Medical Management of Thyroid Disease,

For general practitioners and endocrinologists, the new Second Edition of this bestselling book offers the most up-to-date and practical guidance to diagnose and manage common and uncommon thyroid diseases. New to the Second Edition: • information on thyroid neoplasia, leading to new effective treatments of advanced thyroid cancer • important new research on subclinical thyroid disease in the elderly and thyroid disorders in pregnancy • new research on thyroid physiology, pathophysiology, and therapeutics The new edition is fully evidence-based and updated to include the most current treatment and latest findings: • the screening and case finding for thyroid disease • the use of calcitonin in the diagnosis of medullary thyroid cancer • the diagnosis and management of subclinical hyperthyroidism (mild hyperthyroidism) • thyroid disease related to interferon therapy and amiodarone therapy about the editor... DAVID S. COOPER is Professor of Medicine, The Johns Hopkins University School of Medicine; Professor of International Health, Johns Hopkins Bloomberg School of Public Health; and Physician and Director, the Thyroid Clinic, Johns Hopkins Hospital, Baltimore, Maryland, USA. Dr. Cooper received his M.D. from Tufts University, Boston, Massachusetts, USA. He is a member of the Endocrine Society and is a past president of the American Thyroid Association. Dr. Cooper is currently Deputy Editor of the Journal of Clinical Endocrinology and Metabolism, Editor–inChief of Endocrinology, Up-to-Date, and Contributing Editor of the Journal of the American Medical Association (JAMA). Dr. Cooper was also the editor of the first edition of Informa Healthcare’s Medical Management of Thyroid Disease. Printed in the United States of America

Medical Management of Thyroid Disease

about the book…

Second Edition

Endocrinology

Medical Management of Thyroid Disease Second Edition

Cooper H7064

Edited by

David S. Cooper

Medical Management of Thyroid Disease

Medical Management of Thyroid Disease Second Edition

Edited by

David S. Cooper The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017
C

2008 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-4200-7064-9 (Hardcover) International Standard Book Number-13: 978-1-4200-7064-4 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Medical management of thyroid disease / edited by David S. Cooper. – 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-4200-7064-4 (hardcover : alk. paper) ISBN-10: 1-4200-7064-9 (hardcover : alk. paper) 1. Thyroid gland–Diseases. I. Cooper, David S. [DNLM: 1. Thyroid Diseases–therapy. 2. Thyroid Diseases–diagnosis. WK 267 M489 2009] RC655.M434 2009 616.4’4–dc22 2008042809

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Preface to the First Edition

I have been privileged to be a clinical investigator and thyroidologist for almost 25 years. When I was contacted by an editor of Marcel Dekker, Inc., about the possibility of editing a book on diseases of the thyroid, my first reaction was, “Why do we need another thyroid book?” There are already several standard works that exhaustively cover thyroid physiology, pathophysiology, and clinical thyroid disease. One of these texts is considered to be the “Bible” of thyroidology, and there are several others that are also notable for their comprehensive treatment of the subject. Many of them are on my bookshelf, with broken spines and dogeared pages from frequent use. However, after further reflection, it occurred to me that there was a niche for a smaller book that focused purely on the management of patients with thyroid disease, using a very practical and evidence-based approach. Therefore, I agreed to develop and edit a book that would cover the basics and that would appeal to practitioners. In the last decade, there have been major advances in our understanding of thyroid gland regulation, thyroid hormone synthesis and action, and the genetics of thyroid neoplasia. While an understanding of molecular mechanisms and “translational research” is important for optimal patient care, clinicians also need up-to-date, practical information to help them in the management of common (and not so common) thyroid problems. In this book, every effort has been made to cover the universe of thyroidology in as much detail as possible, and yet provide information that is easily digested and useful. Each chapter considers the epidemiology, diagnosis, and treatment of a specific thyroid disorder or disorders, and serves as a “mini-review” of a particular topic. Because any discussion that involves the care of patients will engender controversy, areas of debate are identified and the contributors’ own preferences are clearly stated. Every effort has been made to provide alternative points of view and to base recommendations on the best available evidence. I was extremely fortunate to attract contributors who have international reputations as authors and thyroid researchers, and who are, most importantly, consummate physicians. I thank all of them for their diligence, intellectual approach, and clinical acumen, without which this volume would not have been possible. And, although this book was written for clinicians, it is my hope that the millions of patients with thyroid disease will be the primary beneficiaries. David S. Cooper iii

Preface

In deciding whether a second edition of Medical Management of Thyroid Disease would be something to pursue, the most obvious question is whether there have been enough new developments in the field to warrant it. To put it succinctly: Would a revised text be sufficiently different from the first edition? The first edition, published in 2001, clearly relied on information that is now almost a decade old. Given the exponential growth in medical knowledge, it would only be logical to assume that there has been a great deal learned in the last decade about thyroid physiology, pathophysiology, and therapeutics. Some of this knowledge is entirely new, leading to novel insights and to innovative therapies for previously untreatable conditions. Some of the knowledge is not necessarily entirely new, but has led us to challenge previous firmly entrenched concepts, and to reconsider methods of diagnosis and treatment that had been traditionally taught, but which, often in retrospect, were based more on expert opinion than on the best sciencific evidence. Several examples come to mind. 1. In the realm of basic science, new knowledge about signaling pathways in thyroid neoplasia is starting to yield startling dividends, especially in the management of advanced thyroid cancer. Drugs that target specific vascular endothelial growth factor (VEGF) receptor signaling, epidermal growth factor (EGF) receptor signaling, and specific oncogenes such as RET and BRAF are on the horizon, and appear to be quite promising in a group of patients where up until recently very little could be offered therapeutically. 2. Recent epidemiologic studies have also yielded important information that impacts directly on patient care. To cite just one example, data from the Cardiovascular Health Study have shown that older adults with even mild degrees of thyroid overactivity (subclinical hyperthyroidism) are at risk for atrial fibrillation. This suggests that intervention should be done earlier than we previously had thought necessary. This observation could have profound implications as the number of elderly citizens increases dramatically. 3. In the realm of clinical research, it has long been known that pregnant women with circulating antithyroid peroxidase (anti-TPO) antibodies are at higher risk for miscarriage. The reason for this association has been a source of great interest, but has remained obscure until recently. A recent prospective clinical trial has shown that women with circulating anti-TPO antibodies and normal thyroid function likely develop very mild thyroid hormone deficiency during v

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pregnancy. Furthermore, treatment with thyroid hormone reverses any risk of adverse pregnancy outcomes. This information has major public health and clinical implications, since 5% to 10% of all women have circulating anti-TPO antibodies. I could cite numerous other examples of how information that has been published in the last few years has led to a change in how we manage a variety of common thyroid conditions. Therefore, not only is a new edition of this text justified, but it is long overdue! The earlier edition was developed to be a practical book on how to manage both common and uncommon thyroid diseases. The information was meant to appeal to practitioners, especially primary care physicians and clinical endocrinologists. Therefore, the focus was on the clinical presentation, laboratory diagnosis, and treatment, leaving the basic aspects of thyroid physiology and pathophysiology to other more traditional textbooks that take a more encyclopedic approach. It is my desire that this second edition continue in that tradition. In addition, when the first edition was published, the concept of “evidence-based medicine” was not as well accepted as a basis for decision making as it is now. Also, although the earlier edition was “evidence based” as much as possible, there were few prospective clinical trials in the field of thyroidology. Over the last decade, there had been a number of clinical trials and meta-analyses, allowing this book to be more “evidence based” than before. However, as with all areas of medicine, expert opinion still prevails in the absence of “good evidence,” and where expert opinion substitutes for evidence in some circumstances, this will be noted, as will differences of opinion, controversies, and alternative points of view. David S. Cooper, M.D.

Contents

Preface to the First Edition . . . . iii Preface . . . . v Contributors . . . . ix 1. The Laboratory Approach to Thyroid Disorders 1 Steven I. Sherman 2. Hyperthyroidism Due to Graves’ Disease, Toxic Nodules and Toxic Multinodular Goiter 39 Kenneth D. Burman and David S. Cooper 3. Thyroiditis and Other More Unusual Forms of Hyperthyroidism 101 Shon E. Meek and Robert C. Smallridge 4. Hypothyroidism 145 Michael T. McDermott and E. Chester Ridgway 5. Thyroid Nodules and Multinodular Goiter 203 Hossein Gharib 6. Differentiated Thyroid Carcinoma 237 Jennifer A. Sipos and Ernest L. Mazzaferri 7. Medullary Thyroid Carcinoma, Anaplastic Thyroid Carcinoma, and Thyroid Lymphoma 297 Jennifer A. Sipos and Ernest L. Mazzaferri 8. Pediatric Thyroid Disorders 331 Rosalind S. Brown 9. Thyroid Disease and Pregnancy 369 Susan J. Mandel 10. Thyroid Disease in the Elderly 401 Anne R. Cappola, Myron Miller and Steven R. Gambert Index . . . . 439 vii

Contributors

Rosalind S. Brown Harvard Medical School, Boston, Massachusetts, U.S.A. Kenneth D. Burman Washington Hospital Center, Georgetown University, and the Uniformed Services of the Health Sciences, Washington, D.C., U.S.A. Anne R. Cappola University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A. David S. Cooper The Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Steven R. Gambert Sinai Hospital of Baltimore and The Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Hossein Gharib U.S.A.

College of Medicine, Mayo Clinic, Rochester, Minnesota,

Susan J. Mandel University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A. Ernest L. Mazzaferri

University of Florida, Gainesville, Florida, U.S.A.

Michael T. McDermott University of Colorado Denver, School of Medicine, Aurora, Colorado, U.S.A. Shon E. Meek College of Medicine, Mayo Clinic, Jacksonville, Florida, U.S.A. Myron Miller Sinai Hospital of Baltimore and The Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. E. Chester Ridgway University of Colorado Denver, School of Medicine, Aurora, Colorado, U.S.A. Steven I. Sherman The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, U.S.A. Jennifer A. Sipos

The Ohio State University, Columbus, Ohio, U.S.A.

Robert C. Smallridge Florida, U.S.A.

College of Medicine, Mayo Clinic, Jacksonville,

ix

1 The Laboratory Approach to Thyroid Disorders Steven I. Sherman The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, U.S.A.

INTRODUCTION The central role of the thyroid gland in controlling metabolism was recognized in the 19th century, but evaluation of the function of the thyroid remains an evolving science. Initial approaches to the assessment of thyroid function centered on measuring end-organ responses as biological markers of thyroid hormone actions. Development of in vitro competitive binding assay methods allowed the direct quantification of hormone levels in serum, and sensitive immunoassays have demonstrated the subtleties of pituitary and hypothalamic control of the thyroid. Abnormalities of hormone binding by serum proteins necessitated sensitive estimation of free hormone levels. With the detection of serum markers of autoimmune and malignant diseases of the gland has come earlier diagnosis and improved monitoring of these conditions, often with greater sensitivity than may be clinically relevant. Limitations to the measurement methods used exist, however, particularly when underlying assumptions about the comparability of patient and control specimens are invalid. Nonetheless, the clinician can now effectively confirm suspected diagnoses of thyroid dysfunction, cost-effectively screen asymptomatic populations for common diseases, and appropriately monitor the treatment of patients with disorders of the thyroid.

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PHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-THYROID AXIS Excellent reviews and books provide detailed exploration of the physiology of the hypothalamic-pituitary-thyroid axis, and the reader is invited to delve into those worthwhile sources. For the purposes of this chapter, a brief review of the biosynthesis and transport of thyroid hormones and the regulation of thyroid function by the neurohypophysis will suffice. The synthesis of thyroxine (T4) and triiodothyronine (T3) begins with the active transport of iodide into the cell via a sodium-iodine symporter located in the basal membrane. Following oxidation by thyroid peroxidase (TPO), the iodide moiety is covalently attached to tyrosyl residues of thyroglobulin, and the resulting iodotyrosines are coupled and cleaved from thyroglobulin to form T4 and T3, normally in a 10:1 ratio. Thyroid hormone secretion requires endocytosis and degradation of iodinated thyroglobulin, followed by release of T4 and T3 into the circulation. This process results in the total daily output of 80 to 100 ␮g of T4. In contrast, only 20% of circulating T3 is produced by the thyroid, the remaining 80% deriving from the enzymatic outer-ring or 5’-monodeiodination of T4 in extrathyroidal tissues such as the liver, kidney, brain, muscle, and skin. Removal of the inner-ring or 5-iodine of T4 forms the inactive metabolite reverse T3 (rT3). Other inactivating pathways for T4 and T3 include glucuronidation, sulfation, deamination, and cleavage. The normal daily fractional turnover rates for T4 and T3 are 10% and 75%, respectively. In serum, at least 99.95% of T4 and 99.5% of T3 molecules are bound by the transport proteins thyroxine-binding globulin (TBG), transthyretin (thyroxinebinding prealbumin), and albumin. Although TBG is present in lower concentration than either transthyretin or albumin, its greater affinity for thyroid hormones makes it the predominant serum carrier of T4 and T3. Variations in binding characteristics among normal and abnormal thyroid hormone-binding proteins are responsible for much of the methodologic limitations in assays that attempt to measure concentrations of free T4 and T3. This large pool of protein-bound hormone provides a stable reservoir that maintains the supply of free, unbound hormone available for transport into the cells. Once within target cells, T4 is further deiodinated to T3, which in the nucleus binds to the thyroid hormone receptor, modulating transcription of thyroid hormone-responsive genes and producing most of the clinical effects recognized as the metabolic effects of thyroid hormones. The primary regulatory influence on thyroid gland function is the circulating level of thyrotropin (thyroid-stimulating hormone or TSH). Produced by thyrotroph cells of the anterior pituitary, TSH is a two-subunit glycoprotein, the specificity of which is conferred by its alpha subunit; the beta subunit is structurally similar to that of follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin. Negative feedback by T4 and T3 influences TSH synthesis and release, as evidenced by the inverse log–linear relationship of the concentrations of TSH and free iodothyronine (1,2). It is likely that each individual has a genetically determined set point for this TSH/free T4 relationship, based on twin studies (3,4). TSH levels peak just before nocturnal sleep, and

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the nadir occurs in the late afternoon; this nocturnal surge is lost early in the course of nonthyroidal illness. TSH levels in various populations conform best to a log-Gaussian rather than Gaussian distribution (5). The hypothalamic tripeptide thyrotropin-releasing hormone (TRH) stimulates TSH secretion and modulates thyrotroph response to altered thyroid hormone levels. In conjunction with the suppressive effects of dopamine, corticosteroids, somatostatin, androgens, and endogenous opioids, TRH may be responsible for modulating the set point for the negative feedback loop that controls thyroid hormone levels. Hypothalamic production of TRH itself is regulated by circulating thyroid hormones as well as by multiple central nervous system factors. LABORATORY EVALUATION OF THYROID FUNCTION Assays of Thyroid Hormones Total Serum Iodothyronine Concentrations When concentrations and binding affinities of thyroid hormone-binding proteins are normal, there exists at physiologic equilibrium a direct relationship between levels of total hormone and free hormone (6). Thus, measurement of total iodothyronine concentration can provide a reasonable surrogate for estimating the amount of free iodothyronine present. Either serum or plasma can be used to assay hormone concentrations, although serum is generally preferred. The most commonly employed technique for the determination of total T4 and T3 concentrations is competitive immunoassay, using either polyclonal or monoclonal “capture” antibodies directed against the specific iodothyronine. To ensure measurement of bound as well as free hormone, inhibitors of iodothyronine binding are added—for example, 8-anilino-1-naphthalene sulfonic or salicylic acids for TBG and barbital for thyroxine-binding prealbumin (TBPA). These agents successfully dissociate the hormone from binding proteins without interfering with hormone binding to immunoglobulin. Radioimmunoassay (RIA) depends upon measurement of the distribution of a tracer quantity of radiolabeled hormone that competes with the endogenous hormone in the patient’s specimen for binding to a capture antibody. The higher the serum hormone concentration, the lower the amount of radiolabel that binds to the antibody. Following the addition of a limited amount of capture antibody and the radiolabeled iodothyronine to be measured, the antibody–antigen complexes are separated from the serum. Separation techniques vary, including ammonium sulfate or second antibody precipitation. Newer methods that facilitate automated separation include attachment of the anti-T4 antibody to a solid phase, such as the wall of the assay tube or magnetizable particles. The concentration of either T4 or T3 is then determined by comparison of the amount of antibody-bound radiolabel with a simultaneously derived standard curve. A fundamental assumption, therefore, is that there is no difference in the assay conditions (including protein binding and other constituents found in the serum) between the patient’s sample and the control standards, an assumption that is often invalid.

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Nonisotopic methods avoid reliance upon radioactive reagents and are now the most commonly used assays. The heterogeneous enzyme-linked immunosorbent assay (ELISA) incorporates colorimetric, fluorescent, or luminescent substrates that create a quantitative signal when interacting with a specific enzyme bound to the tracer hormone—for example, alkaline phosphatase, horseradish peroxidase, or glucose-6-phosphate dehydrogenase. As in RIA, numerous physical and chemical approaches exist for separating signal bound to the antiiodothyronine antibody from unbound signal. In contrast, homogeneous enzyme immunoassays do not require a separation step. Instead, the binding of antibody to a tracer hormone directly affects the activity of the signal-generating enzyme bound to the tracer. Other technologies have also been applied to shorten the time requirements for assays and to facilitate automation. Reference ranges vary to some degree, but commonly cited ranges are 4.5 to 12.6 ␮g/dL (58–160 nmol/L) for total T4 and 80 to 180 ng/dL (1.2–2.7 nmol/L) for total T3 (7). As developed by their manufacturers, these assay techniques have similar performance characteristics, although each may be affected by different sources of interference. In field use, however, a concerning level of inaccuracy exists even in total thyroxine immunoassays; a survey of nearly 2000 clinical laboratories employing 19 different automated thyroxine assays identified that approximately 30% of the laboratories failed to meet accuracy standards defined by the Clinical Laboratory Improvement Amendments of 1988 (8). Testing an identical specimen of fresh frozen serum in 1528 laboratories, 13% of the 16 T4 measurement methods yielded mean results that differed from the overall mean of all methods by at least 10% (8). For total T3, the degree of inaccuracy is worse; testing an identical specimen of fresh frozen serum in 926 laboratories, 58% of the 12 T3 measurement methods yielded mean results that differed from the overall mean of all methods by at least 10% (8). Contributing factors to measurement error include qualitative differences between the protein constituents of sample diluents used for calibration and those found in patient sera, leading to differential dissociation of hormone from binding proteins, and the lack of harmonized standards (7). Determination of Free T4 and T3 Concentrations Because T4 and T3 are highly bound to serum proteins, alterations in either the levels of these proteins or their binding characteristics can significantly alter the concentration of total hormone. As it is the free hormone that is biologically active, however, techniques are required to permit either direct measurement or estimation of the serum free hormone levels. All methods that have been developed face the identical problem: distinguishing between the 3 to 4 orders of magnitude difference in the concentrations of the free and the protein-bound hormones. In all free hormone assays, the central assumption is that the effectiveness of separating the free from the bound hormone is identical in both the patient samples and the standards used to calibrate the assay, an assumption that is difficult to validate in

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all potential clinical situations. As a result, in a study of 1744 clinical laboratories, using 13 different free T4 measurement methods to assay an identical sample of fresh frozen serum, 38% of the methods yielded average concentrations of free T4 that were at least 10% different from the overall group mean and 8% differed by ⬎20% (8). The reference standard for direct measurement of free T4 and T3 is the equilibrium dialysis method, although even this methodology lacks a universal reference measurement procedure (9). Undiluted patient serum is dialyzed overnight across a membrane with pores that allow free but not protein-bound hormone to partition, allowing equilibration of the free hormone concentration across the membrane. A highly sensitive RIA, capable of detecting nanogram (or picomole) quantities of hormone, is then used to measure the hormone content of the protein-free dialysate, comparing to a standard curve generated with gravimetrically determined amounts of hormone (10). Faster turnaround can be achieved by using ultrafiltration rather than equilibrium dialysis, but greater variability can result from minimal amounts of serum proteins that leak through the filtration device as well as hormone that is adsorbed to either the membrane or container surface. Such direct measurements are generally expensive, time-consuming, and not widely used commercially except as calibrators for more commonly used techniques. By estimating the fraction of hormone that is free or unbound and multiplying by the total concentration of hormone, an indirect method will yield an estimate of the free hormone level. In the indirect equilibrium dialysis method, tracer quantities of radiolabeled hormone are added to the patient’s serum, and the mixture equilibrates across a dialysis membrane. A second dialysis step incorporating an anion exchange resin then removes the radioactivity due to labeled inorganic iodine and other contaminating compounds found in the tracer iodothyronine preparation. Alternatively, the radiolabeled hormone can be precipitated by addition of magnesium chloride. Regardless of the second separation step used, the resultant fraction of radiolabel found in the dialysate is proportional to the ratio of free to total hormone in the patient’s serum. Expected free hormone fractions are approximately 0.02% to 0.04% for T4 and 0.2% to 0.4% for T3. The free T4 or T3 estimate can then be calculated by multiplying the free fraction by the total serum hormone concentration obtained using a conventional RIA. Expected adult values are approximately 0.8 to 2.3 ng/dL for free T4 and 210 to 440 pg/dL for free T3. Although these indirect dialysis methods generally correct for most protein-binding abnormalities, considerable variability in results still persist, particularly from impurities in the tracer preparation and occasional failure to achieve equilibrium. The methods are exacting, expensive, and time-consuming, and other approaches to estimating free hormone concentrations have been developed for widespread use. However, a recently developed equilibrium dialysis technique that utilizes liquid chromatography-tandem mass spectrometry to measure free T4 levels may permit rapid and cost-effective assessment of multiple blood samples (11).

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Figure 1 Methods for radioimmunoassay estimation of free thyroxine concentration.

Immunoassay methods for estimation of free hormone concentration are now widely used (Fig. 1). In the “analogue” or “one-step” free T4 method, a labeled T4 analogue that does not bind to serum-binding proteins is added to serum and the mixture is either incubated with an anti-T4 antibody or allowed to bind to antibody attached to a solid phase. At equilibrium, the amount of analogue complexed to the antibody is inversely proportional to the amount of free T4 that is available. Onestep methods require structurally modified analogues that do not displace hormone from protein-binding sites, but a complete lack of displacement is rarely achieved.

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Therefore, these methods depend on the assumption that there is no difference in hormone binding affinity for proteins between the sample to be measured and the assay controls or calibrators, both for the actual analyte as well as the analogue. This assumption is particularly at risk when there are circulating inhibitors of hormone binding in serum, such as renal failure or other nonthyroidal illnesses, or major alterations in hormone-binding protein concentrations (12). Because the analogues used generally bind to albumin, although not with the same kinetics as T4 or T3, this method may not be correct for abnormalities in albumin binding. In “two-step” assays, serum is exposed to a solid phase containing anti-T4 antibody, binding a certain amount of free hormone to the solid phase. By diluting the specimen and limiting the duration of incubation, there should be minimal disruption of endogenous hormone binding to serum proteins (10). After removal of the serum and its proteins, a tracer quantity of radiolabeled T4 is incubated with the solid phase, equilibrating with the remaining unoccupied antibody molecules. The amount of radiolabeled T4 complexed to the solid phase is thus inversely proportional to the free T4 concentration of the serum. Because the label is unable to interact with serum-binding proteins or endogenous inhibitors of hormone binding to protein (due to the physical separation step), the “two-step” method has a good correlation with the free T4 determined by direct equilibrium dialysis. Nonradioactive assays have also been developed, and automated two-step procedures are in common use. For free T3 measurements, methods that rely upon physical separation of bound from free hormone, such as dialysis or ultrafiltration, are not generally commercially available. The same technology for “one-step” assays of free T4 is used to measure free T3. Interference from serum proteins and difficulty avoiding stripping T3 from its binding proteins is a greater problem than in free T4 assays (13). In a study of 404 clinical laboratories, using 11 different free T3 measurement methods to assay an identical sample of fresh frozen serum, 55% of the methods yielded average concentrations of free T3 that were at least 10% different from the overall group mean and 27% differed by ⬎20% (8). New methods that use tandem mass spectrometry following equilibrium dialysis or ultrafiltration may allow faster and more reliable assays (14). The thyroid hormone binding ratio (THBR), another calculated value proportional to the fraction of hormone that is free in circulation, derives from measurement of the availability of protein-binding sites in the patient’s serum. In the traditional uptake method, a tracer quantity of radiolabeled iodothyronine is added to the serum and allowed to partition between unoccupied specific protein binding sites and a nonsaturable adsorbent—for example, talc, charcoal, resin, or anti-iodothyronine antibodies. T3 is generally preferred as the labeled ligand, as it has a lower affinity for TBG and therefore does not displace T4 its binding sites. There is an inverse relationship between the amounts of radiolabel adsorbed by the inert solid phase and unoccupied serum protein-binding sites. The percent uptake derives from the ratio of tracer bound by the adsorbent to the tracer bound by serum proteins; an alternative but less reliable formula expresses the ratio as the

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amount of tracer attached to adsorbent to the amount initially added. The THBR is then calculated as the percent uptake in the patient’s serum and normalized to that of a control or reference serum; the expected normal range is centered around unity. The THBR is increased when there are few endogenous binding sites, which can occur with an increased amount of T4 available to bind (thyrotoxicosis); the presence of competing ligands (certain drugs and nonthyroidal illness); or a decreased amount of binding protein (TBG deficiency). Conversely, hypothyroidism and TBG excess will produce an increased number of available binding sites, producing a decreased THBR. As a general rule, true thyroid function abnormalities produce concordant increases or decreases in the total serum T4 and THBR, whereas discordant changes in the two tests typically result from protein-binding abnormalities. Alternate methods use nonisotopic labels, such as enzyme-linked tracers and light emitters. These all rely on the similar principle of estimating the partitioning of labeled hormone between serum-binding proteins and a solid phase. A free hormone index is estimated by multiplying the total serum hormone concentration by the THBR. In most conditions of endogenous thyroid function abnormalities or protein-binding alterations, the index corrects for effects of protein binding on total T4 levels and correlates well with free T4 levels measured by reference methods. Potential pitfalls in the interpretation of THBR tests occur when there is a ligand that can interfere with binding to both the solid phase and the serum proteins, for example, nonthyroidal illness. Falsely elevated free thyroxine index values can also be present when the protein-binding abnormality is specific for T4 and masked by the use of T3 in the THBR—for example, familial dysalbuminemic hyperthyroxinemia (FDH), in which an abnormal albumin binds only thyroxine with high affinity. Similarly derived from the total T3, the “free T3 index” can be useful in evaluating cases of abnormal serum binding. Causes of Increased T4 and/or T3 Concentrations The majority of patients with hyperthyroidism, regardless of the etiology, have increased total serum concentrations of both T4 and T3, as well as high levels of the free hormones (Table 1). In a minority of cases, there may be an isolated elevation of either iodothyronine. T3-toxicosis is especially prominent in patients with mild and recurrent Graves’ disease or hyperfunctioning adenomas and those patients overtreated with triiodothyronine-containing thyroid hormone preparations. The relative magnitude of T3 elevation is often greater than T4 in forms of hyperthyroidism caused by increased glandular synthesis of hormone; in Graves’ disease, the proportion of circulating T3 that derives from thyroidal production nearly doubles (15). The opposite—that is, a lower T3:T4 ratio—is true in thyrotoxicosis due to an inflammatory thyroiditis, in which there is release of previously formed hormone, iodide-induced hyperthyroidism, and iatrogenic thyrotoxicosis due to exogenous levothyroxine administration. Mild hyperthyroxinemia can even be seen in patients being treated with exogenous levothyroxine for hypothyroidism but whose TSH levels are normal on therapy (16).

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Table 1 Causes of Increased T4 and/or T3 Concentrations Thyrotoxicosis Euthyroid hyperthyroxinemia Increased binding to plasma proteins TBG excess Congenital Hyperestrogenemia: exogenous, endogenous Acute and chronic active hepatitis Acute intermittent porphyria HIV-1 infection FDH Transthyretin excess Congenital Paraneoplastic Antithyroxine immunoglobulins Rheumatoid factor (ex vivo) Impaired T4 to T3 conversion Iodinated contrast agents Amiodarone Propylthiouracil Glucocorticoids Propranolol Congenital Generalized resistance to thyroid hormones Nonthyroidal illness Acute psychosis Acute medical/surgical illness Hyperemesis gravidarum Lead intoxication Drugs Clofibrate 5-fluorouracil Perphenazine Methadone Heroin L-thyroxine therapy

Increased total T4 concentrations without thyrotoxicosis, termed euthyroid hyperthyroxinemia, result from both acquired and congenital etiologies. One commonly encountered situation is acquired TBG excess due to hyperestrogenemia. Elevated hepatic exposure to estrogen leads to increased sialylation of carbohydrate side chains of TBG, thereby decreasing clearance of the glycoprotein and increasing serum TBG levels. This effect is seen within several weeks of the onset of hyperestrogenemia and can occur with exogenous administration of estrogens, increased endogenous production (e.g., pregnancy), and even administration of

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selective estrogen receptor modulators, such as tamoxifen and raloxifene (17,18). Exogenous estrogen administered transdermally, by avoiding first pass metabolism in the liver, does not cause elevated TBG levels and hyperthyroxinemia (19). Acquired TBG excess may also be responsible for the slight increase in T4 levels reported in male cigarette smokers (20). X-linked inherited TBG excess occurs with a frequency of 1 in 25,000 newborns, and can cause up to 2.5-fold elevations in the total serum concentration of T4. Other abnormal serum-binding proteins can contribute to euthyroid hyperthyroxinemia. In the autosomal dominant condition FDH, one or more abnormal species of albumin contain a high-affinity binding site for thyroxine. Because the defect is specific for T4 and does not affect T3 binding, these patients have an elevated total T4; a normal THBR using T3, but a decreased THBR using T4 as the ligand; a normal total T3; and either a normal or increased free T4, depending on the type of direct assay used. Equilibrium dialysis typically yields normal levels of free T4 in this syndrome. The diagnosis is established by paper or gel electrophoresis of serum enriched with radiolabeled T4, which permits identification of the abnormal binding proteins. Elevations of free T4 concentrations can occur as a result of interference in binding to serum proteins. In vivo, hormone can be displaced from protein by medications such as furosemide, causing a true, albeit rapidly reversible, minimal hyperthyroxinemia after rapid intravenous administration of the diuretic. Activation of lipases by both low– and high–molecular weight heparins leads to increased levels of free fatty acids that displace thyroid hormones both in vivo and ex vivo, the latter situation causing an artifactual elevation of measured free hormone (21). In autoimmune thyroid diseases and monoclonal gammopathies, endogenous serum anti-T4 or anti-T3 antibodies bind thyroid hormones, increasing the serum concentrations of protein-bound hormones. More commonly, however, antiiodothyronine autoantibodies have negligible in vivo effects on hormone binding, but interfere with immunoassay measurements (22). In a classic RIA for total hormone concentration, the autoantibody will compete with the capture antibody for radiolabeled ligand, reducing the amount of signal available to be measured and leading to a false high value. A similar spuriously increased result can occur in one-step free T4 assay, in which the autoantibody binds the labeled T4 analogue, preventing it from being measured and yielding a falsely increased free T4 level; this is avoided in a two-step assay in which the labeled ligand is unable to interact with the serum autoantibodies. Another autoantibody that interferes with immunoassays is the rheumatoid factor, an IgM directed against the Fc fragment of human IgG. Because rheumatoid factor is weakly heterophilic, it appears to bind to the nonhuman capture antibody, preventing interaction with the radiolabeled ligand and leading to a falsely increased hormone concentration (23). Preincubation of the serum specimen with a nonspecific animal immunoglobulin, ethanol, or polyethylene glycol reduces this antibody-mediated interference. Decreased function of the 5’-monodeiodinase causes impaired conversion of T4 to T3, decreasing T4 clearance and increasing T4 levels. Iodinated radiocontrast dyes—for example, sodium ipodate—are potent inhibitors of T4 to T3

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conversion and have been used therapeutically in severely hyperthyroid patients, but are no longer commercially available in the United States. Amiodarone, a highly iodinated antiarrhythmic agent, also interferes with T4 deiodination. Since amiodarone-induced hyperthyroidism can also occur, great care must be taken in interpreting hyperthyroxinemia in patients receiving iodinated medications (24). An inherited defect in 5’-monodeiodinase function, due to mutation in a selenocysteine insertion sequence binding protein, has recently been described, and is probably responsible for hyperthyroxinemia observed in these patients (25). Patients with resistance to thyroid hormones have an inherited partial defect in tissue responsiveness to thyroid hormones. Serum concentrations of total and free thyroid hormones are both increased as compensation for partial resistance. Most kindreds that have been evaluated have been found to have a dominant negative mutation in a single allele of the thyroid hormone receptor beta. Although affected individuals are generally described as being clinically euthyroid, considerable variation exists in the measurable degrees of hormone resistance among specific target organs for thyroid hormone (26). Transient elevations of total serum T4 and, less frequently, free T4 levels occur in patients with acute medical and psychiatric illnesses. Although some patients develop increased levels of both T4 and T3 when the nonthyroidal illness resolves, consistent with coexistent hyperthyroidism, in most of these patients normal thyroid hormone levels are restored with recovery (27). Transient increases in total and free T4 and T3 can be seen in 8% to 33% of patients admitted for acute psychiatric disorders (28,29). TSH concentrations have been reported as increased in up to 10% of acutely psychotic patients (30), but they are frequently suppressed in severely depressed outpatients as well as those suffering from posttraumatic stress disorders (31,32). Causes of Decreased T4 and/or T3 Concentrations Reduced serum levels of total and free T4 and T3 are typically seen in patients with overt hypothyroidism, reflecting impairment of hormone synthesis and release by the gland (Table 2). Due to TSH stimulation of residual gland function and elevation in the fractional conversion of T4 to T3 by 5’-monodeiodinase in both thyroid and peripheral tissues, 30% of patients with primary hypothyroidism maintain normal T3 levels despite decreases in T4. Thyroxine synthesis is also suppressed in patients receiving T3 exogenously or with autonomous T3 overproduction. Euthyroid hypothyroxinemia can be due to a variety of mechanisms. Analogous to the abnormalities that can cause hyperthyroxinemia, defects in hormone binding to serum proteins can lead to decreases in T4 levels. Partial deficiency of TBG, caused by impaired production or accelerated degradation of unstable variants, occurs in 1 in 4000 births. X-linked complete TBG deficiency is less common, found in 1 in 15,000 male births; female heterozygotes have TBG levels that are partially reduced. Numerous variants of TBG with reduced affinity for thyroid hormones have been described, with varying frequencies in different populations (33). Acquired impairment of hormone binding develops secondary

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Table 2 Causes of Decreased T4 and/or T3 Concentrations Hypothyroidism Euthyroid hypothyroxinemia Decreased binding to serum proteins TBG deficiency Chronic liver disease Congenital Cushing’s syndrome Drugs L-Asparaginase Androgens Nicotinic acid Growth hormone excess Nephrosis Protein-losing enteropathy TBG and transthyretin variants with reduced affinity Inhibition of T4 binding by drugs Carbamazepine Diphenylhydantoin Fenclofenac Furosemide Heparin Meclofenamic acid Mefenamic acid Salicylates Sertraline Exogenous T3 or triiodothyroacetic acid administration Nonthyroidal illnesses

to decreases in binding protein levels, due to either reduced production (as occurs in hyperthyroidism) or increased clearance (as from nephrotic syndrome). In most patients with quantitative or qualitative defects in TBG, direct and indirect estimates of free T4 levels are normal. In the extreme case of complete deficiency, lack of a linear relationship between free T4 fraction and THBR leads to falsely low free T4 index results, and values of free T4 can be either normal or underestimated by two-step and direct measurements. Hypothyroxinemia and hypotriiodothyroninemia are common findings in patients with nonthyroidal illness, with more severe reductions in total hormone levels associated with more severe or critical illness (34,35). Milder degrees of illness are typically accompanied by reductions in T4 to T3 conversion, resulting in a low T3 state but preservation of T4 levels. In addition to deficiency of albumin and transthyretin, other proposed mechanisms include inhibition of hormone binding to TBG, perhaps due to certain free fatty acids released from damaged tissues or cytokines, such as tumor necrosis factor (36). Numerous medications

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interfere with thyroid hormone binding to serum proteins, including diphenylhydantoin, furosemide, heparin, sertraline, and certain nonsteroidal antiinflammatory agents (37,38). Inhibition of 5’-monodeiodinase activity in nonthyroidal tissues accelerates clearance of T4 through nondeiodinative mechanisms, particularly in nonthyroidal illness and starvation, and may be secondary to increased levels of interleukin-6; the production rate of T3 declines as a result of this monodeiodinase inhibition, but no change is seen in T3 metabolic clearance (39). Medications such as glucocorticoids, amiodarone, oral radiocontrast agents, gold, and high-dose propranolol and propylthiouracil (PTU) also inhibit T4 deiodination to T3; however, clinical signs of hypothyroidism are unlikely to develop. Hypothyroxinemia has been described in patients treated with novel anticancer agents that inhibit vascular endothelial growth factor receptors, with evidence of multiple potential mechanisms that include primary thyroid dysfunction, but also effects on either thyroid hormone absorption or metabolic clearance (40,41). Pituitary TSH production is suppressed by endogenous and/or exogenous glucocorticoids, dopamine, somatostatin, and endorphins and may also be mediated by reduced hypothalamic TRH secretion (42). Alteration of TSH sialylation and bioactivity may occur in critical illness as well (43). With increasing severity of nonthyroidal illness, all of the proposed mechanisms presumably result in a low T4, low T3 state. Often, the decrease in protein binding is reflected by a decreased T4 and increased THBR, yielding a normal free thyroxine index. However, in many instances, the presence of a binding inhibitor (such as heparin or free fatty acids released in inflammation) interferes with hormone attachment to the solid phase, leading to a slightly lower value for the THBR and a falsely low estimate of the free thyroxine index. Most analogue and some two-step procedures for measuring free T4 are also adversely affected by binding inhibition in nonthyroidal illness (6,12). These laboratory abnormalities reverse with recovery from the nonthyroidal illness or discontinuation of the interfering medication. Although most of the effects of nonthyroidal illness may represent energy-conserving adaptive mechanisms, the traditional view of these patients as being euthyroid is not universally held (44). However, no benefit from thyroid hormone supplementation has yet been demonstrated. Assays of Thyroid-Stimulating Hormone Early TSH assays used a single polyclonal antibody in a radioimmunoassay and were capable of detecting elevated levels of TSH in patients who have primary hypothyroidism. With a sensitivity of approximately 1 mU/L, these tests were unable to distinguish the low-normal TSH levels in serum of 25% of euthyroid individuals from subnormal concentrations. With the introduction of immunometric (IMA) methods that use two or more antibodies directed at different antigenic determinants on the TSH molecule, assay sensitivities have been improved by 10to 200-fold. The first antibody, usually a mouse monoclonal construct, is linked to a solid phase, permitting the target molecule to be separated from the serum with

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high affinity; the second antibody, which may be polyclonal, is labeled, providing a signal proportional to the amount of ligand bound. With these more sensitive assays, hyperthyroid patients can be identified on the basis of low or undetectable levels of TSH in IMAs, analogous to detection of primary hypothyroidism with elevated TSH levels. Even more sensitive determinations of low TSH values have been obtained in an assay using a chemiluminescent acridinium ester to generate the antibody-linked signal. High intra-assay and interassay precision with chemiluminometric methods may permit routine detection of TSH levels as low as 0.01 mU/L or lower. The ability of TSH assays to measure accurately low concentrations of the hormone is termed the “functional sensitivity” of the assay, defined as the concentration at which the interassay coefficient of variation is 20%. This contrasts with the “analytical sensitivity,” which is based on intra-assay measurements of the blank calibrator, and does not reflect a clinically meaningful result (7). Whereas the original RIA methods have been termed “first generation” assays, the newer, more sensitive TSH assays, which provide a sufficient separation in serum TSH values between hyperthyroid and euthyroid patients, are defined as “second generation” when the functional sensitivity is 0.1 mU/L, and “third generation” when the functional sensitivity is 0.01 mU/L (45). Multiple sources contribute to the total variation observed in TSH assay results (46). Endogenous, biologic variation exists due to heterogeneity of TSH isoforms, based on posttranslational modifications that can alter the immunoreactivity as well as the bioactivity of the molecule; this potentially may be overcome with use of variants of recombinant TSH that mimic these individual modifications (47,48). Circadian and seasonal effects contribute to within-person variation as well. But, within-person variation during serial measurements is relatively minimal compared with between-person variation, raising concern that population reference standards may be inadequate to distinguish a healthy from diseased state (46,49,50). Debate now exists about the optimal reference range for TSH assays. Typically, the lower and upper limits of a population reference range of the analyte’s concentrations are the 2.5th and 97.5th percentiles (the 95% confidence interval), measured in a rigorously defined normal cohort without any evidence of relevant disease. Applying this criterion to TSH levels, as determined in the recent U. S. National Health and Nutrition Examination Survey (NHANES III), the population reference range would be 0.45 to 4.12 mU/L (51). Similar ranges have been reported in other populations, differing to some degree due to variations in iodine intake, ages, gender, and even the time of day that blood is sampled (52). As most functional thyroid disorders are due to autoimmune thyroid disease, the relationship between levels of thyroid autoantibodies and TSH has also been evaluated, demonstrating a U-shaped curve with the lowest prevalence of autoantibodies at TSH levels between 0.1 and 1.5 mU/L in women and 0.1 and 2.0 mU/L in men (53). Additionally, the likelihood of eventual development of overt primary hypothyroidism has been reported to be markedly higher in the

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setting of a TSH level of at least 2.0 mU/L and elevated levels of anti-TPO antibodies (54). Therefore, it has been proposed that the upper limit of the population reference range should in fact be as low as 2.5 or 3.0 mU/L (55,56). Other studies have suggested that age-specific reference ranges would be appropriate, with the 97.5th percentile being well above 4.5 mU/L with successively increasing deciles of age (57). However, in the absence of definitive evidence that defining hypothyroidism as a TSH ⬎2.5 leads to unequivocal clinical benefit from treatment with thyroid hormone, and given the overall concern that the population reference range may not be optimal for defining a disease state when interindividual variation is relatively large, it does not appear that changing the population reference range is appropriate at this time (58). Interference with TSH immunoassays is uncommon. Patients with endogenous heterophilic antibodies directed against mouse immunoglobulin can have falsely elevated TSH levels, as the heterophilic antibody can substitute for TSH and bridge between the two antibodies in the assay (59). This problem has been eliminated from most commercially available kits by addition of an excess of mouse immunoglobulin. If interference with the assay is suspected, measurement of serial dilutions of the sample may show a nonlinear relationship; alternatively, the sample can be tested using another manufacturer’s assay (7). Causes of Hypothyrotropinemia When conventional TSH radioimmunoassays were used, the inability to differentiate hyperthyroid from euthyroid patients was overcome by measurement of the TSH response to stimulation with exogenous TRH. After the intravenous administration of 500 ␮g of TRH, TSH levels normally increase to 7 to 20 mU/L at 30 minutes. TSH levels usually remain undetectable in hyperthyroid patients when measured by conventional RIA after TRH stimulation. However, recent studies with sensitive assays have demonstrated that there is persistence of the logarithmic relationship between basal and TRH stimulated TSH levels even within the hyperthyroid range (45). In severe hyperthyroidism, TSH levels remain below the functional sensitivity of even third or fourth generation assays, but such degrees of suppression are not seen in other causes of low TSH levels. Therefore, in most cases, the presence of a basal serum TSH level of ⬍0.01 mU/L obviates the need to perform a TRH-stimulation test to diagnose hyperthyroidism. Subnormal but detectable TSH levels can be seen in patients who have mild or asymptomatic hyperthyroidism of any etiology, or they may be due to TSH suppression from nonthyroidal illness. TRH stimulation testing in acutely ill patients is usually unable to distinguish mild hyperthyroidism from the effects of nonthyroidal illness. More sensitive TSH immunoassays provide adequate separation between hospitalized hyperthyroid patients with medical illness, in whom basal TSH levels generally remain undetectably low, and euthyroid patients with nonthyroidal illness, in whom basal TSH levels are usually but not always ⬎0.01 mU/L. In hypothyroidism due to hypothalamic or pituitary disease, low levels of basal TSH may occur. It was initially suggested that TRH stimulation testing was

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able to classify central hypothyroidism as either hypothalamic or pituitary in origin, with the former showing a delayed and exaggerated TSH response 30 to 60 minutes after TRH administration, and the latter having a persistently blunted response. In practice, there was an overlapping spectrum of TRH responses in patients with pituitary and hypothalamic diseases, and TRH is no longer readily available for this purpose. Hypothyroidism due to pituitary or hypothalamic disease can also present with inappropriately normal or even slightly elevated levels of immunologically intact but biologically inactive TSH secondary to alternative glycosylation of the protein (60,61). Among the drugs that can affect TSH production, the rexinoid bexarotene appears to suppress TSH gene transcription directly and causes a dose-dependent central hypothyroidism (62,63). Recently, the hypoglycemic drug metformin was reported to lower TSH levels by an as yet unknown mechanism (64,65). Causes of Hyperthyrotropinemia Elevated serum TSH values are the cornerstone of the diagnosis of primary hypothyroidism. Due to the extreme sensitivity of the hypothalamic-pituitarythyroid negative feedback loop, small decrements in circulating thyroid hormone levels produce logarithmic increases in serum TSH levels (45). At one end of the spectrum are patients with frankly symptomatic thyroid hormone deficiency, whose free T4 levels are subnormal and whose TSH levels are typically ⬎20 mU/L. But, even patients with the earliest stages of thyroid gland impairment can have elevated TSH concentrations. These patients with so-called subclinical hypothyroidism have T4 and T3 levels within the normal range associated with increased serum TSH concentrations. Although the clinical management of such patients remains controversial, those individuals with a predisposition to developing clinical hypothyroidism—for example, those with autoimmune thyroiditis or a history of thyroid irradiation or surgery, should be treated or followed longitudinally for development of overt hypothyroidism. Medications that have been associated with hyperthyrotropinemia include cytokines that can cause autoimmune thyroiditis (such as interferon-alpha) and tamoxifen, although the latter appears to induce a mild and transient increase in TSH levels that is not seen with raloxifene (17,66). In neonates, various maternal causes of fetal distress, including preeclampsia and gestational diabetes mellitus, are associated with elevated TSH levels in cord blood, but whether this reflects transient primary hypothyroidism or a central stimulation of TSH production is unknown (67). The differential diagnosis of hyperthyrotropinemia also includes conditions associated with inappropriate TSH secretion, as in patients whose TSH levels are higher than would be predicted from their circulating free thyroid hormone levels. Patients with TSH-secreting pituitary adenomas may have normal or increased TSH levels in the setting of increased T4 concentrations. These patients usually present with a goiter and clinical evidence of thyrotoxicosis, with or without clinical evidence of a sellar mass lesion. In half of cases, there is cosecretion of other anterior pituitary hormones (e.g., growth hormone or prolactin) and the beta

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subunit of TSH is commonly overproduced. A molar ratio of alpha subunit to intact TSH that is greater than unity is strongly suggestive of a pituitary adenoma. Although thyrotoxic with elevated levels of TSH and T4, patients with the rarer syndrome of isolated pituitary resistance to thyroid hormone do not have radiographic evidence of a pituitary tumor, and their ratio of alpha subunit to intact TSH is usually ⬍1 (68). Resistance of the thyroid to TSH, presenting with nongoitrous congenital hypothyroidism and elevated TSH levels, has been described both in isolated form and in pseudohypoparathyroidism type Ia (68). In this latter congenital condition, deficiency of the stimulatory subunit of the guanine nucleotide-binding proteins that mediate activation of adenylate cyclase can cause resistance to multiple hormones, including TSH and parathyroid hormone. In infants, exposure to cold temperatures immediately following birth or during hypothermic surgery causes TSH concentrations to rise as high as 50 to 100 mU/L, which is thought to reflect the immaturity of the hypothalamicpituitary-thyroid axis (69). Adults, on the other hand, do not demonstrate altered TSH levels after brief periods of cold exposure, despite increases in the concentrations and fractional clearance rates of circulating free T4 and T3. Specialized Studies of Thyroid Function Thyroglobulin In most forms of thyroid disease, thyroglobulin (Tg) is released from thyroid follicular cells proportional to the synthesis and release of T4 and T3, increasing size of the gland, and the degree of cytotoxic inflammation. The reference range in subjects with intact thyroid glands and normal TSH levels is approximately 3 to 40 ng/mL. Markedly elevated levels are seen in most patients with hyperthyroidism and thyroiditis, but mild increases are also observed in cigarette smokers despite slightly lower TSH levels (70). In determining the cause of hyperthyroidism, an undetectable serum thyroglobulin suggests factitious or iatrogenic thyrotoxicosis. Undetectable levels are also seen in hypothyroid patients with congenital or acquired absence of the thyroid. Presently, the primary indication for measurement of serum Tg concentrations is as a tumor marker for the longitudinal follow-up of patients with differentiated thyroid carcinoma, which necessitates greater functional sensitivity at lower concentrations than the euthyroid reference range (71). Although introduced more than 15 years ago, these assays are now being increasingly used to detect Tg in fine-needle aspirations of neck masses or cystic lesions as an adjunct to cytologic interpretation to diagnose recurrent or metastatic cancer (72). Serum Tg is generally measured by either two-antibody immunometric assay or single-antibody immunoassay. The newer immunometric assays require shorter incubation times and have greater sensitivity (≤1 ng/mL) than the immunoassays, but several problems persist. The greatest limitation is the potential for interference by anti-Tg autoantibodies, which can be found in up to 25% of differentiated

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thyroid carcinoma patients. In the immunometric assays, the serum Tg concentration can be falsely lowered by autoantibodies that bind Tg and effectively remove it from the serum, thus making it incapable of binding to the assay’s reporter antibodies. Attempts to abrogate this effect by use of monoclonal antibodies directed against epitopes of Tg that do not react with the autoantibodies have been ineffective. Detecting the presence and degree of autoantibody interference in an immunoassay may also be difficult. Although “recovery tests” that determine whether the addition of known quantities of exogenous Tg to a serum specimen that contains anti-Tg antibodies results in an appropriate increase in the concentration were initially purported to accurately detect the degree of interference, subsequent studies have demonstrated that such assessments are unreliable (73). Conversely, in radioimmunoassays, anti-Tg autoantibodies can cause falsely high values because they bind radiolabeled Tg; as a result, less is available to bind to the assay antibody. Thus, in the presence of anti-Tg antibodies, discordant findings of an undetectable Tg in an immunometric assay and a concentration of at least 2 ng/dL in a radioimmunoassay may suggest the presence of antibody interference, but cannot be used to quantify the problem. Measure of serum Tg should therefore always be preceded by a test for anti-Tg antibodies, and it is recommended that laboratories withhold reporting low results of Tg immunometric assays when autoantibodies are identified (7). Of note, recent reports demonstrate that the presence of anti-Tg antibodies may not preclude identification of the high concentration of Tg seen in fine-needle aspiration specimens (74). Despite a trend toward assay standardization, the variability of results using differing assays remains at least 25%, due to variations in the antithyroglobulin antibodies used and the molecular heterogeneity of Tg. Occasionally, immunometric assays may fail to detect very high serum Tg concentrations due to the so-called hook effect, in which the high concentrations of Tg bind to one antibody, preventing the formation of the two-antibody sandwich upon which the assay depends. If this effect is suspected, the sample should be reanalyzed after dilution. Another cause of a false-negative Tg in patients with differentiated thyroid cancer can be tumor production of variants of Tg that fail to be recognized by the antibodies used in an assay (75). The negative predictive value of an undetectable Tg level to identify differentiated thyroid cancer patients who have no remaining evidence of disease has been markedly improved by the now routine practice of using TSH to try to stimulate Tg production by any remaining tumor cells (76). Whereas higher Tg levels result from more prolonged endogenous TSH stimulation during withdrawal from thyroid hormone, quality of life is preserved without significant loss of diagnostic utility when stimulation is provided by exogenous recombinant human TSH administered to a patient taking thyroid hormone (77,78). Alternatively, the positive predictive value is limited in the presence of remnant normal thyroid cells left after thyroidectomy, and thus one indication for postsurgical adjuvant radioiodine therapy is to eliminate such normal sources of Tg (79). False-positive Tg results can also be caused by heterophilic antibodies, a problem in many immunometric

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assays that has only been partially resolved by the addition of blocking antibodies, but rare false-negative results have also been reported (80,81). Tg assays with functional sensitivity as low as 0.1 ng/dL or less have recently been introduced (82,83). Such more sensitive assays have been proposed as a replacement for use of recombinant TSH stimulation testing, but a limiting factor remains the reduction in specificity that accompanies the higher sensitivity of these procedures, with the possible requirement for multiple additional testing procedures based upon false-positive Tg results. Thyroid Autoantibodies Antibodies directed against the cell surface (TSH receptor), intracellular components (microsomal membranes, thyroglobulin), and extracellular antigens (T4, T3) are often found in sera of patients with autoimmune thyroid diseases. Although autoantibodies tend to target fewer antigenic epitopes than heterologous antibodies, these autoantibodies can still be quite heterogeneous mixtures of proteins, leading to problems with both specificity and sensitivity in assays. In Hashimoto’s disease, cytotoxic antibodies may bind to a thyroid microsomal antigen that is expressed on the apical cell surface, and these antibodies subsequently fix complement. These antithyroid microsomal antibodies can be detected by sensitive hemagglutination techniques in the sera of 95% of patients with histologically proven Hashimoto’s disease, as compared with only 55% for non-complement-fixing antithyroglobulin antibodies. Among commercially available assays, immunometric procedures, including RIA, immunoradiometric assay (IRMA), and enzyme-linked and fluorescent methods, are superior to routine hemagglutination techniques. Marginal improvements in sensitivity and specificity have been obtained using monoclonal antibodies directed against TPO, consistent with evidence that this enzyme is the primary microsomal antigen. Factors limiting the accuracy of anti-TPO assays include the presence of splicing variants of the enzyme as well as differences in posttranslational modifications (84). International standardization now exists against a specific reference preparation, Medical Research Council (MRC) 66/387, permitting reporting of results in “international units,” but concordance among multiple assays remains suboptimal (85). Reference ranges vary widely among different assays, with manufacturers often citing levels ⬎10 kIU/L as being clinically relevant predictors of autoimmune thyroid disease. However, long-term follow-up studies that identified antimicrosomal antibodies as being predictive of eventual hypothyroidism were likely based on far less sensitive assays, and similar studies will be required to determine whether such minimally detectable levels are also predictive (54,84). Antithyroglobulin antibodies are less specific for autoimmune thyroiditis, but have achieved greater significance for their potential to interfere with thyroglobulin assays in thyroid cancer patients. Contemporary immunoassays are considerably more sensitive and specific than older, agglutination methods, and can detect antithyroglobulin antibodies in up to 10% of the clinically disease-free population and 3.4% of those who lack anti-TPO antibodies (51). Nevertheless,

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reference preparations for standardization of these assays still vary considerably, and even use of the accepted international standard reference MRC 65/93 has not resulted in interchangeabilty of assays (84). As with anti-TPO antibody measurements, differences exist in the definitions used for reference ranges. Assays that report detectable levels of antithyroglobulin antibodies ⬍10 kIU/L as abnormal may have low specificity both for actual pathology and for antibodies that can interfere with thyroglobulin assays (86). No correlation exists between the severity of hypothyroidism and titers of antithyroid antibodies, and low levels can be seen in patients with no demonstrable thyroid dysfunction. Anti-TPO and antithyroglobulin antibodies are also present in Graves’ disease, albeit less frequently (85% and 25%, respectively), and may predict the subsequent development of hypothyroidism in some patients with this condition. With appropriate treatment of the thyroid hormone excess or deficiency, antithyroid antibody titers often decrease but are not clinically useful measures of disease activity. Multiple procedures have been developed to measure the TSH-receptor stimulatory immunoglobulins that are pathogenetic for Graves’ disease, detecting either stimulation of biochemical functions in thyroid cells (thyroid-stimulating immunoglobulins) or blockade of receptor binding by TSH (TSH-binding inhibitors). The original long-acting thyroid stimulator (LATS) assay of Adams and Purves had been largely replaced by quantitation of cyclic adenosine monophosphate (AMP) production, iodine uptake, or thymidine incorporation into DNA in cell lines that derive from a rat thyroid follicular cell. False-negative results can occur due to human IgG molecules that do not interact with the rat TSH receptor—an outcome that can be circumvented by use of human thyroid cells in primary culture or Chinese hamster ovary cells expressing a human TSH receptor (87). TSH-binding inhibitors can be detected by quantitation of radiolabeled TSH binding to solubilized porcine thyroid membranes (or more recently recombinant human TSH receptors) in the presence of serum, followed by polyethylene glycol precipitation to separate bound from unbound radiolabel (88). Alternatively, recombinant TSH receptors can be affinity-immobilized on an antibody-coated tube, which is then incubated with TSH with an attached radioactive or chemiluminescent label (89). In general, the most sensitive of these assays can detect thyroidstimulating immunoglobulins in up to 95% of hyperthyroid Graves’ sera, and TSH-binding inhibitors in 60% to 85%. Recent reports differ as to the magnitude of correlation between these two immunoglobulin types as well as their respective utilities for diagnosis and monitoring of response to therapy for Graves’ disease, despite recent adoption of an international standard MRC 90/672 (90). However, thyroid-stimulating immunoglobulins levels may be more useful for identifying Graves’ disease as the cause of exophthalmos (91). Blocking antibodies that bind to but do not stimulate the TSH receptor have also been identified in hypothyroid and euthyroid patients with autoimmune thyroiditis or Graves’ disease. The measurement of thyroid autoantibodies is of value in selected clinical situations. The presence of thyroid-stimulating immunoglobulins in patients in

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whom the etiology of hyperthyroidism is uncertain can lead to a diagnosis of Graves’ disease, although anti-TPO antibodies are also common in this condition and may be a more cost-effective test. With the second generation radioreceptor assays that use recombinant TSH receptors, anti-TSH receptor antibody levels before treatment are better predictors of the likelihood of response to antithyroid drug therapy than earlier assays (92). Persistence of high levels of thyroidstimulating immunoglobulins in Graves’ disease following therapy is associated with increased rates of recurrence (93,94). When detected during the third trimester of pregnancy in a woman with Graves’ disease, significant increases in either TSHbinding inhibitors or thyroid-stimulating immunoglobulins titers correlate with the development of intrauterine and neonatal hyperthyroidism due to transplacental passage of immunoglobulins. Recent evidence-based guidelines suggest that the more easily measured TSH-binding inhibitors level is the preferred method for predicting risk for neonatal hyperthyroidism (31). In the setting of asymptomatic hyperthyrotropinemia with normal thyroid hormone levels, significant anti-TPO antibody levels are prognostic for the development of overt hypothyroidism in approximately 5% of patients per year; the likelihood of thyroidal failure is higher in those patients with higher levels and baseline TSH concentrations ⬎2 mU/L (54). The presence of serum anti-TPO antibodies in a euthyroid pregnant woman greatly increases her risk of developing symptomatic postpartum thyroiditis, as well as her risk for fetal loss (95). Reverse T3 Radioimmunoassays for reverse T3 (rT3) have been developed, but have limited clinical usefulness. Levels are increased in nonthyroidal illness due to impairment of 5’-monodeiodination, a major degradative step for rT3, but this is insufficiently reliable to distinguish euthyroid patients from those with coexisting hypothyroidism (96). Tissue Responses to Thyroid Hormone Action Before the availability of hormone immunoassays, measurement of the end-organ responses—for example, the basal metabolic rate—was the primary means of evaluating thyroid hormone function. Today, regulation of serum TSH levels by T4 and T3 is the most precisely measurable and useful response by tissues to the action of thyroid hormones. Measurements of thyroid hormone effects in extrapituitary tissues are occasionally used to evaluate patients in whom there is a discordance among the clinical evaluation, thyroid hormone levels, and the concentration of TSH (97). Numerous serum constituents have altered levels in hyperthyroidism and hypothyroidism, mostly reflecting changes in synthesis and/or clearance of these substances (Table 3). There is considerable overlap between the normal ranges and values seen in thyroid gland dysfunction. However, they remain useful markers of thyroid hormone effects, especially with serial determination during therapy of underlying thyroid disorders and in the evaluation of patients with discordant

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Table 3 How Various Serum Constituents Are Altered in Hyperthyroidism and Hypothyroidism Increased Hyperthyroidism Alkaline phosphatase Angiotensin converting enzyme Calcium Factor VIII Ferritin Osteocalcin Sex hormone–binding globulin Urine nitrogen excretion Urine pyridinoline cross-links Hypothyroidism Carcinoembryonic antigen Cholesterol (LDL and HDL fractions) Creatine phosphokinase Creatinine Lactic dehydrogenase Myoglobin Norepinephrine Prolactin Corticosteroid-binding globulin

Decreased Cholesterol (total, LDL) Apolipoprotein b, apo (a) Corticosteroid-binding globulin

Aldosterone Angiotensin converting enzyme Factor VIII Osmolarity Sex hormone–binding globulin

thyroid function tests. Combinations of biophysical and serum parameters of thyroid hormone action are particularly useful in the evaluation of patients with possible thyroid hormone resistance states. To characterize the presence and extent of resistance, parameters of pituitary and peripheral tissue response are measured before and during administration of increasing doses of T3 (50, 100, and 200 ␮g/day). Among the various tests performed, changes in sex hormone binding globulin, basal metabolic rate, and body weight provide the strongest distinction between normal responsiveness and generalized resistance to thyroid hormones (98). LABORATORY EVALUATION FOR THYROID DISEASE Distinct strategies for use of thyroid function tests should be designed to satisfy four distinct purposes: screening for the presence of clinically unsuspected disease in an asymptomatic general population, case finding to detect thyroid disease in patients whose symptoms and signs are sufficiently subtle that the examining clinician may not suspect thyroid dysfunction as the etiology, diagnosis to prove the presence of clinically suspected disease, and optimization of management of proven thyroid disease.

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Screening and Case Finding Population screening is generally warranted if the prevalence of such disease is not small, the health consequences of undiagnosed disease are substantial, and treatment is effective. With these criteria in mind, there is considerable controversy about the appropriateness of screening asymptomatic adults for thyroid dysfunction (99,100). The Whickham study demonstrated an annual incidence of thyroid hormone excess and deficiency of 0.5% in women and 0.06% in men in the United Kingdom (54). The hazard rate for developing thyroid dysfunction was higher in women with advancing age, but not men. Using a logit model to evaluate contributors to risk, only the presence of antithyroid antibodies and a baseline TSH of at least 2.0 mU/L were predictive of eventual overt hypothyroidism. More at issue than prevalence, however, is the question of whether undiagnosed mild hypothyroidism or hyperthyroidism has significant enough consequences to justify the costs of screening. Using a decision analysis model, adding a serum TSH determination to the quintennial cholesterol screening recommended starting at age 35 was found to be reasonably cost-effective (101). Deferring periodic TSH screening until older ages and decreasing cost for TSH assays are key factors in improving cost-effectiveness even further. As a result, three endocrine professional organizations (the American Thyroid Association, American Association of Clinical Endocrinologists, and The Endocrine Society) all support routine screening of asymptomatic adults (102). Conversely, other organizations with broader focus than these endocrine groups do not recommend screening for thyroid dysfunction, including the U. S. Preventive Services Task Force, American College of Physicians, Royal College of Physicians, and Institute of Medicine (103–106). There is uniform agreement, however, that screening for neonatal hypothyroidism is necessary (107). Neonatal hypothyroidism occurs with a frequency of 1 in 4000 live births and is associated with significant neurological and developmental morbidity, much of which can be prevented by early treatment with thyroid hormone replacement. Mandatory neonatal screening is based upon the measurement of total (not free) T4 in whole blood collected on filter paper. Determination of TSH concentration is performed if the T4 level is below the 10th percentile, and serum assays are used to confirm a diagnosis of hypothyroidism. The advantage of a T4-first strategy is the ability to detect central hypothyroidism and minimized impact of the neonatal TSH surge (108). An alternative strategy employs primary TSH screening, followed by confirmatory T4 testing; this approach is more commonly used in Europe and in areas of iodine deficiency (109). Case finding is best reserved for patients whose clinical assessment may be sufficiently complex as to obscure suspicion for thyroid dysfunction. Often, these patients are elderly and their symptoms may be primarily constitutional, neuropsychiatric, or cardiovascular. Although dementia is an uncommon presentation of hypothyroidism, the relative ease of diagnosis and treatment of this condition warrants inclusion of a thyroid function test in the evaluation of such patients. As an initial test for case finding, a sensitive TSH assay has excellent sensitivity and

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specificity for both hyperthyroidism and hypothyroidism. In contrast, hospitalized patients with acute illnesses have a high frequency of transient thyroid function abnormalities and are unlikely to have primary thyroid disease diagnosed on the basis of routine tests. In the absence of strong clinical evidence of thyroid dysfunction, patients hospitalized with acute illnesses should probably not undergo thyroid testing for case finding (34). Postpartum women have a high frequency of transient thyroid dysfunction, especially those with preexisting euthyroid autoimmune thyroiditis. Within the first three months after delivery, at least 5% of women develop postpartum thyroiditis, a painless inflammatory condition that can cause thyrotoxicosis and/or hypothyroidism. More than one-half of these patients require therapeutic intervention. Furthermore, 25% of women with postpartum thyroiditis eventually develop chronic hypothyroidism, thus requiring lifelong therapy. Case finding with serum TSH measurements three and six months after delivery is recommended for women with type I diabetes mellitus, personal history of postpartum thyroiditis, or those known to have elevated levels of anti-TPO antibodies (110).

Hypothyroidism Diagnosis Clinical manifestations, hypothyroxinemia, and an increased serum TSH establish the diagnosis of primary hypothyroidism. Nonspecific clinical symptoms and signs alone are a poor predictor of hypothyroidism. Among ambulatory patients evaluated for possible hypothyroidism—with symptoms of weight gain, fatigue, menstrual irregularities, depression, cold intolerance, constipation, or galactorrhea— only 4% have increased TSH levels and fewer than half of these have values ⬎5 mU/L above normal (111). The presence of a goiter on examination increases the likelihood of hypothyroidism sixfold. However, the number and severity of symptoms are poorly correlated with presence or severity of hypothyroidism. Given this low prevalence of disease in symptomatic patients, first-line laboratory testing for suspected hypothyroidism should be a highly sensitive, inexpensive test capable of excluding patients who would not benefit from therapy. In patients with hypothyroid symptoms who lack a history of known thyroid or pituitary disease, the initial diagnostic test should be the serum TSH, with confirmation of diagnosis provided by subsequent determination of the free T4 level. Although rare patients with secondary hypothyroidism may not be detected, a serum TSH assay will accurately diagnose hypothyroidism in almost all patients, including those with subclinical hypothyroidism. An alternative strategy for patients who are not suspected to have thyroxine binding or clearance abnormalities would be measurement of the total T4 with an attenuated normal range, but this strategy is not generally recommended. Confirmation of the diagnosis of primary hypothyroidism can then be made with a TSH assay, a test with specificity and sensitivity for primary hypothyroidism of ⬎95%.

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Other clinical settings present different testing requirements. Hypothyroxinemia can be due to decreased serum binding to proteins, nonthyroidal illness or certain medications. Similarly, hypothyroid patients with increased serum thyroxine binding due to increased TBG may have normal total T4 levels that mask the complexity of the underlying thyroid disorders. If abnormal serum binding is suspected, for example, in patients taking estrogen therapy, measurement of serum TSH is the most appropriate initial test. When the prevalence of primary hypothyroidism is higher than that in the general ambulatory population, as in patients attending an endocrinology clinic or those who present with a goiter or a history of thyroid disease, lithium therapy, neck surgery, or high-dose radiation exposure, the sensitive TSH assay may be the most efficient initial test to perform, followed by free T4 when TSH is elevated. Hypothyroidism due to pituitary or hypothalamic disease is more common as well in an endocrinology clinic, and therefore a TSH assay as the sole evaluation of the pituitary-thyroid axis can be misleading given the frequent lack of elevation of TSH concentrations in this disorder (112). When secondary or tertiary hypothyroidism is also a consideration, the combination of serum free T4 and TSH should be measured. Additional tests can occasionally be helpful in establishing the diagnosis and cause of hypothyroidism. The diagnosis of autoimmune thyroiditis, either chronic or transient, is confirmed by the presence of serum anti-TPO antibodies. Although most hypothyroid patients who develop nonthyroidal illness remain hyperthyrotropinemic, individuals with mild hypothyroidism may have normal TSH concentrations in this situation, especially when exposed to the TSH-suppressive effects of exogenous and endogenous glucocorticoids, dopamine, somatostatin, and opioids. Confirmation of the diagnosis may require follow-up testing when the patient has recovered from the acute illness. If pituitary or hypothalamic disease is suspected, other abnormalities of anterior pituitary function are often found— for example, inappropriately normal gonadotropin levels in a postmenopausal woman, radiological imaging of the sella is also often indicated. When the clinical diagnosis of hypothyroidism is uncertain, supporting evidence can be obtained by examining tissue responses to thyroid hormones—for example, sex hormone binding globulin. Treatment Thyroid hormone replacement therapy for the treatment of primary hypothyroidism should be monitored with a sensitive TSH assay. The goal of therapy for hypothyroidism is to make the patient clinically and biochemically euthyroid, which is usually associated with normalization of the serum TSH level; the target TSH range most commonly recommended by thyroidologists is 0.5 to 2.0 mU/L in the nonelderly and 0.5 to 4.0 mU/L in the elderly (113). When levothyroxine sodium is administered daily by mouth, decreasing serum TSH concentrations plateau within six to eight weeks, and measurement of the TSH level should await this new equilibrium. Patients with persistently elevated serum TSH levels generally require an increased dose of levothyroxine, whereas those patients with a low

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serum TSH concentration usually require a decrease in dose. Serum T4 and T3 levels are usually normal during therapy, although mild hyperthyroxinemia can occur in as many as 20% of patients who are otherwise euthyroid. Once a hypothyroid patient becomes euthyroid, follow-up evaluation should be performed after several months, given the gradual increase of T4 clearance that occurs in these patients. Subsequent evaluations generally are recommended annually, although stable patients may be monitored less frequently (114). To monitor therapy in patients with secondary or tertiary hypothyroidism, the patient’s clinical status and serum free T4 levels should be assessed. The goal of therapy should be attainment of a clinically euthyroid state, with normal or high-normal free T4 levels, since the serum TSH concentration is not a reliable indicator of thyroid hormone status in this setting (115). Patients receiving therapy with T3-containing preparations, which are shorter-acting than levothyroxine sodium alone, may be more difficult to monitor (116). Individuals who take desiccated thyroid or other formulations containing triiodothyronine are likely to have variable T3 levels during the day. Hyperthyroidism Diagnosis Clinical manifestations, increased serum thyroid hormone concentrations, and a subnormal serum TSH level typically establish the diagnosis of thyrotoxicosis. In the evaluation of the patient with hyperthyroid symptoms, two alternative testing strategies can be followed. Measurement of free T4, if near or above the upper range of normal, can detect hyperthyroxinemic patients in whom a low serum TSH level can then confirm the diagnosis of hyperthyroidism. With this approach, most patients with euthyroid hyperthyroxinemia due to increased hormone binding to serum proteins are identified on the basis of a normal free T4. Patients with FDH, nonthyroidal illness, and generalized resistance to thyroid hormones may be recognized by their usually normal serum TSH concentrations. However, patients with T3 toxicosis, due to mild or recurrent Graves’ disease or hyperfunctioning adenomas, can present with normal or occasionally low serum free T4, and the diagnosis of hyperthyroidism may be missed using the T4-first strategy. Alternatively, the serum TSH level, measured in an assay with a detection limit of ⬍0.1 mU/L, is a more sensitive initial test for the diagnosis of thyrotoxicosis. In patients with subnormal TSH levels, increased serum T4 and/or T3 levels confirm the diagnosis of thyrotoxicosis, high-normal T4 and/or T3 suggest subclinical thyrotoxicosis, and low-normal or low–thyroid hormone levels suggest either T3 thyrotoxicosis, nonthyroidal illness, or central hypothyroidism (58). Patients with the rare causes of TSH-mediated hyperthyroidism who may have normal or even elevated TSH levels—that is, TSH-secreting pituitary adenoma or isolated pituitary resistance to thyroid hormones—may be undiagnosed with this strategy. Thus, in settings where unusual causes of hyperthyroidism are more prevalent, such as an endocrinology or neurosurgical clinic, simultaneous

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determinations of serum TSH and thyroid hormone concentrations may be the most appropriate initial tests to perform. Additional tests are occasionally useful in establishing the diagnosis and etiology of thyrotoxicosis. When the clinical and biochemical evidence for thyrotoxicosis are discordant, supplemental evidence for excess thyroid hormone levels can be obtained by examining tissue responses to thyroid hormones that are altered in thyrotoxicosis, such as sex hormone–binding globulin. Once the diagnosis is certain, the clinical presentation of hyperthyroidism may suggest the need for ancillary testing. In a patient with a tender goiter and hyperthyroidism of short duration, an elevated erythrocyte sedimentation rate is characteristic of subacute thyroiditis. An increased radioiodine uptake is typically found in Graves’ disease and hyperfunctioning nodular disease but is not seen in subacute or lymphocytic thyroiditis. Similarly, the serum thyroglobulin and radioiodine uptake are typically low in factitious and iatrogenic thyrotoxicosis. When clinical findings do not provide adequate diagnostic distinction, testing for anti-TPO antibodies or thyroid-stimulating immunoglobulins/thyrotropin receptor antibodies may assist in the discrimination between Graves’ disease and toxic multinodular goiter. Radiologic imaging of the sella and a serum alpha subunit level would be indicated in the evaluation of the patient with TSH-mediated hyperthyroidism. Treatment The goal of therapy for hyperthyroidism is a clinically euthyroid patient with normal serum thyroid hormone and TSH levels. However, because normalization of the serum TSH concentration may lag behind thyroid hormone levels by several months, initial therapy should be directed to reducing thyroid hormone levels. Once the TSH level is detectable, it is again a sensitive indicator of thyroid hormone status. Given the increased T3:T4 ratio typical of increased glandular synthesis of hormone, the T4 level may become normal or even low while the T3 level remains elevated, producing persistent T3 toxicosis. In addition, an elevated T3 level may be the earliest sign of recurrent hyperthyroidism. Thus, both the T3 and free T4 levels should be monitored during treatment of hyperthyroidism. In patients with TSH-mediated hyperthyroidism, clinical assessment and thyroid hormone levels are the only measures of use, as the serum TSH level does not reflect thyroid hormone status. THYROID NEOPLASIA Alterations in thyroid function are unusual in the presentation of thyroid neoplasia. Most neoplastic lesions, both benign and malignant, organify iodine and produce thyroid hormones inefficiently. Unless most of the nonneoplastic follicular tissue is destroyed by infiltrating tumor or is ablated during the treatment of the neoplasm, thyroid hormone levels are normal. Autonomously hyperfunctioning thyroid adenomas can produce hyperthyroidism, thereby suppressing serum TSH levels and reducing hormone production by nonadenomatous tissue. However, only 5% of

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thyroid nodules are hyperfunctioning, and therefore most patients with thyroid nodules are euthyroid. Fine-needle aspiration biopsy is the most important diagnostic test for the solitary or dominant thyroid nodule, capable of distinguishing benign from malignant lesions in a majority of patients. In a patient with differentiated thyroid carcinoma who has undergone total thyroidectomy or remnant ablation with radioactive iodine, serial thyroglobulin determinations can assist in the recognition of residual or metastatic disease. In general, the sensitivity of detecting thyroid carcinoma by measurement of serum Tg after discontinuation of thyroid hormone therapy is 85% to 95% but may be as low as 50% during therapy. Levels of thyroglobulin following recombinant human TSH stimulation may be approximately 50% as high as following endogenous TSH stimulation after thyroid hormone withdrawal, when performed in conjunction with diagnostic radioiodine scanning (117). The results are most likely to be falsely negative in patients with small nodal metastases of papillary carcinoma and in those with tumor dedifferentiation. In immunometric assays, false-negative Tg results can also occur due to interference from antithyroglobulin antibodies. Antithyroglobulin antibodies that persist or are rising beyond the first several years of follow-up after primary therapy can indicate higher risk for residual disease (86). However, persistence of antibodies has been reported as long as 18 years after initial treatment without clinical evidence of disease in patients who had coexistent Hashimoto’s disease in their thyroidectomy specimen (118). It is difficult to generalize from the results of either Tg or antithyroglobulin antibody testing in one center because of interlaboratory variations in assay sensitivity and specificity. With increasing assay sensitivity, Tg levels at least 1 to 2 ng/mL following TSH stimulation should justify further diagnostic evaluation for possible residual or metastatic disease (119). Tg levels that are minimally detectable during TSH suppressive therapy but that do not rise following TSH stimulation may suggest the presence of heterophilic antibodies causing false elevations of the assay (81). C CELLS, CALCITONIN, AND MEDULLARY THYROID CARCINOMA The 32–amino acid peptide calcitonin is principally produced by the thyroid C cells; smaller amounts can be found in neuroendocrine cells throughout the body. Physiological stimuli to calcitonin secretion from the thyroid include hypercalcemia, hypergastrinemia, hypermagnesemia, and beta-adrenergic agonists. Suppression of hormone release is produced by dopamine, somatostatin, and 1, 25dihydroxyvitamin D. In pharmacological amounts, calcitonin induces inhibition of osteoclast-mediated bone resorption, leading to hypocalcemia and hypophosphatemia. However, in humans, neither an excess amount nor the absence of calcitonin leads to demonstrable alterations in calcium or bone metabolism. Other pharmacological effects of calcitonin include a diminution of pancreatic exocrine and endocrine secretion and impaired renal tubular reabsorption of calcium and phosphate.

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Single- or double-antibody immunoassay techniques are used for the routine measurement of serum calcitonin levels, although the latter are markedly more sensitive. Difficulties in the interpretation of these assay results arise from calcitonin species that are immunologically detectable but biologically inactive, such as polymeric forms of the molecule. Passage of the serum through a silica cartridge prior to immunoassay yields mostly monomeric calcitonin, with a normal concentration of ⬍10 pg/mL; calcitonin levels can be undetectable in more than half of normal subjects tested (120). Additional uncertainty can be due to the numerous sites of calcitonin synthesis, including pulmonary neuroendocrine cells, the pancreas, and the small intestine. Thus, thyroidectomized patients may still have detectable levels of calcitonin, and mild elevations occur in diseases that do not involve the C cells of the thyroid. The differential diagnosis of hypercalcitoninemia includes chronic and acute pulmonary diseases (such as pneumonitis, chronic obstructive pulmonary disease, and sarcoidosis), gastrointestinal disorders (e.g., pancreatitis, ileitis, and hypergastrinemic diseases), renal failure (due to impaired clearance), cigarette smoking, and heterophilic antibodies (120,121). In addition to tumors of neuroendocrine derivation (e.g., small-cell lung cancer, carcinoid, and pheochromocytoma), many malignancies are associated with hypercalcitoninemia, although frequently the calcitonins produced by these cancers are biologically inactive. In contrast, the “hook effect” can also affect calcitonin immunoassays, causing false low assay results despite marked elevation of calcitonin concentrations (122). Medullary thyroid carcinoma (MTC) is a malignancy of the C cells that produces marked hypercalcitoninemia. The disease can occur in several clinical settings: sporadic tumors, multiple endocrine neoplasia syndromes (MEN), and familial non-MEN medullary carcinoma. In the MEN syndromes, the disease is bilateral and associated with primary hyperparathyroidism and pheochromocytoma (MEN 2A), or mucosal ganglioneuromata, marfanoid habitus, and pheochromocytoma (MEN 2B). Elevated serum levels of calcitonin (⬎200 pg/mL) are almost always found with palpable medullary carcinomas, and the degree of elevation usually corresponds to the size of the tumor. However, small tumors and MEN patients with the premalignant lesion C-cell hyperplasia may have normal basal levels of calcitonin, thus necessitating stimulation testing. The procedure of greatest discriminant value in this setting is combined calcium-pentagastrin testing, but pentagastrin is no longer available in the United States. To use calcium as a sole stimulatory agent, elemental calcium (2 mg/kg) is administered intravenously in 50 mL of 0.9% saline over 60 seconds, and plasma for calcitonin measurements is collected 5 and 10 minutes after the infusion (123). An alternative provocative test relies upon the calcitonin-stimulatory effects of omeprazoleinduced hypergastrinemia (124). C-cell hyperplasia and medullary carcinoma produce greater than fivefold elevations in the serum calcitonin concentration. Additional tumor markers, such as carcinoembryonic antigen, can be useful in the long-term follow-up of patients with MTC. During follow-up, most patients whose calcitonin levels are doubling in less than 6 months die within 5 years; doubling time less than 24 months is associated with progressive disease (125,126).

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Routine measurement of the serum calcitonin concentration is not recommended as a screen for MTC in a patient with a solitary nodule. However, recent reports suggest that perhaps as many as 3% of patients with nodular thyroid disease will have an elevated serum calcitonin level when measured in a sensitive immunometric assay, many of whom will prove to have MTC at thyroidectomy (127). The cost-effectiveness of adding a single serum calcitonin determination to the evaluation of a patient with nodular thyroid disease has been estimated as nearly $12,000 per life-year saved, and is sensitive to variation in disease prevalence, specificity of fine-needle aspiration, and cost of testing (128). Nonetheless, routine calcitonin measurements have not been recommended in the guidelines for thyroid nodule evaluation by the American Thyroid Association (129). For patients in known kindreds with inherited MTC, prospective family screening increasingly identifies disease carriers long before clinical symptoms or signs are noted. Using the traditional approach of stimulated secretion of calcitonin by either pentagastrin or calcium infusion, 65% of MEN 2A gene carriers will have abnormal calcitonin levels by age 20 years and 95% by age 35 (130). Compared with sporadic disease, the typical age of presentation for familial disease is the third decade, without gender preference. In MEN 2A, it is uncommon for the signs or symptoms of hyperparathyroidism or pheochromocytoma to present before those of MTC, even in the absence of prospective screening. All familial forms of MTC and MEN 2 are inherited in an autosomal dominant fashion. In almost all known kindreds, the disease is caused by a germline mutation in the ret protooncogene, a 21-exon gene located near the centromere on chromosome 10. Ret codes for a cell membrane–associated tyrosine kinase receptor for glial cell linederived neurotrophic factor, a circulating ligand that promotes development of various central and peripheral nervous system neurons. Mutations associated with MEN 2A and familial medullary thyroid carcinoma (FMTC) have been primarily identified in several codons of the cysteine-rich extracellular domains of exon 8, 10, 11, and 13, whereas MEN 2B and some FMTC mutations are found within the intracellular exons 15 and 16 (131). Of note, nearly half of patients with sporadic disease have somatic ret mutations, typically involving the codon 918 mutation that also causes MEN 2B when inherited. Further, approximately 6% of patients with clinically sporadic MTC carry a germline mutation in ret, leading to identification of new kindreds with multiple previously undiagnosed affected individuals. Genetic testing for ret proto-oncogene mutations should be offered to all patients newly diagnosed with clinically apparent sporadic MTC, as well as for screening children and adults in known kindreds with inherited forms of MTC. Given the frequency of mutations in certain exons, a sensible strategy for mutational analysis would start with examination of exon 11, followed sequentially by exons 10, 16, 13, 14, 15, and 8 (132). Although common mutations can be identified by broadly available commercial testing sources, only a limited number of sites perform the more thorough analyses that are required to identify the less common mutations. Studies of genotype:phenotype correlations of various ret mutations have demonstrated the presence of three levels of risk, defined as age of earliest

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diagnosis of malignant disease and risk for mortality due to the cancer (131). At the highest risk are the group 3 mutations, codons 918 and 883 that cause MEN 2B and metastatic disease as early as age 6 months. At higher risk are the group 2 mutations, which include the common mutations at codons 611, 618, 620, and 634 that are associated with malignant disease as early as age 5. At high risk are the group 1 mutations, which include those at codons 609, 768, 790, 791, 804, and 891; with some of the group 1 mutations, fatal MTC has yet to be reported. Recommendations for the aggressiveness and timing of therapeutic intervention are tied to these risk levels (132). REFERENCES 1. Burmeister LA, Goumaz MO, Mariash CN, et al. Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab 1992; 75(2):344–350. 2. Spencer CA, LoPresti JS, Patel A, et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990; 70(2):453–460. 3. Meikle AW, Stringham JD, Woodward MG, et al. Hereditary and environmental influences on the variation of thyroid hormones in normal male twins. J Clin Endocrinol Metab 1988; 66(3):588–592. 4. Hansen PS, Brix TH, Iachine I, et al. Genetic and environmental interrelations between measurements of thyroid function in a healthy Danish twin population. Am J Physiol Endocrinol Metab 2007; 292(3):E765–E770. 5. Jensen E, Hyltoft Petersen P, Blaabjerg O, et al. Establishment of a serum thyroid stimulating hormone (TSH) reference interval in healthy adults. The importance of environmental factors, including thyroid antibodies. Clin Chem Lab Med 2004; 42(7):824–832. 6. Midgley JE. Direct and indirect free thyroxine assay methods: Theory and practice. Clin Chem 2001; 47(8):1353–1363. 7. Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13(1):3–126. 8. Steele BW, Wang E, Klee GG, et al. Analytic bias of thyroid function tests: Analysis of a College of American Pathologists fresh frozen serum pool by 3900 clinical laboratories. Arch Pathol Lab Med 2005; 129(3):310–317. 9. Thienpont LM, Beastall G, Christofides ND, et al. Proposal of a candidate international conventional reference measurement procedure for free thyroxine in serum 1): International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) 2) IFCC Scientific Division. Clin Chem Lab Med 2007; 45(7):934– 936. 10. Holm SS, Hansen SH, Faber J, et al. Reference methods for the measurement of free thyroid hormones in blood: Evaluation of potential reference methods for free thyroxine. Clin Biochem 2004; 37(2):85–93. 11. Yue B, Rockwood AL, Sandrock T, et al. Free thyroid hormones in serum by direct equilibrium dialysis and online solid-phase extraction-liquid chromatography/tandem mass spectrometry. Clin Chem 2008; 54(4):642–651.

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67. Chan LY-S, Chiu PY, Lau TK. Cord blood thyroid-stimulating hormone level in high-risk pregnancies. Eur J Obstet Gynecol Reprod Biol 2003; 108(2):142–145. 68. Beck-Peccoz P, Persani L, Calebiro D, et al. Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis. Best Pract Res Clin Endocrinol Metab 2006; 20(4):529–546. 69. Fisher DA, Nelson JC, Carlton EI, et al. Maturation of human hypothalamicpituitary-thyroid function and control. Thyroid 2000; 10(3):229–234. 70. Bertelsen JB, Hegedus L. Cigarette smoking and the thyroid. Thyroid 1994; 4(3):327–331. 71. Spencer CA, Lopresti JS. Measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer. Nat Clin Pract Endocrinol Metab 2008; 4(4):223–233. 72. Baloch ZW, Barroeta JE, Walsh J, et al. Utility of thyroglobulin measurement in fine-needle aspiration biopsy specimens of lymph nodes in the diagnosis of recurrent thyroid carcinoma. Cytojournal 2008; 5:1–5. 73. Spencer CA, Takeuchi M, Kazarosyan M, et al. Serum thyroglobulin autoantibodies: Prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998; 83(4):1121–1127. 74. Boi F, Baghino G, Atzeni F, et al. The diagnostic value for differentiated thyroid carcinoma metastases of thyroglobulin (Tg) measurement in washout fluid from fine-needle aspiration biopsy of neck lymph nodes is maintained in the presence of circulating anti-Tg antibodies. J Clin Endocrinol Metab 2006; 91(4):1364–1369. 75. Prentice L, Kiso Y, Fukuma N, et al. Monoclonal thyroglobulin autoantibodies: Variable region analysis and epitope recognition. J Clin Endocrinol Metab 1995; 80(3):977–986. 76. Kloos RT, Mazzaferri EL. A single recombinant human thyrotropin-stimulated serum thyroglobulin measurement predicts differentiated thyroid carcinoma metastases three to five years later. J Clin Endocrinol Metab 2005; 90(9):5047–5057. 77. Schroeder PR, Haugen BR, Pacini F, et al. A comparison of short-term changes in health-related quality of life in thyroid carcinoma patients undergoing diagnostic evaluation with recombinant human thyrotropin compared with thyroid hormone withdrawal. J Clin Endocrinol Metab 2006; 91(3):878–884. 78. Robbins RJ, Srivastava S, Shaha A, et al. Factors influencing the basal and recombinant human thyrotropin-stimulated serum thyroglobulin in patients with metastatic thyroid carcinoma. J Clin Endocrinol Metab 2004; 89(12):6010–6016. 79. Torlontano M, Crocetti U, Augello G, et al. Comparative evaluation of recombinant human thyrotropin-stimulated thyroglobulin levels, 131I whole-body scintigraphy, and neck ultrasonography in the follow-up of patients with papillary thyroid microcarcinoma who have not undergone radioiodine therapy. J Clin Endocrinol Metab 2006; 91(1):60–63. 80. Giovanella L, Ghelfo A. Undetectable serum thyroglobulin due to negative interference of heterophile antibodies in relapsing thyroid carcinoma. Clin Chem 2007; 53(10):1871–1872. 81. Preissner CM, O’Kane DJ, Singh RJ, et al. Phantoms in the assay tube: Heterophile antibody interferences in serum thyroglobulin assays. J Clin Endocrinol Metab 2003; 88(7):3069–3074.

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82. Mazzaferri EL. Will highly sensitive thyroglobulin assays change the management of thyroid cancer? Clin Endocrinol (Oxf) 2007; 67(3):321–323. 83. Schlumberger M, Hitzel A, Toubert ME, et al. Comparison of seven serum thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer patients. J Clin Endocrinol Metab 2007; 92(7):2487–2495. 84. Sinclair D. Analytical aspects of thyroid antibodies estimation. Autoimmunity 2008; 41(1):46–54. 85. Dherbomez M, Sapin R, Gasser F, et al. Concordance of eight kits for antithyroid peroxidase autoantibodies determination. Clin Chem Lab Med 2000; 38(6):561–566. 86. Spencer CA, Takeuchi M, Kazarosyan M, et al. Serum thyroglobulin autoantibodies: Prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998; 83(4):1121–1127. 87. Morgenthaler NG. New assay systems for thyrotropin receptor antibodies. Curr Opin Endocrinol Diabetes Metab 1999; 6(4):251–260. 88. Schott M, Feldkamp J, Bathan C, et al. Detecting TSH-receptor antibodies with the recombinant TBII assay: Technical and clinical evaluation. Horm Metab Res 2000; 32(10):429–435. 89. Costagliola S, Morgenthaler NG, Hoermann R, et al. Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves’ disease. J Clin Endo Metab 1999; 84(1):90–97. 90. Gupta MK. Thyrotropin-receptor antibodies in thyroid diseases: Advances in detection techniques and clinical applications. Clin Chem Acta 2000; 293(1–2):1–29. 91. Yamano Y, Takamatsu J, Sakane S, et al. Differences between changes in serum thyrotropin-binding inhibitory antibodies and thyroid-stimulating antibodies in the course of antithyroid drug therapy for Graves’ disease. Thyroid 1999; 9(8):769–773. 92. Carella C, Mazziotti G, Sorvillo F, et al. Serum thyrotropin receptor antibodies concentrations in patients with Graves’ disease before, at the end of methimazole treatment, and after drug withdrawal: Evidence that the activity of thyrotropin receptor antibody and/or thyroid response modify during the observation period. Thyroid 2006; 16(3):295–302. 93. Schott M, Morgenthaler NG, Fritzen R, et al. Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism in Graves’ disease. Horm Metab Res 2004; 36(2):92–96. 94. Giovanella L, Ceriani L, Garancini S. Clinical applications of the 2nd generation assay for anti-TSH receptor antibodies in Graves’ disease: Evaluation in patients with negative 1st generation test. Clin Chem Lab Med 2001; 39(1):25–28. 95. Stagnaro-Green A, Roman SH, Cobin RH, et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990; 264(11):1422–1425. 96. Burmeister LA. Reverse T3 does not reliably differentiate hypothyroid sick syndrome from euthyroid sick syndrome. Thyroid 1995; 5(6):435–441. 97. Klein I. Clinical, metabolic, and organ-specific indices of thyroid function. Endocrinol Metab Clin North Am 2001; 30(2):415–427. 98. Refetoff S. Resistance to thyroid hormone. Clin Lab Med 1993; 13(3):563–581. 99. Surks MI, Ortiz E, Daniels GH,et al. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA 2004; 291(2):228–238.

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100. Helfand M. Screening for subclinical thyroid dysfunction in nonpregnant adults: A summary of the evidence for the U. S. Preventive Services Task Force. Ann Intern Med 2004; 140(2):128–141. 101. Danese MD, Powe NR, Sawin CT, et al. Screening for mild thyroid failure at the periodic health examination. A decision and cost-effectiveness analysis. JAMA 1996; 276(4):285–292. 102. Gharib H, Tuttle RM, Baskin HJ,et al. Subclinical thyroid dysfunction: A joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J Clin Endocrinol Metab 2005; 90(1):581–585. 103. Stone MB, Wallace RB. Committee on the Medicare Coverage of Routine Thyroid Screening BoHCS. Institute of Medicine. Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington, DC: National Academies Press, 2003. 104. Vanderpump MPJ, Ahlquist JAO, Franklyn JA, et al. Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism. Bmj 1996; 313(7056):539–544. 105. U. S. Preventive Services Task Force. Screening for thyroid disease: Recommendation statement. Ann Intern Med 2004; 140(2):125–127. 106. Screening for thyroid disease. Ann Intern Med 1998; 129(2):141–143. 107. LaFranchi S, Dussault JH, Fisher DA, et al. Newborn screening for congenital hypothyroidism: Recommended guidelines. Pediatrics 1993; 152:974–975. 108. Hanna CE, Krainz PL, Skeels MR, et al. Detection of congenital hypopituitary hypothyroidism: Ten-year experience in the northwest regional screening program. J Pediatr 1986; 109(6):959–964. 109. Delange F. Screening for congenital hypothyroidism used as an indicator of the degree of iodine deficiency and of its control. Thyroid 1998; 8(12):1185–1192. 110. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007; 92(8 suppl):s1–s47. 111. Schectman JM, Kallenberg GA, Shumacher RJ, et al. Yield of hypothyroidism in symptomatic primary care patients. Arch Intern Med 1989; 149:861–864. 112. Wardle CA, Fraser WD, Squire CR. Pitfalls in the use of thyrotropin concentration as a first-line thyroid-function test. Lancet 2001; 357(9261):1013–1014. 113. McDermott MT, Woodmansee WW, Haugen BR, et al. The management of subclinical hyperthyroidism by thyroid specialists. Thyroid 2003; 13(12):1133–1139. 114. Viswanath AK, Avenell A, Philip S, et al. Is annual surveillance of all treated hypothyroid patients necessary? BMC Endocr Disord 2007; 7:4. 115. Ferretti E, Persani L, Jaffrain-Rea ML, et al. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999; 84(3):924–929. 116. Saravanan P, Siddique H, Simmons DJ, et al. Twenty-four hour hormone profiles of TSH, Free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy. Exp Clin Endocrinol Diabetes 2007; 115(4):261–267. 117. Haugen BR, Pacini F, Reiners C, et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999; 84(11):3877–3885.

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118. Chiovato L, Latrofa F, Braverman LE, et al. Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens. Ann Intern Med 2003; 139(5 Pt 1):346–351. 119. Mazzaferri EL, Robbins RJ, Spencer CA, et al. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003; 88(4):1433–1441. 120. d’Herbomez M, Caron P, Bauters C, et al. Reference range of serum calcitonin levels in humans: Influence of calcitonin assays, sex, age, and cigarette smoking. Eur J Endocrinol 2007; 157(6):749–755. 121. Papapetrou PD, Polymeris A, Karga H, et al. Heterophilic antibodies causing falsely high serum calcitonin values. J Endocrinol Invest 2006; 29(10):919–923. 122. Tommasi M, Raspanti S. Hook effect in calcitonin immunoradiometric assay. Clin Chem Lab Med 2007; 45(8):1073–1074. 123. Parthemore JG, Bronzert D, Roberts G, et al. A short calcium infusion in the diagnosis of medullary thyroid carcinoma. J Clin Endocrinol Metab 1974; 39(1):108–111. 124. Vitale G, Ciccarelli A, Caraglia M, et al. Comparison of two provocative tests for calcitonin in medullary thyroid carcinoma: Omeprazole vs pentagastrin. Clin Chem 2002; 48(9):1505–1510. 125. Barbet J, Campion L, Kraeber-Bodere F, et al. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endo Metab 2005; 90(11):6077–6084. 126. Laure Giraudet A, Al Ghulzan A, Auperin A, et al. Progression of medullary thyroid carcinoma: Assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol 2008; 158(2):239–246. 127. Elisei R, Bottici V, Luchetti F, et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: Experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab 2004; 89(1):163–168. 128. Cheung K, Roman SA, Wang TS, et al. Calcitonin measurement in the evaluation of thyroid nodules in the United States: A cost-effectiveness and decision analysis. J Clin Endocrinol Metab 2008; 93:2173–2180. 129. Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006; 16(2):109–142. 130. Ponder BA, Ponder MA, Coffey R, et al. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 1988; 1(8582):397–401. 131. Evans DB, Shapiro SE, Cote GJ. Invited commentary: Medullary thyroid cancer: The importance of RET testing. Surgery 2007; 141(1):96–99. 132. Sherman SI, Angelos P, Ball DW, et al. Thyroid carcinoma. J Natl Compr Canc Netw 2007; 5(6):568–621.

2 Hyperthyroidism Due to Graves’ Disease, Toxic Nodules and Toxic Multinodular Goiter Kenneth D. Burman Washington Hospital Center, Georgetown University, and the Uniformed Services of the Health Sciences, Washington, D.C., U.S.A.

David S. Cooper The Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

GRAVES’ DISEASE Introduction Graves’ disease is an autoimmune thyroid disorder characterized by clinical hyperthyroidism and the presence of autoantibodies directed against the thyrotropin (TSH) receptor (1,2). The presentation of this disease varies with age. Younger patients manifest nervousness, weight loss, anxiety, heat intolerance, hyperdefecation, inability to concentrate, and tremulousness, while older patients may manifest few if any of these typical symptoms (3). Circulating TSH receptor–stimulating antibodies are present in at least 90% of patients and are responsible, in large part, for the thyroidal hyperactivity (4). An interesting aspect of Graves’ disease is its association with ophthalmopathy, which can cause tearing, burning, itching, proptosis, double vision, and/or (rarely) visual impairment (5,6). The

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etiology of Graves’ hyperthyroidism and ophthalmopathy remains unclear. There are abnormalities in T-cell function that allow the TSH receptor antibodies to develop; these antibodies not only stimulate TSH receptor action in thyrocytes but may cross-react with orbital antigens (e.g., fibroblasts) as well (5,7–13). The term Graves’ disease commonly refers to patients who manifest clinical and biochemical hyperthyroidism (1), but in certain circumstances this term may require further delineation. For example, patients with Graves’ disease and hyperthyroidism may become spontaneously euthyroid or hypothyroid because, over time, the stimulatory TSH receptor antibodies have become blocking antibodies (7,10) or because the chronic inflammatory process has resulted in thyroid failure. Epidemiology Although it may present in patients of any age, Graves’ disease occurs more commonly in women than in men, especially in women between the ages of about 20 and 50 years (3). Graves’ disease is rare in young children; when it occurs in neonates, it is almost always related to transplacental passage of TSH receptor–stimulating immunoglobulins, a condition that typically persists for several weeks until the IgG antibodies are cleared from the neonate’s circulation (14–17). In adults, the annual incidence of new cases of Graves’ disease is 1 to 10 per 100,000, although, of course, these numbers vary depending upon the method of detection and the iodine content in the geographic area (18–23). People living in all areas of the world are affected with Graves’ disease. It is believed that the incidence correlates directly with the amount of iodine in the diet. Increased iodine intake has been shown to be associated with an increased frequency of hyperthyroidism, possibly related to enhanced thyroid hormone synthesis and possibly because iodine sufficiency is important for maximal antibody production (19,20,24–32). Graves’ disease may present more commonly in the spring and summer months, possibly because warmer weather increases the perception of symptoms rather than a true increased incidence in disease activity. Cigarette smoking (33) and stressful life events (20) have also been linked to the etiology of Graves’ disease. The use of certain drugs, especially interferonalfa, has been associated with the development of Graves’ disease during therapy (34). Pathophysiology Although much has been learned about the immune dysregulation that characterizes Graves’ disease, the precise cause is unknown. There are defects in antigenspecific T cells that result in B-cell production of many antibodies, most notably stimulatory TSH receptor antibodies. The thyroid glands of patients with Graves’ disease are infiltrated with these antigen-specific T cells. Whether the disease is caused by abnormal clones of autoreactive T cells or the initial trigger is abnormal antigen presentation by thyrocytes is not known (35,36).

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Table 1 Clinical Effects of Hyperthyroidism System

Effects

General

Nervousness, insomnia, fatigue, tremulousness, heat intolerance, weight loss Warmth, moistness, hyperidrosis, alopecia, increased pigmentation, onycholysis, acropachy, pretibial myxedema, urticaria, pruritus, vitiligo Exophthalmos, conjunctivitis, chemosis, diplopia, decreased vision Tachycardia, dyspnea, palpitations, atrial fibrillation, heart block, congestive failure, angina pectoris Hyperphagia, diarrhea or hyperdefecation, elevated liver function tests, hepatosplenomegaly Elevated serum calcium, decreased serum magnesium, increased bone alkaline phosphatase, hypercalciuria Fine hand tremor, proximal muscle weakness, myopathy, muscle atrophy, creatinuria, periodic paralysis Osteoporosis, osteopenia Fever, delirium, stupor, coma, syncope, choreaathetosis, hemiballismus Irregular menses, amenorrhea, gynecomastia, decreased fertility Normochromic normocytic anemia, lymphocytosis, lymphadenopathy, enlarged thymus, splenomegaly Restlessness, irritability anxiety, inability to concentrate, emotional lability, depression, psychosis

Skin

Eyes Cardiovascular Gastrointestinal Metabolic Neuromuscular Osseous Neurologic Reproductive/sexual Hematopoietic Mental

Source: From Ref. 2. This table is not intended to be all-inclusive but rather representative.

Diagnosis Signs and Symptoms The typical signs and symptoms of Graves’ hyperthyroidism do not differ significantly from those of any other type of hyperthyroidism (Table 1) (3). The main features of hyperthyroidism relate to the action of excess thyroid hormone at the cellular level and enhanced beta-adrenergic activity. Typical manifestations include weakness, fatigue, anxiety, tremulousness, heat intolerance, and weight loss. Any organ system may be involved. The skin may be warm, smooth, and moist. Tachycardia is common, but atrial arrhythmias, heart block, or high or low cardiac output may occur, especially in older individuals. Mitral valve prolapse, a systolic flow murmur, an S3 gallop, or a Means-Lerman “scratch” murmur may be present. The latter systolic sound is best heard along the left intercostal space during expiration. It is thought to result from either turbulent pulmonic artery blood flow or to friction between the pericardial and pleural surface in a hyperdynamic heart. Recent studies have also shown that older patients with thyrotoxicosis may develop congestive heart failure with evidence of a reversible cardiomyopathy

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and normal or low ejection fraction (37). In addition, some patients may develop reversible, usually asymptomatic, pulmonary hypertension related to increased cardiac output or to left atrial diastolic dysfunction (38). Patients may complain that they are eating voraciously but are still losing weight; hyperdefecation is more frequent than diarrhea. Liver function tests may be elevated secondary to the hyperthyroid process or, less frequently, to related autoimmune disorders, such as primary biliary cirrhosis, systemic lupus erythematosus, or scleroderma. Additional manifestations of hyperthyroidism actually relate to the underlying immunologic abnormalities. Vitiligo or prematurely gray hair may be present, indicating the presence of antimelanocyte autoantibodies. Patients with Graves’ ophthalmopathy may present with or have burning, itching, proptosis, photophobia, or diplopia. Uncommonly, there may be proptosis or optic nerve compression, resulting in decreased visual acuity (Figs. 1–4). Elevated serum calcium, probably related to a direct effect of thyroid hormones on osteoclasts, may occur in approximately 10% of patients. Some believe that the likelihood of having a coincidental parathyroid adenoma is increased in Graves’ disease patients (39). Patients who do have overt hyperthyroidism of any type, especially if chronic, may have lower bone density values than they would otherwise. Even mildly elevated thyroid hormone levels or subclinical hyperthyroidism may be associated with decreased bone mineral density, most notably in postmenopausal women (40–44). The issue of whether Graves’ hyperthyroidism causes sufficient bone loss to induce or aggravate an increased risk of fractures is controversial (40–42,45–47). The risk of fractures is probably increased in

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Figure 1 (A)Patient with Graves’ ophthalmopathy demonstrating proptosis and severe exposure keratitis. This patient had received external radiation therapy, which, along with inability to close the lid completely, contributed to dryness and resultant keratitis (8).

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Figure 2 An orbital CT scan (coronal view) showing diffuse orbital muscle involvement with enlargement, most notably of the right medial and left inferior recti muscles in a patient with Graves’ ophthalmopathy (8).

postmenopausal women with a history of hyperthyroidism as shown in a recent meta-analysis, although further studies are needed in this area (48,49). Hand tremor and generalized proximal muscle weakness are common. Rarely, hypokalemic periodic paralysis may occur, most frequently in Asian males (50–52). Attacks are precipitated by high carbohydrate intake and heavy exercise. In a recent analysis of thyrotoxic periodic paralysis (51), hypokalemia was present in all 24 initial episodes and serum potassium levels varied from 1.1 to 3.4 mmol/L.

Figure 3 A patient with Graves’ ophthalmopathy with predominant superior limbal keratopathy (8).

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Figure 4 A patient with Graves’ disease demonstrating bilateral exophthalmos and achropachy (clubbing) (left panel). The right panel shows a radiograph of the same patient demonstrating phalangeal periosteal reaction (arrow) (8).

Hypophosphatemia was present initially in 12 (80%) of 15 episodes. No patient had a recurrent episode of paralysis after becoming euthyroid. The precise pathophysiology of these events is unknown, but patients may have a genetic predisposition to activation of Na/K-ATPase activity, which is enhanced in hyperthyroidism (53). One suggested treatment regimen is to administer 30 mEq potassium orally every two hours with close monitoring of serum potassium and cardiac status, as rebound hyperkalemia occurs commonly (51). Propranolol, given either orally or intravenously can reverse or prevent attacks (54). Restoration of the euthyroid state prevents future attacks. The central nervous system (CNS) manifestations of Graves’ hyperthyroidism are varied but include restlessness, irritability, nervousness, and impatience. Some patients may realize that they have a decreased ability to concentrate and remember facts; occasionally, they may have demonstrable personality changes (55). These features are difficult to quantify, but relatives may help to identify them. After patients are treated and euthyroidism is restored, patients will frequently comment upon their previous personality changes. Cognitive function may be more severely impaired, especially in hospitalized elderly patients (56), and seizures and coma can be the presenting features of “thyroid storm” (see below). Depression and irrational or even criminal behavior are very unusual. It is difficult to prove that serious personality disorders or criminal behavior are directly associated with hyperthyroidism per se, although hyperthyroidism has been implicated in these circumstances (57). Rarely, hyperthyroid patients may present with other neurologic findings, such as chorea (58). Women may have irregular menses and decreased fertility, but amennorhea is rare (59). Men may have decreased libido and gynecomastia, thought to be

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Figure 5 A patient with Graves’ disease showing gynecomastia. The cause of gynecomastia in this circumstance is thought to be related to increased conversion of testosterone to estradiol. Other causes of gynecomastia, such as hCG-secreting tumors, should also be considered (8).

related to increased estrogen production (Fig. 5) (60). Total serum estrogen levels are usually increased, in part related to increased sex hormone–binding globulin levels. Serum LH concentrations are increased and there may be Leydig cell failure associated with impaired spermatogenesis (61). A recent study suggested that up to 50% of hyperthyroid men have some aspect of sexual dysfunction that is recovered with therapy (62). Generalized lymphadenopathy, splenomegaly, and thymic enlargement may occur, although other causes should be excluded. A normochromic normocytic anemia has been described, probably related to decreased ability to incorporate iron into red blood cell precursors. Pretibial myxedema results from excessive lymphocyte infiltration in the pretibial area, with resultant mucopolysaccharide secretion and deposition by fibroblasts (63–65). The clinical result may simply be a small area of raised discoloration in the pretibial area. Rarely, a large area of induration and nonpitting

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Figure 6 (A and B) Two different patient with pretibial myxedema demonstrating varying degrees of involvement. The left panel illustrates more minimal involvement with skin thickening, while the right panel shows severe thickening, which would make daily activities, such as walking with shoes, difficult. The patient on the right also has a patch of vitiligo (8).

edema may develop, sometimes involving the entire lower leg. In this circumstance, the patient may have difficulty wearing shoes and the area may be pruritic and even painful (Fig. 6). Although the cause of pretibial myxedema is unknown, it seems to be related to anti-TSH receptor antibody levels (63). Pretibial myxedema usually does not occur unless a patient has clinical evidence of ophthalmopathy, and pretibial myxedema may occur in other anatomic sites, such as the feet, face, or preradial area. Topical steroids, usually recommended to be used under an occlusive dressing is the most effective therapy, but the response is poor in patients with more severe disease. The manifestations of Graves’ hyperthyroidism that occur in younger individuals may be different from those in older subjects (66–68). Younger patients tend to have more classic findings, such as nervousness, weight loss, anxiousness, tachycardia, and heat intolerance. Older patients may have none of these manifestations but may only present with weight loss or a cardiac abnormality, especially atrial fibrillation. The explanation for these differences is unknown, and, of course, these comments should be taken as generalizations with many exceptions. A more complete discussion of this topic is found in chapter 10, “Practical Management of Thyroid Disease in the Elderly.”

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Laboratory Diagnosis Thyroid Hormone and TSH Levels In the past, common thyroid hormone measures included total T4, total T3, resin T3 uptake, and TSH. However, recent advances in techniques now allow the direct measurement of free T4 (FT4). This analysis is preferred to the total T4, as ⬎99% of T4 is bound to circulating proteins (thyroxine-binding globulin, albumin, and prealbumin) and ⬍1% is unbound and available to enter cells, and, after conversion to T3, to bind specific nuclear receptors and mediate biologic activity. Total T4 measurements are affected by factors that influence thyroid hormone–binding proteins, including drugs (estrogens, birth control pills, and androgens, opiates), and medical conditions such as hepatitis, cirrhosis, and nephrotic syndrome. FT4 levels remain normal in these situations (3). The resin T3 uptake test was designed to indirectly assess the quantity of thyroid hormone–binding proteins in serum and was used as an adjunct to the total T4 concentrations. However, now that we have the ability to measure FT4 directly, rapidly, and inexpensively, the measurement of FT4 is preferred. Total T3 is still measured because FT3 cannot yet be measured in most laboratories in a reliable, precise, cost-effective manner. Approximately 5% of patients will have a normal serum free T4 level and elevated serum T3 level (“T3 toxicosis”), and some patients, especially the elderly can have “T4 toxicosis” with normal serum T3 levels. Like total T4, total T3 levels are altered by situations that change thyroid hormone–binding proteins. TSH assays have also improved, and “third generation” assays can measure ⬍0.01 mU/L in serum, with the normal range being approximately 0.5 to 4.5 mU/L (51–57). These improvements in sensitivity result from utilizing chemiluminescent techniques. All patients with conventional forms of hyperthyroidism should have an undetectable TSH level in third-generation assays, although many commercial laboratories only report that a value is ⬍0.1 mU/L. 24-Hour Radioiodine Uptake Serum measurements of thyroid hormone and TSH are the cornerstone of the diagnosis of hyperthyroidism, but they do not assess biologic activity or the tissue effects of the circulating thyroid hormone levels. The capacity of the thyroid gland to concentrate radioactive iodine is a physiologic test representing in vivo events. A normal subject will concentrate approximately 8% to 30% of radioactive iodine administered when determined at 24 hours. Patients with hyperthyroidism will usually concentrate higher amounts of radioactive iodine than normal, reflecting the heightened ability of the gland to concentrate iodine. On the other hand, patients with thyrotoxicosis and a low radioiodine uptake generally have a problem associated with increased release into the circulation of preformed thyroid hormone, for example, the various form of thyroiditis. (see chap. 3, “Hyperthyroidism.”) Radiocontrast dyes and other sources of exogenous iodine such as amiodarone will interfere with this test, because the enormous amounts of

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Table 2 Anti-TSH Receptor Antibody Measurements Method cAMP generation 125 I-TSH binding inhibition

Nomenclature

Frequency

Advantage

Disadvantage

TSIa

80–100%

Stimulatory

Difficult to perform

TBIIb

70–90%

Easy to perform

Detects all TSH receptor antibodies

a

TSI, thyroid stimulating immunoglobulins. This test detects cAMP generation in vitro from thyroid cells or cells transfected with TSH receptor. b TBII, thyroid binding inhibitory immunoglobulins. This test detects the ability of serum samples to displace 125 I-TSH binding from thyroid cell membranes or cells transfected with TSH receptor. Source: From Ref. 2.

unlabeled iodine in these compounds dilute out the radioactive tag, resulting in less radioactive iodine being concentrated by the thyroid gland and a very low 24-hour uptake (69). An elevated radioactive iodine uptake can also be seen in euthyroid or even hypothyroid patients with an organification defect, most notably patients with Hashimoto’s thyroiditis (70,71). Therefore, an elevated radioactive iodine test is not specific for hyperthyroidism. Since dietary iodine intake has decreased over time (72), the normal range for the 24-hour uptake may have increased compared to values obtained 20 or 30 years ago. Variations in geographic and individual dietary iodine intake of bread, pastry, seafood, salt, and dairy products may also contribute to changes in the 24-hour uptake. Most institutions have not reassessed their normal range for this test in many years, mainly because it is difficult to justify the administration of radioactive materials to normal subjects. Therefore, the normal range should be considered as a guide and not an absolute limit. Some clinicians feel that a scan should be performed whenever a radioiodine uptake is ordered to assess whether an undetected cold nodule also may be present. TSH Receptor Antibody Measurements Anti-TSH receptor antibody measurements can be performed with one of two possible assays (Table 2) (4,10). Stimulatory TSH receptor immunoglobulins (TSI) are measured in vitro by testing the ability of serum or IgG from a possible Graves’ patient to stimulate thyroid cells and generate cAMP or enhance T3 and T4 secretion (4,73–75). These responses are compared to those of normal control serum or IgG. A ⬎30% increase above control serum is considered to be a positive cAMP response. Usually, sera from Graves’ disease patients will stimulate cAMP by more than two- or threefold. The advantage of the TSI assay is that it measures TSH receptor–stimulating antibodies, which are relevant to hyperthyroidism; but its disadvantages are that it is relatively expensive, and the sensitivity of commercial assays vary. Another test, called a thyrotropin-binding

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inhibitory immunoglobulin assay (TBII assay), measures the total conglomerate amount of TSH receptor antibodies in serum. The ability of serum or IgG from hyperthyroid patients to inhibit radiolabeled TSH binding to bovine, human, or recombinant TSH receptors is compared to control normal serum or IgG (76). Graves’ disease patients’ serum samples cause more than 10% inhibition of binding compared to controls, with values frequently being as high as 50% to 70% in patients with active disease. The potential disadvantage of TBII measurements is that they do not distinguish stimulatory from inhibitory antibodies. There may be wide variability in the nature and type of TSH receptor antibodies identified in different patients (77–79). Di Cerbo et al. (78) have suggested that, in addition to TSH receptor antibodies that stimulate cAMP production, other antibodies may be capable of stimulating alternative pathways. For example, 72% of Graves’ patients’ serum contained immunoglobulins that could stimulate the phospholipase A2 pathway. The measurement of TSH receptor antibodies in clinical settings is only occasionally indicated (4). They can help differentiate Graves’ disease from other causes of hyperthyroidism when this differentiation cannot be made clinically and when it is relevant to do so. Anti-TSH receptor antibody measurements may also be useful to help confirm the presence of Graves’ ophthalmopathy from other nonendocrine causes of proptosis in euthyroid patients. Anti-TSH receptor antibody measurements may also help predict if a patient with Graves’ disease is in remission at the end of a course of antithyroid drug therapy, but this test is not very sensitive or specific (80). Most importantly, anti-TSH receptor antibodies may be elevated in the sera of pregnant women who have (or have had) active autoimmune thyroid disease, such as Graves’ disease. If the TSH receptor antibodies are markedly elevated (e.g., two- to threefold above the upper limit of normal), there is an increased likelihood that these IgG antibodies will cross the placenta and cause neonatal hyperthyroidism (81,82). Anti-TSH receptor antibodies can be found in the sera of pregnant women with Graves’ disease, but they may also be present in the sera of patients who have had Graves’ disease and even in women who have had Hashimoto’s thyroiditis. Many experts suggest measuring these antibodies in the third trimester in women with active Graves’ disease or Graves’ ophthalmopathy, in women treated for Graves’ disease in the recent past, and in women with high-titer antithyroid peroxidase or thyroglobulin antibodies who have been diagnosed recently with autoimmune thyroid disease. There are several additional tests that may occasionally be useful in patients with Graves’ disease. The measurement of serum antithyroid peroxidase and thyroglobulin antibody levels should not be measured in the majority of patients with Graves’ disease. However, elevated antibody titers gives information about the coexistence of Hashimoto’s thyroiditis with Graves’ disease (79,83). High-titer antibodies may help to predict remissions after a course of antithyroid drugs or permanent hypothyroidism following radioiodine therapy or surgery.

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Pitfalls There are several pitfalls that should be avoided in the laboratory assessment of Graves’ disease patients. The assays for iodothyronines and TSH are specific and accurate; as a result, there are few reasons for artifactual results except for mislabeling and rare laboratory errors. Specific antibodies against T3 or T4 may alter their respective measurements. Although unusual, such antibodies can occur in patients with autoimmune thyroid disease, in those who work with animals, and occasionally for no apparent reason. In a study of 115 patients with antithyroid hormone autoantibodies, approximately 42% of patients had antibodies against triiodothyronine, 33% against thyroxine, and 25% of patients had both anti-T3 and anti-T4 antibodies (84). Although 44% of these patients were considered to be euthyroid, 16% were hyperthyroid and almost 40% were hypothyroid. While the effect of antibodies on T4 and T3 measurements depends upon the method of measurement, in general, they cause a laboratory result that is incongruent with the clinical state (84). It is important to ensure that patients with Graves’ hyperthyroidism have an undetectable serum TSH level, so that rare individuals with peripheral hormone resistance or TSH secreting pituitary tumors are not misdiagnosed as having Graves’ disease. Also, certain patients hay harbor heterophilic antibodies that can result in falsely elevated serum TSH levels, causing diagnostic confusion in patients with hyperthyroidism (85). It is also important to exclude other coexistent autoimmune disorders that may be confusing the clinical picture. For example, a patient with Graves’ hyperthyroidism who complains of inordinate weakness and tiredness may, in fact, have coexistent Addison’s disease. The patient’s clinical assessment and history must be integrated with the thyroid function tests. Thyroid function tests should ideally be determined twice prior to treatment and, when possible, measurement of FT4 and T3 is preferred. In patients with mild hyperthyroidism and no clinical features of Graves’ disease, it is important to obtain a radioactive iodine uptake test prior to treatment to confirm high-uptake thyroid disease. Even if the diagnosis of Graves’ disease seems obvious, at least one TSH measurement should be obtained to rule out the unlikely TSH-secreting pituitary tumor. The term euthyroid sick syndrome refers to the thyroid hormone changes that occur in patients with a wide variety of systemic illnesses (86–88). The presence of the euthyroid sick syndrome may interfere with the interpretation of thyroid function tests in a patient being evaluated for possible hyperthyroidism. Early in the euthyroid sick syndrome, T4 and FT4 remain normal, although occasionally they may be decreased or even slightly increased. Total and FT3 are decreased due to diminished T4 to T3 conversion. Serum TSH generally remains within the normal range but may be decreased slightly or may increase during the recovery phase of systemic illness. In this circumstance a systemically ill patient with moderate or severe hyperthyroidism may have few symptoms, and the serum T3

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may be inappropriately within the normal range, because of decreased T4-to-T3 conversion (so-called T4 toxicosis). Treatment Ideally, the treatment of any medical condition is directed at its cause, but the cause of the immune dysregulation in Graves’ disease remains obscure (3,36). Therefore, the available treatments are directed at the thyroid gland rather than the underlying autoimmunity. The therapies that are available to the clinician in the 21st century are the same as those that were available 50 years ago: Antithyroid drugs, radioiodine, and surgery. Although some patients, especially those who are relatively asymptomatic, may wonder whether specific treatment is necessary, overtly hyperthyroid individuals usually require restoration of a euthyroid state because of potentially deleterious skeletal, cardiovascular, and psychologic effects. Antithyroid Drug Therapy Antithyroid drugs remain the first choice for initial therapy of children, adolescents, and young adults in the United States (89,90) and are the usual treatment for almost all patients in the rest of the world (91). Antithyroid drugs are generally safe and effective in controlling the hyperthyroid state. However, they have limitations and toxicities that are important to recognize, and their proper use requires knowledge of their pharmacology as well as clinical experience. Clinical Pharmacology of Antithyroid Drugs Antithyroid drugs do not directly affect iodine uptake or hormone release by the thyroid; hence, contrary to popular belief, the 24-hour radioiodine uptake is not affected very much by antithyroid drug therapy. Within the thyroid, both propylthiouracil (PTU) and methimazole (Tapazole) inhibit thyroid hormone synthesis by interfering with intrathyroidal iodine utilization and the iodotyrosine coupling reaction, both of which are catalyzed by thyroid peroxidase. Extrathyroidally, PTU, but not methimazole, inhibits the conversion of T4 to T3 in peripheral tissues. Although some feel that this difference confers an advantage of PTU over methimazole, there are no data to support this supposition; in fact, comparative studies show that methimazole generally normalizes serum T4 and T3 levels faster than PTU (92–94). There are also in vitro and in vivo data pointing to possible beneficial effects of both drugs on the immune system, although it is far from clear whether this is important clinically in terms of remission rates with antithyroid drug therapy (89). Antithyroid agents are well absorbed from the gastrointestinal tract. In the circulation, PTU is heavily protein-bound, mainly to albumin, while methimazole binding to proteins is negligible. This characteristic may affect antithyroid drug choice in pregnancy and lactation, since PTU would be expected to cross the placenta and breast epithelium less readily than methimazole. The serum half-lives

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of PTU and methimazole are 1 and 4 to 6 hr, respectively. However, the intrathyroidal duration of action of both drugs is longer than that, making the determination of drug blood levels not particularly helpful clinically. Although both drugs are metabolized in the liver and metabolites are excreted by the kidney, in the absence of data to the contrary, the doses used to treat hyperthyroidism do not generally need to be altered in patients with liver or kidney disease. Antithyroid Drugs in Clinical Practice Antithyroid drugs are used in two ways in the therapy of hyperthyroidism (89). They can be employed as primary therapy, and are usually given for one to two years in the hope that the patient will achieve a remission (a remission is usually defined arbitrarily as biochemical euthyroidism for one year following cessation of the antithyroid drug); or, they are used for a few months to “cool the patient down” prior to ablative therapy with radioiodine or surgery. Unfortunately, patients are often started on antithyroid drugs without a clear goal in mind and then remain on them either continuously or intermittently for protracted periods of time. Antithyroid drugs are also mistakenly used in the long-term treatment of toxic nodules or toxic multinodular goiter, situations in which remission is highly unlikely. Antithyroid Drugs for Primary Therapy of Graves’ Disease Prior to initiating antithyroid drug therapy, the physician should carefully discuss the options with patients and their family. Unlike radioiodine and surgery, antithyroid drug treatment will not cause permanent hypothyroidism, but the chances of remission are ⬍50% for an average patient. Even if a remission occurs, the chances of permanent remission are ⬍50%, and late hypothyroidism may develop in up to 20% (95). Also, the potential for allergic reactions is often underestimated or not discussed. Patient preferences are important to take into consideration, even if the decision for or against a particular therapy seems to be based more on emotion than fact. No therapy has been shown to be superior to any other in terms of efficacy or patient satisfaction (96). However, the physician can help the patient make an informed choice. Remissions are less likely with large goiters and in severe disease, especially when the serum T3 concentration is ⬎900 ng/dL (97). In one report that used a proportional hazards analysis to examine various potential factors influencing the outcome of antithyroid drug therapy, only the baseline serum T3 level emerged as an independent risk factor for relapse (97). Some studies have found that “T3 predominant” disease, in which the unitless serum T3/T4 ⬎20, also makes remissions less likely (98), but others have not confirmed this observation (96). A prior history of relapse is another factor that would argue against antithyroid drug use as first-line therapy. On the other hand, a small gland and mild biochemical changes would favor a remission, and in some studies the rates may be as high as 70% to 90%. A negative TSI titer at the beginning of therapy has been shown to predict a high rate of remission (99), but negative titers occur in only approximately 10% of patients, so it is probably not cost-effective to order

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TSI titers routinely. Age, sex, family history of Graves’ disease, the presence of ophthalmopathy, and smoking behavior are not reliably or consistently predictors of remission. Family planning is another factor that should be considered in women. First, many clinicians feel that if pregnancy is desired in the following one to two years, antithyroid drugs are less appropriate, since the patient may be pregnant while taking a drug that could harm the fetus. Also, in patients who have had a remission after a course of antithyroid drugs, relapse is very common in the postpartum period (100). Therefore, some clinicians feel that women desirous of pregnancy in the near future are not optimal candidates for long-term antithyroid drug treatment. Once antithyroid drugs are selected as initial treatment, a choice between PTU and methimazole must be made. Methimazole has a number of advantages over PTU. First, it is a once-a-day drug (101), which improves compliance, and the numbers of methimazole tablets that a typical patient takes daily is fewer, which is important to some patients. Second, the toxicity of methimazole is probably more predictable, in that the frequency of side effects is dose-related; many patients can be treated with doses as low as 5 to 15 mg/day, a dose range in which side effects are few (102). There is no dose relationship with side effects for PTU. Also, the rare side effects of drug-induced lupus, vasculitis, and hepatitis are far more common with PTU (94). Because of its protein binding and lack of teratogenic effects, PTU is preferred in pregnancy and lactation, although methimazole has been used safely. Also, PTU may be preferable in thyroid storm or severe hyperthyroidism because of its ability to block T4-to-T3 conversion. High-dose methimazole is more expensive than PTU, but low doses have a comparable cost. On an average, methimazole costs approximately $80/mo (30 mg/day) as compared to the cost of PTU ($30/mo; 300 mg/day). In mild to moderate thyrotoxicosis, methimazole is usually started at a dose of 10 to 30 mg/day as a single daily dose, and PTU is begun at a dose of 100 mg three times a day. The rapidity of response depends on the severity of the underlying thyroid problem, the size of the gland and its hormonal stores, the dose and frequency of the drugs, and, of course, compliance. Most patients become euthyroid within 6 to 12 weeks, with methimazole possibly acting faster than PTU to normalize both T3 and T4 serum levels (92), especially in patients with more severe degrees of thyrotoxicosis (94). Although it may take longer to achieve control than with higher doses (103), initial doses as low as 10 mg/day can control hyperthyroidism in many patients (102). Although older studies had suggested that remission rates might be increased by using high doses of antithyroid drug, more recent randomized trials have not found this to be the case (102,104). High-dose therapy has the decided disadvantage of being associated with higher rates of side effects (94,102,105). Once antithyroid drugs have been started, thyroid function should be monitored every four to six weeks, at least for the first six months and less frequently thereafter. Normalization of serum T3 can lag behind serum T4, so it is important to follow both measurements. During treatment, some patients can have startling

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degrees of “T3 predominance,” with serum T3 levels two to three times above the upper limit of normal and serum T4 values that are subnormal (106). Also, the serum TSH level can remain suppressed long after the patient has become euthyroid or even hypothyroid, which limits its value early in the course of treatment. In many patients, the drug can be tapered to a lower dose after a few months, once the patient has become biochemically euthyroid. If this tapering is not done, hypothyroidism will often ensue (103). In patients who are hyperthyroid on a low drug dose but hypothyroid on a larger dose, some physicians use a “blockreplacement” regimen. In this method, a dose of antithyroid drug that would cause hypothyroidism is employed in conjunction with thyroxine supplementation to maintain a euthyroid state. This method of treating patients may also be useful in the pediatric population. The “block-replacement’’ regimen has also been used in the hope that the combination will yield a higher remission rate than antithyroid drugs alone (107). This strategy is based on the theory that thyroxine supplementation will suppress the serum TSH, thereby diminishing the immune system’s exposure to thyroidal antigens, especially the TSH receptor. While one well-done, randomized, clinical trial from Japan did show a higher remission rate using combined therapy (107), a number of equally rigorous trials have failed to confirm these original observations (108–112). At the present time, most clinicians have abandoned the idea that combined antithyroid drug–thyroxine therapy enhances the chances of remission. We prefer simply to taper the antithyroid agent dose as required and not to add L-thyroxine, which would also make it more difficult to interpret and follow T4 and T3 levels as a measure of endogenous thyroid function. Once a patient has been placed on long-term therapy with an antithyroid drug, what is the optimal duration of therapy before a remission has been achieved and the drug can be discontinued? Older retrospective data suggested that the longer a person remained on therapy, the more likely a remission would be achieved once the drug was stopped (113,114). More recently, prospective trials have not shown longer treatment periods (e.g., ⬎12–18 months) to be more effective (115,116). Therefore, treatment for a year is reasonable, but data supporting longer periods of time are lacking. After one to two years of therapy, most clinicians discontinue antithyroid drugs to see whether a remission has occurred. If the goiter has gotten smaller and the patient’s disease has been controlled on diminishing doses of drug, the chances of remission are greater. On the other hand, a large goiter, continued requirement for large doses of drugs, and a persistently high-T3/T4 ratio are all poor prognostic signs. Although a number of tests have been proposed to predict the odds that a patient will remain euthyroid off drugs, none has the requisite sensitivity or specificity to be useful clinically; thyroid-stimulating antibody testing is the most widely studied. If it is positive, the chances of remission are very low, but even patients with negative titers have a 20% to 50% chance of relapse (117,118). Practically speaking, it is probably more sensible to taper the antithyroid drug rather than to stop it abruptly. Patients should be monitored closely and

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thyroid function tests checked monthly, and the drug should be gradually tapered to discontinuation. Thyroid function tests are then performed every four to six weeks, but patients are not necessarily seen for an office visit unless they become hyperthyroid, or at three to four months if they remain normal. T3 thyrotoxicosis frequently occurs during a relapse, so that serum T3 should be monitored along with the serum T4 levels. Relapses are most likely to occur within the first six months after drug discontinuation (119). Some patients have persistent subclinical hyperthyroidism, with normal serum T4 and T3 values but suppressed serum TSH concentrations. While the chances that such patients will have a full-fledged relapse are greater (120), relapse is not inevitable. Some experts treat patients with subclinical hyperthyroidism (i.e., suppressed TSH, normal FT4, and T3) as if they had relapsed and recommend another trial of antithyroid drug therapy or radioiodine. Others simply observe them expectantly and only recommend treatment if and when overt hyperthyroidism develops. Remissions are not necessarily lifelong. Older data suggested that eventual relapse was almost inevitable (121). However, more recent long-term follow-up studies have shown that some patients have durable remissions that apparently last for many years (122). A strategy for treatment of relapse should be discussed with the patient in advance. Some patients will opt for another course of antithyroid drug, even though more than one prior relapse is associated with continued relapse. Other patients will wish to move on to definitive radioiodine therapy, or, more uncommonly, to surgery. Some patients end up on chronic antithyroid drug treatment for decades without ill effect (123), but this is unusual unless the patient is highly motivated and the hyperthyroidism relatively mild. As noted above, some patients eventually develop spontaneous hypothyroidism, so that lifelong follow-up is necessary.

Antithyroid Drug Side Effects The side effects of antithyroid drugs are usually classified as “minor” or “major,” depending on the level of potential harm to the patient (Table 3) (124). Overall, side effects develop in 5% to 25% of patients and are among the most frequent reasons for abandoning drug therapy. As noted above, methimazole-related drug reactions are dose-related, but this does not appear to be the case for PTU. The commonest minor reactions are fever, rash, pruritus, arthralgias, gastrointestinal distress, and nausea. Rashes can be urticarial, macular, or morbilliform. A recent prospective study reported that minor reactions occurred in 10% of PTU-treated individuals and 15% of those receiving methimazole, a difference that was not significant (125). In another prospective trial, rash developed in approximately 20% of patients treated with 30 mg of methimazole or 300 mg of PTU daily, versus 6.6% with 15 mg of methimazole daily (94). If a rash develops, it will sometimes resolve spontaneously (even with continued use) with or without the use of antihistamines to treat associated itching. Although switching to the alternative drug is another

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Table 3 Side Effects of Antithyroid Drugs Overall frequencya Minor side effects Skin reactions

4–6%

Arthralgias Hair loss

1–5% 4%

Abnormal taste/smell 0.3% Sialadenitis major side effects Severe polyarthritis Agranulocytosis Aplastic anemia Vasculitis

Comments Dose-related for MMI; possibly more common with MMI Gastrointestinal 1–5% Possibly related to change in thyroid function (hypothy-roidism) only reported with MMI/CBZ

Very rare 1–2% 0.1–0.5% Rare Rare

Severe hepatitis

0.1–0.2%; 1% with high-dose PTU (14)

Cholestasis

Rare

Hypoprothrombi nemia Insulin-autoimmune syndrome

Rare

May be ANCA + drug-induced SLE and other immune syndromes also reported Almost exclusively PTU; transient increases in transaminases seen in 30% Almost exclusively seen with MMI or CBZ; no deaths reported No case reports since 1982

Rare

Seen almost exclusively in Asians

a

Rate of side effects (minor and major) is greater at high doses of MMI and may approach 30% at high doses. Abbreviations: MMI, methimazole; CBZ, carbimazole; PTU, propylthiouracil; ANCA, antineutrophil cytoplasmic antibody.

possibility, the cross-reaction rate may be as high as 50%. Some patients may simply elect to stop the offending drug and accept a definitive form of therapy. Loss of sense of taste, sometimes associated with anosmia, is a rare minor side effect reported only with methimazole (126). It develops suddenly after one to two months of therapy and resolves after the drug is stopped. This side effect has not been reported with PTU, although PTU may cause a metallic taste. A recent report described the development of arthralgias and elevated serum CPK levels in four patients treated with methimazole at a time when they were still clearly hyperthyroid (127). The authors postulated that this side effect was the result of rapid a decline in serum thyroid hormone levels.

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Fever and arthralgias, while technically minor side effects, warrant drug discontinuation since they may be the harbinger of more serious problems. Similarly, leukopenia, defined as a white blood cell (WBC) count ⬍4 × 109 /L, occurs in up to 10% of patients. Leukopenia requires follow-up and prompt cessation of the antithyroid drug if the WBC count falls below 3 × 109 /L, since leukopenia may precede the development of full-blown agranulocytosis (see below). Antithyroid drug-related leukopenia should be distinguished from the leukopenia that can be seen in Graves’ disease and in healthy African-Americans by obtaining a baseline WBC count. The major side effects are quite rare, but the most frequent are agranulocytosis, vasculitis and drug-induced lupus, and hepatic damage (hepatitis and cholestasis). Agranulocytosis develops in approximately 0.2% to 0.5% of patients. In one case series, agranulocytosis developed in 12 of 2190 (0.55%) patients taking PTU and 43 of 13,208 (0.31%) patients taking methimazole (128). Agranulocytosis is usually defined as an absolute granulocyte count ⬍0.5 × 109 /L, but most patients have granulocyte counts that are far lower, often close to zero. It should be distinguished from the exceedingly rare cases of antithyroid drug–induced aplastic anemia by a hematocrit ⬎30% and a platelet count 100 × 109 /L. Agranulocytosis is thought to be autoimmune in origin, developing because of antigranulocyte antibodies that are found in the serum of affected patients (129). Since the development of agranulocytosis may be HLA-linked (130), it is probably wise to avoid giving antithyroid drugs to close relatives of a patient who has had this side effect. Agranulocytosis typically develops in the first three months of therapy, but there are notable exceptions (131). Older patients may be more susceptible, and it can develop after one or more prior innocuous exposures to the drugs. Routine monitoring of the WBC count has not been recommended because it is not cost-effective, but a prospective study has cast doubt on the wisdom of this policy (130). Antithyroid drug–treated patients had serial WBC counts performed every two weeks for the first two months and monthly thereafter. Some patients developed milder forms of agranulocytosis that resolved without progressing once the antithyroid drug was stopped (130). In another study, it was shown that it may be possible to differentiate those patients with modest depression of their granulocyte count (granulocyte counts of 0.2–0.8 × 109 /L) who will go on to develop full-blown agranulocytosis using a single dose of granulocyte-colony stimulating factor (G-CSF) (128). Some clinicians monitor the complete blood count and liver function tests in patients taking antithyroid agents, both prior to and periodically during this treatment. Patients with agranulocytosis may be afebrile until they develop an infection. The typical victim has severe malaise, oropharyngitis and odynophagia, and high fever. Immediate cessation of the antithyroid drug, hospitalization, and administration of broad-spectrum antibiotics is mandatory, with coverage for Pseudomonas aeruginosa, which is frequently isolated from the blood in affected patients (132). Although most patients recover, it should be recalled that agranulocytosis has

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been associated with a mortality rate as high as 16% (133). A bone marrow examination may provide helpful prognostic information; an extreme loss of myeloid precursors suggests a longer time to recovery (133) as well as the potential for a poor response to G-CSF therapy (134). The use of G-CSF has become standard in the management of drug-induced agranulocytosis. However, a randomized controlled trial of G-CSF in antithyroid drug–induced agranulocytosis found no statistically significant difference in the mean time to recovery from G-CSF compared to conservative therapy (135). Other retrospective data supporting the use of G-CSF, however, noted shortened recovery time. In a retrospective review of 109 patients with agranulocytosis related to antithyroid drugs, the mean time to recovery was 5.5 days compared to 9.2 days in historic controls. There were no deaths in either group (136). The doses of G-CSF used in the literature range from 1 to 5 ␮g/kg/day subcutaneously. Common side effects include rashes, bone pain, myalgias, and headache, all of which respond well to acetaminophen (137). If thyrotoxicosis requires treatment during the acute episode of agranulocytosis, beta-adrenergic blocking drugs, lithium, or iodinated contrast agents can be used. Attempting to switch to the other antithyroid drug is not recommended, as cross-sensitivity has been reported. Some patients develop a condition that has been termed the “antithyroid arthritis syndrome” (138). The frequency of this side effect is in the range of 1% to 2%, and it usually develops within 60 days of initiating therapy. The syndrome is characterized by hot, swollen, tender joints involving multiple sites. The specific laboratory studies are not typical of drug-induced lupus. Symptoms usually resolve after one to two weeks of therapy with nonsteroidal anti-imflammatory drugs; glucocorticoid therapy may be necessary in severe cases. A more uncommon and potentially significant development is the appearance fever, rash, arthritis, splenomegaly, glomerulonephritis, and other stigmata of drug-induced lupus, almost always associated with PTU. Patients have elevated sedimentation rates, positive antibodies for double-stranded DNA, and low serum complement levels. The syndrome usually resolves in a few weeks after the drug is discontinued, although it should be remembered that the simultaneous occurrence of other autoimmune disorders is increased in patients with Graves’ disease. Recently, an antithyroid drug–related syndrome that includes renal failure, vasculitic skin changes, pulmonary and respiratory tract involvement, arthritis, and positive circulating anticytoplasmic neutrophil antibodies (ANCA) has been described, mainly in Asian patients (139). ANCA have typically been associated with Wegener’s granulomatosis and polyarteritis nodosa, but they may also be present in drug allergy. In the antithyroid drug–related cases, the antibodies are of the pericytoplasmic variety (so-called pANCA, with myeloperoxidase being the putative antigen), and the vast majority have been patients exposed to PTU (140,141). Although the syndrome usually resolves after a few weeks, some patients with severe renal dysfunction or pulmonary involvement have required high-dose glucocorticoid therapy or cyclophosphamide, and several patients have

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needed short-term hemodialysis. In some antithyroid drug-treated patients, ANCA are present, but patients remain asymptomatic (142). Hepatic involvement with PTU typically presents as clinical hepatitis with malaise, anorexia, jaundice, and tender hepatomegaly. Laboratory data and liver biopsy histology are consistent with hepatocellular injury. The following criteria for the diagnosis of PTU-induced hepatitis have been proposed: Clinical and laboratory evidence of hepatocellular damage; temporal relationship to PTU therapy; exclusion of known infectious agents, drugs, or toxins; and absence of shock or sepsis (143). More than three dozen cases of PTU-related hepatitis have been reported in the literature, with several fatalities and at some patients requiring liver transplant (144). The mean duration of PTU therapy in reported cases is three months, with a range of two days to one year; the average age of affected individuals in one review was 28 years (144). Once the syndrome is recognized, immediate cessation of the drug is mandatory. Expert management of potential complications and hepatic failure is essential. Although glucocorticoid therapy has been used, there is no evidence that it decreases the time to recovery or survival, and glucocorticoids are not recommended (145). There have been several patients whose ongoing hyperthyroidism has been managed successfully with methimazole (146–148); other options would include beta-adrenergic blocking drugs, iodinated contrast agents, and lithium. Approximately one-third of PTU-treated patients develop asymptomatic two-to sixfold elevations of serum tranaminases within two months of starting the drug, which then resolve despite continued therapy (149). Also, up to 35% of patients with Graves’ disease have elevations of liver function tests at baseline (149,150). In one report, PTU therapy led to normalization of liver function tests in two-thirds of patients, while the remaining one-third had a further elevation before levels returned to baseline (149,150). These data suggest that abnormal liver function tests are not an absolute contraindication to PTU therapy, although a serious discussion of these issues must be held with the patient. All patients about to embark on a course of PTU should be warned about the possibility of hepatitis and told to discontinue the drug if malaise, jaundice, dark urine, or light-colored stools develop. Monthly monitoring of liver function, at least for the first 6 months of therapy, is a reasonable approach. Methimazole therapy has not been associated with potentially lethal hepatic involvement. Rather, a cholestatic picture is characteristic, with severe hyperbilirubinemia, bile duct stasis, and preserved hepatocellular architecture on biopsy. Although a recent review collected 30 cases in the literature (151), there are probably many cases that go unreported, as with PTU-induced hepatitis. The syndrome usually resolves slowly over a period of several months after the drug is stopped. In one case report of methimazole-related hepatotoxicity, PTU was substituted for methimazole without sequelae (152). Extreme caution should be used when employing one antithyroid agent in a situation in which the alternative agent has caused hepatic abnormalities.

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Beta-Adrenergic Antagonist Drugs Beta-adrenergic antagonist drugs play an important role in the management of thyrotoxicosis (153). Blockade of adrenergic receptors provides patients with considerable relief from adrenergic symptoms such as tremor, palpitation, anxiety, and heat intolerance. Small decreases in serum T3 concentrations occur in patients treated with large doses of selected beta-adrenergic antagonist drugs (propranolol) because of inhibition of extrathyroidal conversion of T4 to T3 (154), but these are probably clinically insignificant. Although beta-blockers improve the negative nitrogen balance (155) and decrease heart rate (156), cardiac output (157), and oxygen consumption (158) in thyrotoxic patients, these measurements seldom become normal (159) except in the mildest cases. Therefore, these drugs are used as primary therapy only in patients with self-limited forms of thyrotoxicosis (e.g., the various forms of subacute thyroiditis). They are most often used in Graves’ disease as an adjunct to alleviate symptoms during the diagnostic evaluation, while awaiting the effects of antithyroid drugs, the results of ablative therapy with radioiodine, or to prepare patients for surgery. Although propranolol was the drug originally used by most clinicians for therapy of thyrotoxicosis, other beta-blockers have a longer duration of action (e.g., long-acting propranolol, atenolol, metoprolol, and nadolol) or are more cardioselective (atenolol and metoprolol). The usual starting dose of propranolol is in the range of 80 to 160 mg/day; similar effects are produced by 50 to 200 mg/day of atenolol or metoprolol or 40 to 80 mg/day of nadolol. Large doses (e.g., 360–480 mg/day of propranolol) are sometimes necessary for optimum clinical effects, possibly because of accelerated drug clearance (160). Propranolol and esmolol can be given intravenously to patients who are acutely ill (see discussion of thyrotoxic storm). Beta-adrenergic antagonist drugs are well tolerated. Common side effects include nausea, headache, fatigue, insomnia, and depression. Rash, fever, agranulocytosis, and thrombocytopenia are rare. Undesirable effects related to the betaadrenergic antagonist effects are far more common. Patients with a clear history of asthma should not receive these drugs; a cardioselective drug could be used cautiously in patients with mild asthma. Patients with a history of congestive heart failure should not receive a beta-adrenergic blocking drug except when the heart failure is clearly rate-related or caused by atrial fibrillation (161). Even then, the drug should be given cautiously, preferably with digoxin. Beta-blockers are also relatively contraindicated in insulin-treated diabetic patients, in whom hypoglycemic symptoms may be masked. They should not be given to patients with bradyarrhythmias or Raynaud’s phenomenon or patients being treated with a monoamine oxidase inhibitor; they should also probably not be given routinely to pregnant patients. The potential usefulness of diltiazem in thyrotoxicosis has been studied (162). This calcium channel blocking agent reduced resting heart rate by 17%,

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comparable to what can be achieved with a beta-adrenergic antagonist drug. Calcium channel blockers should be considered in patients with severe tachycardia in whom beta-blockers are contraindicated, for example, in patients with both asthma and thyrotoxicosis. Lithium Although lithium has not been extensively used, it is a potential second-line agent in the treatment of hyperthyroidism. Its mechanism of action is unknown but is thought to relate to inhibition of thyroid hormone synthesis and secretion (163,164). Lithium use should be reserved for the unusual patient who has not responded to or is allergic to more standard antithyroid agents. Lithium is mainly indicated for short-term use in hospitalized patients with thyroid storm or to prepare them for surgery. The dose of lithium is usually 300 mg tid, with periodic monitoring of serum levels to ensure that they are in a therapeutic range. Potential complications relate to neuromuscular and CNS perturbations, such as ataxia, tremor, and seizures. Potassium Perchlorate Potassium perchlorate is an antithyroid medication that inhibits thyroidal uptake by the sodium/iodide symporter (165–167), resulting in decreased synthesis and secretion of T4 and T3. This agent is also a second-line alternative to more standard therapy. The typical dose is approximately 400 mg bid po. Potential adverse effects include bone marrow suppression and skin rash. It is unknown if the risk of bone marrow toxicity increases with concomitant PTU or methimazole use. For several decades the use of perchlorate had fallen into disrepute due to its potential bone marrow toxicity. However, interest in employing this medication has resurfaced, as it was found to be effective for amiodarone-induced hyperthyroidism (168). In selected circumstances, its use has now extended to all types of high-uptake hyperthyroidism. Unfortunately, perchlorate is no longer available in the United States. Radioiodine (131 I) Therapy for Graves’ Disease 131

I therapy has been utilized for approximately 50 years for patients with Graves’ disease; it is considered safe and effective (169–171). The goal of therapy is to render the patient permanently hypothyroid, a process that typically takes approximately three months. Radioiodine therapy is considered first-line therapy in most adults with thyrotoxic Graves’ disease (90). Patients and their families must be counseled about the advantages and disadvantages of radioiodine therapy and must participate in the decision process. Elderly or severely thyrotoxic patients considered too ill to undergo the therapeutic manipulations inherent in the process of giving 131 I are usually initially treated with antithyroid agents to render them euthyroid, at which time a decision can be made with regard to definitive radioiodine therapy.

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A 24-hour radioactive iodine uptake test is required before administering 131 I therapy. Measurement of radioactive iodine uptake prior to giving a therapeutic dose of 131 I is important since it documents that the uptake is sufficiently elevated to administer 131 I. On rare occasion, a patient will have had exposure to radiocontrast dye or compounds containing sufficient iodine to suppress the radioactive iodine uptake. In this circumstance, giving a therapeutic dose of 131 I would fail to treat the patient and exposure him or her unnecessarily to radiation. 131 I therapy should not be given to a breast-feeding woman or a patient who may be pregnant. Therefore, a careful medical history and a serum beta-hCG should be obtained within five to seven days prior to giving the therapy. A woman of childbearing age should be counseled not to become pregnant for 6 to 12 months after 131 I therapy. This time period is chosen based on the biologic half-life of the radioiodine, as well as the desire for the patient to be euthyroid prior to becoming pregnant. Careful radiation safety procedures must be followed by the patient and his or her family for about a week following 131 I therapy. For example, if a patient has young children in the house, they should not share eating utensils or be kissed or held closely. The individual instructions vary from institution to institution and with the family situation. There are two general approaches to deciding on the appropriate therapeutic dose of 131 I for a patient with Graves’ disease. The first method attempts to determine the most appropriate dose for an individual by estimating the size of the thyroid gland and delivering approximately 100 to 200 ␮C of 131 I per gram of thyroid tissue. The estimated thyroid gland size is multiplied by the desired delivered dose per gram of tissue (100–200 ␮C of 131 I), and this number is divided by the 24-hour uptake expressed as a decimal (e.g., 80% uptake is converted to 0.80). This method appears to be more quantitative than it actually is because clinicians tend to underestimate the size of large thyroid glands and overestimate the size of smaller ones, and it is impossible to predict radiation sensitivity of a specific thyroid gland. Alternatively, a second method of treatment is to use “fixed doses” of 131 I. With this approach, the physician arbitrarily picks a given 131 I dose that is used in all patients with hyperthyroid Graves’ disease. A typical fixed dose would be 10 to 15 mCi 131 I. This practice has the advantage of simplicity— but, of course, it does not take into effect the size or activity of the thyroid gland. Retrospective and prospective studies have not shown major differences in outcomes for the two methods of dose determination (172,173). Some centers perform dosimetric calculations after a tracer dose of radioiodine in an effort to deliver a specific dose of radiation to the gland (e.g., 10,000 rads), but this method is cumbersome and time-consuming and has not gained wide popularity. The potential complications of radioiodine therapy are listed in Table 4. The follow-up evaluation of a patient after 131 I therapy varies between institutions and physicians, and, of course, depends upon the clinical circumstances and goals of treatment. In the typical patient with Graves’ disease, 131 I is given in order to induce permanent hypothyroidism. In this circumstance, following a therapeutic dose of 131 I, serum FT4, and total T3 levels are determined periodically,

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Table 4 Complications of Radioiodine Therapy and Surgery 131

I therapy Exacerbation of hyperthyroidism, especially in elderly patients who are not euthyroid Transient thyroid gland discomfort or tenderness Sicca syndrome, taste distortion, sialadenitis Fetal hypothyroidism if administered during pregnancy Hypothyroidism (desirable goal) Carcinogenic effects still being evaluated Thyroidectomy Hypothyroidism (desirable goal) Anesthetic complications Hypoparathyroidism with hypocalcemia Transient postoperative hypocalcemia (“hungry bones”) Recurrent or superior laryngeal nerve injury causing voice changes Local hemorrhage Persistent or recurrent hyperthyroidism Exacerbation of hyperthyroidism Jugular vein or carotid artery damage Infection Thoracic duct or lymph drainage damage Source: From Ref. 2.

perhaps every three to six weeks, depending upon the clinical context. After several months, when the thyroid function tests are decreased to the normal range and the patient is being evaluated for possible hypothyroidism, serum TSH is also determined. Most patients develop transient central hypothyroidism following radioiodine therapy, with subnormal serum FT4 that usually, but not always, evolves into permanent primary hypothyroidism (174). Approximately 5% to 10% of patients will require a second dose of 131 I, and approximately 1% of patients require a third dose. It is prudent to wait 6 to 12 months for the full effects of the initial dose to be manifest before another dose is considered. Overall, approximately 50% of patients become permanently hypothyroid after one year, with the rate being dependent on the radioiodine dose, with another 2% to 3% developing hypothyroidism in the ensuing years. Thus, patients who do not become hypothyroid early require lifelong follow up to monitor for the development of hypothyroidism. Prior to definitive therapy most patients will be given a beta-blocker when the diagnosis of thyrotoxicosis is made, the goal being amelioration of symptoms and a pulse rate ⬍100 beats per minute. Young patients who are mildly to moderately thyrotoxic (e.g., minimal symptoms, otherwise healthy, minimal elevations of T4 and T3) do not require methimazole or PTU therapy before or after 131 I treatment, although they usually will continue their beta-blocker or be prescribed one. Because of the possibility of worsening of thyroid function in the weeks following radioiodine therapy (175,176), likely due to a transient increase in TSAb (177),

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older patients with moderate hyperthyroidism or patients with more severe disease (e.g., presence of coexisting medical conditions, elevated FT4 and total T3 perhaps two to three times above normal) are commonly given antithyroid agents before or after radioiodine therapy to maintain normal thyroid hormone levels (178,179). The drug is tapered as the thyroid function tests normalize, and then stopped when the tests show hypothyroidism developing. When it is clear the patient is hypothyroid secondary to the 131 I rather than to the antithyroid agents, thyroxine is started. Patients with very severe hyperthyroidism (e.g., marked symptoms, FT4 and T3 elevated more than three- to fourfold), elderly patients, or patients with known or potential coexisting medical conditions such as cardiac disease will usually be given antithyroid agents prior to 131 I therapy. It is hypothesized, but not proven, that pretreatment with antithyroid drugs will decrease the likelihood of an exacerbation of thyroid function tests following 131 I therapy. Most endocrinologists provide a window of about two to five days prior to and after 131 I therapy when the patient does not receive antithyroid drugs. In a survey of members of the American Thyroid Association, only about one-third of respondents reported that they pretreat patients prior to administering radioiodine (90). In meta-analysis of studies that examined outcomes of patients either pretreated or not pretreated with antithyroid drugs prior to radioiodine (180), new onset atrial fibrillation was reported in 1/660 (0.2%) patients pretreated with ATDs versus 3/646 patients without ATDs (0.5%). Death after radioiodine was reported in 1/660 (0.2%) pretreated with antithyroid agent and in 6/646 (0.9%) without adjunctive drug therapy. Clearly, the routine use of antithyroid drugs in this context is unnecessary and potentially exposes patients to drug toxicity. Antithyroid drug pretreatment may interfere with the efficacy of radioiodine, perhaps by acting as free radical scavengers within the irradiated gland (181– 184). Recent prospective, randomized studies have shown that PTU has a negative effect on radioiodine outcome (185), but methimazole did not have such an effect (186,187). Nevertheless, a meta-analysis of all studies of this question ascertained that both antithyroid drugs lower the success rate whether if they are used before or after radioiodine treatment (180). Therefore, if antithyroid drugs are to be used before or after radioiodine therapy, it is recommended that the radioiodine dose be increased by 25% to compensate for the potential radioprotective effect of the drugs. One study has shown that thyroid hormone levels can be normalized more quickly, and the cure rates with radioiodine-enhanced, with lithium therapy (300 mg tid for six days beginning on the day of radioiodine therapy) (188). Radioiodine and Graves’ Ophthalmopathy I therapy is believed to exacerbate existing ophthalmopathy (189,190), at least when it is more than minimally active on clinical grounds (191); thus it is important to take a relevant history and perform a thorough ophthalmologic examination (5). If there is moderately severe ophthalmopathy or if it seems to be progressive, it is important to obtain an ophthalmology consultation, and an orbital computed tomography (CT) scan (without contrast) or magnetic resonance imaging (MRI)

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should be considered to evaluate the presence and extent of disease. These radiologic studies may be required only in selected patients, but they do provide quantitative, reliable information regarding proptosis, muscle size, and possible optic nerve compression that can be used for comparative purposes later. Tallstedt et al. (189) studied 168 patients with Graves’ hyperthyroidism divided into age group 1 (20–34 years; n = 54 patients) and age group 2 (35–55 years; n = 114 patients). The patients in group 1 were randomly assigned to receive either methimazole treatment for 18 months or subtotal thyroidectomy, while those in group 2 were to receive either of these two treatments or, alternatively, 131 I therapy. All patients were studied for at least 24 months. During the period of evaluation, ophthalmopathy developed for the first time in 22 patients (13%) and worsened in 8 patients (5%). The likelihood of the development or worsening of ophthalmopathy was comparable among the patients in group 1 (medical therapy, 15%, and surgery, 11%). In group 2, ophthalmopathy developed or worsened in 10% of patients treated medically, in 16% treated surgically, and in 33% of patients treated with 131 I (p = 0.02). Bartalena (192) studied 443 patients with Graves’ hyperthyroidism who had either no ophthalmopathy or minimal disease. Patients were randomly assigned to receive radioiodine, radioiodine followed by a 3-month course of prednisone, or methimazole for 18 months. The initial dose of prednisone was 0.4 to 0.5 mg/kg/ day starting two to three days after 131 I therapy and continuing for one month. The dose was tapered and discontinued after two months. Patients were followed closely, biochemically, and clinically for 12 months. In patients treated with radioiodine alone (n = 150), ophthalmopathy developed or worsened in 15% within six months after treatment. No patient in this group had an improvement in ophthalmopathy. In marked contrast, in the group treated with radioiodine and prednisone, 50 of the 75 (67%) with ophthalmopathy at baseline had improvement, and no patient had progression. Of the 148 patients treated with methimazole, three (2%) who had ophthalmopathy at baseline improved, four (3%) had worsening of eye disease, and the remaining 141 had no change. These data clearly show that prednisone therapy can help prevent radioiodine-associated deterioration in ophthalmopathy. Nonetheless, it remains unclear which patients should receive steroids. Ideally, steroid therapy should be considered as a team decision among the patient, family, endocrinologist, and ophthalmologist. Taking into account various regimens in the literature, one reasonable approach in patients with moderate or severe ophthalmopathy is to administer prednisone in doses of 40 to 60 mg prednisone daily starting several days prior to 131 I therapy and continuing for several weeks, trying to taper the drug completely by six to eight weeks. Corticosteroid therapy is reserved for patients with moderate or severe ophthalmopathy. Tallstedt et al. (189,193) noted that the initial serum T3 level was an independent risk factor for the development of ophthalmopathy and that postablative hypothyroidism should be avoided. Bartelena et al. (192) also showed that cigarette smoking was a potent, independent risk factor for the worsening of ophthalmopathy after radioiodine therapy, and patients with Graves’

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disease who smoke should be advised to discontinue. Some endocrinologists avoid radioiodine therapy in patients with moderate to severe eye disease unless it has been stable for at least one year. Radioiodine and Cancer A number of older studies have failed to show any causal relationship between radioiodine therapy and the subsequent development of thyroid cancer, leukemia, or other malignancies. Ron et al. (194) retrospectively analyzed 35,593 hyperthyroid patients (91% had Graves’ disease) who had been treated with radioiodine, antithyroid drugs, or surgery between 1946 and 1954. Some 65% of these patients were treated with radioactive iodine, thus allowing long-term comparison of results between various therapeutic modalities. When studied in December 1990, about half of the patients had died. The total number of cancer deaths in all hyperthyroid patients was comparable in patients treated with radioactive iodine and those treated with surgery or antithyroid agents, although there was a slight excess of cancer-related mortality from lung, breast, kidney, and thyroid. Starting at least one year after treatment, an enhanced risk of cancer mortality was also seen in hyperthyroid patients treated with antithyroid drugs. After more than five years following therapy, radioactive iodine therapy was associated with an increased risk of thyroid cancer mortality, but only in patients with toxic multinodular goiter. Overall, the risk of thyroid cancer in patients treated with radioactive iodine treated resulted in a small, absolute excess in actual patient deaths. Franklyn et al. (195) also suggested that 131 I therapy was associated with a higher incidence of thyroid cancer. They retrospectively studied 7417 patients treated in Birmingham, England, with radioiodine for Graves’ disease. On analyzing 72,073 person-years of follow-up, 634 cancer diagnoses were found as compared with an expected number of 761. The relative risk of cancer mortality was also decreased. The incidence of cancers of the pancreas, bronchus, trachea, bladder, and lymphatic and hematopoetic systems was decreased. However, there were significant increases in incidence and mortality for cancers of the small bowel and thyroid, although the absolute risk of these cancers was small (195). In this English study, the goal of radioiodine therapy had been euthyroidism rather than hypothyroidism. The destruction of all residual thyroid tissue would be expected to lessen possibility of thyroid cancer. Finally, in one recent population based study of 3888 patients treated for hyperthyroidism, there was no increase in cancer mortality over eight years of follow up, but the method of treatment was not specified (196). In another similar study of 2973 patients treated with radioiodine with a nine year follow up, there was an increase in overall and cancer mortality (adjusted RR 1.36; 95% CI 1.12–1.65), mainly due to cancer of the stomach and esophagus. However, the increase in total mortality was only seen in patients with toxic multinodular goiter, but not in patients with Graves’ disease.

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Thyroidectomy for Graves’ Disease A total or near total thyroidectomy is also a reasonable therapeutic option for selected patients with Graves’ disease (90,197–201). This therapy is reserved for patients who are not well controlled on antithyroid agents; who have a particular reason for surgery, for example, a very large goiter or a thyroid nodule with suspicious aspirate; and those who prefer this therapy after a careful consideration of each option. Thyroidectomy must be performed by an experienced thyroid surgeon, although there is still a risk of temporary or permanent hypocalcemia secondary to injury of the parathyroid glands. Hoarseness may also occur as a result of injury to the recurrent laryngeal nerve. These two serious complications occur in approximately 1% of patients treated surgically (202). Other complications of surgery are rare and listed in Table 4. In most circumstances, a euthyroid state should be established prior to surgery with antithyroid agents, although more rapid preparation with beta-adrenergic blocking drugs and saturated solution of potassium iodide (SSKI) has been used as well (203). If there is no immediate need for surgery, antithyroid drug therapy is probably safer, as postoperative fever and tachycardia more commonly develop after preparation with beta-blockers alone (204). When surgery must be done quickly, a 5-day regimen of propranolol, glucocorticoids, and oral cholecystographic agents sodium ipodate or iopanoate have been used (205). Unfortunately, ipodate and iopanoate are not currently available in the United States. It is preferable that patients’ thyroid function tests be normal for several weeks prior to surgery, as this depletes intrathyroidal hormone stores and make releases at the time of surgery less likely. SSKI (10 drops three times a day) given daily for 10 days prior to surgery has been shown to decrease intraoperative blood loss in a recent randomized trial (206). Despite optimal care, perioperative thyroid storm may still occur, and patients should be treated aggressively if signs or symptoms are present (207). Obviously, most patients become hypothyroid immediately following surgery and require lifelong thyroxine therapy. Occasionally, a patient who has had a portion of his or her thyroid gland surgically removed in the past for Graves’ disease will present again with hyperthyroidism (208). The likelihood of this occurring depends upon the extent of thyroidectomy and the titers of TSH receptor–stimulating antibodies. Relapses may occur many years following surgery, often when the patient has been taking L-thyroxine for previously diagnosed hypothyroidism. Patients typically have a gradual development of symptoms and signs of hyperthyroidism in conjunction with elevated serum FT4 and T3 levels. When the exogenous thyroxine is decreased over time, the hyperthyroidism persists. Once the patient has discontinued thyroxine for at least four to six weeks and hyperthyroidism is still present, further evaluation is required. Measurement of TSH receptor antibodies also may be helpful in this circumstance. In the absence of palpable thyroid tissue, determination of serum thyroglobulin levels and performance of a 24-hour radioiodine uptake will help distinguish iatrogenic or factitious hyperthyroidism from recurrent Graves’ disease (3).

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Choice of Therapy for Graves’ Disease: Summary Antithyroid drugs are a reasonable choice for first-line therapy in patients with small goiters and mild disease or in those whose TSI levels are normal. Also, children and adolescents are traditionally treated initially with antithyroid drugs. Because of concern that radioiodine can worsen underlying ophthalmopathy (189,190), some clinicians recommend antithyroid drugs as the treatment of choice in patients with significant eye disease even when the biochemical abnormalities are more severe. In the future, costs of care may become more important in the management of hyperthyroidism. In studies that examined costs of care, radioiodine therapy was the least expensive alternative compared to antithyroid drugs and surgery (209,210). A computer-simulated, cost-effectiveness analysis reached the same conclusion, but when the chances of remission with antithyroid drugs was greater than 50%, they became as cost-effective as radioiodine (211). Patient satisfaction is also an important outcome that has only recently been studied. In the one report in which it was measured, antithyroid drugs, radioiodine, and surgery were equal in terms of patient satisfaction, whether a particular therapy would be recommended to friends or relatives, and in patients’ concern about possible side effects (96).

TREATMENT OF GRAVES’ OPHTHALMOPATHY AND PRETIBIAL MYXEDEMA Although almost all patients with Graves’ disease have radiologic evidence of eye muscle involvement, only approximately 30% of patients have obvious clinical disease (212). Several different methods for assessing disease severity have been described, but none of the classifications is perfect. The “NOSPECS” classification is still in wide use today (Table 5) (213), although it has been criticized for being overly subjective and not quantitative enough (214). In general, the most common symptoms are related to soft tissue swelling due to orbital congestion, with irritation, tearing, burning, and a gritty sensation in the eyes. Diplopia is a more unusual and debilitating problem, and only rarely is vision threatened because of corneal exposure or optic nerve involvement. Symptoms and cosmetic concerns also significantly impact negatively on the quality of life of affected patients (215). The symptoms and signs of Graves’ ophthalmopathy are due to orbital inflammation, with the extraocular muscles and/or retro-orbital fibroblasts being the target of the autoimmune reaction (6,13,216–218). Glycosaminoglycans produced by fibroblasts responding to T-cell infiltration cause edema of the extraocular muscles, and further expansion of the retro orbital tissues is due to increased orbital fat (214). Ultimately, fibrosis of the extraocular muscles can lead to diplopia, and severe enlargement of the muscles can cause an ischemic optic neuropathy due to compression of the optic nerve as it exits the apex of the orbit.

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Table 5 ‘NO SPECS’ Classification of Eye Changes of Graves’ Disease Class O I II III IV V VI

Definition No physical signs or symptoms Only signs, no symptoms (e.g., upper lid retraction, stare, and eyelid lag) Soft tissue involvement (symptoms and signs) Proptosis Extraocular muscle involvement Corneal involvement Sight loss (optic nerve involvement)

The primary autoimmune target in Graves’ ophthalmopathy is unknown, but probably is a cross-reacting antigen or antigens that are present in both in the orbit and the thyroid gland (216). The TSH receptor has been hypothesized be the putative common antigen. TSH receptor transcripts have been isolated from extraocular muscle using PCR (219), TSH receptor protein has been identified in orbital tissues by immunostaining (219), and the levels seem higher in Graves’ ophthalmopathy patients as compared to normal subjects (13). Further, autoantibodies directed against TSHR or the insulin-like growth factor-1 (IGF-1) receptor may play a role in the development or progression of Graves’ ophthalmopathy (13). Since the cause of Graves’ ophthalmopathy is unknown, treatment is directed at symptoms. In most patients, the problem is self-limited, often resolving as the hyperthyroidism is treated (220). Although most experts feel that it is best for the patient to be euthyroid, there is no consistent relationship between a patient’s thyroid function and progression or regression of eye disease. There is good evidence that smoking exacerbates Graves’ ophthalmopathy (221), and it is suggested that smoking cessation has a beneficial effect (222). The mechanism by which smoking affects Graves’ ophthalmopathy is unknown. There is solid evidence that radioactive iodine therapy can exacerbate Graves’ eye disease when it is moderately severe at baseline (189,190). When the condition is mild, symptoms such as irritation, tearing, and photophobia are easily treated with artificial tears and lubricating eye ointments. In more severe cases, high doses of glucocorticoids (e.g., 60–120 mg of prednisone today) usually will result in prompt improvement in local symptoms and ocular motility (5). Unfortunately, as the glucocorticoid is tapered, the ophthalmopathy often flares up, so that other measures are sometimes needed. The use of long-acting octreotide in the treatment of Graves’ ophthalmopathy has also been recently studied and two studies have noted no or minimal improvement (217,223). Orbital radiotherapy is usually the next step after glucocorticoid therapy (5). Although somewhat controversial, orbital radiotherapy has been shown to be effective in several studies, including a recent randomized prospective trial in which half of the patients received sham irradiation (224). In this study, 60% of

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irradiated patients improved versus 31% of sham irradiated patients. However, Gorman et al. (225) also performed a prospective, randomized, double-masked, internally controlled, clinical trial of external beam radiotherapy for patients with mild to moderate Graves’ ophthalmopathy. When analyzed 6 to 12 months after orbital radiation, there was no apparent clinical benefit identified. As a result of these recent studies, the role of external orbital radiation in the treatment of Graves’ ophthalmopathy is uncertain. Patients who fail radiation therapy may require surgical decompression of the orbit if there is rapidly progressive visual loss due to optic neuropathy, steroid dependence, or continuing ocular motility problems. Surgery is also indicated to correct self-perceived cosmetic problems, particularly in patients with severe proptosis or lid retraction. Unfortunately, orbital decompression often results in more significant ocular motility problems that then require additional strabismus surgery for correction (226–229). The cause of pretibial myxedema remains obscure (230), but it probably shares common features with Graves’ opthahlmopathy, including lymphocytic infiltration and a response by fibroblasts to the subsequent inflammation. The usual treatment is topical steroid cream with or without occlusion (231). Intralesional steroids have also been used. Recently, octreotide has been reported to be of use (232), but additional data are needed before this therapy can be recommended outside of a clinical trial. Recent trials have suggested the efficacy of combined pentoxifylline and intralesional triamcinolone acetonide (233,234). SUBCLINICAL HYPERTHYROIDISM Subclinical hyperthyroidism is a term generally utilized to describe patients with normal serum total and FT4 and T3 levels and a decreased serum TSH level (235– 257). A recent consensus panel has published useful guidelines for approaching and treating patients with subclinical hyperthyroidism (258). Patients most frequently have undetectable TSH levels, although a TSH that is subnormal but still detectable also meets the definition assuming that the values are consistent over time. The serum TSH level should be measured in a third-generation assay that is capable of discriminating degrees of low values, and the patient must not be taking or receiving any medications known to alter the hypothalamic-pituitary axis (such as corticosteroids and dopamine). TSH can be suppressed physiologically in the first trimester of some pregnant patients, and the patient must have a normal pituitary-thyroid axis (258). Further, the patient must be relatively healthy, without serious systemic diseases, since the “euthyroid sick syndrome” will also affect the serum TSH level. The patient with subclinical hyperthyroidism typically does not have significant signs or symptoms of hyperthyroidism, such as weight loss, nervousness, or palpitations. Some of the signs and symptoms of overt hyperthyroidism are vague and nonspecific and it may be difficult to determine if a patient is really asymptomatic. In a young patient with subclinical hyperthyroidism due to Graves’ disease, the thyroid is either not palpable or mildly enlarged, but a

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multinodular goiter is often palpable in older patients with multinodular goiters. Although the frequency of this disorder is not well defined, its recognition has increased in part due to the advent of more sensitive TSH assays. When patients with known thyroid disease are excluded, the incidence of subclinical hyperthyroidism is estimated to be approximately 2% (258). More details are available in chapter 10 “Practical Management of Thyroid Disease in the Elderly.” Sawin et al. (259) determined that low serum thyrotropin concentrations are a risk factor for subsequent atrial fibrillation. They studied 2007 persons (814 men and 1193 women) older than 60 years during a 10-year follow-up period to determine how frequently atrial fibrillation would develop. When analyzed cumulatively over the entire study period, atrial fibrillation occurred in 28% of the subjects with low serum thyrotropin values (≤0.1 ␮U/mL), as compared with 11% among those with normal or slightly decreased serum TSH values. The estimated relative risk for atrial fibrillation was 3.1 in Sawin’s study (259), and this elevated risk has been confirmed in other studies (255). Although the most frequent cause of the suppressed TSH levels in the patients in this study was exogenous thyroid hormone therapy, there is no reason to think that the effects of endogenous hormone would differ. Some studies have shown that postmenopausal women with subclinical hyperthyroidism have lower bone mineral density as compared with age-matched control women (260). However, others have not found this to be the case (261). Diagnosis The evaluation of a patient with subclinical hyperthyroidism may vary among physicians, but a reasonable approach in a typical asymptomatic patient is to perform a complete history and physical examination, ensure the thyroid function tests are measured in appropriately sensitive assays, and repeat the thyroid function tests monthly for three months. Thyroid function tests should include FT4 and FT3, since occasionally the free hormone levels may be increased disproportionately compared to the total hormone levels (258,262). If atrial fibrillation, cardiovascular disease, or other significant medical illnesses are present, earlier diagnosis and treatment are appropriate, so it is recommended to repeat thyroid function tests over a shorter period of time, such as two weeks (258). The suppressed TSH level may represent the initial manifestations of hyperthyroidism that will evolve into a more overt form over the ensuing months. Alternatively, the suppressed TSH may be transient and return to the normal range, as a suppressed TSH could represent an episode of transient thyroiditis. If this were correct, the TSH would be expected to return to normal within three months. Therefore, to ensure stability of the laboratory tests and help exclude the possibility of a laboratory error, thyroid function tests are determined monthly for three months prior to further evaluation. If stability in TSH levels is demonstrated, it seems reasonable to perform a radioactive iodine uptake test and to consider measuring TSH receptor antibody levels. Frequently, the radioactive iodine uptake is at the upper range of

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normal or slightly higher, and TSI (and TBII) levels are also minimally elevated or normal, reflecting the minimal degree of hyperthyroidism. The radioactive iodine uptake is measured not only to assess the level of thyroidal activity but also to exclude painless thyroiditis. A thyroid sonogram may be useful in selected patients to help quantitate thyroid gland size and to determine the presence and characteristics of thyroid nodules. Treatment Once the tests are shown to be consistent with persistent subclinical hyperthyroidism, treatment options must be discussed. The first option is simply to continue to monitor the patient and thyroid levels indefinitely. This is a reasonable option in some patients, especially young premenopausal women and young men, but—as noted above—subclinical hyperthyroidism may be associated with a higher risk of accelerated bone loss and osteoporosis in postmenopausal women. It addition, as noted above, it may also be associated with a higher risk of atrial fibrillation, especially in older individuals (259,263,264). The second therapeutic option is to administer radioactive iodine in an effort to induce permanent hypothyroidism. Radioactive iodine is considered safe and effective and is the usual treatment of choice for patients with overt hyperthyroidism. However, this treatment may appear drastic for most patients with subclinical hyperthyroidism, in part because they are asymptomatic and often do not desire definitive therapy. Similar comments apply to the recommendation of a thyroidectomy. Given these considerations, a 6- to 12-month trial of antithyroid agents is a reasonable medical approach. It normalizes the TSH, FT4, and FT3 levels, and yet also takes into account patients’ natural reluctance to have definitive therapy when they are asymptomatic and when treatment directives revolve around a single laboratory test abnormality (i.e., serum TSH). It is uncertain if most patients with subclinical hyperthyroidism have multinodular goiters or Graves’ disease. Therefore, the remission rates with a trial of antithyroid agents are unknown. One approach to a patient with subclinical hyperthyroidism is to treat with low-dose antithyroid medication (e.g., methimazole 5–10 mg/day) for an arbitrary time period, such as 6 to 12 months (265). This course of action might induce a long-lasting remission in a patient with Graves’ disease and, if the disorder subsequently recurs, the patient may be more likely to accept definitive therapy. While a patient is being treated with antithyroid agents, serum FT4, TSH, and possibly T3 or FT3 should be measured periodically. The risk of adverse effects from the antithyroid agents, such as agranulocytosis, liver function abnormalities, and skin rash, is low given the small dose of medication used. Mudde et al. (260) and Faber (266) have shown a benefit of antithyroid agent therapy on bone density values in patients with subclinical hyperthyroidism. Buscemi et al. (267) showed that restoration of euthyroidism with antithyroid agents had a favorable effect on cardiac and bone paratmeters. However, more detailed, prospective studies are required regarding all aspects of subclinical hyperthyroidism to allow a more evidence-based approach to these patients.

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THYROID STORM The term thyroid storm refers to severe and exaggerated symptoms and signs of hyperthyroidism, usually in association with tachycardia, fever, diarrhea, vomiting, dehydration, disorientation, or mental confusion (207,268). Patients usually experience severe restlessness and anxiety and may be unable to reason. There is a continuum between “routine” hyperthyroidism and thyroid storm, and different observers may vary in their definition of thyroid storm. Although there have been attempts to establish a uniform set of criteria for the diagnosis of thyroid storm (207), these have not been generally accepted. Thyroid function tests, for example, FT4 and FT3, overlap between routine hyperthyroidism and thyroid storm, and mean values are similar in most studies (269). Sherman and Ladenson (270) have noted lower socioeconomic status in patients with thyroid storm compared to those with controlled hyperthyroidism, indicating that lack of access to medical care may be an important predisposing factor. Thyroid storm is typically precipitated by a specific event, such as surgery (especially patients having thyroid surgery without adequate preparation), severe systemic illness (e.g., pneumonia, pharyngitis), or parturition. It is important to prevent thyroid storm whenever possible by trying to predict circumstances in which it may occur. It is preferable, in general, to treat patients as if they had thyroid storm when it is suspected, rather than to delay therapy in the hope that thyroid storm will not develop or become fully manifest. Treatment Patients should be treated with antithyroid agents to restore euthyroidism prior to anticipated stressful events, such as surgery. As noted earlier, hyperthyroid patients should be prepared with antithyroid medications for several weeks prior to thyroidectomy. It is generally believed that when thyroid hormone stores are decreased the risk of exacerbating thyroid storm is decreased, since there may be less preformed T3 and T4 that may be released into the circulation at surgery. However, Hermann et al. (271) studied thyroid hormone venous effluent from the thyroid gland in patients with hyperthyroidism undergoing thyroidectomy without antithyroid agent pretreatment. There were no significant differences in T3 and T4 levels in the venous effluent compared to the peripheral levels. It is unclear if, however, if this study applies to all hyperthyroid patients undergoing a thyroidectomy and it is prudent to perform careful monitoring at the time of surgery with an experienced surgical and anesthetic team. The precise pathophysiology underlying a possible increase of thyroidal release of T4 and T3 around the time of thyroidectomy is not known but likely relates to surgery and anesthesia itself. Treatment for a patient with severe thyrotoxicosis or thyroid storm is more aggressive than that for a patient with less severe thyroid dysfunction (207). The doses of medications are higher in patients considered to have thyroid storm.

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Propylthiouracil, 100 to 200 mg q4 h, or methimazole, 10 to 20 mg q4 h, is recommended in conjunction with propranolol, 60 to 80 mg q8 h. In unusual circumstances when patients cannot be administered oral medication effectively PTU or methimazole can be given rectally or, in the case of methimazole, intravenously (272–275). Propanolol can also be given intravenously (2–5 mg every four hours), and if there is a history of pulmonary disease, esmolol, at a dose of 50–100 ␮g/kg/min can be used. Hydrocortisone 100 mg q8 h is added to ensure adequate adrenal function, and an iodine-containing agent may also be employed. An intravenous preparation of sodium iodide is no longer available. SSKI, 5 drops tid, or Lugol’s solution, 5 drops tid, contain sufficient iodine to reduce thyroid production and secretion of T4 and T3, and their effects can be seen within several days (3). These agents are very useful and effective but can have a significant negative impact as well. Iodine-induced inhibition of thyroid gland synthesis (the Wolff-Chaikoff effect) and glandular secretion persist for one to two weeks, especially in previously untreated patients with severe hyperthyroidism. Then there may be “escape” from the inhibitory effects, with enhanced synthesis and release. The mechanism of this effect relates to modulation of function of the sodium iodide symporter (212). This biphasic effect of iodine is extremely important and is the chief reason why hyperthyroid patients are not routinely treated with iodine-containing drugs. Two oral cholecystographic agents, ipodate (Oragraffin) and iopanoate (Telepaque), have been found to contain sufficient iodine to have effects similar to Lugol’s solution and SSKI, but, in addition, both potently inhibit T4-to-T3 conversion (276). Unfortunately, both ipodate and iopanoate have been withdrawn from the commercial market and both are unavailable. Perchlorate inhibits the sodium-iodide symporter and decreases intrathyroidal iodine which is needed for sustained thyroid hormone synthesis (167). Perchlorate also is not presently available commercially. Cholestyramine (or colestipol) administration is mildy effective as adjunctive therapy as it decreases the enterohepatic circulation of T4 and T3 (277). Care must be exercised to separate the interval between the administration of cholestyramine (and colestipol) and other oral medications.

SOLITARY TOXIC NODULES Introduction A solitary autonomous toxic thyroid nodule produces sufficient thyroid hormone to suppress TSH and cause overt or subclinical hyperthyroidism (278–282). Often, a thyroid nodule may be autonomous and not yet be sufficiently functional to suppress serum TSH. The capacity to secrete thyroid hormones varies with the size of the thyroid nodule, and those that are ⬎3 cm in size are much more likely to produce hyperthyroidism (283). The percentage of autonomous nodules that secrete sufficient thyroid hormones to produce overt hyperthyroidism is relatively low, in the range of 20%.

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Pathology Histologically, autonomous nodules are cellular, follicular adenomas with frequent hemorrhage, fibrosis, calcification, and cysts. There is often a dense, fibrous capsule. The vast majority of solitary autonomous thyroid nodules are benign. In adults, as many as several percent of these nodules contain foci of papillary thyroid cancer, whereas in children and adolescents, the percentage of autonomous nodules that contain thyroid cancer is likely higher (284–287). This reported pathologic frequency is higher than found in clinical practice and may represent abnormalities in adjacent tissue rather than the adenoma itself. A fine-needle aspiration biopsy of the nodule should be performed if there is any suspicion of cancer based on clinical, historic, or laboratory studies. For example, the presence of associated cervical lymphadenopathy, recent growth (which could simply represent hemorrhage), or a history of neck radiation may increase the suspicion for associated cancer. The type of thyroid cancer found in this circumstance is usually papillary thyroid cancer, although other types, such as follicular or medullary thyroid cancer, may be identified. Earlier studies suggested that cytologists would read aspirates from autonomous nodules as suspicious for follicular thyroid cancer, given the cellular nature of these nodules (288). However, subsequent analyses show that the fine-needle aspirations are rarely confusing and that the majority of autonomous nodules yield benign cells in the presence of colloid (289,290).

Pathogenesis Autonomous function of the nodule is attributed to either a loss in suppression of normal cell function due to a genetic defect in the TSH receptor or a downstream pathway (e.g., G protein), causing excess stimulation of the thyroid cell and unregulated thyroid hormone production. The TSH receptor consists of seven transmembrane domains with three extracellular and three intracellular loops (291). The TSH receptor is coupled to a G protein, which subsequently initiates cyclic AMP production. Cyclic AMP is essential for production of thyroid cell products such as thyroglobulin, thyroid peroxidase, and hormone production and secretion, as well as cell growth and proliferation. The majority of solitary autonomous thyroid nodule tissue contains mutations in the TSH receptor protein or, less often, in the stimulatory G protein (292–295). Several different mutations in the TSH receptor gene and the resultant mutated protein are associated with cyclic AMP–dependent transcription independent of the presence of TSH. Mutated receptors retain a significant response to TSH stimulation, although it is decreased when compared to normal thyrocytes. The Gs protein regulates cell growth; when it becomes mutated, this protein acts as an oncogene, leading to abnormal cellular regulation. Gs mutations have been found in approximately 5% to 30% of toxic thyroid nodules (293).

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Clinical Considerations Approximately 1% of patients referred for thyroid disease and approximately 5% of hyperthyroid patients have an autonomous thyroid nodule (283). Patients with autonomous functioning thyroid nodules present most frequently with a neck mass but may also have subclinical hyperthyroidism (278,283). Overt symptoms of hyperthyroidism are uncommon. The frequency of toxic adenomas increases with age, and only about half of patients with autonomous nodules over the age of 60 manifest clinical signs or symptoms of hyperthyroidism. Autonomous nodules are much more common in women. A solitary autonomous thyroid nodule is not an autoimmune disease and is not associated with ophthalmopathy or dermopathy. Patients with an autonomous nodule larger than 3 cm have approximately a 20% chance of progressing to overt hyperthyroidism over several years, with smaller lesions having a much lower progression rate (296). Toxic nodules may undergo cystic or necrotic degeneration with return to euthyroidism (278). As many as 20% to 30% patients with solitary autonomous nodules may have a restoration of normal function secondary to hemorrhage (282,297). Iodine deficiency increases the risk of iodine-induced hyperthyroidism in patients with autonomous thyroid nodules (see Chapter 3, “Hyperthyroidism”). Even a small addition of iodine, perhaps 100 ␮g/day, to a low-iodine diet can initiate hyperthyroidism (298). Although iodine deficiency is not a problem in the United States, hyperthyroidism has been reported in patients with autonomous thyroid nodules within one to two months after exposure to radiocontrast dyes as well as after exposure to iodine-containing drugs such as amiodarone (299). Diagnosis Autonomous thyroid nodules are usually diagnosed by integration of the history and physical examination with laboratory and nuclear medicine testing. The serum TSH level is usually suppressed and is often unmeasurable. Free/total T4 and T3 are usually normal or slightly elevated but may vary depending upon nodule size and iodine exposure. Preferential T3 secretion, that is, T3 toxicosis, appears more common in patients with autonomous nodules than in Graves’ disease (262,296). The identification of an autonomous nodule on technetium-99 m or (123 I) scintigraphic scanning is the sine qua non of the diagnosis. When a radionuclide scan is performed, the solitary autonomous thyroid nodule represents the only tissue that appears to be trapping radioactive iodine, with the remainder of the thyroid tissue being suppressed. However, an abnormal thyroid scan alone does not prove autonomous function, since there are technical factors that could make a dominant nodule appear to be the sole area that traps radioactive iodine. When an autonomous thyroid nodule is suspected, it may be appropriate to use radioiodine rather than technetium as the diagnostic agent. Occasionally, a nodule may appear to be “hot” with technetium, when it is actually a “cold” nodule with radioiodine. This discordance is thought to relate to the ability of iodine to be trapped and organified by thyroid tissue, whereas technetium can only be trapped (300).

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Autonomous nodules lack an intact feedback mechanism to control iodine uptake and hormone production. Therefore, several tests have been used in the past to help diagnose the presence of autonomy. The T3 suppression test consists of scintigraphic scanning of the thyroid before and after 10 days of exogenous oral T3 administration at 50 to 100 ␮g/day. In addition, TSH, FT4, and FT3 are drawn at baseline and on completion of the T3 dosing. A normal patient will have suppression of endogenous TSH production; the second thyroid scan will show no thyroid uptake and the FT4 level will have decreased. In contrast, a patient with an autonomous thyroid nodule will show unchanged uptake over the nodule, and the FT4 level will not have changed. T3 suppression testing in hyperthyroid patients, especially elderly subjects, is fraught with potential danger by potentially exacerbating already existing thyrotoxicosis. This test is rarely performed and its use should be discouraged with the advent of third-generation TSH assays. Treatment Therapeutic decisions regarding autonomous nodules depend upon a variety of factors, including patient age, the severity of hyperthyroidism, and associated medical conditions such as coronary artery disease and/or a history of cardiac arrhythmias. Patients with overt hyperthyroidism in the presence of an undetectable TSH and elevated FT4 and T3 should be treated. Older patients with undetectable TSH and normal FT4 and T3 should be strongly considered for treatment because of possible deleterious effects on bone metabolism and the heart (see section “Subclinical Hyperthyroidism” of this chapter). More controversial is whether young patients with subclinical hyperthyroidism or people with nodules ⬎3 cm in diameter should be treated prophylactically. Some patients desire treatment for cosmetic reasons. The most important therapeutic option is radioactive iodine ablation of the toxic adenoma. Radioactive iodine concentrates in the autonomous nodule and may accumulate in extranodular tissue, albeit to a much lesser extent. Although results are variable, based upon size of the nodule, nodule uptake, dose administered, and tissue radiation sensitivity, a typical toxic nodule will shrink approximately 40% within one year following an ablative dose. Radioactive iodine ablation of an autonomous thyroid nodule may decrease the ability of that nodule to secrete excess thyroid hormones; but the nodule itself, although functionally inactive, may remain and must be monitored clinically over time (278,283). The beneficial effects of radioiodine may not be maximal until 4 to 12 months after therapy. Thyroid function may normalize or decrease to below the normal range in this time period, but the nodule may still be palpable in perhaps half the patients. Occasionally, a second or even a third dose of radioiodine is required to render a patient euthyroid. It is recommended to wait at least six months after the initial dose before considering retreatment with radioiodine. Persistent or recurrent hyperthyroidism can be expected in approximately 10% of patients, with studies revealing a range of 0% to 41.3% (279,301,302).

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Following radioiodine therapy, hypothyroidism occurs at an average of approximately 10% within the first year, with an annual rate thereafter of approximately 3% (297,303,304). This occurrence rate may relate to the fact that the contralateral normal tissue is exposed to significant amounts of radiation (279). Underlying autoimmune thyroid disease may also predispose to the development of hypothyroidism. Larger doses of 131 I appear to be a causative factor in studies finding a substantial rate of hypothyroidism. The dose per gram of thyroid tissue, percent radioactive iodine uptake, pre- and/or posttreatment with antithyroid medications, and recent iodine exposure all may affect the outcome. In a retrospective analysis of 45 patients with toxic adenomas receiving an average of 10.3 ± 3.5 mCi of 131 I, euthyroidism was achieved in 91% and 93% at 6 and 12 months, respectively (302), and no patients became hypothyroid. Three patients had recurrent hyperthyroidism between 4.5 to 10 years and became hypothyroid after a second therapy. However, two other studies found that 35% and 36% of patients became hypothyroid following the first dose of 131 I, with an average follow-up of 3.8 years and 8.5 years, respectively (303,305). Of note, these two studies used a mean 131 I dose of 29.1 mCi and 23 ± 10 mCi. Higher doses are associated with more prompt achievement of euthyroidism or hypothyroidism. 131 I is tolerated well by the majority of patients, although radiation thyroiditis with or without exacerbation of the underlying thyrotoxicosis can occur. Repeat scintigraphic scanning following radioactive iodine therapy may reveal relatively normal thyroid distribution of tracer, the nodule may be cold, warm, or hot in relation to the other tissue, or the autonomous nodule may remain evident with continued suppression of extranodular tissue. In the latter case, the serum TSH level will remain suppressed. Surgery can also be performed to remove the affected lobe and isthmus, leaving the remaining lobe intact (278,281,306). In experienced hands, surgery has a low anesthetic risk and a low surgical complication rate of vocal cord paralysis and hypoparathyroidism, especially if only a lobectomy rather than a thyroidectomy is performed (306). Removal of the nodule alone or only a portion of the affected lobe including the nodule is not recommended. Recurrence following surgery is unusual. Multifocal autonomous nodules not appreciated on the initial evaluation, and therefore not surgically removed, might be responsible for some failures. Euthyroidism can be achieved relatively quickly with surgical intervention, although hypothyroidism may occur. The hypothyroidism may be secondary to inadequate residual thyroid tissue or possibly underlying autoimmune thyroid disease. Although controversial, some experts recommend that patients who have had a lobectomy and isthmusectomy be placed on lifelong thyroxine therapy. The use of thyroxine therapy has not been proven to be effective in decreasing growth of thyroid nodules on the contralateral side. However, following a thyroid lobectomy, the risk of developing hypothyroidism is relatively high, being 14% in one study (307). Hedman et al. (307) followed up 95 patients an average of 15 years after thyroid lobectomy had been performed. Nine percent of patients had an elevated TSH with normal serum thyroxine and an additional

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5% of patients had hypothyroidism with elevated TSH and decreased T4. This complication can develop in the immediate postoperative period or may develop after many ensuing years. Periodic clinical examinations and thyroid function tests are needed, regardless of whether or not an individual patient is receiving L-thyroxine therapy. Percutaneous ethanol injection (PEI) is an alternative therapeutic option in patients with an autonomous thyroid nodule. Ethanol (95% to 98%) is injected into the autonomous nodule using a 22-gauge needle under sonographic guidance (308,309). Special attention is given to avoiding leakage of ethanol into the extranodular tissue, which, should it occur, may cause serious complications. Other potential complications of PEI include pain at the local injection site, dysphonia (usually transient), exacerbation of thyrotoxicosis, fever, and hematoma. A case of severe toxic necrosis of the larynx and associated necrotic dermatitis has been reported following ethanol injection of a thyroid nodule (310). Nodules ⬎30 mL in volume are more resistant to this therapy, having almost half the cure rate of smaller nodules. Centers experienced in this modality note that approximately four to eight treatments may be required to achieve success. The total volume of ethanol delivered is usually one and a half times the nodule volume, and 1 to 8 mL is administered in weekly sessions over a 2- to 12-week time frame. A multicenter study (308) reported a success rate six months after PEI of 77.5% and 61.1% in toxic adenomas and “pretoxic” adenomas, respectively. By 12 months, rates of 83.4% and 66.5% can be expected for toxic and pretoxic adenomas. Successful resolution of hyperthyroidism and nodule autonomy can be expected between 3 and 12 months following PEI, with the majority achieving “cure” within the first 6-month period. Further studies assessing the utility of ethanol injection need to be performed. PEI is operator-dependent, requires multiple sessions, and is less effective in larger nodules. Also, there appears to be relatively little experience with this therapy in the United States. Therefore, its use should be limited to experienced clinicians and medical centers in selected circumstances.

TOXIC MULTINODULAR GOITER Introduction A toxic multinodular goiter is a thyroid gland that contains at least two autonomous functioning thyroid nodules that secrete excessive amounts of thyroid hormone, suppressing serum TSH and often causing typical symptoms and signs of hypermetabolism (311). These nodules may be more or less distinct on clinical examination and scan. Autonomous nodules require many years to develop and transition through a phase when the TSH is normal and then subnormal with minimal clinical evidence of hyperthyroidism (subclinical hyperthyroidism). Because of the time required for this process to develop, most patients with toxic multinodular goiter are over the age of 50. Many clinical aspects of patients with toxic multinodular goiters are similar to those found in those with solitary autonomous nodules

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A

B

Figure 7 (A and B) An elderly patient with a toxic multinodular goiter. It is frequently difficult to discern by clinical examination the extent of substernal extension of the thyroid gland (330).

(Figs. 7 and 8). For example, exogenous iodine exposure can precipitate or aggravate thyrotoxicosis (298). A recent analysis has suggested that the likelihood of a toxic multinodular goiter harboring thyroid cancer was 9%, a value relatively similar to the reported incidence of 10.6% in patients with a nontoxic multinodular goiter (312) but lower (3.9%) than in Graves’ disease (6.5%) (313).

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Figure 8 Thyroid radioisotope scans may be helpful in assessing certain patients with hyperthyroidism. Panel A demonstrates symmetric isotope distribution (pertechnetate technetium 99 m) typical of a patient with Graves’ disease. The right lobe appears larger than the left because of rotation. Panel B shows an autonomous functioning thyroid nodule. There is intense activity in the left-lobe nodule with absent activity in the right lobe because of suppression of TSH by thyroid hormone secretion of the nodule. Panel C shows a toxic multinodular goiter. Radioactive isotope activity is heterogenous, with areas of intense activity interspersed with areas of reduced activity (330).

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Pathogenesis The pathogenesis of toxic multinodular goiter is not known, although it is believed that individual thyroid follicles preferentially proliferate. Follicular size, colloid content, and cellular characteristics vary widely in different parts of the multinodular goiter. Indeed, marked cellular variation is the hallmark of multinodular goiters. It is believed that most of these nodules are clonal in origin. It is unknown how particular nodules grow and become autonomous. There are two theories concerning the etiology of multinodular goiters. In the first, it is hypothesized that hyperplastic nodules result from chronic activation by external factors such as TSH, iodide, IGF-1, or thyroid growth–stimulating immunoglobulins (314,315). These factors then cause the growth of polyclonal nodules. This theory does not have widespread support, since trophic hormonal stimulation is not generally thought to result in autonomous growth. The more widely held view is that several individual clones develop, perhaps related to a genetic mutation, and that these cells gradually grow, become autonomous, and finally result in excess hormonal secretion (316–319). A rare entity, McCune-Albright syndrome, may be associated with the presence of a toxic multinodular goiter due to a mutation in the gene encoding the Gs protein alpha subunit which couples transmembrane-domain receptors to adenyl cyclase. This results in constitutive activation of adenyl cyclases and overproduction of cAMP. This syndrome is also associated with precocious puberty, fibrous dysplasia of bone, abnormal gonadal function, and caf´e-au-lait spots on the skin (320). These patients may have a higher risk of thyroid cancer (320). Diagnosis Patients present with typical clinical and biochemical hyperthyroidism and small, medium-sized, or large multinodular goiters. There is nothing particularly unusual about their presentation, signs, or symptoms compared to patients with other causes of hyperthyroidism, except the nodules and goiter may be sufficiently large to cause local compressive symptoms. The radionuclide scan shows heterogenous uptake with areas of hyper- and hypointensity (Fig. 8). There is a spectrum of disease, ranging from minimal thyroid enlargement with small thyroid nodules only detected on scan or sonogram to markedly enlarged thyroid glands and large nodules. Color flow Doppler sonography may also be useful especially in helping to differentiate nodular variants of Graves’ disease from toxic multinodular goiters that are nonautoimmune mediated (321). Some multinodular goiters have a significant substernal component. Treatment Radioiodine and surgery are the two major treatment modalities in patients with toxic multinodular goiters, (311,322–324). Because multinodular goiters probably are not responding to serum anti-TSH receptor immunoglobulins, it is not considered possible to induce a long-term remission with the chronic use of antithyroid

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agents. It may be appropriate to render a patient euthyroid with the use of antithyroid agents prior to radioiodine therapy, especially patients older than 60 years or those with underlying heart disease. Selected patients can be maintained on these agents for an indefinite period of time, for example, elderly patients with accompanying serious medical disorders. However, this approach is applicable to a minority of patients with toxic multinodular goiters. Radioiodine therapy is most often used to restore euthyroidism or induce hypothyroidism (322,323). 131 I therapy is generally thought to be less reliable in controlling the hyperthyroidism, compared with Graves’ disease, and higher doses are usually required (approximately 20–30 mCi 131 I). The explanation for the difference in responses between Graves’ disease and toxic multinodular goiter is unknown, but probably relates to the fact that there are different degrees of autonomy and radiosensitivity among cells comprising the multinodular goiter. The dose of 131 I varies, but it is reasonable to attempt to deliver approximately 160 to 200 ␮C 131 I/g thyroid tissue. In one recent study, following 131 I treatment for a toxic multinodular goiter, 62% of patients were euthyroid, 19% hypothyroid and 19% remained hyperthyroid. The mean size reduction overall was 32% (325). It is often difficult to estimate the size of multinodular goiters, especially because they may have a substernal component. A thyroid sonogram is helpful if the gland is cervical in location, and CT scanning (without intravenous contrast) is useful for estimating the size of a large multinodular goiter with substernal extension. It is difficult to predict the response to a given dose of 131 I; in one study, the cure rate was relatively similar to that seen in Graves’ disease (325,326), but others have not found similar degrees of success (327). Release of preformed and stored thyroid hormones can occur after a dose of 131 I, so that these patients, who are typically older, should be carefully monitored carefully. Not unexpectedly, smaller thyroid glands seem to respond more consistently than larger glands, although there is wide variation. Elderly patients or those with associated medical disorders or heart disease should be treated with antithyroid agents prior to administering 131 I, as this is thought but not proven to reduce the chance of radioiodine-induced worsening of the hyperthyroidism. However, thionamide exposure may cause a higher failure rate of radioiodine therapy (180), so higher doses of radioiodine should be employed. A near total thyroidectomy represents an alternative therapeutic option (327,328). This procedure must be performed by an experienced thyroid surgeon, but even in this circumstance there is a risk of hypocalcemia and recurrent laryngeal nerve paralysis as well as, in unusual circumstances, acute release of stored thyroid hormone, with an exacerbation of hyperthyroidism. It is important to establish a euthyroid state prior to surgery. The procedure of choice is a near total thyroidectomy to remove as much thyroid tissue as the surgeon is comfortable with, and to preserve the parathyroid glands and the recurrent laryngeal nerves. Some clinicians prefer that patients be given thyroxine therapy postoperatively, even if they have sufficient thyroid tissue remaining to prevent hypothyroidism.

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This approach is controversial since, except for patients who have received external radiation therapy in the past, thyroid hormone treatment to euthyroid patients has not been proven to decrease the likelihood of recurrent nodule formation (329). It does obviate the possibility of severe hypothyroidism developing, but periodic monitoring is required whether or not thyroxine therapy is used. Although therapy should be individualized and discussed with patients and their families as appropriate, most patients with hyperthyroidism due to a multinodular goiter should be treated with 131 I therapy. Antithyroid agent therapy may be useful for patients with smaller glands with less severe hyperthyroidism; longterm antithyroid agent therapy should be reserved for selected patients. Surgery addresses the problem expeditiously and can be used quite effectively; it should be considered for patients with very large thyroid glands (above 150–200 g) since the likelihood of such patients responding to 131 I therapy is lower. Compressive symptoms such as hoarseness, superior vena caval syndrome, dysphagia, and/or dyspnea are additional indications for surgery. However, in patients who are not surgical candidates, radioiodine should be used. REFERENCES 1. Burman KD, Baker JR Jr. Immune mechanisms in Graves’ disease. Endocr Rev 1985; 6:183–232. 2. Rapoport B, McLachlan SM. The thyrotropin receptor in Graves’ disease. Thyroid 2007; 17:911–922. 3. Burman K. Hyperthyroidism. In: Becker KA, ed. Principles and Practice of Endocrinology and Metabolism, 2nd ed. Philadelphia, PA: J. B. Lippincott Co., 1995:367–385. 4. Burman KD, Pandian R. Clinical utility of assays for TSH receptor antibodies. The Endocrinologist 1998; 8:284. 5. Burch HB, Wartofsky L. Graves’ ophthalmopathy: Current concepts regarding pathogenesis and management. Endocr Rev 1993; 14:747–793. 6. Bahn RS. Clinical review 157: Pathophysiology of Graves’ ophthalmopathy: The cycle of disease. J Clin Endocrinol Metab 2003; 88:1939–1946. 7. Chen FQ, Okamura K, Sato K, et al. Reversible primary hypothyroidism with blocking or stimulating type TSH binding inhibitor immunoglobulin following recombinant interferon-alpha therapy in patients with pre-existing thyroid disorders. Clin Endocrinol (Oxf) 1996; 45:207–214. 8. Burman K, Becker. K, Cytryn A, Goodglick T. Thyroid Diseases. Philadelphia, PA: Current Medicine, 1999. 9. Kasagi K, Hidaka A, Nakamura H, et al. Thyrotropin receptor antibodies in hypothyroid Graves’ disease. J Clin Endocrinol Metab 1993; 76:504–508. 10. Kraiem Z, Baron E, Kahana L, et al. Changes in stimulating and blocking TSH receptor antibodies in a patient undergoing three cycles of transition from hypo to hyper-thyroidism and back to hypothyroidism. Clin Endocrinol (Oxf) 1992; 36:211– 214. 11. Mengistu M, Lukes YG, Nagy EV, et al. TSH receptor gene expression in retroocular fibroblasts. J Endocrinol Invest 1994; 17:437–441.

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314. Joba W, Spitzweg C, Schriever K, et al. Analysis of human sodium/iodide symporter, thyroid transcription factor-1, and paired-box-protein-8 gene expression in benign thyroid diseases. Thyroid 1999; 9:455–466. 315. Kimura ET, Kopp P, Zbaeren J, et al. Expression of transforming growth factor beta1, beta2, and beta3 in multinodular goiters and differentiated thyroid carcinomas: A comparative study. Thyroid 1999; 9:119–125. 316. Tonacchera M, Vitti P, Agretti P, et al. Activating thyrotropin receptor mutations in histologically heterogeneous hyperfunctioning nodules of multinodular goiter. Thyroid 1998; 8:559–564. 317. Tonacchera M, Chiovato L, Pinchera A, et al. Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma. J Clin Endocrinol Metab 1998; 83:492–498. 318. Gabriel EM, Bergert ER, Grant CS, et al. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. J Clin Endocrinol Metab 1999; 84:3328–3335. 319. Holzapfel HP, Wonerow P, von Petrykowski W, et al. Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab 1997; 82:3879–3884. 320. Chanson P, Salenave S, Orcel P. McCune-Albright syndrome in adulthood. Pediatr Endocrinol Rev 2007; 4(suppl 4):453–462. 321. Boi F, Loy M, Piga M, et al. The usefulness of conventional and echo colour Doppler sonography in the differential diagnosis of toxic multinodular goitres. Eur J Endocrinol 2000; 143:339–346. 322. Huysmans DA, Buijs WC, van de Ven MT, et al. Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters. J Nucl Med 1996; 37:2072–2079. 323. Hurley DL, Gharib H. Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996; 29:527–540. 324. Pradeep PV, Agarwal A, Baxi M, et al. Safety and efficacy of surgical management of hyperthyroidism: 15-year experience from a tertiary care center in a developing country. World J Surg 2007; 31:306–312; discussion 13. 325. Tarantini B, Ciuoli C, Di Cairano G, et al. Effectiveness of radioiodine (131-I) as definitive therapy in patients with autoimmune and non-autoimmune hyperthyroidism. J Endocrinol Invest 2006; 29:594–598. 326. Franklyn JA, Daykin J, Holder R, et al. Radioiodine therapy compared in patients with toxic nodular or Graves’ hyperthyroidism. QJM 1995; 88:175–180. 327. Erickson D, Gharib H, Li H, et al. Treatment of patients with toxic multinodular goiter. Thyroid 1998; 8:277–282. 328. Jensen MD, Gharib H, Naessens JM, et al. Treatment of toxic multinodular goiter (Plummer’s disease): Surgery or radioiodine? World J Surg 1986; 10:673–680. 329. Fogelfeld L, Wiviott MB, Shore-Freedman E, et al. Recurrence of thyroid nodules after surgical removal in patients irradiated in childhood for benign conditions [see comments]. N Engl J Med 1989; 320:835–840. 330. Morris JC, ed. Hyperthyroidism from Toxic nodules and other Causes. Philadelphia, PA: Current Medicine, 1999.

3 Thyroiditis and Other More Unusual Forms of Hyperthyroidism Shon E. Meek and Robert C. Smallridge College of Medicine, Mayo Clinic, Jacksonville, Florida, U.S.A.

THYROIDITIS AND HYPERTHYROIDISM Subacute Thyroiditis Introduction Subacute thyroiditis is a painful, inflammatory thyroid condition associated with thyrotoxicosis. In the past, it has also been called granulomatous thyroiditis, giantcell thyroiditis, noninfectious thyroiditis, acute nonsuppurative thyroiditis, and de Quervain’s thyroiditis. Epidemiology Subacute thyroiditis is not nearly as common as Graves’ disease, but it is more common than silent thyroiditis if postpartum thyroiditis is excluded. It has been reported to occur at the rate of one in five to eight cases of Graves’ disease (1). In Olmsted County, Minnesota, subacute thyroiditis occurred at a rate of 4.9 cases per 100,000/yr (2). Subacute thyroiditis has been reported in North America, Europe, Scandinavia, and Japan, but it is not often reported in the tropical and subtropical areas of the world. In Hawaii, subacute thyroiditis is seen at the same rate among Caucasians and Japanese indicating a similar prevalence among these two races living in the same environment (3). It is not known whether 101

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the lack of occurrence in the tropical and subtropical areas is due to a lower actual frequency or ascertainment bias. However, despite the possible geographic variation, subacute thyroiditis is recognized more frequently during the summer months (4,5). Subacute thyroiditis has been reported in all age groups. It is most common in the third to sixth decades of life, and it is rare in children. Female patients outnumber male patients in a ratio of up to 6:1 (6–8). Pathophysiology The cause of subacute thyroiditis is not known; however, it tends to occur following an upper respiratory tract infection. Mumps, measles, influenza, common colds, adenovirus, Epstein-Barr virus, coxsackievirus, and cat-scratch disease have all been associated with subacute thyroiditis (9–15). Subacute thyroiditis is associated with HLA-B35, approximately 72% of the time (14,16). Subacute thyroiditis has been reported in twins and family members (17,18). Infiltrative diseases, such as amyloid, have also been reported to cause a subacute thyroiditis–like picture (19), and anaplastic thyroid cancer can rarely begin with painful, rapid thyroid enlargement known as “malignant pseudothyroiditis” (20,21). Thyroiditis induced by amiodarone can also occasionally present with a similar clinical picture. The thyroid gland in subacute thyroiditis is enlarged and firm; it may adhere to adjacent tissues. Thyroid tissue obtained by fine-needle aspiration (FNA) biopsy shows an inflammatory infiltrate of neutrophils, lymphocytes, histiocytes, and multinucleated giant cells (22–24). Diagnosis Patients with subacute thyroiditis usually present with an acute onset of malaise, feverishness, and pain in the region of the thyroid gland. The pain may radiate from the thyroid to the jaw and to the ears, or down to the anterior chest wall. Coughing, swallowing, turning the head, or wearing tight clothing around the neck can aggravate the pain. Approximately one-third to one-half of patients may present with unilateral thyroid pain. Approximately one-third of patients can have migratory pain throughout the thyroid, so-called “creeping thyroiditis”. Approximately one-third of cases may present with diffuse pain in the thyroid (1,15,25). Some biopsy-proven cases of subacute thyroiditis have been reported to be painless (23,26,27). Many patients may have systemic symptoms of malaise, myalgia, fever, and anorexia. As noted above, approximately 50% of patients may have a history of an antecedent upper respiratory infection. Symptoms of thyrotoxicosis are also present in 50% to 60% of patients, and these may include heat intolerance, palpitations, tremor, and nervousness. Cases of subacute thyroiditis causing thyroid storm have been reported (28). Physical examination shows an uncomfortable patient with a tender, enlarged, and firm thyroid gland. The process is often asymmetric, and lymphadenopathy is usually not present. Symptoms of thyrotoxicosis may last 4 to

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Figure 1 The graph correlates the time from the beginning of pain to the disappearance of pain and palpable abnormalities in 70 patients observed through the course of the disease. In all instances, pain and tenderness ceased first. The mean duration of pain was 65 days versus 84 days for palpable abnormalities. Source: From Ref. 3.

10 weeks, but the inflammation with a painful, tender thyroid often lasts for eight weeks, and on rare occasions, up to one year. Pain and tenderness resolve first, followed by resolution of the palpable thyroid abnormalities, as shown in Figure 1 (3). If the patient is not seen until late in the course of the disease and after pain resolves, the discovery of a thyroid nodule as the residual of lobar enlargement may lead to unnecessary surgery, unless an FNA is performed. Laboratory evaluation shows increased serum levels of thyroxine (T4) and triiodothyronine (T3) due to follicular disruption, with release of stored thyroid hormones and thyroglobulin into the systemic circulation. The T4/T3 ratio is typically higher than in Graves’ disease, reflecting glandular hormone stores. The serum TSH level is suppressed (29). The white blood cell count is usually normal, but it may be moderately increased. The erythrocyte sedimentation rate is virtually always increased, often to as high or higher than 100 mm/hr (15,25). Thyroid autoantibodies are usually absent or present in low titer, and if present, they are usually transient. The 24-hour radioactive iodine uptake is very low. As the course of subacute thyroiditis progresses, the serum concentration of thyroid hormones returns to normal. In more severe cases, transient hypothyroidism develops (30). Thyroid function usually returns to normal, but permanent hypothyroidism may occur in 15% of patients with extended follow-up. Patients treated with corticosteroid therapy may develop hypothyroidism more commonly than those not treated with corticosteroids (2). Recurrent bouts of subacute thyroiditis may occur in 4%of patients, 6 to 21 years after the initial episode (2). Figure 2 shows the typical phases of thyroid function during subacute thyroiditis.

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Figure 2 Natural history of subacute thyroiditis.

Treatment Nonsteroidal anti-inflammatory drugs (NSAIDs) or salicylates (2 g/day) are used initially to treat subacute thyroiditis (31,32). However, corticosteroids are used for more severe cases or in patients not responding to NSAIDs, and result in rapid clinical improvement (33). Corticosteroids produce partial or near complete relief of pain and neck tenderness within 24 to 48 hours. If symptoms do not respond promptly, an alternate diagnosis, such as acute infectious thyroiditis, should be considered. Typically, prednisone in an initial dose of 40 mg/day is used for about a week, followed by a tapering dose of 10 mg/wk and withdrawal by four weeks. As the drug is tapered, exacerbation of pain may occur in approximately 20% of patients (8,32). If this occurs, the dose can be increased and treatment continued for another month. In extremely rare cases, neck pain and malaise may be prolonged. In these cases, thyroidectomy may be needed (34). Beta-adrenergic antagonist drugs may be helpful in controlling symptoms of thyrotoxicosis. However, they are not usually needed because corticosteroids or NSAIDs usually alleviate thyrotoxicosis as well as the thyroid pain.

Silent Thyroiditis Introduction Silent or “painless” thyroiditis is a painless inflammation of the thyroid that produces a transient hyperthyroid state (35). The terms silent thyroiditis and painless thyroiditis are used most commonly to describe this condition. However, silent thyroiditis has also been called transient painless thyroiditis, painless thyroiditis with transient hyperthyroidism, painless subacute thyroiditis, atypical thyroiditis, occult subacute thyroiditis, lymphocytic thyroiditis, spontaneously resolving lymphocytic thyroiditis, and transient thyrotoxicosis with lymphocytic thyroiditis. Silent thyroiditis often occurs in the postpartum period, and is then called postpartum thyroiditis.

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Epidemiology The incidence of painless thyroiditis was reported with increasing frequency in the late 1970s and early 1980 s in the Great Lakes region of the United States and Canada. Silent thyroiditis has also been reported in South America, India, and Japan. However, it has been reported to be less frequent on the east and west coasts of the United States and in Europe and Argentina (36). Patients are usually between 30 and 60 years of age, but silent thyroiditis can occur in all age groups. There is a female-to-male predominance of approximately 1.5 to 1. There is an 11% chance that patients may have recurrent episodes of silent thyroiditis (37). Pathophysiology In most cases, silent thyroiditis is an autoimmune disease and likely a variant of Hashimoto’s thyroiditis. Histologically, silent thyroiditis is characterized by a lymphocytic infiltration of the thyroid, and it is sometimes associated with lymphoid follicles (38,39). It is associated with other autoimmune diseases, such as autoimmune adrenal insufficiency, lupus erythematosus, idiopathic thrombocytopenic purpura, and rheumatoid arthritis (40–43). Silent thyroiditis has been associated with HLA DR3, which suggests a genetic component to the disease (44). Thyroid autoantibodies are present in the serum in up to 50% of patients, which suggests an autoimmune process (35). No association with a viral infection has been found. However, the lack of antibodies in some patients and lack of clear female predominance suggests that silent thyroiditis maybe a heterogeneous disorder. Diagnosis Patients with silent thyroiditis present with symptoms and signs of thyrotoxicosis. The most common symptoms include palpitations, weight loss, nervousness, heat intolerance, and fatigue. The thyrotoxic phase may last from 1 to 12 months, but it usually lasts about 3 months. Approximately one-half of patients have a goiter, in which the thyroid is 1.5 to 3 times the normal size, diffusely enlarged, symmetric, firm, and nontender (35). The course of the disease typically follows three different phases. The first phase is characterized by hyperthyroidism, and many, but not all patients will go on to develop hypothyroidism as a second stage of silent thyroiditis. Most patients then become euthyroid in the third stage, but permanent hypothyroidism may develop months to years later. During the first phase of silent thyroiditis, the serum T4 and T3 levels are increased and serum TSH is decreased. The T4/T3 ratio is higher in silent thyroiditis than in Graves’ disease, reflecting glandular hormonal stores. The radioactive iodine uptake is very low. Thyroglobulin levels are increased, which may be useful in distinguishing silent thyroiditis from factitious thyrotoxicosis. Serum thyroglobulin concentrations may remain slightly increased even one to two years after recovery of normal thyroid function (45). Thyroid autoantibody levels are increased approximately 30% to 50% of the time. However, approximately

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50% of the positive antibody titers become negative within six months after thyroid recovery (35,37). The white cell count is usually normal. The sedimentation rate is normal in ⬎50% of cases, with only mild elevation in the remaining cases (46). FNA of the thyroid shows lymphocytic infiltration, but aspiration is rarely needed to make the diagnosis. Biopsies show that silent thyroiditis lacks some of the features of chronic lymphocytic thyroiditis, such as no H¨urthle cells or germinal centers (38). Patients with silent thyroiditis have a low radioactive iodine uptake, which distinguishes it from states of high radioactive iodine uptake such as Graves’ disease or toxic nodular goiter. Silent thyroiditis, with its low radioactive iodine uptake, must be distinguished from iodine-induced thyrotoxicosis, excess thyroid hormone ingestion, and amiodarone-induced thyrotoxicosis (AIT). In addition, struma ovarii can cause a low radioactive iodine uptake over the thyroid, but in these cases, uptake over the ovarian tumor will also be increased. Thyroid hormone levels decrease during the hypothyroid phase and then return to normal during the recovery phase. TSH levels often rise transiently in the recovery phase. The radioactive iodine uptake may also rise transiently above the normal range during the recovery phase of silent thyroiditis. Treatment As silent thyroiditis usually presents with mild to moderate symptoms of hyperthyroidism, treatment to relieve symptoms may not be necessary. For patients who are more than mildly symptomatic, beta-adrenergic blocking agents can be administered. Antithyroid drugs are not useful because destroying thyroid cells releases thyroid hormones, causing the thyrotoxic phase of silent thyroiditis. If severe thyrotoxicosis is present, corticosteroids can be administered to decrease the inflammatory process (46). Patients have rarely been treated with thyroidectomy when they have had frequent debilitating episodes of silent thyroiditis (39,46). Once normal thyroid function returns with a normal radioiodine uptake, patients with recurrent episodes of silent thyroiditis may consider radioactive iodine ablation of the thyroid. The hypothyroid phase of silent thyroiditis usually does not need to be treated since it is usually quite mild, and most patients fully recover normal thyroid function, at least initially. However, if the hypothyroid stage is severe or prolonged, thyroxine can be administered for several months. Almost all patients recover normal thyroid function after an episode of silent thyroiditis, but since approximately 50% of patients with silent thyroiditis will ultimately develop hypothyroidism, thyroid function should be monitored yearly (46). Postpartum Thyroiditis Introduction Postpartum thyroiditis is a syndrome of thyroid dysfunction that occurs within the first year following parturition. It is usually characterized by transient painless

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thyrotoxicosis with a low radioactive iodine uptake, often followed by a hypothyroid phase that is then followed by thyroid recovery. However, many postpartum thyroiditis patients ultimately develop permanent hypothyroidism within a few years (47). Epidemiology Postpartum thyroiditis has been reported in North America, South America, Europe, and Asia. An average prevalence figure of about 5% to 9% of postpartum women has been generally accepted (48–55). The lower frequency of 1.1% in Asia may be related to variations in regional, dietary iodine intake or genetic differences in susceptibility (56). Approximately 10% of women in the general population have positive antibodies and approximately one-half of these patients develop postpartum thyroiditis. An increased incidence of postpartum thyroiditis (10–25%) is found among patients with type 1 diabetes mellitus, reflecting the underlying autoimmune diathesis (57–59). Postpartum thyroid dysfunction has also been reported after a miscarriage, although, this case only had postmiscarriage hypothyroidism (60). Pathophysiology Women who are prone to developing postpartum thyroiditis most likely have preexisting, asymptomatic autoimmune thyroiditis. During pregnancy, the maternal immune system is partially suppressed, with a subsequent rise in thyroid autoantibodies after delivery. Studies have shown that higher thyroid antibody levels are associated with a higher risk of thyroid dysfunction and clinical symptoms (61–64). Postpartum thyroiditis has also been related to HLA type. HLA-DR3, -DR4, and -DR5 are increased in patients with postpartum thyroiditis (65–68). Biopsy specimens of thyroid tissue during postpartum thyroiditis have shown a lymphocytic infiltration (52). Smoking was associated with postpartum thyroiditis in two studies, (48,69) but it was not associated with smoking in three other studies (53,70,71). Several studies have shown postpartum thyroiditis to be associated with the presence of goiter during pregnancy (50,61,72). One study using ultrasound showed a significant increase in thyroid volume between 8- and 20-weeks’ gestation in women who went on to develop postpartum thyroiditis (73). However, a prospective study using ultrasound found that thyroid size, before, during, or after pregnancy, was not a useful indicator for the development of postpartum thyroiditis (70). Therefore, even though postpartum thyroiditis may be associated with a goiter, the presence of a goiter is not a predictive indicator for postpartum thyroiditis. Diagnosis Patients with postpartum thyroiditis may present with fatigue, palpitations, heat intolerance, nervousness, emotional liability, and other hyperthyroid symptoms.

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Hypothyroid 40%

Hyperthyroid-Thyroiditis 24%

HyperthyroidGraves’ 11%

Hyper/Hypothyroid 25%

Figure 3 Frequency of hyperthyroidism, hypothyroidism, or both in postpartum thyroid dysfunction.

Many patients will have some enlargement of the thyroid. Postpartum thyroiditis is almost universally painless, although one case of painful disease has been reported (74). In postpartum thyroiditis, there is an absence of exophthalmos and, almost always, an increase in antithyroid antibody titers. Patients may present at a time when thyroid hormones levels are high, normal, or low. Since the hyperthyroid phase is a destructive type of thyroiditis, there is a low 24-hour radioactive iodine uptake. Figure 3 shows the frequency of hyperthyroidism, hypothyroidism, or both in postpartum thyroid dysfunction. The classical triphasic pattern of postpartum thyroiditis is mild hyperthyroidism followed by transient hypothyroidism with subsequent thyroid recovery. This pattern of postpartum thyroiditis occurs in 25% of patients. The thyrotoxic phase usually presents one to six months postpartum. Frequently, a period of hypothyroidism develops over the next three to four months, followed by a return to normal thyroid function. Some patients with postpartum thyroiditis only develop transient hyperthyroidism without subsequent hypothyroidism. This can either take the form of thyroiditis-induced hyperthyroidism in approximately 24% of patients or hyperthyroidism caused by Graves’ disease in approximately 11% of patients. Some patients (40%) with postpartum thyroiditis present only with hypothyroidism that is followed by recovery of thyroid function (75). Figure 4 shows the possible stages of thyroid function in the natural history of postpartum thyroiditis. All patients with postpartum thyroiditis should be monitored for the future development of thyroid failure. Approximately 20% to 64% of patients with transient thyroid disease postpartum become hypothyroid with long-term follow-up (62,65,66,76,77). Factors associated with the development of permanent hypothyroidism include higher titer of thyroid autoantibodies, greater severity of the hypothyroid phase of postpartum thyroiditis, and a previous history of spontaneous abortion (74,76). Microsomal and thyroid peroxidase antibodies have been reported to have a sensitivity range of 0.45 to 0.89 and a specificity range of 0.9 to 0.98 (75).

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Figure 4 Natural history of postpartum thyroiditis.

Treatment Treatment of the thyrotoxic phase of postpartum thyroiditis is often not needed, since the symptoms are usually mild. Beta-adrenergic blocking drugs can be used in symptomatic patients, but should be used with caution in lactating women. The beta-adrenergic blocking drug can be tapered as the thyrotoxic phase resolves. If symptoms are mild and transient, then the hypothyroid phase can also be observed without treatment. If the hypothyroid stage is severe or prolonged, thyroxine should be administered for 6 to 12 months. After several months, the thyroid hormone can be withdrawn and the serum TSH measured to see if the patient is euthyroid. Even if full thyroid recovery occurs, patients with a history of postpartum thyroiditis should be followed long-term for possible development of permanent hypothyroidism. Some authors prefer to keep women on thyroid hormone therapy until they are finished having children. Since postpartum thyroiditis can recur in up to 80% of subsequent pregnancies, future pregnancies should also be monitored (75). Negro et al. treated 85 euthyroid antibody positive women in the first trimester of pregnancy with selenium, 200 ␮g daily starting at 12-weeks gestation, versus placebo. Postpartum thyroiditis developed significantly less frequently in the women administered selenium than in women given placebo (28.6 vs. 48.6% p ⬍ 0.01) (78). This study will require confirmation and determination of possible adverse effects before selenium can be recommended. Acute Infectious Thyroiditis Introduction Infectious thyroiditis is an inflammatory process caused by invasion of the thyroid by bacteria, mycobacteria, fungi, protozoa, or flatworms. Infectious thyroiditis may rarely cause thyrotoxicosis.

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Epidemiology Infectious thyroiditis is a rare disorder. The thyroid is felt to be relatively resistant to infection because of its vascularity, its large concentration of iodine, the presence of hydrogen peroxide, and its encapsulation. Infectious thyroiditis may be more prevalent in the pediatric age group (79). Pathophysiology Many different bacteria can infect the thyroid including Streptococcus, Staphylococcus, Pneumococcus, Salmonella, Bacteroides, Pasteurella, (80) and Treponema pallidum (81). Mycobacterium tuberculosis (82) and several fungi, including Coccidioides immitis, Aspergillus, and Candida albicans (83), have been associated with thyroiditis. Pneumocystis carinii may also cause infectious thyroiditis (84). Patients who are immunocompromised or have acquired immunodeficiency syndrome are at particular risk for infectious thyroiditis. Most often, this infection is caused by a direct extension of an internal fistulous tract between the pyriform sinus and the thyroid (85,86). This tract is more common in children and may represent the course of migration of the ultimobranchial body from its embryonic origin in the fifth pharyngeal pouch. This extension tends to develop more commonly in the left thyroid lobe than in the right. However, infection in the thyroid may occur in a normal thyroid, multinodular goiter, or in a degenerating thyroid nodule as well. Immunocompromised patients may have a higher risk of infectious thyroiditis (87). Infectious thyroiditis has also been reported to occur after FNA by staphylococcus aureus in a patient with atopic dermatitis (88). Diagnosis Patients with infectious thyroiditis usually present with pain and may have a swollen, hot, and tender thyroid (94%) (81). As a result, affected individuals may avoid extension of their neck due to pain, swallowing may be painful, and dysphagia may be present (91%) (81). They may also present with signs of infection in adjacent tissues, cervical lymphadenopathy, and systemic signs of fever and chills (92%) (81). Laboratory data include an increased white blood cell count and increased sedimentation rate. The patient may have increased thyroid hormone levels and present with symptoms of thyrotoxicosis, due to hormonal release from the thyroid (80,89). In one review, 12 of 56 cases had laboratory data suggesting hyperthyroidism (81). However, most patients are biochemically euthyroid, and the radioactive iodine uptake will usually be normal. Thyroid ultrasound or computed tomography (CT) scan of the neck may show a local abscess that can be aspirated and cultured to make the diagnosis (90). A barium swallow can be obtained to evaluate for possible predisposing factors such as a fistulous tract between the pyriform sinus and the thyroid.

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Treatment Treatment depends on the identification of the organism causing the infection. Aspiration of the thyroid should be obtained with appropriate Gram stain and culture of the material. Systemic antibiotics, which are tailored to the specific infectious agent, are administered (79). An abscess will require surgical exploration and drainage, and fistulae also require surgery to prevent recurrent infection (91). Radiation Thyroiditis Introduction Radioactive 131 I and external beam radiation are used to treat thyroid disease. Radiation thyroiditis with a thyrotoxic phase has been reported following radiation treatment with both forms of radiation therapy. Epidemiology Radiation thyroiditis from 131 I occurs in approximately 20% of patients receiving ≥50,000 rads (50 Gy) to ablate residual normal thyroid tissue (92). It is more common with larger thyroid remnants. Transient increases in thyroid hormone are commonly seen in hyperthyroid patients treated with radioactive iodine. However, clinically significant exacerbation of hyperthyroidism was not observed (93). Radiation thyroiditis causing transient thyrotoxicosis has also been reported with external beam radiation. In a prospective study of external beam radiation directed to the neck for metastatic cancer treatment, eight of 22 patients developed a subnormal TSH after receiving 40 Gy of external beam radiation over two weeks. Levels of T4 and T3 tended to rise after 40 Gy of radiation, but the levels were not statistically different from baseline (94). Several case reports of external beam radiation–induced overt thyrotoxicosis have been reported (95,96). Pathophysiology Radiation presumably causes a destructive thyroiditis with release of preformed thyroid hormone into the bloodstream. The thyrotoxicosis is transient. The radiation dose that has been reported to cause external beam radiation–induced thyrotoxicosis varies between 37 and 50 Gy (95,97). It is likely that the greater the external beam radiation dose, the more frequently thyrotoxic thyroiditis and subsequent hypothyroidism occur. Diagnosis In radioactive iodine–induced thyroiditis, manifestations usually occur about four days after radioactive iodine is administered. Symptoms, if present, consist of neck and ear pain, dysphagia, thyroid tenderness, and/or transient symptoms of thyrotoxicosis. External beam radiation–induced thyrotoxic thyroiditis usually occurs within a few weeks of radiation exposure. It is characterized by increased serum

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levels of thyroid hormones and suppressed serum levels of TSH. Serum thyroid autoantibodies are typically negative. The 24-hour radioactive iodine uptake is low. Treatment Since the thyrotoxicosis from radiation thyroiditis is transient, observation may be all that is needed. Treatment with beta-adrenergic blocking agents can be used to control tachycardia and tremor. Patients with 131 I-induced thyrotoxic thyroiditis may have significant neck pain requiring treatment with corticosteroids, especially in thyroid cancer patients treated with large doses to ablate remnant thyroid tissue. After patients are treated with external beam radiation therapy, they should be monitored long-term for the development of hypothyroidism. Trauma-Induced Thyroiditis Several reports of trauma-induced thyroiditis have been described, and this condition may be associated with thyrotoxicosis. Thyroid biopsy, parathyroid surgery, surgical trauma, and trauma induced by a seat belt have all been reported to cause thyrotoxicosis (98–100). The thyroid may be tender due to the trauma. The thyrotoxicosis is transient and associated with a low uptake of radioactive iodine. DRUG-INDUCED HYPERTHYROIDISM Iodine-Induced Hyperthyroidism Introduction Iodine-induced hyperthyroidism was first described in 1821 (101). However, iodine-induced hyperthyroidism is not a single entity, but rather an end result that can occur from a variety of underlying thyroid problems. The common precipitant of the thyrotoxicosis is exposure to high doses of iodine. Epidemiology The incidence of iodine-induced hyperthyroidism has varied according to the underlying thyroid abnormality, the geographic region, and the particular time in history. The highest incidence of iodine-induced hyperthyroidism occurs in areas of iodine deficiency and in individuals with multinodular goiters, when iodine supplementation is introduced into their diet. In four different iodine-deficient European regions, the incidence of iodineinduced hyperthyroidism was determined before and after iodinization of salt. In a region of Holland, the average yearly incidence of iodine-induced hyperthyroidism increased from 0.001% to 0.02% after introduction of dietary iodine. In Yugoslavia, the incidence of newly diagnosed hyperthyroidism increased from 0.0025% to 0.01% in Serbia and from 0.02% to 0.07% in Belgrade. In Tyrol, the number of toxic adenomas doubled to an average incidence of iodide-induced hyperthyroidism of 0.03%. In general, the incidence of hyperthyroidism rose

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Figure 5 Incidence of hyperthyroidism in Tasmania. Ordinate is number of cases, abscissa is year. Separate lines for patients younger and older than 40 years. (Supplied by G. Vidor.) Source: From Ref. 101.

within about six months after introduction of a salt iodinization program, and reached a peak after one to three years. The incidence of hyperthyroidism returned to baseline about three to 10 years after iodinization began (102). The best-documented epidemic of iodine-induced hyperthyroidism occurred in Tasmania and is shown in Figure 5. The incidence of hyperthyroidism increased after the introduction of iodophors for sanitation in the dairy industry in 1963. Potassium iodate was also introduced as a bread dough conditioner. Patients with endemic goiters who were older than 40 years were most likely to develop thyrotoxicosis (101). Pathophysiology Patients with underlying abnormal thyroids, particularly those with nodular goiter, are predisposed to iodine-induced thyrotoxicosis. Iodine-induced thyrotoxicosis can occur from iodine supplementation or pharmacologic doses of iodine in iodine-sufficient or deficient regions. However, iodine-induced thyrotoxicosis occurs much more commonly in iodine-deficient areas. The term Jod-Basedow phenomenon has been used to describe the condition of thyrotoxicosis produced by iodine exposure: Jod is German for iodine, and Basedow is often credited with the first description of thyrotoxicosis on the European continent. Some studies have suggested that the dose of iodine may influence the development of iodine-induced hyperthyroidism. Dietary iodine supplements providing ⬍50 ␮g/day are generally considered safe, whereas doses of 200 to 500 ␮g/day are capable of causing hyperthyroidism in patients with abnormal thyroid physiology (103). However,

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Table 1 Iodine-Containing Drugs and Their Brand Names Radiologic contrast agents Ipodate (Oragrafin) Iopanoic acid (Telepaque) Iothalamate (Angio-Conray) Metrizamide (Amipaque) Topical agents Povidone iodine (Betadine) Iodoform gauze (Nu gauze) Iodochlorhydroxyquin cream (Vioform) Diiodohydroxyquin cream (Vytone) Solutions Saturated potassium iodide Lugol’s lodinated glycerol (Organidin, Tuss Organidin, lophen)a Calcium iodide (Calcidrine syrup) Echothiophate iodide ophthalmic (Phospholine) Hydriodic acid syrup Drugs Amiodarone (Cordarone) Vitamins containing iodine Kelp Iodochlorohydroxyquinolone (Entero-Vioform) Food coloring containing iodine a

Iodine was removed from Organidin and Tuss Organidin in 1995.

even large doses of iodine (1 g/day) do not usually cause hyperthyroidism. Many different iodine sources have been reported to cause iodine-induced hyperthyroidism. Compounds such as potassium iodide and iodoquinolones, which release iodine rapidly, seem to cause hyperthyroidism less frequently than do other compounds, such as amiodarone, which can release high levels of iodine for long periods of time (104). A large number of different iodine-containing substances and drugs have been reported to cause hyperthyroidism. These iodinated substances include seaweed (105), iodinated glycerol (106,107), and topical povidone iodine (108,109). Many cases of hyperthyroidism induced by iodinated contrast agents have also been described (110). In general, it is prudent to avoid administering large doses of iodine to patients with known nontoxic multinodular goiters, since doing so can induce hyperthyroidism (111). Table 1 lists various drugs that contain iodine. Diagnosis Iodine-induced hyperthyroidism occurs in older patients more commonly than in children, and it can lead to serious morbidity in the elderly. Men can be affected as often as women can be affected. Exophthalmos is usually absent. The thyroid may

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be nodular, diffusely enlarged, or normal. Serum TSH levels are suppressed and serum thyroid hormone levels are increased. Thyroid autoantibodies are usually absent. The 24-hour radioactive iodine uptake is usually low at the time of diagnosis of thyrotoxicosis in iodine-sufficient regions. However, radioactive iodine uptake may be normal or high, particularly in iodine-deficient regions, which may represent the onset of Graves’ disease or toxic, multinodular goiter after iodine exposure or supplementation. Thyroid scans are often poorly visualized due to low iodine uptake in iodine-sufficient regions, although they may show patchy areas of iodine uptake in iodine-deficient regions. Urinary iodine levels are increased, confirming the exposure to excess iodine. Therapy Iodine-induced hyperthyroidism may resolve spontaneously over time, usually within a few weeks to a few months. Observation or beta-blocker therapy may be all that is necessary in mild cases. Antithyroid drugs have been used, but they are not uniformly effective (102,104). Corticosteroids can be effective in promptly lowering thyroid hormone levels (102,104). Radioactive iodine has been used, but high doses may be needed since the 24-hour uptake is usually low. Thyroidectomy has occasionally been required to treat iodine-induced hyperthyroidism. Amiodarone-Induced Hyperthyroidism Introduction Amiodarone is an iodine-rich benzofuran derivative that is used to treat supraventricular and ventricular arrhythmias. Approximately 37% of amiodarone, by weight, is organic iodine. Treatment with typical doses of amiodarone leads to a major expansion of the total-body iodine pool (112). Amiodarone, therefore, can have dramatic effects on thyroid function and its use has been associated with hypothyroidism as well as hyperthyroidism. Epidemiology The prevalence of amiodarone-induced hyperthyroidism and hypothyroidism varies geographically and seems to correlate with dietary intake of iodine. The prevalence of AIT has been reported to be 1% to 23% (113). In West Tuscany, Italy, where iodine intake is low, the prevalence of amiodarone-induced hyperthyroidism was reported to be 9.6%, while hypothyroidism was reported in 5% of exposed patients. On the other hand, in Worcester, Massachusetts, where iodine intake is sufficient, amiodarone-induced hyperthyroidism was reported in only 2% of patients, while hypothyroidism occurred in 22% (114). In Los Angeles, California, hyperthyroidism associated with amiodarone was found in 3% of patients, while hypothyroidism was found in 8% (115) of patients. In a retrospective review, amiodarone-induced hyperthyroidism was found in 4.2% of patients seen at the Cleveland Clinic (116). However, in an area of moderately sufficient iodine intake, the incidence of amiodarone-induced hyperthyroidism was 12.1% and the

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Table 2 Amiodarone-Induced Thyrotoxicosis Feature Thyroid abnormality Pathogenesis Thyroid examination Radioactive iodine uptake Thyroid antibodies Interleukin-6 Thyroid ultrasound Doppler flow Therapy options

Type 1

Type 2

Graves’ disease, multinodular goiter, autonomous nodule Thyroid hormone production Diffuse or nodular goiter Low, normal, or increased

Destructive thyroiditis Thyroid hormone release Normal or small goiter Very low

Increased or negative Normal to high (⬍200 fmol/L) Increased

Negative Normal or high (⬎250 fmol/L) Decreased

Stop amiodarone ATD, KClO4 , thyroidectomy

Corticosteroids Stopping amiodarone may not be necessary

Abbreviations: ATD, antithyroid drugs; KClO4 , potassium perchlorate.

incidence of amiodarone-induced hypothyroidism was 6.9% (117). A United States prospective study of atrial fibrillation patients treated with amiodarone, reported 30.8% developed hypothyroidism, primarily subclinical with TSH 4.5 to 10, compared to 6.9% of controls. Hyperthyroidism occurred in 5.3% of patients, all but one was subclinical, compared to 2.4% of controls (p = 0.07) (118). Pathophysiology Two major forms of AIT have been described. The characteristics of each form are outlined in Table 2. Type 1 occurs in patients who have an underlying abnormal thyroid, such as a nodular goiter or latent Graves’ disease. Type 2 AIT occurs in patients who have a normal thyroid gland prior to amiodarone treatment; it is most likely a destructive thyroiditis (119–121). This has also been suggested by FNA biopsy (122). In patients with type 1 AIT, the radioactive iodine uptake is inappropriately normal or even increased in the presence of high levels of iodine, at least in some European studies. For example, in 12 patients with type 1 AIT, 24-hour radioactive iodine uptake ranged from 6% to 50% (mean 17%) (123). In another study, nine of 11 patients with diffuse goiter and eight of 12 patients with nodular goiters and AIT had 24-hour radioactive iodine uptake of greater than 8% (124). In patients with type 2 AIT, 24-hour radioactive iodine uptakes were very low (123–125). Twelve patients with type 2 AIT had 24-hour radioactive iodine uptakes of 0.5% to 2%, with a mean of 1% (123). Interleukin-6 (IL-6) levels have also been used to distinguish type 1 from type 2 AIT, since IL-6 is a marker of inflammation. In theory, IL-6 levels are only mildly increased in patients with type 1 AIT, similar to what is seen in patients with traditional forms of spontaneous hyperthyroidism (119). In contrast, IL-6

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levels in patients with type 2 AIT have been markedly increased in some studies, due to the release of IL-6 produced by destroyed thyrocytes (119). However, the utility of IL-6 levels in the differential diagnosis of AIT has not been confirmed by other authors (126). Continuous-flow Doppler ultrasound has also been used to help distinguish type 1 from type 2 AIT. Patients with type 1 AIT show normal to increased parenchymal blood flow in the thyroid, while patients with type 2 AIT show decreased blood flow consistent with thyroid inflammation (127,128). Although reliable data are not available from the United States, most authorities agree that type 2 AIT is far more common than type 1 AIT. Diagnosis The presentation of AIT may be subtle, with relatively few clinical signs (129). However, patients typically present with tachycardia, tremor, weight loss, nervousness, or irritability. One review found weight loss as the most common presenting symptom, with goiter and tremor being the most common presenting signs (127). Some patients may present with recurrence of the arrhythmia that was once controlled with the use of amiodarone (115,130). However, tachycardia in AIT may not always be present, due to the beta-blocking properties of amiodarone. Amiodarone treatment itself leads to increases in serum T4 and free T4 levels and decreases in serum T3 levels by inhibiting type 1 iodothyronine deiodinase. Soon after therapy commences, serum TSH levels increase due to inhibition of T4 to T3 deiodination in the pituitary. Subsequently, within two to six months, serum TSH levels return to normal. When thyrotoxicosis develops, there is a further increase in T4 levels and an increase in T3 levels in most patients (120). Serum T3 levels may only be in the upper range of normal, but they are higher than before the onset of hyperthyroidism. TSH levels are decreased (116). Treatment The treatment of AIT is often difficult and protracted because of the long 100-day half-life of amiodarone and the high intrathyroidal and tissue concentrations of iodine. If amiodarone is discontinued, it may take up to eight months for thyrotoxicosis to subside (104). Nevertheless, stopping the drug in type 1 AIT is recommended. The appropriate medical treatment of AIT depends on making the distinction between type 1 and type 2 forms of thyrotoxicosis. Type 1 amiodaroneinduced disease has traditionally been treated with large doses of antithyroid drugs and potassium perchlorate. However, potassium perchlorate is no longer available in the United States. Type 2 disease, in contrast, is treated with corticosteroids. Sometimes, when the diagnosis is uncertain or when one treatment fails, the therapies are used in combination. The high concentration of circulating iodine from the amiodarone suppresses the uptake of radioactive iodine, which means it generally cannot be used as a treatment option. In patients with type 1 disease, amiodarone therapy should be discontinued if at all possible, although in many cases this

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may not be feasible. In contrast, type 2 disease resolves even when amiodarone is continued. Patients with type 1 AIT usually respond to an antithyroid drug to decrease thyroid hormone synthesis. Large doses, for example 40 to 80 mg/day of methimazole or 400 to 800 mg/day of propylthiouracil, are often required because the high, intrathyroidal iodine content renders the hyperthyroidism less responsive to thionamide drugs. In areas where potassium perchlorate is available, doses of 200 to 1000 mg/day have been used to decrease intrathyroidal iodine content (123). In general, it may take one to three months before thyroid function has normalized. Since the side-effects of antithyroid drugs are dose-related, and since perchlorate therapy can cause aplastic anemia in higher doses than recommended here, it seems prudent to monitor white blood cell counts in patients receiving both drugs together. When it is very mild, patients with type 2 AIT may not require therapy at all, since it usually resolves spontaneously. All but the mildest cases are treated with prednisone 40 to 60 mg/day for one to two months with subsequent tapering of the prednisone over three months. In classic type 2 amiodarone-induced thyrotoxicosis, elevated levels of free T4 and T3 normalize within 7 to 10 days. Care must be taken not to taper the corticosteroids too quickly, since there can be a rapid recrudescence of hyperthyroidism (123). In a recent study, patients with serum free T4 concentrations ⬍50 pg/mL and lower thyroid volumes achieved more rapid control of hyperthyroidism when treated with prednisone compared to patients with higher serum free T4 levels and larger thyroid glands (131–133). If patients do not respond to corticosteroids alone or if the pathogenesis is unclear, a combination of corticosteroids and antithyroid drugs would be reasonable. In one small study, lithium in combination with antithyroid drugs was reported to help control thyrotoxicosis faster than treatment with antithyroid drugs alone (132). The use of the oral cholecystographic agents, sodium ipodate or sodium iopanoate, in combination with antithyroid drugs have also been reported to be effective in type 2 AIT (133), but these drugs are not available in the United States. Some patients have continuing hyperthyroidism despite combination therapy with prednisone and antithyroid drugs. If drug therapy is unsuccessful after several months, total thyroidectomy should be considered, although these patients are often poor operative candidates because of their underlying cardiovascular disease. Of course, the surgical risks and benefits must be weighed against the risks of continuing hyperthyroidism (134–136). Patients with type 2 AIT have a risk of developing transient or permanent hypothyroidism after resolution of the thyrotoxicosis, similar to other forms of thyroiditis, and periodic surveillance of thyroid status is recommended (137). Although no guidelines exist regarding screening for amiodarone-induced thyroid dysfunction, some authors recommend a baseline thyroid examination, TSH, free T4 and T3, anti-TPO antibodies, along with monitoring of TSH and free T4 every three months (138).

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Cytokine-Induced Hyperthyroidism Introduction Interferon-alpha has been used to treat chronic viral hepatitis and certain neoplasms with promising results. However, the immune-mediated effects of interferon have been shown to increase the frequency of autoimmune thyroid diseases and other immune-mediated disorders. Interferon-alpha has been most often shown to cause hypothyroidism, but hyperthyroidism can also be induced by interferon-alpha therapy. Epidemiology Interferon-alpha has been shown to induce thyroid dysfunction in approximately 6% of patients. The majority (approximately 4%) develop hypothyroidism, but 2% develop hyperthyroidism (139). Twenty percent of patients with multiple sclerosis treated with interferon-beta developed hypothyroidism and 4.9% developed hyperthyroidism, which was transient (140). Females seem to be more susceptible to interferon-induced hyperthyroidism than males, likely because of the higher background prevalence of thyroid autoantibodies in females. Hyperthyroidism has been reported to develop as early as six weeks after the onset of interferon therapy (141), to as late as six months after interferon therapy was completed (142). Some reports indicate hyperthyroidism is more often transient, most likely due to thyroiditis (139,143), while other reports indicate hyperthyroidism is more likely permanent due to Graves’ disease (144–146). Interleukin-2 (IL-2) therapy has also been reported to cause hypothyroidism and transient hyperthyroidism (147). Pathophysiology Thyroid dysfunction in association with interferon is more common among patients who have circulating thyroid antibodies prior to treatment. In a metaanalysis of the literature, thyroid dysfunction occurred in 46% of patients with baseline thyroid antibody positivity, but only in 5% of thyroid antibody–negative patients (139). Approximately 9% of thyroid antibody–negative patients develop thyroid autoantibodies during interferon therapy, and 42% of these patients develop thyroid dysfunction (139) suggesting that the thyroid dysfunction is mediated through an immune mechanism. However, some patients with thyroid dysfunction have no evidence of thyroid antibodies, raising the possibility of a direct toxic effect of interferon on the thyroid (148). Patients with either hepatitis C or malignancy have been found to have a higher frequency of thyroid abnormalities in the absence of interferon therapy, which could also partly explain the higher rate of thyroid dysfunction when interferon is used to treat these conditions (149).

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Diagnosis Hyperthyroidism induced by interferon therapy presents with the usual signs and symptoms. The thyroid may be normal in size or mildly enlarged, serum thyroid hormone levels are increased, with a suppressed serum TSH concentration. In addition to thyroid peroxidase and thyroglobulin antibodies, some patients develop circulating anti-TSH receptor antibodies (TSAb) and have normal to increased radioactive iodine uptakes. These patients may have Graves’ disease precipitated by cytokine therapy. However, most hyperthyroid patients develop transient hyperthyroidism associated with low radioactive iodine uptakes, which may be followed by hypothyroidism. Treatment Interferon therapy–induced hyperthyroidism, when associated with a normal or increased radioactive iodine uptake, may have to be treated with the usual forms of therapy, such as antithyroid drugs or radioactive iodine. Discontinuation of the interferon therapy will not reliably lead to resolution of the hyperthyroidism. Although patients with interferon-induced destructive thyroiditis with low radioactive iodine uptake have been treated with corticosteroids (150), a recent trial showed corticosteroids were not more effective than simple withdrawal of interferon therapy in restoring euthyroidism (151). However, transient thyrotoxicosis may give rise to hypothyroidism, which may require thyroid hormone replacement. Finally, withdrawal of interferon therapy may be associated with resolution of the thyroid dysfunction, and symptomatic therapy may be all that is needed (152). Some authors have suggested screening patients with TSH, free T4, thyroid antibodies, and perhaps thyroid ultrasound before interferon therapy is started, in addition to monitoring thyroid levels periodically during treatment (148,150). Lithium-Associated Thyrotoxicosis Lithium, commonly used to treat manic depressive disorders, is a recognized cause of hypothyroidism. However, some reports have suggested that lithium may also be associated with thyrotoxicosis. One study reported 14 cases of thyrotoxicosis associated with lithium use (153). The majority of these patients had diffuse toxic goiters. A few had toxic multinodular goiters and a few had painless thyroiditis associated with a low uptake of radioactive iodine on scan. These authors suggested that the incidence of lithium-associated thyrotoxicosis was three times higher than predicted based on regional thyrotoxicosis rates. Others have reviewed the cases of lithium-associated thyrotoxicosis, and they have also concluded that the association was not coincidental (154,155). The majority of cases of lithium-associated thyrotoxicosis and increased radioactive iodine uptakes have been successfully treated with antithyroid drugs, even during continued lithium therapy.

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Hyperthyroidism Due to Exogenous Thyroid Hormone Introduction Thyrotoxicosis factitia or factitious thyrotoxicosis describes a condition due to the excess use of exogenous thyroid hormone, leading to symptoms and signs of thyrotoxicosis. The term is used most commonly when the use of thyroid hormone is surreptitious, but may also be applied in cases where the exposure to thyroid hormone is inadvertent. Epidemiology Thyroid hormone has been used for a variety of nonthyroid conditions in the past, ranging from obesity to depression to infertility. Thyrotoxicosis occurs when the thyroid hormone dose is escalated to supraphysiologic doses. The secretive use of thyroid hormone by psychiatrically disturbed patients is another common cause of thyrotoxicosis factitia. Thyrotoxicosis factitia has been noted in young or older women, with a middle-aged predominance (156). Occasionally, patients such as children will present with thyrotoxicosis due to accidental ingestion of thyroid hormone (157). Thyrotoxicosis has been reported in a patient taking herbal supplements that contained thyroid hormone (158). Pathophysiology Thyrotoxicosis factitia–induced thyrotoxicosis is due to the excessive use of a variety of thyroid preparations. These preparations can include L-Thyroxine, triiodothyronine, or desiccated thyroid tablets. Thyrotoxicosis induced by excessive thyroid hormone has also been caused by “hamburger thyrotoxicosis.” Two epidemics of thyrotoxicosis in the United States were caused by bovine thyroid gland, which was included in hamburger made by a meat processor (159,160). Diagnosis Patients with thyrotoxicosis factitia present with the usual symptoms and signs of thyrotoxicosis. However, the thyroid gland is normal to small in size and the patient lacks the eye signs of Graves’ ophthalmopathy. The thyroid is not tender. Serum T4 and T3 levels are increased if the patient is consuming thyroxine or desiccated thyroid. T3 levels are increased, while T4 levels are low if the patient is consuming triiodothyronine. The radioactive iodine uptake is low and scans show no evidence of functioning thyroid tissue elsewhere in the body. Low thyroglobulin measurements are useful in distinguishing thyrotoxicosis factitia from other forms of hyperthyroidism with low uptake of radioactive iodine (161). However, occasionally the test may not be reliable because of circulating antithyroglobulin antibodies. The finding of increased levels of thyroxine in the stool has also been used to confirm the diagnosis of thyrotoxicosis factitia (162).

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Treatment The treatment of thyrotoxicosis factitia is discontinuation of the exogenous thyroid hormone. This can sometimes be difficult in the psychiatrically disturbed patient who is taking thyroid hormone secretly; psychiatric consultation may be helpful. Beta-blocking agents may be needed temporarily while thyroid hormone levels are decreasing. THYROTROPHIN-INDUCED HYPERTHYROIDISM TSH-Secreting Pituitary Adenomas Introduction Since the advent of the TSH radioimmunoassay, TSH-producing pituitary tumors have been recognized as a cause of hyperthyroidism. Earlier reports described large pituitary tumors, but microadenomas are being recognized more frequently in recent case series. Epidemiology TSH-producing pituitary tumors (TSHomas) are rare, occurring in about one per one million people (163). However, the number of cases being reported has increased, along with the introduction of second- and third-generation TSH assays. TSH-producing pituitary tumors may account for 0.5% to 3% of pituitary tumors (164–166). TSH-producing pituitary tumors may occur at any age, with males and females affected about equally (163,167). Pathophysiology TSHomas are macroadenomas approximately 90% of the time in older series, but up to 25% are microadenomas in more recent series (168). Approximately 30% of TSH-producing pituitary tumors are mixed tumors secreting other pituitary hormones. Growth hormone and prolactin are the most common hormones that are cosecreted, but tumors that cosecrete LH and FSH have also been described (163,167). The alpha subunit of the pituitary glycoprotein hormones may also be produced in TSH-producing pituitary adenomas. Two cases of an ectopic TSHsecreting pituitary tumor have also been reported (169,170). Tumor-derived TSH may have varying degrees of glycosylation along with varying molecular weight, which may give rise to variable biologic activity of the TSH (171). In contrast to some growth hormone-secreting tumors, no activating mutation in the gene coding for G proteins has been found in TSH-producing pituitary tumors (163). Diagnosis Patients with TSH-producing pituitary adenomas present with the usual signs and symptoms of thyrotoxicosis, but these may be mild. Most patients have a goiter that is diffusely enlarged. Exophthalmos has been reported rarely. In one

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Table 3 Characteristics of TSH-Producing Pituitary Tumors (TSHoma) Versus Thyroid Hormone Resistance Feature TRH stimulation of TSH T3 suppression of TSH Elevated sex hormone–binding globulin Elevated alpha subunit/TSH ratio Family history MRI pituitary adenoma

TSHoma (%)

Thyroid resistance (%)

8 12 94 81 0 98

96 100 2 2 82 2

Source: Percentages taken from Ref. 144 (163).

case, it was due to orbital invasion by tumor, while Graves’ disease has been present in several patients with coexisting TSHomas. Other manifestations of Graves’ disease, such as dermopathy and acropachy are not found. If the tumor is large, headache (23%) and visual field disturbance (40%) may be present (163). Features of cosecreted hormones may be present, such as acromegaly (15%) or the galactorrhea/amenorrhea (10%) syndrome (163). Hypopituitarism, most commonly hypogonadism, may also be present. Laboratory evaluation shows increased levels of thyroid hormones in the presence of an inappropriately normal or increased serum level of TSH. A pituitary adenoma should be distinguished from pituitary thyroid hormone resistance; both conditions give rise to increased thyroid hormone levels with inappropriately normal or increased serum TSH levels. Table 3 compares the characteristics of TSHproducing pituitary adenomas and thyroid hormone resistance. Thyroid autoantibodies are usually not present, and the radioactive iodine uptake is increased. Circulating levels of alpha subunit are increased in macroadenomas, but are usually normal in microadenomas (172). The alpha subunit/TSH molar ratio, which is the molar concentration of serum alpha subunit divided by the molar concentration of serum TSH, is usually ⬎1 [molar ratio = (alpha subunit ng/mL/TSH mU/L) × 10]. However, the alpha subunit/TSH molar ratio is not reliable in postmenopausal women and in men with primary hypogonadism since increased serum levels of alpha subunit, due to increased serum levels of gonadotrophins, are present in these conditions (163,167,173–175). An increased level of sex hormone–binding globulin and bone carboxyterminal cross-linked telopeptide of type 1 collagen have been proposed to help differentiate patients with TSH-producing adenomas from those with thyroid hormone resistance (172,176). Dynamic testing has also been used to differentiate TSH-producing adenomas from thyroid hormone resistance. In adenoma patients, TRH stimulation testing usually fails to stimulate TSH secretion, and the administration of T3 also fails to suppress TSH- or TRH-stimulated TSH. More recently, treatment with long-acting somatostatin analogues for at least two months has been used to distinguish between cases of TSH-producing pituitary tumors versus thyroid

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hormone resistance syndrome, when the diagnosis was uncertain. Long-acting somatostatin analogues caused a greater than 30% reduction in free T4 and free T3 levels in seven out of eight patients with TSH-producing adenomas, compared to four patients with thyroid hormone resistance of the pituitary, in which thyroid hormone levels did not change (177). Imaging of the sella turcica with CT scan or magnetic resonance imaging (MRI) will usually reveal a pituitary tumor. For patients previously treated erroneously with thyroid ablation due to the mistaken diagnosis of Graves’ disease, the pituitary tumor may enlarge and become invasive. In general, there is no correlation between the serum TSH level and tumor size. In several case reports, routine contrast–enhanced MRI has been normal. In one such case, inferior petrosal sinus sampling disclosed a gradient consistent with a TSH-producing pituitary adenoma (178). In another case, dynamic MRI imaging identified the tumor (179). Treatment Transsphenoidal surgical resection of the pituitary tumor is the treatment of choice for TSH producing pituitary tumors. Approximately 35% to 50% of patients can be cured with surgery alone, and earlier diagnosis improves the prognosis (163,167,168). As is true for all pituitary tumors, the most important prognostic factors for cure are smaller size of the pituitary tumor and the absence of cavernous sinus invasion. Criteria for cure following surgery include biochemical euthyroidism with a normalized TRH test and absence of residual tumor on MRI (164,180). Unfortunately, TRH is not available in the United States. Antithyroid drugs and beta-blockers or octreotide should be used to restore the euthyroid state before surgery. Radiation therapy is used for incompletely resected pituitary tumor. Octreotide, 50 to 100 ␮g subcutaneously two to three times daily, has been successfully used to treat patients with TSH-producing pituitary tumors (181,182). The long-acting somatostatin analogue lanreotide has also been used successfully to treat patients with TSH-producing tumors (183). Octreotide produces therapeutic success in up to 95% of patients, and in about one-half of cases there is tumor regression (172). In addition, octreotide alters the glycosylation pattern, and presumably the bioactivity, of serum TSH (184). Tachyphylaxis may develop in approximately one-fourth of patients, necessitating an increased octreotide dose (181). Approximately 10% of patients may escape from octreotide’s inhibitory effects on TSH suppression. Octreotide has also been used to restore euthyroidism in pregnant women with this disorder without apparent effects on fetal development and thyroid function (185). Dopamine agonists have also been reported to decrease TSH and thyroxine levels in a limited number of cases, but do not cause tumor shrinkage (186). Iopanoic acid has been used to improve hyperthyroidism acutely in the preoperative state in two cases (187), but is not available in the United States. Ablation of the thyroid with radioactive iodine or surgery should be avoided. However, patients who have refused surgery for their TSH producing

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pituitary tumors have been successfully treated with either radioactive iodine or thyroidectomy (172,188). Thyroid Hormone Resistance Introduction Thyroid hormone resistance is a heterogeneous syndrome in which tissues have a reduced response to thyroid hormone. Generalized thyroid hormone resistance is at one end of the spectrum of thyroid hormone resistance. These patients have a normal metabolism because the TSH stimulation of thyroid hormone production maintains increased thyroid hormone levels. However, some patients may exhibit clinical signs and symptoms of hypothyroidism or hyperthyroidism in some organ systems. At the other end of the spectrum of thyroid hormone resistance are patients with pituitary resistance, who have near normal peripheral tissue responsiveness to thyroid hormone. In these patients, there are clinical signs and symptoms of thyrotoxicosis. Epidemiology Thyroid hormone resistance was first described in 1967 (189). Pituitary resistance to thyroid hormone was first described in 1975 (190). Since that time, more than 1000 cases of thyroid hormone resistance have been reported. The exact prevalence of resistance to thyroid hormone is unknown since the condition is not detected by routine neonatal screening for hypothyroidism. However, a screening for high blood T4 found one case per 40,000 births (191). Thyroid hormone resistance occurs in males and females, and it has been reported in all races. The majority of cases of thyroid hormone resistance have generalized tissue resistance to thyroid hormone. Thyroid hormone resistance is usually inherited, and it is usually autosomal dominant. Pathophysiology Thyroid hormone resistance is most often due to a mutation in the thyroid hormone receptor-beta gene (TR-␤), found on chromosome 3 (192–194). However, 15% of patients with thyroid hormone resistance do not have a TR-␤ mutation (195). Mosaicism of the TR-␤ has been reported (196). More recently, mutations in the cell membrane transporter of thyroid hormone, MCT8, and mutations in the SECISBP2 gene, which is required for thyroid hormone deiodinases, have been reported (195). Patients with thyroid hormone resistance are usually heterozygous for mutations that cluster within three areas of the thyroid hormone–binding domain (197,198). The ability of the mutant receptor proteins to bind thyroid hormone is reduced, and therefore, the ability to effect gene transcription is reduced. Analysis of patients with pituitary-only resistance to thyroid hormone with consequent clinical hyperthyroidism indicates that these individuals also are heterozygous for mutations in the hormone-binding region of the TR-␤ receptor (198,199). The same mutations in the TR-␤ gene in patients with pituitary resistance have

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also been identified in patients from unrelated families with generalized thyroid hormone resistance. In addition, within a family, the same receptor mutation may result in generalized thyroid resistance in one family member, but in another, thyrotoxicosis suggestive of pituitary thyroid hormone resistance. Diagnosis Patients with thyroid hormone resistance may have clinical symptoms and signs that vary from hypothyroidism to hyperthyroidism. There is considerable overlap of these findings between generalized resistance patients versus those thought to have pituitary thyroid hormone resistance. Patients with thyroid hormone resistance have a higher frequency of attention deficit disorder, delayed speech development, lower IQ, shorter stature and lower weight, delayed bone age, and hearing loss. There may also be a higher frequency of ear, nose, and throat infections (197,200,201). A goiter is found commonly (65–90%) in patients with thyroid hormone resistance (197,198). Tachycardia and an increased frequency of arrhythmia have been found in some thyroid hormone resistance patients. Increased levels of thyroid hormones, including T4 and T3, are found with inappropriately normal or increased levels of TSH. The 24-hour radioactive iodine uptake is often increased. Failure of serum TSH levels to increase in response to TRH, and failure of serum TSH levels to decrease in response to supraphysiologic doses of thyroid hormone suggest a TSH-producing pituitary adenoma. An increased molar ratio of alpha subunit to TSH and a pituitary adenoma on MRI of the brain are diagnostic of a TSH-producing pituitary adenoma (202). Treatment Most patients with generalized thyroid hormone resistance do not require treatment. Patients who have been mistakenly treated with thyroidectomy or radioactive iodine ablation of the thyroid typically require higher than normal doses of thyroxine replacement to suppress TSH back to normal. One case of pituitary enlargement was demonstrated in a patient previously treated with radioactive iodine ablation. Supraphysiologic doses of thyroid hormone caused regression of the pituitary gland back to normal size (203). Patients with pituitary resistance to thyroid hormone who have mildly symptomatic hyperthyroidism may be treated with beta-blocker therapy. Antithyroid drugs are not ideal because they result in further increases in thyroid size, but rarely may be needed in patients with severe hypermetabolism (195). Radioactive iodine is not recommended as it may cause dramatic increases in TSH (197). Moderate doses of T3 (25–50 ␮g daily) over a period of several months can decrease TSH secretion, thyroid hormone levels, and clinical thyrotoxicosis (204), but they are not often successful. D-thyroxine has also been reported to be beneficial (205,206). Triiodothyroacetic acid (Triac) appears to be able to suppress TSH with minimal peripheral thyromimetic actions (207–209). Bromocriptine and octreotide have been used in some cases to suppress TSH production (193,195,208,210,211). In

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general, it is appropriate to treat patients with pituitary thyroid hormone resistance with conservative measures, if possible, including beta-blockers. If patients do not respond to these measures, antithyroid drugs may be necessary. HYPERTHYROIDISM OF EXTRATHYROID ORIGIN Struma Ovarii Tumor Introduction Struma ovarii, a very rare cause of hyperthyroidism, is due to the presence of an ovarian teratoma that contains hyperfunctioning autonomous thyroid tissue. An ovarian teratoma that contains greater than 50% thyroid tissue or functioning thyroid tissue causing thyrotoxicosis is called a struma ovarii (212). Epidemiology Struma ovarii represents less than 2% of ovarian teratomas, with peak frequency during the fifth decade of life. One review found struma ovarii in five of 1390 (0.4%) ovarian tumors (213). Struma ovarii tumors usually do not cause hyperthyroidism. One review reported that preoperatively, three out of 41 patients (7%) with struma ovarii had clinical symptoms and laboratory signs of hyperthyroidism (212). Hyperthyroidism was found in eight of 25 patients with struma ovarii tumor in another review (214). The frequency of papillary or follicular carcinoma arising in a struma ovarii is unknown but is quite rare. A review in Colorado showed a frequency of 0.3% (215). Pardo-Mindan and Vazquez reviewed the literature on malignant struma ovarii and found only 45 cases of malignant struma ovarii; 17% of these cases were associated with hyperthyroidism (216). Pathophysiology Struma ovarii and associated thyrotoxicosis is due to the presence of autonomous hyperfunctioning thyroid tissue within the teratoma. Struma ovarii tumors are unilateral in 90% of cases, with the left ovary more frequently involved (216). Most struma ovarii tumors are benign (214). However, it is sometimes difficult to determine if the thyroid tissue in the tumor is benign or malignant (212). Papillary carcinomas are more commonly reported than follicular or insular carcinoma (217). Metastatic struma ovarii may spread to the peritoneum, intraabdominal nodes, bone, liver, lung, mediastinum, and brain (214,218). Struma ovarii can be mixed with a carcinoid tumor and has been reported to occur in association with multiple endocrine neoplasia type IIA (219). One case of hyperthyroidism has been reported, which was due to a thyrotoxic adenoma and struma ovarii (220). Diagnosis The diagnosis of struma ovarii–causing hyperthyroidism should be suspected in a female without thyroid enlargement, and a very low thyroid uptake of radioactive

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iodine. However, the thyroid has been reported to be enlarged in several reports (214,221,222). Some patients may present with a pelvic mass, and ascites may be present even in the absence of malignant struma ovarii (214). The TSH is suppressed and thyroid hormone levels are increased. The diagnosis is established by finding radioactive iodine uptake over the pelvis or an ovarian teratoma containing thyroid tissue (223). However, radioactive iodine uptake has been reported in a hemorrhagic ovarian cyst that did not contain thyroid tissue (224). Treatment Treatment of struma ovarii, with or without thyrotoxicosis, consists of surgery to remove the tumor. If thyrotoxicosis is present, beta-blockers and/or antithyroid drugs should be used before surgery. Radioactive iodine should not be used to ablate the thyroid tissue, since the thyroid tissue is neoplastic and potentially malignant. It also often contains nonthyroid tissue (225), and the effect of radiation on the other tissues is unknown. Malignant struma ovarii is treated with hysterectomy, bilateral salpingooophorectomy, and thyroidectomy. Metastatic struma ovarii has been treated with radioactive iodine after thyroidectomy. Thyroid hormone treatment with TSH suppression is also recommended for metastatic struma ovarii.

Trophoblastic Tumors Introduction Molar pregnancy and trophoblastic tumors can cause hyperthyroidism. Human chorionic gonadotrophin (hCG), secreted in large amounts by these tumors, has TSH receptor–binding activity. This hCG cross-reactivity can lead to thyrotoxicosis (226). Epidemiology The prevalence of thyrotoxicosis in patients with trophoblastic tumors is unknown. One study evaluated 20 patients from a referral center over one year, and the researchers found that five of the patients had thyrotoxicosis (227). Another study found that 30 of 52 patients with gestational trophoblastic tumors had thyrotoxicosis (228). It has been estimated that 20% of women with hydatidiform moles have hyperthyroidism (229). Hydatiform mole occurs in about one out of 1500 pregnancies in the United States and is about 10 times more common in Asian and Latin American countries (230). Choriocarcinoma occurs in one of 50,000 pregnancies (226). Thyrotoxicosis is reported more frequently in women with hydatiform mole than in those with choriocarcinoma. In addition, a few men with testicular tumors that produce hCG have been reported with hyperthyroidism (231–233).

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Pathophysiology hCG is composed of an alpha subunit and a beta subunit. The alpha subunit is identical to the alpha subunit of LH, FSH, and TSH. The beta subunit of hCG is larger than the beta subunit of TSH but is similar in structure. Beta-hCG has an additional 33–amino acid peptide at the carboxyl terminal. The thyrotropin effect of hCG is weak. However, when hCG is secreted in large amounts, it can stimulate the TSH receptor in thyroid tissue enough to cause thyrotoxicosis. It is probable that some molecular variants of hCG secreted by trophoblastic tumors have greater thyrotrophic activity than hCG secreted by normal placental tissue (229,234). Removal of the tumor, and therefore the hCG, is associated with rapid resolution of the hyperthyroidism. Diagnosis Women with trophoblastic tumors may or may not have clinical evidence of hyperthyroidism. The nausea, vomiting, and toxemia that occur in molar pregnancy may obscure hyperthyroidism. The thyroid gland is either normal in size or slightly enlarged. Chorionic gonadotrophin, secreted in large amounts by trophoblastic tissue, serves as a marker for the tumor. The hCG levels exceed 100 U/mL in patients with hyperthyroidism and often exceed 300 U/mL (235–238). TSH is suppressed and levels of free T4 and free T3 may be minimally or markedly increased. Hyperthyroid patients with trophoblastic tumors usually have higher T4/T3 ratios than patients with hyperthyroidism due to Graves’ disease (157). The uptake of radioactive iodine is increased (239). Treatment Surgical removal of the hydatidiform mole or choriocarcinoma in a patient with hyperthyroidism rapidly cures the thyrotoxicosis. However, patients with choriocarcinoma who have hyperthyroidism usually have a larger tumor mass that may be metastatic. Chemotherapy is the principle therapy used to achieve remission of metastatic choriocarcinoma with associated hyperthyroidism. Effective chemotherapy provides long-term survival ranges from 86% to 100% (240). The prognosis for men with testicular choriocarcinoma and hyperthyroidism is usually poor. Medical therapy for hyperthyroidism due to trophoblastic disease may include potassium iodide, beta-blockers, and antithyroid drugs. Preoperative iodine can help lower thyroid hormone levels rapidly in patients who require urgent surgery. Beta-adrenergic blockers are given to control tachycardia and tremor. Antithyroid drugs are given to help control hyperthyroidism perioperatively or in patients with metastatic disease. Surgical thyroidectomy is not recommended.

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Metastatic Thyroid Cancer and Hyperthyroidism Introduction Differentiated thyroid cancer usually does not produce thyroid hormone efficiently. However, thyroid cancers do produce thyroglobulin, which can become iodinated and form thyroid hormone. Rarely thyroid hormone production from thyroid cancer can become excessive, giving rise to thyrotoxicosis. Epidemiology Thyrotoxicosis due to thyroid cancer is quite rare. However, the age and sex distribution of patients with hyperthyroidism caused by thyroid cancer is similar to that of patients with thyroid cancer without thyrotoxicosis (241,242). Eightyfive percent of patients with hyperfunctioning thyroid cancer are older than 40 years. The female-to-male ratio is about 3:1 (242). Pathophysiology Malignant thyroid tissue is functionally less efficient than normal thyroid tissue (243). The estimated efficacy of the iodine-concentrating ability of functioning metastases is approximately 10% of normal thyroid tissue (244,245). The inefficient thyroid hormone production is due in part to lower iodine trapping by tumor tissue and in part to abnormal thyroglobulin synthesis. Further, there is evidence that expression of the TSH receptor in malignant thyroid tissue may be absent or low (246). Therefore, many of the cases of thyrotoxicosis caused by thyroid cancer are due to large, bulky metastatic tumors, often weighing 2 to 3 kg (242). Follicular thyroid cancer is the most common thyroid malignancy reported to cause hyperthyroidism (241,242,247), but papillary thyroid cancer may also cause hyperthyroidism. Patients with functioning metastases more commonly come from areas of low iodine intake (241). Thyroglobulin levels have been reported to be higher in patients with functioning metastases, but this finding did not reach statistical significance (241). Finally, the time to metastasis and the 10-year survival rate appear to be equal for metastatic follicular carcinoma with or without thyrotoxicosis (241,242,247). The discovery of metastases precedes or occurs simultaneously with the onset of hyperthyroidism (247). Anaplastic thyroid cancer and thyroid lymphoma have been reported to cause thyrotoxicosis with a low uptake of radioactive iodine, so-called “malignant pseudothyroiditis” (20,21,248,249). Diagnosis In most instances, the diagnosis of thyroid malignancy has been made and thyroidectomy has been accomplished. Since the treatment of thyroid cancer includes suppressive doses of thyroid hormone, the fact that metastatic disease is causing hyperthyroidism may not be recognized if the clinician erroneously believes that

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the thyrotoxicosis is due to overzealous treatment with thyroid hormone. Therefore, thyroid hormone treatment should be stopped to see if the signs and symptoms of thyrotoxicosis resolve, and if the levels of T4 and T3 in the serum decrease. If the signs, symptoms, and levels of thyroid hormone do not decrease, hyperthyroidism may be due to functional thyroid metastases. In many cases, the thyrotoxicosis may be due to T3 toxicosis, with suppressed TSH, and normal or even low serum T4 levels (242,250,251). Hyperfunctioning metastatic cancer may be confirmed by whole-body radioactive iodine scanning. However, uptake of radioactive iodine in metastatic tissue may be low in the presence of the normal thyroid gland. The distribution of hyperfunctioning metastatic thyroid cancer is typically the same as in nonhyperfunctioning thyroid cancer, that is, in bone, lung, and mediastinum. Treatment Treatment of metastatic functioning thyroid cancer usually consists of radioactive 131 I therapy. The usual dose of radioactive iodine ranges from 100 to 200 mCi. Treatment with radioactive iodine may exacerbate the thyrotoxicosis (252). Therefore, radioactive iodine should be administered with caution, and patients are often treated prophylactically with beta-adrenergic blocking agents. Some authors recommend treating the patient with antithyroid drugs to control the hyperthyroid state prior to administering radioactive iodine to prevent exacerbation of the hyperthyroid state (242). If normal thyroid tissue is present, it must be removed prior to administering a therapeutic dose of radioactive iodine to functioning thyroid metastases. If a small number of large, accessible, and isolated metastases are producing the thyrotoxicosis, surgical resection may be the best treatment option, following therapy with antithyroid drugs. REFERENCES 1. Woolner JB, McConahey WM, Beahrs OH. Granulomatous thyroiditis (de Quervain’s thyroiditis). J Clin Endocrinol Metab 1957; 17:1202–1221. 2. Fatourechi V, Aniszewski JP, Fatourechi GZ, et al. Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study. J Clin Endocrinol Metab 2003; 88(5):2100–2105. 3. Nordyke RA, Gilbert FI Jr, Lew C. Painful subacute thyroiditis in Hawaii. West J Med 1991; 155(1):61–63. 4. Martino E, Buratti L, Bartalena L, et al. High prevalence of subacute thyroiditis during summer season in Italy. J Endocrinol Invest 1987; 10 (3):321–323. 5. Saito S, Sakurada T, Yamamoto M, et al. Subacute thyroiditis: Observations on 98 cases for the last 14 years. Tohoku J Exp Med 1974; 113(2):141–147. 6. Hay ID. Thyroiditis: Aclinical update. Mayo Clin Proc 1985; 60(12):836–843. 7. Hamburger JI. The various presentations of thyroiditis. Diagnostic considerations. Ann Intern Med 1986; 104(2):219–224. 8. Singer PA. Thyroiditis. Acute, subacute, and chronic. Med Clin North Am 1991; 75(1):61–77.

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181. Chanson P, Weintraub BD, Harris AG. Octreotide therapy for thyroid-stimulating hormone-secreting pituitary adenomas. A follow-up of 52 patients. Ann Intern Med 1993; 119(3):236–240. 182. Comi RJ, Gesundheit N, Murray L, et al. Response of thyrotropin-secreting pituitary adenomas to a long-acting somatostatin analogue. N Engl J Med 1987; 317(1):12–17. 183. Gancel A, Vuillermet P, Legrand A, et al. Effects of a slow-release formulation of the new somatostatin analogue lanreotide in TSH-secreting pituitary adenomas. Clin Endocrinol (Oxf) 1994; 40(3):421–428. 184. Francis TB, Smallridge RC, Kane J, et al. Octreotide changes serum thyrotropin (TSH) glycoisomer distribution as assessed by lectin chromatography in a TSH macroadenoma patient. J Clin Endocrinol Metab 1993; 77(1):183–187. 185. Caron P, Gerbeau C, Pradayrol L, et al. Successful pregnancy in an infertile woman with a thyrotropin-secreting macroadenoma treated with somatostatin analog (octreotide). J Clin Endocrinol Metab 1996; 81(3):1164–1168. 186. Kienitz T, Quinkler M, Strasburger CJ, et al. Long-term management in five cases of TSH-secreting pituitary adenomas: A single center study and review of the literature. Eur J Endocrinol 2007; 157(1):39–46. 187. Dhillon KS, Cohan P, Kelly DF, et al. Treatment of hyperthyroidism associated with thyrotropin-secreting pituitary adenomas with iopanoic acid. J Clin Endocrinol Metab 2004; 89(2):2708–2711. 188. Daousi C, Foy PM, MacFarlane IA. Ablative thyroid treatment for thyrotoxicosis due to thyrotropin-producing pituitary tumours. J Neurol Neurosurg Psychiatry 2007; 78(1):93–95. 189. Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stippled epiphyses, goiter and abnormally high PBI: Possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 1967; 27(2):279–294. 190. Gershengorn MC, Weintraub BD. Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone. A new syndrome of “inappropriate secretion of TSH”. J Clin Invest 1975; 56(3):633–642. 191. Lafranchi SH, Snyder DB, Sesser DE, et al. Follow-up of newborns with elevated screening T4 concentrations. J Pediatr 2003; 143(3):296–301. 192. Wu SY, Cohen RN, Simsek E, et al. A novel thyroid hormone receptor-beta mutation that fails to bind nuclear receptor corepressor in a patient as an apparent cause of severe, predominantly pituitary resistance to thyroid hormone. J Clin Endocrinol Metab 2006; 91(5):1887–1895. 193. Beck-Peccoz P, Persani L, Calebiro D, et al. Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis. Best Pract Res Clin Endocrinol Metab 2006; 20(4):529–546. 194. Tsunekawa K, Onigata K, Morimura T, et al. Identification and functional analysis of novel inactivating thyrotropin receptor mutations in patients with thyrotropin resistance. Thyroid 2006; 16(5):471–479. 195. Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: Genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 2007; 21(2):277–305. 196. Mamanasiri S, Yesil S, Dumitrescu AM, et al. Mosaicism of a thyroid hormone receptor-beta gene mutation in resistance to thyroid hormone. J Clin Endocrinol Metab 2006; 91(9):3471–3477.

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4 Hypothyroidism Michael T. McDermott and E. Chester Ridgway University of Colorado Denver, School of Medicine, Aurora, Colorado, U.S.A.

INTRODUCTION Hypothyroidism is a condition in which the thyroid gland produces amounts of thyroid hormones that are insufficient to satisfy the requirements of peripheral tissues. The normal thyroid gland secretes both thyroxine (T4) and triiodothyronine (T3). T4 is converted to T3 in peripheral tissues by the enzyme 5’ deiodinase (1); 85% of circulating T3 is produced by peripheral conversion from T4, whereas 15% is directly secreted from the thyroid gland (2,3). Both T4 and T3 are transported across target cell membranes to enter the cytoplasm and later the nucleus where they bind to specific thyroid hormone receptors. T3 binds to these receptors with about 10-fold higher affinity than does T4. The thyroid hormone-receptor complex then binds with other cofactors to the regulatory regions of thyroid hormone responsive genes, where it governs the production of various proteins that mediate thyroid hormone effects (4–7). Receptors for thyroid hormones are located in multiple tissues throughout the body, being most abundant in pituitary, brain, liver, kidney, heart, muscle, bone, and skin cells (6,7). The multitude of thyroid hormone responsive tissues throughout the body underlies the diverse array of clinical features that may be seen in patients experiencing thyroid hormone deficiency. The clinical evaluation and management of patients with hypothyroidism is relatively straightforward in many cases. However, the common symptoms and signs of hypothyroidism are neither sensitive nor specific and may therefore pose numerous potential diagnostic pitfalls. Even the most experienced clinicians may be challenged by the protean and variable clinical features of hypothyroidism. This chapter will discuss the epidemiology, etiology, clinical manifestations, and 145

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diagnosis of hypothyroidism but will focus primarily on practical issues in the management of patients with thyroid hormone deficiency.

EPIDEMIOLOGY Primary hypothyroidism is the most common functional disorder of the thyroid gland. Overt hypothyroidism, or thyroid failure, is defined biochemically as an elevated serum thyroid-stimulating hormone (TSH) and a serum free T4 concentration that is below the population reference range. Subclinical hypothyroidism, or mild thyroid failure, is defined as an elevated serum TSH with a serum free T4 concentration that is still within the population reference range. Hypothyroidism, both overt and subclinical hypothyroidism, is distinctly more common in women than in men and increases in frequency with age. Published statistics regarding prevalence and incidence are variable because existing studies have differed significantly in regard to population age range, geographic location, and criteria used to define the presence and degree of thyroid failure. The annual incidence has been estimated to be 4 to 5 per 1000 population per year in women and 0.6 to 0.9 per 1000 per year in men (8,9). The prevalence of overt hypothyroidism has been reported to be approximately 1% to 3% in large population-based screening studies (9–11). Subclinical hypothyroidism is much more prevalent having been found in 4% to 10% of multiple populations (9–19). The Colorado Thyroid Disease Prevalence Study of 25,862 state residents reported an elevated serum TSH concentration in 9.5% of all subjects and in 8.9% of those who were not already taking thyroid hormone; nearly 75% of these individuals had serum TSH values between 5 and 10 mU/L and ⬎95% had normal serum total T4 levels (18). The National Health and Nutrition Examination Survey III (NHANES III) screened 17,353 adults and children throughout the United States and found elevated serum TSH levels (⬎4.5 mU/L) in 1.4% to 8.1% of subjects in all age brackets younger than 60 years of age (19). This study and others have reported significantly higher prevalence rates in the elderly population, varying from 7% to ⬎17% in subjects older than 60 years of age (10,13–19). A recent reanalysis of the NHANES data suggested, however, that the 97th percentile for TSH in persons older than 80 years without antithyroid antibodies extends to 7.5 mU/L, suggesting that the true prevalence of SCH in the elderly may be considerably lower (20). Progression from subclinical to overt hypothyroidism has been reported to occur in 5% to 18% of patients per year (8,12,16,17,21,22). Individuals most likely to undergo progression are those with higher initial serum TSH levels, positive antithyroid antibodies, and a prior history of radioiodine or external beam radiation therapy (13,23,24). On the other hand, individuals with minimal TSH elevations may remain stable for years without developing overt hypothyroidism (23–26), and up to 37% may have their TSH values return to within the population reference range (24,25). Patients with milder TSH elevations are more likely to

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achieve normal serum TSH levels over a three- to five-year follow-up period (24–26). ETIOLOGY Thyroid hormone deficiency may result from disease of the thyroid gland itself (primary hypothyroidism), disorders of TSH secretion due to pituitary disease (secondary hypothyroidism), or abnormalities of thyrotropin-releasing hormone (TRH) production from the hypothalamus (tertiary hypothyroidism). The latter two situations are more generally referred to as “central hypothyroidism” (27,28). Primary hypothyroidism accounts for over 99.5% of all diagnosed cases of hypothyroidism whereas central hypothyroidism is responsible for less than 0.5% (28), although some sources suggest this may be as high as 5% (29). Conditions that cause primary and central hypothyroidism are listed in Table 1 (30–39). Medications that have been reported to cause primary hypothyroidism (40) include amiodarone (41,42), lithium (43–46), interferon-alpha (47–49), interleukin-2 (50), and the tyrosine kinase inhibitors, sunitinib (51–54) and sorafenib (55). Bexarotene causes central hypothyroidism by interfering with TSH secretion (56,57). CLINICAL MANIFESTATIONS Overt Hypothyroidism General Features Thyroid hormone deficiency results in a broad spectrum of symptoms, signs, and laboratory abnormalities (58–62) that progress gradually over time. Affected patients often experience fatigue, weakness, weight gain (usually ⬍10 lb), cold intolerance, dry skin, facial puffiness, hair loss, constipation, arthralgias, myalgias, decreased libido, menstrual irregularity and menorrhagia, difficulty concentrating, and depression. Common physical findings include bradycardia, hypertension, cool skin with a yellowish discoloration, periorbital edema, coarse hair, thinning of the lateral eyebrow regions, muscle weakness, carpal tunnel syndrome, and delayed relaxation phase of the deep tendon reflexes. The most frequently reported features from studies in the 1930s (60) and in the 1990s (61) are shown in Table 2. Depending upon the underlying etiology, the thyroid gland may be visibly or palpably enlarged, normal, or nonpalpable. Patients whose hypothyroidism occurs acutely (withdrawal of thyroid hormone therapy prior to a radioiodine scan or treatment for thyroid cancer) tend to have more severe symptoms but less prominent physical findings than do patients whose hypothyroidism developed over a more prolonged period of time. Also, elderly patients tend to have fewer symptoms of hypothyroidism than younger patients (63). Hypothyroid patients may also exhibit a number of general laboratory abnormalities such as anemia (macrocytic, normocytic, or microcytic), hyponatremia, hypercholesterolemia, elevated liver-associated enzymes, and increased creatine

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Table 1 Etiology of Hypothyroidism A. Primary hypothyroidism 1. Chronic lymphocytic thyroiditis (Hashimoto’s disease) 2. Thyroidectomy 3. Radioiodine therapy 4. External radiation therapy (⬎2000 R) 5. Infiltrative/infectious diseases 6. Iodine deficiency 7. Genetic disorders a. TSH receptor gene mutations b. Iodide symporter gene mutations c. Defects in thyroid hormone synthesis 8. Disruptive thyroiditis (usually transient) a. Postpartum thyroiditis b. Silent (painless) thyroiditis c. Subacute (granulomatous) thyroiditis 9. Drug-induced hypothyroidism a. Thionamides b. Iodine excess c. Amiodarone d. Lithium e. Interferon alpha f. Tyrosine kinase inhibitors g. Retinoid X receptor ligands B. Central hypothyroidism 1. Mass (tumor, aneurysm) 2. Infiltrative/infectious diseases 3. Pituitary/hypothalamic surgery 4. Pituitary/hypothalamic radiation therapy 5. Genetic disorders a. Pit-1/Prop-1 gene mutations b. TSH␤ gene mutations c. TRH receptor gene mutations

kinase (CK). Prolongation of the bleeding time, suggesting platelet dysfunction, is another frequent finding. Elevation of the serum prolactin level is commonly present and may occasionally present a diagnostic dilemma (discussed further later). Pleural and pericardial effusions may be seen on chest X-rays while electrocardiograms are frequently characterized by bradycardia, diffuse low voltage, and nonspecific ST segment- and T-wave abnormalities. Symptoms of central hypothyroidism are similar to, but tend to be milder than, those seen in patients with primary hypothyroidism. Since this condition most commonly results from neoplastic or inflammatory processes involving the pituitary gland and/or the hypothalamus, central hypothyroidism is often accompanied by pituitary mass effects such as headaches, visual field defects, ophthalmoplegia,

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Table 2 Clinical Symptoms in Patients with Overt Hypothyroidism Symptom

% of Cases

Symptom

% of Cases

A. Early Studies—1930s (57) Weakness Dry skin Coarse skin Lethargy Slow speech Eyelid puffiness Cold intolerance Decreased sweating Cold skin Thick tongue Facial edema Coarse hair Pale skin Memory impairment

99 97 97 91 91 90 89 89 83 82 79 76 67 66

Constipation Weight gain Hair loss Lip pallor Dyspnea Peripheral edema Hoarseness Anorexia Nervousness Menorrhagia Palpitations Deafness Precordial pain

61 59 57 57 55 55 52 45 35 32 31 30 25

B. Recent Study—1990s (58) Dry skin Cold intolerance Coarse skin Periorbital puffiness Diminished sweating Weight gain

76 64 60 60 54 54

Paresthesias Cold skin Constipation Slow movements Hoarseness Impaired learning

52 50 48 36 34 22

Source: Adapted from Refs. 57, 58.

deficiencies of other anterior pituitary hormones and, less commonly, diabetes insipidus. These features often overshadow the manifestations of hypothyroidism (27,28). Pulmonary Abnormalities The fatigue and decreased exercise tolerance commonly seen in hypothyroid patients may be partly related to the associated disorders of pulmonary function. Prominent among the pathophysiological features of thyroid failure are CO2 retention, hypoxemia, decreased diffusing capacity of carbon monoxide (DLCO), and increased alveolar-arterial (A-a) oxygen gradients (64–68). Mechanisms for these effects include upper airway obstruction from goiter and soft tissue enlargement, decreased compliance of the chest wall, respiratory muscle weakness (69–71), increased capillary permeability (72,73), pleural effusions (74,75) and impairment of both hypoxic and hypercapneic ventilatory drives (76–78). This combination of aberrations may also predispose to peripheral or central sleep apnea (79–83). Respiratory muscle weakness and impaired ventilatory drives may also profoundly

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impair the ability of acutely ill hypothyroid patients to be weaned from assisted ventilation devices (84). Cardiovascular Abnormalities Pericardial effusions may occur in up to 50% of patients with overt thyroid failure (74,85,86); the effusions are usually small and have little clinical significance (87), although pericardial tamponade can rarely occur (88). Myocardial dysfunction, both systolic and diastolic, is another well-recognized feature of overt hypothyroidism (89–97); reversible asymmetric septal hypertrophy has been reported as well (98). Thyroid hormone deficiency is known to increase systemic vascular resistance (90,99), which may further impair left ventricular performance. Although hypothyroidism alone rarely causes congestive heart failure (29,100), a severe dilated cardiomyopathy has been reported in a profoundly hypothyroid young man with complete reversal upon institution of thyroid hormone replacement therapy (101). Hypothyroidism also predisposes to the development of coronary artery disease; the most commonly implicated mechanisms are the associated lipid disorders and hypertension (18,102,103). Transient myocardial ischemia, due to regional myocardial perfusion abnormalities, has been demonstrated in some patients with severe thyroid failure (104). Hypothyroidism has also been shown to be associated with increased central arterial stiffness (105) and increased carotid intimamedial thickness (106), both of which improve significantly after the institution of levothyroxine replacement therapy (105,106). Serum CK levels are often increased in hypothyroidism (107–110); although the CK is generally of the MM (skeletal muscle) fraction, there may also be a component of the MB (myocardial) fraction in some patients (111). Elevated CK levels may occasionally lead to a mistaken diagnosis of acute myocardial infarction in hypothyroid patients experiencing atypical chest pain (112). Endocrine Abnormalities Hypothyroidism can cause hyperprolactinemia (113,114). Patients with longstanding hypothyroidism may sometimes develop marked prolactin elevations associated with pituitary enlargement (pseudotumors) due to thyrotrope hyperplasia (115–117). Reported patients have presented with high serum prolactin levels and significant pituitary enlargement on imaging studies, suggesting the presence of pituitary prolactinomas. Upon discovery of elevated serum TSH levels and institution of thyroid hormone replacement therapy, the elevated prolactin levels and pituitary enlargement have completely resolved. Hypothyroidism may, on occasion, be associated with adrenal insufficiency. This most commonly occurs in patients with type 2 autoimmune polyendocrine syndrome (APS 2; Schmidt’s syndrome), humen leucocyte antigen (HLA)-DR3/DR4 related condition in which circulating organ-specific autoantibodies cause thyroid failure; adrenal failure; and, less often, type 1 diabetes mellitus (118). The two disorders may also coexist in patients with tumors or infiltrative disorders of the pituitary gland

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or hypothalamus, resulting in central hypothyroidism and central adrenal insufficiency (119); such patients often have evidence of pituitary mass effects, other anterior pituitary hormone deficiencies and, less frequently, diabetes insipidus (27,28). Since thyroid hormone replacement may acutely lower serum cortisol levels by increasing the cortisol metabolic clearance rate (120–122), initiating thyroid hormone replacement without recognizing and treating coexisting adrenal disease may precipitate an acute adrenal crisis (119). Adrenal function should be assessed in any hypothyroid patient with a positive family history of adrenal insufficiency or Schmidt’s syndrome, hyperkalemia, visual field defects, a known pituitary mass, other anterior pituitary hormone disorders, or diabetes insipidus. Children with hypothyroidism often have short stature, exhibiting an abrupt departure from the normal growth curve corresponding to the onset of thyroid failure; deficiencies of growth hormone secretion and action have been described in these patients (123–126). Both delayed puberty (127,128) and precocious pseudopuberty (129,130) have been described in hypothyroid children; the mechanism for the latter is uncertain but may result from a type of hormonal cross-talk involving the effects of increased TRH and/or TSH on the gonadal axis (130). In adult women, hypothyroidism may cause infertility, anovulation, irregular or heavy menses, amenorrhea, and galactorrhea (128), while in men it may cause infertility, defective spermatogenesis, and erectile dysfunction (131–133). Psychiatric Disorders Depression and other psychiatric disturbances in patients with hypothyroidism were initially reported in the late 19th century (134–137). The term “myxedema madness,” first used in 1949, referred to the relatively frequent discovery of hypothyroidism in patients who were residents of mental hospitals (138). Neuropsychiatric alterations that have since been described in association with hypothyroidism span a wide spectrum of conditions, including irritability, poor concentration, impaired memory, cognitive dysfunction, depression, paranoia, hallucinations, and schizophrenia (139–141). Neurological Disorders Cretinism with mental retardation is a well-known consequence of endemic iodine deficiency and of untreated congenital hypothyroidism, emphasizing the critical role thyroid hormone plays in brain development (142). It has been well demonstrated that euthyroid children whose mothers had untreated or inadequately treated hypothyroidism during pregnancy have an increased likelihood of neuropsychological or cognitive impairment (143–149). Hypothyroid adults may, as discussed earlier, exhibit a variety of psychiatric disorders (139–141). Peripheral metabolic polyneuropathies and multiple entrapment neuropathies, including but not limited to carpal tunnel syndrome, are also well described (150–153). Rarely, hypothyroidism has been reported to cause a central focal neurological disorder such as cerebellar ataxia (154).

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Musculoskeletal Disorders Arthralgias, myalgias and variable degrees of proximal myopathy are wellrecognized features of thyroid hormone deficiency (107,109,155–158). Moderate to marked elevations of serum muscle enzymes are also well described (107–112) and acute exertional rhabdomyolysis has even been reported (159). Less commonly, a peculiar myopathy characterized by muscle hypertrophy, stiffness, weakness, and slowness of movement have been described in association with hypothyroidism; this has been referred to as Hoffman’s syndrome in adults (160,161) and as the Kocher-Debre-Semelaigne syndrome in children (162). Infections Hypothyroid patients have an increased propensity to develop infections, particularly those of the upper and lower respiratory tract, urinary tract, and skin. Symptoms and signs related to these infections may occasionally be the initial manifestations of hypothyroidism. This increased susceptibility to infections is not well understood but likely involves hypothyroid-related alterations of respiratory and bladder function, reduced cutaneous blood flow, and decreased activity of circulating and tissue phagocytic cells (163–165). Subclinical Hypothyroidism Subclinical hypothyroidism (SCH) (Table 3) is often asymptomatic, but up to 30% of affected patients may experience nonspecific physical and psychiatric symptoms (18,166–177). In the Colorado Thyroid Disease Prevalence Study (18), patients with only mild TSH elevations had slightly but statistically significantly more symptoms on a validated thyroid health questionnaire than did euthyroid controls (Table 4). Symptomatic improvement following institution of thyroid hormone replacement has been reported in most published studies (166–170,175), depending largely on the baseline TSH of the affected subjects, with more symptomatic benefit being demonstrated in subjects with TSH levels ⬎ 10 to 12 mU/L (175–179). Subtle disorders of myocardial function have been well described in patients with SCH (166,167,169,177,180–192), but their clinical significance is uncertain (177). Reported abnormalities include impaired myocardial contractility (166,167,169,180–185,187,191) and diastolic dysfunction (185–187,190), at rest (167,180,181,184–187) or with exercise (169,182–187). Abnormal myocardial Table 3 Subclinical Hypothyroidism/ Mild Thyroid Failure—Definition Few or no clinical signs Normal free T4 and free T3 Elevated basal TSH

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Table 4 Clinical Symptoms in Patients with Subclinical Hypothyroidism Percent having symptoms Symptom

Subclinical hypothyroidism (n = 1799)

Euthyroid controls (n = 22,842)

p

28 24 22 22 18 17 15 12 8 7

25 20 18 18 16 15 12 10 7 5

⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.01 ⬍.001 ⬍.001 ⬍.05 ⬍.05 ⬍.05

Dry skin Poor memory Slow thinking Muscle weakness Fatigue Muscle cramps Cold intolerance Puffy eyes Constipation Hoarseness Source: Adapted from Ref. 17.

texture has been demonstrated in SCH subjects by videodensitometric analysis (187). SCH has also been reported to increase the risk of developing congestive heart failure (193) (Fig. 1). Right ventricular systolic and diastolic performance has also been reported to be impaired (192). The reported effects of thyroid hormone replacement on cardiac function in SCH patients include enhanced cardiac contractility (166,169,181–185,187,191), improvement of diastolic function (186,187,190), normalization of videodensitometric myocardial texture (187), and improved right ventricular performance (192). Increases in pulmonary vital capacity, the anaerobic threshold and oxygen uptake at the anaerobic threshold have also been demonstrated (169). Considerable evidence implicates SCH as a risk factor for atherosclerotic cardiovascular disease. Patients with SCH have well documented mild elevations of serum total cholesterol, low density lipoprotein (LDL) cholesterol (18,170,175,194–204) and non-high density lipoprotein (HDL) cholesterol concentrations (203), and abnormal lipoprotein remnant metabolism (204). However, one study of patients with short-term overt hypothyroidism reported that while total cholesterol and LDL cholesterol were increased, the profile was not atherogenic since the increases were predominantly in large LDL particles with small, dense LDL particle concentrations remaining unchanged (205); whether or not this is also true in chronic subclinical hypothyroidism remains to be determined at this time. Some reports suggest that even high normal serum TSH values may adversely affect serum lipid and lipoprotein levels (206–208). It has been estimated that an increase in the serum TSH level of 1 mU/L is associated with a rise in the serum total cholesterol concentration of 3.5 mg/dL in women and 6.2 mg/dL in men (207). The condition is also reported to be associated with insulin resistance and features of the metabolic syndrome (abdominal obesity,

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Figure 1 Congestive heart failure (CHF) cumulative events in older subjects in relation to serum TSH levels. Higher TSH levels were associated with a higher rate of CHF events (p = 0.03 for trend). CHF events were higher in subjects with TSH levels ≥7.0 mU/L compared with euthyroid subjects (p = 0.006); CHF events were not higher in subjects c 2005, with TSH levels between 4.5 and 6.9 mU/L. Source: From Ref. 193. Copyright  American Medical Association. All Rights reserved.

hypertension, elevated triglycerides, and low HDL cholesterol) (209–215). One large cross-sectional study in Australia, however, did not find an association between SCH and hypertension (216). A positive association between serum TSH levels and body mass index and obesity, even within the population reference range for TSH, has also been reported (217,218). Levothyroxine replacement in SCH patients with TSH levels ⬎10 to 12 mU/L results in statistically significant reductions in LDL cholesterol (170,175,197–200,202) and non-HDL cholesterol (203); several studies in patients with milder TSH elevations (5–12 mU/L) have not been conclusive on this issue (177–179,219), but two carefully designed, randomized, controlled studies have reported a similar beneficial reduction in serum total cholesterol and LDL cholesterol (175,200). Two quantitative literature reviews (197,198) of the prospective studies examining this issue have concluded that levothyroxine treatment of patients with SCH lowers both serum total cholesterol and LDL cholesterol by approximately 10 mg/dL. Surrogate markers of cardiovascular disease have been reported to be abnormal in patients with SCH. These include increased pulse wave velocity (220), impaired endothelial function (175,221,222), increased levels of C-reactive

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Figure 2 Carotid intimal medial thickness (IMT) values in individual patients with subclinical hypothyroidism at baseline and on treatment with LT4. (A) Patients whose meanIMT decreased (n = 19). (B) Patients whose mean-IMT did not change (n = 3) or increased (n = 1). Source: From Ref. 200.

protein (210), increased carotid artery intima-media thickness (CIMT) (200) (Fig. 2), and increased arterial stiffness (223). These abnormalities have also been shown to improve with levothyroxine replacement therapy (175,200,220–223). While some studies have demonstrated an association of SCH with the development of atherosclerosis (169,224–229), not all studies are in agreement on this issue (193,230,231,232) (Fig. 3). The Rotterdam Study reported that patients with SCH have a significantly increased prevalence of both aortic atherosclerosis

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Figure 3 Meta-analysis of coronary heart disease (CHD) risk in subclinical hypothyroidism (SH). Odds ratio (OR; diamonds) and 95% confidence intervals (CI; horizontal lines) for CHD in subjects with SH are shown. Abbreviations: CC, case-control study; CS, cross-sectional study; PC, prospective cohort study. Source: From Ref. 228.

and myocardial infarctions and that, after controlling for other known cardiovascular risk factors, SCH was found to be an independent and equally important risk factor for myocardial infarction (224); however, no increase in myocardial infarctions was observed in SCH over a 4.6-year follow-up period. A Japanese study similarly reported that SCH was associated with ischemic heart disease and with all-cause mortality in men only (226) (Fig. 4). The Busselton Health Study also concluded that SCH was a significant and independent risk factor for coronary heart disease (227). In contrast, other large population-based studies, including the Health, Aging, and Body Composition Study (193), the New Mexico Elder Health Study (230), and the Cardiovascular Health Study (231), did not show an association between SCH and cardiovascular disorders or mortality (231). Another study of subjects over age 85 actually reported enhanced four-year survival in a cohort of very elderly subjects with untreated SCH (232). At this time, there is little data concerning the effects of treating SCH on cardiovascular outcomes. One small uncontrolled, retrospective analysis (233) showed progression of coronary atherosclerosis in subjects with elevated serum TSH levels on levothyroxine therapy compared to those with normal TSH levels (p ⬍ 0.02). An observational study

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Figure 4 Survival rates (Kaplan-Meier survival curves) were lower in men (A) with subclinical hypothyroidism than in the controls, but this difference was not seen in women (B). Source: From Ref. 226.

suggested that patients treated for hypothyroidism might have an increased risk of cardiovascular events, although the authors attributed this finding to underlying atherosclerosis from preexisting hypothyroidism, inappropriate thyroid hormone dosing, or both (234). Randomized controlled trials to determine if treatment of SCH improves cardiovascular outcomes are clearly needed (177,178).

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Cross-sectional studies have demonstrated evidence of specific neurobehavioral and neuromuscular symptoms in mild thyroid failure patients (18,174,235– 244). Depression (235–239), memory loss (18,174,235,240,241), cognitive impairment (174,241,242), and a variety of neuromuscular complaints (243,244) have all been reported to occur more frequently in patients with this condition. Other studies, however, have found no evidence of depression (245), cognitive loss (245), or neuropsychological dysfunction (246) in SCH patients. Objective evidence of neurological dysfunction, including decreased peripheral nerve conduction amplitude (247), an abnormal stapedial reflex (248), abnormal cerebral nerve latency (249), and alterations of cerebral blood flow (250) have been demonstrated in these patients. Skeletal muscle abnormalities, including elevated serum creatine phosphokinase levels (110), increased circulating lactate levels during exercise (243) and repetitive discharges on surface electromyography (244) have also been reported. Memory has been shown to improve significantly in one randomized controlled trial (RCT) (240) and in two uncontrolled studies in which mild thyroid failure patients were given levothyroxine therapy (235,241). Other reported benefits from uncontrolled interventional studies include reduction in neuromuscular complaints (235,244) and normalization of abnormal electromyograms (244). Myxedema Coma Myxedema coma is a life-threatening condition that represents the extreme end of the spectrum of thyroid hormone deficiency (251–254). It usually occurs in elderly patients, with inadequately treated or untreated hypothyroidism, who then have a superimposed precipitating event. Conditions reported to precipitate myxedema coma include prolonged cold exposure, infection, trauma, surgery, myocardial infarction, congestive heart failure, pulmonary embolism, stroke, respiratory failure, gastrointestinal bleeding, and the use of medications, particularly central nervous system depressants. Affected patients generally present with hypothermia, bradycardia, hypotension, and hypoventilation along with central nervous system manifestations such as seizures, stupor, and coma. Deep tendon reflexes are absent or exhibit a severely delayed relaxation phase. Typical myxedematous changes of the skin are usually apparent. Pleural, pericardial, and peritoneal effusions are frequent findings. An ileus is common and acute urinary retention may also occur. Treatment, discussed later, must be instituted promptly because of the very high mortality rate in this condition when appropriate therapy is delayed or neglected (255,256). DIAGNOSIS Hormone Assays The key to the accurate diagnosis of hypothyroidism is measurement and appropriate interpretation of serum thyrotropin (TSH) and thyroid hormone levels. Thyroid

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Figure 5 Primary hypothyroidism development. In the earliest stage, mild hypothyroidism, the only detectable abnormality is an elevated serum TSH level. Progression to moderate thyroid failure is characterized by a higher serum TSH concentration and a low serum T4 value; the serum T3 level is relatively preserved by enhanced T4 to T3 conversion. In severe hypothyroidism, the serum TSH is higher still, the T4 is further reduced and the serum T3 declines below the normal range.

gland failure is a gradual but generally progressive process. Although it exists on a continuum, it is instructive to characterize the disorder according to grades of severity as being mild, moderate, or severe (Fig. 5, Table 5). When the thyroid gland first begins to fail, its production and secretion of T4 and T3 diminish. The slight drop in serum thyroid hormone levels is detected by the hypothalamus and pituitary gland, which respond with an increase in pituitary TSH secretion. TSH then stimulates the secretory activity of the damaged thyroid gland, achieving serum T4 and T3 levels within the population reference range but still low for that individual patient. The only detectable abnormality at this early stage, therefore, is a mildly or moderately elevated serum TSH concentration, usually ⬍10 mU/L. As thyroid hormone synthetic capacity worsens, T4 levels begin to decline but serum T3 is preferentially maintained because of increased T4 to T3 conversion due to enhanced 5’ deiodinase activity in both the thyroid gland and peripheral tissues (257–259). Moderate hypothyroidism is thus characterized by a high serum TSH level and low T4 but a normal T3 concentration. Once thyroid function becomes severely impaired, insufficient T4 is generated to sustain adequate T3 production and the T3 level also declines. Accordingly, severe hypothyroidism is characterized by a very high serum TSH level, very low serum T4 and free T4 and a low serum T3 concentration.

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Table 5 TSH and Thyroid Hormone Levels in Primary Hypothyroidism, Central Hypothyroidism, Euthyroid Sick Syndrome and Thyroid Hormone Resistance Syndromes

Primary hypothyroidism Mild Moderate Severe Central hypothyroidism Mild Moderate Severe Euthyroid sick syndrome Mild–Moderate Moderate–Severe Recovery Thyroid hormone resistance

TSH

T4

Free T4

T3

Free T3

T3 RU

↑ ↑↑ ↑↑↑

N ↓ ↓↓

N ↓ ↓↓

N N ↓

N N ↓

N N ↓

N ↓, N ↓, N

N ↓ ↓↓

N ↓ ↓↓

N N ↓

N N ↓

N N ↓

N N, ↓ N, ↑

N ↓ N

N N N, ↓

↓ ↓↓ N

↓ ↓↓ N

N ↑ N

N, ↑

↑

↑

↑

↑

N, ↑

When thyroid gland failure is secondary to inadequate pituitary TSH secretion (central hypothyroidism), the serum TSH level fails to rise, making the diagnosis of mild central hypothyroidism very difficult to make. Progressively more severe degrees of central hypothyroidism are characterized by declining serum T4 and T3 profiles similar to those seen with primary hypothyroidism (Fig. 6, Table 5) with the exception that the serum TSH level remains normal or low (27,28,260). In some cases, however, mildly elevated serum TSH concentrations have been observed; such patients apparently produce a TSH molecule with normal immunological but reduced biological activity due to altered glycosylation (261,262). Hypothyroidism that occurs after antithyroid drug therapy or radioiodine treatment of thyrotoxicosis is often characterized by a mixed hormone profile. Serum T4 and T3 levels commonly decrease rapidly after therapy and become frankly low by six to eight weeks. In approximately 90% of patients, the TSH levels remain low or undetectable for several weeks, giving a picture similar to that seen in central hypothyroidism (263). This transient phenomenon is likely due to delayed recovery of chronically suppressed pituitary thyrotropes caused by the antecedent thyrotoxicosis. Eventually, the thyrotrope cells do recover and serum TSH levels increase as the majority of patients progress to develop typical primary hypothyroidism (263). Approximately 15% of patients, however, may later recover sufficient thyroid function to return to a euthyroid state (264). TSH elevations are almost always indicative of some degree of primary thyroid failure. However, variable elevations of the serum TSH level can sometimes be seen in other conditions such as the recovery phase of the nonthyroidal illness

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Figure 6 Central hypothyroidism development. This disorder results from impaired pituitary TSH secretion and thus there is no increase in serum TSH to signal early or mild dysfunction. Moderate central hypothyroidism is characterized by a low serum T4 concentration, a low or low-normal TSH level and a normal T3 value. In severe central hypothyroidism, the serum T4 is lower still, the T3 becomes depressed and the TSH remains in the low or low-normal range.

syndrome (euthyroid sick syndrome) (265,266), untreated or inadequately treated adrenal insufficiency (267), and rare genetic mutations in the TSH receptor (268). Antithyroid Antibodies Measurement of antithyroid antibodies is useful for determining the etiology of primary hypothyroidism. The major thyroid antigens known to elicit autoantibody formation are thyroglobulin (TG), thyroid peroxidase (TPO), and the TSH receptor. Lymphocytic thyroiditis (Hashimoto’s disease) is characterized by the presence of high titers of anti-TG and anti-TPO antibodies. Anti-TG antibodies are present in approximately 60% of patients with lymphocytic thyroiditis whereas anti-TPO antibodies are present in about 95%; thus, anti-TPO antibodies are the best autoantibody marker for this disorder (30). Knowledge of antithyroid antibody titers may be particularly useful when one is attempting to predict whether patients with subclinical hypothyroidism will progress to overt hypothyroidism since this progression is much more likely in patients who have circulating anti-TPO antibodies (13,23,24). Hypothyroidism may occasionally result from the production of TSH receptor blocking antibodies (269–271) without evidence of anti-TG and anti-TPO antibodies.

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Screening for Hypothyroidism Screening for hypothyroidism among asymptomatic persons is an issue that has sparked significant controversy (11,178,179,272–279). A comprehensive 1996 cost-utility analysis (273) estimated that screening for hypothyroidism at the routine health examination starting at age 35 years in both sexes was as cost effective as several other generally accepted medical practices. American College of Physicians (ACP) publications in 1998 and 2004 (11,274–276), considering both prevalence and cost-effectiveness, recommended screening women over age 50 years with a serum TSH determination; a free T4 measurement was recommended only if the TSH value is undetectable or ⬎10 mU/L. The Institute of Medicine recommended against routine screening of the Medicare population, however, citing insufficient data showing benefit (277). The American Thyroid Association, in contrast, recommended screening women at age 35 and men at age 45, and repeated screening in both genders every five years thereafter (278). A 2004 Consensus Conference, consisting of a multidisciplinary panel, conducted an evidence-based review based on prevalence, outcomes, and cost-effectiveness data available up to 2001, and concluded that there was insufficient evidence to recommend for or against routine population screening for thyroid disease in adults (178,179); however, they did recommend aggressive case finding in select high-risk patients. Subsequently, a panel of thyroidologists reviewed the same and subsequent evidence in 2004 and concluded instead that population screening for thyroid disease was generally warranted (279). Many experts also recommend screening in all women who are planning pregnancy or early in the first trimester of pregnancy, but this is not universally accepted practice (280). Data favoring screening include studies showing that untreated or inadequately treated maternal hypothyroidism may have adverse consequences on fetal neuropsychological and cognitive development (143–149). It has been demonstrated that undertaking a high-risk case finding strategy, as opposed to general screening, will fail to identify a substantial number of hypothyroid mothers (281). TSH testing is also indicated for all patients who have symptoms compatible with thyroid hormone deficiency, palpably enlarged thyroid glands, and conditions associated with an increased prevalence of associated hypothyroidism (Table 6).

TREATMENT Thyroid Hormone Preparations Thyroid hormone replacement therapy was introduced in 1891 when George Murray reported on studies treating myxedema with injections of an extract of sheep thyroid glands (282). Subsequently, Hector MacKenzie demonstrated similar beneficial effects from an oral preparation of whole sheep thyroid and later from a desiccated extract of ovine thyroid (283). Following these reports, desiccated extracts

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Table 6 Conditions Associated with an Increased Risk of Hypothyroidism A. High-risk patients and conditions (prevalence ⬎10%) 1. Chronic lymphocytic thyroiditis 2. Previous treatment for thyrotoxicosis 3. Previous high dose neck radiation therapy 4. Suspected hypopituitarism 5. Amiodarone therapy B. Moderate risk patients and conditions (prevalence 3–10%) 1. Goiter or thyroid nodular disease 2. Hypercholesterolemia 3. Graves’ ophthalmopathy 4. Postpartum women 5. Lithium carbonate therapy 6. Interferon-alpha therapy 7. Tyrosine kinase inhibitor therapy 8. Associated autoimmune disease C. Low-risk patients and conditions (prevalence ⬍2%) 1. Adults and children at routine visits 2. Dementia 3. Psychiatric patients 4. Elderly patients 5. Sleep apnea

from sheep, cow, and pig thyroids became the standard treatment for hypothyroidism. Synthetic liothyronine (LT3) was introduced in 1956 and levothyroxine (LT4) became available in 1958; however, thyroid extracts remained the treatment of choice because of the assumption that the combination of T4 and T3 in these extracts was more physiological than either component given alone. The discovery in the early 1970s that T4 is converted to T3 in peripheral tissues and that only 15% to 20% of circulating T3 comes from direct thyroid secretion (2,3) led to a reconsideration of this premise. Clinical studies subsequently demonstrated the advantages of using LT4 alone as replacement therapy (284,285) and that serum TSH measurements were a superior tool for monitoring LT4 dosage requirements (286,287). Multiple thyroid hormone preparations are currently marketed for use as thyroid hormone replacement therapy. Pure LT4 is available in various oral R R R (Abbott), Levoxyl
(Jones Pharma/King), Levothroid
brand-name [Synthroid
R (Lloyd, distributed by Forest), Unithroid
(Jerome Stevens)] and generic R R R (Alara), Levothyroxine
(Mylan), Levothyroxine
(Genpharm), [Levo-T
R R

Tirosint (Institute Biochimique), and Levolet (Vintage)] products: there is R ). Pure LT3 is available as an oral also a parenteral formulation (Synthroid
R R
). Mixtures of LT4 preparation (Cytomel ) and a parenteral product (Triostat
R R

and LT3 (Liotrix , Thyrolar ) and several brands of desiccated thyroid are also

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manufactured; their use is generally not recommended because these products contain a higher T3/T4 ratio (1:4) (288,289) than is present in human thyroid secretions (approximately 1:10–20). Due to the high T3 content and the rapid, essentially complete absorption of T3 from the intestinal tract, serum T3 levels rise significantly, often into the supraphysiological range, two to six hours after ingestion of these medications (290). Most thyroid specialists today consider LT4 to be the treatment of choice for hypothyroidism (285,291). This is based on the principal that T4 is converted to T3 in peripheral tissues at a regulated rate that is appropriate for the overall metabolic needs of the body. Physiological replacement of LT4 relieves symptoms and normalizes serum TSH in the vast majority of hypothyroid patients. Furthermore, LT4 therapy given to thyroidectomized individuals in doses sufficient to normalize serum TSH levels has been demonstrated to produce serum T3 levels that are similar to those in the euthyroid, prethyroidectomy state (292). LT4 is available in multiple dose sizes, allowing precise titration of the dosage in each individual patient according to their symptoms and serum TSH levels. Furthermore, its relatively slow intestinal absorption and long serum half-life provide stable serum concentrations with minimal diurnal variation. Side effects and toxicity occur only with overtreatment, a condition that can be avoided by choosing a treatment schedule that is appropriate for each patient and by regular monitoring of the serum TSH. Brand-name LT4 preparations are recommended by many thyroidologists. Several early studies suggested that different LT4 brands were not equal in potency (293–296), while a subsequent study called this into question, reporting that four generic and brand-name preparations were all bioequivalent (297); this sparked a burst of controversy over study design, interpretation of results and conflicts of interest (298–300). In 2005, the FDA determined by its own methodology that many of the brands and generic preparations of levothyroxine were bioequivalent. However, subsequent investigations suggested that the FDA bioequivalence methodology was imperfect, indicating that patients who were switched between levothyroxine preparations may need to be retested with serum TSH measurements five to six weeks later to assure adequate control. This would be especially important for patients whose thyroid hormone levels require precise control, most notably thyroid cancer patients and hypothyroid women during pregnancy. In 2009, the FDA will take a step toward enhancing the quality of all levothyroxine products by requiring that they retain from 95% to 105% of their stated potency throughout their entire shelf life; the previous standard was 90% to 110%. At present, considering their overall low cost, and our desire to provide our hypothyroid patients with the most reliable supply of thyroid hormone, we continue to recommend the use of brand-name LT4 preparations for thyroid hormone replacement in order to assure that there is consistency every time patients refill their prescription. If a patient does switch brands or is placed on a generic preparation of thyroxine, reassessment of the serum TSH is recommended six weeks later, since the preparations may not yield the same target serum TSH.

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The absorption of oral LT4 is approximately 80% whereas that of LT3 is 85% to 100% (301–303). Absorption of LT4 occurs at multiple sites throughout the length of the small intestine but nearly two-thirds occurs in the proximal small bowel (301,302). It is recommended that LT4 be taken fasting, on an empty stomach, in the morning since the presence of food decreases LT4 absorption by about 10% (304). Alternatively, taking LT4 in the evening or at bedtime may provide better medication absorption than morning dosing (305), although this study did not control for the fact that study subjects ate after the morning dose but not after the bedtime dose. Administered LT4 accumulates slowly and has a serum half-life of about seven days. It requires approximately five to six weeks for serum levels of T4 to reach a new steady state on a given dose of LT4; therefore, sampling for serum TSH and/or T4 levels should be performed no sooner than five to six weeks after therapy is initiated or a dosage change has been made. Both euthyroid and hypothyroid individuals exhibit a small but significant diurnal variation in TSH secretion, having slightly higher serum TSH levels between the hours of 11:00 p.m. and 4:00 a.m. (306). In addition, hypothyroid patients have small decreases in serum TSH levels (307,308) and increases in serum total and free T4 concentrations (307) several hours after exogenous LT4 administration. When possible, TSH measurements should be obtained prior to LT4 ingestion. Patient-Oriented Approach to Treatment Thyroid hormone replacement therapy must be individualized for each patient. The average full replacement dose of LT4 is 1.6 to 1.7 ␮g/kg/day (303,309,310). Since dose requirements relate more strongly to lean body mass than to total body mass (311), it may be preferable to estimate a starting dose based on ideal body weight rather than actual weight in obese individuals. Alternatively, the initial LT4 dose can be estimated based on the magnitude of the TSH elevation (312). However, the starting dose, titration schedule, final dose, and ultimate goals of therapy depend upon multiple factors such as the patient’s age, symptoms and general state of health as well as the severity, duration, and underlying cause of hypothyroidism. Overt Primary Hypothyroidism The young, otherwise healthy, patient with overt primary hypothyroidism can usually be started directly on a full LT4 replacement dose of 1.6 to 1.7 ␮g/kg/day (310,313). After six weeks, the serum TSH level should be measured and the results used to guide dosage titration until the serum TSH is normal (314) (Table 7). Since TSH levels in the general population are not normally distributed over the reported normal range, but are skewed with the majority of individuals having values at the low end of the range, most practitioners attempt to maintain serum TSH levels between 0.5 and 2.0 mU/L. Once the TSH concentration is in the desired range, it should be rechecked in three months and then on an annual basis.

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Table 7 Fine Tuning LT4 Dosages If serum TSH is ⬎ 5.0 mU/L 0.5–5.0 mU/L ⬍0.5 mU/L

Then Increase daily LT4 dose by 12.5–25 ␮g/day Continue dose; recheck annually Decrease daily LT4 dose by 12.5–25 ␮g/day

When a hypothyroid patient is older than 60 years, it is prudent to adopt a more cautious approach to LT4 replacement therapy. This is because the likelihood is greater that such patients may harbor subclinical coronary artery disease that could become symptomatic if they are initially given a full replacement dose. Therefore, a starting LT4 dose of 50 ␮g/day and a 25 ␮g/day increment six weeks later is recommended. Once a dose of 75 ␮g/day has been reached, further adjustments should be guided by the results of TSH testing. As in younger patients, the goal of treatment is to relieve symptoms and ideally to maintain the serum TSH between 0.5 and 2.0 mU/L. Hypothyroid patients with known or suspected coronary artery disease should be treated even more carefully. In such patients, many practitioners begin with a low LT4 dose of 12.5 to 25 ␮g/day and increase the dose in 12.5 to 25 ␮g increments every six to eight weeks. A goal TSH level of 0.5 to 2.0 mU/L is appropriate if it can be achieved without precipitation or exacerbation of cardiac symptoms. However, for patients who develop chest pain or palpitations at these doses, a more conservative TSH goal of 2.0 to 5.0 mU/L or slightly higher is preferable. Subclinical Hypothyroidism Once a diagnosis of subclinical hypothyroidism is confirmed by retesting, the decision to be made is whether or not thyroid hormone replacement therapy should be initiated. This question has inspired much study and has engendered significant controversy (176–179,279,315,316). The 2004 Consensus Conference evidencebased review concluded that there was insufficient evidence to recommend for or against routine treatment of patients with mildly elevated serum TSH levels of 5 to 10 mU/L but considered the evidence to be fair in support of treating patients whose serum TSH values are ⬎10 mU/L (178,179). A similar view was expressed in a meta-analysis of thyroid hormone replacement therapy in SCH, which noted that such treatment did not result in improved survival, prevent cardiovascular morbidity, or improve quality of life or symptoms (317). The 2005 thyroid specialist panel report recommended instead that all patients with elevated serum TSH values be considered for levothyroxine therapy and that the treating provider should make this determination based on clinical judgment (279). Because patients with SCH may have a variety of nonspecific symptoms (18,166–177), such as subtle cardiac dysfunction (166,167,169,177,180–192), lipid abnormalities (18,170,175,194–204), increases in other cardiovascular risk

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Table 8 Mild Thyroid Failure—Benefits and Costs of Early Detection and Therapy Benefits 1. Treat symptoms related to mild thyroid hormone deficiency 2. Control associated hypercholesterolemia 3. Prevent progression to overt hypothyroidism Costs 1. Serum TSH assays 2. Levothyroxine therapy 3. Follow-up visits 4. Risk of iatrogenic hyperthyroidism

factors (209–215), and an increased risk of cardiovascular disease (169,224–229), and because of the tendency for the condition to progress to overt hypothyroidism (8,12,16,17,21,22), many experts recommend that most, if not all, patients with mild thyroid failure should be considered for treatment with LT4 in doses sufficient to reduce the serum TSH levels to 0.5 to 2.0 mU/L (Table 8). The management of subclinical hypothyroidism in young patients may vary according to the preference of the provider. One approach is to start LT4 in a dose of 25 to 50 ␮g/day, recheck the serum TSH in six weeks, and adjust the dose in 12.5 to 25 ␮g increments, if needed, until the first dose is reached that brings the TSH into the desired range. That dose is then maintained and the patient is monitored annually. When, and if, the TSH again rises above normal, the LT4 dose is increased in 12.5 to 25 ␮g increments to the next level that normalizes the serum TSH. This method is intended to avoid initial overtreatment in patients who may have significant residual thyroid function and possibly autonomous activity (313,318). An alternative approach is to start patients directly on an estimated full LT4 replacement dose of 1.6 to 1.7 ␮g/kg/day. The serum TSH is then checked six weeks later and the LT4 dose adjusted to bring the TSH level into the 0.5 to 2.0 mU/L range. Once there, the patient should be monitored on an annual basis. The rationale for this method is that these patients will likely develop overt hypothyroidism eventually and will require full replacement doses at that time. By starting them on full replacement at the outset, the time and expense required for multiple stepwise adjustments in the future are avoided and patients do not have recurrent periods of subclinical hypothyroidism as their thyroid glands progressively fail. The risk of this option is that the combination of exogenous and endogenous thyroid hormone may prove to be excessive, especially if there is residual autonomous thyroid activity, producing high-normal serum free T4 levels and suppressed serum TSH concentrations (subclinical thyrotoxicosis). Subclinical hypothyroidism in patients over age 60 should be treated cautiously, again because overtreatment can be hazardous at this age. The recommended approach is to start them on 25 to 50 ␮g/day of LT4 and to increase the dose, as described earlier for young patients, until the first dose that lowers the

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serum TSH into the desired range of 0.5 to 2.0 mU/L is reached (300,303). In the oldest old (patients over age 80 years), the data suggest that mild thyroid failure is associated with decreased mortality (232). Therefore, it has been recommended that treatment be initiated when the serum TSH is higher (e.g., ⬎10 mU/L), and that the target serum TSH be higher than it would be for younger patients, for example, 4 to 6 mU/L. (319). Mild thyroid failure in patients with known or suspected coronary artery disease should be treated carefully using the more gradual approach described earlier for heart patients with overt hypothyroidism. The goal TSH range of 0.5 to 2.0 mU/L is reasonable if the required LT4 dose does not worsen cardiac symptoms. Otherwise, a more conservative TSH goal of 2.0 to 5.0 mU/L or slightly higher would be recommended. Postradioiodine Hypothyroidism Since an elevated serum TSH level often occurs relatively late in the development of postradioiodine hypothyroidism (263), LT4 replacement should be initiated when the patient becomes symptomatic or the serum T4 or free T4 level first becomes subnormal, even if the TSH is still suppressed. Such early replacement may reduce the risk of developing subsequent Graves’ orbitopathy (320). Since most of these patients are young and their hypothyroidism is of short duration, initiating low dose LT4 with gradual titration upward is rarely necessary. Nonetheless, some individuals may have residual autonomous thyroid function and become symptomatically thyrotoxic on full LT4 replacement doses. Therefore an initial LT4 replacement dose of 1.2 to 1.3 ␮g/kg/day in these patients may be appropriate, with careful monitoring of their clinical status, free T4 and TSH levels. About three months after radioiodine treatment, TSH secretory capacity usually recovers, after which serum TSH levels can be used to monitor therapy as in other patients with primary hypothyroidism. The goal serum TSH range for these patients should be 0.5 to 2.0 mU/L. Central Hypothyroidism This disorder is significantly more difficult to manage because of the inability to use serum TSH measurements as an indicator of when to treat and as a guide to the appropriate LT4 replacement dose (27,28,260). These decisions therefore require a greater degree of clinical judgment. Treatment should generally be started when patients develop symptoms consistent with thyroid hormone deficiency and the serum free T4 level is in the low normal or frankly low range. As with primary hypothyroidism, LT4 dosing schedules need to be determined with consideration given to the patient’s age, severity of hypothyroidism, and the presence of underlying illnesses. Since TSH levels are usually uninformative and often misleading in this condition, serum free T4 measurements should be used to monitor the adequacy of LT4 replacement (260). The goal of treatment should be amelioration of pertinent symptoms and maintenance of serum free T4 levels in the mid-normal

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to high-normal range (260,321). Because of the possibility of coexisting central adrenal insufficiency, adrenal function should be assessed prior to LT4 treatment. If adrenal function is found to be inadequate, glucocorticoid replacement should be initiated at the same time LT4 replacement is started. Thyroid Cancer Patients with hypothyroidism resulting from thyroidectomy for thyroid cancer may require as much as 20% more LT4 for replacement and suppression than do patients whose hypothyroidism has resulted from autoimmune thyroid disease or radioiodine treatment of Graves’ disease (322). The serum TSH concentration remains the most accurate guide to the proper LT4 dosage (286,287,323). When TSH suppression is the goal, serum TSH levels should be maintained below or at the lower limits of the normal range, whereas for simple replacement the goal TSH range should be 0.5 to 2.0 mU/L. There is considerable controversy over the appropriate degree of TSH suppression in patients with thyroid cancer. Some believe that LT4 doses sufficient to reduce serum TSH levels to between 0.1and 0.5 mU/L are satisfactory for all patients with thyroid cancer (322). Others believe that full suppression of TSH levels to below the detection limits of third generation TSH assays (⬍0.01 mU/L) is ideal (323–325). Evidence-based practice guidelines from the American Thyroid Association recommend that in patients with low-risk disease who have been shown to be free of disease following surgery and radioiodine ablation therapy, the serum TSH be kept between 0.3 and 2 mU/L. For patients with high-risk invasive or metastatic disease, it is recommended that the TSH level be maintained at ⬍0.1 mU/L indefinitely. For patients with high-risk disease who have no evidence of active disease, the TSH target is 0.1 to 0.5 mU/L (326). Transient Hypothyroidism Hypothyroidism may occasionally be transient, as in the early recovery phase of postpartum thyroiditis, silent thyroiditis, and subacute thyroiditis. Thyroid hormone deficiency is rarely severe during recovery from these conditions but it may be symptomatic and may last as long as several months before the patient returns to a euthyroid state. Permanent hypothyroidism is uncommon in subacute and silent thyroiditis, but may occur in up to 25% of patients with postpartum thyroiditis (327–329). Thyroid hormone replacement is advisable for patients who are symptomatic and for those whose serum TSH levels are ⬎20 mU/L. We recommend initiating treatment with an LT4 dose of 50 to 75 ␮g/day and a goal TSH of 1.5 to 3.0 mU/L, thus permitting sufficient TSH secretion to stimulate recovery of thyroid function as the inflammatory process subsides. After three to six months of therapy, LT4 should be tapered in 25 ␮g decrements until eventual discontinuation, provided serum TSH concentrations remain within the normal range.

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Drug-Induced Hypothyroidism Amiodarone is an anti-arrhythmic agent that is highly lipophilic, having a long half-life of approximately 100 days and a propensity to accumulate in multiple tissues, including the thyroid gland. Each molecule of amiodarone contains two iodine atoms and the compound is 37% organic iodine by weight; a 200 mg tablet delivers about 9 mg of iodine into the circulation. This medication inhibits peripheral T4 to T3 conversion and thereby alters circulating thyroid hormone concentrations (high T4, low T3, and transiently high TSH). It may also precipitate overt symptomatic hypothyroidism or hyperthyroidism (40,41), particularly in patients with underlying goiters or antithyroid antibodies living in iodine-replete areas of the world, such as the United States. Hypothyroidism occurs in approximately 20% of patients on chronic amiodarone therapy. The major mechanism of this effect is probably high iodine delivery to the thyroid gland. High concentrations of intrathyroidal iodine acutely inhibit new thyroid hormone synthesis, a phenomenon known as the Wolff-Chaikoff effect (330,331); while patients with normal thyroid glands usually escape from this effect, patients with underlying thyroid disease often do not and hypothyroidism ensues. Other potential mechanisms for amiodarone-induced hypothyroidism include direct cytotoxic effects of the drug on thyroid cells and possible initiation or augmentation of thyroid autoimmunity. The condition resolves in approximately 50% of patients who discontinue amiodarone administration but persists transiently or permanently in the remainder. We recommend treatment in most cases, particularly if they are symptomatic. Because these patients have underlying heart disease, LT4 should be started in low doses of 25 to 50 ␮g/day and increased carefully in 12.5 to 25 ␮g increments every six to eight weeks in order to bring the TSH into the normal range. If arrhythmias appear to be exacerbated with LT4 therapy, mildly elevated serum TSH levels may be a more appropriate goal. Amiodarone treated patients have been reported to require higher than expected LT4 replacement doses, possibly due to impaired T4 to T3 conversion within the pituitary gland (42). Patients treated chronically with lithium also have a high likelihood of developing thyroid dysfunction. Approximately 50% of patients develop goiters, 20% develop subclinical hypothyroidism, and up to 20% develop overt hypothyroidism (40). Lithium administration is known to increase the intrathyroidal iodine concentration (43); lithium-induced hypothyroidism might therefore be due to the Wolff-Chaikoff effect. Alternatively, since the majority of affected patients have circulating antithyroid antibodies, lithium may also somehow enhance underlying thyroid autoimmunity (44–46). If lithium withdrawal is not practical, we recommend LT4 treatment for all patients who have goiters or elevated serum TSH levels. The goal TSH should be 0.5 to 2.0 mU/L. Interferon-alpha administration has been reported to cause thyroid dysfunction in up to 6% of patients; hypothyroidism and silent thyroiditis are the most commonly found conditions and are believed to result from induction or augmentation of preexisting thyroid autoimmunity (40,47–49). Interleukin-2 has also

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been implicated as a possible cause of silent (painless) thyroiditis (40,50). The tyrosine kinase inhibitors, sunitinib and sorafenib, have been reported to cause hypothyroidism, most likely by inducing thyroiditis or blocking iodine entry into the thyroid (51–55). Discontinuation of these medications is often not desirable, especially if they are showing efficacy against the serious disorders they are used to treat. Accordingly, we recommend LT4 replacement therapy if these patients are symptomatic, if their TSH levels are ⬎20 mU/L, or if TSH elevations of any degree persist for more than three months. The goal TSH levels on treatment should be 0.5 to 2.0 mU/L. Bexarotene, a retinoid x receptor ligand (rexinoid) has been reported to cause central hypothyroidism through suppression of TSH secretion (56,57). Administration of LT4 to normalize free T4 levels is the therapy of choice.

Myxedema Coma Patients suspected of having myxedema coma should be managed in an intensive care unit. The cornerstone of treatment is rapid restoration of the thyroid hormone deficit (251–254). Investigators have recommended intravenous LT4 (332,333) or LT3 (334,335) or a mixture of the two. Current commonly used regimens include the following. LT4 regimen: LT4 200 to 300 ␮g intravenously over more than five minutes followed by oral or intravenous LT4 50 to 100 ␮g/day. LT3 followed by LT4 regimen: LT3 50 to 100 ␮g intravenously over more than five minutes followed by oral or intravenous LT4 50 to 100 ␮g/day. LT4 plus LT3 regimen: LT4 200 to 300 ␮g plus LT3 20 to 50 ␮g intravenously over more than five minutes followed by oral or intravenous LT4 50 to 100 ␮g/day plus LT3 20 to 25 ␮g/day in two divided doses. There are no randomized trials available to settle the issue of which approach is best. Myxedema coma is a syndrome in which severe thyroid hormone deficiency is complicated by one or more precipitating events, as discussed earlier. It is therefore critical to identify and treat these precipitating events just as aggressively as the thyroid hormone deficiency (251–254). Ventilatory and circulatory monitoring and support are essential. Hypothermia may be corrected by slow rewarming with blankets. Underlying infections should be actively sought and aggressively treated when present. Hyponatremia and anemia are common features that should be corrected with isotonic fluids, colloid and blood transfusions when indicated. Hydrocortisone, 75 to 100 ␮g intravenously every six to eight hours, should also be started without delay because thyroid hormone administration acutely increases the metabolic clearance rate of cortisol in these patients (120–122) who may have limited adrenal reserve or frank adrenal insufficiency. When initially described, myxedema coma had a mortality rate of 100%, but with appropriate treatment, the outlook for these patients is considerably improved. Even so, the mortality rates in recent studies have been as high as 45% (255,256).

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Pitfalls in the Management of Hypothyroidism Patients Whose Symptoms Do Not Resolve on LT4 Replacement Presenting symptoms persist in some patients despite seemingly adequate LT4 replacement with normalization of serum TSH concentrations (336–339); this is particularly true of patients with mild thyroid failure who have nonspecific symptoms such as fatigue, weight gain, and depression. The most likely explanation is that these patients’ symptoms are unrelated to their thyroid hormone deficiency. Coexisting disorders such as poor physical conditioning, ineffective sleep habits, stress, endogenous depression, anemia, electrolyte and mineral abnormalities, diabetes mellitus, and other systemic disorders should be evaluated and managed appropriately. Theoretically, using an LT4/LT3 combination that approximates the normal thyroidal secretion ratio might be beneficial, particularly in patients whose initial symptoms persist. In 1999, Bunevicius et al. reported that replacing 50 ␮g of the total LT4 dose with 12.5 ␮g of LT3 for a five-week period resulted in significantly improved neuropsychiatric function, memory, mood, and overall sense of well-being compared to full replacement doses of LT4 alone (340,341). The main criticism of this study was that supraphysiological amounts of T3 were used, since 12.5 ␮g of T3 is more than twice what a normal thyroid gland secretes daily (6 ␮g). Multiple subsequent studies of combination LT4/LT3 therapy followed this initial report (342–350). Although a few reported a mild subjective benefit (340,346,347,349), there has been no statistically significant evidence that patients benefit from combined LT4/LT3 therapy compared to monotherapy with levothyroxine alone. A review (351) and a meta-analysis (352) of all the trials concluded there was no benefit from combination T4/T3 therapy. Moreover, it has been clearly demonstrated that LT4 therapy alone given to thyroidectomized individuals in doses that normalize the serum TSH levels produce serum T3 levels that are indistinguishable from those in the euthyroid, prethyroidectomy state (292). Nonetheless, the possibility remains that some patients with suboptimal clinical responses to LT4 treatment might benefit from the addition of a small dose of LT3 (5 ␮g/day) and a trial of combination therapy may be reasonable in select patients. The future use of combination LT4/LT3 therapy will likely involve the development of slow release T3 preparations and careful comparative studies, using physiological amounts of LT4 and LT3, testing their efficacy, safety, and optimal dosing regimens. Changing Thyroid Hormone Requirements LT4 dose requirements may change under various circumstances (Tables 9 and 10). Pregnant women without endogenous thyroid function often require a 30% to 50% LT4 dose increase during the first 20 weeks of pregnancy (280,353–356). This is particularly important to recognize since inadequately treated maternal hypothyroidism may impair intellectual development of the fetus in utero (143–149).

Hypothyroidism

Table 9 Conditions Associated with Altered LT4 Dose Requirements A. Reasons for increased LT4 dose requirements 1. Pregnancy 2. Use of drugs that decrease LT4 absorption 3. Use of drugs that increase LT4 metabolism 4. Use of drugs that decrease T4 to T3 conversion 5. Estrogen use 6. Malabsorption disorders 7. Nephrotic syndrome 8. Nonadherence 9. Progression of endogenous thyroid disease B. Reasons for decreased LT4 dose requirements 1. Aging 2. Androgen use 3. Metformin use 4. Self-administration of excess LT4 5. Reactivation of Graves’ disease 6. Development of autonomous thyroid nodules

Table 10 Drugs That May Increase Exogenous LT4 Dose Requirements A. Drugs that decrease LT4 absorption 1. Ferrous sulfate 2. Calcium carbonate 3. Aluminum hydroxide 4. Sucralfate 5. Cholestyramine/colestipol 6. Fiber supplements 7. Soy supplements 8. Sevelamer 9. Raloxifene 10. Proton pump inhibitors B. Drugs that increase LT4 metabolism 1. Phenytoin 2. Phenobarbital 3. Carbamazepine 4. Rifampin C. Drugs that inhibit T4 to T3 conversion 1. Amiodarone 2. Glucocorticoids 3. Propranolol 4. Propylthiouracil 5. Ipodate

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Food and medications can interfere with the absorption of thyroid hormone in the intestine; the most prominent effects have been reported with iron, calcium, antacids, bile acid resins, fiber supplements, soy protein, raloxifene, and sevelamer (357–365). Taking these products at a time of day that is separated by at least four to eight hours from the LT4 dose will often bring about resolution of this problem. Since gastric acid is important for LT4 absorption, patients with achlorhydria due to chronic proton pump inhibitor use (366), Helicobacter pylori-related gastritis (366), atrophic gastritis (366), or autoimmune gastritis (367) may have increased LT4 requirements due to malabsorption of their medication (366,367). Intestinal malabsorption due to Celiac disease (gluten sensitive enteropathy) (368) or to lactose intolerance (369) should also be considered as a cause of escalating LT4 requirements and should be pursued when other causes are not evident. Moreover, both autoimmune gastritis and Celiac disease occur more commonly in patients with autoimmune thyroid disease (118,367,368). Nephrotic syndrome with massive urinary protein losses can also be a cause of increasing thyroid hormone requirements (370). Other medications, particularly the anti-seizure and antituberculous agents, can significantly enhance hepatic T4 metabolism, resulting in lower circulating serum T4 concentrations and the need for higher LT4 doses in hypothyroid patients (371). Oral estrogen therapy has been shown to increase LT4 dose requirements by increasing circulating concentrations of thyroxine-binding globulin and thereby reducing serum free thyroid hormone levels (372). Sertraline may also increase thyroid hormone requirements but the mechanism of this effect remains uncertain (373). An apparent increase in LT4 requirements can also result from patient nonadherence (374,375). One clue to this is the finding of an elevated serum TSH level associated with a high-normal or elevated free T4. This profile suggests that the patient missed multiple LT4 doses, resulting in elevation of the serum TSH, and then took extra doses several days preceding blood sampling, acutely raising the serum T4 concentration. The importance of adherence should be specifically discussed with all patients. An alternative solution to nonadherence is weekly, rather than daily, ingestion of the calculated seven-day requirement (1.6–1.7 ␮g/kg × 7) under the supervision of a health-care provider (376). Finally, patients who have increasing LT4 needs may simply be having progression of their underlying thyroid disease with worsening of endogenous thyroid function. When alteration of the precipitating circumstances is not an option, the LT4 dose should be gradually increased at six-week intervals as necessary to maintain the serum TSH concentration in the desired range. Conditions in which LT4 requirements are decreased are also listed in Table 9. This is most commonly seen in elderly patients, in whom LT4 doses are on average 25% lower than those in young patients (377,378). Prescribed or surreptitious androgen use may also results in decreasing LT4 dose requirements due to reductions in thyroxine-binding globulin with a consequent increase in free thyroid hormone concentrations (379). Metformin has been reported to suppress serum TSH levels by a postulated central mechanism (380); while this is not

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related to an increase in circulating thyroid hormone levels, dropping TSH levels in response to metformin could lead one to erroneously believe that the LT4 dose is too high. One must additionally consider the possibility that patients whose LT4 dose needs are apparently dropping are intermittently or regularly taking extra doses of their medications because they feel better on higher doses. While difficult to confirm, this possibility can be investigated by reviewing pharmacy refill records. Finally, increased endogenous thyroid hormone production due to reactivation of Graves’ disease or to development of autonomously functioning thyroid nodules must also be considered in patients whose LT4 dose requirements decline. If the precipitating problem cannot be identified and corrected, the LT4 dose should be gradually decreased at six-week intervals in order to maintain normal serum TSH levels. Patients on stable doses of LT4 may have some inconsistency in their serum TSH levels, varying within and slightly outside the normal range (303). We sometimes see patients with highly variable or “erratic” serum TSH levels (low, normal, and high) while on the same doses of LT4. In these circumstances, poor or variable adherence to the prescribed regimen must again be suspected. These patients could also be taking their LT4 dose with iron, calcium, antacids, bile acid resins, fiber supplements, or food without knowing the effects this may have on thyroid medication absorption. Switching preparations between different brands can also cause significant variations in serum TSH levels. Alternatively, minor differences in serum TSH levels might simply result from having blood sampled at different times of the day in relation to when the medication is taken. When serum TSH levels vary significantly despite a seemingly constant LT4 dose, we recommend that providers carefully review the patient’s medication administration habits and instruct them to take their medications at the same time each day, to separate their LT4 dose time by at least four to eight hours from food and drugs that may interfere with LT4 absorption, and to consistently have their blood drawn for TSH monitoring before their daily LT4 dose. Patients Who Miss Their LT4 Dose Patients sometimes inadvertently miss one or more daily doses of LT4. Some may become quite concerned about potential adverse effects of this omission. While missing doses should be discouraged, patients can be assured that LT4 has a long half-life in the serum (seven days) and that there is virtually no harm resulting from the occasional missed dose. However, the long serum half-life and slow absorption of LT4 also allows providers the option of advising patients that taking an extra “catch-up” pill the next day is permissible, particularly for those who appear to be sensitive to even minor drops in their thyroid hormone levels. Patients Who Are Treated With Desiccated Thyroid Desiccated thyroid or “natural” thyroid preparations contain a higher LT3/LT4 ratio (1:4) than that produced by normal endogenous human thyroid secretion

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Table 11 Conversion from a Desiccated Thyroid Preparation to Levothyroxine Therapy Desiccated thyroid Dose 1.0 grain 1.5 grains 2.0 grains 2.5 grains 3.0 grains 3.5 grains 4.0 grains

Levothyroxine

T4 Content

T3 Content

Equivalent Initial Dose

38 ␮g 57 ␮g 76 ␮g 95 ␮g 114 ␮g 133 ␮g 152 ␮g

9 ␮g 13.5 ␮g 18 ␮g 22.5 ␮g 27 ␮g 31.5 ␮g 36 ␮g

100 ␮g 150 ␮g 200 ␮g 250 ␮g 300 ␮g 350 ␮g 400 ␮g

(approximately 1:10–20) (288,289). The excess LT3 content of these products and the rapid absorption of T3 from the gastrointestinal tract often produce supraphysiological serum T3 levels two to six hours following their ingestion (290). Moreover, LT4 alone given in doses sufficient to normalize serum TSH levels has been shown to normalize T3 levels also (292). For these reasons, most experts discourage the use of desiccated thyroid and recommend that patients who are taking these preparations be switched to brand-name LT4 products. Calculations that take into account both T4 and T3 contents and rates of T4 to T3 conversion have estimated that one grain (60 mg) of desiccated thyroid is approximately equal to 100 ␮g of LT4 (29,288,289). Accordingly, the recommended LT4 doses to be used in patients being switch from desiccated thyroid products are shown in Table 11. Once these changes are made, LT4 doses should be titrated by 12.5 to 25 ␮g every six weeks until the serum TSH concentration is in the desired range. A significant proportion of patients who have been converted from desiccated thyroid to LT4 complain of feeling worse, even when their TSH levels are normal and serum T4 levels high normal; this likely results from the lower serum T3 concentrations that are present on LT4 therapy. Most patients, however, report that their symptoms resolve over time. For those with persistent symptoms, deleting 25 to 50 ␮g of LT4 and substituting 5 to 10 ␮g of LT3 might provide symptomatic relief. Caution must still be exercised with such a regimen in order to avoid supraphysiological T3 levels following medication ingestion, particularly in elderly subjects. As discussed earlier, firm recommendations regarding LT4/LT3 combinations must await the future development and careful testing of slow release T3 preparations. Patients Who Are Sensitive to Thyroid Hormone Tablets Patients occasionally complain of being “allergic” to thyroid hormone preparations. Provided the dose is correct, it is unlikely that a patient would have a true allergic reaction to a hormone that is normally present in their body. However, a patient may have sensitivity to a component of the pill such as coloring dye or

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a filler substance. When this is suspected, the 50 ␮g size of LT4, which in most preparations is white with no added dye, can be given in quantities that add up to the total intended dose. If reactions to the medication persist, changing to a different preparation may be helpful. Patients Who Are Temporarily Unable to Take LT4 Orally Hypothyroid patients on LT4 replacement may be unable to take oral medications for several days following a variety of general surgical procedures or during a significant medical illness. If the anticipated duration of abstinence from LT4 is no more than three days, no LT4 replacement during this brief interval is necessary. However, if the period of abstinence is anticipated to be longer than three days, the patient should be treated with intravenous LT4 in a daily dose that is 80% of their usual oral dose; this amount is based on the determination that approximately 80% of an oral dose is absorbed into the circulation (301–303). Surgery in Patients With Hypothyroidism Surgery of various types may sometimes be needed in hypothyroid patients who have been recently diagnosed but are not yet on adequate LT4 replacement. Most studies indicate that hypothyroid patients tolerate surgery well and heal appropriately (381–383). However, in patients with more severe degrees of untreated hypothyroidism, there is greater potential for some complications such as perioperative heart failure, ileus, absence of fever when infected, and neuropsychiatric symptoms (384). It is advisable therefore to postpone elective surgical procedures until patients are on LT4 replacement and have TSH levels that are in or near the normal range (TSH ⬍10 mU/L). Patients requiring emergency surgery, including coronary artery revascularization procedures (382,383,385), can proceed directly to surgery without LT4 replacement until the postoperative period, at which time dose schedules should be initiated, as discussed earlier, according to the patient’s age, severity of hypothyroidism, and underlying general health. Treatment of Nonthyroid Conditions With Thyroid Hormone Obesity Hypothyroidism is commonly associated with mild weight gain while thyrotoxicosis usually causes weight loss. These observations prompted the use of high dose thyroid hormone therapy to induce weight loss in the past (386,387), although this practice was later abandoned because of the catabolic and potentially dangerous consequences of iatrogenic thyrotoxicosis. Nonetheless, studies of obese subjects placed on very low-calorie diets have shown that serum T3 concentrations and resting metabolic rates decline in parallel, suggesting that these changes may contribute to the plateau of body weight that is often seen after initial weight loss occurs (388–391). High-dose T3 given during a very low-calorie diet has been shown to prevent the drop in resting metabolic rate and to promote further weight loss; however, this occurs at the expense of increased nitrogen loss suggesting

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protein catabolism (392–394). In contrast, lower-dose T3 therapy (40 ␮g/day) has been shown in two small studies to promote weight loss in subjects on very low-calorie diets without negatively affecting nitrogen balance (395,396). At this time, there can be no justification for the use of thyroid hormone preparations to assist with weight loss, except in hypothyroid patients in whom only replacement LT4 doses are indicated. Nevertheless, the encouraging results mentioned earlier will hopefully stimulate further study into the potential use of new thyroid hormone analogs as an adjunct in the management of obesity. Depression Depression has been clearly identified as a symptom that may result from both overt (139–141) and subclinical (235–239) hypothyroidism and that improves or resolves with LT4 replacement therapy (141,338). Moreover, depression in apparently euthyroid individuals has been shown to be associated with abnormalities of the hypothalamic-pituitary-thyroid axis including abnormal TSH responses to the administration of intravenous TRH (141). It is not surprising then that thyroid hormone therapy has been used in the treatment of depression, even in patients with normal thyroid function (397,398). LT4 has been used more commonly in bipolar affective disorders, while LT3 has been given more often in depression (398). While there is no substantial evidence that thyroid hormone alone has significant antidepressant activity in euthyroid individuals, existing data do suggest that thyroid hormone supplementation may enhance the effect of standard antidepressant medications in patients with refractory depression (397–400). Premenstrual Syndrome Disorders of the thyroid axis have been postulated to play a role in at least a subset of patients with premenstrual syndrome (401). Controlled studies, however, have failed to reveal any significant abnormalities of thyroid function or beneficial responses to thyroid hormone therapy in patients with this disorder (402–404). Therefore, there does not appear to be a current role for thyroid hormone therapy in the management of premenstrual syndrome. Consequences of Excess Thyroid Hormone Replacement While our emphasis has been on the use of adequate doses of LT4 to alleviate the symptoms of hypothyroidism, a caution regarding overtreatment must be raised as well. If some is good, more is not necessarily better. Excess LT4 administration most commonly occurs when serum TSH is not monitored regularly or when patients request or self-administer higher LT4 doses to improve their energy level or to help with weight loss. LT4 excess must be avoided, however, because of the potentially deleterious effects on the cardiovascular system and the skeleton. Low TSH levels in elderly subjects have clearly been demonstrated to be associated with an increased risk of developing atrial fibrillation (231,405,406). More subtle abnormalities of cardiac function, including increased heart rate, atrial premature beats, increased left ventricular mass, increased left ventricular

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contractility, diastolic dysfunction, and impaired cardiac reserve have been demonstrated in some studies during periods of even mild thyroid hormone excess (407– 410). Thyrotoxicosis has also been shown to stimulate osteoclastic bone resorption, resulting in loss of bone mass. Although not a universal finding, several studies have demonstrated that even mild thyroid hormone excess, as occurs in patients taking excessive thyroid hormone doses, is associated with an increased risk of bone loss and fractures, particularly in postmenopausal women (411–416). Thus, there is ample evidence that even mild degrees of thyroid hormone excess should be avoided in hypothyroid patents on chronic thyroid hormone replacement therapy. Unfortunately, it has been shown that up to 20% of patients taking thyroid hormone are over replaced (18). SUMMARY Hypothyroidism is a common disorder having multiple etiologies. Primary hypothyroidism occurs far more frequently than does central hypothyroidism. Thyroid hormone deficiency affects many tissues and organ systems, resulting in a wide spectrum of clinical manifestations that include multiple symptoms, signs, and laboratory abnormalities. Subclinical hypothyroidism is the mildest form of this condition that may have physiologically relevant consequences and beneficial responses to thyroid hormone replacement therapy. Myxedema coma, the most severe form of hypothyroidism, is an extremely serious disorder with a potentially high mortality rate without the prompt initiation of thyroid hormone administration and appropriate treatment of precipitating causes. Sensitive and accurate measurements of serum TSH levels have greatly simplified the diagnosis of primary hypothyroidism. The diagnosis of central hypothyroidism requires measurement of TSH along with free T4 or total T4 and an assessment of other anterior pituitary functions. Measurement of antithyroid antibodies helps to confirm the diagnosis of lymphocytic thyroiditis and aids in the prediction of which patients with mild thyroid failure will progress on to develop overt hypothyroidism. The cornerstone of treatment of hypothyroidism is thyroid hormone replacement. Treatment schedules and goals should be tailored to the individual patient according to their age, severity of hypothyroidism, and underlying health status. Serum TSH levels should be used to monitor LT4 therapy in patients with primary hypothyroidism while free T4 levels are best when managing central hypothyroidism. The goals of treatment in most cases are to relieve the symptoms of hypothyroidism and to avoid even subtle degrees of biochemical thyroid hormone excess or deficiency. REFERENCES 1. Larsen PR, Berry MJ. Type I iodothyronine deiodinase: Unexpected complexities in a simple deiodination reaction. Thyroid 1994; 4:357–362.

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5 Thyroid Nodules and Multinodular Goiter Hossein Gharib College of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A.

INTRODUCTION Nodular thyroid disease, the presence of single or multiple nodules within the thyroid gland, is a common clinical problem. Most clinicians—particularly primary care physicians, pediatricians, internists, endocrinologists, and general surgeons— should regularly evaluate patients with thyroid nodules and consequently must make diagnostic and management decisions. Solitary nodules may be benign or malignant; multinodular glands may be asymptomatic, toxic, nontoxic, benign, or malignant. Each patient is evaluated for structural and functional abnormalities. It is difficult to overstate the influence of recent technologic developments on examination and treatment of thyroid nodules. The introduction of sensitive thyrotropin [i.e., thyroid-stimulating hormone (TSH)] assays, the universal application of fine-needle aspiration (FNA) biopsy, and the widespread use of high-resolution ultrasonography (US) has markedly improved the management of thyroid nodule. Furthermore, collected data on the efficacy of levothyroxine (T4 ) suppressive therapy have been inconsistent at best and disappointing at worst, resulting in a decline in the routine use of T4 in the treatment of thyroid nodules. Improved technology has not been without unexpected and sometimes undesirable consequences. For example, increased sensitivity of current imaging equipment has resulted in the frequent discovery of subclinical nodules in the thyroid gland, creating difficult treatment decisions for both the clinician and the patient. 203

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Table 1 Classification of Diffuse Goiter Sporadic (nonendemic) Iodine deficiency (endemic) Autoimmune Neoplasms Genetic Goitrogens

This chapter on nodular thyroid disease includes a discussion on the classification and prevalence of thyroid nodules; the pathogenesis of thyroid nodules; laboratory tests; a review on the uses and limitations of FNA biopsy, thyroid scanning, and US; management of clinically solitary nodules and multinodular glands; and the problem of thyroid incidentalomas. It also includes recommendations from recent practice management guidelines published by the American Association of Clinical Endocrinologists in collaboration with the Associazione Medici Endocrinologi (1), by the American Thyroid Association (2), and by the European Thyroid Association (3) in the past 2 years. CLASSIFICATION AND PREVALENCE Thyroid gland enlargement (goiter) is one of the most common endocrine problems in clinical practice. Goiter is classified as “diffuse” or “nodular”; it may be either “toxic” or “nontoxic.” The common conditions considered in the differential diagnosis of diffuse goiters are listed in Table 1. “Nontoxic goiter” refers to thyroid enlargement associated with normal serum levels of TSH and without clinical hyperthyroidism. In some geographic regions, iodine deficiency or environmental goitrogens affect more than 10% of the local population, causing “endemic goiter.” Worldwide, endemic goiter probably represents the most common endocrine disorder. In the United States and Great Britain, nonendemic, or sporadic, goiter affects more than 5% of the adult population (4–6). With declining iodine intake, goiter incidence may increase. Additionally, nonendemic goiter may be caused by excessive iodine intake (e.g., from amiodarone or kelp). Solitary palpable thyroid nodules are found in 4% to 7% of the adult population in North America, 6.4% in women and 1.5% in men from 30 to 59 years old (4,5,7,8). The prevalence of nodules increases throughout life, in women, and in persons exposed to ionizing radiation in infancy or childhood. The data provided by the Framingham, Massachusetts, population study suggest an incidence of 0.1% per year, or approximately 300,000 new nodules in the United States in 2007, and a 10% lifetime expectancy of nodule development (4,5,8). However, these figures on palpable nodules substantially underestimate the problem. For example, in an autopsy series, Mortensen and colleagues (9) reported that in patients whose glands appeared clinically normal, one or more thyroid

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nodules were detected in approximately 50%. Furthermore, 35% of patients had nodules greater than 2 cm that had escaped clinical detection. More recent US data support earlier autopsy results. Brander and associates (10) found that 30% of asymptomatic adults had occult thyroid nodules detected with US, and Horlocker and colleagues (11) reported that 41% of 1000 patients with primary hyperparathyroidism had one or more thyroid nodules detected ultrasonographically and later confirmed by surgery. Overall, most US studies suggest that unsuspected thyroid nodules are present in 20% to 50% of adult women and in 17% to 30% of adult men. Thus, one can conclude that more than 100 million people in the United States have asymptomatic, incidental, or subclinical thyroid nodules (4,7). In a multinodular thyroid, multiple small nodules are often identified by US examination, whereas multiple nodules in an enlarged gland suggest a multinodular goiter (MNG). Recent imaging data have shown that in patients with clinical solitary thyroid nodules, high-resolution US identifies one or more nodules in approximately 50% (12). This finding suggests that the distinction between clinically multinodular glands and clinically solitary nodules is not as sharp as previously considered, and glands with an apparent single nodule likely have many other nodules. Furthermore, the frequency of malignancy in patients with single nodules and patients with multinodular glands seems to be almost identical. In a study of 5637 patients, Belfiore and colleagues (13) reported thyroid cancer in 4.1% of clinically solitary nodules versus 4.7% of clinically multinodular glands. However, another report showed that although cancer rates were similar for patients with glands with one nodule or at least two nodules (14.8% vs. 14.9%, respectively), the rate of malignancy was 14.8% for solitary nodules and 8.1% for nonsolitary nodules (14).

PATHOGENESIS Currently, the molecular mechanisms that stimulate the formation and growth of only a few cells within a thyroid follicle and lead to nodule formation and growth are poorly understood (15–17). TSH is a known stimulator and regulator of differentiated thyroid follicular cell function. TSH interacts with follicular cell receptors to activate adenylate cyclase and generate cyclic adenosine monophosphate; this in turn activates protein kinase A and leads to biochemical events that stimulate the growth of follicular cells (17). Extrathyroidal factors may also act on the intrinsic and abnormal growth potential of thyroid follicular cells, resulting in accelerated nodular growth and development. Another possible mechanism is that fibrous tissue, formed because of follicular necrosis and hemorrhage, may promote thyroid nodularity in MNG. Nodule formation has also been attributed to somatic mutations (15). It is now believed that benign and malignant thyroid tumors are monoclonal neoplasms arising from a single precursor cell that

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presumably gained a growth advantage through somatic mutation of genes critical for growth regulation. The most widely held theory about nodule formation and growth is that chronic TSH stimulation initially causes development of a diffuse enlargement, which in turn leads to thyroid nodule development, and ends with the formation of multiple nodules, typically an MNG. However, it is important to emphasize that the exact role of TSH as a thyroid growth factor remains controversial (18). In recent years, non-TSH growth factors have been identified that stimulate thyroid cell growth: growth-stimulating immunoglobulin(s), epidermal growth factor, insulin-like growth factors, interleukin-1, interferon-␥ , and transforming growth factor-␤ (19). It is also noteworthy that the growth-promoting effects of TSH in vitro depend largely on the presence of insulin-like growth factors. Additionally, somatic mutations known to occur in thyroid follicular cells include ras oncogenes, G proteins, and the TSH receptor gene, which result in hyperfunctioning adenomas (15). In summary, the exact cause(s) or molecular mechanism(s) that stimulate growth of a single cell within a thyroid follicle is not known. It is likely that both intra- and extrathyroidal factors are important in the development and growth of nodules. These factors include follicular cell mutations, stimulation by TSH and other growth factors, and development of follicular necrosis, hemorrhage, and fibrous tissue. HISTORY AND EXAMINATION Thyroid nodules are usually asymptomatic and are often discovered by a patient or a physician after careful palpation of the neck (Fig. 1). MNGs are also often asymptomatic, but they may be associated with hoarseness, neck pressure or pain, cough, dyspnea, or dysphagia. Features that increase the likelihood of thyroid malignancy include a family history of thyroid cancer, age younger than 20 or older than 60 years, and a history of head or neck irradiation (7,20,21). Nodules are more common in women but are more likely to be malignant in men (1,7). On physical examination, common and different causes of thyroid nodules should be kept in mind (Table 2). The characteristics of thyroid nodules, including location, consistency, dimensions, and number, need to be carefully recorded. Physical findings suggestive of malignancy include a hard, nontender nodule, fixation to adjacent tissue, and the presence of regional lymphadenopathy. However, it should be emphasized that history and physical examination are often insufficient for diagnosing thyroid cancer in most patients. LABORATORY AND RADIOLOGIC DIAGNOSIS Serum TSH should be measured in all patients by using a sensitive, third-generation assay. If TSH levels are less than 0.5 mIU/L, levels of free T4 and triiodothyronine (T3 ) in the serum should be measured. If serum TSH is greater than 5.0 mIU/L,

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Figure 1 An 81-year-old woman with a recently discovered 5-cm right thyroid nodule. She reported that nodule size increased during the preceding 10 years. Serum level of thyroid-stimulating hormone was 1.4 mIU/L; findings on fine-needle aspiration biopsy were benign (colloid nodule). Thyroidectomy revealed a large, benign, colloid goiter.

measurement of free T4 and thyroid peroxidase antibodies are necessary (1). Routine measurement of serum thyroglobulin is not recommended (1,2). Currently, the issue of routine serum calcitonin (CT) measurement in patients with thyroid nodules is controversial (1–4). The prevalence of sporadic medullary thyroid carcinoma (MTC) in patients with thyroid nodules ranges from 0.3% to 1.3% (22–27). In these reports, some patients received the correct diagnosis of MTC on the basis of serum CT measurement and not by FNA biopsy. Thus, CT measurement may detect unsuspected MTC, and hence, the recommendation by Table 2 Common Causes of Thyroid Nodules Benign Colloid Cyst Thyroiditis H¨urthle cell lesion Follicular cell lesion Malignant Primary—papillary, follicular, medullary, anaplastic cancer, lymphoma Secondary—breast, lung, kidney (3 most common sources)

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Table 3 Indications for Ultrasonography Palpable nodule(s) Nodule detected incidentally by imaginga Difficult thyroid palpation Unexplained cervical adenopathy History of neck irradiation Family history of papillary or medullary thyroid carcinoma, or multiple endocrine neoplasia type 2 Follow-up of thyroid cancer a Imaging

methods include positron emission tomography, computed tomography, and magnetic resonance imaging.

some experts is that CT assays should be performed routinely in all patients with thyroid nodules (3,28). According to some European groups (3), if basal CT levels exceed 10 pg/mL, pentagastrin stimulation should be performed, and if peak CT levels exceed 100 pg/mL, thyroidectomy should follow. For values between 10 and 100 pg/mL, medical follow-up is suggested (28,29). However, in the United States, routine CT measurement was not endorsed either in a recent expert opinion (29) or in practice guidelines (1), which stated that routine testing of serum CT in all patients with unselected thyroid nodules does not seem to be cost-effective and is not recommended. It is also important to note that pentagastrin is currently not available in the United States, and this issue limits the use of CT measurement. Ultrasonography Indications Three recently published guidelines recommend thyroid US for all patients with one or more suspected nodules (1–3). US is recommended to confirm the presence of a nodule. One study showed that 18% of palpable abnormalities were not thyroid nodules when examined by US (30). This method can also be used to identify any suspicious sonographic features in the nodule and to document the presence of other potentially more clinically significant nodules. Additional indications for US are detailed in Table 3. Technique High-resolution US uses frequencies between 5 and 10 MHz, which allow measurement of the volume of the gland and the number, size, and characteristics of the nodules within it (1,31). Sound waves are produced and received by the transducer. Images are obtained in the longitudinal and transverse planes. Currently, transducers can identify cystic or solid lesions as small as 1 to 2 mm in the gland. High-resolution US equipment has become less expensive and more

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A

B

C

D

Figure 2 Evaluation of thyroid with high-resolution ultrasonography. (A) Transverse view of right thyroid nodule containing both cystic and solid components; nodule was benign on biopsy. (B) Longitudinal view of solid thyroid nodule with a “halo” at nodule periphery. Fine-needle aspiration (FNA) biopsy showed this was a benign follicular adenoma. (C) Nodule with hypoechoic pattern, irregular margins, and punctate microcalcifications; FNA biopsy showed papillary thyroid carcinoma, later confirmed at surgery. (D) Transverse view of right thyroid lobe showing a solid hypoechoic nodule with scattered calcifications suggestive of carcinoma; FNA biopsy suggested medullary thyroid carcinoma, later confirmed with thyroidectomy. Abbreviations: C, carotid artery; T, trachea.

user friendly; many endocrinologists use it in the office for careful evaluation of a broad spectrum of thyroid abnormalities. Results High-resolution US patterns of the thyroid include consistency, echogenicity, patterns of calcification, and color Doppler flow (1,32–34). On the basis of consistency, thyroid nodules are divided into three categories: solid, cystic, and mixed solid and cystic. Simple or pure cystic lesions are extremely rare, and most cystic lesions are considered mixed (or “complex”) lesions [Fig. 2(A)]. Benign nodules are hyperechoic and may have a sonolucent rim (“halo”) surrounding the nodule [Fig. 2(B)]. A malignant thyroid nodule is typically an irregular, solid, hypoechoic

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Table 4 Value of US Features Predicting Thyroid Malignancy

US feature Microcalcifications Hypoechogenicity Irregular margins or no halo Solid Intranodule vascularityb More tall than wide

Sensitivity (%)

Specificity (%)

Positive predictive value (%)

Negative predictive value (%)

Relative risk

26.1–59.1 26.5–87.1 17.4–77.5

85.8–95.0 43.4–94.3 38.9–85.0

24.3–70.7 11.4–68.4 9.3–60.0

41.8–94.2 73.5–93.8 38.9–97.8

4.97 1.92 16.83

69.0–75.0 54.3–74.2

52.5–55.9 78.6–80.8

15.6–27.0 24.0–41.9

88.0–92.1 85.7–97.4

4.2a 14.29

32.7

92.5

66.7

74.8

10.5a

a Unpublished data from a series of 400 patients undergoing surgery for thyroid nodular disease. Regina Apostolorum Hospital, Albano, Rome. Courtesy of Papini E. and Guglielmi R. b Patterns of nodule color Doppler flow and malignancy were described previously (1,4). Abbreviation: US, ultrasonography. Source: From Ref. 33.

mass, although follicular cancers can be hyperechoic. Calcification occurs in 13% of nodules. Types of calcifications are important—peripheral eggshell calcifications are seen in benign, degenerating adenomas, whereas increased blood flow on Doppler imaging and microcalcifications (seen as punctate deposits and indicative of psammoma bodies) suggest papillary carcinoma [Fig. 2(C)]. MTC is suspected when a solid nodule has scattered calcification [Fig. 2(D)]. No single ultrasonographic feature unequivocally differentiates benign from malignant nodules. Although US results are highly operator dependent, in experienced hands, US is useful for predicting the risk of malignancy (Table 4). For example, microcalcifications have 86% to 95% specificity for cancer, whereas hypoechogenicity has a lower value of 43% to 94%. Overall, identification of at least two clinically suspicious sonographic criteria is 85% to 95% accurate for diagnosing malignancy (1,4). Scintigraphy Indications With increasing use of FNA biopsy in the diagnosis of thyroid nodules, the role of thyroid scintigraphy has declined progressively. Indications for radioisotope scanning are summarized in Table 5. If a patient has a palpable nodule and suppressed serum TSH levels, the next appropriate test is a thyroid scan to determine whether the nodule is functional (1,2,4). Thyroid scanning is also useful for determining goiter size because extent of the goiter may influence clinical management. Furthermore, radioisotope scans can evaluate nodule function in MNGs, determine the

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Table 5 Indications for Radioisotope Scan Diagnose hot nodule Determine goiter size Assess nodule function in multinodular goiter Evaluate substernal goiter Identify ectopic thyroid tissue (sublingual thyroid, struma ovarii)

extent and size of substernal goiter, identify ectopic thyroid tissue, and determine function in a nodule of a patient with Graves’ disease. Technique A gamma scintillation camera with a pinhole collimator is generally used for thyroid scanning; it has replaced the rectilinear scanner. The most commonly used radioisotope is radioiodine (123 I); technetium (99m Tc) is being used less frequently (4,35,36). Both isotopes are transported into thyroid follicular cells, but only iodine is organified, that is, incorporated into hormone production. Theoretically, a rare nodule may exhibit discordance between 123 I and 99m Tc scan findings. Because 99m Tc is trapped but not organified, a nodule may appear functional (hot) on pertechnetate imaging and nonfunctional (cold) on 123 I imaging. In practice, this has not been an important problem. For studies with 99m Tc, 1 to 10 mCi is administered intravenously and imaging is performed 20 minutes later. Results The radionuclide scan may show several different patterns of function (Fig. 3). The normal thyroid has a butterfly shape, the two “wings” of which are connected by an isthmus that crosses the trachea anteriorly, below the level of the cricoid cartilage. In a healthy subject, the radioisotope signal appears homogeneously distributed [Fig. 3(A)]. Characteristically, salivary glands are visualized with 99m Tc, whereas they are not visualized with 123 I because images are obtained 6 to 24 hours later (the isotope has cleared from the salivary glands by then). In hyperthyroidism with increased uptake (Graves’ disease), an enlarged gland has intense, diffuse, and homogeneous uptake [Fig. 3(B)]. A hypofunctioning (cold) nodule means no or subnormal isotope concentration in the nodular tissue [Fig. 3(C)]. The likelihood of carcinoma in cold thyroid nodules varies from approximately 5% to 15% (1,35,36). Because approximately 85% of nodules are cold, surgical treatment based on radionuclide scan results is not cost-effective. Another scan pattern is that of a hyperfunctioning (hot) nodule, with the absence or near absence of isotope in the rest of the thyroid gland due to suppression of endogenous serum TSH [Fig. 3(D)]. Some small, hot nodules make insufficient amounts of thyroid hormone to cause TSH suppression, so the remaining normal thyroid tissue is still visible. In MNG, the pattern has an inhomogeneous, irregular, or patchy appearance, with functioning and nonfunctioning areas

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A

B

C

D

Figure 3 Four different 99m Tc scan patterns. (A) Normal thyroid, showing function in both lobes connected by the isthmus. (B) A 38-year-old man with hyperthyroid Graves’ disease, thyroid-stimulating hormone (TSH) of 0.006 mIU/L, and radioiodine uptake of 92%. Note that the scan shows enlarged thyroid gland with intense and diffuse uptake. (C) A 38-year-old woman with a palpable, 2-cm cold nodule in the right thyroid lobe. The nodule was benign on biopsy. (D) A 39-year-old man with a palpable 3-cm right thyroid nodule, hyperfunctioning on scan, with completely suppressed uptake in the rest of the gland. Serum level of TSH was 0.05 mIU/L and radioiodine uptake was 22%.

within an often enlarged gland. Patchy uptake may also be seen in Hashimoto thyroiditis. Other Imaging Techniques Magnetic resonance imaging or computed tomography is used occasionally to evaluate the size and extent of an MNG (Fig. 4). These imaging techniques can be particularly helpful when evaluating substernal goiters and defining the

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Figure 4 Computed tomography scan of the neck showing a large left thyroid mass with tracheal deviation in a 56-year-old woman with long-standing and progressively enlarging nodular goiter. Thyroidectomy uncovered a large benign colloid goiter.

relationship of the goiter to surrounding structures, especially to exclude tracheal compression. Neither technique separates benign from malignant thyroid growths, and because of their relatively high cost, they are used less frequently than US and scintigraphy (1,37). FNA Biopsy FNA biopsy—now clearly considered the most accurate test for the diagnosis of thyroid nodules—has emerged as a safe, accurate, and cost-effective test (1– 4,7,37–52). Indications Biopsies may be performed with direct palpation for clinically solitary thyroid nodules or with US guidance. Ultrasonographically guided FNA (US-FNA) biopsy should be performed on patients with small or impalpable cystic nodules. Patients with diffuse goiters, for example, Hashimoto thyroiditis, subacute (granulomatous) thyroiditis, or amyloid goiter, can undergo diagnostic FNA biopsy. Primary or metastatic malignancy of the thyroid and adenopathy due to thyroid malignancy can be diagnosed reliably by FNA biopsy (39).

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Technique Biopsies can be performed on the examining table in the office or on a hospital bed; the patient is supine and the neck is hyperextended by placing a pillow under the shoulders. This position allows maximal exposure (37,38,45). The area for biopsy is identified clearly and the skin cleansed with alcohol or betadine. Although some physicians use 1% lidocaine for local anesthesia (47) or apply ice cubes contained in a plastic bag (45), some argue that biopsies can be performed without any such preparation (43). A 27- or 25-gauge needle attached to a 10-mL disposable plastic syringe is used; the syringe can be attached to a mechanical syringe holder. After the free hand of the operator locates the nodule, the needle is inserted rapidly into the nodule and mild suction is applied immediately. Too much suction may dilute the specimen with blood; this should be avoided. The needle is moved back and forth several times; after a few seconds, the suction is released and the needle withdrawn. The needle is then dislodged from the syringe, air is drawn into the syringe, the needle is replaced in the syringe, and the aspirated material is forced onto glass slides. (Alternatively, 1 cc of air can be drawn into the syringe before aspiration.) A drop of aspirate is placed on each of several slides, and smears are prepared with an additional glass slide, in a manner similar to that of preparing blood smears. For wet-fixed smears, glass slides are placed immediately in 95% ethyl alcohol. Air-dried slides are left unfixed. Usually, 8 to 12 slides from 2 to 4 aspirations are prepared per nodule; some physicians advocate at least 6 separate aspirations per nodule. Many clinicians also wash the syringe with cytology fluid, centrifuge the suspension, and microscopically examine the cell pellet. For larger nodules, aspirates are obtained from the center and circumferentially from the periphery. Slides are then taken to the laboratory; wet-fixed slides are stained with a modified Papanicolaou stain and air-dried smears are stained with Diff-Quik or other stains (1,39,46). After the procedure is complete, local pressure is applied to the biopsy sites. The patient is observed for a few minutes and is then allowed to leave. Results Results of FNA usually are categorized into four diagnostic groups: benign (negative), clinically suspicious (indeterminate), malignant (positive), and unsatisfactory (nondiagnostic) (1,4,40,51,53). The most common benign cytodiagnosis is that of adenomatoid (or “colloid”) or benign thyroid nodule. The colloid nodule shows abundant colloid, normal follicular cells, and some foam cells. Other benign diagnoses include cystic lesions (usually adenomatoid nodules with cystic degeneration), lymphocytic thyroiditis, and subacute (granulomatous) thyroiditis. The indeterminate category consists of specimens with features that are suggestive of but not diagnostic for malignancy. This group includes cellular specimens (e.g., follicular neoplasms, H¨urthle cell neoplasms, and other specimens with varying degrees of cellular atypia) that require histologic evaluation for a conclusive diagnosis (38,44,45,54,55). Characteristically, these nodules produce hypercellular

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aspirates with microfollicular patterns, or H¨urthle cell changes with scant or no colloid. The malignant (positive) group includes primary or metastatic carcinomas and thyroid lymphoma. Papillary carcinomas account for more than 80% of malignant lesions and are usually diagnosed confidently with FNA (28,43,44). Common cytologic findings of the thyroid are shown in Figure 5. Hypocellular smears, which account for 5% to 15% of specimens, are considered nondiagnostic or unsatisfactory (49,53,56–58). The criteria for judging specimen adequacy are neither well defined nor standardized. The variability between laboratories and clinics regarding the definition of an “adequate” specimen is considerable. Most cytologists believe that a satisfactory smear must contain at least six clusters of well-preserved cells, and each group must be composed of at least 10 cells from separate aspirates (44). Unsatisfactory smears usually result from poor biopsy technique and, less often, from cystic lesions yielding fluid and foam cells, vascular lesions yielding too much blood, excessive air-drying, or poor smear preparation. Published FNA series from many centers in various countries confirm its usefulness and accuracy (38,41,49,50,52). For example, a 1995 review (42) described combined results from more than 16,500 specimens from two institutions—the diagnostic results were as follows: benign, 69%; malignant, 4%; and suspicious or nondiagnostic, 27%. Analysis of published data (Table 6) shows that FNA has a sensitivity of 65% to 98% (mean, 83%), a specificity of 72% to 100% (mean, 92%), and a diagnostic accuracy of 85% to 100% (mean, 95%). The predictive value of a positive or suspicious cytologic result is 75% (range, 50–96%). The false-negative rate may be as low as 1% and as high as 11% (mean, 5%), and false-positive rates range from 0% to 7% (mean, 5%) (38,49). Limitations of FNA biopsy include unsatisfactory or nondiagnostic results, suspicious or indeterminate cytologic findings, and false-negative diagnoses (37,46–52,57–60). Although nondiagnostic results can be as high as 20%, a repeat biopsy yields satisfactory results in half of the cases. US-FNA further reduces Table 6 Summary Characteristics for Thyroid FNA Biopsies: Results of a Literature Survey Feature

Mean

Range

Definition

Sensitivity (%)

83

65–98

Specificity (%)

92

72–100

Positive predictive value (%) False-negative rate (%) False-positive rate (%)

75

50–96

5 5

1–11 0–7

Likelihood that a patient with disease has positive test results Likelihood that a patient without disease has negative test result Fraction of patients with positive test results and disease FNA negative; histology positive for cancer FNA positive; histology negative for cancer

Abbreviation: FNA, fine-needle aspiration. Source: From Ref. 1.

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A

B

C

D

E

F

Figure 5 Thyroid cytology. (A) Nondiagnostic smear. Degenerative foam cells without follicular cells (PAP; ×60). (B) Colloid nodule. Cohesive group of thyroid cells in a patient with multinodular goiter (PAP; ×50). (C) Hashimoto thyroiditis. Lymphocytes and H¨urthle cells showing abundant granular cytoplasm (PAP; ×250). (D). Follicular neoplasm. Hypercellular aspirate with microfollicular pattern lacking colloid is indeterminate (PAP; ×205). Nodule was a benign follicular adenoma at surgery (E) Papillary carcinoma. Cellular specimen showing tumor cells with irregular, enlarged nuclei. Note lack of colloid (PAP; ×100). (F) Medullary carcinoma. Loosely cohesive neoplastic cells with elongated nuclei. (MGG stain; ×400). Abbreviations: MGG, May–Grunwald–Giemsa stain; PAP, Papanicolaou stain.

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nondiagnostic rates, but there may be a residual 5% to 10% frequency of nondiagnostic results. Surgical excision should be considered in patients with solid nodules and persistently nondiagnostic results because the probability of malignancy is not negligible (1,2,56,61). Follicular and H¨urthle cell neoplasms pose a difficult problem because benign nodules cannot be distinguished from malignant lesions by FNA cytology alone, and they usually require histologic examination of the tumor capsule to identify capsular or vascular invasion (or both). Because approximately 20% of cytologically suspicious nodules are malignant, the current recommendation is to excise these nodules surgically (1–4). Before surgery, a radioiodine scan should be considered, even if the serum TSH level is normal, to exclude the admittedly unlikely possibility of an autonomously functioning thyroid nodule. False-negative results mean missed malignancy and are typically the result of sampling errors and errors of interpretation (37,47,61). The adequacy of sampling can be increased by carefully sampling different portions of a nodule, using US-FNA for nodules less than 1 cm in diameter and obtaining multiple FNA samples from large tumors (62–66). Cytologic examination has proved to be both safe and accurate and is now recommended as the primary diagnostic method for benign and malignant thyroid lesions. Complications of FNA biopsy are minor, transient, and very rare. Bruising or hematoma is infrequent and mild, and seeding in the needle tract is extremely rare with FNA. Performance of probably 5 to 10 biopsies with supervision and another 10 biopsies are necessary to acquire adequate experience, and at least 20 FNAs should be performed annually to maintain and upgrade biopsy technique. There is evidence that greater experience with aspiration directly affects (reduces) the insufficiency rate (60). Published reports document the high sensitivity and specificity of the procedure. However, the advantages and limitations of FNA biopsy should be recognized, and the procedure should be applied knowledgeably to the evaluation of nodular thyroid disease. US-FNA In recent years, use of US-FNA in clinical practice has increased (1,4,34,62–65). The indications for US-FNA include evaluation of (1) nodules that are impalpable or difficult to palpate, (2) multiple thyroid nodules, (3) unexplained adenopathy or palpable lymph nodes in patients with a history of thyroid cancer, (4) patients with high risk of cancer such as MTC or multiple endocrine neoplasia type 2, (5) patients whose initial biopsy results were nondiagnostic, and (6) nodules of any size with US features suggestive of malignancy (Table 7). Several studies have shown that US-FNA biopsies have a significantly lower percentage of inadequate samples compared with direct (palpation-guided) FNA (64,65). With US-FNA, the biopsy sites can be precisely selected and the needle correctly positioned to allow sampling of the cyst walls or solid components. As a result, the rate of satisfactory aspirates has increased. Color Doppler imaging may also be used to obtain adequate aspirates (4). The application of US-FNA has resulted in fewer thyroidectomies because of the increased yield of satisfactory aspirates (65,66).

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Table 7 Indications for Ultrasonographically Guided Fine-Needle Aspiration Biopsy Impalpable or small (⬍1.5 cm) nodule with clinically suspicious ultrasonographic features Multiple nodules Unexplained adenopathy or adenopathy in patients with history of cancer Any size nodule in a patient with a history of neck radiation, medullary thyroid carcinoma, or multiple endocrine neoplasia type 2 Initial biopsy was nondiagnostic Any size nodule with ultrasonographic features suggestive of malignancy Source: From Ref. 1.

Neither nodule number nor nodule size is predictive of malignancy (1,4,32). When multiple nodules are present, selection for FNA should be made on the basis of US features rather than size (1,4). When a patient has multiple, identically appearing spongiform nodules with little to no intervening normal thyroid parenchyma, typical of a MNG, only the largest nodules require FNA. Some suggest selecting only nodules larger than 1.0 or 1.5 cm in diameter for FNA (33), citing the usual nonaggressive behavior of small (⬍1.5 cm) thyroid microcarcinomas. This issue is currently a matter of debate and controversy (34). Conclusions Recent treatment guidelines recommend routine serum TSH measurement, US examination, and FNA biopsy in all patients with nodular thyroid disease (1–3). US examination increasingly is used and has value in predicting malignancy. However, the crux of nodule evaluation is thyroid cytology, and management decisions should be made on the basis of FNA biopsy results. In experienced centers, the probability of false-negative FNA rates (missed malignancy) is less than 2%. The limitations of FNA include indeterminate (suspicious) cytology, nondiagnostic smears, and false-negative FNA findings.

MANAGEMENT OF THYROID NODULES AFTER FNA Solitary Nodules A cytologically benign nodule can be monitored with or without additional aspiration and with or without T4 therapy (Table 8). FNA-benign nodules account for 80% of satisfactory aspirates, require no further evaluation, and can be managed expectantly. Considering 1% to 3% rate of false-negative diagnoses in this group, some have suggested follow-up aspiration of benign nodules (67), whereas others do not believe that additional biopsy is necessary (68). Generally, another aspiration is required if nodules increase in size (1,2,4). Table 9 lists other indications for performing additional biopsies.

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Table 8 Management Options for Patients with FNA-Benign Nodules Follow-up evaluation with palpation only Follow-up evaluation with palpation and ultrasonography Repeat FNA biopsy in 1 yr T4 therapy Abbreviation: FNA, fine-needle aspiration.

For patients with malignant FNA biopsy findings, surgical treatment is indicated. The extent of thyroid surgery depends on the histologic type of malignant disease: near-total thyroidectomy for papillary thyroid carcinoma or follicular thyroid carcinoma and total thyroidectomy for MTC. Central compartment node examination should be considered for patients with a diagnosis of papillary thyroid carcinoma or MTC (1–3). Approximately 10% of patients have a cytologic diagnosis that is clinically suspicious for malignancy or otherwise indeterminate, which creates a difficult dilemma for the clinician (Fig. 6). Although about 20% of these nodules are malignant overall, if a cytologic study shows atypical features of papillary cancer, the risk of malignancy is 60%, and if it shows follicular neoplasm, the risk is 15% (4,49,53). Consequently, most clinicians believe that surgical excision of a nodule with clinically suspicious cytologic features is appropriate. Intraoperative frozen section may help the surgeon decide whether to perform only lobectomy and isthmectomy when frozen sections show benign findings or perform a near-total thyroidectomy if a specimen is malignant (34,69,70). Attempts have been made to stratify patients with suspicious cytologic findings. For example, Schlinkert and colleagues (71) studied 219 patients with suspicious follicular neoplasms and reported that younger age, nodule size greater than 4 cm, solitary nodule, and fixed primary nodule were predictive of malignancy. Similarly, Tuttle et al. (72) reported a 21% incidence of malignancy in 103 patients with follicular neoplasia; the risk of malignancy was significantly higher in males, nodules greater than 4 cm, and solitary nodules (shown by palpation). As noted above, it is suggested to have radioisotope scanning for a cytologically suspicious nodule, with surgical treatment for cold nodules and medical treatment for functioning nodules (2,35,43). Table 9 Reasons to Repeat FNA Biopsy Enlarging, cytologically benign nodule Recurrent cyst Large nodule (⬎4 cm)a Initial FNA biopsy was nondiagnostic a

To minimize risk of missed malignancy in a large nodule. Abbreviation: FNA, fine-needle aspiration.

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A

B

C

D

Figure 6 Suspicious thyroid cytology in a 46-year-old woman with a right thyroid nodule (3 × 2 cm) and a history of childhood neck irradiation for acne. (A) Fine-needle aspiration (FNA) biopsy showed a hypercellular specimen with microfollicular pattern, suspicious for follicular neoplasm (PAP; ×25). (B) Thyroid scan showed that right thyroid nodule was hypofunctioning. (C) Thyroidectomy showed area of focal hemorrhage corresponding to FNA biopsy sites (arrow). (D) Histological examination showed benign follicular adenoma with intact capsule (Hematoxylin and eosin; ×50).

Immunohistochemical markers have been studied in an effort to separate benign from malignant nodules when FNA results show cellular smears that are suspicious for follicular or H¨urthle cell neoplasm (73–77). HBME-1 (78), galectin-3 (79), and peroxidase and telomerase (76) have been repeatedly helpful for identifying benign follicular cell lesions. However, none of these markers have sufficiently high sensitivity and specificity for routine clinical use, and current guidelines from the American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi, American Thyroid Association, and European Thyroid Association, as well as expert opinions, do not endorse their clinical use (1–4,34). Approximately 15% of nodules are nondiagnostic on initial biopsy (4,38,44,56,80,81). A nondiagnostic result should prompt a second aspiration, which may be satisfactory for half of the cases; however, US-FNA may be necessary for diagnosis of some cases. The routine removal of all nondiagnostic nodules is not recommended; however, it seems reasonable to surgically remove recurrent

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cysts larger than 4 cm in diameter, repeatedly nondiagnostic solid nodules, or other lesions meeting clinical criteria that increase the risk of malignancy (1,2). Thyroid Hormone Therapy For the past 60 years, thyroid hormones have been used to suppress growth of thyroid nodules. The rationale for suppressive therapy is based on the assumption that because TSH stimulates nodule growth, its suppression should shrink nodules or at least arrest the growth (19). By definition, suppressive therapy requires a sufficiently high T4 dosage to suppress pituitary TSH secretion. The practice of T4 suppressive therapy for nodular thyroid disease is controversial and debatable (4,7,19,34). During the past two decades, a number of randomized, controlled trials have shown that few nodules shrink with thyroxine suppressive therapy (82–93). Because each study included only a small number of subjects, several groups have performed a meta-analysis of the data (94–96). Richter et al. (96) performed a meta-analysis of nine studies (596 patients) and concluded that T4 treatment was associated with decreased nodular volume (defined as ≥50% when measured by US) in only 20% of patients (pooled relative risk, 1.83; 95% confidence interval, 0.9–3.73). Data analysis suggested that T4 therapy did not reach target effectiveness (relative risk of 2.0) (Fig. 7). In 1998, Gharib and Mazzaferri (97) reviewed data on suppressive trials, evolving concepts, and controversies on suppressive therapy and offered their recommendations. They concluded that nodules shrink in response to T4 therapy in less than 20% of patients; the nodules that responded were usually the smallest (⬍2.5 cm in diameter). The data did not show that T4 therapy prevented further growth of existing nodules or emergence of new nodules. Furthermore, T4 therapy in dosages sufficient to suppress TSH may have adverse effects. It is now established that long-term T4 suppressive therapy causes iatrogenic subclinical hyperthyroidism that may be associated with osteopenia or osteoporosis and altered cardiac function, which is especially notable in elderly persons (4,7,8,98,99). A low serum level of TSH in persons 60 years or older is associated with a 3-fold increase in the risk of atrial fibrillation (98). In addition, suppressive therapy may be associated with decreased bone mineral density in postmenopausal women (99). Very little information is available about the outcome of untreated, asymptomatic, benign, thyroid nodules. In reports from Japan, Kuma and associates (100,101) examined the long-term outcome of untreated, cytologically benign, thyroid nodules in 134 patients who received follow-up care for 10 to 30 years (average, 15 years) and observed the following: nodules decreased in size in 53% of patients, remained the same in 34%, and increased in size in only 13%. A striking finding was that nodules were no longer palpable at the end of follow-up in 30% of patients and had decreased in size in another 13%. Of the nodules that completely disappeared, US showed that they were predominantly cystic.

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T4 suppressive therapy change in nodule size Cheung et al. (83) Gharib et al. (82) Papini et al. (93)

pooled RR of 1.83 (95% CI, 0.90–3.73)

Reverter et al. (84) Zelmanovitz et al. (94)

Figure 7 Reduction of nodule volume of at least 50% (random effects model). The right side indicates improvement in reduction. The size of the filled diamond at the middle of the central line (arrow 1) represents the sample size of each study. The box (arrow 2) represents the 95% confidence interval (CI) of the relative risk (RR; marked with a line in the box). The unfilled diamond with a central line (arrow 3) denotes the pooled risk ratio itself. Abbreviation: T4 , levothyroxine. Source: From Ref. 96.

Recent guidelines from the American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi (1) and the American Thyroid Association (2) suggest that patients with cytologically benign nodules preferentially should be monitored by palpation, with US whenever indicated, and without routine T4 suppression. Adverse effects of suppressive therapy include osteoporosis and cardiac arrhythmias, which can be clinically significant risks in postmenopausal women or elderly patients. Percutaneous Ethanol Injection In Europe, percutaneous ethanol injection (PEI) has been used successfully in the treatment of solid and cystic thyroid nodules with normal function and of hyperfunctioning nodules (102–113). Currently, it is recommended only for treatment of cystic nodules and shows a size reduction of 50% or more in almost 90% of cases treated (1,106). The usual treatment protocol is a single bolus of ethanol administered with a 20- to 22-gauge needle using ultrasonographic guidance. The procedure is performed in an outpatient setting. A total of 2 to 50 mL may be injected in 2 to 12 weekly sessions, with 1 to 10 mL of ethanol per injection. For cystic lesions,

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ethanol is injected slowly after cyst fluid is removed; the volume of ethanol injected is decided on the basis of the aspirated fluid volume. Generally, PEI is given once or twice weekly, and treatment is usually completed in 4 to 8 procedures. Complications include transient dysphonia, local pain, hematoma, and mild fever. In experienced hands, adverse effects are transient and minimal, and treatment is generally well accepted by most patients (1,103,106). The recurrence rate of cysts after PEI is low; one injection frequently is curative, and nodule shrinkage persists long after treatment ends (106,109). Although PEI is not used for benign cysts in the United States, Italian physicians have reported large, successful treatment groups and remain enthusiastic about the technique (1,106–108). PEI treatment seems to be appropriate for recurrent, symptomatic, benign thyroid cysts. Percutaneous Laser Thermal Ablation Percutaneous laser thermal ablation is another medical procedure used to treat thyroid nodules. This minimally invasive procedure directs laser beams to nodules, reducing their size and the local symptoms (114–118). The technique requires use of US, local anesthesia, and special training. One adverse effect is local pain that is often transient; other problems have not been reported. Percutaneous laser thermal ablation is currently available in some European centers but is not used widely or routinely in clinical practice; also, it has never been used in the United States. Conclusions Cytologically benign nodules should be monitored without T4 therapy. Nodule shrinkage for its own sake is an outcome that may not be of clinical value to either the patient or physician. The potential risks of long-term T4 therapy outweigh the potential benefits in most patients, particularly postmenopausal women (4,7,97). One study (119) suggested benefit from T4 therapy in previously irradiated patients who had undergone subtotal thyroidectomy for benign nodules. Treatment of this group of patients with T4 seems reasonable. Multinodular Goiter Evaluation of patients with MNG includes determination of thyroid function, estimation of goiter size, exclusion of malignancy, and assessment of local symptoms (120). Evaluation should begin with a US examination and serum TSH determination; if TSH is suppressed, serum levels of thyroid hormone (free T4 and T3 ) are determined and a radioiodine uptake (RAIU) test is performed. Toxic MNG is treated with radioiodine or surgery; subclinical hyperthyroidism may be observed for a period of time and then reassessed. A normal serum concentration of TSH indicates a nontoxic MNG. Cytologic evaluation by US-FNA biopsy helps determine the management strategy (Fig. 8). In patients with benign goiters, periodic evaluation—including thyroid palpation, determination of serum levels of TSH,

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Figure 8 Management of patient with a multinodular goiter (MNG). Evaluation begins by determining thyroid-stimulating hormone (TSH) levels; suppressed TSH (⬍0.1 mIU/L) suggests subclinical or clinical hyperthyroidism and the patient is treated accordingly. Most often, when TSH is normal (nontoxic goiter), fine-needle aspiration (FNA) biopsy results decide management. Benign and/or small goiters are followed without thyroxine therapy. Symptomatic, large MNGs are treated with either surgery or radioiodine (131 I). Malignant goiters are surgically excised. Abbreviations: FT4 , free thyroxine; N, normal; RAIU, radioiodine uptake; Rx, therapy; T3 , triiodothyronine; US, ultrasound.

and cross-sectional imaging studies—is helpful in management. Cytologically suspicious or malignant MNGs should be treated surgically. Surgical excision is preferred in patients with nontoxic MNG and local compression symptoms or cosmetic concerns. Bilateral subtotal thyroidectomy is standard therapy for patients with MNG. The most frequent complications of thyroidectomy include injury of the recurrent laryngeal nerve, hypoparathyroidism, hypothyroidism, and postoperative bleeding. However, with experienced surgeons, complication rates are quite low. Postoperatively, T4 replacement is frequently administered to prevent recurrence of goiter, but recent studies have suggested that this therapy is probably ineffective; hence routine T4 therapy is no longer advised (7,97). In patients with primary lobectomy, T4 therapy is advised only if hypothyroidism develops. Radioiodine (131 I) has been used successfully to treat toxic and nontoxic MNGs (120–126). Radioiodine therapy results in amelioration of hyperthyroidism,

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reduction of goiter size, and decreased local pressure or pain. Huysmans and colleagues (122,123) described patients with nontoxic goiters who were treated with radioiodine and reported symptomatic improvement in 71%, decrease in tracheal deviation in 20%, and increased tracheal lumen in 36%. Therapeutic doses of radioiodine have ranged from 25 to 150 mCi, but the dosage depends on RAIU and the mass of thyroid tissue. Adverse effects include posttherapy hyperthyroidism, hypothyroidism, and thyroiditis. Also, the possibility of malignant change in residual thyroid tissue is always a concern (7,125–127). Currently, radioiodine generally is considered an alternative and effective treatment to surgical thyroidectomy; it is a good choice for treatment of small (volume, ⬍100 mL) and nontoxic MNG, for patients previously treated with thyroidectomy, or for elderly patients with high risk of surgical intervention (124). In areas of high iodine intake, RAIU may be low or low-normal, thus reducing the efficacy of radioiodine treatment and requiring increased doses of radioiodine (120). Recent reports suggest that recombinant human TSH (rhTSH) may increase RAIU and benefit patients who are candidates for this nonsurgical treatment (128,129). The administration of small doses (0.10–0.30 mg) of rhTSH results in 4-fold increased uptake, 24 to 72 hours after injection (127–131). Thus, the 131 I becomes more effective for goiter volume reduction, but rhTSH may increase risk of respiratory problems (attributable to acute goiter enlargement), transient posttherapy hyperthyroidism, and permanent hypothyroidism (132). Smaller doses of rhTSH (0.01 mg) may be as effective and may have fewer serious adverse effects. In conclusion, serum TSH level, FNA biopsy, and imaging with radioisotope scanning, US, computed tomography, or magnetic resonance help delineate function, morphology, and extent of an MNG. Indications for treatment include tracheal compression, cosmesis, and concern about malignancy on the basis of growth or cytologic findings (or both). Thyroxine therapy reduces nodule or goiter size in a minority of patients, and its routine use is no longer endorsed (1,2,7,8,97). However, T4 should never be used in patients who already have low-normal or suppressed serum TSH levels for fear of toxicity in an already autonomous gland. Surgery is standard therapy for nontoxic MNGs, and radioiodine, in large doses, is an attractive alternative therapy in elderly patients and those considered to have high risk for surgery. INCIDENTALOMA Nonpalpable thyroid nodules discovered incidentally on imaging examination are described as “incidentalomas.” They are usually less than 1.5 cm in diameter, are a common clinical problem, and constitute a management dilemma for clinicians (12,42,133). Most of them are discovered when high-resolution US is used for parathyroid evaluation, carotid disease, or other nonthyroid diseases of the neck. Incidentalomas are discovered in 30% to 50% of the normal population without

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thyroid disease who undergo neck US. The prevalence of incidentalomas appears higher in the elderly and in persons with iodine deficiency or radiation exposure (133). The results of an older autopsy study (9) and more recent US-FNA study (66) suggest that fewer than 5% of asymptomatic nodules may be malignant. Schneider and coworkers (21) studied the results of US in patients with a history of upper-body irradiation. They reported that 87% of patients had one or more discrete nodules on US and that 75% of nodules were less than 1 cm in diameter. The authors concluded that thyroid US is more sensitive than physical examination and radioisotope scanning. Patients with no history of radiation exposure should not undergo a US examination when thyroid palpation is normal. Those with radiation exposure may undergo periodic US and US-FNA whenever indicated. However, because US is so sensitive, great caution must be used when interpreting the results. We previously have reviewed the clinical importance of thyroid incidentalomas and proposed practical management guidelines (Fig. 9) (133). If

Figure 9 Diagnostic approach to patient with incidentaloma. The algorithm separates patients into high-risk and low-risk groups on the basis of clinical assessment. Nodule size and appearance on high-resolution ultrasonography (US) also influence management. For low-risk patients with benign-appearing incidentalomas less than 1.5 cm in diameter, observation and follow-up palpation are sufficient. Abbreviation: FNA, fine-needle aspiration. Source: From Ref. 133.

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incidentalomas do not have sonographic features of malignancy and are smaller than 1.0 to 1.5 cm in diameter, and if the clinical history is not suggestive of increased risk for thyroid cancer, follow-up neck palpation and US at 6 months and annually thereafter is a practical, cost-effective approach. However, for patients with nodules larger than 1.0 to 1.5 cm in diameter, with previous neck irradiation, or with imaging characteristics suspicious for malignancy, US-FNA should be performed. Suspicious imaging features include a solid, hypoechoic nodule with irregular borders, sometimes containing punctate microcalcifications and increased blood flow on Doppler imaging. Nonpalpable nodules that are predominately cystic are most likely benign. In conclusion, incidental thyroid micronodules are common, recognized with increasing frequency, and are commonly benign. US-FNA should be performed when clinical history or US examination findings are suspicious for malignancy.

CONCLUSIONS Thyroid nodules are very common and have a malignancy risk of less than 5%. This risk seems independent of either nodule size or number. Initial evaluation should include a serum TSH measurement, US examination, and FNA biopsy. FNA is now established as a safe and accurate diagnostic test. US-FNA biopsy should be performed if the nodule is small (1.0–1.5 cm), impalpable, or if a previous FNA biopsy result was nondiagnostic. Clinically suspicious or malignant nodules should be treated surgically. FNA-benign nodules should have careful follow-up that includes palpation and possibly US in 12 months. Although some recommend routine, additional aspiration of benign nodules, this is not universally accepted. T4 suppression is no longer recommended because few nodules decrease in size with suppressive therapy, and important adverse effects may accompany treatment. Most benign nodules remain stable in size; enlarging nodules should be evaluated by reaspiration. MNGs can be toxic or nontoxic, and patients in either group may require treatment. Standard treatment is surgical thyroidectomy, although radioiodine increasingly is used for patients who refuse surgery or are not candidates for surgical treatment. When RAIU is low, rhTSH can be used to stimulate uptake and improve results of treatment. Certain management issues remain controversial, including routine CT measurement; the application of immunohistochemical markers in nodules with clinically suspicious biopsy findings; how many and which nodule(s) should undergo FNA biopsy when patients have multiple nodules; extent of initial surgery for nodule with clinically suspicious biopsy findings; and the role of radioiodine in the treatment of MNG.

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79. Bartolazzi A, Gasbarri A, Papotti M, et al. Thyroid Cancer Study Group. Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Lancet 2001; 357(9269):1644–1650. 80. McHenry CR, Walfish PG, Rosen IB. Non-diagnostic fine needle aspiration biopsy: A dilemma in management of nodular thyroid disease. Am Surg 1993; 59(7):415– 419. 81. Baloch ZW, Sack MJ, Yu GH, et al. Fine-needle aspiration of thyroid: An institutional experience. Thyroid 1998; 8(7):565–569. 82. Gharib H, James EM, Charboneau JW, et al. Suppressive therapy with levothyroxine for solitary thyroid nodules: A double-blind controlled clinical study. N Engl J Med 1987; 317(2):70–75. 83. Cheung PS, Lee JM, Boey JH. Thyroxine suppressive therapy of benign solitary thyroid nodules: A prospective randomized study. World J Surg 1989; 13(6):818– 821. 84. Reverter JL, Lucas A, Salinas I, et al. Suppressive therapy with levothyroxine for solitary thyroid nodules. Clin Endocrinol (Oxf) 1992; 36(1):25–28. 85. Berghout A, Wiersinga WM, Drexhage HA, et al. Comparison of placebo with l-thyroxine alone or with carbimazole for treatment of sporadic non-toxic goitre. Lancet 1990; 336(8709):193–197. 86. Celani MF. Levothyroxine suppressive therapy in the medical management of nontoxic benign multinodular goiter. Exp Clin Endocrinol 1993; 101(5):326– 332. 87. Celani MR, Mariani M, Mariani G. On the usefulness of levothyroxine suppressive therapy in the medical treatment of benign solitary, solid or predominantly solid, thyroid nodules. Acta Endocrinol (Copenh) 1990; 123(6):603–608. 88. Diacinti D, Salabe GB, Olivieri A, et al. Efficacy of L-thyroxine (L-T4 ) therapy on the volume of the thyroid gland and nodules in patients with euthyroid nodular goiter (ENG) [Italian]. Minerva Med 1992; 83(11):745–751. 89. La Rosa GL, Ippolito AM, Lupo L, et al. Cold thyroid nodule reduction with Lthyroxine can be predicted by initial nodule volume and cytological characteristics. J Clin Endocrinol Metab 1996; 81(12):4385–4387. 90. La Rosa GL, Lupo L, Giuffrida D, et al. Levothyroxine and potassium iodide are both effective in treating benign solitary solid cold nodules of the thyroid. Ann Intern Med 1995; 122(1):1–8. 91. Mainini E, Martinelli I, Morandi G, et al. Levothyroxine suppressive therapy for solitary thyroid nodule. J Endocrinol Invest 1995; 18(10):796–799. 92. Wemeau JL, Caron P, Schvartz C, et al. Effects of thyroid-stimulating hormone suppression with levothyroxine in reducing the volume of solitary thyroid nodules and improving extranodular nonpalpable changes: A randomized, double-blind, placebocontrolled trial by the French Thyroid Research Group. J Clin Endocrinol Metab 2002; 87(11):4928–4934. 93. Papini E, Bacci V, Panunzi C, et al. A prospective randomized trial of levothyroxine suppressive therapy for solitary thyroid nodules. Clin Endocrinol (Oxf) 1993; 38(5):507–513. 94. Zelmanovitz F, Genro S, Gross JL. Suppressive therapy with levothyroxine for solitary thyroid nodules: A double-blind controlled clinical study and cumulative meta-analyses. J Clin Endocrinol Metab 1998; 83(11):3881–3885.

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95. Castro MR, Caraballo PJ, Morris JC. Effectiveness of thyroid hormone suppressive therapy in benign solitary thyroid nodules: A meta-analysis. J Clin Endocrinol Metab 2002; 87(9):4154–4159. 96. Richter B, Neises G, Clar C. Pharmacotherapy for thyroid nodules: A systematic review and meta-analysis. Endocrinol Metab Clin North Am 2002; 31(3):699–722. 97. Gharib H, Mazzaferri EL. Thyroxine suppressive therapy in patients with nodular thyroid disease. Ann Intern Med 1998; 128(5):386–394. 98. Faber J, Galle AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: A meta-analysis. Eur J Endocrinol 1994; 130(4):350–356. 99. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331(19):1249–1252. 100. Kuma K, Matsuzuka F, Kobayashi A, et al. Outcome of long standing solitary thyroid nodules. World J Surg 1992; 16(4):583–587. 101. Kuma K, Matsuzuka F, Yokozawa T, et al. Fate of untreated benign thyroid nodules: Results of long-term follow-up. World J Surg 1994; 18(4):495–498. 102. Livraghi T, Paracchi A, Ferrari C, et al. Treatment of autonomous thyroid nodules with percutaneous ethanol injection: Preliminary results. Work in progress. Radiology 1990; 175(3):827–829. 103. Verde G, Papini E, Pacella CM, et al. Ultrasound guided percutaneous ethanol injection in the treatment of cystic thyroid nodules. Clin Endocrinol (Oxf) 1994; 41(6):719–724. 104. Zingrillo M, Torlontano M, Chiarella R, et al. Percutaneous ethanol injection may be a definitive treatment for symptomatic thyroid cystic nodules not treatable by surgery: Five-year follow-up study. Thyroid 1999; 9(8):763–767. 105. Kim JH, Lee HK, Lee JH, et al. Efficacy of sonographically guided percutaneous ethanol injection for treatment of thyroid cysts versus solid thyroid nodules. AJR Am J Roentgenol 2003; 180(6):1723–1726. 106. Valcavi R, Frasoldati A. Ultrasound-guided percutaneous ethanol injection therapy in thyroid cystic nodules. Endocr Pract 2004; 10(3):269–275. 107. Guglielmi R, Pacella CM, Bianchini A, et al. Percutaneous ethanol injection treatment in benign thyroid lesions: Role and efficacy. Thyroid 2004; 14(2):125–131. 108. Bennedbaek FN, Hegedus L. Treatment of recurrent thyroid cysts with ethanol: A randomized double-blind controlled trial. J Clin Endocrinol Metab 2003; 88(12):5773–5777. 109. Papini E, Panunzi C, Pacella CM, et al. Percutaneous ultrasound-guided ethanol injection: A new treatment of toxic autonomously functioning thyroid nodules? J Clin Endocrinol Metab 1993; 76(2):411–416. 110. Bennedbaek FN, Nielsen LK, Hegedus L. Effect of percutaneous ethanol injection therapy versus suppressive doses of L-thyroxine on benign solitary solid cold thyroid nodules: A randomized trial. J Clin Endocrinol Metab 1998; 83(3):830–835. 111. Lippi F, Manetti L, Rago T. Percutaneous ultrasound-guided ethanol injection for treatment of autonomous thyroid nodules: Results of a multicentric study abstract. J Endcrinol Invest 1994; 17(Suppl. 2):71. 112. Zingrillo M, Collura D, Ghiggi MR, et al. Treatment of large cold benign thyroid nodules not eligible for surgery with percutaneous ethanol injection. J Clin Endocrinol Metab 1998; 83(11):3905–3907.

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113. Zingrillo M, Modoni S, Conte M, et al. Percutaneous ethanol injection plus radioiodine versus radioiodine alone in the treatment of large toxic thyroid nodules. J Nucl Med 2003; 44(2):207–210. 114. Pacella CM, Bizzarri G, Guglielmi R, et al. Thyroid tissue: US-guided percutaneous interstitial laser ablation: A feasibility study. Radiology 2000; 217(3):673–677. 115. Dossing H, Bennedbaek FN, Karstrup S, et al. Benign solitary solid cold thyroid nodules: US-guided interstitial laser photocoagulation: Initial experience. Radiology 2002; 225(1):53–57. 116. Papini E, Guglielmi R, Bizzarri G, et al. Ultrasound-guided laser thermal ablation for treatment of benign thyroid nodules. Endocr Pract 2004; 10(3):276–283. 117. Pacella CM, Bizzarri G, Spiezia S, et al. Thyroid tissue: US-guided percutaneous laser thermal ablation. Radiology 2004; 232(1):272–280 [Epub May 20, 2004]. 118. Dossing H, Bennedbaek FN, Hegedus L. Effect of ultrasound-guided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules: One versus three treatments. Thyroid 2006; 16(8):763–768. 119. Fogelfeld L, Wiviott MB, Shore-Freedman E, et al. Recurrence of thyroid nodules after surgical removal in patients irradiated in childhood for benign conditions. N Engl J Med 1989; 320(13):835–840. 120. Hurley DL, Gharib H. Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996; 29(4):527–540. 121. Huysmans DA, Buijs WC, van de Ven MT, et al. Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters. J Nucl Med 1996; 37(12):2072– 2079. 122. Huysmans DA, Hermus AR, Corstens FH, et al. Large, compressive goiters treated with radioiodine. Ann Intern Med 1994; 121(10):757–762. 123. Huysmans AK, Hermus RM, Edelbroek MA, et al. Autoimmune hyperthyroidism occurring late after radioiodine treatment for volume reduction of large multinodular goiters. Thyroid 1997; 7(4):535–539. 124. Huysmans D, Hermus A, Edelbroek M, et al. Radioiodine for nontoxic multinodular goiter. Thyroid 1997; 7(2):235–239. 125. Wesche MF, Tiel-v-Buul MM, Smits NJ, et al. Reduction in goiter size by 131 I therapy in patients with non-toxic multinodular goiter. Eur J Endocrinol 1995; 132(1):86–87. 126. Hermus AR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med 1998; 338(20):1438–1447. 127. Silva MN, Rubio IG, Knobel M, et al. Treatment of multinodular goiters in elderly patients with therapeutic doses of radioiodine preceded by stimulation with human recombinant TSH. Endocr J 2000; 47(Suppl.):144. 128. Duick DS, Baskin HJ. Significance of radioiodine uptake at 72 hours versus 24 hours after pretreatment with recombinant human thyrotropin for enhancement of radioiodine therapy in patients with symptomatic nontoxic or toxic multinodular goiter. Endocr Pract 2004; 10(3):253–260. 129. Albino CC, Mesa CC Jr, Olandoski M, et al. Recombinant human thyrotropin as adjuvant in the treatment of multinodular goiters with radioiodine. J Clin Endocrinol Metab 2005; 90(5):2775–2780 [Epub Feb 15, 2005]. 130. Duick DS, Baskin HJ. Utility of recombinant human thyrotropin for augmentation of radioiodine uptake and treatment of nontoxic and toxic multinodular goiters. Endocr Pract 2003; 9(3):204–209.

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131. Nielsen VE, Bonnema SJ, Hegedus L. Transient goiter enlargement after administration of 0.3 mg of recombinant human thyrotropin in patients with benign nontoxic nodular goiter: A randomized, double-blind, crossover trial. J Clin Endocrinol Metab 2006; 91(4):1317–1322 [Epub Jan 24, 2006]. 132. Nielsen VE, Bonnema SJ, Boel-Jorgensen H, et al. Stimulation with 0.3-mg recombinant human thyrotropin prior to iodine 131 therapy to improve the size reduction of benign nontoxic nodular goiter: A prospective randomized double-blind trial. Arch Intern Med 2006; 24(14):1476–1482. 133. Tan GH, Gharib H. Thyroid incidentalomas: Management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 1997; 126(3):226–231.

6 Differentiated Thyroid Carcinoma Jennifer A. Sipos The Ohio State University, Columbus, Ohio, U.S.A.

Ernest L. Mazzaferri University of Florida, Gainesville, Florida, U.S.A.

INTRODUCTION Thyroid carcinoma comprises a spectrum of malignancies ranging from rarely lethal, slow-growing neoplasms to among the most deadly aggressive cancers to afflict humanity. Fortunately, most cases are well-differentiated tumors that can be treated successfully. Still, therapy remains controversial because prospective clinical studies are confounded by low disease incidence, prolonged disease time course, and relatively good outcome in the majority of patients. Further, while staging systems predict outcome reasonably well, they remain inexact. Thus, while the majority of patients can be reassured that they are likely to do well, this outcome cannot be absolutely guaranteed. As a result, therapy has remained relatively dogmatic, as the ideal strategy that prevents unnecessary overtreatment while avoiding detrimental undertreatment is not a current reality, leading physicians to essentially choose on which side to err. The goals of patient management are to minimize morbidity and mortality from cancer (tumor recurrence, metastases, and death) as well as from therapy [surgery, hypothyroidism, iodine-131 (131 I) therapy, thyroid-stimulating hormone (TSH) suppression, and cost]. This chapter emphasizes features that predict outcome and current management paradigms.

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Figure 1 Annual incidence of thyroid carcinoma (all types) in the United States according to age at the time of diagnosis and patient gender. Source: Adapted from Ref. 2.

EPIDEMIOLOGY Cancers of the thyroid are rare, comprising approximately 2% of all diagnosed cancers but accounting for ⬎93% of all cancers of the endocrine system (1). Approximately 30,180 new cases and 1500 thyroid cancer deaths occur each year in the United States: (1) ranking it 9th among malignancies for women and 19th for men (2). Thyroid cancer is nearly three times more common in women than men (1). It may occur at any age, but is more common in middle-aged women and in men over the age of 60 years (Fig. 1). Thyroid cancer death rates are ⬍10%, but vary significantly among the various types of thyroid cancer (Table 1) (3). Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, demonstrate that the incidence of thyroid cancer has more than doubled over the past three decades, increasing from a rate of 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002, a twofold increase that is statistically significant (p ⬍ 0.001 for trend) (4). New papillary thyroid cancers

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Table 1 Incidence and 10-Year Relative Survival Rates of the Major Histological Types of Thyroid Carcinoma Among 53,856 Cases Diagnosed Between 1985 and 1995 (3)a Thyroid carcinoma type Papillary Follicular H¨urthle Medullary Anaplastic

Frequency (%)

Survival (%)

80 11 3 4 2

93 85 76 75 14

a

Relative survival is death attributed to thyroid carcinoma after correcting for death from other causes. Source: Adapted from Ref. 3.

represent virtually all of this increased incidence, while the other three major forms of thyroid cancer have remained constant (4). The rising incidence has occurred mostly in women but thyroid cancer is also rising in men, albeit at half the rate of that in women (5). Of major importance, nearly half (49%) the tumors are papillary cancers ⬍1 cm [papillary thyroid microcarcinoma (PTMC)] and most (87%) are papillary tumors ⬍2 cm in largest dimensions (4). One study reported that in spite of this escalating frequency of small thyroid cancers, the overall mortality rate per 100,000 people in the population has remained constant according to death certificate data from the National Vital Statistics System (4). The authors of this study attribute the increasing incidence of papillary thyroid carcinoma to overdiagnosis or “increased diagnostic scrutiny,” which makes it difficult to know which patients need treatment, suggesting that small asymptomatic thyroid nodules should be followed up for a period of time without immediately initiating diagnostic studies. Other data (6) indicate that thyroid cancer deaths have not remained stable over the past several decades. The National Cancer Institute’s SEER database (7) shows that among women, the five-year relative survival rates for thyroid cancer from 1974 to 2001 increased significantly from 92.7% to 97.4% in 1974 to 2003 (Fig. 2, p ⬍ 0.5). During this same time, however, the rates of thyroid cancer distant metastases in men at the time of diagnosis were more than twofold more than those of women (9% vs. 4%), and during 1992 to 2000 the annual percent change in thyroid cancer mortality significantly increased in men by 2.4% (Fig. 2, p ⬍ 0.05), the largest increase of any type of cancer (7). Classification Thyroid carcinomas are classified into four major types, which, in decreasing order of frequency, are papillary (PTC), follicular (FTC), medullary (MTC), and

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(A)

Figure 2 (A) Papillary thyroid carcinoma (PTC): tumor infiltrating thyroid and invading thyroid capsule (top left); FNA cytology specimen showing the typical features of PTC, including large nuclei with inclusion bodies (top right); histology showing typical papillary fronds (lower left); psammoma bodies showing lamellate appearance, which are virtually diagnostic of this tumor (lower right), (B). Follicular thyroid carcinoma (FTC): solid encapsulated tumor with areas of necrosis and invasion of tumor capsule at 3 o’clock (top left); microscopic tumor invasion of tumor capsule (top right); FNA cytology specimen showing sheets of follicular cells without colloid that is suspicious of FTC (lower left); H¨urthle cells showing abundant oxyphilic cytoplasm (lower right), (C). Anaplastic thyroid carcinoma (ATC) and medullary thyroid carcinoma (MTC): ATC with tumor infiltrating the entire gland and invading the thyroid capsule at 4 o’clock (top left); histology of ATC showing large, bizarre-appearing cells (top right); MTC with spindle cells and dense stroma that stains positive for amyloid (lower right); spindle cell tumor that was a MTC, which can mimic ATC (lower right).

anaplastic thyroid carcinomas (ATC) (Table 1). Although categorized as a separate entity in some classifications, Oncocytic [H¨urthle cell (HTC)] carcinomas are considered by the World Health Organization classification of tumors (8) as follicular carcinomas composed exclusively or predominantly (⬎75%) of oncocytic cells, the ultrastructure of which are filled with mitochondria producing a cytologic

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(B)

(C)

Figure 2 (Continued)

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appearance that is unique. PTC, FTC, and HTC—often termed differentiated thyroid carcinomas or DTC— arise from follicular cells, synthesize thyroglobulin (Tg), and tend to be sporadic tumors, although occasionally PTC is familial. MTC, which originates from thyroidal C cells that secrete calcitonin, may be sporadic or familial. ATC usually arises from well-differentiated thyroid carcinomas, particularly PTC (9). PAPILLARY AND FOLLICULAR THYROID CARCINOMAS Papillary Thyroid Carcinoma This tumor accounts for approximately 80% of all thyroid carcinomas in the United States (3,5). It is three times more frequent in women than in men. Incidence is highest in women in midlife, but it occurs at all ages. Often considered a separate disease, occult microscopic PTC (≤1 cm) is found in 10% or more of autopsy and surgical thyroid specimens obtained from men and women throughout adult life (5). A small group of nonmedullary thyroid cancers appear to be inherited, most of which are PTC. Approximately 5% of PTCs are familial tumors inherited as an autosomal dominant trait without other associated pathology. Familial PTC is characterized by an earlier age of onset and more aggressive phenotype (10) than sporadic PTC. One study of 258 cases (11) found that although patient gender, age, and tumor histology were similar to that of sporadic PTC, familial tumors were more likely to have intrathyroidal dissemination (41% vs. 29%) and higher recurrence rates (16% vs. 10%) than sporadic tumors without displaying significant differences in size, local invasion, or macroscopic metastasis. Follicular Thyroid Carcinoma This tumor occurs sporadically and accounts for approximately 10% of all thyroid cancers in the United States, although it is more common in countries with low dietary iodine (12). It usually occurs at a slightly older age than PTC (13,14), but in some studies almost half of the patients are older than 40 years at diagnosis (15). This tumor is rare in children, occurs infrequently after head and neck irradiation, and is not commonly found incidentally. RADIATION-INDUCED THYROID CARCINOMA Epidemiology Exposure to ionizing radiation during childhood is the best understood cause of papillary, and less commonly, follicular thyroid carcinoma. Nevertheless, such a history usually is now elicited in only approximately 5% of patients (16). Some radiation exposure events have been associated with an increased risk of thyroid cancer, while others have not. Possible explanations of this difference may include

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the various sources of radiation involved, which delivered different thyroid doses and different thyroid dose rates. Treatment of benign conditions of the head and neck, such as acne, tonsillitis, and sinusitis, with radiation therapy was commonplace in the 1940s and 1950s. Fortunately, such treatments are no longer used, but their carcinogenic effects are still seen more than 40 years later (17). Similarly, survivors of childhood malignancies treated with radiation to the head/neck and chest are also at increased risk of thyroid carcinoma (18). Factors that increase the risk of developing thyroid cancer after external beam radiation therapy are female gender, radiation for childhood cancer (as opposed to benign conditions), and family history of thyroid cancer (19).

PAPILLARY THYROID CARCINOMA Pathology Papillary thyroid carcinoma (PTC) is typically an unencapsulated invasive tumor with ill-defined margins. In approximately 10% of cases, the thyroid capsule is penetrated by tumor that may invade surrounding tissues, while another 10% are fully encapsulated (20,21). The tumor is typically firm and solid but may develop chronic hemorrhagic necrosis, making it soft, and yielding a thick brownish fluid on needle biopsy that may cause it to be mistaken for a benign cyst (22). In rare cases, the entire thyroid is effaced with large cystic PTC tumors (23). Small tumors ≤1.0 cm in diameter often have a stellate appearance and are usually found by serendipity. Although they generally pose no risk to the patient, PTMCs are occasionally locally invasive and metastatic (24). Most PTCs have a typical microscopic appearance with complex, branching papillae, and a fibrovascular core covered by a single layer of tumor cells intermingled with follicular structures, but some PTCs have a pure follicular appearance that grossly resembles FTC (8). The term mixed papillary–follicular carcinoma has no clinical value because the follicular component does not alter 131 I uptake or prognosis, thus such tumors are considered to be classic PTC. Nuclear features are more important than architectural appearance in establishing a PTC diagnosis. Tumors with a pure microfollicular pattern with virtually no papillary structures but with typical cellular features of PTC are termed follicular variant of PTC (FVPC) (8). The cellular features of PTC distinguish it from other tumors, regardless of its architecture, permitting an accurate diagnosis by fine-needle aspiration (FNA) cytology [Fig. 2(A)]. The large cells contain pink to amphophilic finely granular cytoplasm and large pale nuclei with inclusion bodies, sometimes called “orphan Annie eye” nuclei, and nuclear grooves that identify it as PTC [Fig. 2(A)]. Psammoma bodies—the “ghosts” of infarcted papillae that are virtually pathognomonic of PTC—are calcified, concentric lamellated spheres found in about half the cases [Fig. 2(A)] (25). Multiple histological PTC subtypes or variants have been described (Table 2) (8).

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Table 2 Prognosis of Main Histological Variantsa of Papillary and Follicular Thyroid Carcinoma Better Papillary thyroid carcinoma Encapsulated Cystic Microcarcinoma Macrocarcinoma

Worse Tall cell Columnar cell Diffuse sclerosis Diffuse follicular

Possibly worse

Solid Oncocytic (H¨urthle cell) Associated with Graves’ disease

Insular cell PTC with dedifferentiation Follicular thyroid carcinoma Oncocytic (H¨urthle cell) Insular cell a Other histological variants—such as PTC with lipomatous stroma or fascitis-like stroma or myxoid and cribriform variant PTC—have been reported too rarely to be certain about prognosis. Source: Adapted from Ref. 23.

Multiple tumor foci are found in up to 80% of PTC cases when the thyroid gland is examined in detail but are found in only 20% to 45% of specimens examined routinely (26). This is important because multifocal PTMCs are associated with an increased rate of lymph node and distant metastases. One study (27) found lymph node metastases in 20% of unifocal and 35% of multifocal PTC tumors and that multifocality increased lymph node recurrences almost sixfold. Another study of PTMC found that 89% of distant metastases from these small tumors were associated with multifocal tumors (28). Thought to be intrathyroidal metastases in the past (26), newer studies using X-chromosome (29) BRAF (the gene encoding B-type Rat Kinase) (30,31) or PTC/RET (RET is rearranged during transfection proto-oncogene) analyses (32) find that many of tumors within the same thyroid have different oncogene patterns that support the concept that multicentric tumors arise de novo as independent tumors. Still, one study (33) found that multifocal PTC tumors often have similar X-chromosome inactivation patterns suggesting intrathyroidal metastases are a cause of multicentric tumor. Thus, both intrathyroid metastasis and de novo tumors may play an important role in the intrathyroidal spread of PTC, findings that have important therapeutic, diagnostic, and prognostic implications. Focal areas of infiltration with lymphocytes or plasma cells or classic Hashimoto’s disease are usually present in or around the tumor and are intense in up to 20% of cases (34). The presence of neoplastic cell phagocytosis by macrophages and lymphocytic reaction has been associated with a more favorable prognosis and reduced likelihood of distant metastases (35). It has been hypothesized that this lymphocytic infiltration represents an immune reaction which helps

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to control tumor growth and proliferation (36). Lymphocytic infiltration has been associated with a more favorable clinical outcome (34). Lymph Node Metastases PTC metastasizes to lymph nodes in the lateral and central neck and mediastinum. Lymph node metastases are found in almost half the cases at the time of diagnosis (37), while even more—up to 85% in some studies (38,39)—have microscopic nodal metastases found on more careful histological study (39). The number and size of lymph node metastases increase as the primary tumor size enlarges beyond 5 mm (14). When the isthmus or both lobes are involved with tumor, nodal metastases are often bilateral or extend into the mediastinum, with the most common site being the lower paratracheal area (level VI) (40,41). Level VI is the most common site of lymph node recurrence (42). Lymph node metastases have variably been found to be of no prognostic importance in some studies (43) and of significant prognostic importance in others (37), but a study from the SEER database of 19,919 patients found with multivariate analysis that lymph node metastases predicted a poor outcome. In some cases tumor penetrates the lymph node capsule and invades the soft tissues, which is a particularly poor prognostic sign (44). Distant Metastases Less than 5% of patients have distant metastases at the time of diagnosis and another 5% develop them over the next two or three decades (12). The lung is the most common site of distant metastases and is the most common disease-specific cause of death from PTC. In a review (12) of 1231 patients with distant metastases, 49% were in the lung alone and another 15% were in lung and bone, 25% were in bone alone, and 12% were in the central nervous system (CNS) or in multiple organs (12). Lung metastases may be large and discrete [Fig. 3(A)] or may have a “snow-flake” appearance from diffuse small metastases [Fig. 3(B)]. The lungs may concentrate sufficient 131 I to be detected on whole-body scan. Some lung metastases are not seen on radiographs but are visible only on 131 I whole-body scans, sometimes only after administration of therapeutic amounts of 131 I [Fig. 3(C) and 3(D)] (45,46). In other cases, the lungs do not concentrate 131 I for a variety of reasons. Papillary Microcarcinoma PTMC is a tumor ≤1.0 cm in diameter that is usually impalpable. Histologically malignant, PTMC is generally found by coincidence during surgery for benign thyroid disease and generally displays a benign clinical behavior. Still, not all PTMCs are innocuous. Depending upon the study, up to 43% are multifocal, as many as 69% have lymph node metastases, and up to 2.8% have distant metastases (24). Recurrence rates vary. One study found a recurrence rate of 25.8% (47), but

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Figure 3 X-ray with dense lung infiltrates from PTC (A); X-ray with multiple faint pulmonary metastases and mediastinal metastasis from PTC (B); metastases from thyroid carcinoma: normal chest X-ray in a patient with a serum Tg of 40 ng/mL after neck surgery for PTC (C); scan of same patient 48 hours after 100 mCi 131 I (D); X-ray with multiple pelvic metastases from FTC (E); scan of same patient after 200 mCi 131 I (F).

on average the rate is about 5% (24). Mortality from PTMC is rare, but rates as high as 2% are found in some studies (48). Multifocal tumors tend to be more aggressive than unifocal PTMCs (24,27,28,31). Lung metastases from PTMC are rare but tend to occur more often in tumors with bulky cervical metastases (28,37). Otherwise, the recurrence and cancer-specific mortality rates of PTMC are near zero (24).

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Papillary Cancer within a Thyroglossal Duct PTC within a thyroglossal duct is a rare occurrence but it is usually small (⬍1 cm) and follows a benign course (49). Treatment is controversial, but a Sistrunk procedure for removal of the thyroglossal duct is the mainstay (50,51). Some also advocate thyroidectomy followed by radioiodine ablation as PTC may be found within the thyroid gland upon careful inspection (52–55). PTC within a thyroglossal duct is almost always small and usually has a benign course. Encapsulated Papillary Carcinoma This variant comprises approximately 10% of PTCs. Completely surrounded by a fibrous capsule but otherwise a typical PTC, it is about half as likely as usual to metastasize. It rarely recurs after initial therapy, and almost never causes death (20). Follicular Variant Papillary Carcinoma Classic PTC comprises 55% to 65% (56) and FVPC approximately 20% to 40% of all PTCs (57,58). Opinions differ concerning the exact diagnostic criteria for FVPTC, resulting in the wide prevalence rates among studies. The diagnosis of classic FTC requires the presence of capsular and/or vascular invasion (8), whereas the diagnosis of FVPTC depends upon finding nuclear features of PTC. A major diagnostic feature of FVPTC, according to the original description (59) and that of LiVolsi (60), is that the microfollicular structure must involve the entire tumor; however, some find this too restrictive and make the diagnosis of FVPTC when 80% of the tumor contain microfollicles (56). This distinction is important since 40% (61) to 80% (56) of classic PTCs show areas of follicle formation, thus accounting for the wide range in incidence rates reported for FVPTC. Although there are reports (62,63) that the rates of lung metastases are higher in FVPTC than those in classic PTC, others have been unable to confirm this (56,58,64), and the literature generally reflects that the clinical outcome and behavior of FVPTC and classic PTC are the same (56,57,61). Nonetheless, a few case reports of FVPTC describe metastases to lung (62,63), kidney (65), bone (66), and skin (67). Macrofollicular Variant Macrofollicular PTC is a rare variant of PTC in which ⬎50% of the follicles are macrofollicles. The presence of abundant colloid, macrophages, macrofollicular architectural arrangement and absence of typical cytologic features of PTC can lead to an erroneous diagnosis of benign adenoma or hyperplastic nodule (68). As a result, the tumor may be extremely difficult to diagnose by FNA because the characteristic features of PTC are not present (69). Diffuse Follicular Variant Papillary Carcinoma This uncommon tumor may be confused with typical multinodular goiter or macrofollicular adenoma on frozen section (70). It is seen mainly in younger women with

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goiter, about one-third of whom have hyperthyroidism. These aggressive tumors are more likely to be multicentric, have extrathyroidal extension, nodal and distant metastases, and vascular invasion compared to common PTC and FVPTC (71). Mortality rates are very high with this tumor (70). Tall Cell Variant Ten percent of PTCs have papillae with cells twice as tall as they are wide that constitute at least 30% of the tumor (70). Compared with typical PTC, tall cell variants tend to be diagnosed about two decades later (in patients in their mid50s), are larger, and are more often associated with invasion into local soft tissues and with distant metastases (70,72,73). This tumor can be identified by FNA cytology. It often expresses the p53 oncogene, BRAF mutation, RET/PTC gene rearrangement, or NTRK1 mutation (74,75). Tall cell variant often loses or lacks 131 I uptake and the mortality is two- to threefold higher than those of typical PTC (70,73). Columnar Cell Variant This rare variant, which is possibly related to tall cell carcinoma, is found mainly in males and is composed of rectangular cells with clear cytoplasm (37). Distant metastases develop in 90% and are usually unresponsive to 131 I therapy or chemotherapy, resulting in death in most patients (37,38). When it is encapsulated, it has a much better prognosis (28). Diffuse Sclerosing Variant Approximately 5% of spontaneously occurring PTC and 10% of those found among the Chernobyl children are of this type (70,76). The tumor is usually bilateral and presents as a goiter with extensive squamous metaplasia, sclerosis, psammoma bodies, and abundant lymphatic invasion involving the whole thyroid gland. Almost all develop lymph node metastases and approximately 25% have lung metastases (70). FNA cytology reveals squamous metaplasia, inflammatory cells, and psammoma bodies, but this tumor may be difficult to differentiate from thyroiditis (77). Although local and pulmonary metastases are more frequent than usual, there is disagreement about whether its long-term prognosis is worse than that of typical PTC (78–80). Solid or Trabecular Variant This tumor has a predominantly (⬎75%) solid architectural pattern but maintains the typical nuclear features of PTC. It has a propensity for extrathyroidal spread and lung metastases that impart a poor prognosis (70), but some find it to be more common in children, in whom its prognosis is the same as that of typical PTC (81).

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¨ Oxyphilic (Hurthle Cell) Variant Approximately 2% of PTCs have cellular features resembling those of H¨urthle cell (oxyphilic) FTCs (82). Some cases have multiple oxyphilic thyroid tumors and a familial occurrence (83). This tumor cannot be identified as PTC by FNA cytology but is recognized by its papillary architecture on the final histological sections. Compared with typical PTC, oxyphilic PTC has fewer neck nodal metastases at diagnosis but has higher recurrence and mortality rates and in this respect resembles oxyphilic FTC (70). Insular Carcinoma Approximately 5% of all thyroid carcinomas show solid clusters of cells with small follicles that resemble pancreatic islet cells but contain Tg. Often categorized as a FTC variant, some tumors show papillary differentiation. LiVolsi believes that this tumor should be considered a separate entity derived from follicular epithelium (84). The tumors are unusually large and invasive and tend to grow through the tumor capsule and into tumor blood vessels. Compared with PTC, insular carcinoma presents at an older age (54 vs. 36 years) with larger tumors (4.7 vs. 2.5 cm), fewer neck metastases (36% vs. 50%) but more distant metastases (26% vs. 2%), and has a worse 30-year cancer-specific mortality rate (25% vs. 8%) (73). Insular carcinoma also displays aggressive behavior in children but is usually responsive to thyroidectomy and 131 I therapy (85).

FOLLICULAR THYROID CARCINOMA Pathology Follicular thyroid carcinomas (FTCs) are solid invasive tumors which, unlike PTCs, do not show necrotic degeneration but tend to be solitary and encapsulated, even when they are biologically aggressive (5). Minimally invasive tumors show just enough evidence—usually invasion into the tumor capsule without penetration through it (and no vascular invasion)—to make a diagnosis of carcinoma. Others have multiple foci of tumor capsule and vascular penetration but remain fairly discrete masses, while a few are highly invasive tumors with satellite nodules. Large, aggressive tumors may extend into the opposite lobe or adjacent cervical tissue. Most FTCs cannot be differentiated from follicular adenomas on gross tumor inspection, FNA, or frozen section and must be differentiated from follicular variant PTC and follicular adenoma based on final histological sections (12). FTCs typically are compact, highly cellular tumors composed of microfollicles, trabeculae, and solid masses of cells. Less often, they contain medium-sized or large follicles and such low invasive characteristics that are difficult to differentiate from benign adenomas even on the final histological sections—a finding associated with an excellent prognosis (12).

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FTC has compact cells with small, dark-staining, round nuclei that are more uniform in shape, size, and location than the nuclei of PTCs and are difficult to identify as carcinoma by FNA [Fig. 2(B)] (12,86). ¨ Hurthle Cell Carcinoma Oxyphilic cells, termed H¨urthle or Askanazy cells, contain increased amounts of acidophilic cytoplasm that contains numerous mitochondria on electron microscopy. Greater than 75% of cells must be H¨urthle cells to constitute HTC. Some consider this to be a distinct clinicopathological entity while others consider it to be a variant of FTC (87). HTCs demonstrate lymph node metastases more frequently than typical FTC and metastases rarely respond to 131 I therapy. Regardless of its classification, HTC has a less favorable prognosis than nonoxyphilic FTC, even though the former may not initially appear less differentiated or more invasive (12). Lymph Node Metastases Compared to PTC, FTC metastasizes about half as often to regional lymph nodes, occurring in approximately 20% of cases and is usually caused by the more aggressive tumors that often have distant metastases (14). Distant Metastases FTC tends to metastasize to lung, bone, CNS, and other soft tissues with greater frequency than does PTC, and the metastases often avidly concentrate 131 I. Distant metastases at the time of diagnosis are about twice as common with FTC compared to PTC (5). Unlike small PTCs that rarely metastasize to distant sites, small FTCs can metastasize widely, and tumors ⬎3 cm are associated with a much higher mortality rate (14,88) DIAGNOSIS OF PAPILLARY AND FOLLICULAR THYROID CARCINOMAS Clinical Presentation In the past, PTC was often diagnosed at a late stage, when the tumor was large and invasive. Now, however, most are identified earlier by ultrasound-guided FNA of small, asymptomatic thyroid nodules—frequently discovered incidentally by imaging of the neck for other medical conditions (89). A few come to attention as the result of pain, hoarseness, dysphagia, hemoptysis, or other signs of tissue infiltration or rapid tumor growth. Such findings are associated with a high probability of carcinoma in a nodule (90) and greater than usual mortality rates (37). Sometimes palpably enlarged cervical lymph nodes are the only clue to the diagnosis. A history of exposure to head or neck radiation is important, but only about one-third of such nodules are malignant (17,91). A nodule in the setting of a family history of PTC should be regarded with higher than usual suspicion.

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Nevertheless, the evaluation of familial or radiation-induced tumors is similar to that of sporadic nodules. Most FTCs present as an asymptomatic neck mass without palpable cervical lymphadenopathy. Less often, a distant metastasis is the first manifestation, appearing as lung nodules, osteolytic bone lesion, or pathological fracture or as a CNS tumor with neurological sequelae. Rarely, distant metastases are seen in the absence of a palpable thyroid lesion (24). Bulky metastatic lesions may be functional and cause thyrotoxicosis. DTC usually becomes manifest by a palpably firm thyroid nodule that moves upward when the patient swallows. PTC, however, may be cystic and soft or may diffusely infiltrate one lobe or the entire thyroid gland; or its first manifestation may be a palpable cervical lymph node metastasis. A midline mass above the thyroid isthmus may be a metastatic (Delphian) lymph node or carcinoma within a thyroglossal duct—the latter is suggested by upward movement with tongue protrusion. Distant metastases are found less often at the time of diagnosis of PTC than FTC, but when they are present, the primary tumor is usually large and invasive. Only 10% of thyroid nodules have clear clinical evidence of malignancy such as vocal cord paralysis or signs of invasion or metastases at the time of diagnosis. Most appear benign and are associated with few or no symptoms. Thus neither the history nor physical examination offers enough evidence of a nodule’s benign nature that further testing can be deferred. Fine-needle Aspiration A serum thyrotropin (TSH) level should be measured in every patient found to have a thyroid nodule. If the TSH level is below the lower reference range (Fig. 4), then radionuclide imaging should be performed to determine if the nodule is hyperfunctional (hot). Such a nodule is highly unlikely to be malignant and does not routinely require FNA (92,93). Otherwise, FNA should be done to evaluate a thyroid nodule in a clinically euthyroid patient (Fig. 4), whether the patient has a single nodule or a multinodular goiter (92,93). Other tests—especially imaging studies—are otherwise too nonspecific to be used early in the evaluation, except perhaps in a patient with multinodular goiter and a suppressed TSH. All thyroid nodules ⬎1 to 1.5 cm should undergo FNA (92), especially those with suspicious ultrasound features. Fine-needle aspiration is best performed under ultrasound guidance with on-site evaluation of cytology adequacy. This will decrease the likelihood of obtaining a cytology specimen that is insufficient for diagnosis, a common cause of missed cancer diagnoses, compared with performing the procedure by palpation guidance alone. The ultrasonography-cytology assessment approach is particularly important if the nodule is cystic (94). Thyroxine therapy should not be used as a diagnostic test to identify thyroid carcinoma. Some malignant nodules appear by palpation to shrink as the perinodular thyroid parenchyma reduces in size in response to levothyroxine (86); in other cases, ultrasound documented of reduction in size of malignant nodules has been demonstrated (95).

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Figure 4 Diagnostic paradigm for evaluating a thyroid nodule. Source: Adapted from Ref. 87.

FNA yields cytology that can be categorized as malignant, benign, indeterminate (suspicious), or inadequate for diagnosis (Fig. 4). FNA is highly effective in obtaining sufficient cytology to identify the distinctive features of PTC, including most of its variants as well as most other malignant lesions (86). Benign H¨urthle cell tumors and follicular adenomas may be difficult to differentiate from their malignant counterparts by FNA and frozen tissue sections. Large-needle aspiration biopsies and cutting-needle biopsies usually yield results similar to those of FNA but cause more complications and have lower diagnostic specificity, especially for PTC, than FNA (96). FNA cytology specimens showing normal or atypical follicular or H¨urthle cells are often simply designated as follicular or H¨urthle cell neoplasms because their benign or malignant character cannot

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be determined with certainty until the final histological sections are available. Even then there may be difficulty separating malignant and benign tumors (86). Cytological material sufficient for diagnosis can be obtained in most palpable nodules, but the accuracy of FNA is enhanced by ultrasonographically guided FNA, especially for small solid, cystic, and hypoechoic nodules (94,97). Patients with nodules that yield malignant cytology should undergo total or near-total thyroidectomy (Fig. 4) (86). Before performing surgery on nodules with indeterminate cytology (highly cellular specimens with normal or atypical follicular cells without colloid), an 123 I thyroid scan should be done even in patients without suppressed TSH levels to identify those occasional hyperfunctioning nodules that are not active enough to cause TSH suppression, and which are usually benign (93). Evaluating Patients with a History of Head-and-Neck Irradiation Children and young adults with a history of exposure to ionizing radiation such as X-ray or external beam radiation therapy, and patients irradiated during childhood for tumors or Hodgkin’s disease often develop hypothyroidism (98,99) and thyroid neoplasia (98–100). As a result, measurement of serum TSH is recommended, along with an FNA for those with a palpable thyroid nodule. However, controversy exists regarding the diagnostic approach to an asymptomatic previously irradiated person with a palpably normal thyroid gland. Schneider et al. (101) found that 87% of 54 patients who had been exposed to head-and-neck irradiation (X-ray treatment for acne as a child or young adult) had one or more discrete ultrasounddetected thyroid nodules. Of this group, 25% had nodules ≥1 cm, and about half of the nodules 1.5 cm or larger were impalpable. This study confirmed that irradiated individuals continue to develop thyroid nodules more than 20 years’ follow-up from the time of irradiation (101), prompting the authors to advise indefinite routine ultrasonography every 3 to 5 years in such patients. Still, others argue that routine ultrasonography is too sensitive; it identifies benign thyroid nodules in about half of the healthy middle-aged population and in most people exposed to thyroid irradiation (101–103). Still, most authorities agree that the majority of thyroid nodules ⬍1 cm discovered by serendipity and without ultrasonographically suspicious characteristics are benign and can be followed by ultrasonography for one to two years without FNA, providing the nodule volume grows no more than 50% (104) and the patient understands the small risk imposed by this approach. FACTORS INFLUENCING PROGNOSIS AND AFFECTING OUTCOME The prognosis of DTC is determined by an interaction of three clinical variables— tumor stage, patient age, and therapy—and ranges from excellent to dismal. Overall mortality rates for DTC are low (⬍10% over three decades), but recurrence rates are high. Distant metastases or local recurrences are often detected years after initial therapy (Fig. 5) (37) unless modern follow-up paradigms are employed (105).

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Figure 5 Cancer-specific mortality rates and recurrence rates following initial therapy of DTC (mean and standard error). Source: Adapted from Ref. 36.

Patient Variables Influencing Prognosis Age over 40 years at the time of initial therapy is the most important adverse patient prognostic factor, which becomes progressively worse thereafter, increasing at a particularly steep rate after the age of 60 years (Fig. 6) (12,37). The best responses to therapy are in younger patients whose tumors concentrate 131 I (45,46,106). Although survival rates are most favorable in children, their tumors are typically more advanced at the time of diagnosis, with more local and distant metastases than found in adults (45,46). Up to 80% of children develop cervical lymph node metastases and 15% to 20% develop pulmonary metastases (106,107), rates that are almost twofold than those in adults. Also, tumor recurrence rates over several decades are approximately 40% in children compared with 20% in adults (37). Yet the prognosis for survival in children is excellent, with or without a history of irradiation, except for those younger than 10 years, who have higher mortality rates (106,108). Very young children may have unusual tumors that lack typical papillary architecture and behave more aggressively (109). Gender is an independent prognostic factor for survival (37). Thyroid cancer recurrence and mortality rates are higher in men than in women (72,110). Ten-year cancer-specific mortality rates for PTC among men and women older than 40 years

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Figure 6 Cancer mortality and recurrence rates according to age at the time of diagnosis. See Figure 5 for legend. Source: Adapted from Ref. 36.

are 13% and 7%, respectively (p ⬍ 0.01). Although estrogen and progesterone receptors are expressed in up to 50% of PTCs, this does not explain the risk imposed by male gender. Compared with women at the time of diagnosis, men have higher rates of extrathyroidal tumor (51% vs. 39%), including more regional metastases (40% vs. 32%) and twice the rate of distant metastases (9% vs. 4%). This is most likely because of late diagnosis of thyroid cancer in men, which best explains their higher cancer-mortality rates (7). Serum from patients with Graves’ disease contains thyroid-stimulating immunoglobulin that stimulates thyroid follicular cells in vitro that can produce progression of thyroid carcinoma (111). One study of PTC associated with Graves’ disease found that the tumors were more often multifocal and the rate of distant metastases was three times higher than usual (112). Other studies have failed to show this effect (113,114). Tumor Variables Influencing Prognosis Tumor histology is a major determinant of outcome, being best with PTC, intermediate with FTC, and worst with HTC. Distant metastases at the time of initial diagnosis are found in 2.2%, 5.3%, and 35% of patients with PTC, FTC and HTC, respectively (37). Tumor recurrence at distant sites occurs most often with

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HTC, is intermediate with FTC, and occurs least often with PTC. Recurrence is particularly high with very invasive tumors, and becomes increasingly worse as primary tumors grow ⬎5 mm (12,14,88,109,115,116). Mortality rates follow this pattern. A study of 5925 patients treated in the USA between 1985 and 1995 found 10-year relative survival rates of 7%, 15%, and 25% for PTC, FTC, and HTC, respectively (3). Marked cellular atypia or frank anaplastic transformation also worsens prognosis. Tumor size has an important influence on outcome. The primary tumors with FTC tend to be larger and discovered at an older age than PTC (12,14,37). Primary tumors ⬍1 cm in diameter rarely cause death (117), whereas larger tumors are associated with higher mortality rates (12,37). One review (37) found that the rate of distant metastases from both PTC and FTC was 4% with primary tumors ⬍1.5 cm, 10% with tumors 1.5 to 4.4 cm and 17% with tumors 4.5 cm or larger. Thirty-year cancer-specific mortality rates in the three size groups were 0.5%, 8%, and 22%, respectively. Tumor multifocality may affect prognosis. PTC in one thyroid lobe predicts a tumor rate of approximately 45% in the contralateral lobe in patients undergoing completion thyroidectomy (118,119). This is one of the main reasons why the rates of tumor recurrence or locally persistent disease are significantly higher following hemithyroidectomy (120,121). For example, the recurrence rate in the contralateral lobe was approximately 17% in a study (122) of 35 patients who had initially refused completion thyroidectomy after hemithyroidectomy, a recurrence rate that increases over prolonged periods of time (37). A study of 700 patients (123) found a 1.7-fold risk of recurrence in multifocal compared with unifocal tumors. Still, some report almost no recurrences in the unresected thyroid lobe (124,125). However, a number of studies find otherwise, even with PTMC. One study (28) of PTMC found that only two parameters significantly influenced recurrence: the number of histologic foci (p ⬍ 0.002) and the extent of initial thyroid surgery (p ⬍ 0.01). Another study of PTMC (27) found that three parameters significantly influencing lymph node recurrence: cervical lymph node metastases at presentation, multifocal disease, and the absence of 131 I ablation. Lymph Node Metastases Cervical PTC lymph node metastases (12) reflect aggressive tumor behavior and correlate with primary tumor size and multicentricity (72). The rate of lymph node metastases depends upon the tumor features, the extent of surgery and the age of the patient. A review (12) of 13 studies comprising 7845 PTC cases reported before ultrasonography was widely employed, found a 36% rate of lymph node metastases at the time of initial surgery. When neck ultrasonography is performed preoperatively, a slightly larger number of patients are found to have lymph node metastases (126–128). With immunohistochemical staining to identify microscopic tumor, 53% have lymph node metastases (39) and with routine bilateral cervical lymph node dissection, 60% of adults have them (40). The rates at the

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time of diagnosis are even higher in children, ranging as high as 65% (129) to 90% (130). Although some report that metastatic lymph nodes have no effect on recurrence or survival (125,131), a number of studies find an increased risk for local tumor recurrence when cervical lymph node metastases are present at the time of initial surgery (37,132). Higher than usual cancer-specific mortality rates are seen with bilateral cervical or mediastinal lymph node metastases or when tumor penetrates the lymph node capsule and invades surrounding tissues (37,44,133,134). FTC is less often metastatic to regional lymph nodes, but when it occurs the prognosis is less favorable (12).

Thyroid Capsular Invasion and Extrathyroidal Extension Up to one-third of PTCs penetrate the thyroid capsule, which may result in deep tissue invasion, including tracheal or spinal cord invasion and penetration of the major vessels (135). When this occurs, the mortality rate is approximately 20% at five years, a rate 10-fold greater than that of noninvasive PTC (12,37). Aggressive FTCs may also invade local tissues.

Distant Metastases The main cause of death from DTC, distant metastases were associated with a five-year mortality rate of 47% among 1231 patients with metastatic PTC or FTC (12). A more recent study (136) of 49 patients with distant metastases found that after a median follow-up of 3.5 years, 49% died of cancer; 3-year and 5year actuarial survivals were 69% and 50%, respectively. Children and young adults with pulmonary metastases have a more favorable prognosis when their distant metastases are discovered early, are small, and concentrate 131 I (137,138). For example, 10-year survival rates in one study were approximately 20% in adults with macronodular lung or bone metastases compared with approximately 80% in children and young adults with micronodular pulmonary metastases that concentrate131 I (139). The most recent long-term follow-up study (45) of 444 patients with distant metastases from PTC and FTC treated from 1953 to 1994 found that 50% had only lung metastases, 26% had only bone metastases, 18% had both lung and bone metastases, and 5% had metastases at other sites. Overall 10-year survival after 131 I therapy was 92% in patients who achieved a negative posttreatment 131 I scan and 19% in those who did not. Treatment was highly effective in younger patients with 131 I uptake in the tumor and with small metastases. Thus the most important elements in prolonging disease-free survival and improving the survival rate are early diagnosis before the metastases are apparent on chest roentgenograms or diagnostic 131 I whole-body scans (Fig. 3) and early 131 I treatment of tumors, particularly lung metastases that concentrate the isotope.

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Irradiation-Induced Papillary Thyroid Carcinoma The increase in thyroid carcinoma in post-Chernobyl children has been largely confined to a specific subtype of papillary carcinoma (solid/follicular) that displays more aggressive behavior with advanced primary tumor size and more multifocality and lymph node metastases than usual (140,141). From 44% to 70% express RET/PTC3 mutations, depending upon how the specimens are studied (140–143). Also, RET/PTC rearrangements are found in approximately 53% of benign tumors in the Chernobyl children (144). Cancer mortality rates are typically similar in other forms of radiationinduced PTC compared with spontaneously occurring tumors, although tumors associated with radiation are often large, multicentric and regionally metastatic with high recurrence rates (91,145). Other Tumor Factors The histological variants of PTC and FTC affect prognosis (70). Also, coexistent Hashimoto’s thyroiditis (usually with papillary thyroid carcinoma) is associated with a low tumor stage and may be an independent predictor of a favorable prognosis (34,146). Anaplastic tumor transformation that occurs in well-differentiated thyroid carcinoma dramatically alters its course and results in aggressive local tumor invasion and widespread, rapidly fatal metastases that do not concentrate 131 I (72). Oncogenes Protein tyrosine kinases (TKs) are enzymes that catalyze the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues in polypeptides. The human genome contains 90 TKs and 43 TK-like genes (147). The importance of TKs became apparent when imatinib mesylate, an inhibitor of the BCR-ABL TK, was shown to have a dramatic effect in the treatment of chronic myeloid leukemia. It is now widely recognized that TKs play an important role in thyroid cancer and are now the source of important targets for thyroid cancer chemotherapy. The BRAF V600E mutation is the most common oncogene in sporadic PTC in adults (148). The incidence of this mutation in PTC varies with the geographical location of the study. In the Ukraine and Belarus it can be seen in 22.9% of tumors, while the incidence is as high as 62% in France and Brazil. Pooled data analysis of all patients studied reveals an overall incidence of 39.6% (149). The clinical significance of this mutation has not yet been elucidated. One multicenter study found an association between the presence of this mutation and lymph node metastases, extrathyroidal invasion, and advanced tumor stage at initial surgery (150). The BRAF mutation was also found to be an independent predictor of tumor recurrence regardless of tumor stage, and was associated with absence of 131 I tumor avidity and treatment failure in patients with recurrent disease (150). A recent study in Italy, however, found no correlation among the presence of BRAF and tumor multicentricity, lymph node metastases, stage at diagnosis, or outcome

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(151). This discordance in findings between these two studies may be attributable to geographic differences in the patient populations studied. Treatment Variables Influencing Prognosis Treatment of DTC has a major impact on long-term outcome, as discussed later in sections dealing with surgical and medical therapy. Delay in therapy is an important problem. We found that the median time from the first manifestation of thyroid cancer—nearly always a neck mass—to initial therapy was 4 months in patients who survived and 18 months in those who died of thyroid cancer (p ⬍ 0.001) (37). The 30-year cancer mortality rate was nearly doubled when therapy was delayed longer than a year (13% vs. 6%, p ⬍ 0.0001) (37). TUMOR STAGING SYSTEMS AND PROGNOSTIC SCORING SYSTEMS A number of tumor staging systems have been used to predict outcome with DTC. Still, outcome cannot be accurately forecasted in individual patients. Two studies (152,153) that critically compared the predictive accuracy of available prognostic staging systems found that none accounted for more than a small portion of the uncertainty in predicting outcome and that there was no statistically significant superiority of any system over that of the TNM (tumor, node metastasis) classification of the American Joint Commission on Cancer (AJCC) and the International Union Against Cancer (UICC) (Table 3) (154). The authors advised that, because the TNM classification is universally available and widely accepted for other disease sites, it should be used for all reports of the treatment and outcome of patients with thyroid carcinoma, an opinion also expressed by the American Thyroid Association (ATA) (93) and European Thyroid Associations (ETA) (155). The greatest utility of staging systems is in epidemiological studies and as tools to stratify patients for prospective therapy trials (72). Staging systems may be less useful in determining treatment for individual patients unless a Table 3 TNMa Classification of the AJCC and UICC Sixth Edition Papillary or Follicular Stage I II III IV a

⬍45 yr

≥45 yr

Medullary

M0 M1

T1 T2–3 T4 or N1 M1

T1 T2–4 N1 M1

T is primary tumor: T1 , <2 cm; T2 , 2 cm to 4 cm; T3 , >4 cm; T4 , extension beyond thyroid capsule. N is regional lymph nodes: N1 , regional lymph node metastases (cervical and upper mediastinal nodes). M is distant metastases: M0 , no distant metastases; M1 , distant metastases present. All undifferentiated (anaplastic) carcinomas are stage IV.

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reproducible group of patients can be identified with a very low risk of recurrence and cancer-specific mortality. Because the TNM classification of the AJCC and UICC is universally available and widely accepted for other disease sites, it is often recommended for thyroid carcinoma (152). Still, most patients are classified as stage I with this classification (Table 3), which de facto categorizes most patients as being at low risk (123). One study (123) found that patients with TNM stage-I tumors had a 15% recurrence rate after an 11-year median follow-up, which would argue against less aggressive therapy for this group. The numerous staging and prognostic scoring systems that have been proposed underscore the fact that none fully provides information to guide therapy. TREATMENT OF PAPILLARY AND FOLLICULAR THYROID CARCINOMAS Surgery Subtotal Lobectomy Resection of less than a thyroid lobe, sometimes done as a nodulectomy, is inadequate therapy for thyroid carcinoma and is not the current standard of practice (72,156). Even microscopic thyroid carcinoma requires more surgery than subtotal lobectomy (157). Ipsilateral Lobectomy and Isthmusectomy A few surgeons prefer lobectomy, often referred to as subtotal thyroidectomy, and regional lymph node dissection as the initial therapy for nearly all patients with DTC (158). When the diagnosis of thyroid carcinoma is known preoperatively, however, most advise total or near-total thyroidectomy for all patients (159) because it improves disease-free survival, even in children and adults with low-risk tumors (160). Patients treated with lobectomy alone have a 5% to 10% recurrence rate in the opposite thyroid lobe (5), an overall long-term recurrence rate ⬎30% (12), and the highest frequency (11%) of subsequent pulmonary metastases (161), compared with recurrence rates of only 1% after total thyroidectomy and 131 I therapy (12). Higher recurrence rates are also observed with cervical node metastases. Multicentric tumors—often found on study of the final histological sections—also justify more complete initial thyroid resection (37). Lobectomy may be adequate surgery for PTMC discovered serendipitously on the final pathology studies of surgery done for benign disease provided that the patient has not been exposed to radiation, has no other risk factors, and has a truly low-risk carcinoma—a tumor ⬍1.0 cm that is unifocal and confined to the thyroid without vascular invasion (28,37,157,162). Complications with lobectomy are few, and survival in this latter group is virtually assured (28,37,157,162). Nonetheless, the thyroid remnant tissue hampers long-term follow-up with serum Tg determinations and whole-body 131 I scans; therefore the decision to forgo complete thyroidectomy must be discussed with the patient.

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Total or Near-total Thyroidectomy Total or near-total thyroidectomy (ipsilateral total lobectomy, isthmusectomy, and nearly total contralateral lobectomy) is the preferred surgical approach for the majority of patients with a diagnosis of thyroid cancer. If any of the following criteria are present, the patient should undergo total or near-total thyroidectomy: tumors that are ≥l.0 cm in diameter, multicentric (any size), metastatic, penetrating the thyroid capsule, histological variants with aggressive behavior, if the patient has a first-degree relative with differentiated thyroid cancer, or patients with a history of radiation therapy to the head and neck (163–165). Total thyroidectomy should also be considered if there are contralateral nodules present, or if the patient is older than 45 years. Complete or nearly complete thyroid resection removes multifocal and bilateral carcinoma and provides the opportunity to ablate residual thyroid bed uptake with small doses of 131 I, which substantially facilitates long-term followup. Total thyroidectomy reduces the rates of recurrence and may also improve long-term survival (166). If metastatic lymph nodes have been identified either pre- or postoperatively, modified neck dissection (levels II to VI) that preserves the sternocleidomastoid muscle is performed to remove involved cervical lymph nodes. Radical neck dissection is done only for tumors that extensively invade the strap muscles. Completion Thyroidectomy When subtotal thyroidectomy has been performed, it is best to consider completion thyroidectomy for lesions that are anticipated to have the potential for recurrence and because large thyroid remnants are difficult to ablate with 131 I (167,168). This surgery has a low complication rate and is appropriate to perform routinely for aggressive thyroid cancer variants, metastatic disease, PTC ⬎ 1 cm, FTC ⬎1 cm with more than minimal capsular invasion, or multifocal carcinomas of any size, because about half the patients have residual carcinoma in the contralateral thyroid lobe (Table 4) (169). When there has been a local or distant tumor recurrence following subtotal thyroidectomy, carcinoma is found in ⬎60% of the excised contralateral lobes (170). Table 4 Residual Carcinoma in Contralateral Thyroid Lobe Found with Completion Thyroidectomy Number of Patients (Percent with Residual Disease in Contralateral Lobe) Total number of patients from seven studiesa 545 a

Papillary

Follicular

H¨urthle cell

Total residual cancer

327 (58%)

206 (38%)

12 (57%)

244 (45%)

Sources: Adapted from Refs. 43, 73, 76–78, 272, 273.

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Surgical Complications The main complications of thyroidectomy are hypoparathyroidism and recurrent laryngeal nerve damage, which are most common after total thyroidectomy. The rates of hypoparathyroidism immediately after surgery are as high as 5% in adults (128) and even higher in children (171,172) undergoing total thyroidectomy. However, the rates of persistent hypocalcemia are much lower. For example, one study reported a 5.4% rate of hypocalcemia after total thyroidectomy that persisted in only 0.5% of the patients one year after surgery (173). In a review of seven published surgical series, the average rates of permanent recurrent laryngeal nerve injury and hypoparathyroidism, respectively, were 3% and 2.6% after total thyroidectomy and 1.9% and 0.2% after subtotal thyroidectomy (174). When experienced surgeons perform the surgery and the posterior thyroid capsule is left intact on the contralateral side, hypoparathyroidism occurs at a lower rate. A study of 5860 patients treated in the state of Maryland found that surgeons who performed more than 100 thyroidectomies a year had the lowest overall complication rates (4.3%), which were fourfold lower than those of surgeons who performed ⬍10 cases annually (175). Thyroidectomy during Pregnancy Thyroid carcinoma may occasionally progress rapidly during pregnancy, perhaps due to high maternal ␤-hCG levels, which have a TSH-like effect (133). Nonetheless, most DTCs are slow growing and have an excellent prognosis during pregnancy; therefore, surgery can usually be delayed until after delivery (176). Radioiodine (131 I) Therapy Sodium-Iodide Symporter DTCs concentrate iodide much less avidly than normal thyroid tissue, perhaps due to abnormalities in the sodium-iodide symporter. Increased sodium-iodide symporter activity in PTC was reported in one study (177), but most find reduced sodium-iodide symporter activity and heterogeneous immunohistochemical sodium-iodide symporter staining in DTC (178,179). Rationale for Thyroid Remnant Ablation Because it is nearly impossible to remove all thyroid tissue with routine surgery, I uptake is almost always seen postoperatively in the thyroid bed (including normal tissue of thyroglossal duct remnants). These foci must be ablated before 131 I will optimally detect and be concentrated in metastatic deposits (180). Although there continues to be debate concerning 131 I ablation of thyroid bed uptake after near-total thyroidectomy, there are four compelling reasons to do this. First, a thyroid remnant with high radioiodine uptake can obscure cervical or lung metastases when their contribution to the total radioiodine uptake is low (180). Second, high levels of circulating TSH, necessary to enhance tumor 131 I uptake, cannot

131

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be achieved in the presence of a large thyroid remnant (180). Patients with large amounts of residual tissue in the neck (e.g., an entire lobe) prohibiting adequate hypothyroidism should be strongly considered for completion thyroidectomy, and only under unusual circumstances should 131 I be used to primarily ablate this tissue. Third, serum Tg measurement (and its trend) is the most sensitive test for detection of carcinoma when measured during hypothyroidism after thyroid bed uptake ablation (181). Fourth, ablative doses may destroy undocumented micrometastases, microscopic thyroid bed foci of malignancy, or eliminate “normal” residual tissue otherwise destined to become malignant. These arguments would be consistent with decreased rates of thyroid bed recurrence and metastases in patients treated with 131 I remnant ablation in the absence of residual malignancy. Postoperative 131 I remnant ablation is done when the patient has a tumor with the potential for recurrence (121). There are a large and growing number of studies that demonstrate decreased recurrence and disease-specific mortality rates from DTC attributable to 131 I therapy (Fig. 8) (37,121,132,182–186). The lowest incidence of pulmonary metastases occurs after total thyroidectomy and 131 I. For example, in one study recurrences in the form of pulmonary metastases, analyzed as a function of initial therapy for DTC, were reported to be as follows: thyroidectomy plus 131 I (ablation dose of 100 mCi), 1.3%; thyroidectomy alone, 3%; partial thyroidectomy plus 131 I, 5%; and partial thyroidectomy alone, 11% (121). Preparation for 131 I Therapy Females with childbearing potential must have a negative pregnancy test documented shortly before receiving diagnostic imaging or therapeutic amounts of 131 I. For remnant ablation, 131 I therapy is ideally given approximately six weeks after surgery. During the four to six weeks before 131 I therapy, iodine-containing drugs must be carefully avoided. This is especially important for sources of long-lasting iodine such as intravenous CT contrast, which routinely impairs the response to 131 I for two to three months or longer, depending upon the number of scans that have been done. A low iodine diet should be ingested for two weeks prior to therapy (187). The serum TSH levels must be high enough (⬎30 mIU/mL) to stimulate sodium-iodide symporters in neoplastic and normal thyroid tissues to concentrate 131 I. For decades, the only way to do this was to withdraw levothyroxine therapy and to administer liothyronine (Cytomel) for four weeks and stop it for two more weeks, and then administer 131 I. This causes profound hypothyroidism with TSH levels often well ⬎100 mIU/L (188). However, a prospective randomized study found that administering liothyronine for four weeks is unnecessary after thyroid hormone withdrawal (THW), causing neither fewer symptoms of profound hypothyroidism nor improving the rapidity of the rise in serum TSH levels (189). After THW, serum TSH levels must be measured before diagnostic or therapeutic 131 I dosing because the TSH response to THW is unpredictable or often fails to rise ⬎30 mIU/L. Inability to adequately stimulate TSH elevation should raise suspicion of insufficient

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Figure 7 Preparation for 131 I imaging and/or therapy.

thyroidectomy, functioning metastases, continued thyroid hormone ingestion, or, rarely, hypopituitarism, but is more often related to advanced age more than 60 years (190). On the other hand, elevating the TSH level ⬎30 mIU/L does not improve the therapeutic response to 131 I (191), and the optimal magnitude of TSH elevation is unknown and differs among patients. The other way to increase serum TSH levels is by intramuscular administration of recombinant human TSH (rhTSH), which was approved by the FDA in 2007 for remnant ablation, while the patient continues thyroid hormone therapy and thus avoiding symptomatic hypothyroidism (192). The drug is administered intramuscularly at a dosage of 0.9 mg for two consecutive days and 131 I is administered 24 hours after the last injection (Fig. 7) (193). Mean peak TSH concentrations are reached between 3 and 24 hours after injection (median of 10 hours) and the mean half-life is 25 ± 10 hours (192,194). Serum TSH levels are almost always ⬎50 mU/L (192,195,196). However, measurement of serum TSH is not generally advised after rhTSH injection because by the time the patient undergoes 131 I treatment, the serum TSH levels are below the usual limits recommended for treatment. Still, when given to euthyroid patients taking levothyroxine, rhTSH injection is as effective as thyroid hormone withdrawal in preparing patients for remnant ablation and produces an equally favorable therapeutic response (193). Moreover, the use of rhTSH reduces total body radiation from 131 I by 33% compared with withdrawal-induced hypothyroidism, which delays the renal excretion of 131 I thus increasing whole-body irradiation (193). Also, remnant ablation with

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Figure 8 Recurrence rates of DTC after various forms of medical therapy. The differences are statistically significant between all for treatments shown. Source: Adapted from Ref. 4.

50 mCi of 131 I after rhTSH preparation is as effective as 100 mCi 131 I (197), lowering whole-body irradiation to an even greater extent. Studies show that short-term hypothyroidism after thyroid hormone withdrawal is associated with a significant decline in quality of life that is abrogated by the use of rhTSH (198). Diagnostic Whole-Body 131 I Scan and the Stunning Effect Prior to remnant ablation, some physicians perform a diagnostic (“pretreatment”) whole-body scan in order to establish the size and radioiodine avidity of the thyroid remnant, and to search for the presence of cervical nodal disease. If a diagnostic scan is ordered, it is usually obtained 24 to 72 hours after giving 2 to 4 mCi of 131 I (Fig. 7). Larger amounts of 131 I should not be given because focal abnormalities not seen with 2 mCi are less likely to be ablated successfully (199), and 131 I doses as small as 3 mCi diminish the subsequent uptake of therapeutic 131 I, which is termed the “stunning effect” (200,201). To avoid stunning, doses of 1 to 3 mCi of 131 I have been recommended; however, these doses are slightly less sensitive than larger scanning doses of 131 I in identifying thyroid remnants, and they require longer imaging times (202). Administration of the therapeutic dose as soon as possible after the diagnostic dose of 131 I helps to minimize stunning (202,203). Although 123 I in doses of ≥1.5 mCi has been reported to yield excellent images without stunning, its use to date has been somewhat limited by issues of

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cost and availability. Furthermore, the logistics of doing pretreatment scanning using rhTSH are complex, so that pretreatment scanning is usually not done in this setting. Amount of 131 I for Thyroid Remnant Ablation Usually remnant ablation can be achieved with 30 to 50 mCi of 131 I, which is as effective as larger doses in ablating the thyroid remnant and preventing tumor recurrence (37,197,204). This has been a popular way to avoid hospitalization but is no longer necessary in most states because of changes in federal regulations permitting outpatient use of much larger 131 I doses in most states (205). Even so, considering the differences in cost and radiation exposure and the fact that doses to the thyroid remnant more than 30,000 rad do not substantially improve the rate of successful ablation, it may be reasonable to use a relatively low dose for remnant ablation (206). Successful thyroid remnant ablation with doses of approximately 30 and 51 mCi of 131 I were reported as 63% and 78%, respectively, in one study from New Delhi (206). However, this optimal dose of approximately 51 mCi was reported to deliver approximately 30,000 rad to the thyroid remnant. In comparison, in one American study, 30,000 rad was achieved with a mean I31 I dose of approximately 87 mCi and completely ablated the remnant in 86% of cases (167). Another prospective study comparing 30 and 50 mCi doses of 131 I found no significant difference in ablation rates (207). Increasing the dose to deliver more than 30,000 rad does not increase the success rate (167,206). A recent meta-analysis of all the prospective trials showed no difference among various doses of radioiodine (208). A subsequent prospective randomized study of rhTSH to prepare patients for remnant ablation with 50 or 100 mCi also found that the two were equally successful in achieving remnant ablation (197). The rate of successful ablation is significantly lower when patients have less than a total or near-total thyroidectomy or have a thyroid remnant calculated to be ⬎2g (167). Posttreatment Scans and False-Positive Scans Following therapy with 131 I, a posttreatment scan is performed with 5 to 10 days later in order to visualize areas in the neck (and elsewhere) that contain iodineavid tissue. In most patients, an area in the midline corresponding to the thyroid remnant is all that is seen. However, cervical nodal disease may be visualized in papillary thyroid cancer, and more rarely diffuse lung uptake is seen, especially in children and adolescents. Many things can infrequently cause false-positive 131 I scans, including body secretions, transudates, inflammation, nonspecific mediastinal uptake (e.g., blood pool), and neoplasms of nonthyroidal origin, which may uncommonly concentrate 131 I (209). False-positive scans can also be seen with physiological secretion of 131 I from the nasopharynx, salivary and sweat glands, stomach, and genitourinary tract and from skin and hair contamination with sputum or tears (210). Diffuse hepatic uptake of 131 I is rarely due to occult liver metastases but more commonly due to hepatic clearance of Tg labeled with 131 I by functioning thyroid remnants or extrahepatic thyroid cancer metastases. The

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more 131 I uptake by residual thyroid tissue, the more 131 I appears in the liver. In one large study (211), 12% of all diagnostic scans showed uptake in the liver. The frequency of hepatic uptake in posttherapy scans was related to the dose of 131 I, being 39% with 30 mCi, 61.5% with 75 to 100 mCi, and 71.3% with 150 to 200 mCi. On the other hand, hepatic uptake of 131 I without 131 I uptake elsewhere suggests hidden metastases (211). Treatment of Residual or Recurrent Carcinoma with 131 I Thyroid carcinoma (especially macroscopic disease) should be treated surgically whenever possible. Only 50% to 75% of DTCs and their metastases and about one-third of H¨urthle cell carcinomas concentrate 131 I (212–214). Moreover, the larger the tumor mass, the less likely that 131 I therapy will successfully ablate the tumor. One study found that two-thirds of 283 patients with lung or bone metastases had tumors that concentrated 131 I, which is crucial to survival (215). Another study found that 10-year survival rates were 83% or 0%, respectively, depending on whether pulmonary metastases did or did not concentrate 131 I (139). Lung metastases that concentrate 131 I most avidly are the smallest lesions found in young patients (139). There are three approaches to radioiodine therapy: empiric fixed doses, upper-bound limits set by blood dosimetry, and quantitative dosimetry (205). Dosimetric methods are often reserved for distant metastases or unusual cases, as when renal failure is present or therapy with rhTSH stimulation is deemed necessary. Empirical Fixed Doses With empirical doses, a fixed amount of 131 I is given based on tumor stage. Generally, approximately 30 to 125 mCi are given to ablate thyroid remnants, 150 to 200 mCi for residual carcinoma in cervical nodes or neck tissues, and 200 mCi for distant metastases. Tumor 131 I uptake in amounts adequate for imaging with 4-mCi diagnostic doses is usually sufficient for 131 I therapy, using empirical doses from 30 to 200 mCi (216). However, two retrospective studies (217,218) found that administering ⬍140 mCi of 131 I may rarely expose older patients to blood doses of ⬎200 cGy, the upper allowable exposure limit. Administering 200 to 250 mCi of 131 I frequently exceeded the blood exposure limit in patients 70 years of age or older. Consequently, dosimetry-guided 131 I therapy may be preferable to fixed-dose 131 I treatment in older patients with thyroid cancer and in patients with 131 I-avid diffuse bilateral pulmonary metastases, even when renal function is normal (217,218). Upper-Bound Limits Set by Blood Dosimetry This approach establishes an upper limit on the amount of 131 I in a single dose that can be given safely, which is generally considered to be 200 rad to the whole blood (205). In patients with diffuse pulmonary metastases, the dose is also limited, so that ⬍80 mCi of 131 I remains in the lungs after 48 hours to avoid pulmonary fibrosis.

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Without diffuse pulmonary metastases, most authors suggest that the whole-body retention be ⬍120 mCi at 48 hours; however, this limit is usually greater than that of the blood dosimetry and thus not a limiting factor. Based on these calculations, therapy doses of 450 to 600 ± mCi are sometimes used. However, two studies have shown that larger amounts of 131 I may be given to patients pretreated with rhTSH injections compared with levothyroxine withdrawal with a lower risk of bone marrow suppression (219,220). Quantitative Tumor Dosimetry This approach calculates the amount of 131 I that is required to deliver 30,000 rad to ablate the thyroid remnant or 8000 to 12,000 rad to treat nodal or discrete soft tissue metastases. For pulmonary metastases, an amount of 131 I is administered that will deliver 200 rad to whole blood with no ⬎80 mCi of whole blood retention at 48 hours (205). The mass of residual tissue and the effective half time of 131 I in that tissue are the two most important factors in determining success (205). In one study, an 80% response was found in tumor deposits that received at least 8000 rad (167). Lesions that receive ⬍3000 to 4000 rad from 150 to 200 mCi 131 I should be considered for alternative therapy. Repeat 131 I Treatments Treatment with 131 I should be continued every 6 to 12 months, as long as metastatic deposits are present and continue to concentrate 131 I and a favorable response to previous therapy has been demonstrated, such as a decreasing Tg level or decreasing tumor mass. Repeat 131 I doses should not be given until the bone marrow has fully recovered from the previous dose. Few adverse effects occur with this approach to 131 I therapy (219). Before large cumulative 131 I activities (⬎500–600 mCi) are given over an extended period to treat neck metastases or well-localized disease, especially in the CNS or spine, serious consideration should be given to excising the tumor surgically. Lithium This drug inhibits iodine release from the thyroid without impairing iodine uptake, thus enhancing 131 I retention in normal thyroid and tumor cells (221). One study (222) showed that the mean increase in the biological or retention half-life was 50% in tumors and 90% in thyroid remnants. The effect was greater in lesions with poor 131 I retention (222). Nevertheless, there are no outcome data showing improved survival or efficacy of treatment in patients receiving lithium as an adjunct to radioiodine therapy. In patients withdrawn from thyroid hormone, serum lithium levels should be measured frequently if not daily and maintained between 0.8 and 1.2 nmol/L. Immediate Complications of 131 I There are few immediate serious risks of 131 I therapy except when metastases are in critical locations that will not tolerate posttherapeutic swelling. For example,

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brain or spinal cord metastases can undergo potentially catastrophic edema and hemorrhage 12 hours to 2 weeks after 131 I treatment (223). In patients with disease in “critical areas” such as the CNS, pretreatment with high doses of glucocorticoids has been recommended (224). Another example is severe radiation thyroiditis, which can occur within a week of administering a large dose of 131 I to a patient who has undergone only lobectomy, causing pain, swelling, and rarely airway compromise that may require prednisone therapy (225). Thyroid storm may rarely occur approximately 2 to 10 days after administering a therapeutic amount of 131 I, especially when there is a large burden of functioning tumor (205). Acute bone pain is sometimes experienced after 131 I treatment. Radiation sickness characterized by headache, nausea, and occasional vomiting is experienced by about two-thirds of patients approximately 4 to 12 hours after the oral administration of 200 mCi or more of 131 I, which resolves in approximately 24 hours; this almost never occurs with smaller amounts of 131 I (205). Patients with extensive neck tumor may rarely develop transient vocal cord paralysis, and facial nerve paralysis has been reported after very high doses of 131 I (205). Radiation cystitis does not occur if the patient is well hydrated. Mild radiation sialadenitis, leukopenia, and a slight drop in the number of platelets often occur approximately six weeks after therapy, but ordinarily these effects are mild and transient unless very large doses of 131 I are administered (226). Parotid Dysfunction Transient parotid swelling reminiscent of Stensen’s duct obstruction may occur for nearly a year after 131 I therapy. Having the patient suck on hard lemon candy starting 24 hours after therapy increases salivary flow, which may decrease but does not prevent the adverse effect of 131 I radiation on the salivary gland. In one study approximately 60% of patients reported side effects lasting longer than three months, which included sialoadenitis (33%) and transient loss of taste or smell (27%) (227). More than a year after the last 131 I treatment, 43% suffered from reduced salivary gland function and ⬎4% had complete xerostomia, and approximately 23% of the patients reported chronic or recurrent conjunctivitis, complications that were related to the cumulative dose of 131 I (227). Radiation Pneumonitis Pulmonary fibrosis is a potential complication of 131 I therapy for diffuse pulmonary metastases when the lung retention of 131 I is ⬎80 mCi 48 hours after treatment. Some reports suggest that diffuse pulmonary metastases can be treated with 150 mCi of 131 I without risking pulmonary fibrosis (228) and smaller amounts of 131 I doses in the range of approximately 100 mCi are often given when there is diffuse and intense uptake of the scanning dose in the lungs. However, a randomized controlled study to investigate outcome of distant metastases treated with these relatively low doses versus dosimetrically determined much higher doses (often 200–800 mCi) has not been conducted, so optimal therapy is not known.

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Leukemia, Second Tumors, and Other Bone Marrow Effects of 131 I There is a small risk of developing acute myelogenous leukemia after 131 I therapy, which in several studies has been estimated to range from 3 to 22 excess cases per 1000 patients treated with 131 I, depending upon the cumulative amount of 131 I administered (205,229). The late health effects associated with 131 I therapy for thyroid cancer have been difficult to fully assess since the number of patients who develop leukemia after being treated with 131 I is limited. For example, a Swedish study found only two cases of leukemia among 834 thyroid carcinoma patients treated with 131 I, which was not a statistically significant increase rate over that found in the general population (230). However, much larger studies have found a significantly greater risk of second primary malignancies (SPM) in patients treated with 131 I. A European study of 6841 patients with thyroid cancer (mean age 44 years) that was diagnosed from 1934 to 1995 found that 17% had been treated with external beam radiotherapy and 62% had received 131 I therapy. An SPM was found in 576 (8%) of the thyroid cancer patients, representing a 27% increase over that found in the population (95% CI: 15–40). There was a significantly increased risk of cancer of the digestive tract, bone and soft tissue, skin melanoma, kidney, CNS, and endocrine glands other than thyroid, and leukemia. The risk of solid tumors and leukemias increased as the cumulative amounts of administered 131 I increased, resulting in an excess absolute risk of 14.4 solid cancers and of 0.8 leukemias per GBq (27 mCi) of 131 I per 100,000 person-years of follow-up. A group of Utah investigators determined the risk of a nonthyroidal SPM in 30,278 American patients with thyroid cancer diagnosed between 1973 and 2002 in centers participating in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program (231). Median follow-up was 103 months (range, 2–359). A total of 2158 patients (7%) developed nonthyroidal SPMs, which was significantly more than expected in the general population [observed/expected (O/E) = 1.09; 95% CI: 1.05–1.14; p ⬍ 0.05]. The absolute excess risk per 10,000 person-years was 6.39. Compared with the general population, the risk of SPM was significantly greater than expected (O/E = 1.20; 95% CI, 1.07–1.33; AER = 11.8) as was the increased risk observed in nonirradiated patients (O/E = 1.05; 95% CI, 1.00–1.10; AER = 3.53). Still, the risk of SPM was greater for irradiated patients than the nonirradiated cohort (relative risk = 1.16; 95% CI, 1.05–1.27; p ⬍ 0.05). The greatest risk of second primary cancers occurred within five years of the diagnosis of thyroid cancer and was also elevated for younger patients. When 131 I treatments are given at 12-month intervals and total cumulative doses are limited to 500 mCi in children and 600 mCi in adults, long-term effects on the bone marrow are minimal and few cases of leukemia occur (229,232,233). Limiting the cumulative dose is usually not a problem unless large single doses of 131 I are given, because tumor tissue that concentrates 131 I is likely to be ablated by a few 131 I treatments, leaving either no residual tumor or metastases that do not concentrate 131 I. For example, all patients cured of pulmonary metastases by 131 I

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in one study (234) did so with a cumulative dose of ≤1500 mCi. It is reasonable to give high cumulative doses of 131 I to patients with extensive metastatic disease responsive to therapy, as the risk posed by the known thyroid cancer outweighs the risk of a potential second cancer from radiation. These observations of SPM, including colon cancer following 131 I underscores the need for laxatives and hydration after 131 I treatment, especially for hypothyroid patients. Lacrimal Duct Obstruction Induced by 131 I In 2002, Kloos et al. (235) described a patient who developed complete bilateral nasolacrimal duct obstruction (epiphora) after 131 I therapy for thyroid cancer, which first prompted awareness of this potential complication. After studying 390 patients who had received 131 I for thyroid remnant ablation or tumor therapy, 10 were found to have epiphora. All had evidence of nasolacrimal duct obstruction that occurred after being treated with an individual dose of 180 ± 15 mCi of 131 I (mean ± SE) and a cumulative dose of 467 ± 79 mCi of 131 I. Symptoms appeared 6.5 ± 1.4 months (range, 3–16) after the last 131 I treatment; however, the time from symptom onset to correct diagnosis was 18 ± 5 months. This complication did not develop in patients who did not receive 131 I therapy or were treated with ⬍150 mCi. In all, 3% of the cohort had evidence of the problem, which was manifest by epiphora, discharge on the eyelids, recurring conjunctivitis, dacryocystitis and a mass below the median canthal tendon. Patients reporting epiphora should be promptly evaluated by an oculoplastic surgeon. Management of patients with complete obstructions requires more extensive surgical procedures than does management of patients with an incomplete obstruction. Early intervention with balloon dilation of the nasolacrimal duct and/or stents may prevent complete obstruction until radiation-induced inflammation subsides. Although the natural history of partial obstruction is unknown, data from several patients suggests that spontaneous improvement may occur without intervention. Infertility and Gonadal Failure Gonadal damage may be caused by large doses of 131 I, but it is infrequently observed (205,236). A large European study of 2113 pregnancies in women who had been treated with surgery and 131 I for thyroid cancer found that the miscarriage rate increased from 11% before surgery to 20% after surgery, remaining at this level after 131 I therapy (237). In this study, miscarriages were more frequent when women were treated during the year preceding conception; however, whether this is related to gonadal irradiation or to insufficient control of hormonal thyroid status is uncertain (237). The incidences of stillbirth, preterm birth, low birth weight, congenital malformation, and death during the first year of life were not significantly different before or after 131 I therapy; the incidence of thyroid disease and nonthyroidal malignancy was similar in children born either before or after their mothers were exposed to 131 I. Testicular germinal cell function may be transiently impaired when men are given 131 I therapy, although the damage may

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become permanent when large doses of 131 I are delivered year after year (238). Since this might pose a significant risk of infertility, it seems prudent to advise young men to bank their sperm before repeated high dose 131 I therapy. Thyroid Hormone Therapy Levothyroxine (T4) Suppression of TSH DTCs contain TSH receptors that stimulate the cell growth and iodine uptake of well-differentiated follicular cancer cells (111). Thyroid hormone therapy significantly reduces recurrence rates and cancer-specific mortality rates (Fig. 8) (121). A meta-analysis of thyroid hormone suppression therapy in thyroid cancer patients showed an association with reduced risk of major adverse clinical events, defined as disease progression and/or recurrence and death (239). The National Thyroid Cancer Treatment Cooperative Study (NCTCS) that has prospectively performed follow-up of 2936 patients with DTC found that thyroid hormone therapy significantly reduced recurrence rates and cancer-specific mortality rates in patients with stage II to IV disease (Fig. 8) (240). However, the study was unable to show any impact, positive or negative, of any form of surgical or medical therapy in stage I patients, which may be due to the relatively short duration of follow-up (median three years, range 0–14) in this group of patients. The levothyroxine dosage needed to attain serum TSH levels in the euthyroid range is greater among patients with thyroid cancer (2.11 ␮g/kg/day) than among those with primary hypothyroidism caused by nonmalignant disease (1.62 ␮g/kg/day) (241). One study found that patients who had undergone total thyroid ablation for thyroid carcinoma required 2.7 ± 0.4 (SD) ␮g/kg/d of levothyroxine to achieve an undetectable basal serum TSH level that does not increase after TRH administration (242). A French study found that a constantly suppressed TSH (⬍0.05 ␮U/mL) was associated with a longer relapse-free survival than when serum TSH levels were always 1 ␮U/mL or greater, and that the degree of TSH suppression was an independent predictor of recurrence (243). A more recent study showed a beneficial effect of thyroid hormone therapy, but only in those patients whose serum TSH level was consistently ⬎2 mU/L (244). Hence, these data do not support the concept that a great degree of TSH suppression (into the undetectable, thyrotoxic range) is required in patients with stage I or II disease but may be beneficial in patients with more advanced disease stage. The most appropriate dose of thyroid hormone for patients with DTC who are free of disease is that which reduces the serum concentration to just below the lower limit of the normal range for the assay being used (93). The ATA management guidelines for patients with thyroid cancer recommend that the TSH in patients with persistent disease should be maintained ⬍0.1 mU/L indefinitely as long as there are no contraindications. For patients at high risk of recurrence, the TSH should be maintained at 0.1 to 0.5 mIU/L for 5 to 10 years. Patients with low-risk tumors who are free of disease are advised to maintain the TSH within the low normal range (0.3–2 mU/L).

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Complications of Levothyroxine Therapy Potential problems associated with subclinical thyrotoxicosis are an increased risk of atrial fibrillation (245) in older patients (older than 60 or 65 years), a higher 24-hour heart rate, more atrial premature contractions per day, ventricular hypertrophy, diastolic dysfunction, and impaired cardiac reserve (246). Patients with thyroid carcinoma treated with suppressive doses of levothyroxine have a high rate of bone turnover that decreases acutely after withdrawing treatment (247), which is of most concern in postmenopausal women not receiving estrogen-like or bisphosphonate therapy (248). Studies of fracture risk in women treated with thyroid hormone suggest that there may be an increased risk when suppressive doses are used (249). However, TSH suppression has no significant effects on bone mass in men, according to one study (250). Other Therapy External Beam Radiation Therapy This therapy is generally considered third-line therapy for localized DTC after surgical resection and 131 I therapy. Typical candidate sites of disease for external beam radiation therapy include the neck, upper mediastinum, or bone lesions that are symptomatic or in critical locations to prevent fracture. External beam radiation therapy is frequently reserved for inoperable, non-iodine-avid disease; however, in some iodine-avid situations, it is considered for adjuvant therapy following 131 I therapy such as in patients with T4 N1 disease and over the age of 45 years, aerodigestive invasion, nonresectable local bulk disease, or selected osseous metastases (132). Gamma KnifeTM Brain metastases from thyroid carcinoma are an extremely poor prognostic sign. Surgical resection of brain metastases may be associated with a limited prolongation of survival and rarely with apparent cure (251). While controlled studies are lacking, inoperable CNS metastases should probably be treated with gamma knife rather than external beam radiation therapy if possible (251). Chemotherapy Patients with papillary thyroid cancer who no longer respond to the usual modes of therapy—surgery, radioiodine, and external beam radiotherapy—and still show signs of progressive disease may be candidates for investigational drugs. Historically, traditional chemotherapy (doxorubicin) has proven to be of limited benefit in thyroid cancer and at best provides palliation. However, recent discoveries of the molecular pathogenesis of papillary thyroid cancer have led to the use of promising molecular-targeted therapies. Numerous clinical trials are currently underway to investigate the effects of various targeted therapies. These new agents can be divided into several categories: oncogene inhibitors, angiogenesis inhibitors,

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redifferentiation agents, and gene therapy (252). Two recently published studies suggest some modest benefit from multi-kinase inhibitors such as sorafenib (253) and motesanib (254). The RET/PTC oncogene is targeted by the tyrosine kinase (TK) inhibitors; various steps in the molecular pathway may be inhibited by this family of agents. Potential targets include monoclonal antibodies directed against the tyrosine kinase ligand or its receptor, inhibition of ATP binding to the TK receptor, inhibition of receptor phosphorylation or activation, or blocking downstream signals (252). Several compounds are also being studied to determine their ability to induce redifferentiation of tumors, particularly the ability to restore function of the sodium-iodine symporter and thereby increase uptake of radioactive iodine by the tumor cells. It may be necessary to use combination therapy with these agents to achieve maximal tumor response in light of the complex and overlapping relationships between the various mitogen activated protein kinase pathways (252). The patient should have evidence of disease progression before initiating such therapies as many of these agents offer disease stabilization and a treatment effect cannot be demonstrated unless the tumor is actively growing. In this fast moving area, the best way to get current information on clinical trials for thyroid cancer is to use the National Institutes of Health website or that of the ATA (http://www.thyroid.org) or the National Cancer Institute (http://www.cancer.gov/ clinicaltrials). Follow-up It is convenient to stratify follow-up into three stages (Fig. 9): Phase 1 is four to six weeks after surgery when the completeness of tumor resection is evaluated, Phase 2 occurs approximately 6 to 12 months after remnant ablation to assess the status of the initial surgical and medical therapy together, and Phase 3 is the

Figure 9 The three phases of follow-up in differentiated thyroid cancer.

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long-term follow-up that occurs after patients are deemed free of disease. At each stage of follow-up different studies may be necessary, depending upon the patient’s response to therapy. Changing Follow-up Paradigms The follow-up of patients with PTC has changed considerably over the past decade. In the past, follow-up depended heavily upon the use of diagnostic whole-body 131 I scanning (DxWBS) and the assessment of serum Tg levels performed during levothyroxine suppression of TSH (Tg-on). This approach, which was less accurate than current follow-up strategies, resulted in long delays in identifying patients with persistent metastases (37), which has the potential to reduce survival rates (37,255). Risk stratification is now established immediately after completion of the initial therapy, when follow-up strategy is adapted to fit the patient’s clinical status. Identifying Patients Who Are Free of Disease Identifying patients who are free of disease following initial therapy is a key follow-up issue because this identifies 80% of those who have undergone adequate therapy, which usually consists of total thyroidectomy and 131 I remnant ablation. The ATA (93) and ETA (155) guidelines define disease-free status as follows: (1) no clinical evidence of residual tumor; (2) No imaging evidence of tumor, which generally means that the posttreatment whole-body 131 I scan (RxWBS) shows 131 I uptake only in the thyroid bed and that neck ultrasonography is negative; and (3) an undetectable Tg (⬍1 ng/mL) during both TSH suppression and stimulation, in the absence of interfering serum antibodies. Risk Stratification Based upon the Patient’s Clinical Status After Initial Therapy The AJCC TNM patient risk stratification and most tumor staging classifications depend heavily upon patient age and tumor stage at the time of diagnosis. While this provides a uniform means of comparing patient outcome in studies, it fails to take into account other important tumor features that predict outcome. For example, the TNM system does not account for tumor variables (e.g., tall cell papillary thyroid cancer), tumor molecular features such as BRAF mutation, or patient variables such as familial non-medullary thyroid cancer, all of which have an impact on outcome. The ATA (93) and ETA (155) thyroid cancer guidelines stratify risk on the basis of patient age and tumor stage at the time of diagnosis, and patient response to initial therapy, which is usually defined by TSH-stimulated serum Tg levels and neck ultrasonography. This is considerably more accurate than DxWBS and Tg-on that was used in the past to define patient status after initial therapy. Patients with low-risk tumors undergo a follow-up strategy that is substantially different from that for high-risk patients (Fig. 10). This is done by stratifying risk after initial surgery with or without postoperative radioiodine ablation into three groups as follows:

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Figure 10 Follow-up algorithm for papillary and follicular thyroid carcinoma.

Low-risk patients are those whose tumors have no local or distant metastases; all macroscopic tumors have been resected; no invasion of locoregional tissues or structures by the tumor; no aggressive histology of the tumor (e.g., tall cell, insular, or columnar cell tumors); no vascular invasion; and if radioiodine ablation has been given, there is no evidence of 131 I uptake outside the thyroid bed on posttreatment whole-body scanning (93). Intermediate-risk patients have tumors which show microscopic invasion into perithyroidal soft tissues, have tumors with aggressive histology, or tumors which have vascular invasion (93). High-risk patients have macroscopic tumor invasion, incomplete tumor resection, distant metastases, or 131 I uptake outside the thyroid bed on posttreatment whole-body scanning (93). rhTSH in Follow-up During follow-up, serum TSH concentration must be periodically increased to levels sufficiently elevated to stimulate thyroid tissue sodium-iodide symporters so that serum Tg measurement and radioiodine scanning can be performed. For follow-up rhTSH is given as an intramuscular dose of 0.9 mg for two consecutive days followed by 4 mCi of 131 I orally on the third day and a whole-body scan and Tg

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measurement on the fifth day (Fig. 7). Whole-body 131 I images are acquired after 30 minutes of scanning or after obtaining 140,000 counts, because a 4-mCi dose of 13I I may have the same body retention as a 2-mCi dose given to a hypothyroid patient. When a large- or small-field-of-view camera is used, a minimum of 60,000 and 35,000 counts per view, respectively, are required. Serum Thyroglobulin and Cervical Ultrasound Serum Tg determinations and cervical ultrasonography can almost always detect residual thyroid tissue, whether benign or malignant, in patients who have undergone thyroidectomy. This has been shown in a number of clinical studies that have provided new information regarding optimal surveillance protocols for lowand high-risk patients with differentiated thyroid cancer. A 2003 review (256) of eight follow-up studies comprising 1028 patients found a growing consensus on the clinical value of TSH-stimulated Tg measurements as part of routine surveillance. One of the early findings was that an undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) was often misleading (256). Analysis of eight follow-up studies found that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels ⬍1 ng/dL had a rise in rhTSH-stimulated serum Tg that was ⬎2 ng/mL. When this occurred, 36% of the patients were found to have metastases, about one-third of which were at distant sites, which in almost all the cases (91%) was associated with an rhTSH-stimulated Tg ⬎2 ng/mL (256). On the other hand, a DxWBS performed after either rhTSH stimulation or THW, identified only 19% of the cases of metastases (over an 80% false-negative rate). Ten studies comprising 1599 patients demonstrate that a TSHstimulated Tg using a Tg cutoff of 2 ␮g/L (either after THW or 72 hours after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of DxWBS in follow-up should be discouraged. On this basis, a surveillance paradigm was proposed using TSH-stimulated Tg for patients who have had a total or near-total thyroidectomy and 131 I ablation and have no clinical evidence of residual tumor with a baseline serum Tg ⬍1 ng/mL during THST (256). However, careful analysis found that although the negative predictive value (NPV) of TSH-stimulated serum Tg measurements was approximately 100%, the positive predictive value (PPV) was only approximately 50%, which was the case for both THW (257) and rhTSH (258) stimulation; moreover, when the patient’s TSH-Tg was studied over time, the PPV increased to approximately 85% (257,259). A serum rhTSH-stimulated Tg followed over a span of three to five years showed that the PPV of a serum rhTSH-stimulated Tg was 80% while half the patients with rhTSH-stimulated Tg values ⬍2 ng/mL experienced a gradual decrease in Tg values to undetectable levels. A meta-analysis (260) found that the highest accuracy of Tg-guided follow-up is obtained if treatment includes thyroid remnant ablation, and Tg testing is performed while the patient is off thyroxine (sensitivity 96% and specificity 94%). The sensitivity of rhTSH-stimulated Tg was 93% but specificity was only 76%. For this reason, following serum Tg trends

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after initial therapy has become a widely accepted means of anticipating the result of therapy. Tg and Whole-Body 131 I Scans Serum Tg determinations and whole-body 131 I imaging can almost always detect residual thyroid tissue, whether benign or malignant, in patients who have undergone thyroidectomy. The serum Tg concentration correlates with the mass of normal or malignant thyroid tissue, the amount of thyroid physical damage or inflammation, and the level of TSH receptor stimulation. Tg measurement is more sensitive when thyroid hormone has been stopped or rhTSH is given to elevate the serum TSH and, under these conditions, has a lower false-negative rate than whole-body 131 I scanning (256). The highest NPV (99.5%) and sensitivity (96%) was achieved with rhTSH-stimulated serum Tg and neck ultrasonography compared with a 93% sensitivity and 99% NPV for DxWBS and rhTSH-stimulated Tg measurements (261). Serum Anti-Tg Antibodies Serum antithyroglobulin antibodies must be measured in the serum sample obtained for Tg assay because they are present in up to 25% patients with thyroid carcinoma and almost always invalidate serum Tg measurement (181,262). These antibodies must be quantitated because they can serve as a surrogate marker for Tg, rising when there is an exacerbation of tumor and falling when the tumor burden declines (263). Imaging Studies Although imaging with 131 I is the “gold standard” in detecting thyroid tissue, several other scanning techniques are available. Some are particularly useful in identifying the location of tumor in patients with high serum Tg levels and negative diagnostic 131 I scans and negative neck ultrasonography. Whole-Body Positron Emission Tomography Scanning with F-18-fluorodeoxyglucose (FDG) provides two important pieces of information. First, it may identify DTC metastasis that cannot be identified by scintigraphy with 131 I or 99m Tc. Second, Fluorine-18-FDG uptake is an indicator of poor functional differentiation and poor prognosis in thyroid cancer (264). A retrospective study of 400 patients with thyroid cancer studied at one institution (265) found an inverse relationship between patient survival and the glycolytic rate of the most active lesion. Likewise, the number of FDG-avid lesions was inversely correlated with survival (265). The likelihood of observing an FDGavid lesion increases with the serum Tg level, especially when the serum Tg is ⬎10 ng/mL (266). False-positive 18 F-FDG uptake may occur with benign lung disease, inflammatory conditions, and other malignancies (267). Positron

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Emission Tomography (PET) scanning may be of most value in the setting of high serum Tg levels and negative neck ultrasonography and other imaging studies. Treatment of Patients with High Serum Tg Levels and Negative Imaging Studies When the serum Tg level is elevated and a tumor cannot be found by localizing techniques—including 131 I diagnostic scans, neck ultrasonography, and CT or MRI scans—metastases are sometimes found only after administrating therapeutic doses of 131 I. Tg Cutoffs for Treatment with 131 I A serum Tg above the lower detection limit (usually 0.2–1.0 ng/mL in newer assays) during levothyroxine therapy in a patient who has undergone total or neartotal thyroidectomy and 131 I ablation is a sign of persistent normal tissue (thyroid remnant) or DTC. This is an indication for repeat 131 I scanning in high-risk patients or neck ultrasonography alone in low-risk patients when there is no other evidence of disease (Fig. 9). If serum Tg rises ⬎10 ng/mL after levothyroxine is discontinued or rises ⬎5 ng/mL after rhTSH is administered, normal or malignant thyroid tissue is usually present, even if a 2 to 4 mCi (74–148 MBq) 131 I diagnostic scan is negative (⬍1% 131 I uptake) (159,192). A serum Tg that is rising over time and increases to ⬎10 ng/mL after rhTSH stimulation or THW may be an indication of persistent tumor. If tumor is not identified by ultrasound and other imaging modalities, it is reasonable to give one therapeutic dose of 131 I, usually 100 mCi, and to perform a posttreatment scan. Depending upon the age of the patient, as many as 20% of children and young adults with greatly elevated serum Tg levels and negative diagnostic 131 I scans have lung metastases. When the RxWBS is negative, an 18 FDG-PET/CT scan may detect occult tumor that is amenable to surgical excision. Even if it does not identify tumor, this is a good prognostic sign (265) that can reassure the patient. Rationale for 131 I Therapy Although some skepticism has been voiced about empirically treating patients with 100 mCi of 131 I without imaging evidence of disease, there is increasing evidence that this approach is beneficial to some patients. A multivariate analysis has shown the independent prognostic significance of the size of pulmonary metastases at the time of therapy (268). Another multivariate analysis of prognostic factors in 134 patients with pulmonary metastases showed that an early diagnosis (a normal chest roentgenogram with pulmonary metastases found only on 131 I scintigraphy) and treatment of the metastases with 131 I were the most important elements giving rise to a significant improvement in survival rate and a prolonged disease-free time interval (269). Two studies (270,271) found clearly beneficial effects of 131 I therapy for such patients: 80% achieved a negative whole-body 131 I posttherapy scan, 60% had a serum Tg ⬍5 ng/mL off thyroid hormone and six of eight patients

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had normalization of the CT scan, and two patients had negative lung biopsies. Improvement sometimes occurs with one or two 131 I treatments, but complete resolution of pulmonary metastases after 131 I therapy is often difficult to achieve (137). When a partial reduction of metastatic disease is achieved, patients usually have a good quality of life with no further disease progression and a low mortality rate (137). It seems intuitively wrong to withhold therapy in this group of patients who are usually young and have a small tumor burden. Withholding therapy seems especially harsh given the fact that 131 I treatment directly targets the metastatic deposits and is effective in reducing tumor burden. Early diagnosis and treatment of cancer is a desirable and effective therapeutic goal, especially when the treatment has relatively few serious side effects. On the other hand treating patients on the basis of a rising Tg when distant metastases are not found on a previous RxWBS on the basis of an elevated serum Tg level is not advisable. Some patients are found in retrospect to have regional lymph node metastases or a thyroid remnant not seen on the diagnostic 131 I scan to account for the high serum Tg level. In other cases, the Tg begins to gradually fall spontaneously without treatment or following an apparently unsuccessful treatment. Giving repeated 131 I treatments without clear evidence of efficacy is strongly discouraged. REFERENCES 1. American Cancer Society. Cancer Facts and Figures. American Cancer Society. 9–4–2007. 2. Edwards BK, Brown ML, Wingo PA, et al. Annual report to the nation on the status of cancer,1975–2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst 2005; 97(19):1407–1427. 3. Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US,1985–1995. Cancer 1998; 83:2638–2648. 4. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States,1973–2002. JAMA 2006; 295(18):2164–2167. 5. Hayat MJ, Howlader N, Reichman ME, et al. Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 2007; 12(1):20–37. 6. Mazzaferri EL. Managing small thyroid cancers. JAMA 2006; 295(18):2179–2182. 7. Ries LAG, Harkins D, Krapcho D, et al. SEER Cancer Statistics Review,1997–2003 Based on November 2005 SEER data submission, posted to the SEER web site, 2006. SEER Surveillance Epidemiology and End Results Cancer Stat Fact Sheets, 2006:6–13. 8. World Health Organization. Pathology & Genetics Tumours of Endocrine Organs. Lyon, Farnce: IARC Press, 2004. 9. Begum S, Rosenbaum E, Henrique R, et al. BRAF mutations in anaplastic thyroid carcinoma: Implications for tumor origin, diagnosis and treatment. Mod Pathol 2004; 17(11):1359–1363. 10. Bevan S, Pal T, Greenberg CR, et al. A comprehensive analysis of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer: Confirmation of linkage to TCO1. J Clin Endocrinol Metab 2001; 86(8):3701–3704.

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259. Kloos RT, Mazzaferri EL. A single recombinant human thyrotrophin-stimulated serum thyroglobulin measurement predicts differentiated thyroid carcinoma metastases three to five years later. J Clin Endocrinol Metab 2005; 90(9):5047–5057. 260. Eustatia-Rutten CF, Smit JW, Romijn JA, et al. Diagnostic value of serum thyroglobulin measurements in the follow-up of differentiated thyroid carcinoma, a structured meta-analysis. Clin Endocrinol (Oxf) 2004; 61(1):61–74. 261. Pacini F, Molinaro E, Castagna MG, et al. Recombinant human thyrotropinstimulated serum thyroglobulin combined with neck ultrasonography has the highest sensitivity in monitoring differentiated thyroid carcinoma. J Clin Endocrinol Metab 2003; 88(8):3668–3673. 262. Spencer CA. Recoveries cannot be used to authenticate thyroglobulin (Tg) measurements when sera contain Tg autoantibodies. Clin Chem 1996; 42:661–663. 263. Chiovato L, Latrofa F, Braverman LE, et al. Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens. Ann Intern Med 2003; 139(5 Pt 1):346–351. 264. Feine U, Lietzenmayer R, Hanke JP, et al. Fluorine-18-FDG and iodine-131-iodide uptake in thyroid cancer. J Nucl Med 1996; 37:1468–1472. 265. Robbins RJ, Wan Q, Grewal RK, et al. Real-time prognosis for metastatic thyroid carcinoma based on 2-[18 F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab 2006; 91(2):498–505. 266. Kloos RT. Approach to the patient with a positive serum thyroglobulin and a negative radioiodine scan after initial therapy for differentiated thyroid cancer. J Clin Endocrinol Metab 2008; 93(5):1519–1525. 267. Bakheet SMB, Powe J. Fluorine-18-fluorodeoxyglucose uptake in rheumatoid arthritis-associated lung disease in a patient with thyroid cancer. J Nucl Med 1998; 39:234–236. 268. Schlumberger M, Challeton C, De Vathaire F, et al. Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med 1996; 37:598–605. 269. Casara D, Rubello D, Saladini G, et al. Different features of pulmonary metastases in differentiated thyroid cancer: Natural history and multivariate statistical analysis of prognostic variables. J Nucl Med 1993; 34:1626–1631. 270. Schlumberger M, Arcangioli O, Piekarski JD, et al. Detection and treatment of lung metastases of differentiated thyroid carcinoma in patients with normal chest X-rays. J Nucl Med 1988; 29:1790–1794. 271. Pineda JD, Lee T, Ain K, et al. Iodine-131 therapy for thyroid cancer patients with elevated thyroglobulin and negative diagnostic scan. J Clin Endocrinol Metab 1995; 80:1488–1492. 272. Filie AC, Asa SL, Geisinger KR, et al. Utilization of ancillary studies in thyroid fine needle aspirates: A synopsis of the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008; 36(6):438–441. 273. Basolo F, Giannini R, Monaco C, et al. Potent Mitogenicity of the RET/PTC3 Oncogene Correlates with Its Prevalence in Tall-Cell Variant of Papillary Thyroid Carcinoma. Am J Pathol 2002; 160(1):247–254.

7 Medullary Thyroid Carcinoma, Anaplastic Thyroid Carcinoma, and Thyroid Lymphoma Jennifer A. Sipos The Ohio State University, Columbus, Ohio, U.S.A.

Ernest L. Mazzaferri University of Florida, Gainesville, Florida, U.S.A.

MEDULLARY THYROID CANCER Prevalence and Demographics Medullary thyroid carcinoma (MTC) accounts for approximately 4% of all thyroid malignancies (1). Familial MTC occurs with equal frequency in both sexes, while sporadic MTC has a female/male ratio of 1.5:1. Only about 10% to 20% of MTC cases occur as familial tumors. The other 80% to 90% are sporadic and may occur at any age, but usually are detected later in life than familial MTC. For instance, the median age of patients with sporadic MTC seen at the Mayo Clinic was 51 years, compared with 21 years for those with familial tumors (2). Familial Non-MEN Medullary Thyroid Carcinoma (FMTC) is usually detected later, around 40 to 50 years, as compared with an average age of 20 to 30 years for Multiple Endocrine Neoplasia type 2A (MEN-2A) when detected by screening affected kindreds with calcitonin tests. The diagnosis is made even earlier now that genetic testing is available.

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Classification MTC was first recognized in 1959 as a pleomorphic neoplasm with amyloid stroma. A few years later, it became apparent that the tumor arises from the calcitonin-secreting C cells of the thyroid. Approximately 70% to 80% are sporadic tumors and 20% to 30% are familial tumors that are transmitted as an autosomal dominant trait, which is often associated with other endocrine neoplasms. The genes that are responsible for the familial forms of MTC map to the pericentromeric region of chromosome 10 and typically cause three familial syndromes, described below (3). Multiple Endocrine Neoplasia Type 2 Syndromes MEN Type 2A This is the most common Multiple endocrine neoplasia type 2 (MEN-2) syndrome, which comprises bilateral MTC that occurs in more than 90% of the gene carriers, and bilateral pheochromocytoma and hyperparathyroidism approximately 40% and 25% of the carriers, respectively (4). The syndrome is also associated with cutaneous lichen amyloidosis, a pigmented pruritic lesion that typically is found on the back (5). Also, MEN-2A may occur with congenital absence of enteric innervation resulting in Hirschsprung’s disease (6). MEN Type 2B This is the most distinctive and aggressive but least common familial MEN2 syndrome (7). Patients have bilateral MTC and pheochromocytomas but not hyperparathyroidism. They have a distinct phenotype with a marfanoid habitus with a decreased upper/lower segment body ratio, long limbs, hyperextensible joints, scoliosis, and anterior chest deformities; however, this is not associated with the ectopic lens or cardiovascular abnormalities characteristic of Marfan’s syndrome. The other unique phenotypic characteristic is ganglioneuromatosis involving the salivary glands, pancreas, intestine, gallbladder, upper respiratory tract, and urinary bladder. Patients also have visible ganglioneuromas on the tongue, lips, and eyelids, producing a lumpy patulous appearance of the lips. Alimentary ganglioneuromas may be associated with constipation, diarrhea, and megacolon. Familial Non-MEN Medullary Thyroid Carcinoma This syndrome consists of bilateral MTC with no other endocrine tumors or somatic abnormalities. It is transmitted as an autosomal dominant trait and is the least common form of MTC, manifest at a later age than the other familial syndromes (4). There is, however, considerable overlap in the presentation of this syndrome and MEN-2A (8).

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Genetic Alterations in MEN-2 and FMTC Syndromes Point mutations of the Rearranged during transfection (RET) proto-oncogene occur in germ-line and tumor DNA of unrelated patients from kindreds with MEN2A, MEN type 2B (MEN-2B), and FMTC (9). Several different and independent point mutations in the genomic sequence of the RET proto-oncogene have been identified, all involving codons for cysteine residues, which provides an important direct means of identifying affected MEN-2 and FMTC kindreds. Nonetheless, the normal function of RET is not yet known and its role in the development of these inherited syndromes remains unclear. There is, however, a relationship between specific RET proto-oncogene mutations and the MEN-2 phenotypes (9). MTC Tumor Location MTC in the familial syndromes is generally bilateral and multicentric, as opposed to sporadic MTC, which is usually unilateral. The C cells, which are normally located in the upper and middle thirds of the lateral thyroid lobes, initially undergo hyperplasia in the familial syndromes before developing into MTC. A European study (10) of 207 patients with familial MTC from 145 families found significant age-related progression from C-cell hyperplasia (CCH) to MTC and ultimately to nodal metastasis in patients whose RET mutations were grouped according to the affected extracellular and intracellular-domain codons and in those with the codon 634 genotype. No lymph-node metastases were found in patients younger than 14 years. The authors of this study concluded that the codon-specific differences in the age at presentation of MTC and the familial rates of concomitant adrenal and parathyroid involvement suggest that the risk of progression was based on the transforming potential of each individual RET mutation (10). The earliest reported ages for the onset of MEN-2 was the first year of life for families with a 918 mutation (MEN-2B) to 20 years of age or older with RET codon 791 and 768 mutations (10). Parathyroid Disease Hyperparathyroidism develops in one-third to half of the patients with the MEN-2A syndrome, most of whom (85%) develop parathyroid hyperplasia (11), which almost never occurs in MEN-2B (7). MEN-2A patients seldom present with symptoms of hypercalcemia but often form renal stones. When MTC develops in MEN-2A patients, parathyroid hyperplasia is often discovered during thyroidectomy even when there is no clinical or biochemical evidence of hyperparathyroidism (7). Pheochromocytoma Adrenal medullary disease occurs in both MEN-2A and MEN-2B syndromes. Its manifestations range from diffuse or nodular adrenal hyperplasia to large, bilateral, multilobular pheochromocytomas. These abnormalities are typically bilateral and occur in approximately 40% of affected family members, although this ranges

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widely occurring in 6% to 100% in different kindreds (11). Recent studies suggest a codon-specific, age-related development of pheochromocytoma in RET carriers (12). A study of (11) of 206 RET carriers with a mean observation period of 27 years found that pheochromocytomas developed in 28% of the carriers with mutations in codon 918, 29% of carriers with mutations in 634, 14% of carriers with mutation in codon 618, 13% of carriers with mutations in codon 620, and 13% of carriers with mutations in codon 791. The earliest age of manifestation for each genotype was 22, 18, 29, 22, and 39 years. Contralateral pheochromocytomas developed after four years in carriers of codon 618 and after 5.2 years in carriers with mutations in codon 634. No pheochromocytomas were identified in carriers of mutations in codons 609, 611, 630, 768, 790, 804, and 891. The authors of this study recommended annual screening for pheochromocytoma from age 10 in carriers of RET mutations in codons 918, 634, and 630, and from age 20 in the remainder (11). Pheochromocytoma symptoms are typically subtler than those encountered with sporadic pheochromocytoma (2). The diagnosis is established by demonstrating high urinary or plasma catecholamine, or metanephrine levels, although total urinary catecholamines may be normal, and only the epinephrine/norepinephrine ratio may be increased, particularly with medullary hyperplasia (2). Genetic Alterations in Sporadic MTC Approximately 50% of sporadic MTC tumors harbor a somatic mutation at codon 918 of the RET proto-oncogene without showing a similar mutation in other tissues (13). One study (14) detected a RET somatic mutation at codon 918 in fine-needle aspiration (FNA) cytology specimens obtained from both a thyroid nodule and two enlarged neck lymph nodes but not in the peripheral blood, thus establishing a diagnosis of sporadic MTC before surgery. This is important because excluding MEN-2 preoperatively permits immediate thyroidectomy without search for pheochromocytoma (14). The Relationship Between Somatic RET Mutation and Prognosis Although an association has been described between somatic mutations and a poor prognosis, this has until recently been controversial, mainly because the studies were small and had inadequate follow-up. However, a recent study of 100 patients with sporadic MTC who had a mean follow-up of 10.2 years found a strong relationship between somatic RET mutations and outcome (15). After analyzing RET exons, 10 to 11 and 13 to 16, a somatic RET mutation was found in 43% of the patients. The most frequent mutation (79%) was M918 T. Patients with a RET mutation were more likely to have larger tumors (p = 0.03) with more lymph node and distant metastases (p ⬍ 0.0001 and p = 0.02, respectively). Thus, there was a significant correlation between the RET somatic mutation and more advanced disease stage at the time of diagnosis (p = 0.004). Multivariate analysis found that only advanced disease stage at the time of diagnosis and the presence of a RET mutation were independent factors predicting poor outcome (p ⬍ 0.0001 and

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Figure 1 Anaplastic thyroid carcinoma (ATC) and medullary thyroid carcinoma (MTC): ATC with tumor infiltrating the entire gland and invading the thyroid capsule at 4 o’clock (top left); histology of ATC showing large, bizarre-appearing cells (top right); MTC with spindle cells and dense stroma that stains positive for amyloid (lower right); spindle cell tumor that was a MTC, which can mimic ATC (lower right).

p = 0.01, respectively). Survival curves showed a significantly lower rate of survival in patients with RET mutations (p = 0.006). Pathology Primary Tumor Ranging from large bulky tumors to microscopic lesions, sporadic and familial tumors are nonetheless histologically similar. However, the widest spectrum is encountered in familial tumors, which range from isolated microscopic C cells that are hypertrophied to large, bilateral, multicentric tumors that are usually in the superior portions of the thyroid lobes. Sporadic MTC is usually unilateral. MTC is typically composed of fusiform or polygonal cells surrounded by irregular masses of amyloid and abundant collagen (Fig. 1). About half the tumors have calcifications, which occasionally appear as trabecular bone formation. Calcitonin can usually be demonstrated in the tumors by immunohistochemical studies. Metastases Cervical lymph node metastases occur early in the disease and can be seen with primary lesions as small as several millimeters. Tumors larger than 1.5 cm in diameter are more likely to metastasize to distant sites, especially to lung, bone, and liver but also to the CNS. Metastatic deposits usually contain calcitonin and stain for amyloid.

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Tumor Calcitonin Immunohistochemical staining for calcitonin serves not only to identify MTC but also, by the staining pattern, to differentiate virulent from less aggressive tumors. In one study, patients with primary tumors that showed intense homogeneous calcitonin staining were all clinically well on follow-up examination, while those with tumors that showed patchy localization of calcitonin either developed metastatic disease or died of cancer within six months to five years of initial surgery (16). Still, the presence of RET oncogene in sporadic tumors appears to be the most helpful prognostic marker (15).

Diagnosis Clinical Features Patients with sporadic disease or unrecognized familial MTC usually present with one or more painless thyroid nodules in an otherwise normal gland, although some experience pain, dysphagia, and hoarseness. The presenting feature may be enlarged cervical lymph nodes or occasionally distant metastases, most commonly to the lung, followed in frequency by metastases to the liver, bone (osteolytic or osteoblastic lesions), and brain. Cervical lymph node metastases are present at the time of diagnosis in about half the patients with sporadic MTC. The thyroid nodule is usually solid on ultrasonography and malignant on FNA, and may be cold or warm on 123 I imaging. Radiographs may show dense, irregular calcifications of the primary tumor and cervical nodes, and mediastinal widening due to metastases. The abnormal phenotype of MEN-2B may lead to the clinical diagnosis. Rarely, a paraneoplastic syndrome such as diarrhea or flushing may be the presenting manifestation. Hormonal Features In addition to calcitonin, MTC may synthesize calcitonin gene-related peptide, Ldopa decarboxylase, serotonin, prostaglandins, adrenocorticotropin (ACTH), histaminase, carcinoembryonic antigen (CEA), nerve growth factor, and substance P (2). Elevated serum levels of calcitonin, histaminase, L-dopa decarboxylase, and CEA are frequently found in MTC patients. Approximately 10% of patients have episodes of flushing, often induced by alcohol ingestion, calcium infusion, and pentagastrin injection; these episodes may be due to tumor release of prostaglandins and serotonin (2). Approximately 30% of patients also experience a secretory diarrhea that may be related to the high circulating levels of calcitonin, though this is typically seen in those with advanced tumors. Because of the indolent course of MTC in many patients, ectopic ACTH produced by the tumor may cause typically Cushing’s syndrome, which is not seen in most other tumors that produce ACTH such as lung cancer (2).

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Calcitonin and Tumor Mass Elevated basal plasma calcitonin levels are almost always found once the MTC becomes palpable, and correlate directly with tumor mass (2). As a result, basal calcitonin often is not elevated with small tumors and is almost invariably normal in those with CCH; however, after stimulation with pentagastrin and/or calcium, serum calcitonin levels increase to abnormally high levels. Calcitonin in the Evaluation of Thyroid Nodules Some clinicians advise routine measurement of basal serum calcitonin in those with nodular thyroid disease undergoing FNA biopsy, finding that it allows early preoperative diagnosis of subclinical MTC and improves the outcome of surgery. Most of the studies that advocate this approach are from Europe where the incidence of multinodular goiter is high and pentagastrin is available for clinical use (17). This has not been the practice among U.S. thyroidologists, mainly because it is viewed as not being cost-effective because baseline serum calcitonin levels are often falsely elevated in patients without MTC. Still, there is incontrovertible evidence that the survival rate of patients with MTC is substantially better than usual when the tumor is limited to the thyroid. Elisei et al. (17) found that calcitonin screening in a cohort of 10,864 patients with thyroid nodular disease had a higher diagnostic sensitivity and specificity compared with FNA biopsy. Calcitonin screening resulted in a diagnosis of MTC at an earlier stage compared with those in whom the test was not performed (p = 0.004). Moreover, normalization of serum calcitonin levels (undetectable) after surgery was more frequently observed in patients who had calcitonin screening before surgery. Complete remission was observed in 59% of the group that had calcitonin testing compared with 2.7% of the group without calcitonin testing 9 (p = 0.0001). This study confirms that MTC is a relatively frequent finding among patients with thyroid nodules—nearly 1 in 250 patient—that benefits patients with MTC. The American Thyroid Association (ATA) guidelines for the management of thyroid nodules and differentiated thyroid carcinoma suggest that if the test is done, patients should undergo surgery if in the serum calcitonin level is higher than 100 pg/mL (18). Stimulation Tests Some patients with small MTC tumors have normal basal calcitonin levels, which rise to high levels with stimulation. The combination of intravenous pentagastrin and calcium is a more potent stimulus for calcitonin release than either agent alone. Unfortunately, pentagastrin is no longer available in the United States. In the calcium stimulation test, elemental calcium (2 mg/kg) in 50 mL of 0.9% saline is given intravenously over one minute and plasma is collected for calcitonin determination every 10 minutes for 30 minutes. Patients with CCH and MTC generally have plasma calcitonin levels that rise fivefold above baseline. Basal and stimulated levels are higher in men than in women and decline with age. Of

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course, the diagnosis of inherited MTC is now possible with genetic screening long before the thyroid tumor is clinically manifest or calcitonin levels are elevated, rendering stimulation testing obsolete in most situations. Omeprazole Stimulation Test Omeprazole stimulates intrinsic gastrin release, which may stimulate calcitonin and be useful in the diagnosis and follow-up of MTC, but it is less potent than pentagastrin for this indication (17). Differential Diagnosis of Hypercalcitoninemia An elevated serum calcitonin level is not absolutely diagnostic of MTC because it occurs in other conditions (2) such as patients on chronic hemodialysis and other neuroendocrine tumors. When the differential diagnosis of a high plasma calcitonin value is between MTC and another malignancy, a higher calcitonin value and a palpable thyroid tumor usually identify patients with MTC. In addition, calcitonin secretion by other cancers is poorly stimulated by pentagastrin. Factors Influencing Prognosis Age and Tumor Stage MTC is more aggressive than papillary and follicular carcinoma, having a cancerspecific mortality rate of approximately 25% at 10 years (1). However, pheochromocytoma causes a number of deaths among those with familial MTC (19). The mortality rate is substantially worse with sporadic tumors or when metastases are found at the time of diagnosis, or with the MEN-2B phenotype, and among patients older than 50 years at the time of diagnosis. Children with familial disease operated on during the first decade of life generally have no evidence of residual disease postoperatively (2). However, persistent or recurrent disease occurs in about one-third of patients operated on in the second decade and it gradually increases in frequency until the seventh decade when about two-thirds of patients have persistent disease after surgery (2). This is largely due to the patient’s age, tumor stage at the time of surgery, and the genetic makeup (RET mutation) of the tumor, which are the three most powerful prognostic factors predicting outcome (20,21). Familial Medullary Thyroid Carcinoma Prognosis is best with FMTC and MEN-2 A. Early detection and treatment have a profound impact on the clinical course of MTC. The 10-year survival rates are nearly similar to those in unaffected subjects when nodal metastases are not present, but the rates fall to approximately 45% when nodal metastases are present (2). Before 1970, MTC was usually diagnosed in the fifth or sixth decade of life. For the next 20 years, biologic markers (pentagastrin- or calcium-stimulated calcitonin) assumed a preeminent role in diagnosis. With periodic calcitonin screening, patients from MEN kindreds were diagnosed at a much earlier age, usually in

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the second decade or earlier, when they had CCH or microscopic carcinoma confined to the thyroid (22). Nonetheless, the results of long-term studies using this approach are somewhat disappointing. One large study comparing calcitonin with genetic testing found 14 young gene carriers (18% of the 80 known gene carriers in the study) who had normal plasma calcitonin tests, eight of whom had undergone thyroidectomy at the time of the report and were found to have foci of MTC (23). Another study (24) reported long-term follow-up of 22 children in whom pentagastrin-stimulated calcitonin screening studies were routinely performed once a year and thyroidectomy was recommended for any elevation in serum calcitonin levels. MTC had already developed in 17 children (77%), and only five of them had CCH. Of the 17 with MTC, 13 had macroscopic tumors, and recurrent disease developed in four children (24%) (24). Therapy Initial Surgery Surgery offers the only chance for cure and should be performed as soon as the disease is detected (20,21). However, pheochromocytoma must be rigorously searched for and excised before thyroidectomy is performed. The treatment of MTC confined to the neck is total thyroidectomy because the disease is often bilateral, even with a negative family history, because patients are often unsuspected relatives of affected MEN-2 kindred (20,21). All patients with palpable MTC or clinically occult disease that is visible on cut section of the thyroid should undergo routine dissection of lymph nodes in the central neck compartment because nodal metastases occur early and adversely influence survival. The lateral cervical lymph nodes should be dissected when they contain tumor, but radical neck dissection is not recommended unless the jugular vein, accessory nerve, or sternocleidomastoid muscle in invaded by tumor (25). Residual or Recurrent MTC Persistent or recurrent disease, which is ordinarily manifest by elevated calcitonin levels postoperatively, occurs commonly following primary treatment of the tumor. Nonetheless, survival is often good. For example, a French study reported that 57% of 899 patients were not cured (57%), but that survival was 80% at 5 years and 70% at 10 years. Thus, reoperation in appropriately selected patients is advisable. It is the only treatment that consistently and reliably reduces calcitonin levels and often results in excellent local disease control. There is no curative therapy for widely metastatic disease, but preoperative neck microdissections may normalize calcitonin levels when metastatic MTC is confined to regional lymph nodes. Improved results have been reported in recent years with the surgical management of recurrent MTC, mainly through better preoperative selection of patients and the use of routine laparoscopic liver examination preoperatively, which identifies hepatic metastases in MTC patients with normal computed tomography (CT) scan and magnetic resonance imaging (MRI) (26). Although patients with

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widely metastatic MTC often live for years, many develop symptoms from disease progression. Despite the presence of widespread incurable tumor, patients with metastatic MTC causing significant symptoms or physical compromise may respond to palliative, preoperative resection (27) or tumor embolization (28). Judicious, palliative, preoperative resection of discrete symptomatic lesions provides substantial long-term relief of symptoms with minimal operative mortality and morbidity (27). Inoperable Disease Patients with inoperable disease are often given palliative treatment with external radiation for localized disease or with doxorubicin or other chemotherapy combinations for widespread, life-threatening disease, which is of limited benefit. Radiolabeled metaiodobenzyguanidine (MIBG) or somatostatin analogues and 131 I or yttrium-90 (99 Y)-labeled humanized anti-CEA monoclonal antibodies are potentially useful toward tumor debulking. Nonradioactive somatostatin analogues may importantly control the paraneoplastic symptoms of flushing or diarrhea, but they do not improve the natural course of advanced stages of MTC (29). Embolization is especially effective for liver metastases, often relieving symptoms of flushing and diarrhea that are characteristic of hepatic metastases (28,30). Recent trials (31,32) of multikinase inhibitors have not proven effective at inducing a remission in these tumors, however, several studies involving different agents are currently underway and may reveal treatments that offer stabilization of disease. Follow-up The success of surgery is assessed postoperatively by measuring plasma calcitonin levels. Although it may require up to six months for calcitonin to normalize, undetectable basal and stimulated calcitonin levels usually indicate a cure. Persistent basal calcitonin elevations are often seen after surgery in patients who remain well for many years, particularly those from MEN-2A kindred who should be followed without further aggressive therapy. If postoperative plasma calcitonins are extremely high or the patient has flushing and/or diarrhea, imaging studies must be performed. There are conflicting data concerning which imaging studies have the highest sensitivity in this situation. However, a prospective study of 55 consecutive patients with MTC who had elevated serum calcitonin levels found that the most efficient imaging work-up for detecting MTC tumor was as follows: ultrasonography for the neck, CT scan for the chest, MRI for the liver, bone scintigraphy, and axial skeleton MRI for bone metastases (33). Unlike papillary and follicular thyroid carcinoma, FDG-PET scanning was less sensitive and of low prognostic value for MTC. Another prospective study of the same cohort of 55 patients with MTC found that calcitonin and CEA levels were correlated with tumor burden and their doubling times were strongly related to disease progression (34). When the CEA and calcitonin doubling times were shorter than

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25 months, 94% of the patients had progressive disease while most (86%) of the patients with doubling times longer than 25 months had stable disease. Family Screening Genetic Screening Affected patients can be identified at birth with proper genetic RET testing of codons 10, 11, 13 to 16, which hopefully will result in prevention of disease when the patient is operated on early in life. To do this, all patients with presumed sporadic MTC should undergo genetic screening, although only approximately 3% of such cases turn out to have familial disease. Nonetheless, this is an extremely important concept given the possibility of overlooking potentially lethal occult pheochromocytoma and the implications for failing to identify affected kindred. All first-degree relatives of any patient who tests positive for a MEN-2 or FMTC mutation should be screened. One study found that without genetic testing, even when the mean age at the time of thyroidectomy was about 10 years, a significant number of patients (21%) with MEN-2A or -2B developed persistent or recurrent MTC over a follow-up of about a decade (35). However, the sensitivity of genetic screening for MEN-2A offered by diagnostic laboratories that limit RET analysis to exons 11, 13–16 results in a more complete and accurate analysis with a sensitivity of nearly 95% (35). It is recommended that clinicians confirm the comprehensiveness of a laboratory’s genetic screening approach for MEN-2A to ensure thoroughness of sample analysis. Prophylactic Total Thyroidectomy In 1993, when mutations of the RET proto-oncogene were identified in hereditary MTC, surgeons began to operate on patients prophylactically before the disease was clinically manifest. Nonetheless, microscopic or grossly evident MTC was often present in the excised thyroid glands but almost none were metastatic to regional lymph nodes at the time of surgery (36). The debate now is focused on the optimal age for operating on children and the extent of lymph node resection. There are differing views on this issue from three authoritative sources on this issue. The Gubbio Conference Recommendation This consensus opinion comes from the Seventh International Workshop on MEN held in Gubbio, Italy in June 1999 (4). The report from this meeting represents a consensus opinion from an international group of experts (4). Patients with familial MTC are stratified into three groups. Level 3 (highest risk group) is children with MEN-2B and/or RET codon 883, 918, or 922 mutation. The participants recommended that all of these children should have thyroidectomy performed within the first six months and preferably within the first month of life. This is based upon the fact that microscopic MTC

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within the first year of life in this group is common and metastases may occur during the first year. They recommended a central neck lymph node dissection, and that more extensive surgery may be appropriate if metastases are identified at surgery. Level 2 (high-risk group) is children with any RET codon 611, 618, 620, or 634 mutation (MEN-2A). For these children the participants recommended total thyroidectomy before the age of five years, including removal of the thyroid posterior capsule. However, there was no consensus regarding the need for prophylactic central lymph node dissection, which recommended by surgeons but not by internists. This differing opinion is related to the high risk of hypothyroid and laryngeal nerve damage by such aggressive surgery. Level 1 (least high-risk group) is children with RET codon 609, 768, 790, 791, 804, and 891 mutations. Total thyroidectomy, including the posterior thyroid capsule, was recommended for this group of children. However, there was no consensus as what age the thyroidectomy should be done. This is based upon the fact that the biologic behavior of MTC with the RET codon mutations indicated is variable, but generally grows more slowly than tumors in the other two groups. No recommendation was made for several other RET codon mutations. The EUROMEN Study This is a European multicenter study (10) of 207 patients from 145 families that was conducted from July 1993 to February 2001. The patients who were 20 years of age or younger, were asymptomatic and had undergone total thyroidectomy for MTC after confirmation of the RET mutation. As noted above, the main findings of the study were that there is a significant age-related progression from CCH to MTC, and ultimately, to lymph-node metastases among patients with a RET codon 634 genotype (MEN-2A and FMTC). As a result, the EUROMEN authors provide initial age guidelines for prophylactic total thyroidectomy based upon the earliest age at which MTC was identified for each of the known RET mutations for each of the MEN-2 syndromes. It is important to note that the authors provide the following caveat “. . . but the benefit of cure offered by prophylactic thyroidectomy is offered by the potential overtreatment of some carriers of RET mutations” (10). ANAPLASTIC THYROID CARCINOMA Its extremely aggressive behavior and poor prognosis distinguish this exceptionally virulent and invasive neoplasm. Occurring in an older population, Anaplastic thyroid carcinoma (ATC) demonstrates a biologic behavior that is among the worst encountered in humans. Incidence and Demographics The frequency of ATC relative to other thyroid cancers was approximately 5% to 10% in the past (37), but more recently it has been approximately 2% in the United States (1). Part of this apparent reduction in incidence may be to improvements in

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discrimination of this tumor from other poorly differentiated tumors of the thyroid as a result of consensus conferences and improved histopathologic classification. In a review of 475 patients with ATC from six large studies, the mean age was 65 years, with only a slight female predominance (37). It is almost never seen before age 20. The incidence of ATC is influenced by dietary iodine. In one study (38) the frequency of ATC was threefold higher in an iodine-deficient area compared with an iodine-rich area. This finding may account for differences in disease frequency reported from around the world, which were especially evident several decades ago. Origin Although some ATCs appear to arise de novo (38,39), there are many examples in laboratory animals and humans of well differentiated tumors transforming into ATCs, events that may evolve over many years (40). One large study (41) demonstrated elements of differentiated thyroid carcinoma in almost 90% of ATC specimens, which, in more than 20% of the cases, came from persons previously diagnosed and treated for well-differentiated thyroid carcinoma. Pathology These tumors are composed wholly or in part of undifferentiated cells and tend to behave according to their most aggressive tumor element. Small-Cell Carcinoma In the past, ATCs or undifferentiated thyroid carcinomas were divided into two broad categories: spindle- or giant-cell carcinomas and small-cell carcinoma. Now, however, almost all small-cell carcinomas are recognized both by electron microscopy and immunohistochemical study as primary thyroid lymphomas (PTLs), MTCs, insular variants of thyroid carcinoma, or occasionally a small-cell metastasis from lung cancer. The WHO classification of thyroid tumors recommends against using the term. Large-Cell Carcinoma The three major cell types of ATC are spindle cells, giant cells, and squamoid patterns. Subdivision based upon these cellular features is not clinically helpful and is not recommended in the current WHO classification. For example, one large study (42) found spindle cells in 53%, giant cells in 50%, and a squamoid element in 19% of the tumors, but outcome was similar regardless of these features. Gross Features ATCs often involve both thyroid lobes and are typically invasive and poorly demarcated from surrounding neck tissues (Fig. 1). Extensive local invasion into the soft tissues and other structures of the neck is common at the time of presentation. On

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gross examination, the tumors are gray-white, fibrous, calcified, or even ossified, and they frequently show areas of necrosis. Histologic Features ATCs exhibit the three distinct morphologic patterns (Fig. 1)—spindle cell, giant cell, and squamoid features—often with frequent mitotic figures. The tumors are very pleomorphic and may resemble a fibrosarcoma or rhabdomyosarcoma, or they may contain multinucleated giant cells that resemble osteoclasts and, very rarely, malignant osteoid or cartilage may be seen simulating an osteogenic sarcoma or chondrosarcoma. Immunohistochemical Studies The immunohistochemical proof of the follicular origin of ATC is its staining with epithelial markers, the most useful of which is low-molecular-weight keratin (cytokeratin), expressed in up to 80% of the cases (37). Other markers may be detected, but some (43) show that 30% of ATCs express none of the tumor markers examined. Less than one-third react with epithelial membrane antigen or CEA and some (0–70%) stain for Tg. An occasional case of anaplastic MTC occurs (37). p53 Suppressor Gene Mutations in this gene occur in thyroid carcinoma almost exclusively in the poorly differentiated tumors and thyroid cancer cell lines, suggesting that inactivation of p53 may confer aggressive properties and further loss of differentiated function. For example, one study found the frequency of p53 mutations to be zero in normal thyroid, follicular adenomas, PTCs, and MTCs; however, it was approximately 9% in FTCs and 83% in ATCs (44). Diagnosis Clinical Presentation History A study (45) from MD Anderson found that almost two-thirds of patients presented with a rapidly enlarging neck mass and about one-third had symptoms of tracheal compression with invasion. Another study (46) from the Mayo Clinic also found that about two-thirds had a rapidly enlarging neck mass, either with (37%) or without (32%) a preexisting goiter, and about half had dyspnea at the time of diagnosis. In this series, symptoms had been present for less than three months in almost half the patients, while 20% had them for a year before diagnosis. Rapid tumor enlargement often causes neck pain that may mimic subacute thyroiditis, probably due to tumor necrosis and invasion of neck tissues (so-called “malignant pseudothyroiditis”). Hoarseness and cough, with systemic symptoms such as fever or weight loss, are often present. Most patients have normal thyroid function, although thyrotoxicosis rarely occurs, probably from rapid thyroid tissue necrosis releasing thyroid hormone.

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Physical Examination The tumor is typically hard, poorly circumscribed, and fixed to surrounding structures. In the Mayo Clinic series (46), 60% presented as a multinodular goiter and 38% presented as an apparently isolated thyroid nodule, while only 2% caused diffuse thyroid enlargement. The tumors are characteristically quite large and may be associated with palpable cervical lymph nodes. In the Mayo Clinic series (46), approximately 80% were ⬎5 cm, half the patients had palpably enlarged cervical lymph nodes, and one-third of the patients had vocal cord paralysis. Stridor that occurs when the patient’s neck is extended portends serious airway obstruction and should raise the question of elective tracheostomy to protect the airway. The tumor may cause a superior mediastinal syndrome with venous distention and edema of the face, arms, and neck.

Distant Metastases Only about one-third of patients have distant metastases, mostly to the lung, recognized at the time of diagnosis, but about half the patients eventually developed them (45,46). The lung is the most common site of distant metastases, comprising 75% to 90% of all distant metastases reported in large series (37). They are typically manifest as large isolated metastases that do not concentrate 131 I. Skeletal metastases are the second most frequent but only account for approximately 5% of the distant metastases at the time of diagnosis and approximately 15% of all distant metastases that eventually develop (37). Uncommonly, patients with ATC have distant metastases to other sites, such as the CNS (37). The diagnosis of malignancy is usually quite evident with ATC because of the ominous symptoms and physical findings suggesting an aggressive tumor. The main diagnostic problems are differentiating ATC from less aggressive undifferentiated thyroid tumors and delineating the extent of the neck disease.

Fine-Needle Aspiration Most cases of ATC diagnosed by FNA should at least have open biopsy with immunohistochemical staining to confirm the diagnosis. Although a diagnosis of thyroid malignancy is almost always possible by FNA cytology, ATC may be difficult to distinguish from thyroid lymphoma, MTC, and other forms of poorly differentiated thyroid carcinoma or cancers metastatic to the thyroid gland. Nonetheless, the giant- and spindle-cell patterns of ATC usually predominate, sometimes with multinucleated giant cells, suggesting the correct diagnosis. Although MTC often shows a spindle-cell population, it can usually be correctly identified by FNA cytology that may stain for amyloid or calcitonin (37). Non-Hodgkin’s thyroid lymphoma can be identified by FNA, usually by its small cells, but open biopsy and histochemical staining are often necessary to differentiate it from ATC, especially when the lymphoma is composed of large cells.

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Radionuclide Studies Thyroid scanning with radioiodine usually discloses one or more cold nodules in ATC, which is a nonspecific finding. However, gallium-67 (67 Ga) uptake is low in well-differentiated thyroid carcinomas but high in anaplastic carcinomas and malignant lymphomas and may detect distant metastases (47). Thyroid Ultrasonography The majority of differentiated carcinomas and all anaplastic tumors present as hypoechoic masses by ultrasonography. Tumor clearly extending beyond the thyroid capsule or infiltrating adjacent tissues strongly suggests a malignant diagnosis. Computed Tomography CT scan is indispensable preoperatively since it may alter surgical planning, especially when the tumor extends into the thorax or invades the larynx, esophagus, or other neck structures. ATC appears as a large mass of low attenuation accompanied by dense calcification in over half the patients in most of whom there is also evidence of tumor necrosis (48). CT scan usually identifies tumor infiltrating neck structures, including the carotid artery, internal jugular vein, larynx, trachea, esophagus, mediastinum, and regional lymph nodes. CT scan with contrast identifies lymph nodes, which are often necrotic, more consistently than palpation (48).

Natural History and Mortality Rates ATC has a dismal prognosis. In 1961, Woolner et al. (49) reported from the Mayo Clinic that 61% of ATC patients were dead within six months and 77% died within a year of diagnosis. Almost 50 years later, a study from MD Anderson (45) reported a mean survival of seven months. Only 8% (20 of 240 patients) from both series survived longer than one year. Median survival in a later Mayo Clinic series was only four months (37). Overall cause-specific mortality of 516 patients from the SEER database was 69.3% at 6 months and 80.7% at 12 months (50). This is why lymphomas and MTCs, which histologically resemble ATC but have a substantially better prognosis, must be carefully identified by immunohistochemical studies. Cause of Death Death occurs most commonly from the effects of local tumor invasion, particularly asphyxiation. In one large study (51) over half of the patients died of suffocation, while the others died of a combination of effects from the primary tumor and metastases.

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Prognostic Factors Although prognosis with ATC is very poor, certain features predict a more favorable response to therapy. Like differentiated thyroid carcinoma, patient age (45) and tumor stage at the time of diagnosis are the most important variables influencing prognosis. In one large study (45), mean survival was 8.1 months if the disease was confined to the neck, compared with 3.3 months when it was distantly metastatic. The Mayo Clinic (46) reported that relatively favorable prognostic features were unilateral tumors, a tumor diameter ⬍5 cm, no invasion of adjacent tissue, and absence of cervical node involvement. Cox multivariate analysis showed that extent of disease, tumor size, histologic cell type, and surgical treatment were the most significant variables. In a recent report spanning 1985–1995 years, with 893 cases (1), the 10-year relative survival in the United States was 14%, with 77% of deaths within 1 year and 100% of all deaths by year 4. Age ⬍45 years at diagnosis demonstrated dramatically better 5-year survival at 55%. Small tumor size and absent extrathyroidal extension were more common in patients surviving more than five years. In a study of 516 patients from the SEER database, on multivariate analysis only age ⬍60, extent of disease, and combined therapy with surgical resection and external beam radiotherapy were independent prognostic factors (50).

Treatment ATCs are very resistant to any form of therapy and are rarely cured. Surgery, chemotherapy, or radiotherapy used separately generally have not been effective (52–54). The best survival rates occur with combined surgery, accelerated and hyperfractionated external irradiation, and chemotherapy (55).

Surgical Therapy Thyroid Surgery Less than total thyroidectomy, with resection of the involved adjacent neck tissues and cervical lymph nodes, should be done if possible, without resorting to radical surgery in surgically incurable patients. In the Mayo Clinic series (46), 41% of the patients had surgical resection—mostly total lobectomy with subtotal resection of the contralateral lobe—in an attempt to cure the patient. In the MD Anderson series (45), approximately 45% of patients underwent total thyroidectomy. However, in neither series did the surgical extent influence the survival. Total thyroidectomy and radical neck dissection result in an increased complication rate without conferring a clear advantage over a more conservative approach. When the tumor is resectable, an appropriately aggressive and safe surgical approach is to resect the tumor with wide margins of adjacent soft tissue on the involved side. When the tumor is not resectable, attention is directed toward airway management.

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Airway Management Tumor may compromise the airway by compression, displacement, infiltration, and less often as the result of neurogenic dysfunction. Management involves thyroid gland resection with decompression of the airway and tracheostomy when the airway is infiltrated with tumor. Many patients require tracheostomy during their course, mainly to relieve airway obstruction but also as a precautionary measure before initiating external radiation therapy. External irradiation may cause tumor edema that acutely exacerbates airway obstruction. More than half the patients in the Mayo Clinic series required tracheostomy at some time during the course of their disease (46). In patients who are not surgical candidates or who do not wish to have invasive procedures, tracheal stenting is an alternative therapy which may provide symptomatic relief from the dyspnea while maintaining quality of life without requiring a tracheostomy (56). Medical Therapy External Radiotherapy After treatment with surgery and conventional radiotherapy, ⬍5% of patients with ATC survive five years, although survivors who are disease-free at two years may live for longer periods (37). Because conventional external irradiation fails to eradicate local disease, larger doses of radiation have been given at closer intervals with limited success in controlling local disease, but the toxicity is very high, resulting in severe esophagitis, dysphagia, spinal cord necrosis, and death (54,57). Chemotherapy There is no consensus regarding the selection of chemotherapeutic agents for ATC, mainly because this tumor is so resistant to chemotherapy. None provides clearly superior therapeutic efficacy, and the selection is often based as much upon the side-effect profiles of the drugs as its potential efficacy. Doxorubicin is perhaps the most commonly used, administered either alone or in combination with other drugs. There is a dose–response relationship such that patients receiving lower doxorubicin doses, in the range of 45 mg/m2 , show little or no response, while those treated with larger doses demonstrate therapeutic responses more consistently (37). The most frequently applied doxorubicin dosage has been between 60 and 90 mg/m2 body surface (37). With this dosage, one study (58) found the response rate (complete or partial remission) to be almost 40% in patients with advanced thyroid carcinoma of all types, although the response rate was only 22% for ATC treated with doxorubicin monotherapy. Even when remission does occur, its duration is relatively short, with a median period of 90 (33–560) days in the 20% to 30% who responded to doxorubicin (37). Others believe that doxorubicin alone does not improve the extremely poor prognosis of ATC. When there is a response to doxorubicin, pulmonary metastases most frequently respond, followed

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by bone metastases and local tumor growth; however, the drug may not control local disease (37). Because of the poor response to standard chemotherapy, it is reasonable to recommend a clinical trial of one of the new targeted molecular therapies. Doxorubicin and Hyperfractionated Radiation Therapy In 1983, a new treatment regimen consisting of combination doxorubicin and hyperfractionated radiation therapy was reported for the treatment of ATC (59). The protocol consisted of once-weekly administration of low-dose doxorubicin (10 mg/m2 ) and hyperfractionated radiation therapy carried out with a fractional dose of 160 cGy per treatment twice a day for 3 day/wk. The total tumor dose was 5760 cGy delivered in 40 days. The protocol was well tolerated with little morbidity. Complete tumor response was observed in 84% of the patients and rate of local tumor control was 68% at two year. Median survival was one year, but most patients developed distant metastases and died from the disease. In 1990, a Swedish group (55) reported prospectively treating 16 patients with a protocol of hyperfractionated radiotherapy, doxorubicin, and debulking surgery. The radiotherapy was administered preoperatively to a target dose of 30 Gy in three weeks and postoperatively to an additional dose of 16 Gy in 1.5 weeks. Radiotherapy was administered twice daily, five days a week, with a target dose of 1 Gy per fraction and with a minimum interval of six hour. Doxorubicin (20 mg) was administered intravenously one to two before the first radiotherapy session every week. Debulking surgery was feasible in nine patients. Complete remission of local disease was achieved in 5 of 16, of whom three were alive and disease-free at 10, 30, and 30 months after diagnosis. Only six patients died of local disease. This combination regimen was well tolerated despite the patients’ advanced age and disease stage. In 1994, the same group (60) reported prospectively treating 33 consecutive patients with ATC according to the above protocol except that the daily fraction of radiotherapy was increased to 1.3 Gy per fraction after 1988. No patient failed to complete the protocol because of toxicity. There were no local recurrences in 16 patients (48%). Death was attributed to local failure in only eight patients (24%). In four patients, survival with no evidence of disease exceeded two years. Local tumor control was marginally improved in patients treated in the latter part of the study. The authors concluded that combination-modality treatment of ATC is feasible and effective despite the patients’ advanced age and locally advanced disease. In 1991, a French group (61) reported their results in 20 ATC patients treated prospectively according to a combination protocol of chemotherapy and external radiation therapy. Depending on the patient’s age, two types of chemotherapy were used every four weeks. For those younger than 65 years, a combination of doxorubicin (60 mg/m2 ) and cisplatin (90 mg/m2 ) was employed; for older patients, mitoxantrone (14 mg/m2 ) alone was used. Between days 10 and 20 of the first four chemotherapy cycles, radiotherapy (17.5 Gy) was given in seven fractions

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to the neck and superior mediastinum. Of the total, three patients (15%) survived longer than 20 months. Complete tumor response was seen in distant metastases, which were the cause of death in 70% of the patients in this series. Toxicity was the main limiting factor—all patients developed pharyngoesophagitis and tracheitis after the first or second cycle of radiotherapy. It was severe in 60% of the patients, requiring one to two weeks’ rest before resuming treatment. Hematologic toxicity occurred in 40% of the patients, while cardiotoxicity was seen in 25% of those treated with doxorubicin. PRIMARY THYROID LYMPHOMA PTL is an uncommon but potentially life-threatening disorder that often poses a major diagnostic and therapeutic dilemma because most clinicians rarely see these tumors. PTL typically arises in the setting of chronic thyroiditis, sometimes in patients with long-standing hypothyroidism. The true character of the neoplasm may go unrecognized for several months, until the development of airway obstruction symptoms; then, unfortunately, an erroneous diagnosis of ATC is sometimes made. It is important to identify the tumor correctly as a PTL, since treatments and prognoses differ, and diagnosis at an early stage is associated with an excellent prognosis. Incidence The annual incidence of PTL in the United States is less than one in two million persons (62). It is 10-fold less frequent than gastrointestinal lymphoma, the most common extranodal non-Hodgkin’s lymphoma, and only slightly more common than breast lymphoma (62). The likelihood that a thyroid nodule is a lymphoma is ⬍1 per 1000, whereas secondary involvement of the thyroid with lymphoma occurs in approximately 10% of patients who die of the disease (62). Despite the relative rarity of PTL, its incidence has been rising, and it now constitutes approximately 5% of all thyroid malignancies, with estimates ranging from 2% to 8% (62). Its frequency may be increasing for several reasons. Many PTLs were incorrectly diagnosed in the past as anaplastic small-cell thyroid carcinoma (62). Also, pathologists now have become more adept at separating lymphoma from advanced Hashimoto’s thyroiditis, which is important, since PTL typically develops in the setting of preexisting lymphocytic thyroiditis (62). Some of the increase seems related to more aggressive diagnostic evaluation of thyroid nodules. Finally, the increasing frequency of PTL has paralleled the rising incidence of Hashimoto’s thyroiditis in the United States. Age and Sex Distribution Contrary to other lymphomas in which males predominate, female preponderance is the rule for PTL (62), probably because it originates from active lymphoid cells in chronic lymphocytic thyroiditis, which occurs more often in women. Among

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812 PTL patients, females outnumbered males almost 3:1, and the mean age was 62.7 years (62). However, the female-to-male ratio for those younger than 60 years was 1.5:1 compared with 5:1 in those older than 60 years (62). Although primarily a disease of older women, about one-third of these patients are younger than 60 years (62). Hashimoto’s Thyroiditis (Chronic Lymphocytic Thyroiditis) and Thyroid Lymphoma An association exists between PTL and Hashimoto’s thyroiditis, but how this occurs is unclear. In one study, the relative risk of PTL among people in Sweden with Hashimoto’s thyroiditis, after an average follow-up of 8.5 years, was 67fold greater than expected (63). Another study (64) from Japan found an 80fold increased frequency of PTL among 5592 women aged 25 years or older with chronic thyroiditis. The average interval between the diagnosis of chronic thyroiditis and PTL was 9.2 years. Pathology Lymphoma Cell Types Virtually all PTLs are B-cell types, which can be identified by monoclonal antibodies (62). Many extranodal lymphomas, including those in the thyroid, arise from mucosa-associated lymphoid tissue (MALT); they are a special group of Bcell lymphomas (62). Most are diffuse (as opposed to nodular) lymphomas, with variable cellular features typical of low-grade malignancies. Cases classified as immunoblastic B-cell lymphoma are uncommon but are typically quite aggressive. Histologic Features of Hashimoto’s Disease The histologic features of Hashimoto’s disease and PTL are often difficult to differentiate. Hashimoto’s features include well-differentiated lymphocytes, plasma cells, macrophages, and lymphoid follicles with germinal centers and scattered Langerhans-type giant cells. The reactive lymphoid follicles are largely composed of B lymphocytes that mainly produce polyclonal IgG. The inflammatory cells are associated with both damage and stimulation of the thyroid follicular cells, causing atrophy, metaplasia, and hyperplasia, which leads to considerable loss of thyroid colloid. Most of the inflammatory cells lie in the interstitial tissue between thyroid follicles and are typically confined to the thyroid parenchyma, with minimal infiltration of the thyroid capsule. Histologic Features of Lymphoma The normal thyroid tissue is extensively infiltrated with abnormal lymphoid cells that often penetrate the thyroid capsule, extending into adjacent soft tissues. The lymphoma is usually composed of small cells monotonously similar to one another, which represents a distinct difference from those seen in autoimmune thyroiditis.

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The border between the two may be sharply defined, or there may be a transitional zone in which elements of both are mixed. The lymphoma cells tend to displace, distort, and replace the thyroid epithelium. Most thyroid follicles are packed and distended with lymphoma cells and loose colloid (62). Lymphoma cells infiltrate blood vessel walls in at least one-fourth of the cases and lymphoma cells may undergo necrosis. Leukocyte common antigen can usually be found and substantial proportions of lymphomas contain both monoclonal heavy and light chain immunoglobulins, characteristics that allow their differentiation from small-cell carcinomas. Also, identification of monoclonal light chains usually allows differentiation of a malignant proliferation from a polyclonal benign lymphocyte inflammation, although monoclonal gammopathy occasionally can be demonstrated in Hashimoto’s disease. Clinical Features Symptoms and Signs Duration of Symptoms Most patients with PTL have compressive symptoms caused by a rapidly expanding goiter that is invading and compressing neck structures. Symptoms typically are short in duration, averaging less than five months (62), which contrasts sharply with the indolent course of Hashimoto’s thyroiditis. Compression Symptoms Patients characteristically have a subacute onset of symptoms caused by tumor pressing and growing into vital neck organs, particularly the trachea, laryngeal nerve, esophagus, and neck muscles. The most common complaints are hoarseness (21%); dysphagia, dyspnea, and stridor (19%); neck pressure (5%); and neck pain (5%) (62). These are important signals of extrathyroidal tumor extension that should alert the clinician to the malignant nature of the goiter. Stridor and hoarseness often occur together, and when they do, laryngeal nerve paralysis is almost invariably seen on laryngoscopy. Symptoms of invasion, particularly dyspnea and dysphagia, are ominous and portend a poor outcome. Goiter The most common presenting feature is recent growth of goiter, which is experienced by about half the patients (62). A rapidly enlarging goiter typically becomes apparent to the patient over several weeks to a few months before the diagnosis of lymphoma is established, although longer periods have been reported. A goiter was present for a year or more in 16% of 556 patients reported in nine large studies (62). Only one thyroid lobe may enlarge or a discrete nodule may be palpable within the gland, or there may be diffuse thyromegaly. The goiter is nearly always firm or hard, is usually nontender and is often fixed to adjacent tissues, a sign that tumor is invading neck structures. Other signs of extrathyroidal spread include ill-defined thyroid borders with extension laterally or retrosternally.

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Lymph Node Involvement and Retrosternal Extension Large (⬎2 cm), nontender, and matted cervical lymph nodes are found on physical examination in up to half the patients (62). The chest roentgenogram may show retrosternal involvement or mediastinal widening, although lymph nodes elsewhere are seldom enlarged. Coexisting Hashimoto’s Thyroiditis Almost all patients with PTL have clinical or histologic evidence of lymphocytic thyroiditis at the time of diagnosis (62). In 10 large series (62), antithyroglobulin and antimicrosomal antibodies are found in almost 75% of 539 patients, and 83% had histologic evidence of Hashimoto’s thyroiditis. Thyroid Dysfunction Although laboratory evidence of autoimmune thyroiditis is common, few patients have overt hypothyroidism. Most are euthyroid or only mildly hypothyroid, showing minimal elevation in serum thyroid-stimulating hormone (TSH) and otherwise normal thyroid function tests at the time PTL is discovered. When lymphoma was diagnosed, overt hypothyroidism was seen in only approximately 8% of 366 patients from seven large studies (62). However, despite its relative infrequency, a goiter that suddenly enlarges during appropriate long-term levothyroxine therapy is an important clinical clue to the diagnosis of lymphoma. Thyrotoxicosis is extremely uncommon but can occur in patients with lymphoma. Diagnosis Differential Diagnosis The diagnoses that should be considered in a patient with a rapidly enlarging thyroid mass are PTL, ATC, MTC, multinodular goiter, or colloid nodule with acute hemorrhage, and various inflammatory disorders including acute, subacute, and Hashimoto’s thyroiditis. Early Diagnosis It is important to diagnose PTL at an early stage. A German study showed that non-Hodgkin’s lymphomas with a low-grade histology can, over time, undergo transformation into high-grade tumors (62). In one large study from Japan (65), the frequency of high-grade PTLs decreased significantly after 1982, which the authors attributed to early diagnosis and therapy. Although the diagnosis is usually made in response to a rapidly enlarging and symptomatic thyroid mass, PTL can sometimes be discovered at an earlier stage by investigating more subtle clues in patients with known Hashimoto’s thyroiditis. PTL should be considered in a patient with Hashimoto’s thyroiditis with a discrete hypofunctional area on 123 I scanning, whether or not there is a palpable nodule (62). PTL also should be suspected when the entire thyroid gland with Hashimoto’s disease or any portion of it enlarges

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Table 1 Indications for Fine-Needle Aspiration or Open Surgical Biopsy in Patients Suspected of Having Thyroid Lymphoma Thyroid mass with Rapid enlargement Hoarseness Laryngeal paralysis Dysphagia Stridor Dyspnea Pain Hashimoto’s thyroiditis Hypofunctional (cold) nodule Hypofunctional area on scan without nodule goiter or nodule enlargement despite thyroid hormone therapy Monoclonal gammopathy Source: From Ref. 62.

during thyroid hormone therapy or when palpable cervical or supraclavicular lymph nodes develop. Routine Laboratory Studies Serum Chemistries and Immunoglobulins Routine serum chemistries and hematologic studies are usually normal. The serum immunoglobulins are occasionally abnormal, showing a monoclonal gammopathy, and—very rarely—the bone marrow is involved by lymphoma (62). Thyroid Tests Thyroid function testing may disclose subclinical or overt hypothyroidism, and serum antimicrosomal and antithyroglobulin antibodies are often positive. FNA Biopsy Selection of Patients FNA should be considered in patients with features summarized in Table 1 (62). A diagnosis of lymphoma may be established by FNA cytology or by open surgical biopsy. Immunophenotyping with flow cytometry or Southern blot analysis for lymphocytic clones may also be helpful (66). Imaging Studies Timing of Studies Thyroid imaging done with radionuclides, CT scan, MRI, and ultrasonography usually demonstrate nonspecific abnormalities and are not first-line tests. However, once the diagnosis is established by FNA, imaging is useful in defining the extent of disease.

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Ultrasonography PTL usually appears as a well-delineated hypoechoic sold mass intermingled with echogenic structures. It is easily distinguishable from the surrounding thyroid tissue even though the latter often shows low echogenicity and nodularity due to coexisting Hashimoto’s thyroiditis. Most PTLs are discrete solid nodules in a diffuse goiter. Ultrasonography may disclose contiguous tumor spread into both thyroid lobes and is sensitive in detecting cervical lymph nodes. It is an important adjunct to physical examination that is useful both on initial evaluation with FNA and in follow-up. Computed Tomography PTL usually is manifest as one or more areas of low thyroid density. CT scan appearances are of three types: solitary nodules (80%), multiple nodules (13%), and diffuse goiter (7%) (62). Both lobes are usually involved with advanced disease. The tumors have a strong tendency to compress (80%) or infiltrate (53%) surrounding structures and less often show calcification (7%) and necrosis (7%) (62). Lymphomas often completely encircle the trachea, which is a characteristic feature of malignancy sometimes termed the “donut sign.” although CT scan and ultrasonography are both highly sensitive in detecting thyroidal abnormalities caused by lymphoma, CT scan is better at demarcating intrathoracic tumor extension and laryngeal invasion and is the preferred radiologic technique for staging (62). Magnetic Resonance Imaging Lymphomas appear as homogeneous iso- or high-intensity areas on T1-weighted images compared with uninvolved thyroid tissue, which appears homogeneously high-intensity on T2-weighted images (62). The distinction between tumor and uninvolved thyroid gland is sometimes more apparent by MRI than CT scan, but the two are comparable in identifying extrathyroidal extension, and cervical lymphadenopathy and in staging of lymphoma (67). Hashimoto’s thyroiditis often shows homogeneous signal intensities on MRI that are indistinguishable from those of lymphoma. Radionuclide Scanning Various radionuclides, including compounds labeled with radioactive iodine, 201 Tl, Ga, 111 In-octreotide, FDG-PET, MIBG, and 99m Tc may be used to study patients with PTL, but none is specific for the diagnosis. Lymphoma appears as a hypofunctional lesion with 123 I or 99m Tc-pertechnetate thyroid scanning. Like 99m Tc-labeled compounds, 201 Tl may demonstrate uptake in PTL. Perhaps the best-studied agent is 67 Ga, which demonstrates uptake not only in malignant lymphoma (86%) but also in anaplastic carcinoma (90%) and other high-grade malignancies (62). 67

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Staging Initial Disease Stage The disease is confined to the thyroid gland (stage IE) in almost half the patients and within regional lymph nodes (stage IIE) in 43% at the time of diagnosis (62). In a study of 245 patients (68), ⬍2% had disease outside of regional lymph nodes when they presented, but 10 eventually developed involvements of bone marrow, retroperitoneal nodes, and other tissues outside the neck. Gastrointestinal Lymphoma Although opinions differ, some suggest that there is an association between PTL and gastrointestinal lymphomas. Among the approximately 500 cases of PTL reported from the mid-1930s to 1986, gastrointestinal involvement was found in 62% of those dying with metastatic PTL—a frequency more than twofold greater than that reported for all non-Hodgkin’s lymphomas (69). Accordingly, gastrointestinal infiltration by PTL does not appear to occur by serendipity, which poses certain practical questions regarding the initial staging evaluation of patients with thyroid lymphoma. Staging Workup Since site-directed radiation alone is often used for lymphoma, accurate staging of the disease is important, although there is little agreement regarding the extent of staging evaluation (62). We believe that all patients should have a complete blood count, blood chemistries, and chest roentgenogram in addition to studies to investigate the extent of local disease, including regional lymph node involvement and tumor extension into surrounding neck structures and disease in the chest and abdomen. Thyroid ultrasonography may be helpful but CT scan or MRI of the neck, chest, and abdomen should be done routinely. Whether a bone marrow examination should be done in every patient is even less certain. Several studies suggest that almost no patients with PTL have bone marrow involvement, and they conclude that such an examination is usually unnecessary (62,70). There is also lack of consensus about gastrointestinal evaluation, and at our institution dedicated gastrointestinal studies are not done routinely. Others routinely examine the gastrointestinal tract in almost all patients with PTL, although when this was done in one study only 2.5% had stage IV disease (65). Prognostic Features Long-Term Survival Five-year survival with PTL was almost 60% in 368 patients reported in seven large series (62). However, survival is dependent upon several variables, particularly tumor stage and grade.

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Stage In a large study in 1966 from the Mayo Clinic (71), when tumor was limited to the thyroid (stage IE), only one death occurred; however, involvement of local lymph nodes (stage IIE) or infiltration of adjacent soft tissues reduced average survival rate to only 18 months. A more recent study (72) found 5-year survival rates were 91% in stage IE and only 62% in stage IIE patients. Over the past several decades, 5-year survival rates have been at least 75% to 100% when tumor is confined to the thyroid compared with only 35% to 60% when it is outside the gland (62,73,74). Tumor Grade In one study (65), 5-year survival rates were 92% for patients with low-grade lymphomas, 79% for intermediate-grade lymphomas, and 13% for immunoblastic type (high-grade) tumors. Other Prognostic Factors Reported favorable prognostic factors include longer duration (⬎six months) of goiter, age ⬍60 years at the time of diagnosis, goiter smaller than 10 cm, and preexisting Hashimoto’s thyroiditis (65). Reported negative prognostic factors include large tumor size and fixation, extracapsular extension, retrosternal involvement, large-cell lymphoma, unresectable tumor, possibly male sex, advanced age (⬎65), hoarseness, stridor, hepatosplenomegaly, and axillary lymph nodes (73,75,76). Therapy Treatment is not standard because large, randomized, multicenter trials for this uncommon disorder have not yet been done. Although external radiation has become the treatment of choice in many centers, controversy exists about the optimal extent of surgery and the use of chemotherapy. Although survival has improved over the past few decades, it is not clear which factors are responsible. There are indications that PTL is being diagnosed at an earlier stage and at a lower grade, that adequate staging is being performed more regularly, and that radiation therapy is being used in nearly all cases (62). Surgery Some (70) report stated that patients undergoing total macroscopic tumor removal fare considerably better than those with persistent tumor after surgery; 5-year survival rates in the two groups, respectively, were approximately 65% and 22%. Similar results were reported from the Mayo Clinic (75), where 5-year survival rates were lower (49 vs. 75%) when patients had obvious residual disease postoperatively. Perhaps the least controversial reasons for surgery are for diagnosis and tumor staging and to relieve airway obstruction. Since the cytologic diagnosis of lymphoma may be difficult to establish with certainty by FNA, open biopsy may be necessary. In our institution, this is frequently the case, and surgeons excise as

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much malignant tissue as possible without performing radical surgery. In addition, a tracheostomy is done if there is any question about the integrity of the airway. Airway Protection Patients commonly present with a rapidly enlarging thyroid mass. On occasion— and sometimes with striking swiftness—this leads to severe tracheal compression with respiratory distress that may necessitate emergency surgery (62). This complication should be anticipated and an elective tracheostomy performed whenever airway compromise is a possibility, because death from laryngeal obstruction can occur in the immediate postoperative period or later with uncontrolled disease (62). Almost 25% of the patients in a large series from the Mayo Clinic (77) required an elective tracheostomy; however, there was a 10% rate of infection, sepsis, or bleeding. Radiotherapy This therapy is employed in most centers, especially for patients with stage IE or IIE thyroid lymphoma. Control of disease in the neck is related both to radiation dosage and selection of radiation fields and may also be dependent upon the degree of surgical debulking prior to radiotherapy. The thyroid, bilateral neck, and mediastinum are treated with at least 40 Gy (4000 rad) given in divided doses over four to five weeks (62). There are differences of opinion, however, concerning the radiation fields with some (70) recommending radiation only to the neck and others (75) advocating irradiation of the axilla and mediastinum. One group (75) achieved a 59% disease-free survival with about 40 (24–60) Gy in 38 patients, most of whom had intermediate grade histology and stage IE or IIE disease. None experienced substantial side effects. Despite important differences in patient cohorts and radiation techniques, overall 5-year survival rates range from 55% to 70% following external radiation given either alone or with surgery (62). Results are best for patients with stage IE and IIE disease. For example, one group (72) reported 5-year survival rates of 91% in patients with stage IE disease who were treated with 40 Gy. Chemotherapy Although chemotherapy is often used as salvage therapy, PTL recurrence rates as high as 50% and the predominance of diffuse histiocytic lymphoma (which responds particularly well to chemotherapy) have led some to propose using chemotherapy either alone or as an adjuvant to surgery or radiotherapy in most patients (62). Others recommend chemotherapy only for patients with poor prognostic factors (62). Most chemotherapy regimens consist of cyclophosphamide, adriamycin, vincristine, and prednisone, with or without bleomycin (CHOP ± bleomycin) or minor alterations of this combination (62). A review of the published literature suggests that the addition of chemotherapy to radiation significantly lowered distant and overall recurrence (78).

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Failure Patterns Recurrence rates vary dramatically among various series because authors do not always explicitly distinguish between persistent and recurrent disease, but most (75%) recurrences are detected within the first year following therapy and commonly involve lymph nodes (68,75,79). The gastrointestinal tract, lung, liver, pancreas, and kidney are much less frequently involved. Local Disease Failure Local disease failure usually occurs in 25% to 35% of patients after 40 Gy of external radiation, although results vary (62,70,72,78). The rate of local failure is related to the amount of residual disease after initial thyroidectomy and to the placement of the radiation fields and the use of chemotherapy. One study (75) reported no failures within the treatment fields in patients without residual disease when radiation therapy was started, but otherwise there were twice as many failures following radiotherapy to the neck alone compared with radiotherapy to both the neck and mediastinum (60 vs. 36%). Distant Recurrence Distant recurrences occur to lung, gastrointestinal tract, liver, central nervous system, and kidneys. One study (68) of 245 patients found that the gastrointestinal tract was infrequently involved, but others (69) reported its involvement in 62% of patients dying with metastatic thyroid lymphoma. An autopsy study (80) found the most common sites of involvement were the gastrointestinal tract (100%), lung and kidney (each 63%), and liver and pancreas (each 50%). Survival Following Relapse Salvage therapy has little impact upon the disease once relapse occurs (62). One group (70) reported that disease-free survival was almost identical to overall actual survival, emphasizing the poor response of recurrent disease to therapy. Another study (79) reported an eight month (1–21 months) mean survival in six patients following relapse. REFERENCES 1. Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985–1995. Cancer 1998; 83:2638–2648. 2. Sizemore GW. Medullary carcinoma of the thyroid gland. Semin Oncol 1987; 14:306– 314. 3. Mulligan LM, Kwok JBJ, Healey CS, et al. Germ-line mutations of the RET protooncogene in multiple endocrine neoplasia type 2A. Nature 1993; 363:458–460. 4. Brandi ML, Gagel RF, Angeli A, et al. CONSENSUS: Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2. J Clin Endocrinol Metab 2001; 86(12):5658– 5671.

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5. Verga U, Fugazzola L, Cambiaghi S, et al. Frequent association between MEN 2A and cutaneous lichen amyloidosis. Clin Endocrinol (Oxf) 2003; 59(2):156–161. 6. Eng C. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschprung’s disease. N Engl J Med 1996; 335:943–951. 7. Raue F, Zink A. Clinical features of multiple endocrine neoplasia type 1 and type 2. Horm Res 1992; 38(suppl 2):31–35. 8. Gagel RF, Robinson MF, Donovan DT, et al. Medullary thyroid carcinoma: Recent progress. J Clin Endocrinol Metab 1993; 76:809–814. 9. Eng C, Clayton D, Schufenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET mutation consortium analysis. JAMA 1996; 276:1575– 1579. 10. Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003; 349(16):1517–1525. 11. Howe JR, Norton JA, Wells SA Jr. Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: Results of long-term followup. Surgery 1993; 114:1070–1077. 12. Machens A, Brauckhoff M, Holzhausen HJ, et al. Codon-Specific Development of Pheochromocytoma in Multiple Endocrine Neoplasia Type 2. J Clin Endocrinol Metab 2005; 90(7):3999–4003. 13. Gimm O, Neuberg DS, Marsh DJ, et al. Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene 1999; 18:1369–1373. 14. Russo D, Arturi F, Chiefari E, et al. A case of metastatic medullary thyroid carcinoma: Early identification before surgery of an RET proto-oncogene somatic mutation in fine-needle aspirate specimens. J Clin Endocrinol Metab 1997; 82:3378–3382. 15. Elisei R, Cosci B, Romei C, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: A 10 years follow up study. J Clin Endocrinol Metab 2008; 93(3):682–687. 16. Mendelsohn G. Markers as prognostic indicators in medullary thyroid carcinoma. Am J Clin Pathol 1991; 95:297–298. 17. Elisei R, Bottici V, Luchetti F, et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: Experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab 2004; 89(1):163–168. 18. Cooper DS, Doherty GM, Haugen BR, et al. Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2006; 16(2):109– 141. 19. Cohen R, Buchsenschutz B, Estrade P, et al. Causes of death in patients suffering from medullary thyroid carcinoma: Report of 119 cases. Presse Med 1996; 25:1819–1822. 20. Dottorini ME, Assi A, Sironi M, et al. Multivariate analysis of patients with medullary thyroid carcinoma—Prognostic significance and impact on treatment of clinical and pathologic variables. Cancer 1996; 77:1556–1565. 21. Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: Results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a calcitonine. Clin Endocrinol (Oxf) 1998; 48(3):265–273. 22. Wells SA, Baylin SB, Leight Geal. The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Ann Surg 1982; 195:204.

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23. Lips CJM, Landsvater RM, H¨oppener JWM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994; 331:828–835. 24. Iler MA, King DR, Ginn-Pease ME, et al. Multiple endocrine neoplasia type 2A: A 25-year review. J Pediatr Surg 1999; 34:92–96. 25. Dralle H, Gimm O, Simon D, et al. Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg 1998; 22:744–751. 26. Moley JF, DeBenedetti MK, Dilley WG, et al. Surgical management of patients with persistent or recurrent medullary thyroid cancer. J Intern Med 1998; 243:521–526. 27. Chen HB, Roberts JR, Ball DW, et al. Effective long-term palliation of symptomatic, incurable metastatic medullary thyroid cancer by operative resection. Ann Surg 1998; 227:887–893. 28. Fromigue J, De Baere T, Baudin E, et al. Chemoembolization for liver metastaes from medullary thyroid carcinoma. J Clin Endocrinol Metab 2006; 91(7):2496–2499. 29. Frank-Raue K, Ziegler R, Raue F. The use of octreotide in the treatment of medullary thyroid carcinoma. Horm Metab Res 1993; 27(suppl):44–47. 30. Machens A, Behrmann C, Dralle H. Chemoembolization of liver metastases from medullary thyroid carcinoma. Ann Intern Med 2000; 132(7):596–597. 31. de Groot JW, Zonnenberg BA, Quarles vU-M, et al. A phase-II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab 2007; 92(9):3466–3469. 32. Frank-Raue K, Fabel M, Delorme S, et al. Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. Eur J Endocrinol 2007; 157(2):215–220. 33. Giraudet AL, Vanel D, Leboulleux S, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab 2007; 92(11):4185– 4190. 34. Laure GA, Al Ghulzan A, Auperin A, et al. Progression of medullary thyroid carcinoma: Assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol 2008; 158(2):239–246. 35. Skinner MA, DeBenedetti MK, Moley JF, et al. Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 1996; 31:177–182. 36. Wells SA Jr, Skinner MA. Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Exp Clin Endocrinol Diabetes 1998; 106:29–34. 37. Mazzaferri EL. Undifferentiated thyroid carcinoma and unusual thyroid malignancies. In: Mazzaferri EL, Samaan N, eds. Endocrine Tumors. Boston, MA: Blackwell Scientific Publishing Co., 1993:378–398. 38. Belfiore A, La Rosa GL, Padova G, et al. The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine-deficient area. Cancer 1987; 60:3096–3102. 39. Wallin G, Backdahl M, Tallroth E, et al. Co-existent anaplastic and well differentiated thyroid carcinomas: A nuclear DNA study. Eur J Surg Oncol 1989; 15:43–48. 40. Mooradian AD, Allam CK, Khalil MF, et al. Anaplastic transformation of thyroid cancer: Report of two cases and review of the literature. J Surg Oncol 1983; 23:95–98. 41. Aldinger KA, Samaan NA, Ibanez ML, et al. Anaplastic carcinoma of the thyroid: A review of 84 cases of spindle and giant cell carcinoma of the thyroid. Cancer 1978; 41:2267–2275.

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42. Carcangiu ML, Steeper T, Zampi G, et al. Anaplastic thyroid carcinoma. A study of 70 cases. Am J Clin Pathol 1985; 83:135–158. 43. LiVolsi VA, Brooks JJ, Arendash Durand B. Anaplastic thyroid tumors. Immunohistology. Am J Clin Pathol 1987; 87:434–442. 44. Fagin JA, Matsuo K, Karmakar A, et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 1993; 91:179– 184. 45. Venkatesh YS, Ordonez NG, Schultz PN, et al. Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Cancer 1990; 66:321–330. 46. Nel CJ, van Heerden JA, Goellner JR, et al. Anaplastic carcinoma of the thyroid: A clinicopathologic study of 82 cases. Mayo Clin Proc 1985; 60:51–58. 47. Higashi T, Ito K, Mimura T, et al. Clinical evaluation of 67 Ga scanning in the diagnosis of anaplastic carcinoma and malignant lymphoma of the thyroid. Radiology 1981; 141:491–497. 48. Takashima S, Morimoto S, Ikezoe J, et al. CT evaluation of anaplastic thyroid carcinoma. AJNR 1990; 11:361–367. 49. Woolner LB, Beahrs OH, Black BM, et al. Classification and prognosis of thyroid carcinoma. Am J Surg 1961; 102:354–387. 50. Kebebew E, Greenspan FS, Clark OH, et al. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 2005; 103(7):1330–1335. 51. Tallroth E, Wallin G, Lundell G, et al. Multimodality treatment in anaplastic giant cell thyroid carcinoma. Cancer 1987; 60:1428–1431. 52. Asakawa H, Kobayashi T, Komoike Y, et al. Chemosensitivity of anaplastic thyroid carcinoma and poorly differentiated thyroid carcinoma. Anticancer Res 1997; 17:2757–2762. 53. Lu WT, Lin JD, Huang HS, et al. Does surgery improve the survival of patients with advanced anaplastic thyroid carcinoma? Otolaryngol Head Neck Surg 1998; 118:728–731. 54. Mitchell G, Huddart R, Harmer C. Phase II evaluation of high dose accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 1999; 50:33–38. 55. Tennvall J, Lundell G, Hallquist A, et al. Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma: Report on two protocols. Cancer 1994; 74:1348–1354. 56. Ribechini A, Bottici V, Chella A, et al. Interventional bronchoscopy in the treatment of tracheal obstruction secondary to advanced thyroid cancer. J Endocrinol Invest 2006; 29(2):131–135. 57. Simpson WJ. Anaplastic thyroid carcinoma: A new approach. Can J Surg 1980; 23:25–27. 58. Ahuja S, Ernst H. Chemotherapy of thyroid carcinoma. J Endocrinol Invest 1987; 10:303–310. 59. Kim JH, Leeper RD. Treatment of anaplastic giant and spindle cell carcinoma of the thyroid gland with combination Adriamycin and radiation therapy. A new approach. Cancer 1983; 52:954–957. 60. Tennvall J, Tallroth E, el Hassan A, et al. Anaplastic thyroid carcinoma. Doxorubicin, hyperfractionated radiotherapy and surgery. Acta Oncol 1990; 29:1025–1028. 61. Schlumberger M, Parmentier C, Delisle MJ, et al. Combination therapy for anaplastic giant cell thyroid carcinoma. Cancer 1991; 67:564–566.

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62. Mazzaferri EL, Oertel YC. Primary malignant lymphoma and related lymphoproliferative disorders. In: Mazzaferri EL, Samaan N, eds. Endocrine Tumors. Boston, MA: Blackwell Scientific Publishing, 1993:348–377. 63. Holm LE, Blomgren H, Lowenhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med 1985; 312:601–606. 64. Kato I, Tajima K, Suchi T. Chronic thyroiditis as a risk factor of B-cell lymphoma in the thyroid gland. Jpn J Cancer Res (Amsterdam) 1985; 76:1085–1090.1985. 65. Aozasa K, Inoue A, Tajima K, et al. Malignant lymphomas of the thyroid gland. Analysis of 79 patients with emphasis on histologic prognostic factors. Cancer 1986; 58:100–104. 66. Wozniak R, Beckwith L, Ratech H, et al. Maltoma of the thyroid in a man with Hashimoto’s thyroiditis. J Clin Endocrinol Metab 1999; 84:1206–1209. 67. Takashima S, Nomura N, Noguchi Y, et al. Primary thyroid lymphoma: Evaluation with US, CT, and MRI. J Comput Assist Tomogr 1995; 19:282–288. 68. Compagno J, Oertel JE. Malignant lymphoma and other lymphoproliferative disorders of the thyroid gland. A clinicopathologic study of 245 cases. Am J Clin Pathol 1980; 74:1–11. 69. Stone CW, Slease RB, Brubaker D, et al. Thyroid lymphoma with gastrointestinal involvement: Report of three cases. Am J Hematol 1986; 21:357–365. 70. Tupchong L, Hughes F, Harmer CL. Primary lymphoma of the thyroid: Clinical features, prognostic factors, and results of treatment. Int J Radiat Oncol Biol Phys 1986; 12:1813–1821. 71. Woolner LB, McConahey WM, Beahrs OH, et al. Primary malignant lymphoma of the thyroid: Review of forty-six cases. Am J Surg 1966; 111:502–523. 72. Vigliotti A, Kong JS, Fuller LM, et al. Thyroid lymphomas stages IE and IIE: Comparative results for radiotherapy only, combination chemotherapy only, and multimodality treatment. Int J Radiat Oncol Biol Phys 1986; 12:1807–1812. 73. Pedersen RK, Pedersen NT. Primary non-Hodgkin’s lymphoma of the thyroid gland: A population based study. Histopathology 1996; 28:25–32. 74. Sasai K, Yamabe H, Haga H, et al. Non-Hodgkin’s lymphoma of the thyroid – A clinical study of twenty-two cases. Acta Oncol 1996; 35:457–462. 75. Blair TJ, Evans RG, Buskirk SJ, et al. Radiotherapeutic management of primary thyroid lymphoma. Int J Radiat Oncol Biol Phys 1985; 11:365–370. 76. Shaw JH, Dodds P. Carcinoma of the thyroid gland in Auckland, New Zealand. Surg Gynecol Obstet 1990; 171:27–32. 77. Devine RM, Edis AJ, Banks PM. Primary lymphoma of the thyroid: A review of the Mayo Clinic experience through 1978. World J Surg 1981; 5:33–38. 78. Doria R, Jekel JF, Cooper DL. Thyroid lymphoma: The case for combined modality therapy. Cancer 1994; 73:200–206. 79. Makepeace AR, Fermont DC, Bennett MH. Non-Hodgkin’s lymphoma of the thyroid. Clin Radiol 1987; 38:277–281. 80. Souhami L, Simpson J, Carruthers JS. Malignant lymphoma of the thyroid gland. Int J Radiat Oncol Biol Phys 1980; 6:1143–1147.

8 Pediatric Thyroid Disorders Rosalind S. Brown Harvard Medical School, Boston, Massachusetts, U.S.A.

INTRODUCTION Because of the important maturational effects of thyroid hormone, abnormalities in thyroid function in the pediatric age range may have profound effects on linear growth and skeletal development. In addition, both hypothyroidism and hyperthyroidism in infants and children younger than 3 years can cause permanent cognitive deficits, reflecting the pivotal role of thyroid hormone on brain development at this time. The practitioner caring for infants and children with thyroid disorders should be familiar with these unique aspects of the growing child, and also with differences in clinical presentation, etiology, consequences, and treatment of thyroid disease in the pediatric age range.

MATURATION OF THYROID FUNCTION AND REGULATION Thyroid Gland Development The thyroid gland is derived from the fusion of a medial out-pouching from the floor of the primitive pharynx, the precursor of the T4-producing follicular cells, and bilateral evaginations of the fourth pharyngeal pouch, which give rise to the parafollicular or calcitonin (C-) secreting cells. Commitment toward a thyroid-specific phenotype as well as the growth and descent of the thyroid anlage into the neck results from the coordinate action of a number of transcription factors, including thyroid transcription factor (TTF) 1 (also called TTF1, Nkx2-1, or T/ebp), TTF2 (also called FOXE1), and PAX8 (1). When the pharyngeal region 331

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The timing of fetal thyroid gland organogenesis and function Fetus partially dependent on maternal T4 Maturation of hypothalamic-pituitary axis Increasing thyroid sensitivity to TSH Increasing TSH accompanied by ↑T4,fT4,TBG

T4, T3,TSH levels low

Embryogenesis and descent of thyroid

T3 remains low, rT3 high

rT3 high 10

20

30

40

Weeks gestation Figure 1 The timing of fetal thyroid gland organogenesis and function. See text for details. Abbreviations: T4, thyroxine; T3, triiodothyronine; TSH, thyrotropin; fT4, free T4; rT3, reverse T3.

of the thyroid anlage contracts, a narrow stalk, known as the thyroglossal duct, remains and subsequently atrophies. Usually the median anlage grows caudally so that no lumen is left in the tract of its descent. An ectopic thyroid and persistent thyroglossal duct or cyst form as a consequence of abnormalities of the thyroid descent. Caudal migration of the thyroid anlage is also related to the descent of the heart and great vessels (2).

Fetal Thyroid Function Embryogenesis is largely complete by 10 to 12 weeks gestation (Fig. 1). At this stage, tiny follicle precursors are first seen, thyroglobulin (Tg) can be detected in follicular spaces, and evidence of iodine uptake and organification is first obtained. Low concentrations of thyroxine (T4) and triiodothyronine (T3) are detectable in fetal serum at 10 to 12 weeks (3), although it is likely that a fraction of the thyroid hormone measurable at this early stage of development is maternal in origin (4). Thyrotropin (TSH), first detectable in fetal serum at 12 weeks’ gestation, increases from 18 weeks to term. This is accompanied by an increase in fetal thyroid radioiodine uptake and a progressive increase in the serum concentrations of both total T4 and free T4 (5). Pituitary responsiveness to both feedback inhibition and to stimulation by thyrotropin releasing hormone (TRH) is observed by the end of the second trimester.

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The maturation of fetal thyroid function in the second half of pregnancy is due not only to increasing pituitary maturation and secretion of TSH, but to the concomitant appearance and increasing expression of the TSH receptor, which enables the fetal thyroid to respond (6). Thus, there is a progressive increase in the ratio of free T4 to TSH that rises out of proportion to the increase in total T4 to TSH ratio, strongly suggesting that there is a change in the thyroid follicular cell sensitivity to TSH. The increase in total T4 is also due to an increase in thyroxine binding globulin (TBG) as the liver matures. Fetal T4 metabolism differs markedly from that of postnatal life. Activity of Type 1 deiodinase (D1), the major activating deiodinase that converts T4 to T3, is low throughout gestation. In contrast, D3, the major inactivating deiodinase that converts T4 to reverse T3, a metabolically inactive compound, is highly expressed in fetal tissues and in the placenta. As a result, circulating T3 concentrations in the fetus are low, but reverse T3 and sulfated conjugates of T4 are markedly elevated (5). Similarly, D2, an activating deiodinase that converts T4 to T3, is highly expressed in fetal brain and pituitary as early as mid-gestation. As a consequence, fetal brain T3 levels are 60% to 80% those of the adult by fetal age 20 to 26 weeks, despite the low levels of circulating T3 (7). In the presence of fetal hypothyroidism, D2 increases while D3 decreases. These coordinate adjustments are of critical importance and serve to preserve near-normal brain T3 levels providing that maternal T4 levels are maintained at normal levels (8). The Role of the Placenta and of Maternal T4 Under normal circumstances, the placenta has only limited permeability to T4 and the fetal hypothalamic-pituitary-thyroid system develops relatively independently of maternal influence. This relative barrier to thyroid hormone transport results primarily from the high placental content of D3, which serves to inactivate most of the thyroid hormone presented from the maternal circulation. The iodide released in this way can then be used for fetal thyroid hormone synthesis. When a significant T4 gradient between the maternal and fetal compartment exists, however, there is an increased net flux of maternal thyroid hormone to the fetus. Thus, babies with severe congenital hypothyroidism (CH) nonetheless have cord T4 concentrations between 25% and 50% of normal (9). Maternal-fetal T4 transfer is also thought to be important in the first half of pregnancy before the onset of mature fetal thyroid function (4). The transplacental passage of maternal T4, coupled with the adjustments in brain deiodinase activity discussed earlier, plays a critical role in minimizing the adverse effects of fetal hypothyroidism. Not only may it help to explain the normal or near-normal cognitive outcome of hypothyroid fetuses as long as postnatal treatment is early and adequate, it may also provide a partial explanation of the relatively normal clinical appearance at birth of over 90% of infants with CH. In contrast, when both maternal and fetal hypothyroidism occurs, patients are symptomatic at birth and there is a significant impairment in neuro-intellectual

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development despite the initiation of early and adequate postnatal thyroid replacement (10). Isolated maternal hypothyroidism and/or hypothyroxinemia have also been reported to cause significant cognitive and/or motor delay in the offspring, although the magnitude of the deficit is not as great as when both fetal and maternal hypothyroidism are present (11,12). Other Hormones and Factors In contrast to thyroid hormone, the placenta is freely permeable to TRH and to iodide, the latter being essential for fetal thyroid hormone synthesis (13). The placenta is also permeable to certain drugs and to immunoglobulins of the immunoglobulin (Ig)G class. Thus, the administration to the mother of excess iodide, certain drugs [especially propylthiouracil (PTU) or methimazole (MMI)] or the transplacental passage of TSH receptor Abs from mothers with severe Graves’ disease or primary myxedema may have significant effects on fetal and neonatal thyroid function. On the other hand, maternal TSH does not cross the placenta. Similarly, Tg is undetectable in the serum of athyreotic infants, indicating the absence of any transplacental passage of this large protein. Neonatal Thyroid Function Within minutes after birth, a dramatic release of TSH occurs in the newborn infant, reaching peak levels at 30 minutes of age and persisting with decreasing intensity for the next 6 to 24 hours (3). The acute increase of TSH may be stimulated in part by the drop in body temperature of the fetus at birth. In response to the early postnatal TSH surge, T4, free T4, and T3 levels increase progressively during the first hours of extrauterine life and peak by 48 hours. The marked increase in T3 is not only due to the increase in TSH but also due to the maturation of D1 activity and the loss of placental D3 at the time of delivery. In contrast, the elevated concentrations of the other substrates of D1, reverse T3 and T3 sulfate, decrease relatively rapidly during the newborn period. Thyroid Function in Premature Infants Thyroid function in the premature infant reflects the relative immaturity of the hypothalamic-pituitary-thyroid axis found in comparable gestational age infants in utero. Following delivery, there is a surge of T4 and TSH analogous to that observed in term infants, but the magnitude of the increase is less. In very premature babies (≤30 weeks, approximately equivalent to 1.5 kg), there may be a fall rather than an increase in the T4 concentration over the first 1 to 2 weeks of life (14). Reasons for this fall in total T4 include the clearance of maternal T4 from the neonatal circulation, relatively immature hypothalamic-pituitary axes, decreased thyroidal iodide stores, inability to regulate iodide balance, and increased sensitivity to the thyroid-suppressive effects of excess iodide found in certain skin antiseptics and drugs to which these babies may be exposed. Also, premature infants are frequently

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sicker than their more mature counterparts and may be treated by drugs that affect neonatal thyroid function (particularly dopamine and steroids). In most cases, the total T4 is more affected than the free T4 (15), a consequence of abnormal protein binding and/or the decreased TBG in these babies with immature liver function. Despite the reduced total T4, the TSH concentration is not usually abnormal. The occasional finding of an elevated TSH may reflect true primary hypothyroidism in some cases but probably reflects recovery from the sick euthyroid syndrome in most infants, analogous to the situation in adults who are recovering from severe illness. Infants and Children After the acute perturbations of the neonatal period, there is a slow and progressive decline in the concentrations of T4, free T4, T3, and TSH during infancy and childhood age- and gender-specific normative values of thyroid function in a large population of infants and children have been published and should be referred to (16–19), although precise values may vary somewhat, depending upon the commercial method employed. Both the serum TSH and T3 concentrations, in particular, tend to be higher in children than in adults, especially in the first 2 years of life. Use of adult values, provided by many hospital laboratories, should be interpreted with caution as it may result in inappropriate concern and referral. The 24-hour thyroidal 123 I uptake is also much greater in the neonate, although similar to adult values after the first month. The T4 turnover rate is also higher and its serum half-life reduced. THYROID DISEASE IN INFANCY Congenital Hypothyroidism CH, that is, hypothyroidism at birth, is the commonest treatable cause of mental retardation. Worldwide, the most common cause of CH is iodine deficiency, a problem that continues to afflict almost one billion people despite international efforts aimed at its eradication. In such cases, CH is endemic (“endemic cretinism”). In iodine-sufficient areas and in areas of borderline iodine deficiency, CH is usually sporadic and occurs in 1 in 3000 to 1 in 4000 infants. Females are affected twice as often as males. In the United States, CH is less frequent in African-Americans and more common among Hispanics and Asians. There is an increased incidence of mild, transient CH in patients with Down syndrome (20). Because optimal outcome treatment must be initiated soon after birth before affected infants are recognizable clinically, neonatal screening programs have been introduced in most industrialized areas of the world. There continues to be some disagreement as to whether minor neuro-intellectual sequelae remain in the most severely affected infants, but there is no doubt that the main objective of screening, the eradication of mental retardation, has been achieved. Newborn screening has also permitted an elucidation of the prevalence of the various causes

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of CH, including a series of transient disorders found predominantly in premature infants. Screening Strategies for CH Three screening strategies for the detection of CH are used. In much of North America, primary T4 screening is performed with TSH reserved for those specimens with a low T4 (usually the lowest 3rd-20th percentile). In other programs, a primary TSH is employed, or, alternately, both T4 and TSH are measured. In practice, the choice of strategy used depends on the preference of the individual screening program. Although measurement of both T4 and TSH is optimal, this approach is more expensive and so most screening programs opt for primary measurement of one or the other analyte. Both primary T4/backup TSH and primary TSH strategies have their advantages and disadvantages, but the two approaches appear to be equivalent in the detection of babies with permanent forms of CH (21). Both strategies will miss the rare infant whose T4 and TSH levels on initial screening are normal but who later develop low T4 and elevated TSH concentrations (“atypical” CH or “delayed TSH rise”) (22). In both strategies there is the possibility of human error in failing to identify affected infants. Newborn screening was performed initially at between three and four days of life, and the normal values that were derived reflected this postnatal age. The practice of early discharge from the hospital of otherwise healthy full-term infants has resulted in a greater proportion of babies being tested before this time. Because of the neonatal TSH surge and the dynamic changes in T4 and T3 concentrations that occur within the first few days of life, early discharge increases the number of false-positive results, particularly in primary TSH screening programs. Another complicating factor is the dramatically increased survival of very premature infants. Causes of CH Thyroid Dysgenesis The causes of permanent nonendemic CH are listed in Table 1. Thyroid dysgenesis is the most common cause, accounting for 85% to 90%. It is almost always a sporadic disease. Thyroid dysgenesis may result in the complete absence of thyroid tissue (agenesis), or it may be partial (hypoplasia); the latter is often accompanied by a failure to descend into the neck (ectopia). Both genetic and environmental factors have been implicated in the etiology of thyroid dysgenesis, but the cause is unknown in most cases. Genetic abnormalities in the transcription factors TTF1, TTF2, and PAX8 have been identified rarely in isolated CH (23,24). Heterozygous deletions of TTF1 have been reported in a few patients with CH, unexplained neonatal respiratory distress, and neurological manifestations (25,26). Usually the CH is mild. Similarly a homozygous missense

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Table 1 Causes of Permanent Congenital Hypothyroidism Primary hypothyroidism Thyroid dysgenesis (agenesis/dysgenesis) -Syndromic -Non syndromic Thyroid dyshormonogenesis -Iodide concentrating defect -Defective organification -Thyroid peroxidase mutation -Abnormal H2 O2 generation -Defective thyroglobulin synthesis or transport TSH resistance Secondary or tertiary hypothyroidism Isolated TSH deficiency -TRH deficiency or resistance -TSH␤ mutation Multiple pituitary hormone deficiencies -Septo-optic dysplasia -Pituitary transcription factor mutation, e.g., PROP1, PIT1

mutation in the TTF2 gene has been associated with the syndrome of thyroid agenesis, bifid epiglottis, cleft palate, kinky hair, and choanal atresia (27). Inborn Errors of Thyroid Hormonogenesis Decreased T4 synthesis due to an inborn error of thyroid hormonogenesis is responsible for most of the remaining cases (10–15%) of permanent CH (24,28). A number of different defects have been characterized and include (1) failure to concentrate iodide, (2) defective organification of iodide due to an abnormality in the thyroid peroxidase (TPO) enzyme or in the H2 O2 generating system, (3) defective Tg synthesis or transport, and (4) abnormal iodotyrosine deiodinase activity. A partial organification defect can also be due to mutations in the gene for pendrin, an iodine transport protein located in the apical border of the thyrocyte (29). Affected patients may have the classical triad of goiter, may have partial organification defect and congenital sensorineural defect, or they may have congenital sensorineural deafness alone. Thyroid function is usually not affected in the newborn period. All the inborn errors of thyroid hormonogenesis are associated with a normally placed thyroid gland of normal or increased size, and this feature forms the basis for the clinical distinction from thyroid dysgenesis. Unlike thyroid dysgenesis, a sporadic condition, the inborn errors of thyroid hormonogenesis tend to have an autosomal-recessive form of inheritance, consistent with a single gene mutation. It is not surprising, therefore, that a molecular basis for many of these abnormalities has now been identified.

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TSH Resistance Decreased T4 synthesis resulting from resistance to the action of TSH is a rare cause of CH. Babies with this abnormality have a normal or hypoplastic gland in the normal location in the neck; in rare cases, no thyroid gland at all is discernible on thyroid imaging. TSH resistance may be caused by a loss of function mutation of the TSH receptor and is usually autosomal recessive (30,31). In other patients with TSH resistance, a postreceptor defect has been hypothesized. Rarely, TSH resistance may result from an inactivating mutation of the stimulatory guanine nucleotide-binding protein (GSa) gene (Albright’s hereditary osteodystrophy). The hypothyroidism at birth is usually mild. Decreased TSH Synthesis or Secretion CH resulting from TSH deficiency is only detected by newborn screening programs that use a primary T4 strategy; the reported incidence is 1 in 50,000 to 1 in 100,000. TSH deficiency may be isolated, or, more commonly, it is associated with other pituitary hormone deficiencies. Reported causes of isolated TSH deficiency have included to an abnormality in TSH␤, TRH deficiency, and TRH resistance. Congenital hypopituitarism is suggested by the presence of additional clinical features, such as hypoglycemia, microphallus, abnormal midline facial and brain structures, and/or nystagmus. An important cause of congenital hypopituitarism is septo-optic dysplasia (De Morsier syndrome); abnormalities in PIT-1, PROP-1, and TTFs important in pituitary gland development may also cause congenital hypopituitarism. Abnormal T4 Action Abnormal T4 action (thyroid hormone resistance) can result from a mutation in the T4 receptor or in a postreceptor signaling abnormality. Affected babies usually do not present in the newborn period. A novel, recently described, cause of abnormal T4 action is a mutation in the MCT8 thyroid hormone transporter, which is essential for the transport of T4 into the cell (32). Transient Congenital Hypothyroidism The true frequency of transient CH is unknown but is probably greater than the earlier estimate of 10% of babies detected on newborn screening in view of the greater incidence and survival of increasingly premature infants in recent years. The most common causes of transient neonatal hypothyroidism are iodine deficiency or excess, maternal antithyroid medication, and maternal TSH receptor blocking Abs (Table 2). Transient hypothyroidism due to both iodine deficiency and iodine excess is more common in relatively iodine-deficient areas of Europe than in North America, an iodine-sufficient region (33,34). Premature infants are particularly at risk of iodine-induced hypothyroidism, whether administered to the mother during pregnancy or delivery or directly to the baby. Reported sources of iodine

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Table 2 Causes of Other Thyroid Hormone Abnormalities in the Newborn Period Tansient primary hypothyroidism Iodine deficiency or excess Maternal antithyroid drug therapy Maternal TSH receptor–blocking antibodies Transient secondary or tertiary hypothyroidism Drugs (dopamine, steroids) Maternal hyperthyroidism Other Prematurity Illness Undernutrition Isolated hyperthyrotropinemia

have included drugs (e.g., potassium iodide, amiodarone, or radiocontrast agents) and antiseptic solutions (e.g., povidone-iodine) used for skin cleansing or vaginal douches. Transient neonatal hypothyroidism may develop in babies whose mothers are being treated with antithyroid medication for the treatment of Graves’ disease. The fetus appears to be particularly sensitive to the effects of these drugs, even when the dosage used in the mother is within currently recommended guidelines (35). Babies with antithyroid drug-induced hypothyroidism characteristically develop an enlarged thyroid gland. Replacement therapy is usually not required because the hypothyroidism tends to be short lived. Maternal TSH receptor blocking Abs may be transmitted to the fetus in sufficient titer to cause transient CH. Transient CH has been reported most often in babies born to mothers who have been treated earlier for Graves’ disease or who have the nongoitrous form of chronic lymphocytic thyroiditis (CLT) (primary myxedema) (36). Occasionally, these mothers are not aware that they are hypothyroid and the diagnosis is made in them only after CH has been recognized in their infants. Because TSH-induced growth is blocked, these babies do not have a goiter. Affected babies have been misdiagnosed with thyroid agenesis because the blocking Abs inhibit TSH-stimulated radioactive iodine (RAI) uptake. In contrast to findings on scintiscan, a normally placed thyroid gland can be visualized on ultrasound. The hypothyroidism generally resolves in three or four months when Ab is cleared from the neonatal circulation. Unlike babies with thyroid dysgenesis in whom a normal cognitive outcome is found if postnatal therapy is early and adequate, babies with maternal blocking Ab-induced hypothyroidism may have a permanent deficit in intellectual development if feto-maternal hypothyroidism was present in utero (10). Transient central hypothyroidism may be due to drugs (particularly steroids or dopamine) commonly used in the newborn intensive care unit or may be

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observed in neonates born to mothers with Graves’ disease (see later). A low free T4 associated with a normal TSH may also be observed in premature infants whose hypothalamic-pituitary axis is immature and in babies who are sick or undernourished. Other Abnormalities of Thyroid Function Discovered on Newborn Screening Isolated Hyperthyrotropinemia Isolated hyperthyrotropinemia may be detected in screening programs that use a primary TSH method or postnatally, particularly in premature infants. While some of these babies represent cases of “compensated” hypothyroidism, in other instances the etiology is not clear. In one study, babies diagnosed with hyperthyrotropinemia in infancy had a higher serum TSH compared to control children when reexamined in early childhood (37). Also, these infants have a higher prevalence of both thyroid morphological abnormalities, antithyroid antibodies (Abs) and mutations in the thyroperoxidase and TSH receptor genes than do normal babies (38). In other cases, the serum TSH normalized without treatment within the first year of life (39). Clinical Manifestations Clinical evidence of hypothyroidism is usually difficult to appreciate in the newborn period. Many of the classic features (large tongue, hoarse, cry, facial puffiness, umbilical hernia, hypotonia, mottling, cold hands and feet and lethargy) are subtle and develop only with the passage of time (Fig. 2). Nonspecific signs that suggest the diagnosis of CH include prolonged, unconjugated hyperbilirubinemia; gestation longer than 42 weeks; feeding difficulties; delayed passage of stools; hypothermia; or respiratory distress in an infant weighing more than 2.5 kg. A large anterior fontanelle and/or a posterior fontanelle ⬎0.5 cm is frequently present in affected infants, but may not be appreciated. Babies with CH are of normal size at birth. However, if diagnosis is delayed, subsequent linear growth is impaired. The finding of palpable thyroid tissue suggests that the hypothyroidism is due to an abnormality in thyroid hormonogenesis or that it will be transient. Laboratory Evaluation Infants detected by newborn screening should be evaluated without delay, preferably within 24 hours. The diagnosis of primary CH is confirmed by the demonstration of a decreased concentration of free T4 and an elevated TSH level in serum. Most infants with permanent abnormalities of thyroid function have a serum TSH concentration ⬎40 mU/L. A bone age X-ray may be performed as a reflection of the duration and severity of the hypothyroidism in utero. Thyroid imaging provides information about the location and size of the thyroid gland. A radionuclide scan

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Figure 2 Baby with congenital hypothyroidism diagnosed clinically at the age of three months. Baby was born in Puerto Rico prior to the advent of newborn screening and moved to the United States shortly after birth. Note the dull facies and large tongue.

(either 123 I or 99 m pertechnetate) is the classical approach, but ultrasonography, which avoids the potential risk of radiation exposure, is a suitable alternative. Thyroid ultrasound is not as sensitive as scintiscan in identifying ectopic tissue (40) and, unlike 123 I, cannot evaluate iodine transport defects or abnormalities in thyroid oxidation. Nonetheless, it provides information as to whether a normally located thyroid is present, and, therefore, whether the condition is likely to be transient or permanent. It is also helpful in genetic counseling as thyroid dysgenesis is almost always a sporadic condition, whereas abnormalities in thyroid hormonogenesis are usually autosomal recessive. TSH receptor blocking Abs should be measured in babies with a normally located thyroid gland. Autoimmune thyroid disease in the mother or a history of a previously affected sibling should alert the physician to this diagnosis, but such information is not always known. A binding assay (TSH Receptor Abs, TRAbs, or TSH Binding Inhibitory IgGs, TBII, discussed further under Graves’

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Abnormal thyroid screen Serum free T4, TSH, Tg, ultrasound (BA optional) No thyroid visible

Tg nl or ↑

Tg ↓ or ND

Thyroid eutopic

Thyroid ectopic

TSH receptor Abs Positive

Probably ectopic

Probably agenesis

Can confirm with thyroid uptake/scan (optional)

Negative Tg ND or ↓

Blocking AbInduced CH

Tg ↑ or normal

Tg synthetic defect

Trapping defect

TSH insensitivity

Organification defect

Iodine excess

Maternal ATDs

Figure 3 Suggested strategy for the investigation of a child with an abnormal newborn thyroid screen. Abbreviations: Tg, thyroglobulin; ND, not detected; nl, normal; ATDs, antithyroid drugs; CH, congenital hypothyroidism; Ab, antibody.

disease) is appropriate for screening; bioassay can be done later, if desired, to demonstrate the biological action of the Abs, that is, whether it is a stimulating or a blocking antibody. In cases of TSH receptor Ab-induced CH, the blocking activity is extremely potent (36); a weak or borderline result should cause a reconsideration of this diagnosis. TPO Abs, although frequently detectable in babies with blocking Ab-induced CH, are neither sensitive nor specific in predicting the presence of transient CH. Measurement of urinary iodine is helpful if the diagnosis of iodine-induced hypothyroidism is suspected. The serum Tg concentration reflects the amount of thyroid tissue and is low or undetectable in patients with agenesis. It can also be used to distinguish a defect in Tg synthesis or secretion (low serum level) from other causes of thyroid dyshormonogenesis in which a high value is found. In babies in whom hypothyroxinemia unaccompanied by TSH elevation is found, free T4 should be measured, preferably by a direct dialysis method, and the TBG concentration should be evaluated as well. The finding of a low free T4 in the presence of a normal TBG may suggest the diagnosis of secondary or tertiary hypothyroidism, particularly if the patient has a microphallus, hypoglycemia, or a midline facial abnormality. In premature, low birth weight or sick babies in whom a low T4 and “normal” TSH are found, the free T4 when measured by a direct dialysis method is frequently not as low as the total T4 (15). In these infants, T4 (and/or free T4) and TSH should be repeated every one to two

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weeks until the T4 normalizes because of the rare occurrence of delayed TSH rise (22). Thyroid function should also be monitored in other infants at risk of a delayed TSH rise, such as severely ill babies in an intensive care setting (41) and monozygotic twins (42) in whom fetal blood mixing may initially mask the presence of CH. Even though in many ill babies the hypothyroidism will be transient, treatment should be considered if values do not normalize within one to two weeks. In any infant, if signs or symptoms suggestive of hypothyroidism are present, thyroid function testing should be repeated because of the possibility of delayed onset of hypothyroidism and because of rare errors in the screening program. Therapy Replacement therapy with thyroxine should begin as soon as the diagnosis of CH is confirmed (43). Parents should be counseled regarding the causes of CH, the importance of compliance, and the excellent prognosis in most babies if therapy is initiated early. Educational material should be provided. Treatment need not be delayed in anticipation of performing a thyroid scan as long as this is done within before suppression of the serum TSH. Until recently, an initial daily thyroxine dosage of 10 to 15 ␮g/kg (equivalent to 37.5 ␮g in a full-term infant) was recommended to normalize the T4 as soon as possible, but a slightly higher dose (50 ␮g, equivalent to 12–17 ␮g/kg/day), which results in more rapid normalization of the serum T4 and TSH concentrations, may be even better (44). Babies with compensated hypothyroidism may be started on the lower dosage, while those with severe CH (e.g., T4 ⬍ 5 ␮g/dL), such as those with thyroid agenesis, should be started on the higher dosage. Thyroid hormone may be crushed and administered with juice or water, but care should be taken that all the medicine has been swallowed. Medication should be administered at least 30 minutes to an hour before feeding and never with substances that interfere with its absorption, such as iron, soy, or fiber. Many babies will swallow the pills whole or chew the tablets with their gums even before they have teeth. A brand name preparation of levothyroxine is preferred. Liquid preparations are unstable and should be used with caution. If a dose is missed or thought to be missed, a double dose should be given the next day. The aims of therapy are to normalize the serum T4 and TSH as soon as possible preferably within three days and two weeks, respectively. Subsequent adjustments in the dosage of medication are made according to the results of thyroid function tests and the clinical picture. Some infants develop supraphysiological serum T4 values, but the serum T3 concentration usually remains normal, most affected infants are not symptomatic, and these short-term T4 elevations have not been reported to be associated with adverse effects on growth, bony maturation, or cognitive development. Both initial dosage and timing of onset of therapy are independent prognostic variables of cognitive development (45). Combined therapy with T4 and T3 offers no advantage over T4 alone.

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Current recommendations are to repeat T4 and TSH at two and four weeks after the initiation of thyroxine treatment, every 1 to 2 months during the first year of life, every 2 to 3 months between 1 and 3 years of age, and every 3 to 12 months thereafter until growth is complete (43). In hypothyroid babies in whom an organic basis was not established and in whom transient disease is suspected, a trial of replacement therapy can be initiated after the age of three years when most thyroid hormone-dependent brain maturation has occurred. Alternatively, recombinant hTSH may prove to be a suitable alternative to thyroid hormone, although it is not yet FDA approved for use in children (46). Normalization of the TSH concentration may sometimes be delayed because of relative pituitary resistance. In such cases, characterized by a normal or increased serum T4 and an inappropriately high TSH level, the T4 value is used to titrate the dosage of medication, but noncompliance is the most common cause and should be excluded. Whether or not premature infants with hypothyroxinemia should be treated remains controversial and prospective clinical trials are needed (47). At the very least, every effort should be made to avoid the use of iodine and drugs that can suppress thyroid function (e.g., dopamine, steroids) in these infants (48). The initial finding of an 18-point increase in the Bayley Mental Development Index score in T4-treated infants ⬍27 weeks gestation (49) was not sustained when these children were reevaluated at 10 years of age (50). Neonatal Hyperthyroidism Transient Neonatal Hyperthyroidism Unlike CH, which is usually permanent, neonatal hyperthyroidism is almost always transient, secondary to the transplacental passage of maternal TSH receptor-stimulating Abs. Hyperthyroidism develops only in babies born to mothers with the most potent stimulatory activity in serum (51,52), corresponding to 2% to 3% of mothers with Graves’ disease, or 1 in 50,000 newborns. The incidence is approximately four times higher than that for transient neonatal hypothyroidism due to maternal TSH receptor-blocking Abs (36). Both TSH receptor potency, the severity, and duration of in utero hyperthyroidism, and the dose and duration of maternal antithyroid medication are important determinants of neonatal thyroid status. In one study of 230 infants born to mothers with Graves’ disease, 83.5% had normal function while 10% had transient hypothyroidism (7.8% subclinical, 2.2% overt) due to increased fetal sensitivity to the maternally administered antithyroid drugs (ATD). Transient hyperthyroidism was a much less common sequela, occurring in 5.6%, only 2.6% being clinically symptomatic. Transient central hypothyroidism occurred in two infants (0.9%) (53). Rarely, mothers have mixtures of stimulating and blocking Abs in their circulation, resulting in a more complicated clinical picture in the infant (54). It is important to appreciate that neonatal hyperthyroidism may occur in infants born to hypothyroid mothers whose thyroid was destroyed by prior radioablation, surgery, or destructive autoimmune

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processes since in these mothers potent stimulating Abs might still be present but would not be apparent clinically. Iodine-Induced Hyperthyroidism Iodine exposure is a rare cause of transient neonatal hyperthyroidism (55). Clinical Manifestations Although maternal TSH receptor Ab-mediated hyperthyroidism may present in utero, the onset is often toward the end of the first week of life. This is both due to the clearance of maternally administered antithyroid drugs from the infant’s circulation and due to the increased conversion of T4 to T3 after birth. The onset of neonatal hyperthyroidism may be delayed if higher affinity blocking Abs are also present, but this is rare. Fetal hyperthyroidism is suspected in the presence of fetal tachycardia (pulse ⬎160/min), especially if a goiter is seen on ultrasound and if there is evidence for intrauterine growth retardation. In the newborn infant, characteristic signs and symptoms include tachycardia, irritability, poor weight gain, and prominent eyes. Infants may be born prematurely. Goiter may be related to maternal antithyroid drug treatment, to consequent neonatal hypothyroidism, or to neonatal Graves’ disease. Rarely, infants with neonatal Graves’ disease present with thrombocytopenia, hepatosplenomegaly, jaundice, and hypoprothrombinemia, a picture that may be confused with congenital infections. Dysrhythmias and cardiac failure may develop and may cause death, particularly if treatment is delayed or inadequate. In addition to a significant mortality rate that approximates 20% in some older series, untreated fetal and neonatal hyperthyroidism is associated with deleterious long-term consequences, including premature closure of the cranial sutures (cranial synostosis), failure to thrive, and developmental delay (56). The half-life of TSH receptor Abs in the blood is one to two weeks. The duration of neonatal hyperthyroidism, a function of Ab potency and metabolic clearance rate, is usually two to three months, but may be longer. Laboratory Evaluation Because of the importance of early diagnosis and treatment, fetuses and infants at risk for neonatal hyperthyroidism should undergo both clinical and biochemical assessment. A high index of suspicion is necessary in babies of women who have had thyroid ablation because a high titer of TSH receptor Abs would not be evident clinically. Similarly, women with persistently elevated TSH receptor Abs and with a high requirement for antithyroid medication during pregnancy are at an increased risk of having an affected child. The diagnosis of hyperthyroidism is confirmed by the demonstration of an increased concentration of T4, free T4, and T3 accompanied by a suppressed TSH. Fetal ultrasonography may help to detect a goiter and to monitor fetal growth. If necessary, blood can be obtained by fetal umbilical cord catheterization and results

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can be compared with normal values during gestation. Demonstration of a high titer of TSH receptor Abs in the baby or mother will confirm the etiology of the hyperthyroidism, and in babies whose thyroid function testing is normal initially, it indicates the degree to which the baby is at risk. In general, babies likely to become hyperthyroid have the highest TSH receptor Ab titer, whereas, if TSH receptor Abs are not detectable, the baby is most unlikely to become hyperthyroid (57,58). The sensitivity of different TSH receptor Ab assays varies greatly, so specific values that are recommended in the literature should be interpreted with caution. Close follow-up of all babies with abnormal thyroid function tests or detectable TSH receptor Abs is mandatory. Therapy Treatment of the fetus is accomplished by maternal administration of antithyroid medication. The minimal dosage of PTU or MMI necessary to normalize the fetal heart rate and render the mother euthyroid or slightly hyperthyroid is usually chosen. In the neonate, treatment is expectant. Either PTU (5–10 mg/kg/day) in three divided doses or MMI (0.5–1 mg/kg/day) twice a day can be used initially. If the hyperthyroidism is severe, a strong iodine solution (Lugol’s solution or saturated solution of potassium iodine, one drop every eight hours) is added to block the release of thyroid hormone immediately because the effect of PTU and MMI may be delayed for several days. Therapy with both antithyroid drug and iodine is adjusted subsequently, depending on the response. Propranolol (2 mg/kg/day) in two or three divided doses is added if sympathetic overstimulation is severe, particularly in the presence of pronounced tachycardia. If cardiac failure develops, treatment with digoxin should be initiated, and propranolol should be discontinued. Rarely, prednisone (2 mg/kg/day) is added for immediate inhibition of thyroid hormone secretion and is added for decreased generation of T3 from T4 in peripheral tissues. Measurement of TSH receptor Abs in treated babies may be helpful in predicting when antithyroid medication can be safely discontinued. Lactating mothers on antithyroid medication can continue nursing as long as the dosage of PTU or MMI does not exceed 400 mg or 40 mg, respectively. At higher dosages, close supervision of the infant is advisable. Permanent Neonatal Hyperthyroidism Rarely, neonatal hyperthyroidism is permanent and is due to a germline mutation in the TSH receptor, resulting in its constitutive activation (59). A gain-of-function mutation of the TSH receptor should be suspected if persistent neonatal hyperthyroidism occurs in the absence of detectable TSH receptor Abs in the maternal circulation. An autosomal dominant inheritance has been noted in many of these infants, but other cases have been sporadic, arising from a de novo mutation. Early recognition is important because the thyroid function of affected infants is frequently difficult to manage medically (60). When diagnosis and therapy

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Table 3 Causes of Hypothyroidism in Childhood and Adolescence Primary hypothyroidism Primary hypothyroidism Chronic lymphocytic thyroiditis Thyroid dysgenesis or dyshormonogenesis Iodine deficiency/goitrogenes Drugs Miscellaneous -Mantle irradiation -Cystinosis -Histiocytosis X -Mitochondrial disease -Hemangiomas (“consumptive hypothyroidism”) Secondary or tertiary hypothyroidism Brain irradiation/surgery Brain tumor (craniopharyngioma) Congenital hypopituitarism Abnormal thyroid hormone action Thyroid hormone resistance (TR␤ mutation) Abnormal T4 transport (MCT8 mutation)

are delayed, irreversible sequelae, such as cranial synostosis and developmental delay, may result (61). For this reason, early, aggressive therapy with either thyroidectomy or radioablation has been recommended. THYROID DISEASE IN CHILDHOOD AND ADOLESCENCE Hypothyroidism Chronic Lymphocytic Thyroiditis The causes of hypothyroidism after the neonatal period are listed in Table 3. The most frequent cause is CLT, an autoimmune disease that is closely related to Graves’ disease. Both a goitrous (Hashimoto’s disease) and a nongoitrous (primary myxedema) variant of thyroiditis have been distinguished. The disease has a striking predilection for females, and a family history of autoimmune thyroid disease (both CLT and Graves’ disease) is found in 30% to 40% of patients. Adolescence is the most common age at presentation during childhood, but it can occur at any age after the neonatal period, even in infants as young as six months of age (62). Patients with insulin-dependent mellitus have an increased prevalence of CLT. CLT may also occur as part of autoimmune polyglandular syndrome (APS). In APS-1, also called APECED (Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy) syndrome, CLT is found in 10% of patients (63); CLT is much more common in APS types 2 (Addison’s disease, CLT with or with T1DM) and 3 (CLT and another organ-specific autoimmune disease, not Addison’s

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disease). Unlike APS-1, which usually presents in early childhood, APS-2 tends to occur later in childhood or in the adult. There is an increased prevalence of CLT in patients with Down, Turner, Klinefelter and Noonan syndromes. CLT may also be associated with chronic urticaria and with immune complex glomerulonephritis. Antibodies to Tg and TPO, the thyroid Abs measured in routine clinical practice, are detectable in a majority of patients with CLT. They are useful as markers of underlying autoimmune thyroid damage, TPO Abs being more sensitive. TSH receptor Abs are also found in a small proportion of patients. When stimulatory TSH receptor Abs are present they may give rise to a clinical picture of hyperthyroidism, the coexistence of CLT and Graves’ disease being known as “Hashitoxicosis”. TSH receptor blocking Abs, on the other hand, have been postulated to underlie both the hypothyroidism and the absence of goiter in some patients with primary myxedema, but are detectable in only a minority of children (64). Occasionally, the disappearance of blocking Abs has been associated with normalization of thyroid function in previously hypothyroid patients (65). Goiter is present in approximately two-thirds of children with CLT. Most patients are euthyroid. Although the most common functional disturbance is hypothyroidism, less commonly, as noted earlier, patients may be hyperthyroid. When present, an initial thyrotoxic phase is usually not due to true hyperthyroidism, but is due to the discharge of preformed T4 and T3 from the damaged gland, similar to “silent” thyroiditis in adults. Thyroid Dysgenesis and Inborn Errors of Thyroid Hormonogenesis Occasionally, patients with mild thyroid dysgenesis will escape detection by newborn screening and present later in childhood with nongoitrous hypothyroidism or with an enlarging mass at the base of the tongue, or along the course of the thyroglossal duct. Similarly, children with milder inborn errors of thyroid hormonogenesis may only be recognized later in childhood because of the detection of a goiter. Iodine and Other Micronutrient Deficiency: Natural Goitrogens In areas of endemic iodine deficiency, hypothyroidism may be exacerbated by the coincident ingestion of goitrogen-containing foods, such as cassava, soybeans, broccoli, cabbage, sweet potatoes, and cauliflower, or by certain water pollutants. Iodine deficiency may be endemic or can be due to dietary restriction (for multiple food allergies) or the result of dietary fadism. Iodine deficiency may also be exacerbated by lack of selenium, a component of the selenocysteine thyroid hormone deiodinases. Drugs A number of drugs used in childhood may affect thyroid function. These include antithyroid medication, certain anticonvulsants, lithium, aminosalicylic acid, amiodarone, and aminoglutethimide.

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Miscellaneous Causes of Acquired Hypothyroidism Mantle irradiation for Hodgkin’s disease or lymphoma may result in hypothyroidism. The thyroid gland may be involved in generalized infiltrative (cystinosis), granulomatous (histiocytosis X), or infectious disease processes that are of sufficient severity to result in a disturbance in thyroid function. Hypothyroidism may also occur in patients with mitochondrial disease. Rarely in infancy a large hemangioma with high D3 activity can be associated with rapid inactivation of T4 and severe hypothyroidism (66). Extremely high T4 replacement doses may be required in this syndrome. Secondary or Tertiary Hypothyroidism Like primary hypothyroidism, milder forms of congenital hypopituitarism often present after the newborn period. Acquired damage to the pituitary or hypothalamus is most commonly a consequence of brain tumors (particularly craniopharyngioma) or their therapy (surgery or irradiation). Other causes include granulomatous disease, infection, and trauma. Thyroid Hormone Resistance Children with thyroid hormone resistance usually come to attention when thyroid function tests are performed because of poor growth, hyperactivity, a learning disability, or other nonspecific signs or symptoms. A small goiter may be present. The presentation is highly variable, and some individuals may be completely asymptomatic. Thyroid hormone resistance is most frequently caused by a point mutation in the hinge region or ligand-binding domain of the thyroid hormone receptor (TR) ␤ gene (67). As a consequence, there is a dramatic reduction in T3 binding. Less frequently, it results from impaired interaction with one of the cofactors involved in the mediation of thyroid hormone action. Because these mutant TRs interfere with the function of the normal TRs, a dominant pattern of inheritance is seen. Rarely, thyroid hormone resistance may be found in patients with cystinosis (68). Clinical Manifestations The onset of hypothyroidism in childhood is insidious. Affected children are usually recognized either because of the detection of a goiter on routine examination or because of poor growth, sometimes for several years prior to diagnosis (Fig. 4). Because linear growth tends to be more affected than weight, patients are relatively overweight for their height, although they are rarely significantly obese. Dental and skeletal maturation are delayed, the latter often significantly. Patients with secondary or tertiary hypothyroidism tend to be even less symptomatic than those with primary hypothyroidism.

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B Dx F M

Figure 4 Adolescent female with severe primary hypothyroidism who presented with secondary amenorrhea at the age of 16 years. Note the progressive change in facial appearance over time (A) and the decreased growth velocity (B) prior to diagnosis. With treatment, growth rate increased but weight decreased. Heights of mother (M) and father (F) are indicated at the right. Despite adequate thyroid hormone replacement, adult height was only 47, well below her genetic potential.

The classical clinical manifestations of hypothyroidism (lethargy, cold intolerance, constipation, dry skin, or hair texture) can be elicited on careful evaluation; however, they are often not the presenting complaints. School performance is not usually affected, in contrast to the severe irreversible sequelae that occur in inadequately treated babies with CH. A delayed relaxation time of the deep tendon reflexes may be appreciated in more severe cases. The typical thyroid gland in CLT is diffusely enlarged and has a rubbery consistency. Occasionally asymmetric enlargement occurs and must be distinguished from thyroid neoplasia. An enlarged pyramidal lobe or Delphian lymph node superior to the isthmus can be found and may be confused with a thyroid nodule. The absence of goiter suggests the diagnosis of primary myxedema, thyroid dysgenesis, or secondary/tertiary hypothyroidism. Puberty tends to be delayed in hypothyroid children, although sexual precocity has been described in long-standing, severe hypothyroidism. Females may menstruate but commonly have breast development with little sexual hair. Ovarian

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cysts may be demonstrated on ultrasonography due to follicle stimulating hormone secretion. Galactorrhea due to hyperprolactinemia may occur occasionally. In boys, isolated testicular enlargement may be found. There is an increased incidence of slipped femoral capital epiphyses in hypothyroid children. In patients with severe hypothyroidism of long-standing duration, the sella turcica may be enlarged due to thyrotrope hyperplasia. Laboratory Evaluation Measurement of TSH is the best initial screening test for the presence of primary hypothyroidism. If the TSH is elevated, measurement of free T4 will distinguish whether the child has compensated (normal free T4) or overt (low free T4) hypothyroidism. Measurement of TSH is not helpful in secondary or tertiary hypothyroidism. Hypothyroidism in these cases is demonstrated by the presence of a low free T4 with an inappropriately low or normal TSH. Occasionally, mild TSH elevation is seen in individuals with hypothalamic hypothyroidism, a consequence of the secretion of a TSH molecule with impaired bioactivity but normal immunoreactivity. Thyroid hormone resistance is characterized by elevated levels of free T4 and T3 and an inappropriately normal or elevated TSH concentration. CLT is diagnosed by elevated titers of Tg and/or TPO Abs. Ancillary investigations (thyroid ultrasonography and/or thyroid scintigraphy) may be performed if thyroid Ab tests are negative or if a nodule is palpable, but are rarely necessary. If thyroid Ab tests are negative and no goiter is present, thyroid ultrasonography and/or scan identify the presence and location of thyroid tissue and thereby distinguish primary myxedema from thyroid dysgenesis. Therapy In contrast to CH, rapid replacement is not essential in the older child. This is particularly true in children with long-standing, severe thyroid underactivity in whom rapid normalization may result in unwanted side effects (deterioration in school performance, short attention span, hyperactivity, insomnia, and behavior difficulties). Replacement doses should be increased very slowly as tolerated over several weeks to months. Severely hypothyroid children should also be observed closely for complaints of severe headaches when therapy is initiated because of the rare development of pseudotumor cerebri. In contrast, full replacement can be initiated at once without much risk of adverse consequences in children with mild hypothyroidism. The typical replacement dose of thyroxine in childhood is approximately 4 to 6 ␮g/kg for children 1 to 5 years of age, 3 to 4 ␮g/kg for those 6 to 10 years and 2 to 3 ␮g/kg for those 11 years of age and older, but treatment should be individualized. In patients with a goiter, a somewhat higher thyroxine dosage is used in order to keep the TSH in the low normal range (0.3–1 mU/L) and thereby

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minimize its goitrogenic effect. Whether and how patients with thyroid hormone resistance should be treated is controversial. After the child has received the recommended dosage for at least six to eight weeks, T4 and TSH should be measured. Once a euthyroid state has been achieved, patients should be monitored every 6 to 12 months. Some children with severe, long-standing hypothyroidism at diagnosis may not achieve their genetic potential for height even with optimal therapy, emphasizing the importance of early diagnosis and treatment. Treatment is usually continued indefinitely. Thyroid suppression in children with a euthyroid goiter causes a small reduction in the size of the gland that is detectable on ultrasonography (69) but is not appreciable clinically (70). Whether this small effect is sufficient to warrant lifetime therapy is not clear. Similarly, whether or not children with subclinical hypothyroidism should be treated is controversial. Some physicians treat all such patients while others choose to reassess thyroid function in three to six months before initiating therapy because thyroid function will normalize spontaneously in approximately 30% to 50% of children and adolescents (71,72). Treatment has been advocated both for symptom relief and because of the risk of progression to overt hypothyroidism, a risk seen particularly in older individuals with positive thyroid Abs. An expert U.S. panel recently recommended observation without treatment of adult patients whose TSH level was ⬍10 mU/L regardless of Ab titer (73). When signs and symptoms suggestive of hypothyroidism are present, a trial of thyroxine therapy can be tried. Whether or not therapy is initiated, regular follow-up of thyroid function is important. Painful Thyroid Painful thyroid enlargement is rare in pediatrics and suggests the probability of either acute (suppurative) or subacute thyroiditis. Occasionally, CLT may be associated with intermittent pain and be confused with these disorders. Acute Suppurative Thyroiditis In acute thyroiditis, the thyroid is very tender and the child appears toxic from the infection, but is not thyrotoxic. Serial thyroid ultrasound examinations are very important to perform to detect abscess formation early, so that proper incision and drainage can be performed. Intravenous antibiotics and fluids are essential. Recurrent attacks and involvement of the left lobe suggest a pyriform sinus fistula between the oropharynx and the thyroid as the route of infection (74). In the latter case, surgical extirpation of the pyriform sinus will frequently prevent further attacks. No residual thyroid disease is expected. Subacute Thyroiditis Subacute thyroiditis is much less common in children and adolescents than in older individuals. The disease presumably results from a viral infection of the thyroid gland that typically is tender. During the early phase of the disease, the child may

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Table 4 Causes of Hyperthyroidism in Childhood and Adolescence Hyperthyroidism Graves’ disease Functioning thyroid adenoma Gain of function mutation in TSH receptor McCune Albright syndrome Iodine-induced hyperthyroidism Miscellaneous -TSH secreting adenoma -Hydatidiform mole Thyrotoxicosis without hyperthyroidism Toxic phase of chronic lymphocytic thyroiditis Subacute thyroiditis Thyrotoxicosis factitia

have mild thyrotoxicosis, the result of the release of preformed T4 and T3 into the circulation. Either negative or low titers of thyroid Abs may be found, and, unlike in Graves’ disease, RAI is low or absent. The erythrocyte sedimentation rate is usually markedly elevated, but may be normal to slightly elevated whenever the thyroid is not tender. Mild thyrotoxicosis is controlled with low-dose betaadrenergic blockade. The clinical course of subacute thyroiditis is variable, but often progresses through three phases (thyrotoxicosis, mild hypothyroidism, and euthyroid goiter) before the patient finally recovers with completely normal thyroid function. The transient phase of hypothyroidism during recovery will vary in length and severity that usually does not require a course of thyroxine therapy. Full recovery is expected; late recurrences may occur, but are rare. Hyperthyroidism Graves’ Disease Graves’ disease is by far the most common cause of hyperthyroidism in childhood and adolescence, responsible for ⬎95% of cases (Table 4). It is an autoimmune disorder that, like CLT, occurs in a genetic predisposed population. Graves’ disease is caused by TSH receptor Abs that mimic the action of TSH, causing increased thyroid hormonogenesis and growth (75). There is a strong female predisposition. As in adults, there is an increased frequency of Graves’ disease in children with other autoimmune diseases, such as type 1 diabetes mellitus, Addison’s disease, and myasthenia gravis, as well as in patients with Down syndrome. Rarer Causes of Hyperthyroidism Hyperthyroidism may be caused by a functioning thyroid adenoma, by constitutive activation of the TSH receptor, or may be part of the McCune–Albright syndrome.

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Hyperthyroidism due to a TSH-secreting pituitary adenoma or a hydatidiform mole (76) is exceedingly rare in childhood. In the rare patient with thyroid autonomy (e.g., multinodular goiter), hyperthyroidism may be induced by iodides. Thyrotoxicosis (elevated thyroid hormone levels with or without increased thyroid hormonogenesis), but not hyperthyroidism (increased thyroid hormonogenesis), may also be seen in patients with thyroiditis or after thyroid hormone ingestion (thyrotoxicosis factitia), for example, in adolescents who are trying to lose weight or as a suicide gesture. Accidental thyroid hormone poisoning has also been described in infants and toddlers (77). Clinical Manifestations All but a few children with Graves’ disease present with some degree of thyroid enlargement and most have symptoms and signs of excessive thyroid activity, such as tremors, inability to fall asleep, weight loss despite an increased appetite, proximal muscle weakness, heat intolerance, headache, and tachycardia. Often the onset is insidious. Shortened attention span and emotional lability may lead to severe behavioral and school difficulties. Occasionally, the diagnosis is made accidentally during investigation of unexplained tachycardia or a heart murmur. Acceleration in linear growth may occur, often accompanied by advancement in skeletal maturation, but adult height is not affected. In the adolescent child, puberty may be delayed. If menarche has occurred, secondary amenorrhea is common. If sleep is disturbed, the patient may complain of fatigue. Physical examination reveals a diffusely enlarged, soft, or “fleshy” thyroid gland; smooth skin and fine hair texture; excessive activity; and a fine tremor of the tongue and fingers. A thyroid bruit may be audible. The finding of a thyroid nodule suggests the possibility of a toxic adenoma. The hands are often warm and moist. Tachycardia, a wide pulse pressure, and a hyperactive precordium are common. Caf´e-au-lait spots, particularly in association with precocious puberty, on the other hand, suggest a possible diagnosis of McCune–Albright syndrome rather than Graves’ disease. If a goiter is absent, thyrotoxicosis factitia should be considered. Severe ophthalmopathy is considerably less common in children than in adults, although a stare and mild proptosis are frequently observed. Laboratory Evaluation The clinical diagnosis of hyperthyroidism is confirmed by the finding of increased concentrations of circulating free T4 and total T3 associated with a suppressed TSH. If the TSH is inappropriately “normal,” thyroid hormone resistance or a TSH-secreting adenoma should be considered. An elevated total T4 associated with a normal free component would suggest an abnormality of TBG (either familial or acquired) or familial dysalbuminemic hyperthyroxinemia (78). An important acquired cause of TBG excess that is often not considered in pediatric patients is elevated estrogen, for example, secondary to oral contraceptives or

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pregnancy. Thyrotoxicosis factitia can be distinguished from hyperthyroidism by the demonstration of a low serum Tg (79). If the diagnosis of Graves’ disease is unclear, TSH receptor Abs should be evaluated. Current commercially available radioreceptor or enzyme-linked immunosorbent assay kits that measure the binding of Abs to the TSH receptor (called TSH Receptor Abs, TRAbs or TSH Binding Inhibitory IgGs, TBII) are highly sensitive and specific for Graves’ disease in children as in adults, and are technically simple, rapid, and reproducible (80–84). Measurement of thyroidstimulating activity by bioassay (Thyroid-Stimulating IgGs, TSI), although theoretically preferable and sensitive when performed in a research setting (82), is more expensive and technically demanding and its results tend to be more variable, depending on the sensitivity of the assay employed by the individual clinical laboratory. Measurement of TSH receptor Abs may be particularly useful in distinguishing the toxic phase of CLT and subacute thyroiditis (TSH receptor Ab negative) from patients with Graves’ disease. Tg Abs and/or TPO Abs are also frequently found in children and adolescents with Graves’ disease but their measurement is less sensitive and less specific than TSH receptor Abs measurement (82). RAI uptake and scan can also be used to distinguish Graves’ disease from other causes of thyrotoxicosis (e.g., the thyrotoxic phase of either CLT or subacute thyroiditis, thyrotoxicosis factitia, or a functioning thyroid nodule), but this procedure is much more expensive and involves exposure to radioactivity. In practice, scintigraphy is necessary to confirm the diagnosis of Graves’ disease only in atypical cases, particularly if measurement of TSH receptor Abs is negative or borderline. Therapy In the absence of specific therapy for the immunological abnormality, treatment of hyperthyroidism secondary to Graves’ disease is aimed at preventing the thyroid gland from responding to the stimulation by TSH receptor Abs. The choice of which of the three therapeutic options (antithyroid drugs, radioactive iodine, or surgery) to use should be individualized and discussed with the patient and his/her family. Each approach has its advantages and disadvantages with respect to efficacy, short- and long-term complications, time required to control the hyperthyroidism, and the requirement for compliance. Medical therapy with one of the thionamide derivatives (propylthiouracil, PTU; methimazole, MMI; or carbimazole, converted to MMI) is the initial choice of most pediatricians, although RAI is gaining increasing acceptance. Medical Therapy The traditional first-line approach to therapy is pharmacological blockade of thyroid hormone synthesis. It is hoped that the immunological disease will remit spontaneously and that permanent destruction of the thyroid can be avoided. An additional use of medical therapy in younger children is to postpone definitive

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therapy with RAI to a later age when the theoretic risks of irradiation are not as great. Of the ATDs, MMI is preferred by many pediatric endocrinologists because, for an equivalent dose, it requires taking fewer tablets and has a longer duration of action, an advantage in noncompliant adolescents. In addition, MMI is associated with a more rapid resolution of the hyperthyroidism and has a better safety profile (see later). On the other hand, PTU, but not MMI, inhibits the conversion of T4 to the more active isomer T3, a potential advantage if the thyrotoxicosis is severe. The usual initial dosage of MMI is 0.5 to 1 mg/kg/day (given once or twice a day) and that of PTU is 5 to 10 mg/kg/day given three times daily. In adults a low initial MMI dose (15 mg daily) is almost as effective as a high dose (30 mg daily) in normalizing thyroid function tests within three to six months (85) but whether or not a similar approach would be effective in children who tend to have more severe, persistent disease has not been evaluated. In view of the apparent relationship between dose of MMI and serious side effects (86), use of the smallest effective dose necessary to control the hyperthyroidism would appear prudent. A long-acting beta-adrenergic blocker (e.g., metoprolol or atenolol) can be added to control adrenergic symptoms and the cardiovascular overactivity until a euthyroid state is obtained. The serum concentrations of T4 and T3 normalize in most patients in three to six weeks, but the TSH concentration may not return to normal for several months. Therefore, measurement of TSH is useful as a guide to therapy only after it has normalized, but not initially. Once the T4 and T3 concentrations have fallen by ⬎50% and/or normalized, one can either decrease the dose of thionamide drug by 30% to 50% or, alternatively, wait until the TSH begins to rise and add a supplementary dose of thyroxine in a block-replace regimen. Advocates of the block-replace regimen cite the fewer visits, but a larger MMI dose is required, perhaps exposing the patient to a greater risk of side effects. Initial studies suggesting that combined therapy might be associated with an improved rate of remission have not been confirmed. As long as patients are compliant, hyperthyroidism is readily controlled with ATDs in 90% of individuals. Thus, the major difficulty relates to the persistence of the disease in pediatric patients as compared with their adult counterparts. Unlike most adults in whom TSH Receptor Abs disappear from the circulation within six months of treatment initiation, in children TSH receptor Abs remain elevated in ⬎80% of children and adolescents with Graves’ disease even after one to two years of treatment (83). The median time to remission is three to four years (87,88) and in one study only 25% of pediatric patients remitted after two years, with an additional 25% remitting every two years for up to six years of ATD therapy (89). Prepubertal children, especially those younger than 4 years, appear to have particularly severe and persistent disease (90,91). Thus, treatment for a fixed duration of time, for example, one to two years, as recommended in adults is likely to result in relapse in many children, and therapy needs to be individualized. However, in patients who are compliant and in whom the hyperthyroidism can

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be controlled readily and tapered to a relatively small dose of ATD, medical therapy is a reasonable approach and is well tolerated. Lack of eye signs, small goiter, and a small drug requirement suggest that drug therapy can be tapered and withdrawn (86). Persistence of TSH Receptor Abs, on the other hand, predicts a high likelihood of relapse (92). Currently, it is not possible to predict at diagnosis which patient is likely to undergo a sustained remission. Initial disease severity and TSH receptor Ab titer have been of limited prognostic assistance, being predictive of failure to remit in some (93) but not in most other studies (94,95). Usually, drug withdrawal is done during a school vacation so as to minimize any potential interference with school performance. After cessation of ATD therapy, relapses usually occur within six months. Toxic drug reactions (erythematous rashes, urticaria, arthralgias, and transient granulocytopenia—⬍1500 granulocytes/mm3 ) may be slightly more common in children than in adults but the precise frequency varies greatly, depending on the series. These side effects, considered to be allergic reactions, are almost always seen in the first three months of therapy and in patients treated with higher doses of medication. Usually they subside spontaneously or with substitution of an alternative thionamide drug. Urticaria can be treated with antihistamine therapy, and thus may not warrant discontinuation of the drug. An estimate of transient abnormalities in liver enzymes and mild leukopenia in 20% to 30% of patients was quoted in one recent review (96). In contrast, in a review of 651 children from 10 centers treated with ATD, the incidence of granulocytopenia was 5.0% and the mean incidence of abnormal liver function was 1.9% (97). A transient increase in liver enzymes, with levels less than three times the upper limit of normal, may occur with PTU therapy (98). Routine monitoring of the white blood cell count and liver enzymes is not usually recommended because of lack of cost-effectiveness, although some authors favor initial evaluation of these parameters prior to starting therapy. The overall frequency of agranulocytosis (usually defined as a granulocyte count ⬍500 cells/␮L) has been estimated to be 0.1% to 0.5%. There is some evidence that this life-threatening complication is more common in the first three months of therapy, in adults over the age of 40 years, and in patients given larger doses of MMI (⬎40 mg/day) (86). Hepatitis, on the other hand, has been reported to occur almost exclusively with PTU and may be more common in childhood, whereas a cholestatic reaction is typically seen with MMI. Other rarer side effects of ATDs include a lupus-like syndrome, polyarteritis and antineutrophil cytoplasmic antibodies, positive vasculitis, thrombocytopenia, aplastic anemia, and nephrotic syndrome. Like hepatitis, the latter very rare side effects are more common in patients treated with PTU. It is important to caution all patients to stop their medication immediately and consult their physician should they develop unexplained fever, sore throat, gingival sores, or jaundice. Approximately 10% of children treated medically will develop long-term hypothyroidism later in life, a consequence of coincident cell- and cytokinemediated destruction and/or the development of TSH receptor blocking Abs.

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Radioactive Iodine Definitive therapy with radioiodine ablation is usually reserved for patients who have failed to remit or who relapse on drug therapy, developed a toxic drug reaction, are noncompliant, or choose this modality. RAI is being favored increasingly in some centers, even as the initial approach to therapy, particularly in older adolescents (99). The advantages are the relative ease of administration, the reduced need for medical follow-up, and the lack of demonstrable long-term adverse effects. On the other hand, as the goal of therapy is thyroid ablation, one is substituting daily medication with thyroxine for MMI, and continued medical follow-up is nonetheless necessary. RAI therapy in younger children, particularly in those younger than 10 years, is controversial because of the increased susceptibility of the thyroid gland in the young to the proliferative effects of ionizing radiation. For this reason, an ablative dose of RAI is preferred to eliminate the possibility of neoplasia in thyroid remnant tissue. Some advocates employ a fixed radioiodine dose while others use a formula that considers both the approximate thyroid weight and the 24-hour RAI uptake. Pretreatment with ATDs prior to RAI therapy is not necessary unless the hyperthyroidism is severe. Thyroid hormone concentrations may rise transiently 4 to 10 days after RAI administration owing to the release of preformed hormone from the damaged gland. Beta-blockers may be useful to prevent worsening of symptoms. Other acute complications of RAI therapy (nausea, significant neck pain or swelling) are rare. One usually sees a therapeutic effect within six weeks to three months. Worsening of ophthalmopathy, described in adults after RAI, does not appear to be common in childhood, but if significant ophthalmopathy is present, RAI therapy should be used with caution and treatment with corticosteroids for six to eight weeks after RAI administration may be wise. Alternatively, another permanent treatment modality (surgery) should be considered. In approximately 1000 children with Graves’ disease treated with RAI and followed for ⬍5 to ⬎20 years to date, there did not appear to be any increased rate of congenital anomalies in offspring, leukemia or thyroid cancer (96). However, in most of these series, only a few were younger than or equal to 11 years and even fewer were younger than 5 years, the population of patients who are most at risk (100). Furthermore, given the rarity of thyroid cancer in childhood (1 in a million) and even in the adult (1 in 100,000) as well as the long latency period, small increases would not be detectable in such a small series and much more data are needed. Surgery Surgery, the oldest form of therapy, is performed less frequently now than in the past. An advantage of surgery is the rapid resolution of the hyperthyroidism. Surgery is appropriate for patients who have failed medical management, those in whom rapid control of the hyperthyroidism is important, those who have a

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markedly enlarged thyroid (⬎60–80 g), those who refuse RAI, and for the rare patient with significant eye disease in whom RAI therapy is contraindicated. Near-total thyroidectomy is preferred to minimize the risk of recurrence. Pretreatment, usually with antithyroid medication for four to six weeks until the hyperthyroidism is controlled followed by iodide (Lugol’s solution, 5–10 drops daily) for one to two weeks to decrease the vascularity of the gland, is usually recommended, although successful surgery has been reported after pretreatment with ␤-adrenergic antagonist drug alone or in combination with iodide for only 10 to 14 days. Surgery is associated with a higher morbidity than the other therapeutic modalities, greatly limiting its popularity. When the results of six separate studies involving more than 2000 children treated with surgery were pooled, the most common complication (aside from temporary pain and discomfort, present in all patients) was transient hypocalcemia (10%). Keloid formation occurred in 2.8% of patients. Other less common side effects were recurrent laryngeal nerve paralysis (2%), permanent hypoparathyroidism (2%), and, very rarely, death (0.08%) (96). However, in a recent review of 82 children and adolescents from one institution, no instances of either recurrent laryngeal paralysis or permanent hypoparathyroidism were recorded and no patients died (101). Thus, when an experienced thyroid surgeon is available and modern methods of anesthesia and pain control are used, this therapeutic option is a safe and effective alternative. Unfortunately, with the increased use of RAI, there has been a reduction in the number of experienced surgeons. After both medical and surgical thyroid ablation, most patients become hypothyroid and require lifelong thyroid replacement therapy. On the other hand, if therapy is inadequate, hyperthyroidism may recur. Treatment of Other Causes of Thyrotoxicosis Usually, treatment of other causes of thyrotoxicosis, for example, thyroiditis or thyroid hormone ingestion, is not necessary as the signs and symptoms are selflimited and well tolerated. Rarely, ingestion of massive doses of thyroid hormone has resulted in severe thyrotoxicosis. In these cases, beta-blockade and iopanoic acid (to block T4 to T3 conversion) may be useful (77).

THYROID NODULES Thyroid carcinoma is rare in children, with an incidence of 0.5 to 1 case per million children per year (102). In the older literature, children and adolescents were reported to have an increased risk of malignancy (30%) in thyroid but other studies suggest that the risk of malignancy is the same as it is in adults, 5% to 10%. Follicular adenomas and colloid cysts account for the majority of benign thyroid nodules. Other causes of benign nodular enlargement include CLT and embryological defects, such as intrathyroidal duct cysts or unilateral thyroid agenesis (usually left-sided), which can mimic a nodule. Nonthyroidal masses include teratomas,

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branchial cleft and thyroglossal duct cysts, hemangiomas, lymphangiomas, and neurofibromas. Papillary thyroid carcinoma is the most common form of cancer, but other histological types found in the adult, such as follicular carcinoma and, less often, the oxyphil (Hurthle cell) variant, may also occur. Patients with Cowden syndrome, and Bannayan–Riley–Ruvalcaba syndrome are at increased risk of thyroid carcinoma. Children whose thyroid has been exposed to therapeutic irradiation to the head and neck area comprise a particularly high-risk group. Although most malignancies of the thyroid are carcinomas, other malignant tumors, such as lymphoma and sarcoma, may rarely occur. Anaplastic thyroid carcinoma is not seen during the first 2 decades of life. Medullary thyroid carcinoma (MTC), a rare carcinoma of the calcitonin producing or C-cells of the thyroid, is usually seen as part of the multiple endocrine neoplasia syndromes (MEN-2a and MEN-2b). Clinical Evaluation A high index of suspicion is necessary if the nodule is painless; of firm or hard consistency; or if it is fixed to surrounding tissues, especially if it has undergone rapid growth; or if there is cervical adenopathy, hoarseness, or dysphagia. Occasionally, unexplained, persistent cervical adenopathy can be the first clinically evident manifestation of thyroid cancer. MTC should be considered if there is a family history of thyroid cancer, pheochromocytoma or unexplained death on the operating table, and/or if the child has findings suggestive of MEN-2b (multiple mucosal neuromata and a marfanoid habitus). Laboratory Evaluation The initial investigation includes evaluation of thyroid function with a serum TSH. A suppressed serum TSH concentration, with or without an elevation in the circulating T4 and/or T3 levels, suggests the possibility of a functioning nodule. Positive Ab, although indicating the presence of underlying CLT, does not exclude the possibility of coexistent thyroid cancer. Serum calcitonin should be measured if MTC is a concern but its routine measurement in the evaluation of thyroid nodules is controversial. Genetic screening for a mutation of the Rearranged during Transfection (RET) proto-oncogene should be performed if MEN-2a or -2b is suspected (103). Other Screening Tools Ultrasound examination has replaced thyroid scintiscan as the preferred imaging procedure to confirm and evaluate the morphological characteristics of a thyroid nodule. Although nodules that are cystic or homogeneously hyperechoic are reputed to carry a lower risk of malignancy, ultimately there are no sonographic findings that reliably predict the likelihood of malignancy. Therefore, a biopsy is indicated for all thyroid nodules ≥1 cm in diameter. Fine-needle aspiration

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biopsy (FNAB), popular in the investigation of thyroid carcinoma in adults, has gained increasing acceptance in the pediatric population, particularly in older children. Guidelines developed for the evaluation of nodules in adults should be followed (104). Ultrasound guidance improves the diagnostic accuracy and safety of this procedure. If the child is very young or very anxious, sedation and/or open excisional biopsy are suitable alternatives. Ultrasonography, FNAB, and cytology should be performed by individuals experienced in these procedures. Due to the relative rarity of thyroid nodules in children, this often means referral to adult thyroidology centers. Therapy Surgery Therapy of differentiated thyroid cancer is similar in childhood as in the adult, although controversies exist, particularly in children younger than 10 years who tend to have more persistent disease and who are at a higher risk of recurrence (105–107). Total or near-total thyroidectomy with preservation of the parathyroid glands and recurrent laryngeal nerves is the optimal therapy for malignant thyroid tumors, as it facilitates RAI ablation and subsequent monitoring for recurrence and disease progression. However, one can reserve initial bilateral surgery for patients at high risk for malignancy, such as those whose cytology predicts a ⬎50% likelihood of differentiated thyroid cancer or who have bilateral nodules with abnormal cytology. For other patients, thyroid lobectomy can be performed initially, followed by completion thyroidectomy only if lobectomy confirms the diagnosis of cancer. Radioactive Iodine Even after total thyroidectomy, RAI uptake usually persists in the thyroid bed as a result of residual normal thyroid tissue. Ablation of this thyroid remnant with RAI has been shown to lower recurrence rates and, in some series, to reduce cancer mortality. Similar to completion thyroidectomy, RAI also facilitates disease surveillance by increasing the specificity of Tg measurements and the sensitivity of diagnostic whole body scans. It is important to note that for any given administered dose, the absorbed radiation dose to normal tissues will be higher in young children secondary to their smaller organ volumes and increased cross-radiation due to the shorter distances between organs. Formulae for the estimation of relative pediatric doses should be consulted. In patients with diffuse pulmonary metastases, pulmonary fibrosis is another potential consequence of RAI. The efficacy of radiation therapy is enhanced by clinical interventions that increase thyroidal iodine uptake, such as withdrawal from thyroid hormone therapy to produce an elevated circulating TSH concentration and a low-iodine diet for one to two weeks before the procedure. The use of rhTSH to stimulate radioiodine uptake for ablation is FDA approved in adults. Prepubertal children are more likely to experience nausea and vomiting with 131 I therapy so antiemetic medications

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should be available. After RAI therapy, the dosage of thyroxine replacement is adjusted to keep the serum TSH concentration suppressed (between 0.05 and 0.1 mU/L in sensitive assays). Measurement of serum Tg, a thyroid follicular cell-specific protein, is used to detect evidence of metastatic disease. Follow-up Treatment and Surveillance After RAI therapy, the dosage of thyroxine is adjusted to keep the serum TSH concentration suppressed. Measurement of Tg on suppression and after thyroid hormone withdrawal or rhTSH stimulation is used to detect recurrent disease. The presence of Tg Abs, present in 15% to 30% of patients, interferes with Tg assessment, so serum should be screened for Abs whenever Tg is measured. Surveillance should also include annual neck imaging with ultrasound since the majority of thyroid cancer recurrences are local (cervical or mediastinal lymph nodes). Children with thyroid nodules ⬍1 cm or with benign cytology are followed by serial ultrasound every 6 to 12 months, with ultrasound-guided FNAB if there is any evidence of growth. Prognosis In comparison with adults, pediatric thyroid cancers are characterized by high rates of regional lymph node involvement and distant metastases, especially pulmonary micrometastases. Rates of recurrence are also higher in children, particularly those younger than 10 years. Despite this, long-term survival is common. Overall, there appears to be a modest decline in life expectancy, but accurate data are limited by both the rarity of the disease in the pediatric population and the longer duration of follow-up that is necessary. Careful lifetime follow-up is mandatory. Medullary Thyroid Carcinoma The clinical presentation, diagnostic evaluation, and management of children and adolescents with MTC are the same as described for adults. Where there is a family history of familial MTC or MEN-2a or -2b syndromes, or a positive test for a mutation in the RET proto-oncogene in a proband, every member of the family is tested for the RET proto-oncogene mutation, including infants (103). Genetic screening permits the identification of affected individuals during the preclinical stage of the disease when C-cell hyperplasia without macroscopic cancer is seen, offering the best opportunity for cure. Because different mutations are associated with varying degrees of aggressiveness, optimal timing of prophylactic thyroidectomy varies. In MEN-2b, MTC has been described in infancy, so early detection and surgery is necessary in affected individuals. REFERENCES 1. De Felice M, Di Lauro R. Thyroid development and its disorders: Genetics and molecular mechanisms. Endocr Rev 2004; 5:722–746.

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2. Fagman H, Grande M, Edsbagge J, et al. Expression of classical cadherins in thyroid development: Maintenance of an epithelial phenotype throughout organogenesis. Endocrinology 2003; 144(8):3618–3624. 3. Fisher DA, Klein AH. Thyroid development and disorders of thyroid function in the newborn. N Engl J Med 1981; 304(12):702–712. 4. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 2000; 85(11):3975–3987. 5. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J Med 1994; 331(16):1072–1078. 6. Brown RS, Shalhoub V, Coulter S, et al. Developmental regulation of thyrotropin receptor gene expression in the fetal and neonatal rat thyroid: Relation to thyroid morphology and to thyroid-specific gene expression. Endocrinology 2000; 141(1): 340–345. 7. Costa A, Arisio R, Benedetto C, et al. Thyroid hormones in tissues from human embryos and fetuses. J Endocrinol Invest 1991; 14(7):559–568. 8. Ruiz de Ona C, Obregon MJ, Escobar del Rey F, et al. Developmental changes in rat brain 5’-deiodinase and thyroid hormones during the fetal period: The effects of fetal hypothyroidism and maternal thyroid hormones. Pediatr Res 1988; 24(5):588–594. 9. Vulsma T, Gons MH, de Vijlder JJ. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989; 321(1):13–16. 10. Matsuura N, Konishi J. Transient hypothyroidism in infants born to mothers with chronic thyroiditis—A nationwide study of twenty-three cases. The Transient Hypothyroidism Study Group. Endocrinol Jpn 1990; 37(3): 369–379. 11. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341(8):549–555. 12. Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999; 50(2):149–155. 13. Roti E, Gnudi A, Braverman LE. The placental transport, synthesis and metabolism of hormones and drugs which affect thyroid function. Endocr Rev 1983; 4(2):131– 149. 14. Mercado M, Yu VY, Francis I, et al. Thyroid function in very preterm infants. Early Hum Dev 1988; 16(2–3):131–141. 15. Deming DD, Rabin CW, Hopper AO, et al. Direct equilibrium dialysis compared with two non-dialysis free T4 methods in premature infants. J Pediatr 2007; 151(4):404– 408. 16. Zurakowski D, Di Canzio J, Majzoub JA. Pediatric reference intervals for serum thyroxine, triiodothyronine, thyrotropin, and free thyroxine. Clin Chem 1999; 45(7):1087–1091. 17. Williams FL, Simpson J, Delahunty C, et al. Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J Clin Endocrinol Metab 2004; 89(11): 5314–5320. 18. Carrascosa A, Ruiz-Cuevas P, Potau N, et al. Thyroid function in seventy-five healthy preterm infants thirty to thirty-five weeks of gestational age: A prospective and longitudinal study during the first year of life. Thyroid 2004; 14(6):435–442.

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19. Frank JE, Faix JE, Hermos RJ, et al. Thyroid function in very low birth weight infants: Effects on neonatal hypothyroidism screening. J Pediatr 1996, 128(4);548–554. 20. Von Trotsenburg ASP, Vulsma T, Van Santen HM, et al. Lower neonatal screening thyroxine concentrations in Down syndrome newborns. J Clin Endocrinol Metab 88(4):1512–1515. 21. Dussault JH, Morissette J. Higher sensitivity of primary thyrotropin in screening for congenital hypothyroidism: A myth? J Clin Endocrinol Metab 1983; 56(4): 849–852. 22. Mandel SJ, Hermos RJ, Larson CA, et al. Atypical hypothyroidism and the very low birthweight infant. Thyroid 2000; 10(8): 693–695. 23. Brown RS, Demmer LA. The etiology of thyroid dysgenesis—Still an enigma after all these years. J Clin Endocrinol Metab 2002; 87(9):4069–4071. 24. Djemli A, Van Vliet G, Delvin EE. Congenital hypothyroidism: From paracelsus to molecular diagnosis. Clin Biochem 2006; 39(5):511–518. 25. Devriendt K, Vanhole C, Matthijs G, et al. Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med 1998; 338(18):1317–1318. 26. Krude H, Schutz B, Biebermann H, et al. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest 2002; 109(4):475–480. 27. Clifton-Bligh RJ, Wentworth JM, Heinz P, et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 1998; 19(4):399–401. 28. Knobel M, Medeiros-Neto G. An outline of inherited disorders of the thyroid hormone generating system. Thyroid 2003; 13(8):771–801. 29. Kopp P, Pesce L, Solis-S JC. Pendred syndrome and iodide transport in the thyroid. Trends Endocrinol Metab 2008; 19(7):260–268. 30. Sunthornthepvarakui T, Gottschalk ME, Hayashi Y, et al. Brief report: Resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med 1995; 332(3):155–160. 31. Biebermann H, Schoneberg T, Krude H, et al. Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. J Clin Endocrinol Metab 1997; 82(10):3471–3480. 32. Dumitrescu AM, Liao XH, Best TB, et al. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004; 74(1):168–175. 33. Delange F. Neonatal screening for congenital hypothyroidism: Results and perspectives. Horm Res 1997; 48(2):51–61. 34. Brown RS, Bloomfield S, Bednarek FJ, et al. Routine skin cleansing with povidoneiodine is not a common cause of transient neonatal hypothyroidism in North America: A prospective controlled study. Thyroid 1997; 7(3):395–400. 35. Cheron RG, Kaplan MM, Larsen PR, et al. Neonatal thyroid function after propylthiouracil therapy for maternal Graves’ disease. N Engl J Med 1981; 304(9):525–528. 36. Brown RS, Bellisario RL, Botero D, et al. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies. J Clin Endocrinol Metab 1996; 81(3):1147–1151. 37. Daliva AL, Linder B, DiMartino-Nardi J, et al. Three-year follow-up of borderline congenital hypothyroidism. J Pediatr 2000; 136(1):53–56.

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38. Calaciura F, Motta RM, Miscio G, et al. Subclinical hypothyroidism in early childhood: A frequent outcome of transient neonatal hyperthyrotropinemia. J Clin Endocrinol Metab 2002; 87(7):3209–3214. 39. Miki K, Nose O, Miyai K, et al. Transient infantile hyperthyrotrophinaemia. Arch Dis Child 1989; 64(8):1177–1182. 40. Ohnishi H, Sato H, Noda H, et al. Color Doppler ultrasonography: Diagnosis of ectopic thyroid gland in patients with congenital hypothyroidism caused by thyroid dysgenesis. J Clin Endocrinol Metab 2003; 88(11):5145–5149. 41. Larson C, Hermos R, Delaney A, et al. Risk factors associated with delayed thyrotropin elevations in congenital hypothyroidism. J Pediatr 2003; 143(5):587–591. 42. Perry R, Heinrichs C, Bourdoux P, et al. Discordance of monozygotic twins for thyroid dysgenesis: Implications for screening and for molecular pathophysiology. J Clin Endocrinol Metab 2002; 87(9):4072–4077. 43. Rose SR, Brown RS, Foley T, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006; 117(6);2290–2303. 44. Selva KA, Harper A, Downs A, et al. Neurodevelopmental outcomes in congenital hypothyroidism: Comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr 2005; 147(6):775–780. 45. Bongers-Schokking JJ, Koot HM, Wiersma D, et al. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000; 136(3):292–297. 46. Osborn DA, Hunt RW. Postnatal thyroid hormones for preterm infants with transient hypothyroxinaemia Cochrane Database Syst Rev 2007; (1):CD005945. 47. Williams FL, Ogston SA, van Toor H, et al. Serum thyroid hormones in preterm infants: Associations with postnatal illnesses and drug usage. J Clin Endocrinol Metab 2005; 90(11):5954–5963. 48. Tiosano D, Even L, Shen Z, et al. Recombinant Thyrotropin in the diagnosis of congenital hypothyroidism. J Clin Endocrinol Metab 2007; 92(4):1434–1437. 49. van Wassenaer AG, Kok JH, de Vijlder JJ, et al. Effects of thyroxine supplementation on neurologic development in infants born at less than thirty weeks’ gestation. N Engl J Med 1997; 336(1):21–26. 50. van Wassenaer AG, Westera J, Houtzager BA, et al. Ten-year follow-up of children born at ⬍30 weeks’ gestational age supplemented with thyroxine in the neonatal period in a randomized, controlled trial. Pediatrics 2005; 116(5):e613–e618. 51. Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves’ disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab 1983; 57(5):1036–1040. 52. Skuza KA, Sills IN, Stene M, et al. Prediction of neonatal hyperthyroidism in infants born to mothers with Graves disease. J Pediatr 1996; 128(2):264–268. 53. Mitsuda N, Tamaki H, Amino N, et al. Risk factors for developmental disorders in infants born to women with Graves disease. Obstet Gynecol 1992; 80(3 pt 1):359– 364. 54. Zakarija M, McKenzie JM, Munro DS. Immunoglobulin G inhibitor of thyroidstimulating antibody is a cause of delay in the onset of neonatal Graves’ disease. J Clin Invest 1983; 72(4):1352–1356. 55. Bryant WP, Zimmerman D. Iodine-induced hyperthyroidism in a newborn. Pediatrics 1995; 95(3):434–436.

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56. Daneman D, Howard NJ. Neonatal thyrotoxicosis: Intellectual impairment and craniosynostosis in later years. J Pediatr 1980; 97(2):257–259. 57. Matsuura N, Konishi J, Fujieda K, et al. TSH-receptor antibodies in mothers with Graves’ disease and outcome in their offspring. Lancet 1988; 1(8575–8576):14–17. 58. Tamaki H, Amino N, Aozasa M, et al. Universal predictive criteria for neonatal overt thyrotoxicosis requiring treatment. Am J Perinatol 1988; 5(2):152–158. 59. de Roux N, Polak M, Couet J, et al. A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. J Clin Endocrinol Metab 1996; 81(6):2023–2026. 60. Holzapfel HP, Wonerow P, von Petrykowski W, et al. Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab 1997; 82(11):3879–3884. 61. Gruters A, Schoneberg T, Biebermann H, et al. Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor. J Clin Endocrinol Metab 1998; 83(5):1431–1436. 62. Foley TP, Jr., Abbassi V, Copeland KC, et al. Brief report: Hypothyroidism caused by chronic autoimmune thyroiditis in very young infants. N Engl J Med 1994; 330(7):466–468. 63. Betterle C, Greggio NA, Volpato M. Clinical review 93: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab 1998; 83(4):1049–1055. 64. Matsuura N, Konishi J, Yuri K, et al. Comparison of atrophic and goitrous autoimmune thyroiditis in children: Clinical, laboratory and TSH-receptor antibody studies. Eur J Pediatr 1990; 149(8):529–533. 65. Takasu N, Yamada T, Takasu M, et al. Disappearance of thyrotropin-blocking antibodies and spontaneous recovery from hypothyroidism in autoimmune thyroiditis. N Engl J Med 1992; 326(8):513–518. 66. Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000; 343(3):185–189. 67. McDermott MT, Ridgway EC. Thyroid hormone resistance syndromes. Am J Med 1993; 94(4):424–432. 68. Bercu BB, Orloff S, Schulman JD. Pituitary resistance to thyroid hormone in cystinosis. J Clin Endocrinol Metab 1980; 51(6):1262–1268. 69. Svensson J, Ericsson UB, Nilsson P, et al. Levothyroxine treatment reduces thyroid size in children and adolescents with chronic autoimmune thyroiditis. J Clin Endocrinol Metab 2006; 91(5):1729–1734. 70. Rother KI, Zimmerman D, Schwenk WF. Effect of thyroid hormone treatment on thyromegaly in children and adolescents with Hashimoto disease. J Pediatr 1994; 124(4):599–601. 71. Rallison ML, Dobyns BM, Keating FR, et al. Occurrence and natural history of chronic lymphocytic thyroiditis in childhood. J Pediatr 1975; 86(5):675–682. 72. Maenpaa J, Raatikka M, Rasanen J, et al. Natural course of juvenile autoimmune thyroiditis. J Pediatr 1985; 107(6):898–904. 73. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA 2004; 291(2):228–238. 74. Mali VP, Prabhakaran K. Recurrent acute thyroid swelling because of pyriform sinus fistula. J Pediatr Surg 2008; 43(4):e27–e30.

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75. Rapoport B, Chazenbalk GD, Jaume JC, et al. The thyrotropin (TSH) receptor: Interaction with TSH and autoantibodies. Endocr Rev 1998; 19(6):673–716. 76. Misra M, Levitsky LL, Lee MM. Transient hyperthyroidism in an adolescent with hydatidiform mole. J Pediatr 2002; 140(3):362–366. 77. Brown RS, Cohen JH Jr, Braverman LE. Successful treatment of massive thyroid hormone poisoning with iopanoic acid. J Pediatr 1998; 132(5):903–905. 78. Ruiz M, Rajatanavin R, Young RA, et al. Familial dysalbuminemic hyperthyroxinemia: A syndrome that can be confused with thyrotoxicosis. N Engl J Med 1982; 306(11):635–639. 79. Mariotti S, Martino E, Cupini C, et al. Low serum thyroglobulin as a clue to the diagnosis of thyrotoxicosis factitia. N Engl J Med 1982; 307(7):410–412. 80. Costagliola S, Morgenthaler NG, Hoermann R, et al. Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves’ disease. J Clin Endocrinol Metab 1999; 84(1):90–97. 81. Foley TP Jr, White C, New A. Juvenile Graves disease: Usefulness and limitations of thyrotropin receptor antibody determinations. J Pediatr 1987; 110(3):378– 386. 82. Botero D, Brown RS. Bioassay of thyrotropin receptor antibodies with Chinese hamster ovary cells transfected with recombinant human thyrotropin receptor: Clinical utility in children and adolescents with Graves disease. J Pediatr 1998; 132(4):612– 618. 83. Smith J, Brown RS. Persistence of thyrotropin (TSH) receptor antibodies in children and adolescents with Graves’ disease treated using antithyroid medication. Thyroid 2007; 17(11):103–107. 84. Bolton J, Sanders J, Oda Y, et al. Measurement of thyroid-stimulating hormone receptor autoantibodies by ELISA. Clin Chem 1999; 45(12):2285–2287. 85. Reinwein D, Benker G, Lazarus JH, et al. A prospective randomized trial of antithyroid drug dose in Graves’ disease therapy. European Multicenter Study Group on Antithyroid Drug Treatment. J Clin Endocrinol Metab 1993; 76(6):1516–1521. 86. Cooper DS. Antithyroid drugs in the management of patients with Graves’ disease: An evidence-based approach to therapeutic controversies. J Clin Endocrinol Metab 2003; 88(8):3474–3481. 87. Vaidya VA, Bongiovanni AM, Parks JS, et al. Twenty-two years’ experience in the medical management of juvenile thyrotoxicosis. Pediatrics 1974; 54(5):565–570. 88. Barnes HV, Blizzard RM. Antithyroid drug therapy for toxic diffuse goiter (Graves disease): Thirty years experience in children and adolescents. J Pediatr 1977; 91(2):313–320. 89. Lippe BM, Landaw EM, Kaplan SA. Hyperthyroidism in children treated with long-term medical therapy: Twenty-five percent remission every two years. J Clin Endocrinol Metab 1987; 64(6):1241–1245. 90. Shulman DI, Muhar I, Jorgensen EV, et al. Autoimmune hyperthyroidism in prepubertal children and adolescents: Comparison of clinical and biochemical features at diagnosis and responses to medical therapy. Thyroid 1997; 7(5):755–760. 91. Segni M, Leonardi E, Mazzoncini B, et al. Special features of Graves’ disease in early childhood. Thyroid 1999; 9(9):871–877. 92. Davies TF, Roti E, Braverman LE, et al. Thyroid controversy—Stimulating antibodies. J Clin Endocrinol Metab 1998; 83(11):3777–3785.

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93. Vitti P, Rago T, Chiovato L, et al. Clinical features of patients with Graves’ disease undergoing remission after antithyroid drug treatment. Thyroid 1997; 7(3):369–375. 94. Ikenoue H, Okamura K, Sato K, et al. Prediction of relapse in drug-treated Graves’ disease using thyroid stimulation indices. Acta Endocrinol (Copenh) 1991;125(6):643–650. 95. van Ouwerkerk BM, Krenning EP, Docter R, et al. Cellular and humoral immunity in patients with hyperthyroid Graves’ disease before, during and after antithyroid drug treatment. Clin Endocrinol (Oxf) 1987; 26(4):385–394. 96. Rivkees SA, Sklar C, Freemark M. Clinical review 99: The management of Graves’ disease in children, with special emphasis on radioiodine treatment. J Clin Endocrinol Metab 1998; 83(11):3767–3776. 97. Zimmerman D, Lteif AN. Thyrotoxicosis in children. Endocrinol Metab Clin N Am 1998; 27(1):109–126. 98. Liaw YF, Huang MJ, Fan KD, et al. Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. A cohort study. Ann Intern Med 1993; 118(6):424– 428. 99. Rivkees SA, Dinauer C. An optimal treatment for pediatric Graves’ disease is radioiodine. J Clin Endocrinol Metab 2007; 92(3):797–800. 100. Nikiforov Y, Gnepp DR, Fagin JA. Thyroid lesions in children and adolescents after the Chernobyl disaster: Implications for the study of radiation tumorigenesis. J Clin Endocrinol Metab 1996; 81(1):9–14. 101. Sherman J, Thompson GB, Lteif A, et al. Surgical management of Graves disease in childhood and adolescence: An institutional experience. Surgery 2006; 140(6):1056– 1061. 102. Harach HR, Williams ED. Childhood thyroid cancer in England and Wales. Br J Cancer 1995; 72(3):777–783. 103. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86(12):5658–5671. 104. Mazzaferri EL, Kloos RT. Clinical review 128: Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001; 86(4):1447–1463. 105. Hung W, Sarlis NJ. Current controversies in the management of pediatric patients with well-differentiated nonmedullary thyroid cancer: A review. Thyroid 2002; 12(8):683–702. 106. Newman KD, Black T, Heller G, et al. Differentiated thyroid cancer: Determinants of disease progression in patients ⬍21 years of age at diagnosis: A report from the Surgical Discipline Committee of the Children’s Cancer Group. Ann Surg 1998; 227(4):533–541. 107. Dinauer C, Francis GL. Thyroid cancer in children. Endocrinol Metab Clin N Am 2007; 36:779–806.

9 Thyroid Disease and Pregnancy Susan J. Mandel University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION When pregnancy is associated with alterations in maternal thyroid function, the fetus can be affected in two ways: either directly by transplacental passage of maternal thyroid hormone, antithyroid antibodies, or medications, or indirectly by adverse influences on maternal physiology. It is important to recognize the expected alterations in thyroid hormone levels during gestation. The clinician must be able to differentiate normal physiologic changes from true thyroid disease. Hyperthyroidism and hypothyroidism may first be detected during pregnancy and patients with preexisting thyroid dysfunction require close monitoring, and frequently need adjustment of therapy. THYROID HORMONE PHYSIOLOGY DURING GESTATION During normal gestation, there are changes in thyroid hormone physiology that are reversible after delivery. Serum thyroxine binding globulin (TBG) levels begin to increase within the first weeks after conception, usually more than doubling in concentration, with peak levels reached at the middle of gestation (1). Levels remain elevated until delivery and then normalize in the postpartum period. The rise in serum TBG concentration results from an estrogen-induced increase in the sialylation of the protein, which subsequently decreases its hepatic clearance and prolongs its serum half-life (2). Associated with the rise in TBG are increases in both serum total T4 and T3 levels, which also plateau at the midtrimester or slightly earlier (1,3). Because of 369

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Figure 1 Serum thyroxine (TT4) and free thyroxine (FT4) levels by trimester. Interquartile ranges are shown by the shaded boxes, with the median value indicated by the line. Serum TT4 levels rise to approximately 1.5 times the normal nonpregnant reference range. Although serum FT4 ranges were method-dependent, as shown by the differences in measurement by the Elecsys (Roche, Basel, Switzerland) and Tosoh (Fisher Scientific International, Hampton, NH) methods, both methods show a consistent decrease in FT4 as pregnancy progresses. Abbreviations: NP, nonpregnant (n = 62); 1st , first trimester (n = 105); 2nd , second trimester (n = 39); 3rd , third trimester (n = 64). Source: Photo courtesy of Carole Spencer. From Ref. 59.

these TBG changes, normal serum T4 and T3 levels throughout pregnancy are predictably approximately 1.5 times the normal nonpregnant reference range (Fig. 1) (4). Interestingly, it has been observed the serum T4 and T3 concentrations do not increase as much during pregnancy as would be expected given the rise in TBG, and this may be due to decreased TBG saturation (1). The increase in maternal T4 production that occurs in normal gestation is most evident from observations of levothyroxine replaced hypothyroid women, who require a 25% to 45% dosage increase in order to maintain normal serum TSH levels in pregnancy (5–8). Furthermore, the findings of relative hypothyroxinemia and slightly increased serum TSH levels during pregnancy in women from areas of borderline iodine sufficiency (⬍100 ␮g/day) support the view that pregnancy constitutes a stress for the maternal thyroid by stimulating thyroidal production (9). There are several possible explanations for this increased T4 requirement. Early in pregnancy, the rise in serum TBG results in expansion of the extrathyroidal T4 pool. In addition, transplacental passage of T4 and placental T4 degradation may contribute to the increased demand on maternal thyroidal production to maintain euthyroid status. Lastly, renal clearance of iodide increases because of the higher glomerular filtration rate in pregnancy (3).

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Determination of free T4 (FT4) levels may reflect both methodological differences as well as alterations due to gravid physiology. With their sensitivity to binding proteins, however, automated assays appear to show a decrease in serum FT4 levels as pregnancy progresses compared to their own nonpregnant reference range. By the third trimester, serum FT4 levels are often lower than the normal nonpregnant reference range (Fig. 1) (10,11). Serum TSH levels also fluctuate during pregnancy. The hCG-mediated, increased thyroid hormone synthesis coinciding with the first trimester peak in hCG is reflected by a reciprocal fall in serum TSH levels. It has been hypothesized that hCG has thyrotropic activity because of its structural similarity to TSH, and that the high serum hCG levels stimulate the TSH receptor via a hormone specificity “spillover” syndrome (12). In fact, a positive correlation between individual FT4 and hCG levels in early gestation has been reported, consistent with TSH-like activity of hCG (1). Recent studies have documented the 95% confidence interval lower and upper limits for the first trimester median serum TSH values in healthy pregnant women to be 0.02 to 0.03 mIU/L and 2.5 to 3.0 mIU/L respectively (13,14). It is critical for clinicians to recognize this appropriate decrease in the TSH range during normal pregnancy, since 9% of women without thyrotoxic symptoms have first trimester TSH levels that are subnormal but detectable compared to the nonpregnant reference range (greater than 0.05 mU/L but less than 0.4–0.5 mU/L) and an additional 9% have values that are frankly suppressed (⬍0.05 mU/L). Median serum TSH levels then rise during the second and third trimesters (95% CI 0.03–3.1 mIU/L and 0.13–3.4 mIU/L, respectively) (13,14). Renal iodine clearance increases as a result of an increase in glomerular filtration rate and there is transplacental passage of iodine and iodothyronines as the fetal-placental unit grows (3). In areas of borderline iodine sufficiency, such as in many European countries, this loss of iodine, combined with the increase in thyroid hormone pools from the marked increase in serum TBG levels, may result in goiter formation. In a prospective study from Belgium, thyroid volume increased on an average of 18% between the first and third trimesters and was associated with the biochemical features of thyroid stimulation, a high T3/T4 ratio, and elevated thyroglobulin levels (9). In areas where iodine intake is more than sufficient, such as the United States, a palpable goiter should not occur during normal gestation and if present, this should direct the clinician to investigate possible thyroid hormone abnormalities (15). THYROID AUTOIMMUNITY AND EUTHYROIDISM Among euthyroid women in the reproductive years, up to 18% may have detectable antithyroid antibodies (16). These asymptomatic euthyroid women with thyroid autoimmunity have been reported to be at risk for three complications during or after pregnancy: increased rates of spontaneous miscarriage and very preterm delivery (⬍32 weeks gestation) (17), possible development of subclinical

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hypothyroidism during gestation, and risk of postpartum thyroiditis (PPT) (see section “Postpartum Thyroiditis” of this chapter). Several studies have reported a twofold increase in the spontaneous miscarriage rate early in pregnancy among those euthyroid women who have serum antithyroid antibodies (either antithyroid peroxidase or antithyroglobulin) detected in the first trimester (16,18). The majority of these antibody positive women who miscarry have normal thyroid function. Furthermore, the presence of antithyroid antibodies either prior to pregnancy or in the first trimester is not correlated with anticardiolipin antibody positivity, which is also known to be associated with pregnancy loss (16,19). The mechanism linking thyroid autoimmunity and miscarriage is not known. Thyroid autoimmunity may be a marker either for a more generalized activation of the immune system or for subtle changes in maternal/fetal thyroid metabolism. However, a recent, randomized, controlled trial of levothyroxine therapy in euthyroid women with positive serum antithyroid peroxidase antibodies demonstrated that, compared to untreated women, levothyroxine therapy is associated with decreased rates of both miscarriage (13.85 versus 3.5%, p ⬍ 0.05) and preterm delivery (22.4 versus 7%, p ⬍ 0.05); these lower rates are similar to a control antithyroid antibody negative population (20). Euthyroid women with detectable antithyroid antibodies may have slightly higher first trimester serum TSH values, still remaining within the normal range, compared to normal pregnant controls. Despite the decrease in antithyroid antibody titers with pregnancy progression in these antibody positive women, thyroid function parameters have been reported to show a progressive deterioration toward hypothyroidism (20). At term, up to 16% of previously euthyroid women developed mild subclinical hypothyroidism as indicated by an elevated serum TSH level (21). However, this study was conducted in an area of borderline iodine sufficiency, which may have further compromised maternal thyroid gland reserve. There are no data on the possible development of subclinical hypothyroidism in an iodine-replete antibody positive pregnant population. HYPOTHYROIDISM Overt hypothyroidism is reported to occur in approximately 1 in 1600 pregnancies (22). However, the prevalence of subclinical hypothyroidism is reported to be significantly higher, affecting 2.2% of American women screened at 16 to 18 weeks gestation (23). Hypothyroxinemia and increased serum TSH levels may occur if true hypothyroidism is present, or if the mother has been overtreated with antithyroid drugs (ATD) for hyperthyroidism. The obstetric complications that have been associated with hypothyroidism are linked to the decreased maternal thyroid hormone levels that provide a less than optimal environment for both fetal and maternal health. The majority of cases of hypothyroidism are caused by Hashimoto’s thyroiditis and prior radioiodine or surgical treatment of Graves’ disease. Transient hypothyroidism may occur as part of autoimmune or PPT, especially if a

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woman has had a recent miscarriage (see section “Postpartum Thyroiditis” of this chapter). Diagnosis It is important to diagnose hypothyroidism because of its potential adverse impact on pregnancy (see section “Pregnancy Outcome” of this chapter), and yet most patients are relatively asymptomatic. Only 20% to 30% of women with overt biochemical hypothyroidism (low T4 and high TSH) have symptoms (24) and complaints of fatigue and weight gain are often attributed to the pregnancy itself. The majority of patients with subclinical hypothyroidism are asymptomatic as well. The diagnosis of hypothyroidism is confirmed by finding an elevated serum TSH concentration, except in the rare instance when hypothyroidism is secondary to pituitary or hypothalamic disease. A cost-effectiveness analysis of universal screening for hypothyroidism during pregnancy has not been done, in part because the true costs with respect to fetal outcome are not known. The recently published Endocrine Society guidelines for the management of thyroid disorders during pregnancy acknowledged that universal screening based upon the current published evidence could not be justified but did recommend targeted case-finding in asymptomatic women at high-risk for thyroid disease (25). These include those with evidence of thyroid autoimmunity because of either a past history of PPT, prior detection of antithyroid antibodies, or previous treatment for hyperthyroidism, even if they are euthyroid without levothyroxine therapy. In such women, autoimmune damage may not affect basal thyroid hormone output in the nonpregnant state, but may impair the thyroid’s ability to compensate for the increased production needed during pregnancy. In addition, 15% of diabetic women with type 1 diabetes may develop clinical hypothyroidism during pregnancy (26). Thyroid function testing is also recommended for women with other autoimmune disorders, a family history of thyroid disease, prior miscarriage (see section “Thyroid Autoimmunity and Euthyroidism” of this chapter), and potentially decreased thyroid gland synthetic function because of a prior lobectomy or head and neck irradiation. In addition, all levothyroxine-replaced hypothyroid women must be monitored during pregnancy (see section “Treatment” of this chapter) (25). Unfortunately, such targeted screening will still miss up to 30% of women with hypothyroidism in the first trimester (27). Pregnancy Outcome Overt hypothyroidism can be associated with anovulatory cycles and subsequent infertility. However, hypothyroid women may become pregnant and several retrospective case series have investigated pregnancy outcome in these women (Table 1). The likelihood of complications is correlated with the severity of the hypothyroidism (overt versus subclinical) and the adequacy of maternal treatment (5,17,24,28–32). The majority of women reported in these studies had less than

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Table 1 Pregnancy Complications Reported in Hypothyroid Women

Spontaneous abortion (5,32) Pregnancy-induced hypertension/Preeclampsia (24,28,30,31) Abruption (5,28–31) Stillbirth (24,28–30) Anemia (29,30) Postpartum hemorrhage (29–31) Preterm birth majority from premature delivery due to preeclampsia (low birth weight) (5,17,29,30)

Subclinical hypothyroidism (%)

Overt hypothyroidism (%)

10–70 0–17

60 0–44

0 0–3 0–2 0–17 0–9

0–19 0–12 0–31 0–19 20–31

optimal, prenatal care as the average initial antenatal visit occurred between 16 and 20 weeks gestation. However, a recent prospective study investigated pregnancy outcome in women with untreated subclinical hypothyroidism diagnosed prior to 20 weeks by gestational age-specific serum TSH and FT4 levels. Compared to euthyroid women, the rates of preterm delivery (⬍34 weeks gestation) and placental abruption were significantly higher (relative risk 1.8 and 3.0 respectively, p ⬍ 0.03) (14). Levothyroxine therapy, especially if optimized by the midgestation, may ameliorate some of these complications (5,24). In addition to pregnancy complications, does maternal hypothyroxinemia pose a threat to fetal development? A recent report documented severe retardation of fetal development, with biparietal diameter and femur length of less than the third centile in a woman with inadequately treated hypothyroidism and a serum TSH level of 72 mU/L at 29 weeks gestation. With appropriate increase in her levothyroxine dosage and normalization of her serum TSH level, these fetal parameters normalized by 39 weeks gestation (33). Although the fetus had normal thyroid function, this case illustrates the pivotal role of maternal thyroid hormone for fetal somatic growth. Thyroid hormone is also necessary for normal fetal neurologic development and the fetal thyroid does not begin to function until 12 weeks of life. It is now evident that maternal T4 crosses the placenta (34). As early as 7 weeks, gestation, T3 is present in the fetal neurologic tissues, which originates from the transplacental passage of maternal T4 that undergoes intracellular deiodination in the fetal brain (35). The relative contribution of maternal thyroid hormone versus fetal thyroid hormone to fetal neurologic development is unknown. In areas of iodine deficiency where both maternal and fetal thyroid status are compromised, neurologic cretinism occurs. In contrast, infants born with congenital hypothyroidism

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in areas of iodine adequacy have normal neurologic function at birth and postnatal levothyroxine therapy is required to continue normal neuronal maturation. Therefore, it is presumed that the transplacental passage of maternal T4 is sufficient to maintain normal fetal neurologic development in utero. The contribution of maternal thyroid hormone to the brain maturation of a fetus with intact thyroid function is inadequately understood. Cognitive function is impaired and brain DNA and protein content are decreased in rats born to thyroidectomized mothers and thereby deprived of maternal thyroid hormone (36). These deficits are not as severe if maternal hypothyroidism occurs only during the second half of gestation, when the rat fetal thyroid gland activity is adequate (37). Data in humans are less direct. Although, early studies of children born to women who were hypothyroximeic during pregnancy reported impaired mental development (38), they have been criticized for their lack of accurate biochemical assessment of hypothyroidism. However, this issue has been addressed by a more recent study. Haddow and colleagues performed neuropsychological testing of 62 children (of average age eight years) born to women who had elevated serum TSH levels at 17 weeks gestation and compared these to results for 124 control children matched for maternal educational level and age. Children born to hypothyroid women (partially treated or untreated) scored on average four points lower than control children (p = 0.06) on the full-scale IQ score of the Wechlser Intelligence Scale for Children. This difference was even more marked, a decrease of seven IQ points (p = 0.005), when the subset of 48 children born to untreated hypothyroid mothers was compared to control children (39). Furthermore, the decrease in the IQ score was inversely proportional to the degree of maternal serum TSH elevation (40). Although differences in the postnatal environment cannot be excluded as etiologic factors, this study strongly suggests that untreated or inadequately treated maternal hypothyroidism during pregnancy adversely affects fetal brain development. Lastly, a very small percentage of women with atrophic Hashimoto’s thyroiditis may have antibodies that block thyroidal stimulation by TSH. These antibodies may be detected by assays for TSH receptor binding inhibitory immunoglobulins (TBII), which assess the ability of maternal immunoglobulin to block TSH binding to the TSH receptor in vitro. Transient congenital hypothyroidism may be caused by the transplacental passage of these antibodies that then block TSH stimulation of the neonatal thyroid, analogous to but opposite of the situation of neonatal Graves’ disease. The estimated prevalence of this disorder is 1 in 180,000 births, or 2% of infants with congenital hypothyroidism (41). The antibodies can be measured in both the mother and the neonate, and if present, may indicate that lifelong levothyroxine therapy may not be necessary for the infant. Treatment Several studies have documented that levothyroxine requirements increase in many hypothyroid women during pregnancy (5–8). There are various possible

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explanations for this increased requirement and each may have relative importance at different times in gestation. In early pregnancy, the concentration of TBG rapidly increases and more thyroid hormone may be needed to saturate binding sites. Glomerular filtration rate increases resulting in increased iodide clearance. Later, with placental growth, there is increased metabolism of T4 to its inactive metabolite reverse T3 by the high levels of placental type 3 deiodinase (3). In addition, there is transplacental passage of T4 (34). Lastly, there may be alterations in the volume of distribution of thyroid hormone because of both gravid physiology and the fetal/placental unit. For patients initially diagnosed with overt hypothyroidism during pregnancy, a daily dose of 2 ␮g/kg/day should be started, which is higher than the full replacement dose in the nonpregnant patient and accounts for the higher requirement in pregnancy (22). If the serum TSH is first found to be only minimally elevated (⬍10 mU/L) in pregnancy, a levothyroxine dose of 0.1 mg/day may be adequate. In those with known hypothyroidism taking levothyroxine replacement, the need for dosage adjustment may depend upon the etiology of hypothyroidism, with an increase needed in 76% of women who have undergone prior radioiodine ablation or surgery, but only in 47% who have Hashimoto’s thyroiditis (8). Levothyroxine requirements generally increase in the first trimester and persist through gestation. A recent, prospective study documented the median time for levothyroxine dosage increase was 8 weeks gestation. However, this was using the upper limit of a nonpregnant TSH reference range (5.0 mIU/L) for dosage adjustment (7). If a trimester-specific reference TSH range were used, then it is possible that the increased requirement would be manifest earlier. It is also important to remember that 25% of those with initial normal serum TSH levels in first trimester and 37% of those with initial normal serum TSH concentrations in second trimester will later require dosage increases (8). The increased dosage requirement appears to plateau after 20 weeks gestation (7). Women with subclinical hypothyroidism, who are taking less than replacement dosages of levothyroxine may not require a dosage increase during gestation because the residual thyroid gland is able to increase synthesis of thyroid hormone. These women may be at increased risk for PPT, however (see section “Postpartum Thyroiditis” of this chapter). Levothyroxine replaced hypothyroid women should have thyroid function monitored as soon as they become pregnant and every four to six weeks in the first half of pregnancy (Table 2) (25,42). There are two schools of recommendations for adjustment of levothyroxine dosage requirements during pregnancy. The first is to increase the dose only once the serum TSH is abnormal compared to trimester-specific values; pragmatically, the upper limit of 2.5 mIU/L may be used during gestation. Kaplan has proposed that the increment in levothyroxine dosage can be based upon the initial degree of TSH elevation. For those with serum TSH levels ⬍10 mU/L, the average increase was approximately 50 ␮g/day; for those with serum TSH values between 10 and 20 mU/L, it was approximately 75 ␮g/day; and for those with serum TSH values ⬎20 mU/L, the average increase was approximately 100 ␮g/day (8). The second is to recommend that women with

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Table 2 Guidelines for Clinical Management of Maternal Hypothyroidism During Pregnancy (25,42) 1. Optimize levothyroxine dosage prior to pregnancy (TSH 0.5–2.5 mIU/L) 2. Check serum TSH level as soon as pregnancy is confirmed 3. Adjust levothyroxine dosage to maintain a serum TSH level ⬍2.5 mIU/L. Increment in dosage may depend upon etiology of hypothyroidism Athyreosis (Graves’ after 131 I therapy, thyroid cancer) approximately 45% increment Hashimoto’s thyroiditis approximately 25% increment Subclinical hypothyroidism may not require increment 4. TSH should be monitored every 4–6 wks in the first half of pregnancy; subsequently, it can be checked every 8 wks, unless a dose adjustment is made. 5. Patients should be instructed to separate levothyroxine ingestion and prenatal vitamins containing iron, iron or calcium supplements, or soy products by at least 4 hrs. 6. After delivery, the levothyroxine dose should reduced to the prepregnancy dosage and the serum TSH level should be rechecked at 6-wk postpartum.

hypothyroidism should be instructed to increase their usual levothyroxine intake by two additional doses each week immediately on confirmation of pregnancy and to contact their health care provider so that a program of TSH guided dose adjustments can be instituted (7). Patients should be instructed to separate levothyroxine ingestion from that of prenatal vitamins containing iron and especially iron supplements, calcium supplements, and soy products which may interfere with levothyroxine absorption (42,43). Thyroid function should be rechecked four to six weeks after any dose change. The dose may be lowered to prepregnancy levels at delivery and thyroid function should be measured at the 6-week postpartum visit. HYPERTHYROIDISM HCG-Associated Thyrotoxicosis and Hyperemesis Gravidarum A spectrum of hCG-induced hyperthyroidism occurs during pregnancy and this entity has recently been referred to as “gestational thyrotoxicosis” (44,45). As previously noted, it is postulated that hCG activates the TSH receptor by a spillover mechanism because of the molecular similarity between these two glycoproteins (12). Findings range from an isolated subnormal serum TSH concentration (up to 18% of pregnancies) to elevations of free thyroid hormone levels in the clinical setting of hyperemesis gravidarum. In women without symptoms of thyrotoxicosis, the serum TSH level may be subnormal but detectable in approximately 9% and undetectable (⬍0.05 mU/L) in an additional 9% (46). Systematic screening of 1900 consecutive pregnant women at their initial antenatal visit demonstrated low serum TSH and elevated FT4 levels in 2.4%, half of whom had weight loss, lack of

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weight gain, or unexplained tachycardia (45). In all these women, normalization of the FT4 paralleled the decrease in hCG. It has been observed that hyperemesis gravidarum, defined as severe nausea and vomiting in pregnancy resulting in weight loss and fluid and electrolyte disturbances, has been associated with abnormal thyroid function tests. Suppressed serum TSH levels may occur in 60% of these patients, with elevated FT4 levels in almost 50% (47). Serum hCG concentrations correlate positively with the serum FT4 levels and inversely with serum TSH determinations. The magnitude of the deviation from normal values increases with the severity of nausea and vomiting (48). Furthermore, thyroid stimulating activity as measured by adenylate cyclase activity per IU of hCG is reported to be greatest in women with hyperemesis gravidarum when compared to those with occasional or no vomiting (44). The vomiting may be related to the elevated, hCG-mediated estradiol production since estradiol levels are higher in hyperemesis subjects than controls, rather than to the thyroid stimulation itself (49). Similar thyroid hormone changes and emetic symptoms may be present with multiple gestations, which are associated with higher peak and more sustained hCG levels (7,44). In addition, a recent case report further supports the concept of hCG-induced thyrotoxicosis. A woman and her mother with recurrent gestational thyrotoxicosis were found to have a missense mutation in the extracellular domain of their TSH receptor that caused a two- to –threefold increase in activation (cAMP generation) when exposed to hCG compared to wild type receptor (50). Gestational thyrotoxicosis is transient and usually resolves within 10 weeks of the diagnosis (47). In one study of 44 women with hyperemesis gravidarum, serum FT4 levels normalized by 15 weeks gestation while serum TSH remained suppressed until 19 weeks gestation (51). Clinically, this disorder differs from Graves’ disease in several ways: (1) nonautoimmune origin, with negative antithyroid and anti-TSH receptor antibodies; (2) absence of goiter; (3) resolution in almost all patients after 20 weeks gestation (52). Hyperthyroid symptoms such as weight loss, or lack of normal pregnancy weight increase and tachycardia are present in 50% of women with gestational thyrotoxicosis (45). However, ophthalmopathy, which is autoimmune in origin, is not seen with this disorder. Treatment with ATD is not recommended unless coincident Graves’ disease is present (25). Patients with hyperemesis who remain symptomatic after 20 weeks gestation with elevated thyroid hormone concentrations and suppressed TSH levels may be considered for antithyroid drug therapy. More than likely, such patients probably have mild Graves’ disease. Graves’ Disease Hyperthyroidism is reported to affect 1 in 500 pregnancies, with Graves’ disease accounting for the vast majority of cases (85%), with less common causes being toxic nodular disease in 10% and thyroiditis in 1% to 2% (53). Autoimmune thyroiditis should also be considered as a possible cause, especially if a woman

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has had a recent miscarriage, which has been reported to trigger “postpartum” thyroiditis (see section “Postpartum Thyroiditis” of this chapter) (54). The activity of Graves’ disease fluctuates through pregnancy with TSH receptor antibody (TRAb) patterns generally reflecting the clinical course of the disease (55). TRAb may be elevated in the first trimester, but values often decrease over the second and third trimesters and may become undetectable before increasing again postpartum (56,57). Clinically, patients may experience relapse or exacerbation of Graves’ disease by 10 to 15 weeks of gestation. However, Graves’ disease may remit in the late second and third trimesters, a time of known immune tolerance (58). This disease pattern is thought to be due to decreases in TRAb, as described above, rather than increases in inhibitory anti-TSH receptor antibodies (56). Often, antithyroid drug dosage can be reduced or even discontinued late in gestation, only to be followed by a worsening of the disease in the postpartum period (58). Graves’ disease may affect a pregnancy in three scenarios. First, women may have active Graves’ disease (either treated or untreated) that can be exacerbated in the first trimester. Second, women in remission may experience a relapse during pregnancy. Third, Graves’ disease may occur for the first time during gestation (59). In women who have been euthyroid throughout pregnancy, but have been treated with ATD for Graves’ disease previously, hyperthyroidism may recur in the postpartum period. However, this may represent either the thyrotoxic phase of PPT in up to 25% or relapse of Graves’ disease. Even in those with PPT, Graves’ disease may recur after resolution of PPT (60). Diagnosis The clinical diagnosis of hyperthyroidism may be difficult because pregnancy is itself a hypermetabolic state with symptoms of palpitations and heat intolerance. In addition, patients will usually have increased irritability, decreased exercise tolerance, and fatigue. Patients may describe an inability to control their emotions, with otherwise small irritants culminating in what may be perceived as exaggerated emotional responses. They are aware of increasing shortness of breath climbing stairs. The astute clinician must be cognizant of this constellation of symptoms so that the patient can be appropriately screened for hyperthyroidism. The examination usually reveals the presence of a diffuse goiter, sometimes with a bruit or thrill. Other clinical signs may be present as described in Chapter 2. Laboratory studies reveal a serum TSH level below the trimester-specific 95% lower confidence limit, usually with elevated serum thyroid hormone concentrations. However, it must be remembered that up to 50% of women with hyperemesis gravidarum may have a suppressed serum TSH level and/or elevated FT4 (49). An elevated free T3 index or free T3 level may be the most clinically useful test to distinguish hyperthyroid patients from those with hyperemesis gravidarum as less than 15% of hyperemetic women with have elevations in these

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Table 3 Pregnancy Complications Reported in Hyperthyroid Women Controlled hyperthyroidism on ATD therapy Miscarriage (62,65) Preterm delivery (53,62,63) Preeclampsia (53) Heart failure (63) Stillbirth (62,63) Small for gestational age (64,65) Thyroid storm

8–10% 3–14% 2% 3% 0% less less

Untreated hyperthyroidism 21% 21–88% 11% 63% 7–50% more more

Abbreviation: ATD, antithyroid drug.

measures (49). TSH receptor antibodies are usually detectable and may also be of diagnostic utility. Pregnancy Outcome Throughout the discussion of the risks and treatment of Graves’ disease during pregnancy, it is important to remember that in reality there are two patients, the mother and the fetus. Maternal hyperthyroidism is associated with increased morbidity for both mother and fetus. Prior to the development of ATD, only about 50% of hyperthyroid women were even reported to be able to conceive. Of those who conceived, spontaneous miscarriage and premature delivery occurred in half (61). The frequency of poor outcomes for both mother and fetus is correlated with the degree and duration of hyperthyroidism, with the highest rates in those women with uncontrolled disease and a decreased risk in those appropriately treated with ATD (Table 3) (53,62–65). In addition, one study reported an increased incidence of congenital malformations (imperforate anus, polydactyly, harelip) if maternal hyperthyroidism is uncontrolled at the time of embryogenesis in the first trimester, although ATD therapy itself is not associated with a higher incidence of structural anomalies (66). These results highlight the importance of control of maternal hyperthyroidism to ensure optimal pregnancy outcome. Significantly, subclinical hyperthyroidism, defined as a serum TSH level below the 2.5th percentile for gestational age and a normal serum FT4 level, has not been found to be associated with adverse pregnancy outcomes (67). Treatment Antithyroid Drugs ATD are the main treatment for Graves’ disease during pregnancy. Propylthiouracil R ) have both been used during gestation. (PTU) and methimazole (MMI, Tapazole
They inhibit thyroid hormone synthesis via reduction in iodine organification

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and iodotyrosine coupling (see chap. “Graves’ Disease”). Pregnancy itself does not appear to alter the maternal pharmacokinetics of MMI, although serum PTU levels may be lower in the latter part of gestation compared to the first and second trimesters (68). PTU is more extensively bound to albumin at physiologic pH, whereas MMI is less bound, which hypothetically might result in increased transplacental passage of MMI relative to PTU. Historically, PTU was preferred over MMI, partly due to early experimental data suggesting that PTU, which is more highly protein bound than MMI, had more limited transplacental passage than MMI (69). Since then, however, other studies have found that both drugs readily cross the placenta (70,71). No such data evaluating simultaneous maternal and cord levels are available for MMI. The goals of treatment of Graves’ disease during pregnancy are to control maternal hyperthyroidism with vigilant monitoring of maternal thyroid function and to optimize fetal outcome with careful surveillance of fetal development. Throughout gestation, it is critical that the endocrinologist and obstetrician communicate frequently so that biochemical and clinical parameters may be correlated. Signs of clinical improvement include maternal weight gain and decrease in pulse rate, as well as appropriate fetal growth. For example, if there is concern because of lack of maternal weight gain in conjunction with mild elevations in thyroid hormone levels, the initiation of a low dose of ATD should be discussed. ATD: Effect on the Fetus The clinician must assume that both PTU and MMI cross the placenta and may decrease fetal thyroid hormone production. For women with Graves’ disease, fetal thyroid status reflects the influence of two maternal factors, both of which cross the placenta: maternal ATD dosage and maternal TRAb activity. Different assays for maternal TRAb exist. The more commonly used radioreceptor assay is the TBII. This assay does not distinguish between those antibodies that bind to and block the TSH receptor versus those that stimulate the receptor, resulting in increased thyroid production (72). However, in the majority of women with Graves’ disease, TBII levels are reported to represent stimulating antibodies and correlate with maternal disease activity (73). The currently available bioassay is the thyroid stimulating immunoglobulin (TSI), which measures the generation of cyclic adenosine monophosphate by cells that express TSH receptor when incubated with the patient’s serum (73). Therefore, given these two potential opposing influences on fetal thyroid function, what are the data correlating fetal thyroid function with maternal ATD dosage? There are seven published studies examining a dose-response relationship between maternal ATD dose and neonatal thyroid function. Three have reported a direct correlation (64,73,74) and four have not demonstrated this (70,74–76). In fact, one study reported that even low daily ATD dosages (PTU 100 mg or less, MMI 10 mg or less) at term may affect the fetal thyroid function; an elevated cord TSH level was found in 23% of babies born to such PTU-treated mothers and in 14% of those treated MMI (76). The lack of correlation between maternal dosage

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and fetal thyroid function may also reflect maternal factors as well, because there is individual variability in serum PTU levels after a standard oral dose (72,77). The second factor influencing fetal thyroid function is the transplacental passage of maternal TRAb resulting in excessive fetal thyroid stimulation. Clinically, this becomes relevant at 24 to 26 weeks, and maternal levels reflect the degree of fetal exposure (78). There is a strong correlation between maternal and cord TBII levels at term with development of neonatal hyperthyroidism (see section “Fetal/Neonatal Hyperthyroidism” of this chapter). In contrast, the continued use of maternal ATD therapy at term, in conjunction with low maternal TBII levels may result in elevated serum TSH levels in approximately 50% to 60% of infants (73). In this scenario, fetal thyroid function may reflect the relative importance of maternal ATD dosage when maternal immune thyroid stimulation is low. It is possible that in pregnant women with toxic nodules, a dose relationship may be more likely to be seen, since there is no contribution of fetal thyroid stimulation by the maternal immune system. Therefore, given these varied influences on fetal thyroid function, coupled with maternal individual differences in ATD pharmacology, it is not surprising that fetal thyroid status is not strictly correlated with maternal ATD dosage. Based on the literature, current maternal thyroid status rather than ATD dose, is the most reliable marker for titration of ATD therapy to avoid fetal hypothyroidism (75). A recently published abstract analyzed fetal cord FT4 and TSH levels at birth in relation to maternal serum FT4 levels in 249 women with Graves’ disease who continued ATD through delivery (79). The authors reported that low fetal cord blood FT4 levels were avoided only when the maternal serum FT4 concentration was ⬎1.9 ng/dL, although one infant whose mother’s serum FT4 level was 2.1 ng/dL developed central congenital hypothyroidism. The normal nonpregnant reference range for FT4 in this study was 0.8 to 1.9 ng/dL (10.3–24.5 pmol/L). However, if the maternal serum FT4 is in the lower two-thirds of the nonpregnant normal reference range, 36% of neonates have a decreased FT4 and a decreased FT4 is found in all neonates if the maternal FT4 is below normal (75). In addition, overdosage with ATD alone may result in fetal or neonatal goiter, which may cause respiratory distress at birth if markedly enlarged. Goiter is reported to have occurred more frequently in older reports where concomitant iodide therapy was used. Because of either transplacental ATD or iodide-induced inhibition of fetal thyroid hormone production, fetal serum TSH levels increase, resulting in stimulation of thyroid growth. A fetal utrasound should be obtained for all women who are still taking relatively high ATD doses at 26 to 28 weeks (PTU ≥450 mg/day, MMI ≥30 mg/day) (55). If a fetal goiter is detected on a late pregnancy ultrasound, the clinician must consider whether this represents “Fetal Hyperthyroidism” (see below) or fetal “hypothyroidism” because of transplacental passage of maternal ATD therapy. Intrauterine growth retardation may occur with either condition, but fetal tachycardia (⬎160–180 beats per minute) and advanced fetal bone age is highly suggestive of hyperthyroidism (55,80,81). In cases where neonatal goiter has occurred because of maternal ATD use, resolution usually

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occurs within the first two weeks of life with dissipation of the drug (74). Therefore, one approach is to stop maternal ATD therapy and monitor the fetal goiter by ultrasound. There are several case reports of intra-amniotic levothyroxine injections for treatment of the fetal goiter due to maternal ATD exposure. However, in two recent reports (82,83), the injections occurred while the maternal PTU dose was lowered. Therefore, it is difficult to distinguish the relative importance of each factor on the resolution of the fetal goiter. A third recent case report demonstrated that cessation of maternal ATD therapy alone resulted in decrease in the fetal goiter documented ultrasonographically (84). In cases of fetal goiter where hypothyroidism is suspected because of transplacental ATD, it may be prudent to discontinue or substantially decrease maternal ATD, and follow the goiter with sequential ultrasounds. If reduction in size does not occur within two to three weeks, periumbilical blood sampling should be performed to determine fetal thyroid function. If still low, intra-amniotic levothyroxine therapy should be given. Four studies have reported no defects in either the cognitive and somatic development of children exposed to maternal ATD in utero (85–88), even after accounting for higher dosage or first trimester exposure. These were crosssectional studies that measured cognitive development by intelligence quotient. Therefore, it is unknown if transient, or more subtle developmental changes might have been present. However, maternal thyroid hormone levels were not reported, so it is unknown if maternal hypothyroxinemia, a possible risk factor for cognitive impairment, was present. There have been reports of an association of maternal MMI therapy with aplasia cutis, a heterogeneous group of disorders in which localized or widespread areas of skin are absent at birth. The lesions seen in infants born to MMI treated mothers have all been all localized scalp defects. However, the reported frequency of this disorder in infants born to MMI-treated mothers is not higher than the expected sporadic frequency (68). No cases to date have been reported with PTU therapy despite its more widespread use. For this reason, the recently published Endocrine Society guidelines on management of thyroid disorders during pregnancy recommend, if available, PTU to MMI for initial therapy of maternal hyperthyroidism, at least in the first trimester when organogenesis occurs (25). In addition, the rare disorder of absent or hypoplastic nipples associated with choanal atresia has been reported in two infants born to mothers treated with MMI during the first trimester (89). ATD: Treatment Guidelines (Table 4) ATD dosage should be titrated to maintain either maternal serum FT4 levels at or up to 10% above the normal limit of the nonpregnant reference range reported by that laboratory or maternal total T4 at the upper limit of the pregnancy appropriate reference range (1.5 times the nonpregnant reference range) (25). Maternal serum T3 levels may not be as helpful because there is no correlation with fetal thyroid function (75). Practically this means that ATD dosage should be adjusted to

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Table 4 Guidelines for Clinical Management of Maternal Hyperthyroidism During Pregnancy (25,59) Treatment goal: Subclinical hyperthyroidism FT4: Use nonpregnant reference range Titrate to or 10% above upper normal limit Total T4: Use pregnant reference range (1.5 times nonpregnant reference range) Titrate to upper normal limit TSH: May consider measuring TSH after 2–3 mo Titrate at or just below lower trimester-specific limit 1. Use the lowest dose of ATD to maintain maternal thyroid hormone levels at above targets. Because PTU has not been implicated in causing aplasia cutis, initiating therapy with PTU is preferred. 2. Check maternal function tests monthly 3. ATD dose can usually be lowered or discontinued (30%) by 32–36 weeks gestation 4. If either high maintenance ATD doses are required (PTU ⬎450 mg/day, MMI ⬎40 mg/day or if a patient is nonadherent or allergic to ATD therapy, surgery (subtotal thyroidectomy) should be considered. 5. Low doses of iodides may be used transiently, especially preoperatively. 6. Frequent communication between the endocrinologist and obstetrician is essential so that ATD dose titration is done with monitoring of fetal growth. 7. TRAb measurement and fetal ultrasound should be considered as discussed in Table 6. Abbreviations: ATD, antithyroid drug; PTU, propylthiouracil; MMI, methimazole; TRAb, TSH receptor antiobodies.

maintain a serum FT4 of 1.7 to 2.0 ng/L. If a woman has mild Graves’ disease with these values as her initial indices, treatment may be withheld and her thyroid status monitored as long as she has satisfactory clinical progression of pregnancy. Later, if the serum TSH becomes detectable, it should be kept at or just below at or just below the 95% confidence interval trimester-specific lower limit. (25). Therefore, the therapeutic treatment goal for Graves’ disease during pregnancy is actually subclinical hyperthyroidism compared to normal pregnant physiology. However, as mentioned before, there are no reported gestational adverse effects of maternal subclinical hyperthyroidism (67,90) and this slight degree of undertreatment of the mother optimizes fetal outcome. The initial ATD dosage may vary depending upon the degree of hyperthyroidism. We prefer to begin therapy with PTU because there are no reported cases of PTU-associated aplasia cutis. However, if a woman cannot tolerate PTU or finds it difficult to take the prescribed number of pills (PTU usually requires multiple daily dosages, whereas MMI can often be given once daily), MMI may be substituted. It is our approach generally not to use more than 450 mg of PTU or 30 mg of MMI daily. The median time to normalization of the maternal FT4 index is seven to eight weeks for both PTU and MMI (91), although improvement in

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parameters may be seen earlier at three to four weeks. One should reassess maternal FT4 or total T4 three to four weeks later and adjust ATD dosage based upon the decrement in thyroid hormone levels. As in nonpregnant women with Graves’ disease, maternal serum TSH levels may remain suppressed for several weeks after normalization of thyroid hormone levels, and it is not helpful to monitor the serum TSH early in treatment. Graves’ disease may improve in the third trimester and with progressive decreases in ATD dosage throughout pregnancy, therapy may be stopped by 32 to 34 weeks gestation in 30% of women (92). Of course, the same spectrum of adverse effects related to ATD therapy in the nonpregnant state applies to use during gestation (see chap. “Graves’ Disease”). Beta-Adrenergic Blockers Beta-adrenergic blocking agents may be used transiently to control adrenergic symptoms, until ATD therapy decreases thyroid hormone levels. There is a recent report of a higher rate of spontaneous first trimester miscarriages in women who were treated with combined ATD and propranolol therapy compared to ATD alone, although both groups had similar levels of thyroid hormone (93). However, this was a small series and propranolol was prescribed for 6 to 12 weeks, which may be longer than would be typically necessary in most patients. Iodides Chronic use of iodides during pregnancy has been associated with hypothyroidism and goiter in neonates, sometimes resulting in asphyxiation because of tracheal obstruction (68). However, a recent report of low-dose potassium iodide (6–40 mg/ day) administered to selected pregnant hyperthyroid women with maintenance of maternal FT4 levels in the upper half of the nonpregnant reference range did not cause goiter, although 6% of newborns had an elevated serum TSH level (94). Since the experience with iodides is more limited, iodides should not be used as a first line therapy for women with Graves’ disease, but could be used transiently if needed in preparation for thyroidectomy. Surgery Subtotal thyroidectomy is usually only considered during pregnancy as therapy for maternal Graves’ disease if consistently high levels of ATD (PTU ⬎450 mg/day, MMI ⬎40 mg/day) are required to control maternal hyperthyroidism, if a patient is nonadherent or allergic to ATD therapy, or if compressvie symptoms exist because of goiter size. If a woman has experienced severe ATD-related side-effects such as agranulocytosis, she should receive transient therapy with supersaturated potassium iodide solution (50–100 mg/day) for 10 to 14 days prior to surgery. The timing of surgery is usually in latter half of the second trimester. The rationale for not performing surgery in the first trimester is that this is the time of the highest spontaneous abortion rate and surgery could possibly further increase the risk. However, there are no definitive data supporting an increased miscarriage rate

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related to the surgical procedure and anesthesia if performed in the first trimester (95) and subtotal thyroidectomy may be done if clinically indicated. 131

I Therapy

Because of its adverse effects on the fetus, the use of 131 I therapy is completely contraindicated in pregnancy, especially after 12 weeks gestation when the fetal thyroid begins to concentrate radioiodine with an even greater avidity than the maternal thyroid. In addition, other fetal tissues are generally more radiosensitive (96). A pregnancy test should be performed in all women prior to radioiodine therapy. However, inadvertent administration of 131 I in early pregnancy may occur and a survey was sent to endocrinologists regarding their experience with this situation. Of 237 cases, therapeutic abortion was advised and performed for 55 patients. In the remaining 182 pregnancies, the risk of stillbirths, spontaneous abortions, and fetal abnormalities was not higher than the general population (97), perhaps because the fetal whole-body irradiation from a therapeutic 131 I dose for Graves’ disease at this time is calculated to be below the threshold associated with increased congenital defects (96). However, six infants were hypothyroid at birth, four of them were mentally retarded. 131 I therapy had been given after 12 weeks in three of the mothers of the hypothyroid infants, at a time when the fetal thyroid had already begun to concentrated iodine (97). Therefore, fetal hypothyroidism is more likely to occur if 131 I treatment is given after 12 weeks and congenital defects would be the major concern after 131 I therapy in the early first trimester. Dosimetry studies could quantitate the actual fetal exposure, but experts have suggested that the “relatively low fetal whole-body irradiation is probably not sufficient to justify termination of pregnancy.” (96). If inadvertent 131 I therapy has been administered to a pregnant woman, PTU therapy may be initiated within seven days of 131 I, which may reduce 131 I recycling by the fetal thyroid, thereby lowering radiation exposure (96). All infants exposed to maternal 131 I therapy need to be evaluated immediately at birth with institution of levothyroxine therapy if congenital hypothyroidism is documented. The therapeutic administration of 131 I to a nursing mother is contraindicated and lactation should be stopped immediately if this occurs. Lactation Traditionally, many texts have advised against breast-feeding in women treated with ATDs because of the presumption that the ATD was present in breast milk in concentrations sufficient to affect the infant’s thyroid. However, over the last two decades, several studies have prospectively monitored thyroid function in infants nursed by mothers taking ATD therapy. PTU is more tightly protein bound than MMI; consequently, the ratio of milk to serum levels is lower for PTU (0.67) (98) than for MMI (1.0) (99). In addition, the amount of ingested drug secreted in breast milk is approximately six times higher for MMI than for PTU (0.14 vs. 0.025% of the ingested dose) (98).

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Several studies reported no alteration in thyroid function in a total of 56 newborns breast-fed by mothers treated with daily doses of PTU (50–300 mg), MMI (5–20 mg), or carbimazole (5–15 mg) for periods ranging from three weeks to eight months Even in women who were overtreated and developed elevated serum TSH levels, the babies’ thyroid function tests remained normal (100). Therefore, ATD therapy (PTU ⬍300 mg/day, MMI ⬍20 mg/day) may be considered during lactation, although the number of reported infants is small. PTU would be preferred because of its decreased appearance in breast milk, and the drug should be taken by the mother after a feeding. In addition, the theoretic possibility of the infant developing ATD side-effects via ATD ingestion through lactation has not been reported (101). Fetal/Neonatal Hyperthyroidism In either women with active Graves’ disease or those with radioiodine ablated, surgically treated Graves’ disease, fetal or neonatal hyperthyroidism is reported to occur in 1% of pregnancies (102). However, there are no data evaluating whether the incidence rate is higher in those with active versus “thyrodectomized” Graves’ disease. This disorder is caused by the transplacental passage of maternal TRAb that stimulate fetal thyroid hormone production and may cause goiter. Maternal to fetal IgG transport becomes clinically significant at the end of the second trimester, which is when fetal hyperthyroidism usually becomes apparent. Measurement of maternal TSI or TBII at 26 to 28 weeks provides prognostic information about the development of fetal Graves’ disease (55,64). However, the measurement of these antibody levels is not standardized and may depend upon the individual laboratory’s reference range. Therefore, the magnitude of the TRAb elevation compared to that assay’s normal range may be more practical for prediction of fetal/neonatal hyperthyroidism (Table 5) (55,57,64,73,81,103–106). Table 5 Prediction of Fetal/Neonatal Graves’ Disease

Zakarija 1983 (57) Matsuura 1988 (104) Mortimer 1990 (73) Mitsuda 1990 (64) Smith 2001 (105) Peleg 2002 (106) Nachum 2003 (81) Luton 2005 (55)

TRAb methodology

Fold (x) above upper normal limit

TSI TBII TSI TBII TBII TBII TSI TSI TBII

5 3 3.5 5 3 3.5 5 2 3

Abbreviations: TRAb, TSH receptor antibody; TSI, thyroid stimulating immunoglobuin; TBII, thyroid binding inhibitory immunoglobulin.

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Table 6 TRAb Measurement and Fetal Ultrasound to Predict Fetal Thyroid Dysfunction(55,103)

Maternal TRAb measurement Timing of TRAb measurement

Graves’ disease on ATD therapy

Graves’ disease after 131 I therapy or thyroidectomy

YES

YES

Early 3rd trimester

End of 1st trimester if negative: no repeat if positive: repeat early 3rd trimester

Graves’ disease in remission on no therapy NO

If mother is TRAb + or taking ATD → Fetal ultrasound at 28–32 wks to check for fetal goiter, tachycardia, and bone growth. Abbreviations: TRAb, TSH receptor antibody; ATD, antithyroid drug.

Fetal thyroid ultrasound at 32 weeks in screening for clinically relevant fetal thyroid dysfunction has a reported sensitivity of 92% and a specificity of 100% (55). However, if a fetal goiter is detected, fetal hyper- and hypothyroidism must be differentiated. Signs suggestive of fetal hyperthyroidism include intrauterine growth retardation, arrhythmias, congestive heart failure, advanced bone age, craniosynostosis, and hydrops (80,81). Another suspicious feature is a diffuse Doppler ultrasound signal throughout the thyroid gland (55). Tachycardia (⬎ 160 beat per minute) may indicate, but is not always present in, fetal thyrotoxicosis (55). If necessary, periumbilical blood sampling will confirm the diagnosis. Although there are no established normal ranges for fetal thyroid hormone levels, the serum TSH is greater than 20 mU/L in the published cases of fetal hypothyroidism (82) or the serum T4 level is markedly elevated in those of fetal hyperthyroidism (107,108). Periumbilical blood sampling has risks of fetal bleeding, bradycardia, infection, and death (82) and is usually not indicated as the diagnosis can often be made clinically. A rational approach for the detection of fetal and neonatal hyperthyroidism using TRAb measurement and fetal ultrasound is presented in Table 6. Treatment of fetal hyperthyroidism is accomplished by giving the mother ATD therapy, which then crosses the placenta and inhibits fetal thyroid hormone synthesis. Hypothetically, because MMI is less protein bound, it might more readily cross the placenta and have a greater effect on fetal thyroid function. Generally, in the United States, PTU has been used in cases of suspected fetal hyperthyroidism, and can be initiated at doses of 150 mg/day, with subsequent normalization of fetal heart rate within two weeks (78). The dose can then be titrated to maintain a normal fetal heart rate. In a woman who has received prior radioablation or surgery for Graves’ disease, levothyroxine therapy may have to be initiated or increased if maternal hypothyroxinemia occurs. Since TSI and TBII

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levels usually decline toward term, ATD dosage can be decreased as fetal heart rate and growth are monitored. If antibody levels remain elevated at term, the risk of neonatal hyperthyroidism is increased (Table 6). Cord blood should be assayed for serum TSH and FT4 levels. However, if these are normal and the mother has been taking ATD at term, the baby’s thyroid function tests should be rechecked at four to six days of life to dectect delayed hyperthyroidism because the clinical manifestations of hyperthyroidism in the newborn may be masked for the first week of life until maternal ATD dissipate (103,109). ATD therapy is necessary for treatment of neonatal Graves’ disease. As maternal antibody levels decrease over the first three months of life, therapy can usually be discontinued (109). THYROID NODULES AND THYROID CANCER Although goiter may occur during pregnancy in areas of borderline iodine deficiency (110), thyroid size does not increase in iodine replete areas (111). The prevalence of nodules has been reported to be higher in middle-aged women with a history of three or more prior pregnancies (112), but solitary thyroid nodules or thyroid cancer do not arise de novo more frequently during pregnancy. The detection of thyroid nodules in pregnant women usually reflects the careful examination by an obstetrician of a healthy pregnant woman who had not regularly seen a physician prior to her conception. As in the nonpregnant patient (see chapter 5 “Thyroid Nodules and Multinodular Goiter”), diagnostic thyroid ultrasound for nodule characterization and fineneedle aspiration (FNA) as indicated should be performed for diagnosis in nodules identified during pregnancy (113); the spectrum of cytologic results is the same as in the nonpregnant patient (114). Radioactive iodine scanning is contraindicated at this time, but ultrasound can be performed either for characterization and monitoring of the nodule or for guidance of the FNA. Nodules with a benign cytology may be observed, and those with a cytology suggestive of follicular neoplasm may require further evaluation and probable surgery after delivery. If the FNA cytology shows evidence of a thyroid cancer, surgery is recommended. However, the timing of surgery, either during or after pregnancy, is debatable with some recommending surgery during the midtrimester (114) and others advocating waiting until after delivery (115). A recent study has reported no significant difference in recurrence or survival rates between women with malignant nodules who had surgery either during or after pregnancy (116). Furthermore, thyroid cancer discovered during pregnancy is not more aggressive than that found in a similar aged group of nonpregnant women (115). For women with previously treated thyroid cancer, most reports confirm that subsequent pregnancy does not increase recurrence rates (117). For a nodule with malignant cytology, the recently published American Thyroid Association guidelines recommend that “if discovered early in pregnancy, [it] should be monitored sonographically and if it grows substantially by 24 weeks’

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gestation, surgery should be performed at that point. However, if it remains stable by midgestation or if it is diagnosed in the second half of pregnancy, surgery may be performed after delivery.” (113) In such women, levothyroxine therapy may be considered to maintain the serum TSH level in the subnormal, but detectable range (0.1–0.3 mU/L), which would theoretically slow TSH-responsive tumor growth and should not be associated with pregnancy complications. Radioactive iodine therapy, if needed, must be delayed until the postpartum period. POSTPARTUM THYROIDITIS PPT is a painless, destructive inflammation of the thyroid characterized by transient hyperthyroidism and/or hypothyroidism that occurs within the first 6 to 12 months after delivery in women who were euthyroid during pregnancy. It is reported to occur in 2% to 17% of women. The discrepancies in prevalence may reflect differences in diagnostic criteria, as well as variable predisposing genetic factors and iodine intake that differ among screened populations (118). PPT is thought to be an autoimmune disorder for several reasons. It is temporally related to the time of immunologic “rebound” that occurs in the first months after delivery (119). On cytology, lymphocytic thyroiditis is evident and similar HLA haplotypes are found in patients with PPT and Hashimoto’s thyroiditis (118). Several studies have documented a correlation between antithyroid antibody positivity and the development of PPT. The presence of antithyroid peroxidase antibodies in the first trimester is associated with a 33% risk of developing PPT. Women who develop PPT have consistently higher titers of antithyroid antibodies throughout gestation, compared to women who have detectable antibodies but do not develop PPT (120). If antithyroid antibodies are detectable two days postpartum, PPT is reported to affect 67% of women (121). There may also be a contribution of cellular immunity to the development of PPT. The ratio of helper to suppresser T-cells declines progressively during pregnancy followed by an increase postpartum. Although women who develop PPT manifest a decline in the helper/suppresser ratio during pregnancy, the ratio is higher compared to unaffected women (120). In addition, women with type 1 diabetes mellitus, another autoimmune disease, have an increased incidence of PPT compared to the general population (122). Lastly, euthyroid patients with a history of Graves’ disease may develop PPT initially after delivery, which may subsequently be followed by Graves’ hyperthyroidism (60). The thyrotoxic phase of PPT thyroiditis generally occurs within the first one to four months after delivery and is transient, lasting for one to two months. There is release of stored thyroid hormone from the damaged thyroid gland, rather than increased thyroidal production of thyroid hormone. Hypothyroidism may follow and last from two to six months until follicular cell synthetic activity recovers and euthyroidism returns. Not all patients experience both hyper- and hypothyroidism. In fact, either transient hyper- or hypothyroidism alone is observed in the majority of reported patients (123). However, this may reflect differences in screening protocols and the monitoring schedule of postpartum thyroid function.

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The majority of patients recover from the hypothyroid phase of PPT. However, up to 10% of patients may have persistent hypothyroidism and 20% may later develop permanent hypothyroidism over the next 2 to 10 years (124). The risk of permanent hypothyroidism is correlated with the severity of the hypothyroid phase of PPT and the elevation of the serum TSH level as well as the elevation in antithyroid antibody levels (125). In addition, for those women who recover, there is a 70% risk of developing recurrent PPT after a subsequent pregnancy (126). There are no data addressing the future risk to these women of developing “silent” autoimmune thyroiditis, not associated with pregnancy. Diagnosis The clinical manifestations of the thyrotoxic phase of PPT are not usually severe. Fatigue and emotional lability may be prominent features, both of which are often attributed to the postpartum state itself. Fatigue is the most consistent finding during the hypothyroid phase, but again is a nonspecific symptom. When compared to postpartum euthyroid women, hypothyroid patients with PPT have significantly increased symptoms of impaired concentration and memory, carelessness, and depression (121). Among women diagnosed with postpartum depression, PPT is present twice as often as in women without depression (127). In addition, in one study depressive symptoms in the postpartum period were associated with positive antithyroid antibody status even without thyroid dysfunction (128). On examination, a painless goiter is often detected. The clinician should consider the diagnosis of PPT in any postpartum woman who presents with a goiter and/or the nonspecific symptoms of fatigue, emotional lability, or palpitations. The serum TSH concentration will be suppressed during the thyrotoxic phase and elevated during the hypothyroid phase. However, in the transition period from thyrotoxicosis to hypothyroidism, changes in the serum TSH level may lag behind the decline in thyroid hormone levels, and may therefore be in the normal range when serum thyroid hormone concentrations are low. Consequently, when assessing patients for PPT, it is important to obtain measurements of both serum TSH and FT4 levels. Thyroid receptor antibody levels are usually elevated in patients with Graves’ disease and not in PPT, unless a patient has a prior history of Graves’ disease (60). During the thyrotoxic phase, a radioiodine uptake (contraindicated in pregnant women) is low, differentiating hyperthyroidism in PPT caused by leakage of stored thyroid hormone from the postpartum presentation of Graves’ disease with increased hormone production. If a patient is nursing and an uptake is considered critical for diagnosis, radiation safety and nuclear medicine should be consulted. 123 I is excreted in breast milk and has an effective half-life of five to eight hours. An radioiodine uptake with 123 I (scan is not necessary) can be performed after counseling and nursing should be stopped for at least 48 hours after 123 I administration (129). Afterwards, she may bring in an aliquot of milk for assessment of any residual radioactivity and at that time, lactation can usually be resumed. If the patient has entered the recovery phase of PPT at the time of the uptake evaluation,

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the uptake may not be low as the serum TSH has now normalized or become elevated. The clinician should also be aware that PPT may occur in two other settings. PPT may develop in women after a miscarriage or therapeutic abortion, even if the pregnancy loss occurs as early as 5 weeks gestation (54). In addition, women previously diagnosed with subclinical hypothyroidism prior to conception and treated with subreplacement levothyroxine doses (0.025–0.075 mg/day) to normalize the serum TSH level may not require a dosage increase in pregnancy, which indicates that the residual thyroid is capable of functioning and synthesizing thyroid hormone. After delivery, the same residual thyroid is subject to the immunologic insult that causes PPT. These women will develop a suppressed serum TSH level during the thyrotoxic phase and levothyroxine should be stopped. However, during the hypothyroid phase, they may require a larger dose than their previous subreplacement dose to restore euthyroidism, since they have transiently lost thyroid hormone secretory capacity from the residual functioning thyroid (130). Treatment Treatment is usually not required during the thyrotoxic phase of PPT. Generally, by the time a patient recognizes the symptoms and seeks medical attention, thyroid function normalizes. ATD are not beneficial because the increase in circulating thyroid hormone is a result of a destructive process affecting the thyroid gland, not increased thyroidal synthesis. If palpitations are a prominent symptom, betaadrenergic blocking drugs may be used transiently. Diagnosis of the hyperthyroid phase of PPT is important because it identifies a group of women who likely will develop hypothyroidism, which has a more prolonged duration. Levothyroxine therapy can be initiated in patients with symptoms or TSH elevation ≥10 mU/L. Often, women may be treated with a subreplacement dose (0.05–0.075 mg/day) if the serum TSH level is between 10 and 20 mU/L, but may require a larger dose if the serum TSH is ⬎20 mU/L. The serum TSH level should be rechecked at four to six weeks, with dosage adjustment as needed. Since the hypothyroid phase may last up to six months, levothyroxine therapy may be continued empirically for several months after attaining a normal serum TSH level. At that point, it may either be discontinued or reduced by half, with monitoring of a serum TSH level three to four weeks later. If the serum TSH concentration is normal at that time, it should be rechecked an additional time four to six weeks later if levothyroxine was previously stopped or four to six weeks after discontinuation of the halved dose. If the serum TSH level increases above normal on a lower dose or off therapy, levothyroxine therapy is still required. Patients who recover from PPT should have periodic annual monitoring of thyroid function. However, the presence of autoimmune thyroid disease with positive antithyroid antibodies may confer a higher risk of miscarriage for future pregnancies and reinitiating levothyroxine therapy should be strongly considered prior to the next conception.

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Consensus recommendations for screening for PPT are controversial and universal screening cannot be justified currently (131). However, two populations, women with type 1 diabetes and those with a prior history of PPT, have a sufficiently high incidence of PPT that they might benefit from screening with TSH measurements at 6-week, 3-month, and 6-month postpartum. REFERENCES 1. Glinoer D, de Nayer P, Bourdoux P, et al. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 1990; 71(2):276–287. 2. Ain KB, Mori Y, Refetoff S. Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: A mechanism for estrogen-induced elevation of serum TBG concentration. J Clin Endocrinol Metab 1987; 65(4):689–696. 3. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J Med 1994; 331(16):1072–1078. 4. Demers LM, Spencer CA. Laboratory medicine practice guidelines: Laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf) 2003; 58(2):138–140. 5. Abalovich M, Gutierrez S, Alcaraz G, et al. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002; 12(1):63–68. 6. Mandel SJ, Larsen PR, Seely EW, et al. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990; 323(2):91– 96. 7. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004; 351(3):241–249. 8. Kaplan MM. Assessment of thyroid function during pregnancy. Thyroid 1992; 2(1):57–61. 9. Glinoer D, Delange F, Laboureur I, et al. Maternal and neonatal thyroid function at birth in an area of marginally low iodine intake. J Clin Endocrinol Metab 1992; 75(3):800–805. 10. Sapin R, D’Herbomez M, Schlienger JL. Free thyroxine measured with equilibrium dialysis and nine immunoassays decreases in late pregnancy. Clin Lab 2004; 50(9– 10):581–584. 11. Mandel SJ, Spencer CA, Hollowell JG. Are detection and treatment of thyroid insufficiency in pregnancy feasible? Thyroid 2005; 15(1):44–53. 12. Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonadotropin. Thyroid 1995; 5(5):425–434. 13. Panesar NS, Li CY, Rogers MS. Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 2001; 38(Pt 4):329–332. 14. Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005; 105(2):239–245. 15. Nelson M, Wickus GG, Caplan RH, et al. Thyroid gland size in pregnancy. An ultrasound and clinical study. J Reprod Med 1987; 32(12):888–890. 16. Stagnaro-Green A, Roman SH, Cobin RH, et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990; 264(11):1422–1425.

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72. Davies TF, Roti E, Braverman LE, et al. Thyroid controversy–stimulating antibodies. J Clin Endocrinol Metab 1998; 83(11):3777–3785. 73. Mortimer RH, Tyack SA, Galligan JP, et al. Graves’ disease in pregnancy: TSH receptor binding inhibiting immunoglobulins and maternal and neonatal thyroid function. Clin Endocrinol (Oxf) 1990; 32(2):141–1452. 74. Cheron RG, Kaplan MM, Larsen PR, et al. Neonatal thyroid function after propylthiouracil therapy for maternal Graves’ disease. N Engl J Med 1981; 304(9):525– 528. 75. Momotani N, Noh J, Oyanagi H, et al. Antithyroid drug therapy for Graves’ disease during pregnancy. Optimal regimen for fetal thyroid status. N Engl J Med 1986; 315(1):24–28. 76. Momotani N, Noh JY, Ishikawa N, et al. Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves’ hyperthyroidism. J Clin Endocrinol Metab 1997; 82(11):3633–3636. 77. Cooper DS, Saxe VC, Meskell M, et al. Acute effects of propylthiouracil (PTU) on thyroidal iodide organification and peripheral iodothyronine deiodination: Correlation with serum PTU levels measured by radioimmunoassay. J Clin Endocrinol Metab 1982; 54(1):101–107. 78. Fisher DA. Fetal thyroid function: Diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 1997; 40(1):16–31. 79. Momotani N, Iwama S, Noh J, et al. Anti-thyroid drug therapy for Graves’ disease during pregnancy: Mildest thyrotoxic maternal free thyroxine concentrations to avoid fetal hypothyroidism. In: 77th Annual Meeting of the American Thyroid Association.; 2006; Phoenix, AZ. 80. Chopra IJ. Fetal and neonatal hyperthyroidism. Thyroid 1992; 2(2):161–163. 81. Nachum Z, Rakover Y, Weiner E, et al. Graves’ disease in pregnancy: Prospective evaluation of a selective invasive treatment protocol. Am J Obstet Gynecol 2003; 189(1):159–165. 82. Davidson KM, Richards DS, Schatz DA, et al. Successful in utero treatment of fetal goiter and hypothyroidism. N Engl J Med 1991; 324(8):543–546. 83. Van Loon AJ, Derksen JT, Bos AF, et al. In utero diagnosis and treatment of fetal goitrous hypothyroidism, caused by maternal use of propylthiouracil. Prenat Diagn 1995; 15(7):599–604. 84. Ochoa-Maya MR, Frates MC, Lee-Parritz A, et al. Resolution of fetal goiter after discontinuation of propylthiouracil in a pregnant woman with Graves’ hyperthyroidism. Thyroid 1999; 9(11):1111–1114. 85. McCarroll AM, Hutchinson M, McAuley R, et al. Long-term assessment of children exposed in utero to carbimazole. Arch Dis Child 1976; 51(7):532–536. 86. Burrow GN, Klatskin EH, Genel M. Intellectual development in children whose mothers received propylthiouracil during pregnancy. Yale J Biol Med 1978; 51(2):151–156. 87. Messer PM, Hauffa BP, Olbricht T, et al. Antithyroid drug treatment of Graves’ disease in pregnancy: Long-term effects on somatic growth, intellectual development and thyroid function of the offspring. Acta Endocrinol (Copenh) 1990; 123(3):311– 316. 88. Eisenstein Z, Weiss M, Katz Y, et al. Intellectual capacity of subjects exposed to methimazole or propylthiouracil in utero. Eur J Pediatr 1992; 151(8):558–559.

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89. Greenberg F. Brief clinical report: Choanal atresia and athelia: Methimazole teratogenicity or a new syndrome? Am J Med Gen 1987; 28:931–934. 90. Casey BM. Subclinical hypothyroidism and pregnancy. Obstet Gynecol Surv 2006; 61(6):415–420; quiz 23. 91. Wing DA, Millar LK, Koonings PP, et al. A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 1994; 170(1 Pt 1):90–95. 92. Mestman JH. Hyperthyroidism in pregnancy. Clin Obstet Gynecol 1997; 40(1):45– 64. 93. Sherif IH, Oyan WT, Bosairi S, et al. Treatment of hyperthyroidism in pregnancy. Acta Obstet Gynecol Scand 1991; 70(6):461–463. 94. Momotani N, Hisaoka T, Noh J, et al. Effects of iodine on thyroid status of fetus versus mother in treatment of Graves’ disease complicated by pregnancy. J Clin Endocrinol Metab 1992; 75(3):738–744. 95. Brodsky JB, Cohen EN, Brown BW Jr, et al. Surgery during pregnancy and fetal outcome. Am J Obstet Gynecol 1980; 138(8):1165–1167. 96. Masiukiewicz US, Burrow GN. Hyperthyroidism in pregnancy: Diagnosis and treatment. Thyroid 1999; 9(7):647–652. 97. Stoffer SS, Hamburger JI. Inadvertent 131 I therapy for hyperthyroidism in the first trimester of pregnancy. J Nucl Med 1976; 17(02):146–149. 98. Kampmann JP, Johansen K, Hansen JM, et al. Propylthiouracil in human milk. Revision of a dogma. Lancet 1980; 1(8171):736–737. 99. Johansen K, Andersen AN, Kampmann JP, et al. Excretion of methimazole in human milk. Eur J Clin Pharmacol 1982; 23(4):339–341. 100. Azizi F, Khoshniat M, Bahrainian M, et al. Thyroid function and intellectual development of infants nursed by mothers taking methimazole. J Clin Endocrinol Metab 2000; 85(9):3233–3238. 101. Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001; 86(6):2354–2359. 102. Burrow GN. Thyroid function and hyperfunction during gestation. Endocr Rev 1993; 14(2):194–202. 103. Laurberg P, Nygaard B, Glinoer D, et al. Guidelines for TSH-receptor antibody measurements in pregnancy: Results of an evidence-based symposium organized by the European Thyroid Association. Eur J Endocrinol 1998; 139(6):584– 586. 104. Matsuura N, Konishi J, Fujieda K, et al. TSH-receptor antibodies in mothers with Graves’ disease and outcome in their offspring. Lancet 1988; 1(8575–8576):14– 17. 105. Smith C, Thomsett M, Choong C, et al. Congenital thyrotoxicosis in premature infants. Clin Endocrinol (Oxf) 2001; 54(3):371–376. 106. Peleg D, Cada S, Peleg A, et al. The relationship between maternal serum thyroidstimulating immunoglobulin and fetal and neonatal thyrotoxicosis. Obstet Gynecol 2002; 99(6):1040–1043. 107. Porreco RP, Bloch CA. Fetal blood sampling in the management of intrauterine thyrotoxicosis. Obstet Gynecol 1990; 76(3 Pt 2):509–512. 108. Wenstrom KD, Weiner CP, Williamson RA, et al. Prenatal diagnosis of fetal hyperthyroidism using funipuncture. Obstet Gynecol 1990; 76(3 Pt 2):513–517.

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109. Skuza KA, Sills IN, Stene M, et al. Prediction of neonatal hyperthyroidism in infants born to mothers with Graves disease. J Pediatr 1996; 128(2):264–268. 110. Rasmussen NG, Hornnes PJ, Hegedus L. Ultrasonographically determined thyroid size in pregnancy and post partum: The goitrogenic effect of pregnancy. Am J Obstet Gynecol 1989; 160(5 Pt 1):1216–1220. 111. Berghout A, Endert E, Ross A, et al. Thyroid function and thyroid size in normal pregnant women living in an iodine replete area. Clin Endocrinol (Oxf) 1994; 41(3):375–379. 112. Struve CW, Haupt S, Ohlen S. Influence of frequency of previous pregnancies on the prevalence of thyroid nodules in women without clinical evidence of thyroid disease. Thyroid 1993; 3(1):7–9. 113. Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006; 16(2):109– 142. 114. Tan GH, Gharib H, Goellner JR, et al. Management of thyroid nodules in pregnancy. Arch Intern Med 1996; 156(20):2317–2320. 115. Herzon FS, Morris DM, Segal MN, et al. Coexistent thyroid cancer and pregnancy. Arch Otolaryngol Head Neck Surg 1994; 120(11):1191–1193. 116. Moosa M, Mazzaferri EL. Outcome of differentiated thyroid cancer diagnosed in pregnant women. J Clin Endocrinol Metab 1997; 82(9):2862–2866. 117. Rosen IB, Korman M, Walfish PG. Thyroid nodular disease in pregnancy: Current diagnosis and management. Clin Obstet Gynecol 1997; 40(1):81–89. 118. Browne-Martin K, Emerson CH. Postpartum thyroid dysfunction. Clin Obstet Gynecol 1997; 40(1):90–101. 119. Roti E, Emerson CH. Clinical Review 92 postpartum thyroiditis. J Clin Endocrinol Metab 1992; 74:3–7. 120. Stagnaro-Green A, Roman SH, Cobin RH, et al. A prospective study of lymphocyteinitiated immunosuppression in normal pregnancy: Evidence of a T-cell etiology for postpartum thyroid dysfunction. J Clin Endocrinol Metab 1992; 74(3):645– 653. 121. Hayslip CC, Fein HG, O’Donnell VM, et al. The value of serum antimicrosomal antibody testing in screening for symptomatic postpartum thyroid dysfunction. Am J Obstet Gynecol 1988; 159(1):203–209. 122. Gerstein HC. Incidence of postpartum thyroid dysfunction in patients with type I diabetes mellitus. Ann Intern Med 1993; 118(6):419–423. 123. Solomon BL, Fein HG, Smallridge RC. Usefulness of antimicrosomal antibody titers in the diagnosis and treatment of postpartum thyroiditis. J Fam Pract 1993; 36(2):177–1782. 124. Tachi J, Amino N, Tamaki H, et al. Long term follow-up and HLA association in patients with postpartum hypothyroidism. J Clin Endocrinol Metab 1988; 66(3):480– 484. 125. Othman S, Phillips DI, Parkes AB, et al. A long-term follow-up of postpartum thyroiditis. Clin Endocrinol (Oxf) 1990; 32(5):559–564. 126. Lazarus JH, Ammari F, Oretti R, et al. Clinical aspects of recurrent postpartum thyroiditis. Br J Gen Pract 1997; 47(418):305–308. 127. Pop VJ, de Rooy HA, Vader HL, et al. Postpartum thyroid dysfunction and depression in an unselected population. N Engl J Med 1991; 324(25):1815–1816.

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128. Harris B, Othman S, Davies JA, et al. Association between postpartum thyroid dysfunction and thyroid antibodies and depression. BMJ 1992; 305(6846):152– 156. 129. Gorman CA. Radioiodine and pregnancy. Thyroid 1999; 9(7):721–726. 130. Mandel SJ. Postpartum thyroiditis in women with subclinical hypothyroidism. In: Annual Meeting of the American Thyroid Association; 1998. 131. Amino N, Tada H, Hidaka Y, et al. Therapeutic controversy: Screening for postpartum thyroiditis. J Clin Endocrinol Metab 1999; 84(6):1813–1821.

10 Thyroid Disease in the Elderly Anne R. Cappola University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.

Myron Miller and Steven R. Gambert Sinai Hospital of Baltimore and The Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

INTRODUCTION A 30-year-old woman presents with unintentional weight loss, difficulty concentrating, insomnia, and palpitations. An 80-year-old woman presents with “not feeling right.” What is the diagnosis? Both have overt hyperthyroidism. Yet in the elderly woman, the initial list of differential diagnoses is far greater, the diagnostic testing likely to be more extensive, and the time for diagnosis is potentially longer than in her young counterpart. The 80-year-old woman may attribute some of the same symptoms— the weight loss, difficulty concentrating, and insomnia—to old age. She is more likely to be taking a medication, such as amiodarone, that could play a role in the etiology of hyperthyroidism, and she is more likely to see an exacerbation of a preexisting chronic disease, such as osteoporosis, in conjunction with the hyperthyroidism. Even after diagnosis, her other medical problems will potentially affect the older woman’s treatment course. This chapter will begin with a summary of normal age-related changes in the anatomy and function of the thyroid, followed by consideration of the factors in the management of each type of thyroid disorder that are unique to the care of older individuals. 401

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NORMAL AGING AND THYROID FUNCTION Morphology The normal aging process is accompanied by changes in the gross and microscopic appearance of the thyroid gland. Autopsy data have indicated that overall thyroid gland mass declines with age from its normal range of 15 to 25 g; with increasing age, a progressively larger proportion of individuals will have glands weighing ⬍20 g (1). Other confounding factors were considered in a study of thyroid ultrasounds in healthy subjects (2). This study showed that effects of aging on the size of the thyroid gland were quite small, and that body weight was a greater determinant of thyroid volume than was age, suggesting that thyroid size is maintained with increasing age. With advancing age, progressive fibrosis, the appearance of lymphocytes, a decrease in follicle size, and a reduction in the amount of colloid in the thyroid gland are more likely to be seen (3). Although these changes are common in the elderly, they are not characteristic of all aged persons. More importantly, there does not appear to be a decline in thyroid function as a result of the morphological changes, and neither weight nor histological appearance correlates with common measures of thyroid function (4). Thyroid Hormone Physiology and Regulation Table 1 details the effect of aging on thyroid hormone physiology. The changes in thyroid function attributable solely to aging are subtle and of questionable clinical significance. Instead, there is an increase in thyroid disease with increasing age. Thus, there is little impact of aging on a normal thyroid, but there is an increase in the incidence of thyroid disease with increasing age. TRH–TSH Axis A study of healthy elderly subjects reported a blunted increase in nocturnal thyroidstimulating hormone (TSH) secretion (5). This suggested a resetting of the pituitary threshold of TSH feedback suppression, leading to a decrease in TSH secretion for a given concentration of circulating thyroid hormone. The ability of the pituitary gland to synthesize TSH does not appear to be diminished by the aging process, as reflected by observation that pituitary TSH content undergoes no significant change over the life span (6). The 24-hour TSH secretion has been reported to be decreased in healthy elderly men (7), but the secretion rate of TSH has also been reported to be higher in elderly subjects than in young individuals (8). Some have postulated, nevertheless, that TSH secretion may decline slightly with age; the slower clearance of T4 and T3 in older persons implies that less TSH is needed to maintain thyroid secretion. Studies measuring the serum TSH response to thyrotropin-releasing hormone (TRH) in elderly people are conflicting, with some studies showing a decreased response and others showing an increased response (7,9–14). In men aged 30 to 96 years given a continuous TRH infusion instead

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Table 1 Influence of Aging on Measures of Thyroid Function Measure TSH TSH response to TRH T4 T3 Free T4 Free T3 rT3 TBG T4 synthesis/secretion T3 synthesis/secretion T4 half-life Antithyroid antibodies Thyroglobulin Radioiodine uptake

Healthy elderly (65–96 yr)a

Healthy centenarians (⬎100 yr)a

N or Inc N or Dec N N or Dec N N N N Dec Dec Inc Inc N N or Dec

Dec ND ND ND N Dec Inc ND ND ND Inc N ND N or Dec

a Compared to values in young, healthy adults. Abbreviations: N, no change; Inc, increased; Dec, decreased; ND, no data available.

of bolus TRH administration, the serum TSH response was biphasic, with neither phase being affected by age (11). TSH exerts its effects by binding to the membrane of thyroid follicular cells. The serum T4 response to the TSH secreted after bolus TRH administration does not appear to be altered by age, although the serum T3 response may decrease (15). Administration of large doses of exogenous TSH has been reported to increase serum T4 to a lesser extent in older subjects than in younger subjects (16). TSH The neuroendocrine mechanisms controlling TSH release may be altered during the normal aging process. There is some disagreement regarding the effect of aging on circulating levels of serum TSH. Recent analyses from the U.S. National Health and Nutrition Examination Survey (NHANES) showed a shift in the distribution of TSH levels toward higher levels with increasing age, even when individuals with positive thyroid peroxidase or thyroglobulin antibodies were excluded (Fig. 1) (17). However, in an Italian study of healthy centenarians aged 100 to 110 years, serum TSH was lower in the centenarians compared to both healthy elderly (aged 65–80 years) and healthy younger adults (aged 20–64 years) (median 0.97 mU/L vs. 1.17 mU/L vs. 1.70 mU/L) (18,19). For the older groups as a whole, there was an inverse relationship between serum TSH and age. These disparate findings may reflect differences in the iodine sufficiency of these two populations, with a greater prevalence of Hashimoto’s thyroiditis in iodine sufficient countries such as the United States and thyroid nodularity with autonomy in Italy (18,20,21).

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30 25 Age 20–29

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Upper TSH concentration in bin

Figure 1 TSH distribution by age groups in the United States. (A) Disease-free population. (B) Reference population, NHANES III (1988–1994). Source: From Ref. 17.

The lack of consensus on what a “normal” TSH level is for an older person in turn leads to disparate recommendations for screening for thyroid disease, the threshold for initiating therapy for thyroid dysfunction, and the target TSH level during therapy. For example, if an upper limit of TSH of 2.5 mU/L was used in the NHANES disease-free population, 39% of those over the age of 70 years would be considered to have abnormally high TSH levels (17). Using the standard reference cutoff of 2.5%, the upper limit of TSH would be ⬎9 mU/L in this age group. The more clinically relevant approach is to link a specific TSH level to an increase in adverse outcomes, as discussed in the sections on hypothyroidism and hyperthyroidism later.

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T4 and T3 In older individuals, there is evidence for a decrease in thyroid hormone clearance that is paralleled by a decrease in thyroid hormone secretion rate (18). As a result, the normal range for total and free concentrations of T4 and T3 is unchanged in older individuals, and deviations from normal must be considered as evidence for thyroid disease or for other illness or states that may affect hormone measurement (15,22–25). However, these age-related changes in thyroid hormone metabolism have important effects on dosing of thyroid hormone replacement, with lower dose requirements and longer times to achieve steady state in the older adult. In the normal adult, approximately 80 ␮g of T4 and 30 ␮g of triiodothyronine (T3) are produced daily (26). In elderly individuals, T4 and T3 production declines to approximately 60 and 20 ␮g/day, respectively. These decreases in hormone production may be related to the decrease in thyroidal iodide accumulation that has been observed with aging (27). In addition, the half-life of thyroxine (T4) increases with age, with a mean half-life of 6.7 days for adults aged 23 to 36 years and approximately 9 days for those older than 80 years (28). The decrease in T4 clearance is thought to result from decreases in both the fractional turnover rate and distribution space of T4. Levels of thyroid-binding globulin (TBG), the primary thyroid hormone transport protein for T4 and T3, do not appear to differ between healthy young and old individuals (11). While a greater T4-binding capacity of TBG has been observed in the elderly, this does not have clinical significance (29,30). Comorbid conditions or concomitant use of medications that affect levels of thyroid-binding proteins may be more common in the elderly. Levels of thyroid-binding prealbumin may be acutely lowered in the presence of infectious disease, protein-wasting states, surgery, and malnutrition and may be accompanied by a decline in total T4. TBG levels can be depressed as a result of severe catabolic illness, chronic hepatic disease, glucocorticoids, and androgen administration (31). Binding of T4 to TBG can be inhibited by drugs such as highdose salicylates and furosemide (32). TBG levels may increase due to therapy with estrogen or tamoxifen or as an acute-phase reactant during acute hepatocellular injury. In all of these circumstances, serum free T4 will be normal in those with normal underlying thyroid reserve, but in those who require thyroid hormone replacement, dose adjustments may be required to compensate for altered-binding protein states. A small decline in serum T3 concentration with age has been found, but the decline is more likely attributable to mild nonthyroidal illness than age itself (22,23). While there is little change in mean values for serum T3 as a function of advancing age, fewer persons have values in the “upper range of normal” as derived from data on individuals across the life span. In a study of healthy centenarians, serum FT3 was slightly lower than that of healthy elderly aged 65 to 80 years, suggesting mild impairment of peripheral 5’-deiodination in advanced age (18,19). Other data derived from both animal and human models have reported a small but significant decrease in cellular responsiveness to thyroid hormone

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action (33,34). What clinical significance, if any, this latter phenomenon may have remains controversial, but could explain the relative lack of adrenergic symptoms in older patients with thyrotoxicosis (see later). Autoimmunity Thyroid antibodies in the serum increase in prevalence progressively with increasing age, reaching a peak prevalence of 20% to 25% in women above the age of 50 years and 5% to 10% in similarly aged men (35–37). These numbers are similar to those recently reported using data from NHANES (20). In an Italian study with a highly selected population of healthy elderly ranging in age from 65 to 110 years, the prevalence of antithyroid antibodies was low and did not differ from the prevalence seen in healthy young persons (18). These findings suggest that the high prevalence of antithyroid antibodies in certain aging populations is a reflection of disease and not a consequence of normal aging. Thus, the finding of high serum antithyroglobulin and/or antithyroid peroxidase antibody titers and an elevation of basal serum TSH concentration is consistent with autoimmune thyroiditis (38). NONTHYROIDAL ILLNESS The serum concentration of total T3 is reduced in many nonthyroidal illnesses, giving rise to the “low T3 syndrome.” This consequence of systemic illness is the earliest and most common of the alterations in thyroid hormone levels (16,22,25,39–41). In response to many acute illnesses, there is decreased peripheral 5
-monodeiodination of T4 to T3, with consequent reduction in serum T3 concentration and an increase in serum rT3. Lowering of thyroid-binding prealbumin and TBG in the presence of acute and chronic illness further contributes to the marked decrease in serum T3 that is characteristic of the sick elderly. Although there are limited animal data to suggest that age may alter responses to stressors, such as cold exposure and starvation, human studies are lacking. The finding of a low T4 concentration in the presence of nonthyroidal illness has been termed the “euthyroid sick syndrome” (42). In mild-to-moderate forms, measurement of free T4 will be normal even though total T4 concentration is reduced (43). A putative inhibitor of T4 binding to TBG has been detected in 20% to 74% of hospitalized patients with nonthyroidal illness; this may contribute to the measurement of a low T4 in these patients (44). However, severe illness can result in a marked reduction of both total and free T4 concentrations. When this circumstance occurs, the prognosis of the patient is poor, with a mortality rate of approximately 80% having been reported (45). Since the serum TSH may also be low in critically ill patients, the ability to differentiate these patients from those with secondary hypothyroidism is often difficult, although neither T4 nor T3 therapy improves prognosis in nonthyroidal illness (46–48). Cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor could be involved as intermediaries in the development of low-T4 and low-T3 states. Many patients with

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nonthyroidal illnesses and low T4 and/or T3 also have elevated serum concentrations of cytokines (49,50). Experimental increase of tumor necrosis factor-alpha has been observed to induce low serum concentrations of T4, T3, and TSH (51). Occasionally mild to moderately elevated concentrations of TSH are found in the recovery phase of the illness, when TSH values can rise to as high as 20 mIU/L. This does not indicate true hypothyroidism, since all measures of thyroid function return to normal in a few weeks (52). Biologically inactive reverse T3 (rT3) is generated by 5’-monodeiodination of the inner ring of T4 (26,53). A variety of factors—including starvation, febrile illness, elevation of glucocorticoid concentration, and drugs such as high-dose propranolol, amiodarone, and iodinated contrast materials—can result in impaired T4 conversion to T3, with a decline in serum T3 and a parallel increase in rT3 concentration due to decreased rT3 clearance (26). Serum rT3 may be affected by normal aging, although an increase may also be a consequence of illness or drug-induced alteration in rT3 degradation (23,24,54). However, the measurement of rT3 is not clinically useful.

HYPOTHYROIDISM IN THE ELDERLY Epidemiology Several population-based studies report a prevalence of overt hypothyroidism in the elderly of approximately 1% to 2%, as determined by an elevated TSH and low free T4 level at a single point in time (55–57). Pathophysiology The most common cause of hypothyroidism in the elderly is autoimmune thyroiditis (58). Another major cause of hypothyroidism is the prior treatment of hyperthyroidism with radioiodine or subtotal thyroidectomy (58,59). Hypothyroidism may also be the natural sequel to previous Graves’ disease (60). Medications may precipitate hypothyroidism, particularly in individuals with autoimmune thyroiditis; these include iodine-containing radiographic contrast agents, amiodarone, and iodine-containing cough medicines. Long-term lithium therapy can lead to interference with thyroid hormone synthesis and to inhibition of thyroid hormone release, with up to a 20% prevalence of subclinical hypothyroidism and a similar prevalence of up to 20% of overt hypothyroidism in patients taking this medication (32). Although infrequent, hypothyroidism in the elderly may also result from pituitary or hypothalamic disease. Diagnosis The diagnosis of hypothyroidism in the elderly is often missed, because the presenting complaints are often confused with other age-prevalent disorders. This

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Table 2 Clinical Features of Elderly Patients (Mean Age 84.5 Years) with Overt Hypothyroidism (n = 100) and with Subclinical Hypothyroidism (n = 20)

Symptom/sign Presenting Feature Falls/deteriorating mobility/collapse Hypothermia General malaise Confusion Angina Congestive cardiac failure Cerebrovascular accident Other conditions Total Signs Hypothyroid facies Hoarse voice Slow relaxing reflexes Myopathy Cerebellar signs Effusions Total

Overt hypothyroidism

Subclinical hypothyroidism

17 2 2 4 1 6 4 64 100

3

17 20

4 1 2 2 2 9

4

15

5

1a

a Also had myopathy. Source: From Ref. 62.

problem is further compounded by the often-insidious onset of illness. Doucet and colleagues reported on the presenting symptoms and signs of hypothyroidism in young (mean age 40.8 ± 9 years) and elderly subjects (mean age 79.3 ± 6.7 years). Statistical differences in presenting findings were noted for weight gain (59% vs. 24%), cold intolerance (65% vs. 35%), paresthesias (61% vs. 18%), and muscle cramps (55% vs. 20%). Complaints of fatigue and weakness were present in more than 50% of the elderly patients (61). Many persons who are later discovered to be hypothyroid will be unable to identify when the symptoms actually began. Even patients known to have hypothyroidism may not have classic physical findings, and it often escapes recognition until late in its course, after cognitive changes and functional decline interfere with independent living (Table 2) (62–64). Neurological findings may include dementia, ataxia, and carpal tunnel syndrome. On physical examination, delay in the relaxation of deep tendon reflexes may be more difficult to elicit with advancing age, due to other age-prevalent conditions affecting neurological function. Classic signs and symptoms of dry skin, cold intolerance, paresthesias, constipation, and hypothermia, among others, are worth looking for despite the patient’s age, but

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some of these findings can be due to aging itself. For example, with normal aging, there may be changes in the skin and hair. The hair becomes coarser and there is a tendency to lose the hair in the lateral aspects of the eyebrows. The skin becomes dry, and scaling may be noted. Hypercholesterolemia may be more common in both circumstances as well. For these reasons, the physician should maintain a high index of suspicion of hypothyroidism when evaluating older persons, especially women and those with prior histories or family histories of some form of thyroid disease. The diagnosis of primary hypothyroidism in the elderly is best made by measuring the serum TSH concentration (29). Changes in protein binding may reduce the level of total T4; T3 may be reduced in persons with significant medical illness or who are malnourished. For these reasons, an increase in serum TSH remains the best way to detect primary hypothyroidism regardless of age. However, as noted earlier, during the recovery phase after acute nonthyroidal illnesses, an elevated serum TSH level may not represent true clinical hypothyroidism; in this case the serum TSH returns to the normal range within four to six weeks. While uncommon in the elderly, hypothyroidism can be secondary to pituitary failure or hypothalamic disease. In this case, both serum TSH and T4 levels are low. While antithyroid antibodies are detectable in the circulation of many persons with hypothyroidism, these are not indicated in the workup of every patient suspected of having hypothyroidism. Treatment L-Thyroxine is the preferred medication to treat hypothyroidism. While other preparations are available, elderly persons tolerate the effects of T3 less well due to its “burst effect” on the myocardium, causing an acute increase in oxygen demand as well as the need for more frequent dosing. In general, brand names are suggested to minimize the potential variability that may occur when generic preparations are refilled. It is also easier for the elderly person to identify a medication with a consistent color and shape. Due to decreases in lean body mass and T4 clearance, elderly patients require a smaller amount of L-thyroxine, on average 110 ± 8 ␮g/day, as compared with younger subjects, who on average require a weight-related dose of approximately 1.6 ␮g/kg body weight per day (65–67). Due to the increase in half-life for thyroxine that accompanies the aging process, it will take longer to reach a steady state; therefore, a longer time between dose increases is necessary in order to reduce unwanted side effects. The commonly used adage of “start low and go slow” is usually followed in this age group, although this is based on widespread acceptance rather than controlled clinical trials in older people. One randomized clinical trial of initiation of a full replacement dose of levothyroxine compared to gradual dose titration included a small number of individuals over the age of 65 years without preexisting cardiovascular disease (68). No adverse sequelae were noted in the group of older individuals initiated on a full replacement dose, but the generalizability of these findings to a larger population of older individuals

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has been questioned (69). Because many elderly patients with hypothyroidism may have an underlying cardiovascular problem, the conservative approach of initial therapy with 25 to 50 ␮g/day, with gradually increasing increments of 25 ␮g every four to six weeks, remains the most consistently recommended approach. Individuals with significant cardiac disease may require dose changes as low as 12.5 ␮g and could even be started at that low level. Once a dose of 75 ␮g/day is achieved without side effects, increments of 12.5 ␮g are advised. The final dose required is the amount of L-thyroxine that reduces the serum TSH into the range of normal and does not have associated side effects. Caution is advised to avoid iatrogenic subclinical hyperthyroidism with L-thyroxine. Surveys of the general population have shown that only 60% of those taking thyroid hormone have TSH levels in the euthyroid range, with 20% over-replaced (low TSH) and another 20% under-replaced (high TSH) (70). These data may underestimate the scope of the problem in older individuals taking thyroid hormone, with euthyroid levels in only 40% of individuals aged 60 years and over in the Framingham Heart Study, and low TSH levels in an alarming 48% (71). The most likely explanation for the high degree of over-replacement is a lack of physician monitoring or awareness of adverse consequences of over-replacement. The limited data about the clinical consequences of mild over-replacement with thyroid hormone (exogenous subclinical hyperthyroidism) suggest that these consequences parallel those of endogenous subclinical hyperthyroidism, with increased risk of atrial fibrillation (72,73) and lower bone mineral density (74,75). Myxedema Coma Myxedema coma is a rare but serious consequence of untreated or inadequately treated hypothyroidism. It occurs almost exclusively in the elderly (76). While the name implies the presence of coma, the term also encompasses patients with altered cognition, lethargy, seizures, psychotic symptoms, and/or confusion and disorientation thought secondary to hypothyroidism. Most affected persons have experienced a precipitating event such as severe infection, cold exposure, alcoholism, or use of psychoactive medications. Exposure to sedatives and/or narcotics has also been associated with this entity. While some patients will have a prior history of being treated for hypothyroidism, many will be diagnosed for the first time. Diagnosis Recognition of myxedema coma may be difficult, since its clinical presentation can be attributed to a host of other problems. For those who can provide information, a history of increased fatigue and somnolence is common. A past history of treatment for thyroid illness—including medication, surgery, or radioactive iodine— should raise concern. Use of narcotics, sedatives, or antipsychotic medication may precipitate myxedema coma. Infections such as pneumonia and urosepsis

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are commonly found at the time of diagnosis; cold exposure, as often occurs in poorly heated residential environments, has also been associated with myxedema coma. Physical examination may demonstrate many of the classic signs and symptoms of a hypothyroid state, such as dry scaly skin, edema, and bradycardia. Profound hypothermia is often present and may be underestimated, because many commonly used thermometers do not read temperatures less than 35◦ C. Patients with myxedema coma may also demonstrate hypoventilation and hypotension. Severe frontal and occipital headaches, psychotic behavior, ataxia, nystagmus, muscle spasms, and sinus bradycardia may be signs of impending coma and must not be dismissed. Other findings of severe hypothyroidism include pericardial effusion, ileus, megacolon, and easy bruising. Laboratory data may not be available early in the diagnostic process, although the classic findings are a markedly reduced total and free serum T4 and elevated serum TSH levels. Hyponatremia and hypoglycemia are not uncommon. Hyponatremia is thought to result from inappropriately increased levels of antidiuretic hormone (ADH) as well as decreased water excretion due to a decrease in glomerular filtration rate. Hypoglycemia is thought to result from impaired gluconeogenesis and, in some patients, from cortisol deficiency. Since hypothyroidism in the elderly is often due to autoimmune thyroiditis, other autoimmune deficiency states must be looked for, including diabetes and adrenal insufficiency. Creatine phosphokinase is often elevated and may suggest the presence of a myocardial infarction. Fractionation, however, usually demonstrates a muscle etiology for the elevated creatine phosphokinase. Myocardial infarction can occur in the presence of myxedema coma and may complicate initiation of thyroid hormone therapy. Rarely, associated myoglobinuria and rhabdomyolysis have been reported, although it is unclear if these findings result from circulatory collapse or are directly related to the primary hypothyroid state. Arterial blood gases usually show a decrease in PO2 and an increase in PCO2 , indicating acute or impending respiratory failure. Anemia is also a common finding and may range from a normochromic, normocytic variety to a macrocytic form suggestive of B12 and/or folate deficiency. On chest X-ray, cardiomegaly is often reported, which may be due to either a pericardial effusion or dilated myocardium. Evoked potentials may have an abnormal amplitude or latency and the electroencephalogram may demonstrate the presence of triphasic waves that disappear after initiation of thyroid hormone replacement therapy. Treatment In patients with severe illness and coma, the decision to initiate thyroid replacement therapy must often be based on clinical evidence prior to obtaining confirming laboratory data (76–78). No controlled, blinded, or randomized studies exist to clearly define the optimal therapeutic regimen at any age. The following principles and guidelines should be followed:

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1. Myxedema coma has a very high mortality rate if left inadequately treated. 2. There is the need to balance the uncertainty of diagnosis prior to receiving laboratory results with empiric treatment and its complications, especially if the individual is later found not to be hypothyroid. 3. Supportive therapy must be provided promptly and includes ventilatory support for respiratory failure, antibiotics for infection as indicated, and management of hypothermia by external rewarming. Hypotension can be treated with fluid replacement or dopamine. Hyponatremia must be treated. Occasionally, severe hypoglycemia and anemia will require prompt therapy. Careful attention should be given to avoid aspiration of secretions, fecal impaction, and urinary retention. 4. Prompt initiation of therapy with L-thyroxine is necessary to treat the hypothyroid state. The initial dose is 300 to 500 ␮g given intravenously once. Following that, the dose should be reduced to 50 to 100 ␮g intravenously (76). T3 or combinations of T4 and T3 are not recommended in the elderly, since the acute metabolic impact of T3 can precipitate cardiac arrhythmia or myocardial infarction. The main principle is that a severely thyroid hormone-deficient individual may require a high initial dose of thyroxine in order to occupy hormone-binding sites that have been left free as a result of significant and prolonged hormone deficiency. In addition, problems such as infection may increase the turnover of thyroxine and thus further increase the need for a higher initial replacement dose. The risk, however, is that this high dose can increase myocardial oxygen consumption and increase the potential for a myocardial infarction. Therefore, clinical judgment must prevail, especially in the setting of other comorbidities prevalent in the elderly. 5. Whether or not intravenous glucocorticoids should be administered to all persons with myxedema coma remains controversial. Adrenal insufficiency can coexist with myxedema coma, so that suspicion of cortisol deficiency as based on history, physical examination, or electrolyte abnormalities deserves prompt treatment. In life-threatening situations, blood for measurement of plasma cortisol should be drawn and intravenous stress doses of corticosteroids should be administered and continued until there is laboratory confirmation of status of adrenal function. At that time, the decision can be made either to treat for concomitant adrenal insufficiency or to taper and stop the corticosteroid. In summary, this condition is largely a problem of elderly hypothyroid persons. It requires aggressive supportive therapy and hormone replacement while contributing factors are evaluated and appropriately treated. Close monitoring is required when treatment is initiated to avoid toxicity from large doses of thyroid hormone. Subclinical Hypothyroidism Overt hypothyroidism usually causes at least one symptom, can progress to a lifethreatening condition if untreated (myxedema coma), and has been associated with

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adverse clinical sequelae. Therefore, management of overt thyroid dysfunction is not controversial, and treatment is universally recommended. Clinical controversy surrounds the management of patients with subclinical hypothyroidism, and at what levels of TSH do the risk/benefit ratios favor therapy. Subclinical hypothyroidism is characterized by relatively few clinical and biochemical abnormalities (Table 2) (79–81). In fact, in one study of men and women aged 60 years and over, there was no difference in the frequency in any of the symptoms of hypothyroidism between subclinically hypothyroid and euthyroid individuals (82). By definition, the circulating level of TSH is increased in subclinical hypothyroidism, with serum T4 and T3 within the range of normal. When measured in population-based studies at a single point in time, subclinical hypothyroidism is highly prevalent in women and with increasing age, with a prevalence of up to 20% of women over the age of 60 years (56,57,70,83). Rates of persistence vary depending on the duration of follow-up and the degree of initial TSH elevation, with rates ranging from 42% to 80% (56,84,85). In all of these studies, an increase in progression to overt hypothyroidism was found in those with positive antithyroid antibodies. In one study with a mean follow-up of 31.7 months, normalization of serum TSH was common in those with minimally elevated TSH levels, occurring in 52% of those with TSH levels ⬍10 mU/L, whereas 66% of those with TSH levels ⬎10 mU/L progressed to overt thyroid dysfunction (85). The majority of data supporting adverse sequelae from untreated subclinical hypothyroidism are derived from cohort studies with baseline thyroid function testing, with additional data from small case-control studies and clinical trials. The major findings are outlined later. Cardiovascular Outcomes Mechanistic data support the potential for thyroid hormone deficiency to accelerate atherosclerosis, via decreased cholesterol metabolism and increased systemic vascular resistance, and congestive heart failure, via decreased ventricular filling and cardiac contractility (86). Analyses of incident cardiovascular disease have been performed in eight major cohort studies (57,87–93). Three of these studies showed an increase in cardiovascular risk in subclinical hypothyroidism (87–89), four showed no difference (57,90–92), and one showed a decrease in cardiovascular death with increasing TSH (93). Interestingly, when these cohorts were examined by age distribution, a pattern emerges of increased risk during middle age and no appreciable risk or possibly even benefit of subclinical hypothyroidism in old age. One published study has shown an increase in incident congestive heart failure in those with a TSH of 7 mU/L or greater (HR 2.33; 95% CI: 1.10–4.96) (92). Neurocognitive Outcomes Hypothyroidism has long been considered to be one of the reversible causes of dementia (94) and of depression (95). In two large studies of older people, there

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Abnormally low thyrotropin

Cumulative mortality

Normal thyrotropin Abnormally high thyrotropin Normal free thyroxine Low free thyroxine

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Cox regression P = .03 for Trend 85

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Abnormally high thyrotropin Normal free thyroxine Low free thyroxine

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Figure 2 Cumulative mortality of Leiden 85-Plus study participants by thyroid status. Thyrotropin levels below 0.3 mIU/L were considered to be abnormally low; levels above 4.8 mIU/L were considered to be abnormally high. Free thyroxine levels below 1.01 ng/dL were considered to be abnormally low; levels between 1.01 and 1.79 ng/dL were considered to be normal. Source: From Ref. 93.

were no differences between those with subclinical hypothyroidism and euthyroid individuals in cognitive scores or mood (96,97). This is in agreement with the Leiden 85+ Study, in which there was no association between subclinical hypothyroidism and cognitive impairment, depression, or disability (93). Interestingly, in this study of men and women aged 85+ years, those with higher TSH levels had lower mortality (Fig. 2), which has led some in the field to postulate that subclinical hypothyroidism represents an adaptive mechanism in the oldest-old (98). These studies demonstrate that subclinical hypothyroidism is a prevalent condition, with high rates of normalization in mild subclinical hypothyroidism and progression to overt hypothyroidism in more severe subclinical hypothyroidism. Furthermore, the potential adverse sequelae from untreated subclinical hypothyroidism are not consistent across studies, with reports of increased cardiovascular disease, congestive heart failure, and dementia in some, but not all studies. Limited data also suggest differential risk by degree of subclinical hypothyroidism and age strata, supporting the need for risk group refinement. The central, currently unresolved question is whether older individuals with subclinical hypothyroidism benefit from replacement therapy with thyroid hormone. There are no substantive data as yet to indicate that early treatment of subclinical hypothyroidism with thyroid hormone replacement is effective in reducing the risk of subsequent

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development of cardiovascular or improvement in neurocognitive outcomes. Some physicians advocate replacement therapy for all persons with subclinical hypothyroidism, even those with minimally elevated levels of TSH. However, it is more widely viewed that treatment should be given to those individuals with TSH levels that are persistently ≥10 mU/L (80). For individuals with serum TSH levels between 4.5 and 10 mU/L, follow-up without treatment is a reasonable course, although many practitioners advocate a therapeutic trial. When the TSH level is in this range, measurement of antithyroid peroxidase antibodies may influence the decision about treatment, given the higher rate of progression to overt disease. The goal of treatment, when initiated, is the same as for overt hypothyroidism, to normalize serum TSH values. However, the target serum TSH may be higher in the very old (17,98). This is usually accomplished with lower doses of L-thyroxine than for those who present with overt hypothyroidism. HYPERTHYROIDISM IN THE ELDERLY Overproduction of thyroid hormone leads to the clinical condition of hyperthyroidism or thyrotoxicosis. This disorder is accompanied by a broad array of symptoms and signs that can differ markedly between young and old patients. Epidemiology In the past, hyperthyroidism was regarded as a disorder with preferential expression in young to middle-aged individuals, especially women. It is now clear that this disorder is also common in the elderly population. The proportion of patients with hyperthyroidism who are older than 60 years is estimated to be 15% to 20% (99,100). Several studies of prevalence indicate the presence of hyperthyroidism in 1% to 2% of community-residing individuals (70). In a study of the population of Whickham, England, hyperthyroidism was identified in 19 per 1000 women, a prevalence rate 10 times greater than that in men. The mean age at diagnosis was 48 years and the estimate of new cases was 2 to 3 per 1000 women per year (101). Many other studies confirm that hyperthyroidism is far more common in women than in men, with estimates of female preponderance ranging from 4:1 to as high as 10:1 (99,101–103). Population-based data from Tayside, Scotland, obtained using record-linkage technology show both an increase in the incidence of hyperthyroidism and a decrease in the gender difference with increasing age (103). In those aged 80 years or older, the annual incidence rate was 1.05 per 1000 women and 0.45 per 1000 men. Pathophysiology In young persons, Graves’ disease remains the most common cause of hyperthyroidism. With increasing age, there is a change in etiology, so that more cases are due to multinodular toxic goiter and fewer to Graves’ disease (99,104,105). Multinodular goiters are common in the elderly and may not be clinically apparent

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(4). Many clinical observations support the concept that long-standing euthyroid multinodular goiters may evolve to become toxic multinodular thyroid goiters (99). Toxic adenoma is another less common cause of hyperthyroidism in the elderly, usually identifiable on thyroid scanning by the demonstration of a solitary hyperfunctioning nodule with suppression of activity in the remainder of the thyroid gland. Hyperthyroidism can also rarely occur in a previously euthyroid elderly person following ingestion of iodide- or iodine-containing substances. Most commonly, this occurs following exposure to iodinated radio-contrast agents and to amiodarone. Although up to 40% of patients taking amiodarone will have serum T4 levels above the normal range due to the drug’s effect on T4 metabolism, far fewer (5%) will develop true thyrotoxicosis (106). This form of hyperthyroidism can be of rapid onset and severe in magnitude. Because of amiodarone’s fatsolubility and long half-life, drug-induced thyrotoxicosis can be prolonged and difficult to treat (107,108). The possibility of hyperthyroidism must always be considered in the elderly person who is receiving thyroid hormone, especially if the dose is ⬎0.15 mg of L-thyroxine daily. Patients who have received such doses for many years without evidence for hyperthyroidism may insidiously develop hyperthyroid features as their age passes 60 years owing to the age-associated reduction in rate of thyroid hormone metabolism (109). Rare causes of hyperthyroidism in the elderly include TSH-producing pituitary tumors (110). These can be recognized by the finding of nonsuppressed levels of serum TSH in the presence of increased amounts of circulating thyroid hormone. An additional uncommon cause of hyperthyroidism is overproduction of thyroid hormone by widespread metastatic follicular carcinoma. Transient hyperthyroidism may occur in patients with silent or subacute thyroiditis as a result of increased discharge of thyroid hormone into the circulation during the inflammatory phase of the illness. In a similar fashion, radiation injury to the thyroid can be accompanied by a transient increase in circulating thyroid hormone levels with associated symptoms. T3 and T4 Toxicosis In a small proportion of cases of hyperthyroidism, the expected increase in serum T3 is noted, but serum T4 is either within the normal range or at the upper end of normal. This circumstance has been designated as T3 toxicosis and can occur with any type of hyperthyroidism; however, it commonly occurs in older patients with toxic multinodular goiter or solitary toxic adenoma (111). The diagnosis will not be missed if serum T3 is measured in patients with clinically suspected hyperthyroidism or who have suppressed levels of serum TSH. T4 toxicosis, or an isolated increase in serum T4 without an elevation in serum T3, is more commonly noted in the sick elderly patient with hyperthyroidism owing to the higher prevalence of medical conditions and nutritional inadequacies that interfere with T4-to-T3 conversion.

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Table 3 Frequency of Symptoms and Signs of Hyperthyroidism in Elderly Versus Young Kawabe et al. (112) Symptom/sign Palpitation Goiter Tremor Excessive perspiration Weight loss Eye signs Arrhythmias (atrial fibrillation and ventricular premature contraction)

Davis and Davis (99)

Young (n = 48) (%)

Elderly (n = 45) (%)

Elderly (n = 85) (%)

100 98 96 92 73 71 4.6

60 58 71 66 85 28 16.4

63 64 55 38 69 57 62

Source: From Ref.113.

Diagnosis As with other disorders occurring in the elderly person, the clinical presentation of hyperthyroidism often differs from the classical description of the disease in younger individuals (99,100,104,112–114) (Table 3). The presenting feature may be a progressive functional decline including muscle weakness, fatigue, changes in mental status, loss of appetite, weight loss, cardiac arrhythmia, and/or congestive heart failure. A symptom complex peculiar to the geriatric hyperthyroid patient is “apathetic hyperthyroidism,” in which the patient lacks the hyperactivity, irritability, and restlessness common to the young patient with thyrotoxicosis and presents instead with weakness, lethargy, listlessness, depression, and the appearance of a chronic, wasting illness. Often, the initial impression is depression, malignancy, or cardiovascular disease (115,116). Clinically detectable thyroid enlargement, present in almost all younger patients, is absent in as many as 37% of elderly patients (99). Infiltrative ophthalmopathy with severe proptosis and exophthalmos occurs infrequently in the elderly. Thus, none of the elements of the classic triad of Graves’ disease (clinical hyperthyroidism, diffuse goiter, and infiltrative ophthalmopathy) may be recognizable in the elderly patient, in whom the diagnosis may be suspected only on the basis of laboratory studies (99,112,113). Symptoms less commonly present in the elderly include nervousness, increased sweating, tremor, increased appetite, and increased frequency of bowel movements. Symptoms more common in the elderly include marked weight loss, present in ⬎80% of patients, poor appetite, worsening angina, edema, agitation, and confusion. There may be correction of previously existing constipation. Similarly, physical findings differ in elderly patients. In addition to the absence of a

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palpable goiter and eye signs of exophthalmos, the pulse rate tends to be slower, and hyperreflexia may not be present. Lid lag and lid retraction are frequently seen (99,112–116). The spectrum of symptoms and findings due to thyroid hormone excess is broad and can involve almost all body systems. Cardiac manifestations are particularly important in the elderly person who may have coexisting heart disease. An increased heart rate with a related increase in myocardial oxygen demand, stroke volume, cardiac output, and shortened left ventricular ejection time underlie the clinical consequences of palpitations, increased risk of atrial fibrillation—often with slow ventricular response, exacerbation of angina in patients with preexisting coronary artery disease, and precipitation of congestive heart failure that responds less readily to digoxin treatment (117). Gastrointestinal consequences of hyperthyroidism in the elderly include weight loss, poor appetite, and occasionally abdominal pain, nausea, and vomiting (99,100). Diarrhea and increased frequency of bowel movements resulting from thyroid hormone action on intestinal motility can occur, but these symptoms are often absent in the elderly, in whom constipation is as likely to be present. Hepatic actions of thyroid hormone can lead to alterations in liver enzymes, including elevation of alkaline phosphatase and gamma-glutamyl transpeptidase levels, which return to normal following restoration of thyroid function to euthyroid values. Weakness, especially of the proximal muscles, is a major feature of hyperthyroidism in the elderly and is often accompanied by muscle wasting (99,116). As a consequence, disorders of gait, postural instability, and falls can take place. Tremor occurs in ⬎70% of elderly thyrotoxic patients, but this sign must be distinguished from other causes of tremor that are common in the elderly and are usually more coarse in nature or primarily resting tremors (112,113). A rapid relaxation phase of the deep tendon reflexes is common in young patients but is often difficult to assess in the older patient. Central nervous system manifestations may be prominent in the elderly patient and include confusion, depression, forgetfulness, agitation/anxiety, and a shortened concentration span (95,104). These cognitive impairments may point to a diagnosis of dementia with failure to consider the presence of hyperthyroidism. Other clinical manifestations of hyperthyroidism in the elderly may include glucose intolerance; occasionally, latent diabetes mellitus may be unmasked. Mild elevations of serum calcium can occur, and hyperthyroidism should be ruled out as a secondary cause of osteoporosis in persons with decreased bone mass. Because of the altered clinical presentation of hyperthyroidism in the elderly, suspicion must always be high and the laboratory should be used for any patient with possible symptoms. Many have advocated screening tests for thyroid status in all geriatric patients undergoing initial clinical evaluation (118,119). Measurement of serum TSH by ultrasensitive methods and serum free T4 or free T4 index is the preferable test for diagnosing thyroid dysfunction. The findings of a normal or low serum free T4 with suppressed serum TSH raises the possibility of T3 toxicosis and calls for measurement of serum T3. Demonstration

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of anti-TSH receptor antibodies can be helpful in making a diagnosis of Graves’ disease, but this is not a routine test (120). Thyroid scanning and measurement of the 24-hour 131 I uptake can be useful in distinguishing Graves’ disease from toxic multinodular goiter. Scanning may also demonstrate the presence of a small, diffusely active goiter that could not be detected on physical examination. Very low 131 I uptake in a patient with elevated circulating thyroid hormone levels suggests exogenous thyroid hormone ingestion (factitious or iatrogenic hyperthyroidism), the hyperthyroid phase of painless or subacute thyroiditis, or iodine-induced hyperthyroidism. Treatment The first step in the management of the elderly patient with hyperthyroidism is to determine the underlying etiology and exclude the possibility of one of the transient forms, which may require therapy directed toward the primary process (hormone ingestion, iodine exposure, and subacute thyroiditis). While the vast majority of patients with either Graves’ disease or multinodular toxic goiter can be treated using antithyroid drugs, radioactive iodine, or surgery, radioactive iodine ablation of the thyroid is the preferred treatment for both etiologies in the elderly (121). In the older patient with suspected hyperthyroidism who is still undergoing investigation, a useful initial step in treatment is the administration of betaadrenergic blocking agents such as long-acting propranolol, metoprolol, nadolol, or atenolol. In patients who have palpitations, tachycardia, angina, or agitation, these symptoms of thyrotoxicosis can be quickly controlled with use of the betablockers, although caution is advised in elderly persons with congestive heart failure, chronic obstructive pulmonary disease, or diabetes being treated with insulin. Once a diagnosis of Graves’ disease or toxic nodular goiter is established, treatment should be started with the antithyroid drug methimazole (122). The antithyroid drugs impair biosynthesis of thyroid hormone; this will lead to depletion of intrathyroidal hormone stores and ultimately to decreased hormone secretion. A decline in serum T4 concentration is usually seen within two to four weeks after initiation of antithyroid drug therapy, and the dose should be tapered once thyroid hormone levels reach the normal range in order to avoid hypothyroidism. In 1% to 5% of patients, the antithyroid drugs may cause fever, rash, and arthralgia. Drug-induced agranulocytosis may be more common in the elderly and is most likely to occur within the first 3 months of treatment, especially in those patients who receive more than 30 mg/day of methimazole (123). Some but not all experts recommend periodic monitoring of the white blood cell count and discontinuation of the drugs if there is evidence of the development of neutropenia. Long-term antithyroid drug administration can be an effective therapy in patients above the age of 60 years with Graves’ disease who, in comparison to younger persons, appear to respond more quickly and have a greater likelihood of long-lasting

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remission (124). In contrast, this approach is rarely successful in elderly patients with a toxic multinodular goiter, since it is not an autoimmune disease. Ablation of the thyroid with 131 I is the recommended treatment in most elderly persons. Because of the necessary contact precautions immediately following treatment with 131 I, there may be radiation safety issues for caretakers, especially if patients have urinary incontinence. Once the patient has been rendered euthyroid by antithyroid drugs, these agents can be stopped for three to five days, following which 131 I is given orally. Therapy with beta-blockers can be maintained and antithyroid agents can be restarted five days after radiotherapy and continued for one to three months until the major effect of radioiodine is achieved. The treatment goal in all elderly patients is to assure ablation of thyroid tissue and avoid the possibility of recurrence of hyperthyroidism. Using this approach, patients are monitored following treatment until their serum thyroid hormone levels reach the hypothyroid range; they are then put on permanent replacement therapy. Hypothyroidism may be evident as early as four weeks after treatment but can occur at any time. In some circumstances, when clinical and laboratory features of hyperthyroidism are mild and there are no significant cardiac problems, it may be appropriate to treat the elderly hyperthyroid patient with 131 I without antithyroid drug pretreatment. When this option is chosen, the patient is started on beta-blocker therapy before administering 131 I and the beta-blocker is continued until there is evidence that thyroid hormone levels have fallen into the normal range. Surgery is not recommended as a primary choice for the treatment of hyperthyroidism in the elderly. The frequent accompaniment of hyperthyroidism by other coexisting illnesses puts the patient at increased operative risk. Surgery may be of value for the patient with poor response to medical treatment, severe ophthalmopathy, or tracheal compression secondary to a large goiter. Atrial Fibrillation Atrial fibrillation occurs in 10% to 20% of older hyperthyroid patients (103), and raises several management issues regarding cardioversion and anticoagulation. In a retrospective study of 163 thyrotoxic patients with atrial fibrillation, approximately 60% had spontaneous reversion to sinus rhythm after return to a euthyroid state. Most of these reversions took place within three weeks of becoming euthyroid; none occurred if the patient still had atrial fibrillation after 4 months of euthyroidism; and none occurred when atrial fibrillation had been present for more than 13 months before becoming euthyroid. Thus, the patient who still has atrial fibrillation beyond 16 weeks of return to euthyroidism is a candidate for cardioversion (125). Current practice guidelines recommend anticoagulation for patients with thyrotoxic atrial fibrillation (126). In the absence of contraindications, warfarin should be given in a dose that will increase the International Normalization Ratio (INR) to 2.0 to 3.0 and continued until the patient is euthyroid and there has been restoration of normal sinus rhythm. While in the hyperthyroid state, the patient

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with atrial fibrillation is more sensitive to the anticoagulant effect of warfarin, which causes a greater lowering of activity of coagulation factors II and VII and greater increase in prothrombin ratio and partial thromboplastin time (127). Thyroid Storm Acute hyperthyroidism or “thyroid storm” can occur in the patient with either known or undiagnosed hyperthyroidism who is subjected to acute stress, such as an operative procedure, trauma, or infection or who is exposed to iodine-containing drugs (128). It can also occur in the elderly hyperthyroid patient treated with 131 I who did not receive adequate antithyroid medication prior to therapy. The features of severe hyperthyroidism can develop over several hours and include fever, tachycardia, arrhythmia, dyspnea, vomiting, diarrhea, dehydration, severe restlessness, and delirium. Acute heart failure can be precipitated. Elderly patients with cardiac disease are at especially high risk for the development of acute myocardial ischemia or congestive heart failure. Thyroid storm is a life-threatening condition and must be treated vigorously and promptly (128). Immediate treatment focuses on inhibition of thyroid hormone production and the inhibition of conversion of T4 to T3 in peripheral tissues. This is accomplished by administration of antithyroid drugs, especially propylthiouracil, in an initial dose of 200 to 400 mg orally every six to eight hours. The first dose of sodium iodide or oral Lugol’s solution should follow the first antithyroid drug dose. High-dose beta-blockers such as propranolol and high-dose corticosteroids are also given to blunt peripheral action of thyroid hormone and to inhibit T4-to-T3 conversion. Supportive measures are provided and may include sedation, correction of fluid and electrolyte imbalances, antipyretics (not aspirin), and cooling blankets and antibiotics if infection is present. Subclinical Hyperthyroidism By definition, these individuals have normal circulating levels of free T4 and T3 and levels of TSH below the lower limit of normal (usually 0.3–0.5 mU/L), implying that the circulating level of thyroid hormone is more than is required for hormonal balance. However, clinical symptoms may not be present. Although the Wayne score, a clinical index of thyrotoxicosis, was noted to be higher than in a group of similarly aged euthyroid persons, there were few or no classic features of hyperthyroidism (129). The prevalence of subclinical hyperthyroidism on a single serum TSH test is 1% to 6% in an older population (55–57,72). Persistence of this testing abnormality ranges from 24% to 88%, depending on the degree of TSH lowering (56,130). In a recent very large study of more than 400,000 persons, 3000 of whom had a low serum TSH level, about 50% of such individuals had a normal serum TSH on follow-up (131). Progression to overt hyperthyroidism is uncommon, estimated at approximately 1% per year (72), and may be more likely in patients with toxic multinodular goiter compared to those with Graves’ disease (132).

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The majority of data supporting adverse sequelae from untreated subclinical hyperthyroidism are derived from cohort studies in which thyroid function testing was performed at baseline, with additional data from small case-control studies and clinical trials. Findings from the major studies are presented by organ system. Cardiovascular Outcomes One of the most important findings in the field was the report in 1994 by Sawin et al., using data from the Framingham Heart Study, of an increased risk of atrial fibrillation in those with subclinical hyperthyroidism compared to the euthyroid state (71). They found that individuals with TSH values ≤0.1 mU/L, many of whom were receiving thyroid hormone therapy, had an adjusted relative risk of 3.8 (95% CI: 1.7–8.3) for developing atrial fibrillation and those with TSH values between 0.1 and 0.4 mU/L had an adjusted relative risk of 1.6 (95% CI: 1.0–2.5). The lack of a statistically significant difference led to lingering questions about the risks of milder subclinical hyperthyroidism. Furthermore, individuals with elevated thyroxine levels, indicating overt hyperthyroidism, were included in their category of TSH values ≤0.1 mU/L, which could have led to an overestimate of the effect of subclinical hyperthyroidism. Additional analyses in the Cardiovascular Health Study in 2006 by Cappola et al. confirmed the atrial fibrillation risk (57). After adjustment for age, sex, clinical cardiovascular disease at baseline, subsequent thyroid hormone use, and other known risk factors for atrial fibrillation, participants with subclinical hyperthyroidism had nearly twice the risk of developing atrial fibrillation (HR 1.98; 95% CI, 1.29–3.03). When these analyses were repeated, limiting to subjects with mild subclinical hyperthyroidism (TSH 0.1–0.44 mU/L), the adjusted hazard ratio remained significantly elevated, at 1.85 (95% CI 1.1–3.0). Despite the increase in the frequency of atrial fibrillation found in this study, overall mortality was not increased. This is at odds with another study of older persons with subclinical hyperthyroidism, where higher all cause and cardiovascular mortality rates were observed (91). Increased left ventricular mass relative to euthyroid individuals has also been noted in small studies, although the clinical significance of this finding is unclear (133). Musculoskeletal Outcomes Using data from the Study of Osteoporotic Fractures, Bauer et al. have shown that postmenopausal women with serum TSH concentrations of 0.1 mU/L or less had an increased risk of both hip (HR 3.6; 95% CI: 1.0–12.9) and vertebral fractures (HR 4.5; 95% CI: 1.3–15.6) compared to women with normal TSH levels (134). However, T4 levels were not measured, so that the proportion of women with overt and subclinical hyperthyroidisms is not known, although the intermediate risk from TSH levels of 0.1–0.5 mU/L (HR 1.9; 95% CI: 0.7–4.8 for hip fractures and HR 2.8; 95% CI: 1.0–8.5 for vertebral fractures) suggests a valid dose– response relationship. An additional limitation to this study is that 86% of those

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with low TSH levels were taking thyroid hormone, so that it was not possible to distinguish between effects from endogenous and exogenous hyperthyroidism. Other evidence indicates that treatment of subclinical hyperthyroidism may have a beneficial effect on bone mineral density. In a nonrandomized prospective study, postmenopausal women with subclinical hyperthyroidism and nodular goiter who were treated with 131 I with subsequent restoration of serum TSH into the normal range demonstrated increases in bone mineral density at the spine and hip after two years of follow-up, while a similar group of women who were not treated showed progressive decline in bone mineral density (135). Neurocognitive Outcomes An analysis from the Rotterdam Study has shown a more than threefold increased risk of dementia over a two- to four-year period in those with subclinical hyperthyroidism (RR 3.5; 95% CI: 1.2–10.0), although this analysis was only adjusted for age and sex (136). However, two other large studies have shown no association of subclinical hyperthyroidism with cognitive impairment or depression (93,97). These studies demonstrate that subclinical hyperthyroidism is a prevalent condition, with the available data showing a high rate of persistence and low rate of progression to overt hyperthyroidism. There are potential adverse sequelae from untreated subclinical hyperthyroidism, with reports of increased incidence of atrial fibrillation, fracture, and dementia. Largely based on the atrial fibrillation and bone data, many practitioners treat older individuals with a suppressed TSH (⬍0.1 mU/L) (137), and this is recommended in current practice guidelines (80). The benefit of treatment of those with a TSH of 0.1 to 0.4 mU/L remains undefined, although reasonable if there are any clearly associated symptoms such as a worsening of cardiovascular function or cardiac arrhythmias, excessive muscle wasting, anorexia, or depression. SCREENING FOR THYROID DYSFUNCTION IN THE ELDERLY The goal of screening is to apply a test to identify disease in an unsuspecting population without any clinical indication of disease, under the assumption that early detection provides benefit. Because of the high prevalence of thyroid testing abnormalities in older people and the nonspecificity of individual symptoms, screening has particular appeal for the elderly population. Screening for thyroid dysfunction presents several unique challenges: how to incorporate nonspecific symptoms in narrowing the tested population, the transience of some thyroid testing abnormalities, and, most importantly, how to manage subclinical thyroid dysfunction. Several guidelines have been published regarding screening for thyroid dysfunction. The U.S. Preventive Services Task Force, The Institute of Medicine, and an expert panel do not recommend generalized screening for thyroid disease (80,138,139). The American College of Physicians at one time recommended screening women older than 50 years for unsuspected but symptomatic thyroid disease, although

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this guideline is currently inactive (140), and the American Thyroid Association recommends screening adults every five years beginning at the age of 35 years (141). Without data showing the threshold TSH levels for treatment, clinical trials showing benefits that outweigh risks, and the benefits of early diagnosis of mildly abnormal serum TSH levels, a universal screening strategy for thyroid dysfunction seems premature. NODULAR THYROID DISEASE AND NEOPLASIA Epidemiology The development of thyroid nodules is clearly an age-related process that occurs more commonly in women than in men. Autopsy studies have demonstrated that thyroid nodules are frequently found in the elderly even when clinical examination of the neck has failed to reveal abnormality (142). These data show an increase in frequency of nodules in women and men over the age of 30 years, with a progressive increase to a frequency of 90% in women and 50% in men over the age of 70 years. In the Whickham study, clinically detectable nodules were found in 0.8% of men without a relationship to age (101). However, 5.3% of women had palpable nodules and the frequency increased from about 4% in those under the age of 50 years to 9.1% in those aged 75 years or more. By means of ultrasonographic study, thyroid nodules have been found in approximately 50% of women beyond the age of 50 years (143). Pathophysiology Patients with thyroid nodules should be questioned for a history of childhood external radiation exposure of the head, neck, and upper thorax, since it is well established that radiation to this area markedly increases the risk of developing thyroid malignancy. It was common practice from the 1930s to the early 1960s to treat facial acne, tonsillar enlargement, cervical adenitis, and thymic enlargement with external radiation. It is estimated that several million people were irradiated, many of whom are now older than 60 years. Although a history of irradiation in a patient with nodular thyroid increases the likelihood of malignancy, it is important to note that irradiation also increases the development of benign nodules of the thyroid as well as parathyroid adenomas. Some 16% to 29% of individuals who as children received low-dose head and neck irradiation will develop palpable thyroid nodules, approximately one-third of which will be malignant. Nodules become apparent after a latency of 10 to 20 years, and the incidence of malignant nodules reaches a peak 20 to 30 years after exposure (144). Multinodular thyroid glands occur more commonly in individuals who come from areas of iodine deficiency. Often there is a history of goiter dating back to childhood or young adult years. Very large multinodular goiters, particularly those with a sizable substernal component, may compress the trachea and lead to complaints of dyspnea or wheezing. Disturbances of swallowing may also

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occur. These compressive symptoms are most common in older women. A large substernal goiter is often first recognized when the patient has had a chest X-ray and is noted to be associated with compression or deviation of the trachea or a superior mediastinal mass (145). Diagnosis Thyroid nodules are most commonly asymptomatic. They may be discovered accidentally by the patient or found by the physician during the course of a physical examination. Occasionally, a thyroid nodule will be associated with acute onset of neck pain and tenderness. This circumstance may be the result of acute or subacute thyroiditis but is more likely due to hemorrhage into a preexisting nodule. The finding of a solitary palpable nodule raises the possibility of thyroid malignancy. In many patients, further evaluation will reveal the presence of multiple nodules. The likelihood of thyroid cancer per patient is independent of the number of thyroid nodules present in the gland, and approximately 15% of solitary nodules ⬎10 mm are malignant (146). Many histological entities can present as a thyroid nodule. The vast majority is benign, including follicular and colloid adenomas, Hashimoto’s thyroiditis, and thyroid cysts. Malignant thyroid neoplasms include papillary, follicular, medullary, and anaplastic carcinomas as well as thyroid lymphoma and metastases to the thyroid. Nonthyroid lesions may also appear to be thyroid nodules; these include lymph nodes, vascular structures, parathyroid adenomas and cysts, and thyroglossal duct cysts. The likelihood that a single nodule is malignant is increased if there is a history of radiation exposure, if it occurs in a man over the age of 60 years, has been observed to undergo an increase in size, is accompanied by hoarseness of the voice suggestive of impingement on the recurrent laryngeal nerve, and is stony-hard on palpation (147). Data derived from the 53,856 patients with thyroid cancer in the National Cancer Data Base indicate that approximately 25% of all thyroid cancers are first diagnosed in individuals older than 60 years (Fig. 3) (148). Age is a factor in predicting the histological type of malignancy. The overall histological distribution of thyroid cancer is 79% papillary, 13% follicular, 3% H¨urthle cell, 3.5% medullary, and 1.7% anaplastic. In patients over the age of 60 years, papillary carcinoma accounts for approximately 67% of thyroid cancers. Follicular carcinoma has a peak frequency of diagnosis in both the fourth and sixth decades of life, with a mean age of 44 years. It, along with related H¨urthle cell carcinoma, makes up approximately 23% of the thyroid malignancies in the over-60 population. Medullary carcinoma has a peak incidence in the fifth and sixth decades and make up about 5% of thyroid cancers in the elderly (Table 4). Anaplastic carcinoma of the thyroid is almost exclusively a disease of older persons and accounts for approximately 10% of thyroid cancers in this age group. It is invariably fatal in a short period of time from its first diagnosis, especially

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35 30 25 20 15 10 5 0 0-29

30-39

40-49

50-59

60-69

70-79

80+

Age (Years) Papillary

Follicular

Hurthle Cell

Medullary

Anaplastic

Figure 3 Histological types of thyroid cancer by age. Source: From Ref. 148.

when it is ⬎5 cm in diameter (149). Clinically, it often arises in a background of previous multinodular goiter or papillary thyroid cancer and is recognized by its rapid growth, rock-like consistency, and local invasiveness—with recurrent laryngeal nerve involvement and tracheal compression common consequences. Lymphoma and metastatic cancers make up the remaining thyroid malignancies of the older person. Lymphoma is characterized by a rapidly enlarging painless neck mass, which may cause compressive symptoms. Initially, it may be difficult to differentiate from anaplastic carcinoma on clinical appearance alone. Hashimoto’s thyroiditis, identified by histological or antibody testing, is commonly present in patients with lymphoma (150). The major objective of evaluating an elderly patient with a thyroid nodule, especially an apparently single nodule, is to determine whether the nodule is benign or malignant. A number of diagnostic modalities are available that will then point the way to appropriate treatment (151). Blood tests of thyroid function will usually give normal results with the exception of the patient with a hyperfunctioning adenoma or toxic multinodular goiter. In some patients with nodular Table 4 Occurrence and Survivorship of Thyroid Malignancy in the Older Patient

Cancer type Papillary/mixed Follicular Medullary Anaplastic Lymphoma

% of patients with type

% of patients with type

10-yr survival

Age ⬎ 40

Age ⬎ 60

Age ⬎ 60 (%)

79 13 3 2 3

60–67 20–25 5 6 5

⬍65 ⬍57 ⬍63 0 ≤100

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disease due to Hashimoto’s thyroiditis, serum TSH may be increased. Serum thyroglobulin is often elevated in patients with thyroid cancer but cannot reliably differentiate malignancy from benign adenoma or thyroiditis. Its major usefulness is in the early recognition of recurrence or metastasis in patients with papillary or follicular carcinoma who had previously undergone total thyroidectomy. Elevation of serum calcitonin concentration is highly supportive of a diagnosis of medullary carcinoma but is not cost-effective as a routine test unless there is a family history of multiple endocrine neoplasia. Fine-needle aspiration (FNA) of the thyroid to obtain tissue for cytological or histological examination is the most reliable and accurate method of separating benign from malignant disease (151). FNA is indicated in any patient with a solitary nodule and when there is suspicion of thyroid malignancy based on clinical assessment, ultrasound findings, or thyroid scan. In skilled hands, the procedure is safe, inexpensive, and capable of determining presence or absence of malignancy with 95% accuracy. The reliability of FNA can be further increased if it is done in conjunction with real-time sonographic guidance. The cytopathological findings from FNA are assigned to four categories: positive for malignancy, suspicious for malignancy, negative for malignancy, and nondiagnostic. In the case of a nondiagnostic aspirate, a repeat FNA is recommended. If FNA reveals malignant cells, surgery is recommended with little need for further study. The combination of suspicious cytology by FNA and cold appearance on scanning indicates the need for surgical excision. Demonstration of benign cytology in either a solid or cystic nodule indicates that the patient can be managed subsequently by observation. The patient with clinical or FNA features suggestive of lymphoma should have a large-needle or surgical biopsy done to establish the diagnosis (152). Isotopic scanning is no longer considered as an initial diagnostic test because it is not cost-effective. The major role for isotope imaging is in the evaluation of the patient with a thyroid nodule who has had a nondiagnostic result from FNA. Malignant tissue is rarely able to take up iodine, so that identification of a nodule as “hot” by 123 I or technetium scanning makes malignancy in the nodule less likely. The finding of a nonfunctioning or “cold” nodule does not establish a diagnosis of malignancy, since 95% of thyroid nodules are cold, with the frequency of malignancy in cold nodules being 5%. Nodules identified as being “hot” and with associated normal thyroid hormone production and no compressive symptoms warrant only observation, with examination at intervals of 6 to 12 months. If evidence of hyperthyroidism is subsequently found, appropriate treatment for this condition should be initiated. High-resolution ultrasonography can detect lesions as small as 2 mm and can permit classification of a nodule as solid, cystic, or mixed solid-cystic. The technique will often demonstrate multinodularity in a gland with a single palpable nodule. The value of ultrasonography in establishing a diagnosis of malignancy is limited, since there is considerable overlap in the ultrasound characteristics of benign and malignant nodules. The procedure may be useful in detecting recurrent or residual thyroid cancer and in screening individuals who have had a history of

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irradiation exposure. It also may be of value in the patient suspected of having lymphoma of the thyroid, since this malignancy often produces a characteristic asymmetrical pseudocystic pattern (152). Computed tomography and magnetic resonance imaging can provide detailed information on thyroid anatomy. These procedures are expensive and appear to add little to the initial clinical assessment of malignancy. However, they may be useful in evaluating the extent of disease in patients who are found to have anaplastic carcinoma or lymphoma of the thyroid. They can also provide information about compression of structures in the neck as well as on the size and substernal extent of larger nodules and goiters. Treatment In the past, thyroid hormone has been used to suppress TSH on the assumption that benign lesions were more likely to be TSH dependent and therefore likely to decrease in size. The procedure involves giving L-thyroxine in a dose sufficient to suppress serum TSH and monitoring the size of the thyroid nodule for a period of three to six months. Although a meta-analysis of randomized, controlled trials supports a decrease in thyroid nodule volume with L-thyroxine (153), this therapy is no longer standard practice. In addition, the administration of suppressive doses of L-thyroxine to elderly patients carries substantial risk for precipitation or aggravation of ischemic heart disease and for acceleration of bone loss. The basic principles in management of thyroid cancer do not differ significantly between elderly and young patients, other than comorbidities that may affect the ability of the older person to undergo surgery. As the first line therapy for thyroid cancer, this approach should be encouraged, as the impact on survival is significant, even in this age group (154). If a diagnosis of papillary or follicular carcinoma has been confirmed prior to surgery, near total thyroidectomy should be carried out because older individuals present with more aggressive disease and a high frequency of multicentricity, and there is the need to remove functional thyroid tissue in order to monitor the patient with total-body radioiodine scanning and basal and stimulated serum thyroglobulin levels (155). If radioactive iodine therapy is required after surgery, an additional factor in the elderly is the dosage of 131 I employed. Rather than empiric dosing, dosimetry should be considered in the elderly, due to increased likelihood of exceeding maximum tolerable activity safety limits to the blood and bone marrow, even in those with normal renal function (156). Remnant ablation after surgery can be achieved using recombiR ) (157), which is an attractive option in nant human TSH (rhTSH, Thyrogen
the elderly, in whom iatrogenic hypothyroidism after thyroid hormone withdrawal may be associated with significant morbidity. After surgery and following radioiodine administration, patients are maintained on suppressive doses of L-thyroxine with the desired objective of reducing the serum TSH level to below normal. The older patient will need to be followed carefully and the dose of L-thyroxine reduced if cardiac symptoms develop. Acceleration of bone loss, particularly in the

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postmenopausal woman, may also be a limiting factor in maintaining long-term TSH suppression. For medullary carcinoma, the operative procedure of choice is total thyroidectomy, since the disease is often multicentric. Medullary carcinomas do not respond to 131 I therapy, so that patients with inoperable residual or recurrent disease are treated palliatively with external irradiation or could be considered for a clinical trial of newer chemotherapeutic agents. Patients should undergo testing for mutations in the RET protooncogene even if there is no family history of multiple endocrine neoplasia syndrome type 2, since they may be the proband in a kindred. The patient with thyroid lymphoma should have clinical staging carried out by means of CT or MRI imaging. The survival rate can approach 100% in response to aggressive therapy with external irradiation in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (152).

Outcome Age at time of diagnosis is an important factor in predicting cancer aggressiveness and mortality from differentiated thyroid cancer. Individuals who are diagnosed after the age of 50 years have a higher rate of recurrence and death (Table 4) (158). The 10-year survival for patients with papillary carcinoma is estimated to be 97% in those under the age of 45 years at the time of diagnosis and ⬍65% in those older than 60 years at the time of diagnosis. Similarly, 10-year survival for patients with follicular carcinoma is estimated to be 98% in those under the age of 45 years and ⬍57% in those older than 60 years (148,158). It appears that the biologic behavior of thyroid cancer in older individuals is more aggressive, suggesting that both the features of the thyroid cancer and delayed diagnosis contribute to the increased thyroid cancer-specific mortality rate in older people (159–162). The 10-year survival rate for patients with medullary carcinoma is 84% in patients younger than 45 years. Rate of survival declines with increasing age at time of initial diagnosis, with rates substantially lower for persons over the age of 60 years. In patients in their seventh decade of life, approximately two-thirds will have persistent disease after surgery (163). Efficacy of surgery can be monitored postoperatively by measurement of blood calcitonin concentration, both in the basal state and after stimulation (164). Blood levels of carcinoembryonic antigen may also be elevated in patients with residual or recurrent medullary carcinoma. The outcome of anaplastic carcinoma of the thyroid remains unsatisfactory, with rare survivorship more than one year after diagnosis (163). Palliative relief of compression symptoms can sometimes be achieved by surgery followed by high-dose (40–60 Gy) external irradiation (165). Chemotherapy with doxorubicin and/or cisplatin may be beneficial in combination with surgery and external irradiation, and there is increasing use of taxane neoadjuvant therapy (165).

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Compressive Goiter Subtotal thyroidectomy has traditionally been the recommended therapy for compressive goiter. However, in elderly patients, particularly those who may be at operative risk, thyroid ablation with large doses of 131 I (i.e., 25–125 mCi) can produce significant shrinkage of the thyroid with accompanying relief of compressive symptoms such as stridor, dyspnea, and dysphagia (145,166). Recent studies have demonstrated the efficacy of rhTSH to increase the uptake of radioiodine in a goiter, and possibly enhance the efficacy of the therapy (167). However, iatrogenic transient hyperthyroidism is a potential serious adverse event that may occur after rhTSH administration (168), so caution is necessary if rhTSH is used in this setting. Replacement of L-thyroxine is required following surgery, and may also be needed after radioiodine treatment in order to maintain serum TSH within the normal range and prevent regrowth of thyroid tissue. REFERENCES 1. Mochizuki Y, Mowafy R, Pasternack B. Weights of human thyroids in New York city. Health Phys 1963; 9:1299–1301. 2. Hegedus L, Perrild H, Poulsen LR, et al. The determination of thyroid volume by ultrasound and its relationship to body weight, age, and sex in normal subjects. J Clin Endocrinol Metab 1983; 56:260–263. 3. Blumenthal HT, Perlstein IB. The aging thyroid. I. A description of lesions and an analysis of their age and sex distribution. J Am Geriatr Soc 1987; 35:843– 854. 4. Denham MJ, Wills EJ. A clinico-pathological survey of thyroid glands in old age. Gerontology 1980; 26:160–166. 5. Barreca T, Franceschini R, Messina V, et al. 24-hour thyroid-stimulating hormone secretory pattern in elderly men. Gerontology 1985; 31:119–123. 6. Ryan N, Kovacs K, Ezrin C. Thyrotrophs in old age. An immunocytologic study of human pituitary glands. Endokrinologie 1979; 73:191–198. 7. Van CA, Laurent E, Decoster C, et al. Decreased basal and stimulated thyrotropin secretion in healthy elderly men. J Clin Endocrinol Metab 1989; 69:177–185. 8. Cuttelod S, Lemarchand-Beraud T, Magnenat P, et al. Effect of age and role of kidneys and liver on thyrotropin turnover in man. Metabolism 1974; 23:101– 113. 9. Snyder PJ, Utiger RD. Response to thyrotropin releasing hormone (TRH) in normal man. J Clin Endocrinol Metab 1972; 34:380–385. 10. Utiger RD. Thyrotropin-releasing hormone and thyrotropin secretion. J Lab Clin Med 1987; 109:327–335. 11. Harman SM, Wehmann RE, Blackman MR. Pituitary-thyroid hormone economy in healthy aging men: Basal indices of thyroid function and thyrotropin responses to constant infusions of thyrotropin releasing hormone. J Clin Endocrinol Metab 1984; 58:320–326. 12. Targum SD, Marshall LE, Magac-Harris K, et al. TRH tests in a healthy elderly population. Demonstration of gender differences. J Am Geriatr Soc 1989; 37:533– 536.

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Index

Acute infectious thyroiditis diagnosis, 110 epidemiology, 110 pathophysiology, 110 treatment, 111 Acute suppurative thyroiditis, 350–351 Addison’s disease, 50, 346 Adrenal medullary disease, 299 Agranulocytosis, 57, 60 Aluminum hydroxide, 173 Amennorhea, 44 Amiodarone, 11, 13, 47, 115, 170, 173 Amiodarone-induced hyperthyroidism, 11 diagnosis, 117 epidemiology, 115–116 pathophysiology, 116–117 treatment, 117–118 Amiodarone-induced thyrotoxicosis (AIT), 106 Anaplastic thyroid carcinoma (ATC), 240 diagnosis, 310–312 incidence and demographics, 308–309 natural history and mortality rates, 312 origin, 309 pathology, 309–310 prognostic factors, 313 treatment chemotherapy, 314–315 combination doxorubicin and hyperfractionated radiation therapy, 315–316 external radiotherapy, 314 surgery, 313–314 Anticytoplasmic neutrophil antibodies (ANCA), 58 Antithyroglobulin antibodies, 19 Antithyroid arthritis syndrome, 58 Antithyroid drugs, 115 clinical pharmacology, 51–52 in clinical practice, 52 drug-related leukopenia, 57

and family planning, 53 as primary therapy, 52–55 side effects, 55–59 Anti-TSH receptor antibody measurements, 48 APECED (Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy) syndrome, 346 Atrial arrhythmias, 41 Atrial diastolic dysfunction, 42 Atrial fibrillation, 60, 412–413 Atrophic gastritis, 174 Atypical thyroiditis. See Silent or “painless” thyroiditis Autoimmune gastritis, 174 Benign nodules, 209 Beta-adrenergic blocking agents, 106, 109, 115, 129, 356, 377 Bexarotene, 171 Bleomycin, 324 “Block-replacement’’ regimen, 54 Blood dosimetry, 267–268 BRAF mutation, 248 BRAF V600E mutation, 258 Bromocriptine, 126 Caf´e-au-lait spots, 81 Calcitonin, 301 in the evaluation of thyroid nodules, 303 pentagastrin-stimulated screening of, 304–305 secretion, physiological stimuli to, 28 and tumor mass, 303 Calcium, impact on thyroid hormones, 42 Calcium carbonate, 173 Calcium stimulation test, 303–304 Cancer and radioactive iodine therapy, 66 Carbamazepine, 173 Cat-scratch disease, 102 C-cell hyperplasia (CCH), 29, 299 C cells, thyroid, 28 Celiac disease, 174

439

440

Index

Cervical lymphadenopathy, 110 Cervical lymph node metastases, 302 Cervical ultrasonography, 277–278 Chemotherapy, 273–274, 324 Chernobyl children, 258 Children and thyroid functions, 335 Cholestyramine (or colestipol), 74, 173 Choriocarcinoma, 128 Chronic lymphocytic thyroiditis, 346 Coccidioides immitis, 110 Columnar cell variant, 248 Congenital hypothyroidism, 335–339 Corticosteroid therapy, 65, 104, 106, 115 Cowden syndrome, 357 Coxsackievirus, 102 Cranial synostosis, 345 Creeping thyroiditis, 102 Cushing’s syndrome, 302 Cyclophosphamide, 58 Cytokine-induced hyperthyroidism diagnosis, 120 epidemiology, 119 pathophysiology, 119 treatment, 120 Cytomel, 164

hypothyroidism diagnosis, 399–401 epidemiology, 399 myxedema coma, 402–404 pathophysiology, 399 subclinical, 404–407 treatment, 401–402 nodular thyroid disease and neoplasia diagnosis, 417–420 epidemiology, 416 pathophysiology, 416–417 treatment, 420–421 occurrence and survivorship of thyroid malignancy, 418 outcome of anaplastic carcinoma of the thyroid, 421 screening, 415–416 Embryogenesis, 332 Encapsulated papillary carcinoma, 247 Euthyroid hyperthyroxinemia, 9–10 Euthyroid hypothyroxinemia, 11 Euthyroidism and thyroid autoimmunity, 363–364 Euthyroid sick syndrome, 50, 160, 398 External beam radiation therapy, 273

De Morsier syndrome, 337 Diffuse follicular variant papillary carcinoma, 247–248 Diffuse sclerosing variant, 248 Diltiazem, 60 Diphenylhydantoin, 13 Diplopia, 68 Distant metastases, 245 Dopamine agonists, 124 Down syndrome, 346 Doxorubicin, 314 and hyperfractionated radiation therapy, 315–316

Familial dysalbuminemic hyperthyroxinemia (FDH), 8 Familial medullary thyroid carcinoma, 304–305 Ferrous sulfate, 173 Fetal hyperthyroidism, 344, 379–380 Fetal hypothyroidism, 333 Fetal thyroid function, 332–333 Fetal T4 metabolism, 333 Fiber supplements, 173 Fibroblasts, 68 Fine-needle aspiration biopsy, 28, 75, 102, 203, 209, 251–253, 311, 320, 358, 419 indications, 213 reasons for repetition, 219 results, 214–217 stains, 214 technique, 214 ultrasonographically guided, 217–218 Follicular cell neoplasms, 217 Follicular thyroid carcinoma diagnosis clinical presentation, 250–251 evaluating patients with a history of head-and-neck irradiation, 253 FNA biopsy, 251–253

Elderly compressive goiter, 422 hyperthyroidism atrial fibrillation, 412–413 diagnosis, 409–411 epidemiology, 407 pathophysiology, 407–408 subclinical, 413–415 T3 and T4 toxicosis, 408 thyroid storm, 413 treatment, 411–412

Index incidence, 242 pathology, 249–250 prognosis patient variables influencing, 254–255 treatment variables influencing, 259 tumor variables influencing, 255–259 treatment chemotherapy, 273–274 completion thyroidectomy, 261 external beam radiation therapy, 273 follow up, 274–278 gamma knife therapy, 273 ipsilateral lobectomy, 260 isthmusectomy, 260 radioiodine (131 I) therapy, 262–272 subtotal lobectomy, 260 surgical complications, 262 thyroidectomy during pregnancy, 262 thyroid hormone therapy, 272–273 total or near-total thyroidectomy, 261 Follicular variant of PTC (FVPC), 243, 247 Free T3 index, 8 Free T3/T4 measurements, 4–8 Furosemide, 13 Galactorrhea, 349 Gallium-67 (67 Ga), 312 Gamma knife therapy, 273 Gestation and thyroid hormone functions, 361–363 Glomerulonephritis, 58 Glucocorticoid therapy, 13, 58–59, 173 Gluten sensitive enteropathy, 174 Goiter, 54, 318, 346. See also Thyroid gland enlargement (goiter) elderly, 422 Gonadal damage, 271 G proteins, 75, 81, 206 Granulocyte-colony stimulating factor (G-CSF), 57 Granulocyte counts, 57 Graves’ disease, 8, 20–21, 26–27, 339, 346 association with ophthalmopathy, 39, 49, 121 treatment, 68–70 in elderly, 410–411 epidemiology, 40 impact of cigarette smoking and stressful life events, 40 laboratory diagnosis, 47–51 pitfalls, 50–51 ‘NO SPECS’ classification of eye changes, 69

441 orbitopathy, 168 pathophysiology, 40 during pregnancy, 370–371 presentation, 39 signs and symptoms, 41–46 treatment antithyroid drugs, 51–59 beta-adrenergic antagonist drugs, 60–61 choice of, 68 131 I therapy, 61–66 lithium, 61 potassium perchlorate, 61 thyroidectomy, 67 Hamburger thyrotoxicosis, 121 Hashimoto’s disease, 19, 28, 161, 212, 244, 317, 319 Hashimoto’s thyroiditis, 48–49, 105, 319, 321, 364, 368 Hashitoxicosis, 346 Helicobacter pylori-related gastritis, 174 Hepatitis C and thyroid abnormalities, 119 Hodgkin’s disease, 253 Hook effect, 18 Hormone-binding protein concentrations, 7 Hormone specificity “spillover” syndrome, 363 24-hour radioiodine uptake test, 47–48, 62, 103, 112, 335 Human chorionic gonadotrophin (hCG), 128–129 H¨urthle cells, 106 carcinomas, 240 neoplasm, 214, 217 tumors, 252 Hyperdefecation, 42 Hyperparathyroidism, 299 Hyperthyroidism, 22 caused by thyroid cancer, 130–131 causes, 351–352 clinical effects, 41 clinical manifestations, 352 diagnosis, 26–27 drug-induced, 112–122 due to exogenous thyroid hormone, 121–122 in elderly atrial fibrillation, 412–413 diagnosis, 409–411 epidemiology, 407 pathophysiology, 407–408 subclinical, 413–415 T3 and T4 toxicosis, 408

442 Hyperthyroidism (cont.) thyroid storm, 413 treatment, 411–412 of extrathyroid origin, 127–131 Graves’ disease, 351 laboratory evaluation, 352–353 pediatric, 351–352 during pregnancy fetal or neonatal, 379–381 Graves’ disease, 370–371 hCG-induced, 369–370 hyperemesis gravidarum, 369–370 pregnancy outcome, 372 therapy, 372–378 therapy, 353–357 thyrotrophin-induced, 122–127 treatment, 27 Hyperthyrotropinemia causes, 16–17 isolated, 339–343 Hyperthyroxinemia, 8 Hypokalemia, 43 Hypokalemic periodic paralysis, 43 Hypophosphatemia, 44 Hypothalamic-pituitary-thyroid axis, physiology of, 2–3 Hypothalamic tripeptide thyrotropin-releasing hormone (TRH), 3 Hypothyroidism, 22 cardiovascular abnormalities with, 150 clinical manifestations myxedema coma, 158 overt, 147–152 subclinical, 152–158 conditions associated with an increased risk of, 163 diagnosis, 24–25 assay analysis, 158–161 measurement of antithyroid antibodies, 161 drug-induced treatment, 170–171 in elderly diagnosis, 399–401 epidemiology, 399 myxedema coma, 402–404 pathophysiology, 399 subclinical, 404–407 treatment, 401–402 endocrine abnormalities with, 150–151 epidemiology, 146–147 etiology, 147

Index and Hodgkin’s disease, 347 infections, 152 laboratory evaluation, 349 musculoskeletal disorders, 152 neurological disorders, 151 pitfalls in management of changing thyroid hormone requirements, 172–175 consequences of excess thyroid hormone replacement, 178–179 depressed patients, 178 desiccated thyroid, 175–176 obesity patients, 177–178 patients allergic to thyroid hormone tablets, 176–177 patients unable to take oral medications, 177 patients who miss LT4 dose, 175 patients with premenstrual syndrome, 178 presenting symptoms post LT4 replacement, 172 surgery, 177 during pregnancy diagnosis, 365 overt, 364 pregnancy outcome, 365–367 treatment, 367–369 psychiatric disturbances, 151 pulmonary abnormalities with, 149–150 screening for, 162 secondary and tertiary, 347 subclinical (SCH), 152–158 treatment, 25–26 patient-oriented approach, 165–171 thyroid hormone replacement therapy, 162–165 Hypothyrotropinemia causes, 15–16 Hypothyroxinemia, 12–13, 364 Iatrogenic thyrotoxicosis, 8, 177 imaging, 211 Immunoassay methods, of free hormone concentration, 6 Immunoglobulins, 320 Immunometric (IMA) methods, 13 Incidentalomas, 225–227 Infants and thyroid functions, 335 Infectious thyroiditis. See Acute infectious thyroiditis Infiltrative diseases, 102 123 I

Index Inflammatory thyroiditis, 8 Insular carcinoma, 249 Interferon-alpha, 119 Interferon therapy–induced hyperthyroidism, 119–120 Interleukin-6 (IL-6), 13, 116–117 Iodide-induced hyperthyroidism, 8 Iodides, during pregnancy, 377 Iodine-induced hyperthyroidism diagnosis, 114–115 epidemiology, 112–113 neonatal, 344 pathophysiology, 113–114 therapy, 115 Iodine supplements, dietary, 113 Iodothyronine concentration, measurement of total, 3–4 Iopanoate (Telepaque), 74 Iopanoic acid, 124 Ipodate, 74, 173 Ipsilateral lobectomy, 260 Ischemic optic neuropathy, 68 Isthmusectomy, 260 131 I therapy, 61–66, 72, 77–78, 81–83, 224–225, 355–356, 378, 412. See also Radioiodine (131 I) therapy Jod-Basedow phenomenon, 113 Klinefelter syndrome, 346 Laboratory evaluation of thyroid disease hyperthyroidism, 26–27 hypothyroidism, 24–26 screening and case finding, 23–24 of thyroid function assays of thyroid-stimulating hormone, 13–15 causes of hyperthyrotropinemia, 16–17 causes of hypothyrotropinemia, 15–16 reverse T3 (rT3), 21 T4 and T3 concentrations, 4–8 causes of decrease, 11–13 causes of increase, 8–11 thyroglobulin (Tg), 17–19 thyroid autoantibodies, 19–21 thyroid hormone effects in extrapituitary tissues, 21–22 total serum iodothyronine concentrations, 3–4

443 Lanreotide, 124 Large-cell carcinomas, 309 Leukopenia, 57 Levothyroxine (LT4). See LT4 replacement therapy Levothyroxine sodium, 25–26 Liquid chromatography-tandem mass spectrometry, 5 Lithium, 61, 268 Lithium-associated thyrotoxicosis, 120 Liver function tests, 42 L-thyroxine therapy, 54, 67, 79, 121, 408 LT4/LT3 combination therapy, 172 LT4 replacement therapy, 8, 154, 156, 163–166, 365–366, 368 absorption of, 165 amiodarone-induced hypothyroidism, 170 brand-name preparations, 164–165 complications, 273 dosages, 166 drugs that decrease absorption, 173 drugs that increase absorption, 173 myxedema coma, 171 overt primary hypothyroidism, 166 pitfalls, 176–179 postradioiodine hypothyroidism, 168 subclinical hypothyroidism (SCH), 166–168 suppression of TSH, 272 Lugol’s solution, 74, 413 Lung metastases, 248 Lymphadenopathy, 45 Lymph node metastases, 245 Lymphocytic thyroiditis. See Silent or “painless” thyroiditis Lymphoma, 317–318 Macrofollicular PTC, 247 Malignant pseudothyroiditis, 102, 130, 310 Maternal-fetal T4 transfer, 333, 366–367 McCune-Albright syndrome, 81 MCT8 thyroid hormone transporter, 338 Means-Lerman “scratch” murmur, 41 Medullary thyroid carcinoma (MTC), 29–31, 207 association of somatic mutations and prognosis, 300–301 classification, 298 demographics, 297 diagnosis, 302–304 elderly, 421 EUROMEN study, 308

444 Medullary thyroid carcinoma (MTC) (cont.) family screening, 307–308 Gubbio Conference recommendations, 307–308 multiple endocrine neoplasia type 2 (MEN-2) syndrome familial, 298 genetic alterations, 299 type 2A, 298 type 2B, 298 parathyroid hyperplasia, 299 pathology, 301–302 pediatric, 360 pheochromocytomas, 299–300 prevalence, 297 prognosis, 304–305 sporadic, 300 therapy, 305–306 follow-up, 306–307 tumor location, 299 MEN2A gene, 30 Metaiodobenzyguanidine (MIBG), 306 Metastases, 245, 257, 301–302, 311 Metastatic lesions, 251 Metastatic lymph nodes, 256–257 Metformin, 16, 174 Methimazole (MMI), 51–53, 55–56, 59, 65, 334–335, 353–355, 372–373, 378–380 Metoprolol, 60 Mitral valve prolapse, 41 Mucosa-associated lymphoid tissue (MALT), 317 Multikinase inhibitors, 306 Multinodular goiter (MNG), 110, 205 management, 223–225 Myxedema coma, 171 Nadolol, 60 Neonatal hyperthyroidism, 343–346 Neonatal thyroid function, 334 in premature infants, 334–335 Neonates and TSH level, 16 Nephrotic syndrome, 174 Nodular thyroid disease, 203 incidentalomas, 225–227 thyroid gland enlargement (goiter), 204–225 Non-Hodgkin’s lymphomas, 319 Nonsteroidal anti-inflammatory drugs (NSAIDs), 104 Nonthyroidal illness, 15, 398–399

Index Noonan syndrome, 346 Normal aging and thyroid function autoimmunity, 398 morphological changes, 394 T4 and T3, 397–398 TRH–TSH axis, 394–395 TSH, 395–396 ‘NO SPECS’ classification of eye changes, of Graves’ disease, 69 NTRK1 mutation, 248 Occult subacute thyroiditis. See Silent or “painless” thyroiditis Octreotide, 124, 126 Omeprazole-induced hypergastrinemia, 29 Omeprazole stimulation test, 304 Oragraffin. See Ipodate Orbital radiotherapy, 69 Ovarian teratoma, 128 Overt primary hypothyroidism LT4 replacement therapy, 166 Oxyphilic PTC, 249 Painless thyroiditis. See Silent or “painless” thyroiditis Papillary cancer within a thyroglossal duct, 247 Papillary carcinomas, 127 Papillary microcarcinoma, 245–246 Papillary thyroid carcinoma (PTC) diagnosis clinical presentation, 250–251 evaluating patients with a history of head-and-neck irradiation, 253 FNA biopsy, 251–253 familial, 242 FNA biopsy, 243 imaging studies, 278–280 incidence, 242 microscopic appearance, 243 multiple tumor foci, 244 pathology, 243–249 prognosis, 244 patient variables influencing, 254–255 treatment variables influencing, 259 tumor variables influencing, 255–259 sporadic, 242 treatment chemotherapy, 273–274 completion thyroidectomy, 261 external beam radiation therapy, 273

Index follow up, 274–278 gamma knife therapy, 273 ipsilateral lobectomy, 260 isthmusectomy, 260 radioiodine (131 I) therapy, 262–272 subtotal lobectomy, 260 surgical complications, 262 thyroidectomy during pregnancy, 262 thyroid hormone therapy, 272–273 total or near-total thyroidectomy, 261 Papillary thyroid microcarcinoma (PTMC), 239 Parathyroid hyperplasia, 299 PAX8, 332 Pediatric thyroid disorders in childhood and adolescence chronic lymphocytic thyroiditis, 346 clinical manifestations, 348–349, 352 drug-induced disorder, 347 hyperthyroidism, 351–352 iodine deficiency, 347 laboratory evaluation, 349, 352–353 other causes, 347 painful thyroid enlargement, 350–351 secondary or tertiary, 347 therapy, 349–350, 353–357 thyroid dysgenesis, 347 thyroid hormone resistance, 347–348 infants congenital hypothyroidism, 335–339 isolated hyperthyrotropinemia, 339–343 neonatal hyperthyroidism, 343–346 thyroid nodules clinical evaluation, 358 laboratory evaluation, 358 other screening tools, 358 prognosis, 360 therapy, 359–360 Perchlorate, 74 Percutaneous ethanol injection (PEI), 79, 222–223 Percutaneous laser thermal ablation, 223 Phenobarbital, 173 Phenytoin, 173 Pheochromocytomas, 299–300 PIT-1, 337 Pituitary or hypothalamic disease, 25 Pituitary responsiveness, fetal, 332 Placenta and thyroid functions, 333–334 Postpartum thyroiditis, 104 diagnosis, 107–109

445 epidemiology, 107 pathophysiology, 107 during pregnancy, 382–385 treatment, 109 Postradioiodine hypothyroidism, LT4 replacement therapy, 168 Potassium iodate, 113 Potassium iodide, 114 Potassium perchlorate, 61 Prednisone, 65, 104, 117, 345 Pregnancy euthyroidism and thyroid autoimmunity, 363–364 glomerular filtration rate, 368 guidelines for clinical management of maternal hyperthyroidism, 376 guidelines for clinical management of maternal hypothyroidism, 369 hyperthyroidism complications reported, 372 fetal or neonatal, 379–381 Graves’ disease, 370–371 hCG-induced, 369–370 hyperemesis gravidarum, 369–370 outcome, 372 therapy, 372–378 hypothyroidism complications reported, 366 diagnosis, 365 outcome, 365–367 overt, 364 treatment, 367–369 renal iodine clearance, 363 thyroid hormone physiology, 361–363 Premature infants, thyroid function in, 334–335 Pretibial myxedema, 45–46, 70 Primary biliary cirrhosis, 42 Primary thyroid lymphoma clinical features, 318–319 demographics, 316–317 diagnosis, 319–320 and Hashimoto’s thyroiditis, 317 imaging studies, 320–321 incidence, 316 pathology, 317–318 prognostic features, 322–325 staging of, 322 PROP-1, 337 Propranolol, 13, 44, 60, 74, 173, 413

446 Propylthiouracil (PTU), 13, 74, 173, 334–335, 353–355, 372–373, 378–380 Proton pump inhibitors, 173 Psammoma bodies, 243 P53 suppressor gene, 310 PTU-induced hepatitis, 59 Pulmonary hypertension, 42 Quantitative tumor dosimetry, 268 Radiation-induced thyroid carcinoma epidemiology, 242–243 Radiation–induced thyrotoxic thyroiditis, external beam, 111 Radiation thyroiditis diagnosis, 111–112 epidemiology, 111 pathophysiology, 111 trauma-induced thyroiditis, 112 treatment, 112 Radioiodine (131 I) therapy and ablation of thyroid bed, 262–263 amount estimation for remnant ablation, 266 diagnostic (“pretreatment”) whole-body scan, 266–266 immediate complications, 268–269 infertility and gonadal failure, 271–272 lacrimal duct obstruction, 271 leukemia and second primary malignancies after, 270–271 with lithium, 268 parotid dysfunction, 269 posttreatment scans and false-positive scans, 266–267 preparation, 263–265 radiation pneumonitis, 269 sodium-iodide symporter activity in PTC, 262 stunning effect, 265 treatment of residual or recurrent carcinoma with, 267–268 Radionuclide scanning, 321 Raloxifene, 10, 16, 173 Ras oncogenes, 206 Raynaud’s phenomenon, 60 Recombinant human TSH (rhTSH), 225 Renal iodine clearance, during pregnancy, 363 Resin T3 uptake test, 47 RET protooncogene, 421 RET/PTC gene rearrangement, 248 Reverse T3 (rT3), 2, 21 RhTSH, 276–278

Index RhTSH-stimulated Tg measurements, 278 Rifampin, 173 Salicylates, 104 Salvage therapy, 325 Saturated solution of potassium iodide (SSKI), 67 Scintigraphy indications, 210–211 results, 211–212 technique, 211 Screening, for thyroid disease, 23–24 Selenium, 109 Septo-optic dysplasia, 337 Sertraline, 13, 174 Sevelamer, 173 Silent or “painless” thyroiditis, 161, 169 diagnosis, 105–106 epidemiology, 105 pathophysiology, 105 treatment, 106 Small-cell carcinomas, 309 Sodium ipodate, 10 Solid or trabecular variant PTC, 248 Solitary autonomous thyroid nodules clinical considerations, 76 diagnosis, 76–77 pathogenesis, 75 pathology, 75 treatment, 77–79 Somatic RET mutation, 300–301 Somatostatin analogues, 123–124 Soy supplements, 173 Spermatogenesis, impaired, 45 Splenomegaly, 45, 58 Spontaneously resolving lymphocytic thyroiditis. See Silent or “painless” thyroiditis Staphylococcus, 110 Streptococcus, 110 Struma ovarii tumor diagnosis, 127–128 epidemiology, 127 pathophysiology, 127 treatment, 128 Subacute thyroiditis, 351 diagnosis, 102–103 epidemiology, 101–102 pathophysiology, 102 treatment, 104

Index Subclinical hypothyroidism (SCH) clinical symptoms, 153 definition, 152 diagnosis, 71–72 and hypertension, 154 LT4 therapy, 166–168 neurobehavioral and neuromuscular symptoms in, 158 risk factor for myocardial infarctions, 156 role in development of atherosclerosis, 155 skeletal muscle abnormalities, 158 treatment, 72 treatment and cardiovascular outcomes, 157 Subtotal lobectomy, 260 Subtotal thyroidectomy, 377, 422 Sucralfate, 173 Supraphysiologic doses, of thyroid hormone, 126 Surgical excision treatment, 224 Surveillance, Epidemiology, and End Results (SEER) program, 238 Tachycardia, 41 Tall cell variant, 248 Tamoxifen, 10, 16 T4 and fetal hypothalamic-pituitary-thyroid system, 333–334 T3 and T4 toxicosis, 408 Technetium (99m Tc) scanning, 76, 211 Thrombocytopenia, 60 Thymic enlargement, 45 Thyroglobulin (Tg), assessment, 17–19 Thyroid autoantibodies, 19–21, 105 Thyroid autoimmunity, during pregnancy, 363–364 Thyroid cancer, 169 during pregnancy, 381–382 Thyroid carcinoma classification, 239–242 diagnosis, 250–253 epidemiology, 238–239 factors influencing prognosis and affecting outcome, 253–259 follicular, 242, 249–250 incidence, 239 papillary, 242–249 radiation-induced, 242–243 treatment chemotherapy, 273–274 completion thyroidectomy, 261 external beam radiation therapy, 273

447 follow-up, 274–278 gamma knife therapy, 273 imaging studies, 278–279 ipsilateral lobectomy, 260 isthmusectomy, 260 of patients with high serum Tg levels and negative imaging studies, 279–280 during pregnancy, 262 radioiodine (131 I) therapy, 262–272 subtotal lobectomy, 260 surgical complications, 262 thyroid hormone therapy, 272–273 total or near-total thyroidectomy, 261 tumor staging systems and prognostic scoring systems, 259–260 Thyroid dysgenesis, 336, 347 Thyroidectomy, 67, 115, 169 completion, 261 during pregnancy, 262 prophylactic total, 307 Thyroid function tests, 50, 55 Thyroid gland development, 331–332 functions of, 2 role of, 1 Thyroid gland enlargement (goiter) classification and prevalence, 204–205 history and examination, 206 laboratory and radiologic diagnosis FNA biopsy, 213–218 other imaging techniques, 212–213 scintigraphy, 210–212 serum calcitonin (CT) measurement, 207–208 ultrasonography, 208–210 management multinodular goiter, 223–225 solitary nodules, 218–223 pathogenesis, 205–206 Thyroid hormone binding ratio (THBR), 7–8 Thyroid hormone receptor-beta gene (TR-␤), 125 Thyroid hormone replacement therapy, 25 Thyroid hormone resistance syndromes, 160, 337 diagnosis, 126 epidemiology, 125 pathophysiology, 125–126 pediatric, 347–348 treatment, 126–127 Thyroid hormone therapy, 272–273

448 Thyroid hormonogenesis, inborn error of, 337 Thyroid neoplasia, 27–28 Thyroid nodules, during pregnancy, 381–382 Thyroid nodules, pediatrics clinical evaluation, 358 laboratory evaluation, 358 other screening tools, 358 prognosis, 360 therapy, 359–360 Thyroid peroxidase (TPO), 2 Thyroid replacement therapy, 350 Thyroid storm, 73–74, 413 Thyroid transcription factor (TTF), 331–332 Thyrotoxicosis, 16, 41 due to thyroid cancer, 130–131 symptoms of, 102–103 Thyrotoxicosis factitia, 121 diagnosis, 121 epidemiology, 121 pathophysiology, 121 treatment, 122 Thyrotoxic periodic paralysis, 43 Thyrotropin-binding inhibitory immunoglobulin assay (TBII assay), 48–49 Thyroxine-binding globulin (TBG), 2, 333 Thyroxine suppressive therapy, 221 Thyroxine (T4), 2 Tirosint (Institute Biochimique), 164 Tissue responses, to thyroid hormone action, 21–22 T3 measurement methods, 4 decreased, 11–13 free hormone, 4–8, 47 increased, 8–11 T4 measurement methods, 4 decreased, 11–13 free hormone, 4–8 increased, 8–11 TNM classification, 259–260 Total or near-total thyroidectomy, 261 Toxic multinodular goiter diagnosis, 81 pathogenesis of, 81 treatment, 81–83 Transient hypothyroidism, 169, 338–339 Transient painless thyroiditis. See Silent or “painless” thyroiditis Transient thyrotoxicosis with lymphocytic thyroiditis. See Silent or “painless” thyroiditis Transthyretin (thyroxine-binding prealbumin), 2

Index Treponema pallidum, 110 Triiodothyronine-containing thyroid hormone preparations, 8 Triiodothyronine (T3), 2, 121 Triostat, 164 Trophoblastic tumors diagnosis, 129 epidemiology, 128 pathophysiology, 129 treatment, 129 TSH-binding inhibitors, 20 TSH/free T4 relationship, 2 TSH levels, implications of, 16–17 TSH-producing pituitary tumors (TSHomas) diagnosis, 122–124 epidemiology, 122 pathophysiology, 122 treatment, 124–125 TSH receptor gene, 206 TSH receptor–stimulating antibodies, measurement of, 48–49 TSH receptor–stimulating immunoglobulins, 40 TSH-secreting pituitary adenomas, 16 TSI titers, 52–53 T4 suppressive therapy, 221 TTF2, 332 T3 thyrotoxicosis, 26, 55 T3-toxicosis, 8, 47 T4 toxicosis, 47 Tumor calcitonin, 302 Tumor histology, 255 Tumor necrosis factor, 12 Turner syndrome, 346 “Two-step” assay method, 7 Type 1 deiodinase (D1), 333 Tyrol, 112 Tyrosine kinases (TKs), 258 Ultrasonography, 253, 321 Unithroid (Jerome Stevens), 164 US-FNA, 217–218 Vitiligo, 42 Wechlser Intelligence Scale for Children, 367 Wolff-Chaikoff effect, 74 X-linked inherited TBG excess, 10 Yttrium-90 (99 Y)-labeled humanized anti-CEA monoclonal antibodies, 306

For general practitioners and endocrinologists, the new Second Edition of this bestselling book offers the most up-to-date and practical guidance to diagnose and manage common and uncommon thyroid diseases. New to the Second Edition: • information on thyroid neoplasia, leading to new effective treatments of advanced thyroid cancer • important new research on subclinical thyroid disease in the elderly and thyroid disorders in pregnancy • new research on thyroid physiology, pathophysiology, and therapeutics The new edition is fully evidence-based and updated to include the most current treatment and latest findings: • the screening and case finding for thyroid disease • the use of calcitonin in the diagnosis of medullary thyroid cancer • the diagnosis and management of subclinical hyperthyroidism (mild hyperthyroidism) • thyroid disease related to interferon therapy and amiodarone therapy about the editor... DAVID S. COOPER is Professor of Medicine, The Johns Hopkins University School of Medicine; Professor of International Health, Johns Hopkins Bloomberg School of Public Health; and Physician and Director, the Thyroid Clinic, Johns Hopkins Hospital, Baltimore, Maryland, USA. Dr. Cooper received his M.D. from Tufts University, Boston, Massachusetts, USA. He is a member of the Endocrine Society and is a past president of the American Thyroid Association. Dr. Cooper is currently Deputy Editor of the Journal of Clinical Endocrinology and Metabolism, Editor–inChief of Endocrinology, Up-to-Date, and Contributing Editor of the Journal of the American Medical Association (JAMA). Dr. Cooper was also the editor of the first edition of Informa Healthcare’s Medical Management of Thyroid Disease. Printed in the United States of America

Medical Management of Thyroid Disease

about the book…

Second Edition

Endocrinology

Medical Management of Thyroid Disease Second Edition

Cooper H7064

Edited by

David S. Cooper