Endocrinology

Series Editor Andrea Lenzi Department of Experimental Section of Medical Pathophysiology Food Science and Endocrinology Sapienza University of Rome Rome, Series Co-Editor Emmanuele A. Jannini Department of Systems Medicine University of Rome Tor Vergata Rome, Italy Within the health sciences, Endocrinology has an unique and pivotal role. This old, but continuously new science is the study of the various hormones and their actions and disorders in the body. The matter of Endocrinology are the glands, i.e., the organs that produce hormones, active on the metabolism, reproduction, food absorp- tion and utilization, growth and development, behavior control, and several other complex functions of the organisms. Since hormones interact, affect, regulate, and control virtually all body functions, Endocrinology not only is a very complex science, multidisciplinary in nature, but is one with the highest scientific turnover. Knowledge in the Endocrinological sciences is continuously changing and growing. In fact, the field of Endocrinology and Metabolism is one where the highest number of scientific publications continuously flourishes. The number of scientific journals dealing with hormones and the regulation of body is dramatically high. Furthermore, Endocrinology is directly related to genetics, neurology, immunology, rheumatology, gastroenterology, nephrology, orthopedics, cardiology, oncology, gland , psychology, psychiatry, internal medicine, and basic sciences. All these fields are interested in updates in Endocrinology. The aim of the MRW in Endocrinology is to update the Endocrinological matter using the knowledge of the best experts in each section of Endocrinology: basic endocrinology, neuroendocri- nology, endocrinological oncology, pancreas with diabetes and other metabolic disorders, thyroid, parathyroid and bone metabolism, adrenals and endocrine hyper- tension, sexuality, reproduction, and behavior.

More information about this series at http://www.springer.com/series/14021 Paolo Vitti • Laszlo Hegedüs Editors

Thyroid Diseases

Pathogenesis, Diagnosis, and Treatment

With 117 Figures and 101 Tables Editors Paolo Vitti Laszlo Hegedüs Department of Endocrinology Department of Endocrinology and University of Metabolism Pisa, Italy Odense University Hospital Odense, Denmark

ISBN 978-3-319-45012-4 ISBN 978-3-319-45013-1 (eBook) ISBN 978-3-319-46284-4 (print and electronic bundle) https://doi.org/10.1007/978-3-319-45013-1

Library of Congress Control Number: 2018939426

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This Springer imprint is published by the registered company Springer International Publishing AG part of Springer Nature. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Series Preface

Is there an unmet need for a new MRW series in Endocrinology and Metabolism? It might not seem so! The vast number of existing textbooks, monographs and scientific journals suggest that the field of hormones (from genetic, molecular, biochemical and translational to physiological, behavioral, and clinical aspects) is one of the largest in biomedicine, producing a simply huge scientific output. However, we are sure that this new Series will be of interest for , academics, students, and specialists alike. The knowledge in Endocrinology and Metabolism almost limited to the two main (from an epidemiological perspective) diseases, namely hypo/hyperthy- roidism and diabetes mellitus, now seems outdated and closer to the interests of the general practitioner than to those of the specialist. This has led to endocrinol- ogy and metabolism being increasingly considered as a subsection of internal medicine rather than an autonomous specialization. But endocrinology is much more than this. We are proposing this series as the manifesto for “Endocrinology 2.0”, embrac- ing the fields of medicine in which hormones play a major part but which, for various historical and cultural reasons, have thus far been “ignored” by endocrinologists. Hence, this MRW comprises “traditional” (but no less important or investigated) topics: from the molecular actions of hormones to the pathophysiology and man- agement of pituitary, thyroid, adrenal, pancreatic and gonadal diseases, as well as less common arguments. Endocrinology 2.0 is, in fact, the science of hormones, but it is also the medicine of sexuality and reproduction, the medicine of gender differences and the medicine of wellbeing. These aspects of Endocrinology have to date been considered of little interest, as they are young and relatively unexplored sciences. But this is no longer the case. The large scientific production in these fields coupled with the impressive social interest of patients in these topics is stimulating a new and fascinating challenge for Endocrinology. The aim of the MRW in Endocrinology is thus to update the subject with the knowledge of the best experts in each field: basic endocrinology, neuroendocrinol- ogy, endocrinological oncology, pancreatic disorders, diabetes and other metabolic disorders, thyroid, parathyroid and bone metabolism, adrenal and endocrine

v vi Series Preface hypertension, sexuality, reproduction and behavior. We are sure that this ambitious aim, covering for the first time the whole spectrum of Endocrinology 2.0, will be fulfilled in this vast Springer MRW in Endocrinology Series.

Andrea Lenzi, M.D. Series Editor Emmanuele A. Jannini, M.D. Series Co-Editor Volume Preface

Despite the availability of a number of endocrine textbooks, we believe that there is a need for a comprehensive volume on the thyroid, which can be used by trainees, general endocrinologist, and experts in the field alike. The present one, available as a book, but also electronically, and intended to be updated online whenever develop- ments warrant this, in our minds fills a void. Covering the majority of clinically relevant phenotypes, and thyroid physiology as well as pathogenesis, diagnosis, and treatment, we have been fortunate to profit from the dedicated service of a number of recognized and authoritative experts. Challengingly, being the first in a series of volumes intended to eventually cover all of endocrinology, there has been little precedence to learn from and to use as a point de référence. The original idea for this volume was nurtured in the garden of the Italian Society of Endocrinology and was then developed together with another European as co-editor. The cutting-edge information is provided by a bouquet of mainly European colleagues but also some from the USA, Canada, and . With this in mind, we can only hope that the many instruments, or at least their players, orchestrated a tune that to the readers appears as one harmonious melody and not a cacophony of contradictions and overlaps. The two conductors have agreed and followed the same score, and a strong friendship has developed over the nearly 3 years from conception to delivering a final product. The first of seven sections covers regulation of thyroid function, synthesis of thyroid hormones, and their mechanism of action. To be followed by thyroid tests and imaging and moving into thyroid diseases highlighting basic concepts, clinical diagnoses, and in greater detail. The solitary thyroid nodule and multinodular goiter constitute the second part, while the next covers Hashimoto’s and the other types of thyroiditis. The fourth section deals with different types of hypothyroidism, while thyrotoxicosis and hyperthyroidism, autoimmune and non-autoimmune, are covered in the fifth section. Here, also the newest development in the diagnosis and management of the very challenging and complex Graves’ ophthalmopathy is given much attention. The section on thyroid carcinomas, in addition to describing the various histiotypes, discusses pathogenesis and the newest medical therapies as well as the most recently elucidated molecular mechanisms and genetic defects. In the last section, a number of other conditions influencing thyroid function, or inducing thyroid dysfunction, come in focus. Pregnancy, nonthyroidal

vii viii Volume Preface illness, and the ever expanding and complicated effects of drugs and other sub- stances that influence and interfere with thyroid function are offered competent attention. A separate pharmacopeia has not been deemed necessary. However, pharmacological treatments are included in the chapters where relevant. Just a few weeks after delivering his chapter on “Regulation of Thyroid Function, Synthesis and Function of Thyroid Hormone” the chocking message of the untimely passing away of professor Theo J. Visser reached us. It is with sadness, but also great affection and respect, that we dedicate this book to the memory of a gentle, humorous giant of a researcher and colleague. Needless to say, we are indebted to all our colleagues who have kindly and generously dedicated time and enthusiasm to contribute so competently to this text. As ever, our thanks go to our families for their patience and support during our absence with this endeavor at mind.

Pisa and Odense Paolo Vitti, M.D., Ph.D. April 2018 Laszlo Hegedüs, M.D., D.M.Sc. Contents

Part I Thyroid Physiology and Laboratory Evaluation of the Thyroid ...... 1

1 Regulation of Thyroid Function, Synthesis, and Function of Thyroid Hormones ...... 3 Theo J. Visser 2 Tests of Thyroid Function ...... 33 Giovanni Ceccarini, Ferruccio Santini, and Paolo Vitti 3 Thyroid Autoantibodies ...... 57 R. A. Ajjan and A. P. Weetman 4 Nonisotopic Thyroid Imaging ...... 89 E. Papini, R. Guglielmi, G. Bizzarri, and A. Frasoldati

Part II Goiter and Thyroid Nodule ...... 125

5 Nontoxic Goiter ...... 127 Steen Joop Bonnema and Laszlo Hegedüs 6 Thyroid Nodule ...... 165 Markus Eszlinger, Laszlo Hegedüs, and Ralf Paschke

Part III Thyroiditis ...... 203

7 Hashimoto’s Thyroiditis ...... 205 Wilmar M. Wiersinga 8 Postpartum Thyroiditis and Silent Thyroiditis ...... 249 Lakdasa D. Premawardhana, Onyebuchi E. Okosieme, and John H. Lazarus 9 Acute and Subacute Thyroiditis ...... 277 Karen M. Rothacker and John P. Walsh

ix x Contents

Part IV Hypothyroidism ...... 299

10 Classification and Etiopathogenesis of Hypothyroidism ...... 301 Luca Chiovato, Stefano Mariotti, and Flavia Magri

11 Congenital Hypothyroidism ...... 333 Caterina Di Cosmo and Massimo Tonacchera

12 Central Hypothyroidism ...... 373 Andrea Lania, Claudia Giavoli, and Paolo Beck-Peccoz

13 Diagnosis and Treatment of Hypothyroidism ...... 391 Suhel Ashraff and Salman Razvi

Part V Hyperthyroidism and Thyrotoxicosis ...... 427

14 Graves’ Disease ...... 429 Catherine Napier and Simon H. S. Pearce

15 Graves’ Ophthalmopathy ...... 451 Claudio Marcocci and Terry J. Smith

16 Treatment of Graves’ Disease ...... 489 Luigi Bartalena

17 Toxic Adenoma and Multinodular Toxic Goiter ...... 513 Massimo Tonacchera and Dagmar Führer

Part VI Thyroid Carcinoma ...... 541

18 Pathogenesis of Thyroid Carcinoma ...... 543 Massimo Santoro and Francesca Carlomagno

19 Differentiated Thyroid Carcinoma of Follicular Origin ...... 563 Furio Pacini, Maria Grazia Castagna, and Martin Schlumberger

20 Medullary Carcinoma ...... 589 Rossella Elisei and Barbara Jarzab

21 Anaplastic and Other Forms of Thyroid Carcinoma ...... 629 Leonard Wartofsky

22 New (Medical) Treatment for Thyroid Carcinoma ...... 645 Sebastiano Filetti and Steven I. Sherman Contents xi

Part VII Other Conditions Influencing Thyroid Function or Inducing Thyroid Dysfunction ...... 671

23 Thyroid Physiology and Thyroid Diseases in Pregnancy ...... 673 Bijay Vaidya and Shiao-Yng Chan 24 Non-thyroidal Illness ...... 709 Theodora Pappa and Maria Alevizaki 25 Drugs and Other Substances Interfering with Thyroid Function ...... 733 Lucia Montanelli, Salvatore Benvenga, Laszlo Hegedüs, Paolo Vitti, Francesco Latrofa, and Leonidas H. Duntas Index ...... 763 About the Editors

Professor Laszlo Hegedüs, 65, is trained in Copenha- gen, Denmark. In 1992, having defended his thesis, he became a consultant at the Department of Endocrinology in Odense, Denmark. Here he built up a thyroid research group and became a Full Professor in 2006. Publications, more than 480, include chapters in leading endocrine textbooks and include diagnostic imaging; radioiodine therapy; ultrasound-guided diag- nosis and treatment of thyroid diseases; environmental and hereditary aspects of the regulation of thyroid func- tion and size; environmental and genetic background for thyroid disorders utilizing Danish twins; and late effects of thyroid diseases. Developing and utilizing ThyPRO to evaluate thyroid-related quality of life and the role of selenium in thyroid diseases are also in focus. Dr. Hegedüs has served as editor of Clinical Endo- crinology and as editorial board member of a number of journals. He has mentored around 50 individuals defending their academic theses. He is President-Elect of the European Thyroid Association and a former Pres- ident of the Danish Thyroid Association. He is exten- sively used at endocrine and thyroid teaching courses and has given more than 200 invited talks. Professor Hegedüs is the recipient of several prizes, including the George Murray lecture and the Pitt-Rivers lecture from the British Thyroid Association and the Frontiers in Science Award from the American Association of Clinical Endocrinologists.

xiii xiv About the Editors

Paolo Vitti is Full Professor of Endocrinology and Director of the School of Endocrinology at the Medical School, , Italy, and Chief of Endocri- nology at the University Hospital of Pisa. Dr. Vitti is a past member of the Executive Committee of the European Thyroid Association and a past Secretary of the Italian Thyroid Association. He was appointed with the European Thyroid Association – Merck Serono Prize 2014. He has been a member of the International Council for the Control of Iodine Deficiency Disorders (ICCIDD) since 1996 and an ICCIDD board member since 2003. He has also been Deputy-Regional Coordi- nator for the ICCIDD in West Central Europe since 2001 and a member of expert WHO/ICCIDD teams for exter- nal reviews in Kenya, Macedonia, and Peru. He is currently the President of Italian Society of Endocrinol- ogy. He is the author of over 150 articles, most of which have been published in authoritative international journals, and of a number of chapters of international and national endocrine textbooks. Contributors

R. A. Ajjan Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds Institute for Cardiovascular and Metabolic Medicine (LICAMM), Leeds, UK Maria Alevizaki Endocrine Unit, Department of Medical Therapeutics, Alexandra Hospital, School of Medicine, National Kapodistrian University, Athens, Greece Suhel Ashraff Institute of Genetic Medicine, Central Parkway, Newcastle Univer- sity, Newcastle upon Tyne, UK Luigi Bartalena Department of Medicine and Surgery, , Endocrine Unit, ASST dei Sette Laghi, Ospedale di Circolo, Varese, Italy Paolo Beck-Peccoz , Milano, Italy Salvatore Benvenga Department of Clinical and Experimental Medicine, Master Program of Childhood, Adolescent and Women’s Endocrine Health, Interdepartmental Program of Molecular and Clinical Endocrinology, and Women’s Endocrine Health, and A.O.U. Policlinico G. Martino, Messina, Italy G. Bizzarri Department of Diagnostic Imaging, Ospedale Regina Apostolorum, Albano (Rome), Italy Steen Joop Bonnema Department of Endocrinology, Odense University Hospital, DK, Odense, Denmark Francesca Carlomagno Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy Maria Grazia Castagna Department of Medical, Surgical and Neurological Sciences, University of , Siena, Italy Giovanni Ceccarini Endocrine Unit, University Hospital of Pisa, Pisa, Italy Shiao-Yng Chan Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

xv xvi Contributors

Luca Chiovato Department of Internal Medicine and Medical Therapy, - Unit of Internal Medicine and Endocrinology, IRCCS ICS Maugeri, Pavia, Italy Caterina Di Cosmo Department of Clinical and Experimental Medicine, Endocri- nology Unit, University Hospital of Pisa, University of Pisa, Pisa, Italy Leonidas H. Duntas Evgenideion Hospital, Unit of Endocrinology, Diabetes and Metabolism, University of Athens, Athens, Greece Rossella Elisei Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital, University of Pisa, Pisa, Italy Markus Eszlinger Department of Oncology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Sebastiano Filetti Department of Internal Medicine and Medical Specialties, Uni- versity of Rome Sapienza, Rome, Italy A. Frasoldati Department of Endocrinology, Ospedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy Dagmar Führer Department of Endocrinology, Diabetes and Metabolism, Univer- sity Hospital Essen, University Duisburg-Essen, Essen, Germany Claudia Giavoli Endocrinology and Metabolic Diseases Unit, Fondazione IRCCS Cà Granda-Ospedale Maggiore, Milano, Italy R. Guglielmi Department of Endocrinology and Metabolism, Ospedale Regina Apostolorum, Albano (Rome), Italy Laszlo Hegedüs Department of Endocrinology and Metabolism, Odense Univer- sity Hospital, Odense, Denmark Barbara Jarzab Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Institute – Cancer Center, Gliwice Branch, Gliwice, Poland Andrea Lania Department of Medical Sciences, and Endocrinology Unit, Humanitas Research Hospital, Rozzano, Italy Francesco Latrofa Department of Clinical and Experimental Medicine, Endocri- nology Unit 1, University Hospital of Pisa, Pisa, Italy John H. Lazarus Thyroid Research Group, Institute of Molecular and Experimen- tal Medicine, School of Medicine, Cardiff University, Cardiff, UK Flavia Magri Department of Internal Medicine and Medical Therapy, University of Pavia - Unit of Internal Medicine and Endocrinology, IRCCS ICS Maugeri, Pavia, Italy Contributors xvii

Claudio Marcocci Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Stefano Mariotti Departmet of Medical Sciences and Public Health, , Monserrato, CA, Italy Lucia Montanelli Department of Clinical and Experimental Medicine, Endocri- nology Unit 1, University Hospital of Pisa, Pisa, Italy Catherine Napier Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK Onyebuchi E. Okosieme Endocrine and Diabetes Department, Prince Charles Hospital, Cwm Taf University Health Board, Merthyr Tydfil, UK Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK Furio Pacini Department of Medical, Surgical and Neurological Sciences, , Siena, Italy E. Papini Department of Endocrinology and Metabolism, Ospedale Regina Apostolorum, Albano (Rome), Italy Theodora Pappa Section of Endocrinology, Diabetes and Metabolism, Depart- ment of Medicine, The University of Chicago, Chicago, IL, USA Ralf Paschke Section of Endocrinology and Metabolism, Departments of Medi- cine, Oncology, Biochemistry and Molecular Biology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Simon H. S. Pearce Institute of Genetic Medicine, Newcastle University, Newcas- tle upon Tyne, UK Lakdasa D. Premawardhana Section of Endocrinology, Department of Medicine, YYF Hospital, Aneurin Bevan University Health Board, Caerphilly, UK Centre for Endocrine and Diabetes Sciences, C2 Link Corridor, University Hospital of Wales, Cardiff, UK Salman Razvi Institute of Genetic Medicine, Central Parkway, Newcastle Univer- sity, Newcastle upon Tyne, UK Karen M. Rothacker Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia Ferruccio Santini Endocrine Unit, University Hospital of Pisa, Pisa, Italy Massimo Santoro Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy Martin Schlumberger Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, xviii Contributors

Steven I. Sherman Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA Terry J. Smith Department of Ophthalmology and Visual Sciences Kellogg Eye Center and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA Massimo Tonacchera Department of Clinical and Experimental Medicine, Endocrinology Unit, University Hospital of Pisa, University of Pisa, Pisa, Italy Bijay Vaidya Department of Endocrinology, Royal Devon and Exeter Hospital, University of Exeter Medical School, Exeter, UK Theo J. Visser Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands Paolo Vitti Department of Endocrinology, University of Pisa, Pisa, Italy John P. Walsh Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, Australia Leonard Wartofsky Department of Endocrinology, MedStar Washington Hospital Center, Georgetown University School of Medicine, Washington, DC, USA A. P. Weetman School of Medicine and Biomedical Sciences, University of Shef- field, Sheffield, UK Wilmar M. Wiersinga Department of Endocrinology and Metabolism, Academic Medical Center, , Amsterdam, The Netherlands