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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