrar, Christie Hospital NHS Foundation Trust, Manchester, UK Alistair Lumb Consultant in Diabetes and Acute General Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Oxford University Hospitals Foundation Trust, Churchill Hospital, Oxford, UK Anne Marland Endocrine Lead Nurse, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Oxford University Hospitals Foundation Trust, Churchill Hospital, Oxford, UK Andrew McGovern Academic Clinical Fellow, Royal Devon and Exeter Hospital, Exeter, UK Phillip Monaghan Consultant Clinical Scientist, The Christie Pathology Partnership, The Christie NHS Foundation Trust, Manchester, UK Helen Murphy Professor of Medicine (Diabetes and Antenatal Care), University of East Anglia, Norwich Research Park, Norwich, UK Paul Newey Senior Lecturer in Endocrinology, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK Ken Ong Professor of Paediatric Epidemiology and Paediatric Endocrinologist, University of Cambridge, Cambridge, UK Katherine Owen Associate Professor of Diabetes and Honorary Consultant Physician, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK Ana Pokrajac Consultant in Diabetes and Endocrinology, West Hertfordshire Hospitals NHS Trust, Watford, UK Peter Scanlon Ophthalmologist and Associate Professor, Department of Neuroscience, University of Oxford, John Radcliffe Hospital, Oxford, UK Rebecca Scott Obstetric Physician and Specialist Registrar in Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, London, UK Leighton Seal Consultant and Honorary Reader in Diabetes and Endocrinology, St George’s University Hospitals NHS Foundation Trust and St George’s Hospital Medical School, London, UK Mike Tadman Senior Clinical Nurse Specialist in Neuroendocrine Tumours, Oxford University Hospitals Foundation Trust, Churchill Hospital, Oxford, UK Solomon Tesfaye Consultant Endocrinologist and Honorary Professor of Diabetic Medicine at the University of Sheffield, Sheffield Teaching Hospitals, Royal Hallamshire Hospital, Sheffield, UK Gaya Thanabalasingham Consultant in Diabetes and Acute General Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Oxford University Hospitals Foundation Trust, Churchill Hospital, Oxford, UK Chris Thompson Professor of Endocrinology, Beaumont Hospital/RCSI Medical School, Dublin, Ireland Layla Thurston Clinical Research Fellow, Imperial College London at Hammersmith Campus, London, UK Jeremy Tomlinson Professor of Metabolic Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK Peter Trainer Consultant Endocrinologist, The Christie NHS Foundation Trust, Manchester, UK Helen Turner Consultant in Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK Mark Vanderpump Consultant Physician and Endocrinologist, OneWelbeck Endocrinology, London, UK John Wass Professor of Endocrinology, University of Oxford, Oxford, UK John Wilding Professor of Medicine and Honorary Consultant Physician, Clinical Sciences Centre, Aintree University Hospital, Liverpool, UK Catherine Williamson Professor of Women’s Health and Honorary Consultant in Obstetric Medicine, King’s College London, London, UK  Symbols and abbreviations cross-reference website ~ approximately ↑ increased ↓ decreased ↔ normal → leads to 1° primary 2° secondary α alpha β beta δ delta γ gamma κ kappa % 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 ▶ important warning AAS androgenic anabolic steroid ACA adrenocortical adenoma ACC adrenocortical carcinoma ACE angiotensin-converting enzyme ACEI angiotensin-converting enzyme inhibitor aCGH array comparative genomic hybridization ACLY adenosine triphosphate citrate lyase ACMG American College of Medical Genetics and Genomics ACR albumin:creatinine ratio ACTH adrenocorticotrophic hormone AD autosomal dominant ADA American Diabetes Association ADH antidiuretic hormone; autosomal dominant hypocalcaemia ADI adipsic diabetes insipidus aFP alpha fetoprotein AGE advanced glycation end-product AGHDA Adult Growth Hormone Deficiency Assessment (score) AHC adrenal hypoplasia congenita AI adrenal insufficiency AIDS acquired immune deficiency syndrome AIH amiodarone-induced hypothyroidism AIMAH ACTH-independent macronodular adrenal hyperplasia AIP aryl hydrocarbon receptor interacting protein AIT amiodarone-induced thyrotoxicosis AITD autoimmune thyroid disease 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 antineutrophil cytoplasmic antibody ANP advanced nurse practitioner aPCA adrenal phaeochromocytoma apo apoprotein APS autoimmune polyglandular syndrome; artificial pancreas system AR autosomal recessive ART assisted reproductive technique AST aspartate transaminase ATA American Thyroid Association ATD antithyroid drug ATDT antithyroid drug therapy ATP adenosine triphosphate AVP arginine vasopressin AVS adrenal vein sampling BAM bile acid malabsorption bd bis in die (twice daily) BMD bone mineral density BMI body mass index BMT bone marrow transplantation BP blood pressure bpm beat per minute Ca calcium CAH congenital adrenal hyperplasia cAMP cyclic adenosine monophosphate CASR calcium-sensing receptor CBG cortisol-binding globulin CCF congestive cardiac failure CDKI cyclin-dependent kinase inhibitor CEA carcinoembryonic antigen CF cystic fibrosis CFS chronic fatigue syndrome CGH comparative genomic hybridization CGM continuous glucose monitoring cGMP cyclic guanosine monophosphate cGy centigray CHD coronary heart disease CHH congenital hypogonadotrophic hypogonadism CHO carbohydrate CK creatine kinase CKD chronic kidney disease CLA cutaneous lichen amyloidosis CLAH congenital lipoid adrenal hyperplasia cm centimetre CMV cytomegalovirus CNC Carney complex CNS central nervous system COCP combined oral contraceptive pill COPD chronic obstructive pulmonary disease COVID-19 coronavirus disease CPA cyproterone acetate CPI checkpoint inhibitor CPK creatine phosphokinase CPRD Clinical Practice Research Datalink 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 CTLA-4 cytotoxic T lymphocyte antigen-4 CVA cerebrovascular accident CVD cardiovascular disease CVOT cardiovascular outcome trial CVP central venous pressure CXR chest X-ray 4D four-dimensional DCCT Diabetes Control and Complications Trial DCT distal convoluted tubule DD disc diameter ddPCR digital polymerase chain reaction DHEA dehydroepiandrostenedione DHEAS dehydroepiandrostenedione sulphate DHT dihydrotestosterone DI diabetes insipidus DIT di-iodotyrosine DKA diabetic ketoacidosis dL decilitre DM diabetes mellitus DMSA dimercaptosuccinic acid DN diabetic neuropathy DNA deoxyribonucleic acid DOC deoxycorticosterone DPN diabetic peripheral neuropathy DPP-IV dipeptidyl peptidase IV DR diabetic retinopathy DRS Diabetic Retinopathy Study DSD disorders of sexual differentiation; disorder of sex development DSN diabetes specialist nurse DTC differentiated thyroid cancer DVA Driver and Vehicle Agency DVLA Driver and Vehicle Licensing Agency DVT deep vein thrombosis DXA dual-energy absorptiometry E2 oestradiol EASD European Association for the Study of Diabetes ECF extracellular fluid ECG electrocardiogram EDC endocrine disrupting chemical EDTA ethylenediaminetetraacetic acid EE2 ethinylestradiol EEG electroencephalogram eFPGL extra-adrenal functional paraganglioma eGFR estimated glomerular filtration rate ELST endolymphatic sac tumour EM electron microscopy EMA European Medicines Agency ENaC epithelial sodium channel ENETS European Neuroendocrine Tumor Society ENT ear, nose, and throat EOSS Edmonton Obesity Staging System EPO erythropoietin ER (o)estrogen receptor ERT (o)estrogen replacement therapy ESC European Society of Cardiology ESN endocrine specialist nurse ESR erythrocyte sedimentation rate ESRD end-stage renal disease ESRF end-stage renal failure ETDRS Early Treatment of Diabetic Retinopathy Study EUA examination under anaesthesia EU-AIR European Adrenal Insufficiency Registry FAI free androgen index FAZ foveal avascular zone FBC full blood count FCH familial combined hyperlipidaemia FCS familial chylomicronaemia syndrome FDA Food and Drug Administration FDG fluorodeoxyglucose FGD familial glucocorticoid deficiency FGF fibroblast growth factor FGFR1 fibroblast growth factor receptor 1 FH familial hypercholesterolaemia FHA functional hypothalamic amenorrhoea FHH familial hypocalciuric hypercalcaemia FIH familial isolated hypoparathyroidism FIHP familial isolated hyperparathyroidism FIPA familial isolated pituitary adenoma FISH fluorescence in situ hybridization FMTC familial medullary thyroid carcinoma FNA fine needle aspiration FNAC fine needle aspiration cytology FPG fasting plasma glucose FRIII fixed-rate intravenous insulin infusion FSH follicle-stimulating hormone FT3 free tri-iodothyronine FT4 free thyroxine FTC follicular thyroid carcinoma FTO fat mass and obesity associated FU fluorouracil g gram 68 gallium-68 Ga GAD glutamic acid decarboxylase GAG glycosaminoglycan GBM glomerular basement membrane GBq giga becquerel GC glucocorticoid GCK glucokinase GCS Glasgow Coma Scale gCSF granulocyte colony-stimulating factor GDF15 growth differentiation factor GDM gestational diabetes mellitus 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 GI gastrointestinal GIP gastric inhibitory polypeptide GK glycerol kinase GLP-1 glucagon-like peptide-1 GLUT4 glucose transporter type 4 GnRH gonadotrophin-releasing hormone GO Graves’ orbitopathy GO-QOL Graves’ Ophthalmopathy Quality of Life GP general practitioner GPCR G-protein-coupled receptor GRA glucocorticoid-remediable aldosteronism GRS genetic risk score GTN glyceryl trinitrate GTT glucose tolerance test GWAS genome-wide association studies Gy gray h hour HA hypothalamic amenorrhoea HAART highly active antiretroviral therapy Hb haemoglobin HbA1c glycated haemoglobin hCG human chorionic gonadotrophin HCl hydrochloric acid HCL hybrid closed loop Hct haematocrit HD Hirschsprung’s disease HDL high-density lipoprotein HDL-C high-density lipoprotein cholesterol HDU high dependency unit HEEADDSS Home, Education and employment, Exercise and eating, Activity and peers, Drugs, Depression, Sexuality and sexual health, Sleep, Safety HELLP haemolysis, elevated liver enzymes, and low platelet HERS Heart and Oestrogen-Progestin Replacement Study HFEA Human Fertilisation and Embryology Authority hGH human growth hormone HH hypogonadotrophic hypogonadism HHS hyperglycaemic hyperosmolar state 5-HIAA 5-hydroxyindoleacetic acid HIF hypoxia-inducible factor HIV human immunodeficiency virus HLA human leucocyte 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 HPA hypothalamic–pituitary–adrenal HPO hypothalamic–pituitary–ovarian HPT hypothalamo–pituitary–thyroid HPT-JT hyperparathyroidism jaw tumour (syndrome) HPV human papillomavirus HRT hormone replacement therapy HSCT haematopoietic stem cell transplantation 11β-HSD2 11β-hydroxysteroid dehydrogenase type 2 HSG hysterosalpingography 5-HT2B 5-hydroxytryptamine 2B HTLV-1 human T lymphotropic virus type 1 HU Hounsfield unit HVFT fibrous variant of Hashimoto’s thyroiditis HyCoSy hysterosalpingo contrast sonography Hz hertz IADPSG International Association of Diabetes and Pregnancy Study Groups ICA islet cell antibodies ICSI intracytoplasmic sperm injection IDDM insulin-dependent diabetes mellitus IDL intermediate-density lipoprotein IFCC International Federation of Clinical Chemistry IFG impaired fasting glycaemia Ig immunoglobulin IGF insulin-like growth factor IGFBP3 insulin-like growth factor-binding protein 3 IGF-1R insulin-like growth factor-1 receptor IGT impaired glucose tolerance IHD ischaemic heart disease IHH idiopathic hypogonadotropic hypogonadism IM intramuscular IMRT intensity-modulated radiotherapy IPSS inferior petrosal sinus sampling IQ intelligence quotient IRMA intraretinal microvascular abnormality IRT immune reconstitution therapy ITT insulin tolerance test ITU intensive treatment unit IU international unit IUGR intrauterine growth restriction IUI intrauterine insemination IV intravenous IVC inferior vena cava IVF in vitro fertilization IVII intravenous insulin infusion J joule K+ potassium ion kb kilobase kcal kilocalorie kDa kilodalton kg kilogram KPD ketosis-prone diabetes L litre LADA latent autoimmune diabetes of adulthood LCAT lecithin:cholesterol acyltransferase LCCSCT large cell calcifying Sertoli cell tumour LDL low-density lipoprotein LDL-C LDL cholesterol LDLR LDL receptor LFT liver function test LH luteinizing hormone LHRH luteinizing hormone-releasing hormone LMWH low-molecular weight heparin LOH loss of heterozygosity Lpa lipoprotein a LPL lipoprotein lipase LSCS lower-segment Caesarean section LVEF left ventricular ejection fraction LVH left ventricular hypertrophy m metre M molar MAI Mycobacterium avium cellulare MAOI monoamine oxidase inhibitor MAPK mitogen-activated protein kinase MBq mega becquerel MC mineralocorticoid MCA Medicines Control Agency MC1R melanocortin 1 receptor MC4R melanocortin 4 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 MHRA Medicines and Healthcare Products Regulatory Agency MI myocardial infarction MIBG metaiodobenzylguanidine min minute MIT monoiodotyrosine mIU milli international unit MJ megajoule mL millilitre MLPA multiplex ligation-dependent probe amplification mm millimetre mmHg millimetre of mercury mmol millimole MODY maturity-onset diabetes of the young mOsm milliosmole MPH mid-parental height MPNST malignant peripheral nerve sheath tumour MRAP MC2R accessory protein MRI magnetic resonance imaging mRNA messenger ribonucleic acid MS mass spectrometry MSH melanocyte-stimulating hormone MSU midstream urine MTC medullary thyroid carcinoma mTESE microdissection testicular sperm extraction mTOR mammalian target of rapamycin mU milliunit Na sodium NaCl sodium chloride NAFLD non-alcoholic fatty liver disease NASH non-alcoholic steatohepatitis NDA National Diabetes Audit NEFA non-esterified fatty acid NET neuroendocrine tumour NF neurofibromatosis NFA non-functioning pituitary adenoma NFPA non-functioning pituitary adenoma ng nanogram NG nasogastric NGS next-generation sequencing NHS National Health Service NICE National Institute for Health and Care Excellence NIDDM non-insulin-dependent diabetes mellitus NIFTP non-invasive follicular thyroid neoplasm with papillary-like nuclear features NIH National Institutes of Health NIPD non-invasive prenatal genetic diagnosis NIPT non-invasive prenatal genetic testing NIS sodium/iodide symporter NMC Nursing and Midwifery Council nmol nanomole NPHPT normocalcaemic primary hyperparathyroidism NSAID non-steroidal anti-inflammatory drug NTI non-thyroidal illness NT-proBNP N-terminal pro B-type natriuretic peptide NVD new vessels on the disc NVE new vessels elsewhere O2 oxygen OA osteoarthritis OCP oral contraceptive pill od omne in die (once daily) OGTT oral glucose tolerance test OHA oral hypoglycaemic agent 25OHD 25-hydroxyvitamin D 1,25(OH)2D 1,25-dihydroxyvitamin D 17OHP 17-hydroxyprogesterone OHSS ovarian hyperstimulation syndrome OR odds ratio PAI plasminogen activator inhibitor PAK pancreas after kidney PAR-Q Physical Activity Readiness Questionnaire PBC primary biliary cirrhosis PCC phaeochromocytoma PCOS polycystic ovary syndrome PCSK9 proprotein convertase subtilisin/kexin 9 PD-1 programmed death 1 PDE phosphodiesterase PD-L1 programme death ligand 1 PDR proliferative diabetic retinopathy PE pulmonary embolism PED performance-enhancing drug PEG polyethylene glycol PERT pancreatic enzyme replacement therapy PET positron emission tomography pg picogram PGD prenatal/preimplantation genetic diagnosis PGL paraganglioma PHPT primary hyperparathyroidism PI protease inhibitor PID pelvic inflammatory disease PIH pregnancy-induced hypertension PitNET pituitary neuroendocrine tumour PKA protein kinase A p.m. post meridiem (after noon) PMC papillary microcarcinoma of the thyroid pmol picomole PMS psammomatous melanotic schwannoma PNDM permanent neonatal diabetes mellitus pNET pancreatic neuroendocrine tumour PNMT phenylethanolamine- N-methyltransferase PO per os (orally) PO4 phosphate POEMS progressive polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin change POF premature ovarian failure POI premature ovarian insufficiency POMC pro-opiomelanocortin POME pulmonary oil microembolism POP progesterone-only pill PPAR peroxisome proliferator-activated receptor PPGL phaeochromocytoma/paraganglioma PPI proton pump inhibitor PPNAD primary pigmented nodular adrenocortical disease PPT post-partum thyroiditis PR per rectum PRA plasma renin activity PRH postprandial reactive hypoglycaemia PRL prolactin PRRT peptide receptor radionuclide therapy PSA prostate-specific antigen PTA pancreas transplantation alone PTC papillary thyroid carcinoma PTH parathyroid hormone PTHrP parathyroid hormone-related peptide PTU propylthiouracil PVD peripheral vascular disease QCT quantitative computed tomography qds quarter die sumendus (four times daily) QoL quality of life QTc corrected QT interval RAA renin–angiotensin–aldosterone RAI radioactive iodine RANK receptor activator of nuclear factor kappa-B RANKL receptor activator of nuclear factor kappa-B RAS renin–angiotensin system RCAD renal cysts and diabetes (syndrome) RCC renal cell carcinoma RCN Royal College of Nursing RCPCH Royal College of Paediatrics and Child Health RCT randomized controlled trial RECIST response evaluation criteria in solid tumours RED-S relative energy deficiency in sport RFA radiofrequency ablation rhGH recombinant human growth hormone RNA ribonucleic acid RR relative risk RRT renal replacement therapy rT3 reverse T3 RTH resistance to thyroid hormone RTK receptor tyrosine kinase s second SARS-Cov- severe acute respiratory syndrome coronavirus 2 2 SC subcutaneous SD standard deviation SDH succinate dehydrogenase SDHx succinate dehydrogenase enzyme complex SERM selective (o)estrogen receptor modulator SGA small-for-gestational age SGLT2 sodium–glucose cotransporter 2 SH severe hypoglycaemia SHBG sex hormone-binding globulin SIAD syndrome of inappropriate SIADH syndrome of inappropriate antidiuretic hormone SLE systemic lupus erythematosus SNP single nucleotide polymorphism SNRI serotonin–noradrenaline reuptake inhibitor SNV single-nucleotide variant SPECT single-photon emission computed tomography SPK simultaneous pancreas kidney (transplant) SSA somatostatin analogue SSRI selective serotonin reuptake inhibitor SST short Synacthen®test StAR steroidogenic acute regulatory protein STED sight-threatening diabetic eye disease STI sexually transmitted infection SU sulfonylurea 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 TERT telomerase reverse transcriptase TFT thyroid function test Tg thyroglobulin TG triglyceride TgAb thyroglobulin antibody TGF transforming growth factor TIND treatment-induced neuropathy of diabetes TI-RADS thyroid imaging, reporting, and data system TK tyrosine kinase TKI tyrosine kinase inhibitor TNDM transient neonatal diabetes mellitus TNF tumour necrosis factor TPO thyroid peroxidase TPOAb antithyroid peroxidase antibody TPP thyrotoxic periodic paralysis TR thyroid hormone receptor TRAb thyroid-stimulating hormone receptor antibody TRE thyroid hormone response element TRH thyrotropin-releasing hormone tRNA transfer ribonucleic acid TSA transsphenoidal approach TSH thyroid-stimulating hormone TTR transthyretin TZD thiazolidinedione U unit U&E urea and electrolytes UFC urinary free cortisol UK United Kingdom UKPDS United Kingdom Prospective Diabetes Study US ultrasound USA United States of America USP8 ubiquitin-specific peptidase 8 V volt VA visual acuity VDDR vitamin D-dependent rickets VEGF vascular endothelial growth factor 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 VUS variant of uncertain significance WBS whole-body scan WES whole-exome sequencing WGS whole-genome sequencing WHI Women’s Health Initiative WHO World Health Organization w/v weight by volume XLAG X-linked acrogigantism XLR X-linked recessive ZES Zollinger–Ellison syndrome ZnT8 zinc transporter 8 Chapter 1 Thyroid Mark Vanderpump Anatomy Physiology Molecular action of thyroid hormone Tests of hormone concentration Tests of homeostatic control Rare genetic disorders of thyroid hormone metabolism Antibody screen Screening for thyroid disease Scintiscanning Ultrasound scanning Fine needle aspiration cytology Computed tomography Positron emission tomography Additional laboratory investigations Non-thyroidal illness (sick euthyroid syndrome) Atypical clinical situations Thyrotoxicosis—aetiology Manifestations of hyperthyroidism Medical treatment Radioiodine treatment Surgery Preparation for surgery Thyroid crisis (storm) Subclinical hyperthyroidism Thyrotoxic periodic paralysis (TPP) Thyrotoxicosis in pregnancy Hyperthyroidism in children Secondary hyperthyroidism Graves’ orbitopathy Medical treatment of Graves’ orbitopathy Surgical treatment of Graves’ orbitopathy Thyroid dermopathy and acropachy Goitre Thyroid multinodular goitre and solitary adenomas Thyroiditis Chronic autoimmune (atrophic or Hashimoto’s) thyroiditis Other types of thyroiditis Hypothyroidism Subclinical hypothyroidism Treatment of hypothyroidism Congenital hypothyroidism Amiodarone and thyroid function Epidemiology of thyroid cancer Aetiology of thyroid cancer Prognostic factors, staging, and risk stratification in differentiated thyroid cancer Papillary microcarcinoma of the thyroid Papillary thyroid carcinoma Follicular thyroid carcinoma Follow-up of DTC Medullary thyroid carcinoma Anaplastic thyroid cancer and lymphoma Suggestions: how do I … ? 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 pretracheal fascia, which anchors it to the trachea, so that the thyroid moves up on swallowing. Histology Fibrous septae 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 (Tg). The peptide sequences of thyroxine (T4) and tri-iodothyronine (T3) are synthesized and stored as a component of Tg. 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 parafollicular C cells, derived from the ultimo-branchial body (4th 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 T4 crosses the placenta at a time when fetal thyroid gland is not functional. Maternal thyrotropin-releasing hormone (TRH) readily crosses the placenta; maternal thyroid-stimulating hormone (TSH) does not. The fetal pituitary–thyroid axis as a functional unit, distinct from that of the mother, is active at 18–20 weeks. T4 from the fetal thyroid is then the major thyroid hormone available to the fetus. 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. 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’ disease (treated or untreated). Occasionally, inspiratory stridor can be heard, with a large or retrosternal goitre causing tracheal compression (for Pemberton’s sign, see Thyroid multinodular goitre and solitary adenomas, pp. 72–75). 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, reduced colour vision, reduced visual acuity. 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 Tg first to produce monoiodotyrosine (MIT) and then di-iodotyrosine (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) (see Fig. 1.1). 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, e.g. brassica vegetables. Perchlorate and thiocyanate inhibit iodide transport. Thioureas (e.g. carbimazole and propylthiouracil (PTU)) 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 decreasing order of affinity to thyroid-binding globulin (TBG), transthyretin (TTR), and albumin. T3 is bound 10–20 times less avidly by TBG and not significantly by TTR. Only 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 summarizes those states associated with 1° alterations in the concentration of TBG. When there is primarily an alteration in the concentration of thyroid hormones, the concentration of TBG changes little (see Table 1.2). The concentration of free hormones does not necessarily vary directly with that of total hormones, e.g. while the total T4 level rises in pregnancy, the free T4 (FT4) level remains normal (see Thyrotoxicosis in pregnancy, pp. 50–54). The levels of thyroid hormone in the blood are tightly controlled by feedback mechanisms involved in the hypothalamo–pituitary–thyroid (HPT) axis (see Fig. 1.2). 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 sulfate. Enzyme inducers, such as phenobarbital, carbamazepine, and phenytoin, increase the metabolic clearance of the hormones without decreasing the proportion of free hormone in the blood. Table 1.1 Disordered thyroid hormone–protein interactions Serum total T4 and T3 Free T4 and T3 Primary abnormality in TBG ↑ concentration ↑ Normal ↓ concentration ↓ Normal Primary disorder of thyroid function Hyperthyroidism ↑ ↑ Hypothyroidism ↓ ↓ Table 1.2 Circumstances associated with altered concentration of TBG ↑ TBG ↓ TBG Pregnancy Androgens Newborn state Large doses of glucocorticoids (GCs); Cushing’s syndrome Oral contraceptive pill and other sources of Chronic liver disease oestrogens 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) Fig. 1.1 Thyroid hormone biosynthesis. Iodine is transported via NIS located in the basal membrane of follicular thyrocytes (a). Iodine is organified onto tyrosyl residues in Tg at the apical membrane, requiring the presence of TPO, first to produce MIT and then DIT (b). TPO links two DITs to form T4, and MIT and DIT to form small amounts of T3 and rT3 (b). Once formed, thyroid hormone is stored in the colloid as part of the structure of Tg (b). After TSH stimulation, Tg enters the thyroid cell from colloid (c). It is cleaved by endopeptidases in lysosomes (d), thus allowing thyroid hormone to be released into the circulation, mostly in the form of levothyroxine (e). H2O2, hydrogen peroxide. Fig. 1.2 Regulation of thyroid function. Solid arrows indicate stimulation; broken arrow indicates inhibitory influence. I, iodine; T3, tri-iodothyronine; T4, thyroxine; TBG, thyroid-binding globulin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. Molecular action of thyroid hormone T3 is the active form of thyroid hormone and binds to thyroid hormone receptors (TRs) in target cell nuclei to initiate a range of physiological effects, including cellular differentiation, postnatal development, and metabolic homeostasis. The actions of thyroid hormone are mediated by two genes (TRα, TRβ), which encode three nuclear receptor subtypes with differing tissue expression (TRα1: central nervous system (CNS), cardiac and skeletal muscle; TRβ1: liver and kidney; TRβ2: 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 the 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, the 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 (see Fig. 1.3). 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 TRβ 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 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 ribonucleic acid (RNA) polymerase II and hormone-dependent activation of transcription. The roles of TRα and TRβ 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, while TRβ mediates T3 action in the liver and is responsible for regulation of the HPT axis. Fig. 1.3 Thyroid hormone action. 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 the ‘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). Further reading Luongo C, et al. (2019). Deiodinases and their intricate role in thyroid hormone homeostasis. Nat Rev Endocrinol 15, 479–88. Tests of hormone concentration Highly specific and sensitive chemiluminescent and radioimmunoassays are used to measure serum T4 and T3 concentrations.1 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 (TFTs) (Association for Clinical Biochemistry, British Thyroid Association, British Thyroid Foundation, https://www.british-thyroid- association.org/sandbox/bta2016/uk_guidelines_for_the_use_of_thyroid _function_tests.pdf). The International Federation of Clinical Chemistry (IFCC) Committee for Standardization of Thyroid Function Tests have developed a global harmonization approach for FT4 and TSH measurements, based on a multiassay method comparison study with clinical serum samples and target setting with a robust factor analysis method.2,3 References 1. Favresse J, et al. (2018). Interferences with thyroid function immunoassays: clinical implications and detection algorithm. Endocr Rev 39, 830–50. 2. De Grande LAC, et al. (2017). Standardization of free thyroxine measurements allows the adoption of a more uniform reference interval. Clin Chem 63, 1642–52. 3. Thienpont LM, et al. (2017). Harmonization of serum thyroid-stimulating hormone measurements paves the way for the adoption of a more uniform reference interval. Clin Chem 63, 1248–60. Tests of homeostatic control (See Table 1.3.) Serum TSH concentration is used as 1st line in the diagnosis of 1° hypothyroidism and hyperthyroidism. The test is misleading in patients with 2° thyroid dysfunction due to hypothalamic/pituitary disease, including TSH-secreting pituitary adenoma (see Anterior pituitary hormone replacement, p. 144), recent treatment for thyrotoxicosis (TSH may remain suppressed, even when thyroid hormone concentrations  have normalized), non-thyroidal illness (NTI), TSH assay interference, resistance to thyroid hormone (RTH), and disorders of thyroid hormone transport or metabolism. The TRH stimulation test, which can be used to assess the functional state of the TSH secretory mechanism, is now rarely used to diagnose 1° thyroid disease since it has been superseded by sensitive TSH assays. Its main use is in the differential diagnosis of elevated TSH in the setting of elevated thyroid hormone levels and the differential diagnosis of RTH (see Box 1.1) and TSH-secreting pituitary adenoma. 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 TFTs. Table 1.3 Thyroid hormone concentrations in various thyroid abnormalities Condition TSH Free T4 Free T3 1° hyperthyroidism Undetectable ↑↑ ↑ T3 toxicosis Undetectable Normal ↑↑ Subclinical hyperthyroidism ↓ Normal Normal 2° hyperthyroidism (TSHoma) ↑ or normal ↑ ↑ Thyroid hormone resistance ↑ or normal ↑ ↑ 1° hypothyroidism ↑ ↓ ↓ or normal Subclinical hypothyroidism ↑ Normal Normal 2° hypothyroidism ↓ or normal ↓ ↓ or normal Table 1.4 Influence of drugs on thyroid function tests Metabolic ↑ ↓ process TSH secretion Amiodarone (transiently; becomes normal GCs, dopamine agonists, after 2–3 months), sertraline, St John’s wort phenytoin, dopamine, octreotide, (Hypericum) paroxetine T4 Iodide, amiodarone, interferon alfa, lithium Iodide, amiodarone, interferon synthesis/release alfa, lithium, tyrosine kinase inhibitors (TKIs) Binding proteins Oestrogen, clofibrate, heroin GCs, androgens, phenytoin, carbamazepine T4 metabolism Anticonvulsants, rifampicin T4/T3 binding in Heparin Salicylates, furosemide, serum mefenamic acid Table 1.5 Atypical thyroid function tests Test Possible cause Suppressed TSH and T3 toxicosis (~5% of thyrotoxicosis) normal FT4 Suppressed TSH and Subclinical hyperthyroidism Recovery from thyrotoxicosis Excess normal FT4 and free thyroxine replacement NTI T3 (FT3) Detectable TSH and TSH-secreting pituitary tumour Thyroid hormone resistance Heterophile elevated FT4 and antibodies, leading to spurious measurements of FT4 and FT3 Thyroxine FT3 replacement therapy (including poor compliance) Elevated FT4 and Biotin FT3, and suppressed TSH Elevated FT4 and Amiodarone low-normal FT3, normal TSH Elevated free T4 and Heparin T3 Suppressed or NTI Central hypothyroidism Isolated TSH deficiency normal TSH, and low-normal FT4 and FT3 Knowledge of HPT axis physiology, the factors governing thyroid hormone action at a tissue/cellular level, and the different patterns of TFTs that may be encountered in clinical practice is central to establishing the correct diagnosis when clinical features and TFT results appear discordant/incongruous. Reappraisal of the clinical context and exclusion of confounding intercurrent illness or medication usage, coupled with reassessment of thyroid status, are the 1st step to resolving such cases. Targeted investigation to definitively exclude assay interference may require specialist laboratory input. It may be helpful to send specimens to different labs to use a different assay. Genetic and acquired disorders of the HPT axis are rare but should be considered if all other steps have failed to identify a cause for anomalous/discordant TFTs. Ingestion of 5–10 mg of biotin can cause spurious results in thyroid test assays.1 Biotin will cause falsely ↓ values in immunometric assays used  to measure TSH, and falsely ↑ values in competitive binding assays used to measure T4, T3, and TRAbs. These biochemical findings suggest a diagnosis of Graves’ disease; however, discontinuation of biotin supplements results in resolution of the biochemical abnormalities. Thyroid tests should be repeated at least 2 days after discontinuation of biotin supplements. In heparin-treated subjects, serum non-esterified fatty acid (NEFA) concentrations may increase markedly as a consequence of heparin- induced activation of endothelial lipoprotein lipase in vivo, leading to increased NEFA generation in vitro during sample storage or incubation. In the presence of normal serum albumin concentrations, NEFA concentrations >2–3mmol/L exceed normal serum binding capacity, resulting in direct competition for T4 and T3 binding sites on TBG either by NEFAs themselves or as a result of displacement of other ligands from the albumin sites that normally limit their free concentration. This artefact is more pronounced in hypertriglyceridaemia and hypoalbuminaemia, and with laboratory methods that require long incubation periods. Even very low-dose intravenous (IV) heparin (equivalent to that used to maintain the patency of an indwelling cannula) and subcutaneous (SC) low- molecular weight heparin (LMWH) prophylaxis can lead to ↑ FT4 (and FT3). The heparin effect has been observed with a variety of assay platforms, including equilibrium dialysis, ultracentrifugation, and direct immunoassay. References 1. Kummer S, et al. (2016). Biotin treatment mimicking Graves’ disease. N Engl J Med 375, 704–6. Further reading Cambridge Addenbrooke’s Hospital Endocrine Laboratory. Service Supra-Regional Assay Service. http://www.sas-centre.org/centres/hormones/Cambridge/html Koulouri O, et al. (2013). Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab 27, 745–62. Rare genetic disorders of thyroid hormone metabolism RTH is caused by heterozygous mutations in TRβ (see Box 1.1). Inactivating mutations in TRα have now been identified which are associated with growth retardation, macrocephaly, delayed closure of fontanel, delayed motor and mental milestones in childhood, constipation, mild normocytic anaemia, and excessive skin tags in adulthood. TFTs may show normal TSH with normal/↓ FT4, ↑ FT3, and ↓ rT3 levels. Beneficial effects of levothyroxine have been described.1 Allan–Herndon–Dudley syndrome is an X-linked disorder of childhood onset with psychomotor retardation, including speech and developmental delay and spastic quadriplegia, caused by defects in the MCT8 (SLC16A2) gene encoding a membrane transporter. In addition to neurological abnormalities, ♂ patients have ↑ FT3, ↓ FT4, and normal TSH levels. Triac, a T3 analogue, has been shown to be of clinical benefit. 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 ♂ infertility, skeletal myopathy, photosensitivity, and hearing loss in adults. TFTs show ↑ FT4, normal/↓ FT3, and normal TSH levels due to functional D2 deficiencies. Box 1.1 Thyroid hormone resistance (RTH) Rare syndrome (incidence 1:40,000) characterized by reduced responsiveness to elevated circulating levels of FT4 and FT3, 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 TRβ gene defects, and identification by gene sequencing can confirm diagnosis in 80–85%.  Differential diagnosis includes TSH-secreting pituitary tumour (see Thyrotrophinomas, pp. 200–201). Most cases require no treatment. If needed, it is usually β-adrenergic blockers to ameliorate some of the tissue effects of raised thyroid hormone levels. References 1. Moran C, Chatterjee K (2015). Resistance to thyroid hormone due to defective thyroid receptor alpha. Best Pract Res Clin Endocrinol Metab 29, 647–57. Antibody screen Raised serum concentrations of thyroid antibodies (antithyroid peroxidase (microsomal) (TPOAb) and anti-thyroglobulin (TgAb)) correlate with the presence of focal thyroiditis in thyroid tissue obtained by biopsy and at autopsy from patients with no evidence of hypothyroidism during life. Early postmortem studies confirmed histological evidence of chronic autoimmune thyroiditis in 27% of adult ♀, with a rise in frequency over 50 years, and 7% of adult ♂, and diffuse changes in 5% of ♀ and 1% of ♂. Patients with hypothyroidism caused by either atrophic or goitrous autoimmune thyroiditis usually have high serum concentrations of these same antibodies. These antibodies also are often detected in serum of patients with Graves’ disease and other thyroid diseases, but the concentrations are usually lower. There is considerable variation in the frequency and distribution of antithyroid antibodies because of variations in techniques of detection, definition of abnormal titres, and inherent differences in the populations tested. A significant proportion of subjects in the community have asymptomatic chronic autoimmune thyroiditis of whom a substantial proportion have subclinical hypothyroidism. The percentage of subjects with high serum TPOAb and TgAb concentrations increase with age in both ♂ and ♀, and high concentrations were more prevalent in ♀ than in ♂, and less prevalent in blacks than in other ethnic groups. A hypoechoic ultrasound (US) pattern may precede TPOAb positivity in autoimmune thyroid disease (AITD), and TPOAb may not be detected in >20% of individuals with US evidence of thyroid autoimmunity (see Table 1.6). Table 1.6 Antithyroid antibodies and thyroid disease Condition Anti-TPO Anti-Tg TRAb Graves’ disease 70–80% 30–50% 70–100% (stimulating) Autoimmune hypothyroidism 95% 60% 10–20% (blocking) NB. TRAbs may be stimulatory or inhibitory. Heterophile antibodies present in patient sera may cause abnormal interference, causing abnormally low or high values of FT4 and FT3, and can be removed with absorption tubes. Screening for thyroid disease Controversy exists as to whether healthy adults living in an area of iodine sufficiency benefit from screening for thyroid disease (see Box 1.2). The benefit from a screening programme must outweigh the physical and psychological harm caused by the test, diagnostic procedures, and treatment. The prevalence of unsuspected overt thyroid disease is low, but a substantial proportion of subjects tested will have evidence of thyroid dysfunction, with ~10% with subclinical hypothyroidism and 1% with subclinical hyperthyroidism. No appropriately powered prospective, randomized controlled, double-blinded interventional trial of either levothyroxine therapy for subclinical hypothyroidism or antithyroid therapy for subclinical hyperthyroidism exists.1,2 Box 1.2 Recommendations for screening for thyroid dysfunction in an iodine-replete community Screening in ♀ 10mU/L, irrespective of whether FT4 is low.  Subjects with serum TSH between 5 and 10mU/L and normal FT4 are at ↑ risk of developing hypothyroidism, and repeat measurement of serum TSH is warranted at least every 3 years, if not annually. If suppressed serum TSH is found at screening, it should be remeasured 2 months later, and if it is still suppressed, FT3 should be measured. After levothyroxine replacement is initiated, for whatever indication, long-term follow-up with at least an annual measurement of serum TSH is required. The following categories of patients should be screened for thyroid disease: The value of screening for congenital hypothyroidism in heel-prick blood specimens is unquestioned (1:2000 newborns). There is no consensus on whether healthy pregnant ♀ should be screened for thyroid disorders or post-partum thyroiditis, although it has been shown to be cost-effective in analytical models. Patients with a goitre, atrial fibrillation, and hyperlipidaemia. Subfertility and osteoporosis. Annual review of people with diabetes mellitus (DM) appears cost- effective. ♀ with type 1 diabetes mellitus (T1DM) in the 1st trimester of pregnancy and post-delivery (because of 3-fold increase in incidence of post-partum thyroid dysfunction in such patients) (see Post-partum thyroid dysfunction, p. 477).3,4,5 Periodic (6-monthly) assessments in patients receiving amiodarone, lithium, and interferon-alfa, and within 3 months of initiation of immune checkpoint inhibitor therapy. ♀ with past history of post-partum thyroiditis. Annual check of thyroid function in people with Down’s syndrome, Turner syndrome, and autoimmune Addison’s disease6 and following head and neck irradiation, in view of the high prevalence of hypothyroidism in such patients. All patients with hyperthyroidism who receive ablative treatment should be followed indefinitely for the development of hypothyroidism  beginning 4–8 weeks after treatment, and then at 3-monthly intervals for 1 year and annually thereafter. Among patients hospitalized for acute illness, testing should be limited, but with a high index of clinical suspicion and with an awareness of the difficulties in interpreting TFTs in the presence of acute illness. ♀ with thyroid autoantibodies—8× risk of developing hypothyroidism over 20 years, compared to antibody −ve controls. ♀ with thyroid autoantibodies and isolated elevated TSH—38× risk of developing hypothyroidism, with 4% annual risk of overt hypothyroidism. Maternal thyroid antibodies are associated with recurrent miscarriage and preterm birth.4 Levothyroxine in euthyroid ♀ with TPOAbs did not increase the rate of live births.7 References 1. Taylor PN, et al. (2018). Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol 14, 301–16. 2. Rugge JB, et al. (2015). Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive services task force. Ann Intern Med 162, 35–45. 3. Biondi B, et al. (2019). Thyroid dysfunction and diabetes mellitus: two closely associated disorders. Endocr Rev 40, 789–824. 4. De Leo S, Pearce EN (2018). Autoimmune thyroid disease during pregnancy. Lancet Diabetes Endocrinol 6, 575–86. 5. Dosiou C, et al. (2012). Cost-effectiveness of universal and risk-based screening for autoimmune thyroid disease in pregnant women. J Clin Endocrinol Metab 97, 1536–46. 6. Fallahi P, et al. (2016). The association of other autoimmune diseases in patients with autoimmune thyroiditis: review of the literature and report of a large series of patients. Autoimmun Rev 15, 1125–8. 7. Dhillon-Smith RK, et al. (2019). Levothyroxine in women with thyroid peroxidase antibodies before conception. N Engl J Med 380, 1316–25. Scintiscanning Permits localization of sites of accumulation of radioiodine or sodium pertechnetate (99mTc), which gives information about the activity of the iodine trap by the NIS. After IV pertechnetate, imaging and uptake measurements are obtained within 10–20 minutes, rather than hours or days, as is the case with radioiodine. The percentage uptake is usually in the range of 1.5–3.5%.  123 Oral I has a clinically useful half-life of 13 hours and can be used in routine diagnostic scans or whole-body scans (WBS) at 24–48 hours with high-quality images at low radiation dose, providing quantitative information in imaging residual thyroid and functioning metastases after thyroidectomy in thyroid cancer. Oral 131I, with a half-life of 8 days, is used for WBS 5–10 days post- therapeutic 131I but provides lower-quality imaging and has a higher dose of radiation. Thyroid isotope imaging can be used: To define areas of ↑ or ↓ function within the thyroid (see Table 1.7), which occasionally helps in cases of uncertainty as to the cause of the thyrotoxicosis. To distinguish between Graves’ disease and thyroiditis (autoimmune or viral—de Quervain’s thyroiditis). To detect retrosternal goitre. To detect ectopic thyroid tissue. Factors that can alter thyroid imaging 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 that can potentially interfere with the interpretation of the scan. Table 1.7 Radionuclide scanning (scintigram) in thyroid disease Condition Scan appearance Graves’ Enlarged gland Homogeneous radionucleotide uptake hyperthyroidism Thyroiditis (e.g. de Low or absent uptake Quervain’s or autoimmune) Toxic nodule A solitary area of high uptake Thyrotoxicosis Depressed thyroid uptake factitia Thyroid cancer Successful 131I uptake by tumour tissue requires an adequate level of TSH, achieved by giving recombinant TSH injection or stopping T3 replacement 10 days before scanning Ultrasound scanning Provides an accurate indication of thyroid size and assesses if focal or diffuse thyroid disease. US is useful for differentiating cystic nodules from solid ones, whether a nodule is solitary or part of a multinodular process, and sequential scanning can assess changes in size over time. It is not routinely indicated in a patient with a goitre. In Hashimoto’s thyroiditis and Graves’ disease, the lymphocytic infiltration and damage to tissue architecture result in a variable decrease in echogenicity. Colour Doppler imaging shows ↑ blood flow in Graves’ disease, while in Hashimoto’s thyroiditis, vascularization may be either moderately ↑ or nearly completely absent. de Quervain’s thyroiditis is characterized by multiple ill-defined hypoechoic areas. US is useful for differentiating cystic nodules from solid ones, whether a nodule is solitary or part of a multinodular process, and sequential scanning can assess changes in size over time. It is not routinely indicated in a patient with a goitre. When performed by an experienced sonographer, it can be used to distinguish between benign and malignant disease. A few well-defined ultrasonographic prognostic finding are recognized:1,2 Benign lesion: simple cyst (fluid collection with thin, regular margins), spongiform nodule, and mostly cystic nodule (>80%) containing colloid fluid (comet tail signs) with regular margins devoid of vascular signals. Suspicious for thyroid cancer: hypoechoic, microcalcifications (4cm), US-guided FNAC directed at several areas within the nodule may reduce the risk of a false −ve biopsy. It is impossible to differentiate between benign and malignant follicular neoplasm using FNAC. Therefore, surgical excision of a follicular neoplasm is usually indicated (see Follicular thyroid carcinoma, p. 112). An FNAC which initially yields benign cytology (Thy2) should be repeated if there is any clinical suspicion of malignancy and/or when the US is indeterminate or suspicious. There is a false −ve rate for benign (Thy2) cytology results (usually 98% risk of malignancy). Radiotherapy/chemotherapy for anaplastic thyroid cancer, lymphoma/metastases References 1. Xing M, et al. (2013). Progress in molecular-based management of differentiated thyroid cancer. Lancet 381, 1058–69. 2. Nikiforov YE (2017). Role of molecular markers in thyroid nodule management: then and now. Endocr Pract 23, 979–88. Computed tomography Computed tomography (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. Further reading Kim DW, Jung SJ, Baek HJ (2015). Computed tomography features of benign and malignant solid thyroid nodules. Acta Radiol 56, 1196–202. Positron emission tomography Up to 20% of thyroid incidentalomas found on positron emission tomography (PET) scans may be malignant and usually require US- guided FNAC. However, overall survival may be poor because of the prognosis associated with underlying malignancy, which must be considered before investigation and certainly before aggressive treatment. Active surveillance can be considered in this group of patients.1,2 18F-fluorodeoxyglucose (FDG)-PET/CT is a useful technique for imaging dedifferentiation of metastatic thyroid cancer and is also valuable for risk stratification and prediction of survival in high-risk thyroid cancer patients. Recurrent thyroid cancer that is FDG avid-positive on FDG PET scanning is unlikely to respond to even high-dose radioiodine therapy. 124I PET/CT is more sensitive in detecting metastatic thyroid cancer than γ camera imaging with 131I. References 1. Abdel-Halim CN, et al. (2019). Risk of malignancy in FDG-avid thyroid incidentalomas on PET/CT: a prospective study. World J Surg 43, 2454–8. 2. Chung SR, et al. (2018). Thyroid incidentalomas detected on 18F-fluorideoxyglucose positron emission tomography with computed tomography: malignant risk stratification and management plan. Thyroid 28, 762–8. Further reading Pattison DA, et al. (2018). 18F-FDG-avid thyroid incidentalomas: the importance of contextual interpretation. J Nucl Med 59, 749–55. Russ G, et al. (2014). Thyroid incidentalomas: epidemiology, risk stratification with ultrasound and workup. Eur Thyroid J 3, 154–63. Additional laboratory investigations Haematological tests Long-standing thyrotoxicosis may be associated with normochromic anaemia, and occasionally mild neutropenia and lymphocytosis, and rarely thrombocytopenia. In hypothyroidism, a macrocytosis is typical, although concurrent vitamin B12 deficiency should be considered. There may also be a microcytic anaemia due to menorrhagia and impaired iron utilization. Biochemical tests Alkaline phosphatase (ALP) may be elevated in thyrotoxicosis. Mild hypercalcaemia occasionally occurs in thyrotoxicosis and reflects ↑ bone resorption. Hypercalciuria is commoner. In a hypothyroid patient, hyponatraemia may be due to reduced renal tubular water loss or, less commonly, due to coexisting cortisol deficiency. In hypothyroidism, creatinine kinase is often raised and the lipid profile altered with ↑ low-density lipoprotein cholesterol (LDL-C). Endocrine tests In untreated hypothyroidism, there may be inadequate responses to provocative testing of the hypothalamic–pituitary–adrenal (HPA) axis. In hypothyroidism, serum prolactin (PRL) may be elevated because ↑ TRH leads to ↑ PRL secretion (may be partly responsible for ↓ fertility in young women with hypothyroidism). In thyrotoxicosis, there is an increase in sex hormone-binding globulin (SHBG) and a complex interaction with sex steroid hormone metabolism, resulting in changes in levels of androgens and oestrogens.  The net physiological result is an increase in oestrogenic activity, with gynaecomastia and a decrease in libido in ♂ presenting with thyrotoxicosis. Non-thyroidal illness (sick euthyroid syndrome) Multiple mechanisms have been identified to contribute to the development of sick euthyroid syndrome, including alterations in iodothyronine deiodinases, TSH secretion, thyroid hormone binding to plasma protein, transport of thyroid hormone in peripheral tissues, and TRr activity. Sick euthyroid syndrome appears to be a complex mix of physiologic adaptation and pathologic response to acute illness. The underlying cause for these alterations has not yet been elucidated. Biochemistry: ↓ T4 and T3. Inappropriately normal/↓ TSH. Tissue thyroid hormone concentrations are very low. Context—starvation. Severe illness, e.g. ITU, severe infections, renal failure, cardiac failure, liver failure, end-stage malignancy. Treatment of euthyroid sick syndrome with thyroid hormone to restore normal serum thyroid hormone levels in an effort to improve disease prognosis and outcomes continues to be a focus of many clinical studies However, thyroxine replacement is not indicated because there is no evidence that treatment provides benefit or is safe. Pitfalls with TFTs in NTI are shown in Box 1.3. Box 1.3 Pitfalls with thyroid function tests in non-thyroidal illness TSH suppressed in hospitalized patients with acute illness. Dopamine and steroids may suppress TSH, e.g. in critically ill patients. TSH increase during recovery from acute illness. TSH may fall during 1st trimester of pregnancy (human chorionic gonadotrophin (hCG)). TSH inhibited by SC octreotide.  Anorexia nervosa is associated with low TSH and FT4. Heterophilic antibodies, including rheumatoid factor, may falsely elevate TSH. Adrenal insufficiency (AI) may be associated with raised TSH which reverses on treatment with GCs. Heparin leads to ↑ FT4 and no change in TSH. Further reading Fliers E, et al. (2015). Thyroid function in critically ill patients. Lancet Diabetes Endocrinol 3, 816– 25. Lee S, Farwell AP (2016). Euthyroid sick syndrome. Compr Physiol 15, 1071–80. Atypical clinical situations Thyrotoxicosis factitia (usually unprescribed intake of exogenous thyroid hormone in non-thyroid disease): No thyroid enlargement. ↑ FT4 and suppressed TSH. Depressed thyroid uptake on scintigraphy. ↓ Tg differentiates from thyroiditis (which shows depressed uptake on scintigraphy, but ↑ Tg) and all other causes of elevated thyroid hormones. Struma ovarii (ovarian teratoma containing hyperfunctioning thyroid tissue): No thyroid enlargement. Depressed thyroid uptake on scintigraphy. Body scan after radioiodine confirms diagnosis. Trophoblast tumours. hCG has structural homology with TSH and leads to thyroid gland stimulation and usually mild thyrotoxicosis. Hyperemesis gravidarum. TFTs may be abnormal with suppressed TSH (see Thyrotoxicosis in pregnancy, pp. 50–54). Choriocarcinoma of the testes may be associated with gynaecomastia and thyrotoxicosis—measure hCG. Thyrotoxicosis—aetiology Epidemiology Ten times commoner in ♀ than in ♂ in the UK. Prevalence is ~2% of the ♀ population. Annual incidence is three cases per 1000 ♀. Definition of thyrotoxicosis and hyperthyroidism The term thyrotoxicosis denotes the clinical, physiological, and biochemical findings that result when the tissues are exposed to excess thyroid hormone. It can arise in a variety of ways (see Table 1.10). It is essential to establish a specific diagnosis, as this determines therapy choices and provides important information for the patient regarding prognosis. The term hyperthyroidism should be used to denote only those conditions in which hyperfunction of the thyroid leads to thyrotoxicosis. Genetics of autoimmune thyroid disease1 AITD consists of Graves’ disease, Hashimoto’s thyroiditis, atrophic autoimmune hypothyroidism, post-partum thyroiditis, and Graves’ orbitopathy (GO) that appear to share a common genetic predisposition. There is a ♂ preponderance, and sex steroids appear to play an important role. Twin studies show ↑ concordance (20–40%) for Graves’ disease and autoimmune hypothyroidism in monozygotic, compared to dizygotic, twins. It is estimated that genetic factors account for ~70% of the susceptibility for Graves’ disease. Sibling studies indicate that sisters and children of ♂ with Graves’ disease have a 5–8% risk of developing Graves’ disease or autoimmune hypothyroidism. On the background of a genetic predisposition, environmental factors are thought to contribute to the development of disease. A number of interacting susceptibility genes are thought to play a role in the development of disease—a complex genetic trait. Data emphasize  the complex nature of genetic susceptibility and the likely interplay of environmental factors. CTLA-4 (cytotoxic T lymphocyte antigen-4) is associated with Graves’ disease in Caucasian populations. In particular, the CT60 allele has a prevalence of 60% in the general population but is also the allele most highly associated with Graves’ disease. Association of major histocompatibility complex (MHC) loci with Graves’ disease has been demonstrated in some populations, but not in others. HLA-DR3 is associated with Graves’ disease in whites. HLA- DQA1*0501 is associated in some populations, especially for men. However, the overall contribution of MHC genes to Graves’ disease has been estimated to be only 10–20% of the inherited susceptibility. There is evidence of ↑ risks associated with polymorphisms of intron 1 in the TSH receptor gene and the Tg gene. Table 1.10 Classification of the aetiology of thyrotoxicosis Associated with hyperthyroidism Excessive Graves’s disease, Hashitoxicosis Pituitary thyrotroph adenoma Pituitary thyroid thyroid hormone resistance syndrome (excess TSH) (see Secondary hyperthyroidism, stimulation pp. 58–59) Trophoblastic tumours producing hCG with thyrotrophic activity Thyroid Toxic solitary nodule, toxic multinodular goitre Very rarely, thyroid cancer nodules with autonomous function Not associated with hyperthyroidism Thyroid Silent and post-partum thyroiditis, subacute (de Quervain’s) thyroiditis Drug- inflammation induced thyroiditis (amiodarone, interferon-alfa, lithium, TKIs, immunotherapy) Exogenous Overtreatment with thyroid hormone Thyrotoxicosis factitia (thyroxine use in non- thyroid thyroidal disease) hormones Ectopic Metastatic thyroid carcinoma Struma ovarii (teratoma containing functional thyroid tissue thyroid tissue) Thyrotoxicosis in COVID-19 Early studies2 have shown preliminary evidence that coronavirus disease (COVID-19) may affect thyroid function, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may act directly on thyroid cells. Data suggest a high risk of thyrotoxicosis in parallel with the systemic immune reaction induced by infection. References 1. Brix TH, Hegedüs L (2011). Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity. Ann Endocrinol (Paris) 72, 103–7. 2. Lania A, et al. (2020). Thyrotoxicosis in patients with COVID-19: the THYRCOV study. Eur J Endocrinol 183, 381–7. Further reading Marino M, et al. (2015). Role of genetic and non-genetic factors in the etiology of Graves’ disease. J Endocrinol Invest 38, 283–94. Manifestations of hyperthyroidism (See Box 1.4.) Box 1.4 Manifestations of hyperthyroidism (all forms) Symptoms Hyperactivity, irritability, altered mood, insomnia. Heat intolerance, ↑ sweating. Palpitations. Fatigue, weakness. Dyspnoea. Weight loss with ↑ appetite (weight gain in 10% of patients). Pruritus. ↑ stool frequency. Thirst and polyuria. Oligomenorrhoea or amenorrhoea, loss of libido, erectile dysfunction (50% of men may have sexual dysfunction). Signs Sinus tachycardia, atrial fibrillation. Fine tremor, hyperkinesia, hyperreflexia. Warm, moist skin. Palmar erythema, onycholysis. Hair loss. Muscle weakness and wasting.  Congestive (high-output) heart failure, chorea, periodic paralysis (primarily in Asian ♂), psychosis (rare). Investigation of thyrotoxicosis (See Table 1.11.) TFTs—↑ FT4 and suppressed TSH (↑ FT3 in T3 toxicosis). TRAbs1 (see Table 1.6). The 2nd- and 3rd-generation TRAb assays have >95% sensitivity and specificity for the diagnosis of Graves’ disease and have improved the utility of TRAb to predict relapse. TRAb levels decline with antithyroid drug (ATD) therapy and after thyroidectomy. Levels increase for a year following radioiodine therapy, with a gradual fall thereafter. TRAb ≥5IU/L in pregnant ♀ with current or previously treated Graves’ disease is associated with ↑ risk of fetal and neonatal thyrotoxicosis, and hence close monitoring is needed. TRAb levels parallel the course of GO, and elevated TRAb is an indication for steroid prophylaxis to prevent progression of orbitopathy with radioiodine therapy. Radionucleotide thyroid scan if diagnosis uncertain (see Ultrasound scanning, p. 20), but now seldom required, unless radioiodine is planned. Manifestations of Graves’ disease2,3,4 (In addition to those in Box 1.4) Diffuse goitre with bruit. Orbitopathy (see Graves’ orbitopathy, pp. 60–62). A feeling of grittiness and discomfort in the eye. Retrobulbar pressure or pain, eyelid lag or retraction. Periorbital oedema, chemosis,>Combination scleral injection.* Exophthalmos (proptosis).* Extraocular muscle dysfunction.* Exposure keratitis.* Optic neuropathy.* Localized dermopathy (pretibial myxoedema; see Graves’ dermopathy, p. 68). Lymphoid hyperplasia. Thyroid acropachy (see Thyroid acropachy, p. 68). Table 1.11 Tests which help to differentiate different causes of thyrotoxicosis Cause Thyroid iodine uptake TPO antibodies TRAbs Tg Graves’ disease ↑ Usually +ve + ↑ Toxic nodular goitre ↑ − − ↑ TSH-secreting pituitary adenoma ↑ − − ↑ Hyperemesis gravidarum ↑ − − ↑ Trophoblastic tumour ↑ − − ↑ de Quervain’s thyroiditis ↓ − − ↑ Drugs, e.g. amiodarone ↓ Usually −ve − ↑ Struma ovarii ↓ − − ↑ Thyrotoxicosis factitia ↓ − − ↓ * Combination of these suggests congestive ophthalmopathy. Urgent action necessary if: corneal ulceration, congestive ophthalmopathy, or optic neuropathy (see Graves’ orbitopathy, pp. 60–62). Conditions associated with Graves’ disease5 T1DM. Addison’s disease. Vitiligo. Pernicious anaemia. Alopecia areata. Myasthenia gravis. Coeliac disease (4.5%). Other autoimmune disorders associated with the HLA-DR3 haplotype. References 1. Hesarghatta Shyamasunder A, Abraham P (2017). Measuring TSH receptor antibody to influence treatment choices in Graves’ disease. Clin Endocrinol (Oxf) 86, 652–7. 2. Gilbert J (2017). Thyrotoxicosis: investigation and management. Clin Med (Lond) 17, 274–7. 3. De Leo S, et al. (2016). Hyperthyroidism. Lancet 388, 906–18. 4. Burch HB, Cooper DS (2015). Management of Graves’ disease: a review. JAMA 314, 2544–54. 5. Ferrari SM, et al. (2019). The association of other autoimmune diseases in patients with Graves’ disease (with or without ophthalmopathy): review of the literature and report of a large series. Autoimmun Rev 18, 287–92. Medical treatment In general, the standard policy in Europe is to offer a course of ATD first. However, recent National Institute for Health and Care Excellence (NICE) guidance has recommended early consideration of radioactive iodine (RAI) ( https://cks.nice.org.uk/topics/hyperthyroidism/). In the United States (USA), radioiodine is more likely to be offered as 1st-line treatment. Regardless of the method of treatment, early and effective control of hyperthyroidism among patients with Graves’ disease is associated with improved survival, compared with less effective control. Rapid and sustained control of hyperthyroidism should be prioritized in the management of Graves’ disease, and early definitive treatment with radioiodine should be offered to patients who are unlikely to achieve remission with ATD alone. Aims and principles of medical treatment To induce remission in Graves’ disease. Monitor for relapse off treatment, initially 6- to 8-weekly for 6 months, then 6-monthly for 2 years, and then annually thereafter or sooner if symptoms return. For relapse, consider definitive treatment, such as radioiodine or surgery. A 2nd course of ATD rarely results in remission. Choice of drugs—thionamides Carbimazole, which can be given as a once-daily (od) dose, is usually the drug of 1st choice in the UK. Carbimazole is converted to methimazole by cleavage of a carboxyl side chain on 1st liver passage. It has a lower rate of side effects when compared with PTU (14% vs 52%). PTU should never be used as a 1st-line agent in either children or adults, with the possible exceptions of pregnant women and patients with life-threatening thyrotoxicosis. PTU use should be restricted to circumstances when neither surgery nor RAI is a treatment option in a patient who has developed a side effect (not agranulocytosis) to carbimazole and ATD therapy is needed. During the 1st trimester of pregnancy, PTU is preferred because of the association of carbimazole with aplasia cutis. Action of thionamides  Thyroid hormone synthesis is inhibited by blockade of the action of TPO. Thionamides are especially actively accumulated in thyrotoxic tissue. PTU also inhibits deiodinase type 1 activity and thus may have advantages when given at high doses in sev