Medical Management of Thyroid Disease (Clinical Guides to Medical Management)

ISBN: 0-8247-0515-7 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http:/ /www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright  2001 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

To my wife Ellen, to our children, Jonathan, Ethan, and Susanna, and to Dr. Farahe Maloof, who introduced me to the mysteries of the thyroid gland.

Foreword

Previous components in the Medical Management program have addressed atherosclerosis, heart disease, diabetes mellitus, pulmonary disease, liver disease, kidney disease, and musculoskeletal and connective tissue disorders. The present volume is a welcome addition. It has been developed to provide practitioners, whether generalists or specialists, with current and comprehensive information pertinent to thyroid disease and its pleomorphic manifestations in patients. The material is presented in a format consistent with the overall objective of the Medical Management program, namely, provision of information that is readily accessible and readily assimilable in a context pertinent to the way issues surface clinically. Thus, cardinal signs and symptoms are used as points of departure for inquiry and elucidation. Dr. David S. Cooper, the editor of this volume, brings broad perspective and wisdom to his task. He has assembled an outstanding group of contributors, each of whom is a genuine authority. The contributors come from diverse institutions throughout the country. Many have contributed not only to the clinical literature but also to fundamental advances in the understanding of thyroid disease. Several sections of the monograph guide the reader through clinical approaches to the diagnosis and treatment of complex thyroid disorders. Thus, authorities deal with nodules and goiters, thyroid cancer, and thyroid disease in special setv

vi

Foreword

tings such as pregnancy, youth, and advanced age. As has been the case for other components of the Medical Management program, the book is written in a fashion designed to provide consultation analogous to that available through personal interactions in a hospital or office setting. Similarly to many other entities in clinical medicine, thyroid disorders may present with manifestations that first lead to involvement of practitioners in diverse specialties. Apathetic hyperthyroidism is a problem often recognized first by cardiovascular specialists. Thyroid cancer is usually recognized initially by a primary care physician. Thyroiditis may initially lead to involvement of experts in infectious disease. Hypo- or hyperthyroidism may confront a generalist with manifestations including lethargy, malaise, change in body weight, simulation of infection with fever without an obvious cause, or psychiatric disturbances. Accordingly, this monograph should be of interest to physicians with diverse interests and diverse skills in diverse disciplines. The clarity, thoroughness, and sophistication of the contents of his monograph make it relevant for medical students, house officers, fellows in specialty training programs, generalists and specialists in clinical practice, and investigators. Its completion should make the Medical Management program even more valuable to our readers. Burton E. Sobel, M.D. Series Editor

Preface

I have been privileged to be a clinical investigator and thyroidologist for almost 25 years. When I was contacted by an editor at 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 dog-eared 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 vii

viii

Preface

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

Contents

Foreword

v

Preface

vii

Contributors

xi

1. The Laboratory Approach to Thyroid Disorders Steven I. Sherman

1

2. The Diagnostic Evaluation and Management of Hyperthyroidism due to Graves’ Disease, Toxic Nodules and Toxic Multinodular Goiter Kenneth D. Burman and David S. Cooper 3. Diagnosis and Treatment of Thyroiditis and Other More Unusual Forms of Hyperthyroidism Shon E. Meek and Robert C. Smallridge

33

93 ix

x

Contents

4.

Diagnosis and Treatment of Hypothyroidism Michael T. McDermott and E. Chester Ridgway

135

5.

Thyroid Nodules and Multinodular Goiter Hossein Gharib

187

6.

Thyroid Carcinoma Richard T. Kloos and Ernest L. Mazzaferri

227

7.

Pediatric Thyroid Disorders Thomas P. Foley

313

8.

Practical Management of Thyroid Disease in the Elderly Myron Miller and Steven R. Gambert

345

9.

Thyroid Disease and Pregnancy Susan J. Mandel

387

Index

419

Contributors

Kenneth D. Burman Chief, Endocrine Section, Washington Hospital Center, and Professor of Medicine, Uniformed Services of the Health Sciences, Washington, D.C. David S. Cooper Director, Division of Endocrinology, Sinai Hospital of Baltimore, and Professor of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland Thomas P. Foley Professor of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Steven R. Gambert Physician-in-Chief, Sinai Hospital of Baltimore, and Professor of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland Hossein Gharib Professor of Medicine, Division of Endocrinology, Mayo Medical School, Mayo Clinic, and Mayo Foundation, Rochester, Minnesota xi

xii

Contributors

Richard T. Kloos Assistant Professor of Medicine and Radiology, The Ohio State University, Columbus, Ohio Susan J. Mandel Assistant Professor of Medicine, Division of Endocrinology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Ernest L. Mazzaferri Emeritus Professor of Internal Medicine and Emeritus Chairman of Internal Medicine, The Center for HOPES, The Ohio State University, Columbus, Ohio Michael T. McDermott Professor of Medicine, Division of Endocrinology, University of Colorado Health Sciences Center, Denver, Colorado Shon E. Meek Assistant Professor of Medicine, Department of Endocrinology, Mayo Clinic, Jacksonville, Florida Myron Miller Director, Division of Geriatric Medicine, Sinai Hospital of Baltimore, and Professor of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland E. Chester Ridgway Professor of Medicine, Division of Endocrinology, University of Colorado Health Sciences Center, Denver, Colorado Steven I. Sherman Chairman ad interim and Associate Professor of Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, M.D. Anderson Cancer Center, University of Texas, Houston, Texas Robert C. Smallridge Chair, Division of Endocrinology, and Professor of Medicine, Mayo Clinic, Jacksonville, Florida

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

1

INTRODUCTION

The central role of the thyroid gland in controlling metabolism was recognized over 100 years ago, but evaluation of the function of the thyroid remains an evolving science. Initial approaches to assessing 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. The clinician can now effectively confirm suspected diagnoses of thyroidal dysfunction, cost-effectively screen asymptomatic populations for common diseases, and appropriately monitor the treatment of patients with disorders of the thyroid. 1

2

2

Sherman

PHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARYTHYROID AXIS

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, 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 µg 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 innerring 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 (thyroxine-binding 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. 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 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 α-subunit; the β-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. TSH levels peak just before nocturnal sleep, and the nadir occurs in the late afternoon; this nocturnal surge is lost early in the course of nonthyroidal illness. 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 respon-

The Laboratory Approach to Thyroid Disorders

3

sible for establishing the setpoint 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. 3

LABORATORY EVALUATION OF THYROID FUNCTION

3.1 Assays of Thyroid Hormones 3.1.1

Total Serum Iodothyronine Concentrations

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—e.g., 8-anilino-1-naphthalene sulfonic acid for TBG and barbital for 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 T4 between antibody-bound and unbound fractions. The higher the serum hormone concentration, the lower the amount of radiolabel that binds to the antibody. Following the addition 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 antibodybound radiolabel with a simultaneously derived standard curve. 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—e.g., alkaline phosphatase, horseradish peroxidase, or glucose-6-phosphate dehydrogenase. As in RIA, numerous physical and chemical approaches exist for separating signal bound to the anti-iodothyronine 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

4

Sherman

assays and to facilitate automation. In general, these assay techniques have similar performance characteristics, although each may be affected by different sources of interference. 3.1.2

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. The reference standard for direct measurement of free T4 and T3 is the equilibrium dialysis method. 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. A highly sensitive RIA, capable of detecting nanogram quantities of hormone, is then used to measure the hormone content of the protein-free dialysate. 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. Such direct measurements are generally expensive 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 about 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 about 0.8 to 2.3 ng/dL for T4 and 210 to 440 pg/dL for 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. Immunoassay methods for estimation of free hormone concentration are now widely used (Fig. 1). In the ‘‘analogue’’ or ‘‘one-step’’ free T4 method, a

The Laboratory Approach to Thyroid Disorders

5

FIG. 1 Methods for radioimmunoassay estimation of free thyroxine concentration.

6

Sherman

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. One-step methods require structurally modified analogues that do not displace hormone from protein binding sites, but a complete lack of displacement is rarely achieved. Because the analogues used generally bind to albumin, this method may not 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. 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, 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. 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—e.g., talc, charcoal, resin, or antiiodothyronine 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 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 proteinbinding abnormalities. Alternate methods use nonisotopic labels, such as enzyme-

The Laboratory Approach to Thyroid Disorders

7

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 serum proteins, e.g., 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—e.g., familial dysalbuminemic hyperthyroxinemia, 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. 3.1.3

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 in 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, such as Graves’ disease. 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. Increased total T4 concentrations without thyrotoxicosis, termed euthyroid hyperthyroxinemia, can 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 selective estrogen receptor modulators, such as tamoxifen (1). Acquired TBG excess may also be responsible for the slight increase in T4 levels reported in male cigarette smokers (2). 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

8

TABLE 1 Causes of Increased T4 and/or T3 Concentrations Thyrotoxicosis Euthyroid hyperthyroxinemia Increased binding to plasma proteins Thyroxine-binding globulin excess Congenital Hyperestrogenemia: exogenous, endogenous Acute and chronic active hepatitis Acute intermittent porphyria HIV-1 infection Familial dysalbuminemic hyperthyroxinemia 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

Sherman

The Laboratory Approach to Thyroid Disorders

9

contribute to euthyroid hyperthyroxinemia. In the autosomal dominant condition familial dysalbuminemic hyperthyroxinemia (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 (3). 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 (4). More commonly, however, anti-iodothyronine autoantibodies have negligible in vivo effects on hormone binding, but interfere with immunoassay measurements (5). 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 (6). Preincubation of the serum specimen with a nonspecific animal immunoglobulin, ethanol, or polyethylene glycol prevents this antibody-mediated interference. Alteration in the function of the 5′-monodeiodinase causes impaired conversion of T4 to T3, decreasing T4 clearance and transiently increasing T4 levels. Iodinated radiocontrast dyes—e.g., sodium ipodate—are potent inhibitors of T4 to T3 conversion and have been used therapeutically in severely hyperthyroid patients. Amiodarone, a highly iodinated antiarrhythmic agent, also interferes with T4 deiodination. Since amiodarone-induced hyperthyroidism can also occur,

10

Sherman

great care must be taken in interpreting hyperthyroxinemia in patients receiving iodinated medications (7). 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 an 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 (8). 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 (9). Transient increases in total and free T4 and T3 can be seen in 8% to 33% of patients admitted for acute psychiatric disorders (10). TSH concentrations have been reported as increased in up to 10% of acutely psychotic patients (11), but they are frequently suppressed in severely depressed patients (12). 3.1.4

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 the 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 (13). Acquired impairment of hormone binding develops secondary 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,

The Laboratory Approach to Thyroid Disorders

11

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

lack of a linear relationship between free T4 fraction and THBR leads to falsely low free T4 index results, but values of free T4 are normal by two-step and direct measurements. Hypothyroxinemia and hypotriiodothyroninemia are common findings in patients with nonthyroidal illness (14). 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 (15). Numerous medications interfere with thyroid hormone binding to serum proteins, including diphenylhydantoin, furosemide, heparin, sertraline, and certain anti-inflammatory agents (16). Inhibition of 5′-monodeiodinase activity in nonthyroidal tissues accelerates clearance of T4 through nondeiodinative mechanisms, particularly in nonthyroidal illness

12

Sherman

and starvation, and may be secondary to increased levels of interleukin-6 (17). 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 (18). 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 (19). Alteration of TSH sialylation and bioactivity may occur in critical illness as well (20). Mild illness is typically accompanied by reductions in T4 to T3 conversion, resulting in a low T3 state. 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 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. 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 (21,22). However, no benefit from thyroid hormone supplementation has ever been demonstrated. 3.2 Assays of Thyroid-Stimulating Hormone Early TSH assays utilized 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 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 10- to 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 high affinity; the second antibody, which may be polyclonal, is labeled, providing a signal proportional to the amount of ligand bound. Whereas euthyroid patients typically have TSH values between 0.5 and 4 mU/L, hyperthyroid patients can be identified on the basis of low or undetectable levels of TSH. Although patients with endogenous antibodies directed against mouse immunoglobulin can have falsely elevated TSH levels, this problem has been eliminated from most commercially available kits by addition of an excess of mouse immunoglobulin (5). Even

The Laboratory Approach to Thyroid Disorders

13

more sensitive determinations of low TSH values have been obtained in an assay utilizing a chemiluminescent acridinium ester to generate the antibody-linked signal. High intraassay and interassay precision with chemiluminometric methods may permit routine detection of TSH levels as low as 0.01 mU/L or lower. A sensitive TSH assay, which provides a sufficient separation in serum TSH values between hyperthyroid and euthyroid patients, is defined as one in which the interassay coefficient of variation is less than 20% at a TSH concentration of 0.1 mU/L or less (23). 3.2.1

Causes of Hypothyrotropinemia

When conventional TSH radioimmunoassays were used, the inability of differentiate hyperthyroid from euthyroid patients was overcome by measurement of the TSH response to stimulation with exogenous TRH. After the intravenous administration of 500 µg of TRH, TSH levels normally increase to 7 to 20 mU/L at 30 min. 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 (24). 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 imunoassays 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 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 min after TRH administration and the latter having a persistently blunted response. In practice, there is an overlapping spectrum of TRH responses in patients with pituitary and hypothalamic diseases. 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 defective glycosylation of the protein. 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 (25).

14

3.2.2

Sherman

Causes of Hyperthyrotropinemia

Elevated serum TSH values are the cornerstone of the diagnosis of primary hypothyroidism. Due to the extreme sensitivity of the hypothalamic-pituitary-thyroid negative feedback loop, small decrements in circulating thyroid hormone levels produce logarithmic increases in serum TSH levels (24). At one end of the spectrum are patients with frankly symptomatic thyroid hormone deficiency, whose T4 levels are subnormal and whose TSH levels are typically ⬎20 mU/L. 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—e.g., 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-α) and tamoxifen, although the latter appears to induce a mild and transient increase in TSH levels (26). 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 α-subunit of TSH is commonly overproduced. A molar ratio of α-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 α-subunit to intact TSH is usually less than one. Resistance of the thyroid to TSH, presenting with nongoitrous congenital hypothyroidism and elevated TSH levels, has been described both in isolated form as well as in pseudohypoparathyroidism type 1a. 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

The Laboratory Approach to Thyroid Disorders

15

100 mU/L. 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. 3.3 Specialized Studies of Thyroid Function 3.3.1

Thyroglobulin

In most forms of thyroid disease, thyroglobulin (Tg) is released from thyroid follicular cells proportional to the production of T4 and T3. Elevated levels are seen in most patients with hyperthyroidism and thyroiditis. In determining the cause of hyperthyroidism, lack of detectable serum thyroglobulin suggests factitious or iatrogenic thyrotoxicosis. Undetectable levels are also seen in hypothyroid patients with congenital absence of the thyroid. Serum Tg is generally measured by either two-antibody immunometric assay or single-antibody immunoassay. The values in normal subjects in most laboratories range from 1 to about 30 ng/mL. The newer assays are quicker and have greater sensitivity (ⱕ1 ng/mL) than the older ones, but several problems persist. The greatest limitation is the potential for interference by anti-Tg autoantibodies. In the immunometric assays, the serum Tg concentration can be falsely lowered by autoantibodies because they bind Tg and effectively remove it from the serum. 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. Conversely, in radioimmunoassays, anti-Tg autoantibodies cause falsely high values because they bind radiolabeled Tg; as a result, less is bound to the assay antibody. Measure of serum Tg should therefore always be preceded by a test for anti-Tg antibodies. As many as 25% of patients with differentiated thyroid cancer have anti-Tg autoantibodies at the time of diagnosis. 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 socalled 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. Use of sensitive polymerase chain reaction methods allows the detection of Tg messenger RNA circulating in the peripheral blood of patients with thyroid cancer, presumably contained within circulating tumor cells. The immediate advantage of such an assay would be bypassing the problem of interference of antithyroglobulin autoantibodies in the Tg assays. Preliminary reports suggest that Tg mRNA assays have excellent sensitivity; however, these assays are not yet clinically available (27).

16

3.3.2

Sherman

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. In Hashimoto’s disease, cytotoxic antibodies may bind to a thyroid microsomal antigen that is also expressed on the cell surface and 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 to only 55% for non-complement-fixing antithyroglobulin antibodies. Among commercially available assays—immunometric procedures, including RIA, 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 thyroid peroxidase, consistent with evidence that this enzyme is the primary microsomal antigen. 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. Antimicrosomal and antithyroglobulin antibodies are also present in Graves’ disease, albeit less frequently (80% 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 has been largely replaced by quantitation of cyclic AMP production, iodine uptake, or thymidine incorporation into DNA in a cultured rat thyroid follicular cell line. 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. TSH-binding inhibitors can be detected by quantitation of radiolabeled bovine TSH binding to solubilized porcine thyroid membranes in the presence of serum. In general, the most sensitive of these assays can detect thyroid-stimulating 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 (28,29). However, thyroid-stimulating immunoglobulins levels may be more useful for identifying Graves’ disease as the cause of exophthalmos (29). Blocking antibodies that bind to but do not stimulate

The Laboratory Approach to Thyroid Disorders

17

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 whom the etiology of hyperthyroidism is uncertain can lead to a diagnosis of Graves’ disease, although antimicrosomal antibodies are also common in this condition and may be a more cost-effective test. Persistence of high titers of thyroid-stimulating immunoglobulins in Graves’ disease after a course of antithyroid drug therapy is associated with increased rates of recurrence (30). When detected during the third trimester of pregnancy in a woman with Graves’ disease, significant increases in either TSH-binding 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 antimicrosomal antibody titers are prognostic for the development of overt hypothyroidism in about 5% of patients per year; the likelihood of thyroidal failure is higher in those patients with higher titers. The presence of serum antimicrosomal antibodies in a euthyroid pregnant woman greatly increases her risk of developing symptomatic postpartum thyroiditis. 3.3.3

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 co-existing hypothyroidism (32). 3.3.4

Tissue Responses to Thyroid Hormone Action

Before the availability of hormone immunoassays, measurement of the end-organ responses—e.g., 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. The basal metabolic rate, determined by indirect calorimetry, provides an integrated assessment of the effect of thyroid hormones on tissue oxygen consumption in the resting state. Decreases of at least 5% in the basal metabolic

18

Sherman

rate are associated with overt hypothyroidism, and increases of at least 20% are commonly seen in hyperthyroidism. However, the lack of specificity for thyroid diseases, the broad overlap of values obtained from euthyroid patients versus those with thyroid dysfunction, and the requirement for basal testing conditions limit the usefulness of whole-body calorimetry techniques to research applications. Resting energy expenditure is more readily measured. This parameter does not require achievement of the basal state but is similarly affected by physiological and psychological variables other than thyroid hormone. Reflecting the narrow intrapatient variability, serial measurements of the resting energy expenditure are quite sensitive to small changes in levothyroxine doses in a hypothyroid patient (33). The effects of thyroid hormones on cardiac contractility can be evaluated with a variety of techniques. The ratio of the preejection period to the left ventricular ejection time—determined with simultaneous recording of the electrocardiogram, phonocardiogram, and carotid artery pulse tracing—is decreased in hyperthyroidism and increased in hypothyroidism. Improvement can be seen even in patients with subclinical hypothyroidism treated with thyroid hormone therapy. Using M-mode echocardiography, a simplified technique to measure the preejection period, isovolumetric contraction time, and left ventricular ejection time has been developed that allows discrimination among hypothyroid, euthyroid, and hyperthyroid individuals without intrinsic cardiac disease. Because the preejection period and isovolumetric contraction time are relatively independent of the heart rate, the chronotropic effects of thyroid hormones and drugs such as βadrenergic receptor antagonists do not invalidate these tests. Other biophysical indices of thyroid hormones actions include the Achilles reflex relaxation time, the stapedial reflex, bone mineral densitometry, hypoxic and hypercapnic ventilatory drives, and visual evoked potentials. 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 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 (34,35). 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 µg per day). Among the various tests performed, changes in sex hormone binding globulin, basal metabolic rate, and body weight provide the strongest distinction

The Laboratory Approach to Thyroid Disorders

19

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

between normal responsiveness and generalized resistance to thyroid hormones (36). 4

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. 4.1 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

20

Sherman

treatment is effective. Although not previously considered as fulfilling these criteria (37), newer findings regarding thyroid function screening have led to revisions of previous practice guidelines (38). The Whickham study demonstrated an annual incidence of thyroid hormone excess and deficiency of 0.5% in nonelderly women in the United Kingdom (39), and the frequency in the elderly may be as high as 10%. 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 (40). The incremental cost of this TSH testing strategy was $9200 per quality-adjusted life year for women and $22,600 for men, figures comparable to those estimated for screening procedures for breast cancer and hypertension. Deferring periodic TSH screening until older ages and decreasing cost for TSH assays are key factors in improving cost-effectiveness even further. By starting with a serum TSH and reflexing to a measure of free T4 only when the TSH is abnormal, screening costs can be minimized without major loss of diagnostic efficacy (41–44). 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 T4 in whole blood collected on filter paper. Determination of TSH concentration is performed if the T4 level is low, and serum assays are used to confirm a diagnosis of hypothyroidism. An alternative strategy employs primary TSH screening, followed by confirmatory T4 testing. 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. Studies of geriatric patients admitted to a hospital for chronic symptoms or exacerbations of chronic disease demonstrate a 5% to 10% prevalence of thyroid dysfunction that can respond to therapeutic intervention. 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 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 (45). Postpartum women have a high frequency of transient thyroid dysfunction. Within the first 3 months after delivery, at least 5% of women develop postpartum thyroiditis, a painless inflammatory condition that can cause hyperthyroidism and/or hypothyroidism. More than one-half of these patients require therapeutic

The Laboratory Approach to Thyroid Disorders

21

intervention. Furthermore, 25% of women with postpartum thyroiditis eventually develop chronic hypothyroidism requiring lifelong therapy. Since patients with high serum titers of antimicrosomal antibodies during the second trimester have a markedly increased risk for developing postpartum thyroiditis, some experts have recommended screening for antimicrosomal antibodies during this period to identify those women likely to require therapy. 4.2 Hypothyroidism 4.2.1

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 (46). 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 estimation or measurement 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. The sensitivity and specificity of commercially available assays being equivalent, cost should be the determinant in choosing between a free T4 immunoassay and a free T4 estimate based upon the THBR (44). 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%. 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 may have normal T4 levels. If abnormal serum binding is suspected, for example, in patients taking estrogen therapy, an estimate of free thyroxine is a more appropriate first test. A serum TSH assay may also be a cost-

22

Sherman

effective initial test in this group. 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. Hypothyroidism due to pituitary or hypothalamic disease is more common as well in an endocrinology clinic, and a TSH assay as the sole evaluation of the pituitarythyroid axis can be misleading given the frequent lack of elevation of TSH concentrations in this disorder. 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 antimicrosomal 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 TSHsuppressive effects of exogenous and endogenous glucocorticoids, dopamine, somatostatin, and opioids. Demonstration of an elevated THBR may signify the presence of euthyroid hypothyroxinemia in the ill patient. Confirmation of the diagnosis may require follow-up testing when the patient has recovered from the acute illness. If pituitary of hypothalamic disease is suspected, other abnormalities of anterior pituitary function are often found—e.g., 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—e.g., resting energy expenditure, creatine kinase, cholesterol, and systolic time intervals. 4.2.2

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. When levothyroxine sodium is administered daily by mouth, decreasing serum TSH concentrations plateau within 4 to 6 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 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

The Laboratory Approach to Thyroid Disorders

23

performed after several months, given the gradual increase of T4 clearance that occurs in these patients. Subsequent evaluations generally are required only annually. 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 (47). Patients receiving therapy with T3-containing preparations, which are shorter-acting than levothyroxine sodium alone, may be more difficult to monitor. Individuals who take desiccated thyroid or other formulations containing triiodothyronine are likely to have variable T3 levels during the day. 4.3 Hyperthyroidism 4.3.1

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. An estimate of the free T4, using either the free thyroxine index or a free T4 assay, 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 thyroxine index. Patients with familial dysalbuminemic hyperthyroxinemia, 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 indices, 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 albeit more expensive 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, whereas normal or low thyroid hormone levels suggest either T3 thyrotoxicosis, nonthyroidal illness, or central hypothyroidism. Patients with the rare causes of TSH-mediated hyperthyroidism who may have normal or even elevated TSH levels—i.e, TSHsecreting 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 determinations of serum TSH and thyroid hormone concentrations may be the most appropriate initial tests to perform.

24

Sherman

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—e.g., resting energy expenditure, systolic time intervals, angiotensin-converting enzyme, sex hormone–binding globulin, and cholesterol. 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. Testing for antimicrosomal antibodies or thyroid stimulating immunoglobulins may assist in the discrimination between Graves’ disease and toxic multinodular goiter. Radiologic imaging of the sella and a serum α-subunit level would be indicated in the evaluation of the patient with TSH-mediated hyperthyroidism. 4.3.2

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. 5

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

The Laboratory Approach to Thyroid Disorders

25

levels and reducing hormone production by nonadenomatous tissue. However, only 5% of 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 about 50% as high as following endogenous TSH stimulation after thyroid hormone withdrawal, when performed in conjunction with diagnostic radioiodine scanning (48). The results are most likely to be falsely negative in patients with small nodal metastases of papillary carcinoma and in those with tumor dedifferentiation. However, it is difficult to generalize from the results in one center because of interlaboratory variations in assay sensitivity and specificity. Nonetheless, many investigators have used a serum Tg value of 5 ng/mL in patients taking T4 to determine whether to undertake a search for persistent or recurrent thyroid carcinoma. With increasing assay sensitivity, 2 ng/mL may be more appropriate. 6

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 hypermagnesemia and β-adrenergic agonists. Suppression of hormone release is produced by dopamine, somatostatin, and 1,25-dihydroxyvitamin 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. Single- or double-antibody immunoassay techniques are used for the routine measurement of serum calcitonin levels. 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 radioimmunoassay yields mostly

26

Sherman

monomeric calcitonin, with a normal concentration of ⬍20 pg/mL. Normal values in unextracted serum are ⬍100 pg/mL. 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 will 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), and renal failure (due to impaired clearance). 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. 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 (⬎300 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 calciumpentagastrin 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 s, and plasma for calcitonin measurements is collected 5 and 10 min after the infusion (49). C-cell hyperplasia and medullary carcinoma produce greater than fivefold elevations in the serum calcitonin concentration (50). Additional tumor markers, such as carcinoembryonic antigen, can be useful in the long-term follow-up of patients with MTC. 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, of whom 40% will prove to have MTC at thyroidectomy (51–53). At an estimated cost of $12,500 per diagnosed case that would not otherwise be identified by FNA, and the lack of widespread availability of such a sensitive immunoassay, routine measurement of serum calcitonin levels in all patients with nodular thyroid disease cannot be recommended (54,55).

The Laboratory Approach to Thyroid Disorders

27

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 (56). 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 (57). All familial forms of MTC and MEN 2 are inherited in an autosomal dominant fashion. In at least 95% of known kindreds, the disease is associated with (and likely caused by) a germline mutation in the ret proto-oncogene, a 21-exon gene located near the centromere on chromosome 10. Ret codes for a cell membrane– associated tyrosine kinase receptor for glial cell line–derived neurotrophic factor, a circulating ligand that promotes development of various central and peripheral

TABLE 4 Ret Protooncogene Mutations in Hereditary Medullary Thyroid Carcinoma Mutated Codon/Exon 609/10 611/10 618/10 620/10 630/11 634/11 635/11 637/11 768/13 790/13 791/13 804/13 883/15 891/15 918/16 922/16

Clinical Syndrome FMTC; MEN 2A with or without Hirschsprung disease FMTC; MEN 2A FMTC; MEN 2A with or without Hirschsprung disease FMTC; MEN 2A with or without Hirschsprung disease FMTC; MEN 2A FMTC; MEN 2A; MEN 2A with cutaneous lichen amyloidosis MEN 2A MEN 2A FMTC FMTC; MEN 2A FMTC FMTC; MEN 2A MEN 2B FMTC MEN 2B MEN 2B

Key : FMTC, familial medullary thyroid carcinoma; MEN, multiple endocrine neoplasia syndromes.

28

Sherman

nervous system neurons (58,59). Mutations associated with MEN 2A and FMTC have been primarily identified in several codons of the cysteine-rich extracellular domains of exon 10, 11 and 13, whereas MEN 2B and some FMTC mutations are found within the intracellular exons 15 and 16 (Table 4) (60). Further, about 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 (61,62). 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, and 15 (60). 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; a summary of available commercial testing sites and the methods employed is maintained at the Internet web site 〈http:// endrcr06.mda.uth.tmc.edu/genetic/avail.htm〉. Presently, a 5% error rate is generally reported, underscoring the importance for repeat testing of at least two independently obtained blood samples in more than one laboratory to minimize the likelihood of both false-positive and false-negative results (63).

REFERENCES 1. Brent GA. Maternal thyroid function: interpretation of thyroid function tests in pregnancy. Clin Obstet Gynecol 1997; 40:3–15. 2. Fisher CL, Mannino DM, Herman WH, Frumkin H. Cigarette smoking and thyroid hormone levels in males. Int J Epidemiol 1997; 26:972–977. 3. Stevenson HP, Archbold GP, Johnston P, Young IS, Sheridan B. Misleading serum free thyroxine results during low molecular weight heparin treatment. Clin Chem 1998; 44:1002–1007. 4. Sakata S, Nakamura S, Miura K. Autoantibodies against thyroid hormones or iodothyronine: implications in diagnosis, thyroid function, treatment, and pathogenesis. Ann Intern Med 1985; 103:579–589. 5. Despres N, Grant AM. Antibody interference in thyroid assays: a potential for clinical misinformation. Clin Chem 1998; 44:440–454. 6. Norden AG, Jackson RA, Norden LE, Griffin AJ, Barnes MA, Little JA. Misleading results from immunoassays of serum free thyroxine in the presence of rheumatoid factor. Clin Chem 1997; 43:957–962. 7. Harjal KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997; 126:63–73. 8. Smallridge RC, Parker RA, Wiggs EA, Rajagopal KR, Fein HG. Thyroid hormone resistance in a large kindred: physiologic, biochemical, pharmacologic, and neuro-

The Laboratory Approach to Thyroid Disorders

9. 10.

11.

12. 13.

14. 15.

16.

17.

18. 19.

20.

21.

22. 23. 24.

25.

29

psychologic studies [published erratum appears in Am J Med 1989 May; 86(5):637]. Am J Med 1989; 86:289–296. DeGroot LJ, Mayor G. Admission screening by thyroid function tests in an acute general care teaching hospital (see comments). Am J Med 1992; 93:558–564. Chopra IJ, Solomon DH, Huang TS. Serum thyrotropin in hospitalized psychiatric patients: evidence for hyperthyrotropinemia as measured by an ultrasensitive thyrotropin assay. Metabolism 1990; 39:538–543. Woolf PD, Nichols D, Porteinsson A, Boulay R. Thyroid evaluation of hospitalized psychiatric patients: the role of TSH screening for thyroid dysfunction. Thyroid 1996; 6:451–456. Hein MD, Jackson IM. Review: thyroid function in psychiatric illness. Gen Hosp Psychiatry 1990; 12:232–244. Refetoff S, Murata Y, Mori Y, Janssen OE, Takeda K, Hayashi Y. Thyroxinebinding globulin: organization of the gene and variants [published erratum appears in Horm Res 1996 Jul; 46(1):37]. Horm Res 1996; 45:128–138. McIver B, Gorman CA. Euthyroid sick syndrome: an overview. Thyroid 1997; 7: 125–132. Feelders RA, Swaak AJ, Romijn JA, Eggermont AM, Tielens ET, Vreugdenhil G, Endert E, van Eijk HG, Berghout A. Characteristics of recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients. Metabolism 1999; 48:324–329. Harel Z, Biro FM, Tedford WL. Effects of long term treatment with sertraline (Zoloft) simulating hypothyroidism in an adolescent. J Adolesc Health 1995; 16:232– 234. Torpy DJ, Tsigos C, Lotsikas AJ, Defensor R, Chrousos GP, Papanicolaou DA. Acute and delayed effects of a single-dose injection of interleukin-6 on thyroid function in healthy humans. Metabolism 1998; 47:1289–1293. Mandel SJ, Brent GA, Weinblatt M, Larson PR. Prospective studies of thyroid function in patients receiving gold therapy. Thyroid 1995; 5:113–116. Fliers E, Guldenaar SE, Wiersinga WM, Swaab DF. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab 1997; 82:4032–4036. Magner J, Roy P, Fainter L, Barnard V, Fletcher PJ. Transiently decreased sialylation of thyrotropin (TSH) in a patient with the euthyroid sick syndrome. Thyroid 1997; 7:807–808. Seppel T, Becker A, Lippert F, Schlaghecke R. Serum sex hormone-binding globulin and osteocalcin in systemic nonthyroidal illness associated with low thyroid hormone concentrations. J Clin Endocrinol Metab 1996; 81:1663–1665. De Groot LJ. Dangerous dogmas in medicine: the nonthyroidal illness syndrome (see comments). J Clin Endocrinol Metab 1999; 84:151–164. Spencer CA, Takeuchi M, Kazarosyan M. Current status and performance goals for serum thyrotropin (TSH) assays. Clin Chem 1996; 42:140–145. Spencer CA, Schwarzbein D, Guttler RB, LoPresti JS, Nicoloff JT. Thyrotropin (TSH)-releasing hormone stimulation test responses employing third and fourth generation TSH assays. J Clin Endocrinol Metab 1993; 76:494–498. Sherman SI, Gopal J, Haugen BR, Chiu AC, Whaley K, Nowlakha P, Duvic M.

30

26. 27.

28.

29.

30.

31.

32. 33.

34.

35.

36. 37. 38. 39.

Sherman Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 1999; 340:1075–1079. Zidan J, Rubenstein W. Effect of adjuvant tamoxifen therapy on thyroid function in postmenopausal women with breast cancer. Oncology 1999; 56:43–45. Ringel MD, Balducci-Silano PL, Anderson JS, Spencer CA, Silverman J, Sparling YH, Francis GL, Burman KD, Wartofsky L, Ladenson PW, Levine MA, Tuttle RM. Quantitative reverse transcription-polymerase chain reaction of circulating thyroglobulin messenger ribonucleic acid for monitoring patients with thyroid carcinoma. J Clin Endocrinol Metab 1999; 84:4037–4042. Takasu N, Oshiro C, Akamine H, Komiya I, Nagata A, Sato Y, Yoshimura H, Ito K. Thyroid-stimulating antibody and TSH-binding inhibitor immunoglobulin in 277 Graves’ patients and in 686 normal subjects. J Endocrinol Invest 1997; 20:452–461. Yamano Y, Takamatsu J, Sakane S, Hirai K, Kuma K, Ohsawa N. Differences between changes in serum thyrotropin-binding inhibitory antibodies and thyroidstimulating antibodies in the course of antithyroid drug therapy for Graves’ disease. Thyroid 1999; 9:769–773. Feldt-Rasmussen U, Schleusener H, Carayon P. Meta-analysis evaluation of the impact of thyrotropin receptor antibodies on long term remission after medical therapy of Graves’ disease. J Clin Endocrinol Metab 1994; 78:98–102. Laurberg P, Nygaard B, Glinoer D, Grussendorf M, Orgiazzi J. Guidelines for TSHreceptor antibody measurements in pregnancy: results of an evidence-based symposium organized by the European Thyroid Association. Eur J Endocrinol 1998; 139: 584–586. Burmeister LA. Reverse T3 does not reliably differentiate hypothyroid sick syndrome from euthyroid sick syndrome. Thyroid 1995; 5:435–441. al-Adsani H, Hoffer LJ, Silva JE. Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metab 1997; 82:1118–1125. Sarne DH, Refetoff S, Rosenfield RL, Farriaux JP. Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration. J Clin Endocrinol Metab 1988; 66:740–746. Hayashi Y, Weiss RE, Sarne DH, Yen PM, Sunthornthepvarakul T, Marcocci C, Chin WW, Refetoff S. Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormonebeta receptors? J Clin Endocrinol Metab 1995; 80:3246–3256. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993; 14:348–399. Helfand M, Crapo L. Screening for thyroid disease. Ann Intern Med 1990; 112: 840–849. Helfand M, Redfern CC. Clinical guideline, part 2. Screening for thyroid disease: an update. Ann Intern Med 1998; 129:144–158. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995; 43:55–68.

The Laboratory Approach to Thyroid Disorders

31

40. Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild thyroid failure at the periodic health examination: a decision and cost-effectiveness analysis. JAMA 1996; 276:285–292. 41. Bauer DC, Brown AN. Sensitive thyrotropin and free thyroxine testing in outpatients: are both necessary? Arch Intern Med 1996; 156:2333–2337. 42. Feldkamp CS, Carey JL. An algorithmic approach to thyroid function testing in a managed care setting: 3 year experience. Am J Clin Pathol 1996; 105:11–16. 43. Klee GG, Hay ID. Biochemical testing of thyroid function. Endocrinol Metab Clin North Am 1997; 26:763–775. 44. Nordyke RA, Reppun TS, Madanay LD, Woods JC, Goldstein AP, Miyamoto LA. Alternative sequences of thyrotropin and free thyroxine assays for routine thyroid function testing: quality and cost. Arch Intern Med 1998; 158:266–272. 45. Stockigt JR. Guidelines for diagnosis and monitoring of thyroid disease: nonthyroidal illness. Clin Chem 1996; 42:188–192. 46. Schectman JM, Kallenberg GA, Shumacher RJ, Hirsch RP. Yield of hypothyroidism in symptomatic primary care patients. Arch Intern Med 1989; 149:861–864. 47. Carrozza V, Csako G, Yanovski JA, Skarulis MC, Nieman L, Wesley R, Pucino F. Levothyroxine replacement therapy in central hypothyroidism: a practice report. Pharmacotherapy 1999; 19:349–355. 48. Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, Cooper DS, Graham KE, Braverman LE, Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri EL, Daniels GH, Ross DS, Luster M, Samuels MH, Becker DV, Maxon HR III, Cavalieri RR, Spencer CA, McEllin K, Weintraub BD, Ridgway EC. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999; 84:3877– 3885. 49. Parthemore JG, Bronzert D, Roberts G, Deftos LJ. A short calcium infusion in the diagnosis of medullary thyroid carcinoma. J Clin Endocrinol Metab 1974; 39:108– 111. 50. Wells SA, Jr., Baylin SB, Leight GS, Dale JK, Dilley WG, Farndon JR. The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Ann Surg 1982; 195:595–599. 51. Pacini F, Fontanelli M, Fugazzola L, Elisei R, Romei C, Di Coscio G, Miccoli P, Pinchera A. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1994; 78:826–829. 52. Niccoli P, Wion-Barbot N, Caron P, Henry J-F, de Micco C, Saint Andre J-P, Bigorgne J-C, Modigliani E, Conte-Devolx B, The French Medullary Study Group. Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. J Clin Endocrinol Metab 1997; 82:338–341. 53. Ozgen AG, Hamulu F, Bayraktar F, Yilmaz C, Tuzun M, Yetkin E, Tuncyurek M, Kabalak T. Evaluation of routine basal serum calcitonin measurement for early diagnosis of medullary thyroid carcinoma in seven hundred seventy-three patients with nodular goiter. Thyroid 1999; 9:579–582. 54. Singer PA, Cooper DS, Daniels GH, Ladneson PW, Greenspan FS, Levy EG, Braverman LE, Clark OH, McDougall IR, Ain KV, Dorfman SG. Treatment guidelines

32

55. 56.

57.

58.

59.

60. 61.

62.

63.

Sherman for patients with thyroid nodules and well-differentiated thyroid cancer. Arch Intern Med 1996; 156:2165–2172. Horvit PK, Gagel RF. Editorial: the goitrous patient with an elevated serum calcitonin. What to do? J Clin Endocrinol Metab 1997; 82:335–337. Ponder BA, Ponder MA, Coffey R, Pembrey ME, Gagel RF, Telenius-Berg M, Semple P, Easton DF. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 1988; 1:397–401. O’Riordain DS, O’Brien T, Weaver AL, Gharib H, Hay ID, Grant CS, van Heerden JA. Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surgery 1994; 116:1017–1023. Durbec P, Marcos-Gutierrez CV, Kilkenny C, Grigoriou M, Wartiowaara K, Suvanto P, Smith D, Ponder B, Costantin F, Saarma M, Sariola H, Pachnis V. GDNF signalling through the Ret receptor tyrosine kinase. Nature 1996; 381:789–791. Trupp M, Arenas E, Fainzilber M, Nilsson A-S, Sleber B-A, Grigoriou M, Kilkenny C, Salazar-Grueso E, Pachnis V, Arumae U, Sariola H, Saarma M, Ibanez CF. Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 1996; 381: 785–789. Gagel RF, Cote GJ. Pathogenesis of medullary thyroid carcinoma. in Fagin JA ed. Thyroid Cancer. Vol. 2. Boston: Kluwer Academic Publishers, 1998:85–103. Romei C, Elisei R, Pinchera A, Ceccherini I, Molinaro E, Mancusi F, Martino E, Romeo G, Pacini F. Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence. J Clin Endocrinol Metab 1996; 81:1619–1622. Wohllk N, Cote GJ, Bugalho MMJ, Ordonez N, Evans DB, Goepfert H, Khorana S, Schultz P, Richards CS, Gagel RF. Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1996; 81:3740– 3745. Gagel RF, Cote GJ, Martins Bugalho MJ, Boyd AE, 3rd, Cummings T, Goepfert H, Evans DB, Cangir A, Khorana S, Schultz PN. Clinical use of molecular information in the management of multiple endocrine neoplasia type 2A. J Intern Med 1995; 238:333–341.

2 The Diagnostic Evaluation and Management of Hyperthyroidism Due to Graves’ Disease, Toxic Nodules and Toxic Multinodular Goiter Kenneth D. Burman Washington Hospital Center and Uniformed Services of the Health Sciences, Washington, D.C.

David S. Cooper Sinai Hospital of Baltimore and The Johns Hopkins University School of Medicine, Baltimore, Maryland

1

GRAVES’ DISEASE

1.1 Introduction Graves’ disease is an autoimmune thyroid disorder characterized by clinical hyperthyroidism and the presence of autoantibodies directed against the thyrotropin (TSH) receptor (1). 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 (2). Circulating TSH receptor–stimulating antibodies are present in at least 90% of patients and are responsible, in large part, for the thyroidal hyperactivity (3). An interesting aspect of Graves’ disease is its association with ophthalmopathy, which can cause tearing, burning, itching, 33

34

Burman and Cooper

proptosis, double vision, and/or (rarely) visual impairment (4). The 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 (4–9). 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 (5,8) or because the chronic inflammatory process has resulted in thyroid failure. 1.2 Epidemiology Although it may present in patients of any age, Graves’ disease occurs more commonly in women than men, especially in women between the ages of about 20 and 50 years (2). 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 (10–12). 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 (13–17). 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 (14,15,18–25). 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. 1.3 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 (26,27). Thyroidal iodide exposure is a critical aspect regulating thyroid hormone physiology. The United States is a geographic area of iodine sufficiency. In a

Evaluation and Management of Hyperthyroidism

35

study published in 1973, Wartofsky voiced concern that iodine excess could be playing a role in increasing recurrence rates of Graves’ disease patients who had been in remission (28). However, a more recent nutritional analysis has indicated that the average urinary iodine excretion in the United States has decreased markedly from 32 µg/dL during the period 1971–1974 to 14 µg/dL in 1988–1994 (29). Concerns about the possible detrimental effects of dietary iodine in provoking hyperthyroidism or recurrent Graves’ disease have been partly assuaged by this decrease in dietary iodine. Currently, the typical American diet now may not contain enough iodine to play a significant role in mediating thyroid dysfunction (30–32). However, exposure to extremely large iodine loads—such as radiocontrast dyes, amiodarone, and kelp—may cause hyperthyroidism and increase the recurrence rates of Graves’ disease (32). Each individual dose of radiocontrast dye contains approximately 1650 to 6300 mg iodine, amiodarone contains 75 to 200 mg iodine, and kelp tablets usually contain 0.15 mg iodine per tablet (32). 1.4 Diagnosis 1.4.1

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) (2). 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. 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 immunological abnormalities. Vitiligo 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 to 4).

36

Burman and Cooper

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 Neurological Reproductive/sexual Hematopoietic

Mental

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

Elevated serum calcium, probably related to a direct effect of thyroid hormones on osteoclasts, may occur in about 10% of patients. Some believe that the likelihood of having a coincidental parathyroid adenoma is increased in Graves’ disease patients (33). 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 (34–36). The issue of whether Graves’ hyperthyroidism

Evaluation and Management of Hyperthyroidism

37

FIG. 1 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. [From (6)]

causes sufficient bone loss to induce or aggravate an increased risk of fractures is controversial (34–39). The risk of fractures is probably increased in postmenopausal women with a history of hyperthyroidism, although further studies are needed in this area (40). Hand tremor and generalized proximal muscle weakness are common. Rarely, hypokalemic periodic paralysis may occur, most frequently in Asian males (41–43). In a recent analysis of thyrotoxic periodic paralysis (42), hypokalemia was present in all 24 initial episodes and serum potassium levels varied from 1.1 to 3.4 mmol/L. 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. 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. 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. More serious abnormalities— such as depression and irrational or even criminal behavior—are very unusual.

38

Burman and Cooper

FIG. 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. [From (6)]

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 (44). Rarely, hyperthyroid patients may present with other neurological findings, such as athetosis (45). Women may have irregular menses and decreased fertility, but amennorhea is rare (46). Men may have decreased libido and gynecomastia, thought to be related to increased estrogen production (Fig. 5). 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 (47). 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 (48). The clinical result may simply be a small area of raised discolor-

Evaluation and Management of Hyperthyroidism

39

FIG. 3 A patient with Graves’ ophthalmopathy with predominant superior limbal keratopathy. [From (6)]

FIG. 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). [From (6)]

40

Burman and Cooper

FIG. 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. [From (6)]

ation in the pretibial area. Rarely, a large area of induration and nonpitting 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 (49). 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.

Evaluation and Management of Hyperthyroidism

41

FIG. 6 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. [From (6)]

The manifestations of Graves’ hyperthyroidism that occur in younger individuals may be different from those in older subjects (50). 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 8, ‘‘Practical Management of Thyroid Disease in the Elderly.’’ 1.5 Laboratory Diagnosis 1.5.1

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

42

Burman and Cooper

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 bind specific nuclear receptors and mediate biological activity. Total T4 measurements are affected by factors that influence thyroid hormone–binding proteins, such as estrogen-containing compounds, birth control pills, and androgen-containing substances. FT4 levels remain normal in these situations (2). 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 rapid, cost-effective manner. Like total T4, total T3 levels are altered by situations that change thyroid hormone–binding proteins. TSH assays have also improved recently, and ‘‘third generation’’ assays can measure 0.01 mU/L in serum, with the normal range being about 0.5 to 4.5 mU/L (51– 57). These improvements in sensitivity result from utilizing chemiluminescent techniques. All patients with 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. 1.5.2

24-Hour Radio Iodine Uptake

Serum measurements of thyroid hormone and TSH are the cornerstone in the diagnosis of hyperthyroidism, but they do not assess biological activity or the tissue effects of the circulating thyroid hormone levels. The capacity of the thyroid gland to concentrate radioactive iodine is a physiological test representing in vivo events. A normal subject will concentrate about 8% to 30% of radioactive iodine administered when determined at 24 h. Patients with hyperthyroidism will usually concentrate higher amounts of radioactive iodine than normal, reflecting the heightened ability of the gland to concentrate iodine. Radiocontrast dyes and other sources of exogenous iodine will interfere with this test, because the enormous amounts of unlabeled iodine in these compounds dilute out the radioactive tag, resulting in less radioactive iodine being concentrated by the thyroid gland (32). 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 (58,59). Therefore, an elevated radioactive iodine test is not specific for hyperthyroidism. Since dietary iodine intake has decreased over time (29), the normal range for the 24-h 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-h 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,

Evaluation and Management of Hyperthyroidism

43

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. 1.5.3

TSH Receptor Antibody Measurements

Anti-TSH receptor antibody measurements can be performed with one of two possible assays (Table 2) (3,8). 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 (3,60–62). 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 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 or human TSH receptors is compared to control normal serum or IgG. 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 (63–65). Di Cerbo et al. (64) 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 (3). 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, but this test is not very sensitive or specific. 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 normal), there is an increased likelihood that these IgG antibodies

44

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

Nomenclature a

TSI TBIIb

Frequency

Advantage

Disadvantage

80–100% 70–90%

Stimulatory Easy to perform

Difficult 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 125I-TSH binding from thyroid cell membranes or cells transfected with TSH receptor. Source: Adapted from Ref. 2.

Burman and Cooper

Evaluation and Management of Hyperthyroidism

45

will cross the placenta and cause neonatal hyperthyroidism. 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 (65,66). Hightiter antibodies may help to predict remissions after a course of antithyroid drugs or permanent hypothyroidism following radioiodine therapy or surgery. 1.5.4

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 anti– thyroid hormone autoantibodies, about 42% of patients had antibodies against triiodothyronine, 33% against thyroxine, and 25% of patients had both anti-T3 and anti-T4 antibodies (67). Although 44% of these patients were considered to be euthyroid, 16% were hyperthyroid and almost 40% were hypothyroid. The effect of antibodies on T4 and T3 measurements depend upon the method of measurement—but, in general, they cause a laboratory result that is incongruent with the clinical state (67). 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. 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,

46

Burman and Cooper

it is important to obtain a radioactive iodine uptake test prior to treatment to confirm high-uptake thyroid disease. Predominant T3 toxicosis may occur, in which the T4 measurements are less elevated than T3. 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 (68–70). 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 may be inappropriately within the normal range, because of decreased T4-to-T3 conversion (so-called T4 toxicosis). 1.6 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 (2,27). 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 twenty-first 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 psychological effects. 1.6.1

Antithyroid Drug Therapy

Antithyroid drugs remain the first choice for initial therapy of children, adolescents, and young adults in the United States (71,72) and are the usual treatment for almost all patients in the rest of the world (73). 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. 1.6.1.1 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-h radioiodine uptake is not affected very much by antithyroid drug therapy. Within the thyroid, both propyl-

Evaluation and Management of Hyperthyroidism

47

thiouracil (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, one of the few comparative studies showed that methimazole normalized serum T4 and T3 levels faster than PTU (74). 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 (71). 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 halflives of PTU and methimazole are 1 and 4 to 6 h, 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. 1.6.1.2 Antithyroid Drugs in Clinical Practice Antithyroid drugs are used in two ways in the therapy of hyperthyroidism. They can be employed as primary therapy, and are usually given for 1 to 2 years in the hope that the patient will achieve a remission (a remission is usually defined arbitrarily as biochemical euthyroidism for 1 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. 1.6.1.3 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 the average patient. Even if a remission occurs, the chances of permanent remission are ⬍50%, and late hypothyroidism may develop in up to 20% (75). Also, the potential for allergic reactions is often underestimated or not discussed. Patient preferences are important to take into consideration,

48

Burman and Cooper

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 (76). 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 (77). 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 (77). Some studies have found that ‘‘T3 predominant’’ disease, in which the unitless serum T3 /T4 ⬎ 20, also makes remissions less likely (78), but others have not confirmed this observation (76). 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 thyroid stimulating immunoglobulin (TSI) titer at the beginning of therapy has been shown to predict a high rate of remission (79), but negative titers occur in only about 10% of patients, so it is probably not cost-effective to order TSI titers routinely. Age, sex, family history of Graves’ disease, the presence of ophthalmopathy, and smoking behavior have not reliably or consistently predicted remissions. Family planning is another factor that should be considered in women. First, many clinicians feel that if pregnancy is desired in the following 1 to 2 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 (80). 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 (81), 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 (82). 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. Because of its protein binding, PTU may be 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. However, no studies have shown this effect to be clinically meaningful, and with the use of potent oral cholecystographic dyes to block T4-to-T3 conversion in this setting (83), this potential advan-

Evaluation and Management of Hyperthyroidism

49

tage is nullified. Methimazole is more expensive than PTU. On average, methimazole costs about $80/month (30 mg/day) as compared to the cost of PTU ($30 per month; 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 (74). Initial doses as low as 10 mg/day can control hyperthyroidism in many patients (82), although it may take longer to achieve control than with higher doses. 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 (82,84). High-dose therapy has the decided disadvantage of being associated with higher rates of side effects, at least for methimazole (82,85). Once antithyroid drugs have been started, thyroid function should be monitored every 4 to 6 weeks, at least for the first 6 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 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 (86). 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. 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 (87). 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 (87), a number of equally rigorous trials have failed to confirm these original observations (88–92). 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

50

Burman and Cooper

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 (93,94). More recently, prospective trials have not shown longer treatment periods (e.g., ⬎12–18 months) to be more effective (95,96). Therefore, treatment for a year is reasonable, but data supporting longer periods of time are lacking. After 1 to 2 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 (97). Practically speaking, it is probably more sensible to taper the antithyroid drug rather than to stop it abruptly. Patients should be monitored closely and thyroid function tests checked monthly, and the drug should be gradually tapered to discontinuation. Thyroid function tests are then performed every 4 to 6 weeks, but patients are not necessarily seen for an office visit until they become hyperthyroid, or at 3 to 4 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 6 months after drug discontinuation (98). 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 (99), 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 (100). However, more recent long-term follow-up studies have shown that some patients have durable remissions that apparently last for many years (101). A strategy for treatment of relapse should be discussed with the patient in advance. Some patients will opt for another course of antithy-

Evaluation and Management of Hyperthyroidism

51

roid 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 (102), 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. 1.6.1.4 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) (103). Overall, side effects develop in 5% to 25% of patients and are among the most frequent reasons for abandoning drug therapy. As noted above, methimazolerelated 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 (104). 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 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 (105). It develops suddenly after 1 to 2 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 (106). The authors postulated that this side effect was the result of rapid a decline in serum thyroid hormone levels. 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 chole-

52

Burman and Cooper

TABLE 3 Side Effects of Antithyroid Drugs Overall Frequency a MINOR SIDE EFFECTS Skin reactions 4–6%

Arthralgias Gastrointestinal Hair loss

1–5% 1–5% 4%

Abnormal taste/smell Sialadenitis MAJOR SIDE EFFECTS Severe polyarthritis Agranulocytosis Aplastic anemia Vasculitis

0.3% Very rare

Severe hepatitis

Cholestasis

Hypoprothrombinemia Insulin-autoimmune syndrome

1–2% 0.1–0.5% Rare Rare

0.1–0.2%; 1% with high-dose PTU (14) Rare

Rare Rare

Comments Dose-related for MMI; possibly more common with MMI

Possibly related to change in thyroid function (hypothyroidism) only reported with MMI/CBZ

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 Seen almost exclusively in Asians

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

stasis). Agranulocytosis develops in approximately 0.2% to 0.5% of patients. In one recent case series, agranulocytosis developed in 12 of 2190 (0.55%) patients taking PTU and 43 of 13,208 (0.31%) patients taking methimazole (107). 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

Evaluation and Management of Hyperthyroidism

53

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 (108). Since the development of agranulocytosis may be HLA-linked (109), 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 3 months of therapy, but there are notable exceptions. 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 recent report has cast doubt on the wisdom of this policy (107). Antithyroid drug–treated patients had serial WBC counts performed every 2 weeks for the first 2 months and monthly thereafter. Some patients developed milder forms of agranulocytosis that resolved without progressing once the antithyroid drug was stopped (107). 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 to 0.8 ⫻ 109 /L) who will go on to develop full-blown agranulocytosis using a single dose of granulocyte-colony stimulating factor (GCSF) (110). 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. Although most patients recover, it should be recalled that agranulocytosis has been associated with a mortality rate as high as 16% (111). A bone marrow examination may provide helpful prognostic information; an extreme loss of myeloid precursors suggests a longer time to recovery (111) as well as the potential for a poor response to G-CSF therapy (112). The use of G-CSF has become standard in the management of drug-induced agranulocytosis. However, a recent 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 (113). Other retrospective data supporting the use of G-CSF, however, noted shortened recovery time and lower death rates. In a review of 71 patients with agranulocytosis due to a variety of drugs, including antithyroid drugs, the mean time to recovery was 5.4 ⫾ 4.5 days compared to 10 ⫾ 8 days in historical controls, and the mortality rate was 5% compared to 16% in the historical controls (114). The doses of G-CSF used in the literature range from 1 to 5 µg/kg/day subcutaneously. Common side effects include rashes, bone pain, myalgias, and headache, all of which respond well to acetaminophen (114). If thyrotoxicosis requires treatment during the acute episode of agranulocytosis,

54

Burman and Cooper

beta-adrenergic blocking drugs, lithium, or iodinated contrast agents can be used. Attempting to switch to the other antithyroid drug is not recommended, as crosssensitivity has been reported. Some patients develop a condition that has been termed the ‘‘antithyroid arthritis syndrome’’ (115). 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 1 to 2 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 Japanese patients (116). Anticytoplasmic neutrophil antibodies 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. 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 needed short-term hemodialysis. 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 (117). Over three dozen cases of PTU-related hepatitis have been reported in the literature, with several fatalities and at least three patients requiring liver transplant (118). The mean duration of PTU therapy in reported cases is 3 months, with a range of 2 days to 1 year; the average age of affected individuals in one review was 28 years (118). 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

Evaluation and Management of Hyperthyroidism

55

is no evidence that it decreases the time to recovery or survival, and glucocorticoids are not recommended (119). There have been several patients whose ongoing hyperthyroidism has been managed successfully with methimazole (120– 122); 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 2 months of starting the drug, which then resolve despite continued therapy (123). Also, up to 35% of patients with Graves’ disease have elevations of liver function tests at baseline (123,124). 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 (123,124). 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 lightcolored stools develop. Routine monitoring of liver function is controversial but is suggested by some thyroidologists. 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 20 cases in the literature (125), 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 (126). Extreme caution should be used when employing one antithyroid agent in a situation in which the alternative agent has caused hepatic abnormalities. 1.6.2

Beta-Adrenergic Antagonist Drugs

Beta-adrenergic antagonist drugs play an important role in the management of thyrotoxicosis (127). 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 (128), but these are probably clinically insignificant. Although beta blockers improve the negative nitrogen balance (129) and decrease heart rate (130), cardiac output (131), and oxygen consumption (132) in thyrotoxic patients, these measurements seldom become normal (133) 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 sub-

56

Burman and Cooper

acute 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 to 480 mg/day of propranolol) are sometimes necessary for optimum clinical effects, possibly because of accelerated propranolol clearance (134). 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 (135). 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 (136). This calcium channel blocking agent reduced resting heart rate by 17%, 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. 1.6.3

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 (137,138). Lithium use should be reserved for the unusual patient who has not responded to or is allergic to more standard antithyroid agents. The dose of lithium is usually 300 mg tid, with periodic monitoring of serum levels to ensure

Evaluation and Management of Hyperthyroidism

57

that they are in a therapeutic range. Lithium is mainly indicated for short-term use in hospitalized patients. Potential complications relate to neuromuscular and CNS perturbations, such as ataxia, tremor, and seizures. 1.6.4

Perchlorate

Perchlorate is an antithyroid medication that inhibits thyroidal uptake by the sodium/iodide symporter (139–141), 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 (142). In selected circumstances, its use has now extended to all types of high-uptake hyperthyroidism. 1.6.5 131

Radioiodine (131 I) Therapy for Graves’ Disease

I therapy has been utilized for approximately 50 years for patients with Graves’ disease; it is considered safe and effective (143–145). The goal of therapy is to render the patient permanently hypothyroid, a process that typically takes about 3 months. Radioiodine therapy is considered first-line therapy in most adults with thyrotoxic Graves’ disease (72). 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. A 24-h 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 5 to 7 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 biological half-life of the radioiodine, as well as the desire for the patient to be euthyroid prior to becoming pregnant.

58

Burman and Cooper

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 120 µC 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 to 120 µC of 131 I), and this number is divided by the 24-h 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 (146). 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, perhaps every 3 to 6 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. Approximately 5% to 10% of patients will require a second dose of 131 I, and about 1% of the total patients treated require a third dose. It would be prudent to wait 6 to 12 months for the full effects of the initial dose to be manifest before another dose is considered. 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

Evaluation and Management of Hyperthyroidism

59

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: Adapted from Ref. 2.

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. 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 that will be 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 2 to 5 days prior to and after 131 I therapy when the patient does not receive antithyroid drugs.

60

Burman and Cooper

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 (72). The rationale for doing so is to attempt to prevent postradioiodine thyroiditis (147), leading to a transient worsening of thyrotoxicosis that could be potentially dangerous in the elderly or in patients with underlying cardiac disease. Since antithyroid drugs do not block the release of thyroid hormones from the gland, pretreatment will deplete the gland of hormonal stores, thereby making it less likely for an increase in hormone levels to occur in the wake of radioiodine therapy. However, data supporting the use of antithyroid drugs in this context are lacking (148). Clearly, the routine use of antithyroid drugs in this context is unnecessary and potentially exposes patients to drug toxicity. Antithyroid drug pretreatment can interfere with the efficacy of radioiodine, perhaps by acting as free radical scavengers within the irradiated gland (149–152). While one study suggested that only PTU interferes with the success of radioiodine therapy (153), other data suggest that administration of methimazole after radioiodine can have a radioprotective effect as well (150). 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. 1.6.5.1 Radioiodine and Graves’ Ophthalmopathy 131 I therapy is believed to exacerbate existing ophthalmopathy (154,155); thus it is important to take a relevant history and perform a thorough ophthalmological examination (4). 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) should be considered to evaluate the presence and extent of disease. These radiological 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. (154) studied 168 patients with Graves’ hyperthyroidism divided into age group 1 (20 to 34 years; n ⫽ 54 patients) and age group 2 (35 to 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 devel-

Evaluation and Management of Hyperthyroidism

61

oped 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 (155) 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 2 to 3 days after 131 I therapy and continuing for 1 month. The dose was tapered and discontinued after 2 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 6 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, 3 (2%) who had ophthalmopathy at baseline improved, 4 (3%) had worsening of eye disease, and the remaining 141 had no change. This large-scale study clearly shows 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 6 to 8 weeks. Corticosteroid therapy is reserved for patients with moderate or severe ophthalmopathy. Tallstedt et al. (154,156) 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. (157) also showed that cigarette smoking was a potent independent risk factor for the worsening of ophthalmopathy after radioiodine therapy, and patients with Graves’ disease who smoke should be advised to discontinue. 1.6.5.1 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. Recently, Ron et al. (158) 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

62

Burman and Cooper

all hyperthyroid patients were 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 1 year after treatment, an enhanced risk of cancer mortality was also seen in hyperthyroid patients treated with antithyroid drugs. After more than 5 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 from a small absolute excess in actual patient deaths. Franklyn et al. (159) 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 (159). 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. 1.6.6

Thyroidectomy for Graves’ Disease

A total or near total thyroidectomy is also a reasonable therapeutic option for selected patients with Graves’ disease (72,160–164). This therapy is reserved for patients who are not well controlled on antithyroid agents; who have a particular reason for surgery—e.g., 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 also may occur as a result of injury to the recurrent laryngeal nerve. 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 (165). 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 (166). When surgery must be done quickly, a 5-day regimen of propranolol, glucocorticoids, and sodium ipodate has been used (167). It is preferable that patients’ thyroid function tests be normal for several weeks prior to surgery, as this depletes intra-

Evaluation and Management of Hyperthyroidism

63

thyroidal hormone stores and make releases at the time of surgery less likely. The oral cholecystographic dye iopanoate (Telepaque) may be given 7 days prior to surgery to decrease thyroid hormone secretion. Alternatively, SSKI or Lugol’s solution could be administered. Despite optimal care, perioperative thyroid storm may still occur, and patients should be treated aggressively if signs or symptoms are present (168). 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 (169). 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 4 to 6 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 (2). 1.6.7

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 (154,155), 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 one study that examined costs of care, radioiodine therapy was the least expensive alternative compared to antithyroid drugs and surgery (170). 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 (171). 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 (76).

64

2

Burman and Cooper

SUBCLINICAL HYPERTHYROIDISM

This term is generally utilized to describe patients with normal serum total and FT4 and T3 levels and a decreased serum TSH level (172–176). 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 any medications known to alter the hypothalamic-pituitary axis. 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. Typically, the thyroid gland in a patient with subclinical hyperthyroidism is either not palpable or mildly enlarged. 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. More details are available in Chapter 8 ‘‘Practical Management of Thyroid Disease in the Elderly.’’ Sawin et al (177) determined that low serum thyrotropin concentrations are a risk factor for subsequent atrial fibrillation. They studied 2007 persons (814 men and 1193 women) ⱖ60 years of age 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 (ⱕ0.1 µU/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. 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 (178). However, others have not found this to be the case (179). 2.1 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 3 months. Thyroid function tests should include FT4 and FT3, since occasionally the free hormone levels may be increased disproportion-

Evaluation and Management of Hyperthyroidism

65

ately compared to the total hormone levels (180). 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 3 months prior to further evaluation. However, after 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 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. 2.2 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, 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 (177,181). 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 (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 to 10 mg/day) for an arbitrary time period, such as 6 to 12 months. This course of action might induce a long-lasting remission and, if the disorder subsequently recurs, the patient may be more likely to accept

66

Burman and Cooper

definitive therapy. While a patient is being treated with antithyroid agents, serum FT4, TSH, and possibly 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. (178) have shown a benefit of antithyroid agent therapy on bone density values in patients with subclinical hyperthyroidism. More recently, Faber et al. (182) have shown similar results. However, more detailed prospective studies are required regarding all aspects of subclinical hyperthyroidism to allow a more evidence-based approach to these patients. 3

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 (168). 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 (168), these have not been generally accepted. Thyroid function tests—e.g., FT4 and FT3 —overlap between routine hyperthyroidism and thyroid storm, and mean values are similar in most studies (183). Sherman and Ladenson (184) have recently 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. 3.1 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.

Evaluation and Management of Hyperthyroidism

67

However, Hermann et al. (185) 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. Nevertheless, careful monitoring at the time of surgery by an experienced surgical and anesthetic team is important. Treatment for a patient with severe thyrotoxicosis or thyroid storm is more aggressive than that for a patient with less severe thyroid disease (168). The doses of medications are higher in patients considered to have thyroid storm. Propylthiouracil, 100 to 200 mg q4h, or methimazole, 10 to 20 mg q4h, is recommended in conjunction with propranolol, 60 to 80 mg q8h. Propanolol can also be given intravenously (2–5 mg every 4 hours), and if there is a history of pulmonary disease, esmolol, at a dose of 50–100 µg/kg/min can be used. Hydrocortisone 100 mg q8h is added to ensure adequate adrenal function, and an iodinecontaining agent may also be employed. An intravenous preparation of sodium iodide is no longer available. Saturated solution of potassium iodide (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 (2). 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 1 to 2 weeks, especially in previously unblocked 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 sodiumiodide symporter (186). This biphasic effect of iodine is extremely important and is the chief the 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 (83). This latter effect on 5′deiodinase activity will markedly decrease serum T3 levels in serum within several days. It is unknown if patients who receive these drugs have the same propensity to escape from iodine-induced inhibition of thyroid hormone synthesis as when they are given Lugol’s or SSKI, but they probably do. A reasonable dose regimen in a patient with thyroid storm is to administer 500 mg to 1 g of ipodate or iopanoate immediately and then give 500 mg daily for about 5 days, depending upon the clinical response. Except in extraordinary situations, when the risk–benefit ratio has been seriously considered, patients with severe liver disease, women who may be pregnant, and children should not be given ipodate or iopanoate until more studies in these groups are performed to assess their safety. Recently, ipodate was withdrawn from the market, so iopanoate is the only drug available in the U.S. at present.

68

4

Burman and Cooper

TREATMENT OF GRAVES’ OPTHALMOPATHY AND PRETIBIAL MYXEDEMA

Although almost all patients with Graves’ disease have radiologic evidence of eye muscle involvement, only approximately 30 percent of patients have obvious clinical disease (187). 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) (188), although it has been criticized for being overly subjective and not quantitative enough (189). 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 (190). 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 (191). 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 (189). Ultimately, fibrosis of the extraocular muscles can lead to diplopia,

TABLE 5 ‘NO SPECS’ Classification of Eye Changes of Graves’ Disease Class

Definition

O

No physical signs or symptoms

I

Only signs, no symptoms (e.g., upper lid retraction, stare and eyelid lag)

II

Soft tissue involvement (symptoms and signs)

III

Proptosis

IV

Extraocular muscle involvement

V

Corneal involvement

VI

Sight loss (optic nerve involvement)

Evaluation and Management of Hyperthyroidism

69

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. 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 (191). The TSH receptor has been hypothesized be the putative common antigen, but it has been difficult to prove that the TSH receptor is expressed in retroorbital tissues. TSH receptor transcripts have been isolated from extraocular muscle using PCR (192) and TSH receptor protein has been identified in orbital tissues by immunostaining (192), but this work remains controversial. Since the cause of Graves’ ophthalmopathy is unknown, treatment is directed at treating symptoms. In most patients, the problem is self-limited, often resolving as the hyperthyroidism is treated (193). 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 (194), but the mechanism is unknown. There is solid evidence that radioactivity iodine therapy can exacerbate Graves’ eye disease when it is moderately severe at baseline (154,155). 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 (4). Unfortunately, as the glucocorticoid is tapered, the ophthalmopathy often flares up, so that other measures are sometimes needed. Although other pharmacological therapies (e.g., octreotide (195)) have been used in this circumstance, orbital radiotherapy is usually the next step after glucocorticoid therapy (4). 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 (196). In this study, 60% of irradiated patients improved versus 31% of sham irradiated patients. 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. The cause of pretibial myxedema remains obscure (197), but it probably shares common features with Graves’ opthalmopathy, including lymphocytic infiltration and a response by fibroblasts to the subsequent inflammation. The usual treatment is topical steroid cream with or without occlusion (198). Intralesional steroids have also been used. Recently, octreotide has been reported to be of use

70

Burman and Cooper

(199), but additional data are needed before this therapy can be recommended outside of a clinical trial.

5

SOLITARY TOXIC NODULES

5.1 Introduction A solitary autonomous thyroid nodule produces sufficient thyroid hormone to suppress TSH and cause hyperthyroidism (200–204). Often, a thyroid nodule may be autonomous and not yet be sufficiently functional to suppress TSH completely. 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 (204). The percentage of autonomous nodules that secrete sufficient thyroid hormones to produce overt hyperthyroidism is relatively low, in the range of 20%. 5.2 Pathology Histologically, autonomous nodules are cellular follicular adenomas with frequent hemorrhage, fibrosis, calcification, and cysts. There is 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 (205–208). This reported pathological 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, historical, 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 (209). However, recent 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 (210,211). 5.3 Pathogenesis Autonomous function of the nodule is attributed to either a loss in suppression of normal cell function or a genetic defect in the TSH receptor or a downstream

Evaluation and Management of Hyperthyroidism

71

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 (212). 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 (213–216). 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 (214). 5.4 Clinical Considerations Approximately 1% of patients referred for thyroid disease and about 5% of hyperthyroid patients have an autonomous thyroid nodule (204). Patients with autonomous functioning thyroid nodules present most frequently with a neck mass but may also have TSH suppression (usually with normal FT4 and T3) (200,204). 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 years 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 (217). Toxic nodules may undergo cystic or necrotic degeneration with return to euthyroidism (200). As many as 20% to 30% patients with solitary autonomous nodules may have a restoration of normal function secondary to hemorrhage (218,219). Iodine deficiency increases the risk of iodine-induced hyperthyroidism in patients with autonomous thyroid nodules. Even a small addition of iodine to a low-iodine diet, perhaps 100 µg/day, can initiate hyperthyroidism (220). Although iodine deficiency is not a problem in the United States, hyperthyroidism has been reported in patients with autonomous thyroid nodules within 1 to 2 months after exposure to radiocontrast dyes as well as after exposure to iodinecontaining drugs such as amiodarone.

72

Burman and Cooper

5.5 Diagnosis Autonomous thyroid nodules are usually diagnosed by integration of the history and physical exam 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—i.e., T3 toxicosis—appears more common in patients with autonomous nodules than in Graves’ disease (180,217). The identification of an autonomous nodule on technetium-99m or ( 121I) 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. 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 µg/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 thyroid tissue uptake, 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. An alternative method to help diagnose autonomy is to administer TRH and measure serum TSH responsiveness. Normal subjects will have a rise in TSH after TRH stimulation, whereas patients with autonomous thyroid glands will not demonstrate this increase in TSH concentrations. With the advent of third-generation TSH assays, these confirmatory tests have become obsolete and are almost never indicated. Recombinant TSH may have a role in identifying suppressed extranodular thyroid tissue, since thyroid hemiagenesis may appear similar on scan to an autonomous nodule, although further assessment of the utility of this diagnostic test is required. Recombinant human TSH is now commercially available for the

Evaluation and Management of Hyperthyroidism

73

detection of thyroid cancer, but it is not presently approved for use in patients with autonomous thyroid nodules. Bovine TSH had previously been used in this manner (221). 5.6 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 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 Sec. 2 above). 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 1 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 (200,204). 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 6 months after the initial dose before considering retreatment with radioiodine. Persistent or recurrent hyperthyroidism can be expected in about 10% of patients, with studies revealing a range of 0% to 41.3% (201,221–226). Following radioiodine therapy, hypothyroidism occurs at an average of approximately 10% within the first year, with an annual rate thereafter of about 3% (218,222,225). This occurrence rate may relate to the fact that the contralateral normal tissue is exposed to significant amounts of radiation (201). 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

74

Burman and Cooper

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 (226), 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 (222,224). 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 (200,203,227). 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 (227). 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 (228). Hedman et al. (228) 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 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

Evaluation and Management of Hyperthyroidism

75

into the autonomous nodule using a 22-gauge needle under sonographic guidance (229,230). 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. 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 11/2 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 (229) reported a success rate 6 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 to 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 little experience with this therapy in the United States. Therefore, its use should be limited to experienced clinicians in selected circumstances. 6

TOXIC MULTINODULAR GOITER

6.1 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 (231). 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 (Figs. 7 and 8). For example, exogenous iodine exposure can precipitate or aggravate thyrotoxicosis (220). 6.2 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

76

Burman and Cooper

FIG. 7 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. [From (232)]

FIG. 8 Thyroid radioisotope scans may be helpful in assessing certain patients with hyperthyroidism. Panel A demonstrates symmetrical isotope distribution (pertechnetate technetium 99m) 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. [From (232)]

Evaluation and Management of Hyperthyroidism

77

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 (233,234). 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 (235–238). 6.3 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. Some multinodular goiters have a significant substernal component. 6.4 Treatment Radioiodine and surgery are the two major treatment modalities in patients with toxic multinodular goiters, involving either antithyroid agents, radioactive iodine, or surgery (231,239,240). 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 agents. It may be appropriate to render a patient euthyroid with the use of antithyroid agents prior to radioiodine therapy. Selected patients can be maintained on these agents for an indefinite period of time—e.g., 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 to restore euthyroidism or induce hypothyroidism in most patients (239,240). 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 to 30 mCi 131 I). The explana-

78

Burman and Cooper

tion 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 µC 131 I/g thyroid tissue. 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 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 similar to that seen in Graves’ disease (241), but others have not found similar degrees of success (242). 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 clinically. 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 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 hyperthyroidism. A near total thyroidectomy represents an alternative therapeutic option (242,243). 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 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. 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 (244). It does obviates 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 to 200 g) since the likelihood of such patients responding to 131 I therapy is lower. Compres-

Evaluation and Management of Hyperthyroidism

79

sive symptoms such as hoarseness, superior vena caval syndrome, dysphagia, and/or dyspnea are indications for surgery. However, in patients who are not surgical candidates, radioiodine should be used.

REFERENCES 1. Burman KD, Baker J. Immune mechanisms in Graves’ disease. Endocr Rev. 1985; 6:183–232. 2. Burman K. Hyperthyroidism. In: Becker KA, ed. Principles and Practice of Endocrinology and Metabolism, 2nd ed. Philadelphia: Lippincott, 1995, pp 367–385. 3. Burman KD, Pandian R. Clinical utility of assays for TSH receptor antibodies. Endocrinologist 1998; 8:284–288. 4. Burch HB, Wartofsky L. Graves’ ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev. 1993; 14:747–793. 5. 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. 6. Burman KD, Becker KL, Cytryn AS, Goodglick TA. Graves’ disease, Graves’ ophthalmopathy. Surks MI, ed. Atlas of Clinical Endocrinology, Vol 1, Current Medicine, Philadelphia, PA. 1999, pp 93–102. 7. Kasagi K, Hidaka A, Nakamura H, et al. Thyrotropin receptor antibodies in hypothyroid Graves’ disease. J Clin Endocrinol Metab 1993; 76:504–508. 8. Kraiem Z, Baron E, Kahana L, Sadeh O, Sheinfeld M. Changes in stimulating and blocking TSH receptor antibodies in a patient undergoing three cycles of transition from hypo- to hyperthyroidism and back to hypothyroidism. Clin Endocrinol (Oxf) 1992; 36:211–214. 9. Mengistu M, Lukes YG, Nagy EV, et al. TSH receptor gene expression in retroocular fibroblasts. J Endocrinol Invest 1994; 17:437–441. 10. Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves’ disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab 1983; 57:1036–1040. 11. Zakarija M, McKenzie JM, Munro D. Immunoglobulin G inhibitor of thyroid-stimulating antibody is a cause of delay in the onset of neonatal Graves’ disease. J Clin Invest 1983; 72:1352–1356. 12. Zakarija M, McKenzie JM, Hoffman WH. Prediction and therapy of intrauterine and late-onset neonatal hyperthyroidism. J Clin Endocrinol Metab 1986;62:368– 371. 13. Burgi H, Kohler M, Morselli B. Thyrotoxicosis incidence in Switzerland and benefit of improved iodine supply (letter). Lancet 1998; 352:1034. 14. Mostbeck A, Galvan G, Bauer P, et al. The incidence of hyperthyroidism in Austria from 1987 to 1995 before and after an increase in salt iodization in 1990. Eur J Nucl Med 1998; 25:367–374. 15. Paunkovic N, Paunkovic J, Pavlovic O, Paunovic Z. The significant increase in

80

16. 17. 18. 19. 20. 21. 22.

23.

24.

25. 26. 27. 28. 29.

30. 31. 32.

33. 34.

Burman and Cooper incidence of Graves’ disease in eastern Serbia during the civil war in the former Yugoslavia (1992 to 1995). Thyroid 1998; 8:37–41. Jankovic SM, Radosavljevic VR, Marinkovic JM. Risk factors for Graves’ disease. Eur J Epidemiol 1997; 13:15–18. Bartley GB, Fatourechi V, Kadrmas EF, et al. The incidence of Graves’ ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalmol 1995; 120:511–517. Delange F, de Benoist B, Alnwick D. Risks of iodine-induced hyperthyroidism after correction of iodine deficiency by iodized salt. Thyroid 1999; 9:545–556. Lind P, Langsteger W, Molnar M, Gallowitsch HJ, Mikosch P, Gomez I. Epidemiology of thyroid diseases in iodine sufficiency. Thyroid 1998; 8:1179–1183. Sundick RS, Bagchi N, Brown TR. The role of iodine in thyroid autoimmunity: from chickens to humans: a review. Autoimmunity 1992; 13:61–68. Brown TR, Bagchi N. The role of iodine in the development of autoimmune thyroiditis. Int Rev Immunol 1992; 9:167–182. Brown TR, Sundick RS, Dhar A, Sheth D, Bagchi N. Uptake and metabolism of iodine is crucial for the development of thyroiditis in obese strain chickens. J Clin Invest 1991; 88:106–111. Sundick RS, Herdegen DM, Brown TR, Bagchi N. The incorporation of dietary iodine into thyroglobulin increases its immunogenicity. Endocrinology 1987; 120: 2078–2084. Sundick RS, Herdegen D, Brown TR, Dhar A, Bagchi N. Thyroidal iodine metabolism in obese-strain chickens before immune-mediated damage. J Endocrinol 1991; 128:239–244. Bagchi N, Brown TR, Urdanivia E, Sundick RS. Induction of autoimmune thyroiditis in chickens by dietary iodine. Science 1985; 230:325–327. Rapoport B, Chazenbalk GD, Jaume JC, McLachlan SM. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev 1998; 19:673–716. Weetman AP. Graves’ disease. New Engl J Med 2000; 343:1236–1248. Wartofsky L. Low remission after therapy for Graves’ disease: possible relation of dietary iodine with antithyroid therapy results. JAMA 1973; 226:1083–1088. Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971–1974 and 1988–1994) (see comments). J Clin Endocrinol Metab 1998; 83:3401–3408. Braverman LE. Adequate iodine intake—the good far outweighs the bad (comment). Eur J Endocrinol 1998; 139:14–15. Stanbury JB, Ermans AE, Bourdoux P, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998; 8:83–100. Nuovo JA, Wartofsky L. Adverse effects of iodine. In: Becker KA, ed. Principles and Practice of Endocrinology and Metabolism, 2nd ed. Philadelphia: Lippincott, 1995, pp 332–338. Burman KD, Monchik JM, Earll JM, Wartofsky L. Ionized and total serum calcium and parathyroid hormone in hyperthyroidism. Ann Intern Med 1976; 84:668–671. Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 1996; 81:4278–4289.

Evaluation and Management of Hyperthyroidism

81

35. Faber J, Galloe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to l-thyroxine treatment: a meta-analysis. Eur J Endocrinol 1994; 130: 350–356. 36. Hanna FW, Pettit RJ, Ammari F, Evans WD, Sandeman D, Lazarus JH. Effect of replacement doses of thyroxine on bone mineral density. Clin Endocrinol (Oxf) 1998; 48:229–234. 37. Duncan WE, Wartofsky L, Burman KD. Influence of clinical characteristics and parameters associated with thyroid hormone therapy on the bone mineral density of women treated with thyroid hormone. Thyroid 1994; 4:183–190. 38. Affinito P, Sorrentino C, Farace MJ, et al. Effects of thyroxine therapy on bone metabolism in postmenopausal women with hypothyroidism. Acta Obstet Gynecol Scand 1996; 75:843–848. 39. Allain TJ, McGregor AM. Thyroid hormones and bone. J Endocrinol 1993; 139: 9–18. 40. Solomon BL, et al. Prevalence of fractures in postmenopausal women with thyroid disease. Thyroid 1993; 3:17–23. 41. Papadopoulos KI, Diep T, Cleland B, Lunn NW. Thyrotoxic period paralysis: report of three cases and review of the literature. J Intern Med 1997; 241:521–524. 42. Manoukian MA, Foote JA, Crapo LM. Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes. Arch Intern Med 1999; 159:601–606. 43. Gonzalez-Trevino O, Rosas-Guzman J. Normokalemic thyrotoxic periodic paralysis: a new therapeutic strategy. Thyroid 1999; 9:61–63. 44. Davis PJ, Rappeport JR, Lutz JH, Gregerman RI. Three thyrotoxic criminals. Ann Intern Med 1971; 74:743–745. 45. Baba M, Teraba A, Hishida R, Matsunaga M, Kawabe Y, Takebe K. Persistent hemichorea associated with thyrotoxicosis. Intern Med 1992; 31:1144–1146. 46. Krassas GE, Pontikides N, Kaltsas T, Papadopoulou P, Batrinos M. Menstrual disturbances in thyrotoxicosis. Clin Endocrinol (Oxf ) 1994; 40:641–644. 47. Carlson H. Current Concepts-Gynecomastia. N Engl J Med 1980; 305:795–799. 48. Rotella CM, Alvarez F, Kohn LD, Toccafondi R. Graves’ autoantibodies to extrathyroidal TSH receptor: their role in ophthalmopathy and pretibial myxedema. Acta Endocrinol Suppl (Copenh) 1987; 281:344–347. 49. Rotella CM, Zonefrati R, Toccafondi R, Valente WA, Kohn LD. Ability of monoclonal antibodies to the thyrotropin receptor to increase collagen synthesis in human fibroblasts: an assay which appears to measure exophthalmogenic immunoglobulins in Graves’ sera. J Clin Endocrinol Metab 1986; 62:357–367. 50. Davis PJ, Davis FB. Hyperthyroidism in patients over the age of 60 years: clinical features in 85 patients. Medicine (Baltimore) 1974; 53:161–181. 51. Davies PH, Franklyn JA, Daykin J, Sheppard MC. The significance of TSH values measured in a sensitive assay in the follow-up of hyperthyroid patients treated with radioiodine. J Clin Endocrinol Metab 1992; 74:1189–1194. 52. Franklyn JA, Black EG, Betteridge J, Sheppard MC. Comparison of second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy, and those with nonthyroidal illness. J Clin Endocrinol Metab 1994; 78:1368–1371. 53. Kasagi K, Kousaka T, Misaki T, Iwata M, Alam MS, Konishi J. Comparison of

82

54.

55.

56.

57.

58.

59. 60.

61.

62. 63.

64.

65. 66. 67.

68. 69.

Burman and Cooper serum thyrotrophin concentrations determined by a third generation assay in patients with various types of overt and subclinical thyrotoxicosis. Clin Endocrinol (Oxf) 1999; 50:185–189. Papadea C, Papadea NA, Cate JCt, Didyk RB. Two sensitive immunometric assays for serum thyroid stimulating hormone evaluated. Ann Clin Lab Sci 1998; 28:88– 98. Rasmussen AK, Hilsted L, Perrild H, Christiansen E, Siersbaek-Nielsen K, FeldtRasmussen U. Discrepancies between thyrotropin (TSH) measurement by four sensitive immunometric assays. Clin Chim Acta 1997; 259:117–128. Ito M, Takamatsu J, Yoshida S, et al. Incomplete thyrotroph suppression determined by third generation thyrotropin assay in subacute thyroiditis compared to silent thyroiditis or hyperthyroid Graves’ disease. J Clin Endocrinol Metab 1997; 82:616–619. Saller B, Broda N, Heydarian R, Gorges R, Mann K. Utility of third generation thyrotropin assays in thyroid function testing. Exp Clin Endocrinol Diabetes 1998; 106:S29–S33. Endo T, Kogai T, Nakazato M, Saito T, Kaneshige M, Onaya T. Autoantibody against Na⫹/I⫺ symporter in the sera of patients with autoimmune thyroid disease. Biochem Biophys Res Commun 1996; 224:92–95. Levy O, De la Vieja A, Carrasco N. The Na⫹/I⫺ symporter (NIS): recent advances. J Bioenerg Biomembr 1998; 30:195–206. Dallas JS, Cunningham SJ, Patibandla SA, et al. Thyrotropin (TSH) receptor antibodies (TSHrAb) can inhibit TSH-mediated cyclic adenosine 3′,5′-monophosphate production in thyroid cells by either blocking TSH binding or affecting a step subsequent to TSH binding. Endocrinology. 1996; 137:3329–3339. Kohn LD, Suzuki K, Hoffman WH, et al. Characterization of monoclonal thyroidstimulating and thyrotropin binding-inhibiting autoantibodies from a Hashimoto’s patient whose children had intrauterine and neonatal thyroid disease. J Clin Endocrinol Metab 1997; 82:3998–4009. Kung AW, Jones BM. A change from stimulatory to blocking antibody activity in Graves’ disease during pregnancy. J Clin Endocrinol Metab 1998; 83:514–518. Grasso YZ, Kim MR, Faiman C, Kohn LD, Tahara K, Gupta MK. Epitope heterogeneity of thyrotropin receptor-blocking antibodies in Graves’ patients as detected with wild-type versus chimeric thyrotropin receptors. Thyroid 1999; 9:531–537. Di Cerbo A, Di Paola R, Menzaghi C, et al. Graves’ immunoglobulins activate phospholipase A2 by recognizing specific epitopes on thyrotropin receptor. J Clin Endocrinol Metab 1999; 84:3283–3292. Reinhardt MJ, Moser E. An update on diagnostic methods in the investigation of diseases of the thyroid. Eur J Nucl Med 1996; 23:587–594. Weetman AP. New aspects of thyroid immunity. Horm Res 1997; 48:51–54. Sakata S, Nakamura S, Miura K. Autoantibodies against thyroid hormones for iodothyronine: implications in diagnosis, thyroid function, and pathogenesis. Ann Intern Med 1985; 103:579–589. McIver B, Gorman CA. Euthyroid sick syndrome: an overview. Thyroid 1997; 7: 125–132. Vexiau P, Perez-Castiglioni P, Socie G, et al. The ‘‘euthyroid sick syndrome’’:

Evaluation and Management of Hyperthyroidism

70. 71. 72. 73.

74.

75.

76.

77. 78.

79.

80.

81.

82.

83.

84. 85.

83

incidence, risk factors and prognostic value soon after allogeneic bone marrow transplantation. Br J Haematol 1993; 85:778–782. Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: the euthyroid sick syndrome. Endocr Rev 1982; 3:164–217. Cooper D. Antithyroid drugs for the treatment of hyperthyroidism caused by Graves’ disease. Endo Metab Clin North Am 1998; 27:225–247. Solomon B, Glinoer D, Lagasse R, Wartofsky L. Current trends in the management of Graves’ disease. J Clin Endocrinol Metab 1990; 70:1518–1524. Wartofsky L, et al. Differences and similarities in the diagnosis and treatment of Graves’ disease in Europe, Japan, and the United States. Thyroid 1991; 1:129– 135. Okamura K, Ikenoue H, Shiroozu A, Sato K, Yoshinari M, Fujishima M. Reevaluation of the effects of methylmercaptoimidazole and propylthiouracil in patients with Graves’ hyperthyroidism. J Clin Endocrinol Metab 1987; 65:719–723. Hirota Y, Tamai H, Hayashi Y, et al. Thyroid function and histology in forty-five patients with hyperthyroid Graves’ disease in clinical remission more than ten years after thionamide drug treatment. J Clin Endocrinol Metab 1986; 62:165–169. Torring O, Tallstedt L, Wallin G, et al. Graves’ hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine—a prospective, randomized study. Thyroid Study Group. J Clin Endocrinol Metab 1996; 81:2986–2993. Young ET, Steel NR, Taylor JJ, et al. Prediction of remission after antithyroid drug treatment in Graves’ disease. Q J Med 1988; 250:175–189. Takamatsu JS, Sugawara M, Kuma K, et al. Ratio of serum triiodothyronine to thyroxine and the prognosis of triiodothyronine-predominant Graves’ disease. Ann Intern Med 1984; 100:372–375. Kawai K, Tamai H, Matsubayashi S, Mukuta T, Morita T, Kubo C, Kuma K. A study of untreated Graves’ patients with undetectable TSH binding inhibitor immunoglobulins and the effect of anti-thyroid drugs. Clin Endocrinol (Oxf ) 1995; 43: 551–556. Amino N, Tanizawa O, H. M, et al. Aggravation of thyrotoxicosis in early pregnancy and after delivery in Graves’ disease. J Clin Endocrinol Metab 1982; 55: 108–112. Messina M, Milani P, Gentile L, et al. Initial treatment of thyrotoxic Graves’ disease with methimazole: a randomized trial comparing different dosages. J Endocrinol Invest 1987; 10:291–295. Reinwein D, Benker G, Lazarus JH, Alexander W. A prospective randomized trial of antithyroid drug dose in Graves’ disease therapy. J Clin Endocrinol Metab 1993; 76:1516–1521. Roti E, Robuschi G, Gardini E, et al. Comparison of methimazole, methimazole and sodium ipodate, and methimazole and saturated solution of potassium iodide in the early treatment of hyperthyroid Graves’ disease. Clin Endocrinol 1988; 28: 305–314. Wilson R, Buchanan L, Fraser W, et al. Do higher doses of carbimazole improve remission in Graves’ disease? Q J Med 1996; 89:381–385. Jorde R, Ytre-Arne K, Stormer J, Sundsfjord J. Short-term treatment of Graves’ disease with methimazole in high versus low doses. J Intern Med 1995; 238:161–165.

84

Burman and Cooper

86. Chen JJ, Ladenson PW. Discordant hypothyroxinemia and hypertriiodothyroninemia in treated patients with hyperthyroid Graves’ disease. J Clin Endocrinol Metab 1986; 63:102–106. 87. Hashizume K, Ichikawa I, Sakurai A, et al. Administration of thyroxine in treated Graves’ Disease. N Engl J Med 1991; 324:947–953. 88. McIver B, Rae P, Beckett G, Wilkinson E, Gold A, Toft A. Lack of effect of thyroxine in patients with Graves’ hyperthyroidism who are treated with an antithyroid drug. N Engl J Med 1996; 334:220–224. 89. Rittmaster RS, Zwicker H, Abbott EC, et al. Effect of methimazole with or without exogenous 1-thyroxine on serum concentrations of thyrotropin (TSH) receptor antibodies in patients with Graves’ disease. J Clin Endocrinol Metab 1996; 81:3283– 3288. 90. Pfeilschifter J, Zeigler R. Suppression of serum thyrotropin with thyroxine in patients with Graves’ disease: effects on recurrence hyperthyroidism and thyroid volume. Eur J Endocrinol 1997; 136:81–86. 91. Lucas A, Salinas I, Rius F, et al. Medical therapy of Graves’ disease: does thyroxine prevent recurrence of hyperthyroidism? J Clin Endocrinol Metab 1997; 2410–2413. 92. Pujol P, Osman A, Grabar S, et al. TSH suppression combined with carbimazole for Graves’ disease: effect on remission and relapse rates. Clin Endocrinol 1988; 48:635–640. 93. Tamai H, Nakagawa T, Fukino O, et al. Thionamide therapy in Graves’ disease: relation of relapse rate to duration of therapy. Ann Intern Med 1980; 92:488–490. 94. Lippe BM, Landaw EM, Kaplan SA. Hyperthyroidism in children treated with long term medical therapy: twenty-five percent remission every two years. J Clin Endocrinol Metab 1987; 64:1241–1245. 95. Maugandre D, Gatel A, Campion L, et al. Antithyroid drugs and Graves’ disease— prospective randomized assessment of long-term treatment. Clin Endocrinol (Oxf ) 1999; 50:127–132. 96. Garcia-Mayor RVG, Paramo C, Luna-Cano R, Perez Mendez LF, Galofre JC, Andrade A. Antithyroid drug and Graves’ hyperthyroidism: significance of treatment duration and TRAb determination on lasting remission. J Endocrinol Invest 1992; 15:815–820. 97. Teng CS, Yeung RTT. Changes in thyroid-stimulating antibody activity in Graves’ disease treated with antithyroid drug and its relationship to relapse: a prospective study. J Clin Endocrinol Metab 1980; 50:144–147. 98. Vitti P, Valente WA, Ambesi-Impiombato FS, Fenzi GF, Pinchera A, Kohn LD. Graves’ IgG stimulation of continuously cultured rat thyroid cells: a sensitive and potentially useful clinical assay. J Endocrinol Invest 1982; 5:179–182. 99. Nagai K, Tamai H, Mukuta T, et al. A follow-up study of 85 patients with Graves’ disease in remission who developed undetectable serum thyroid-stimulating hormone concentrations using sensitive TSH assays. Horm Res 1991; 35:185–189. 100. Sugrue D, McEvoy M, Feely J, Drury MI. Hyperthyroidism in the land of Graves: results of treatment by surgery, radio-iodine and carbimazole in 837 cases. Q J Med 1980; 49:51–61. 101. Hedley AJ, Young RE, Jones SJ, Alexander WD, Bewsher PD. Antithyroid drugs in the treatment of hyperthyroidism of Graves’ disease: long-term follow-up of 434 patients. Clin Endocrinol 1989; 31:209–218.

Evaluation and Management of Hyperthyroidism

85

102. Slingerland DW, Burrows BA. Long-term antithyroid treatment in hyperthyroidism. JAMA 1979; 242:2408–2410. 103. Cooper D. The side effects of antithyroid drugs. The Endocrinologist 1999; 9:457– 467. 104. Werner MC, Romaldini JH, Bromberg N, Werner RS, Farah CS. Adverse effects related to thionamide drugs and their dose regimen. Am J Med Sci 1989; 296:216– 219. 105. Hallman BL, Hurst JW. Loss of taste as toxic effect of methimazole (tapazole) therapy. JAMA 1953; 152:322. 106. Suzuki S, Ichihawa K, Nagai M, et al. Elevation of serum creatine kinase during treatment with antithyroid drugs in patients with hyperthyroidism due to Graves’ disease. Arch Intern Med 1997; 157:693–696. 107. Tajiri J, Noguchi S, Murakami T, Murakami N. Antithyroid drug-induced agranulocytosis: the usefulness of routine white blood cell count monitoring. Arch Intern Med 1990; 150:621–624. 108. Salama A, Mueller-Eckhardt C. Immune-mediated blood cell dyscrasias related to drugs. Semin Hematol 1992; 29:54–63. 109. Tamai H, Sudo T, Kimura A, et al. Association between the DRB1*08032 histocompatibility antigen and methimazole-induced agranulocytosis in Japanese patients with Graves’ disease. Ann Intern Med 1996; 124:490–494. 110. Tajiri J, Noguchi S, Murakami N. Usefulness of granulocyte count measurement four hours after injection of granulocyte colony-stimulating factor for detecting recovery from antithyroid drug-induced granulocytopenia. Thyroid 1997; 4:575– 578. 111. Julia A, Olona M, Bueno J, et al. Drug-induced agranulocytosis: prognostic factors in a series of 168 episodes. Br J Haematol 1991; 79:366–371. 112. Tajiri J, Noguchi S, Okamura S, et al. Granulocyte colony-stimulating factor treatment of antithyroid drug-induced granulocytopenia. Arch Intern Med 1993; 153: 509–514. 113. Fukata S, Kuma K, Sugawara M. Granulocyte colony-stimulating factor (G-CSF) does not improve recovery from antithyroid drug-induced agranulocytosis: a prospective study. Thyroid 1999; 9:29–31. 114. Editorial. Drug-induced agranulocytosis. Drug Ther Bull 1997; 35:49. 115. Shabtai R, Shapiro MS, Orenstein D, Taragan R, Shenkman L. The antithyroid arthritis syndrome reviewed. Arthritis Rheum 1984; 27:227–229. 116. Gunton JE, Steil J, Caterson RJ, McElduff A. Anti-thyroid drugs and antineutrophil cytoplasmic antibody positive vasculitis: a case report and review of the literature. J Clin Endocrinol Metab 1999:13–19. 117. Hanson J. Propylthiouracil and hepatitis. Arch Intern Med 1984; 144:944–996. 118. Williams KV, Nayak S, Becker D, Reyes J, Burmeister LA. Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned? J Clin Endocrinol Metab 1997; 82:1727–1733. 119. Kirsh BM, Lam N, Layden TJ, Wiley TE. Diagnosis and management of fulminant hepatic failure. Comp Ther 1995; 21:166–171. 120. Weiss M, Hassin D, Bank H. Propylthiouracil-induced hepatic damage. Arch Intern Med 1980; 140:1184–1185. 121. Parker W. Propylthiouracil-induced hepatotoxicity. Clin Pharm 1982; 1:471–474.

86

Burman and Cooper

122. Waseem M, Seshadri KG, Kabadi UM. Successful outcome with methimazole and lithium combination therapy for propylthiouracil-induced hepatotoxicity. Endo Pract 1998; 4:197–200. 123. Liaw YF, Huang MJ, Fan KD, Li KL, Wu SS, Chen TJ. Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. Ann Intern Med 1993; 118:424–428. 124. Huang MJ, Li KL, Wei JS, Wu SS, Fan KD, Liaw YF. Sequential liver and bone biochemical changes in hyperthyroidism: prospective controlled follow-up study. Am J Gastroenterol 1994; 89:1071–1076. 125. Schwab GP, Wetscher GJ, Vogl W, Redmond E. Methimazole-induced cholestatic liver injury, mimicking sclerosing cholangitis. Langenbecks Arch Chir 1996; 381: 225. 126. Arab DM, Malatjalian DA, Rittmaster RS. Severe cholestatic jaundice in uncomplicated hyperthyroidism treated with methimazole. J Clin Endocrinol Metab 1995; 80:1083–1085. 127. Geffner DL, Hershman JM. Beta-adrenergic blockade for the treatment of hyperthyroidism. Am J Med 1992; 93:61–68. 128. Cooper DS, Daniels GH, Ladenson PW, Ridgway EC. Hyperthyroxinemia in patients treated with high-dose propranolol. Am J Med 1982; 73:867–871. 129. Georges LP, Santangelo RP, Mackin JF, Canary JJ. Metabolic effects of propranolol in thyrotoxicosis: I. Nitrogen, calcium and hydroxyproline. Metabolism 1975; 24:11–21. 130. Valcavi R, Menozzi C, Roti E, et al. Sinus node function in hyperthyroid patients. J Clin Endocrinol Metab 1992; 75:239–242. 131. Grossman W, Robin NI, Johnson LW, Brooks H, Selenkow HA, Dexter L. Effects of beta blockade on the peripheral manifestations of thyrotoxicosis. Ann Intern Med 1971; 74:875–879. 132. Saunders J, Hall SEH, Crowther A, Sonksen PH. The effect of propanolol on thyroid hormones and oxygen consumption in thyrotoxicosis. Clin Endocrinol 1978; 1978:67–72. 133. O’Malley BP, Abbott RJ, Barnett DB, Northover BJ, Rosenthal FD. Propranolol versus carbimazole as the sole treatment for thyrotoxicosis: a consideration of circulating thyroid hormone levels and tissue thyroid function. Clin Endocrinol 1982; 16:545–552. 134. Feely JS, Stevenson IH, Crooks J. Increased clearance of propranolol in thyrotoxicosis. Ann Intern Med 1981; 94:472–474. 135. Klein I, Ojamaa K. Thyrotoxicosis and the heart. Endocrinol Clin North Am 1998; 27:51–62. 136. Roti E, Montermini M, Roti S, et al. The effect of diltiazem, a calcium channelblocking drug, on cardiac rate and rhythm in hyperthyroid patients. Arch Intern Med 1988; 148:1919–1921. 137. Wolff J. Effects of lithium on thyroid gland function. Neurosci Res Progr Bull 1976; 14:178–180. 138. Boehm TM, Burman KD, Barnes S, Wartofsky L. Lithium and iodine combination therapy for thyrotoxicosis. Acta Endocrinol (Copenh) 1980; 94:174–183. 139. Lawrence JE, Lamm SH, Braverman LE. The use of perchlorate for the prevention

Evaluation and Management of Hyperthyroidism

140.

141. 142.

143. 144. 145. 146.

147. 148.

149.

150.

151.

152.

153.

154.

155. 156.

87

of thyrotoxicosis in patients given iodine rich contrast agents. J Endocrinol Invest 1999; 22:405–407. Spitzweg C, Joba W, Morris JC, Heufelder AE. Regulation of sodium iodide symporter gene expression in FRTL-5 rat thyroid cells. Thyroid 1999; 9:821– 830. Wolff J. Perchlorate and the thyroid gland. Pharmacol Rev 1998; 50:89–105. Bartalena L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996; 81:2930–2933. Graham GD, Burman KD. Radioiodine treatment of Graves’ disease: an assessment of its potential risks. Ann Intern Med 1986; 105:900–905. Levy EG. Treatment of Graves’ disease: the American way. Baillieres Clin Endocrinol Metab 1997; 11:585–595. Hennessey JV. Diagnosis and management of thyrotoxicosis. Am Fam Physician 1996; 54:1315–1324. Peters H, Fischer C, Bogner U, Reiners C, Schleusener H. Radioiodine therapy of hyperthyroidism: standard vs. calculated 131I activity. Results from a prospective, randomized, multicentre study. Eur J Clin Invest 1995; 25:186–193. Tamagna E, Levine GA, Hershman JM. Thyroid hormone concentrations after radioiodine therapy for hyperthyroidism. J Nucl Med 1979; 20:387–391. Andrade VA, Gross JL, Maia AL. Effects of methimazole pretreatment on serum thyroid hormone levels after radioactive treatment in Graves’ hyperthyroidism. J Clin Endocrinol Metab 1999; 84:4012–4016. Velkeniers B, Vanhaelst L, Cytryn R, Vanhaelst L, Jonckheer MH. Treatment of hyperthyroidism with radioiodine: adjunctive therapy with antithyroid drugs reconsidered. Lancet 1988; 1:1127–1129. Marcocci C, Gianchecchi D, Masini I, et al. A reappraisal of the role of methimazole and other factors on the efficacy and outcome of radioiodine therapy of Graves’ hyperthyroidism. J Endocrinol Invest 1990; 13:513–520. Tuttle RM, Patience T, Budd S. Treatment with propylthiouracil before radioactive iodine therapy is associated with a higher treatment failure rate than radioiodine therapy alone in Graves’ disease. Thyroid 1995; 243–247. Hancock LD, Tuttle RM, LeMar H, Bauman J, Patience T. The effect of propylthiouracil on subsequent radioactive iodine therapy in Graves’ disease. Clin Endocrinol (Oxf) 1997; 47:425–430. Imseis RE, Van Middlesworth L, Massie JD, Van Middlesworth NR. Pretreatment with propylthiouracil but not methimazole reduces the therapeutic efficacy of iodine-131 in hyperthyroidism. J Clin Endocrinol Metab 1998; 83:685–687. Tallstedt L, Lundell G, Torring O, et al. Occurrence of ophthalmopathy after treatment for Graves’ hyperthyroidism. The Thyroid Study Group. N Engl J Med 1992; 326:1733–1738. Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy or hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 1998; 73–78. Tallstedt L, Lundell G, Blomgren H, Bring J. Does early administration of thyroxine reduce the development of Graves’ ophthalmopathy after radioiodine treatment? Eur J Endocrinol 1994; 130:494–497.

88

Burman and Cooper

157. Bartelena L, Marcoccie C, Tanda M, et al. Cigarette smoking and treatment outcomes in Graves’ ophthalmopathy. Ann Intern Med 1998; 129:632–635. 158. Reference deleted. 159. Franklyn JA, Maisonneuve P, Sheppard M, Betteridge J, Boyle P. Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study. Lancet 1999; 353:2111–2115. 160. Chou FF, Wang PW, Huang SC. Results of subtotal thyroidectomy for Graves’ disease. Thyroid 1999; 9:253–257. 161. Duh QY. Thyroidectomy for the treatment of Graves’ disease (comment). Thyroid 1999; 9:259–261. 162. Leech NJ, Dayan CM. Controversies in the management of Graves’ disease. Clin Endocrinol (Oxf) 1998; 49:273–280. 163. Linos DA, Karakitsos D, Papademetriou J. Should the primary treatment of hyperthyroidism be surgical? Eur J Surg 1997; 163:651–657. 164. Witte J, Goretzki PE, Roher HD. Surgery for Graves’ disease in childhood and adolescence. Exp Clin Endocrinol Diabetes 1997; 105:58–60. 165. Lennquist S, Jortso E, Anderberg BO, Smeds S. Beta-blockers compared with antithyroid drugs as preoperative treatment in hyperthyroidism: drug tolerance, complications, and postoperative thyroid function. Surgery 1985; 98:1141–1147. 166. Feely J, Crooks J, Forrest A, Hamilton W, Gunn A. Propranolol in the surgical treatment of hyperthyroidism, including severely thyrotoxic patients. Br J Surg 1981; 68:865–869. 167. Baeza A, Aguayo M, Barria M, Pineda G. Rapid preoperative preparation in hyperthyroidism. Clin Endocrinol 1991; 35:439–442. 168. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: thyroid storm. Endocrinol Metab Clin North Am 1993; 22:263–277. 169. Hermann M, Roka R, Richter B, Freissmuth M. Early relapse after operation for Graves’ disease: postoperative hormone kinetics and outcome after subtotal, neartotal, and total thyroidectomy. Surgery 1998; 124:894–900. 170. Levetan C, Wartofsky L. A clinical guide to the management of Graves’ disease with radioactive iodine. Endocr Pract 1995; 1:205–210. 171. Dietlein M, Moka D, Dederichs B, Hunsche E, Lauterbach KW, Schicha H. Costeffectiveness analysis: radioiodine or antithyroid medication in primary treatment of immune hyperthyroidism. Nuklearmedizin 1999; 38:7–14. 172. Gurlek A, Gedik O. Effect of endogenous subclinical hyperthyroidism on bone metabolism and bone mineral density in premenopausal women. Thyroid 1999; 9: 539–543. 173. Koutras DA. Subclinical hyperthyroidism. Thyroid 1999; 9:311–315. 174. Cooper DS. Subclinical thyroid disease: a clinician’s perspective (editorial). Ann Intern Med 1998; 129:135–138. 175. Saadi H. Detecting and managing subclinical hyperthyroidism. Cleve Clin J Med 1998; 65:65–66. 176. Utiger RD. Subclinical hyperthyroidism—just a low serum thyrotropin concentration, or something more? (editorial). N Engl J Med 1994; 331:1302–1303. 177. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331:1249– 1252.

Evaluation and Management of Hyperthyroidism

89

178. Mudde AH, Houben AJ, Nieuwenhuijzen Kruseman AC. Bone metabolism during antithyroid drug treatment of endogenous subclinical hyperthyroidism. Clin Endocrinol (Oxf) 1994; 41:421–424. 179. Bauer D, Nevitt M, Ettinger B, Stone K. Low thyrotropin levels are not associated with bone loss in older women: a prospective study. J Clin Endocrinol Metab 1997; 82:2931–2936. 180. Figge J, Leinung M, Goodman AD, et al. The clinical evaluation of patients with subclinical hyperthyroidism and FTriiodothyronine (FT3) toxicosis. Am J Med 1994; 96:229–234. 181. Kahaly GJ, Nieswandt J, Mohr-Kahaly S. Cardiac risks of hyperthyroidism in the elderly. Thyroid 1998; 8:1165–1169. 182. Faber J, Jensen I, Petersen L, Nygaard B, Hegedus L, Siersback-Nielsen K. Normalization of serum thyrotrophin by means of radioidoine treatment in subclinical hyperthyroidism: effect on bone loss in postmenopausal women. Clin Endocrinol 1998; 48:285–290. 183. Brooks MH, Waldstein SS, Bronsky D, Sterling K. Serum triiodothyronine concentration in thyroid storm. J Clin Endocrinol Metab 1975; 40:339–341. 184. Sherman SI, Simonson L, Ladenson PW. Clinical and socioeconomic predispositions to complicated thyrotoxicosis: a predictable and preventable syndrome? Am J Med 1996; 101:192–198. 185. Hermann M, Richter B, Roka R, Freissmuth M. Thyroid surgery in untreated severe hyperthyroidism: perioperative kinetics of Thyroid hormones in the glandular venous effluent and peripheral blood. Surgery 1994; 115:240–245. 186. Eng PH, Cardona GR, Fang SL, et al. Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinology 1999; 140:3404–3410. 187. Bahn RS, Heufelder AE. Pathogenesis of Graves’ ophthalmopathy. N Engl J Med 1993; 11;329:1468–1475. 188. Werner SC. Classification of the eye changes of Graves’ disease. J Clin Endocrinol Metab 1969; 29:982–984. 189. Major BJ, Busuttil BE, Frauman AG. Graves’ ophthalmopathy: pathogenesis and clinical implications. Aust N Z J Med 1998; 28:39–45. 190. Gerding MN, Terwee CB, Dekker FW, Koornneef L, Prummel MF, Wiersinga WM. Quality of life in patients with Graves’ ophthalmopathy is markedly decreased: measurement by the medical outcomes study instrument. Thyroid 1997; 7:885–889. 191. Bahn RS. Understanding the immunology of Graves’ ophthalmopathy. Is it an autoimmune disease? Endocrinol Metab Clin North Am 2000; 29:287–296. 192. Spitzweg C, Joba W, Hunt N, Heufelder AE. Analysis of human thyrotropin receptor gene expression and immunoreactivity in human orbital tissue. Eur J Endocrinol 1997; 36:599–607. 193. Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Endocrinol (Oxf ) 1995; 42:45–50. 194. Tallstedt L, Lundell G, Taube A. Graves’ ophthalmopathy and tobacco smoking. Acta Endocrinol (Copenh) 1993; 129:147–150. 195. Krassas GE, Kaltsas T, Dumas A, Pontikides N, Tolis G. Lanreotide in the treatment of patients with thyroid eye disease. Eur J Endocrinol 1997; 36:416–422.

90

Burman and Cooper

196. Mourits MP, van Kempen-Harteveld ML, Garcia MB, Koppeschaar HP, Tick L, Terwee CB. Radiotherapy for Graves’ orbitopathy: randomised placebo-controlled study. Lancet 2000; 355:1505–1509. 197. Rapoport B, Alsabeh R, Aftergood D, McLachlan SM. Elephantiasis pretibial myxedema: insight into and a hypothesis regarding the pathogenesis of the extrathyroidal manifestations of Graves’ disease. Thyroid 2000 Aug; 10(8):685–692. 198. Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves’ disease (pretibial myxedema). Review of 150 cases. Medicine (Baltimore) 1994; 73:1–7. 199. Kuyvenhoven JP, van der Pijl JW, Goslings BM, Wiersinga WM. Graves’ dermopathy: does octreotide scintigraphy predict the response to octreotide treatment? Thyroid 1996; 6:385–389. 200. Burch HB, Shakir F, Fitzsimmons TR, Jaques DP, Shriver CD. Diagnosis and management of the autonomously functioning thyroid nodule: the Walter Reed Army Medical Center experience, 1975–1996. Thyroid 1998; 8:871–880. 201. Ferrari C, Reschini E, Paracchi A. Treatment of the autonomous thyroid nodule: a review. Eur J Endocrinol 1996; 135:383–390. 202. Als C, Rosler H, Kinser JA. Radioiodine therapy of the autonomous thyroid nodule in patients with or without visible extranodular activity (letter; comment) J Nucl Med 1996; 37:401–403. 203. David E, Rosen IB, Bain J, James J, Kirsh JC. Management of the hot thyroid nodule. Am J Surg 1995; 170:481–483. 204. Burman KD Solitary autonomous thyroid nodules. Postgrad Med 1974; 56:70–74. 205. Siddiqui AR, Karanauskas S. Hurthle cell carcinoma in an autonomous thyroid nodule in an adolescent. Pediatr Radiol 1995; 25:568–569. 206. Sandrock D, Olbricht T, Emrich D, Benker G, Reinwein D. Long-term follow-up in patients with autonomous thyroid adenoma. Acta Endocrinol (Copenh) 1993; 128:51–55. 207. Caplan RH, Strutt PJ, Kisken WA, Wester SM. Fine needle aspiration biopsy of thyroid nodules. Wis Med J 1991; 90:285–288. 208. Smith M, McHenry C, Jarosz H, Lawrence AM, Paloyan E. Carcinoma of the thyroid in patients with autonomous nodules. Am Surg 1988; 54:448–449. 209. Wool MS. Thyroid nodules. The place of fine-needle aspiration biopsy in management. Postgrad Med 1993; 94:111–112, 115–122. 210. Zelmanovitz F, Gross JL. Cytopathological findings from fine-needle aspiration biopsy are accurate predictors of thyroid pathology in patients with functioning thyroid nodules. J Endocrinol Invest 1998; 21:98–101. 211. Burch HB, Burman KD, Reed HL, Buckner L, Raber T, Ownbey JL. Fine needle aspiration of thyroid nodules: determinants of insufficiency rate and malignancy yield at thyroidectomy. Acta Cytol 1996; 40:1176–1183. 212. Paschke R, Ludgate M. The thyrotropin receptor in thyroid diseases. New Engl J Med 1997; 337:1675–1681. 213. Fuhrer D, Holzapfel HP, Wonerow P, Scherbaum WA, Paschke R. Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab 1997; 82:3885–3891. 214. Derwahl M, Manole D, Sobke A, Broecker M. Pathogenesis of toxic thyroid adenomas and nodules: relevance of activating mutations in the TSH-receptor and

Evaluation and Management of Hyperthyroidism

215.

216.

217.

218. 219. 220. 221. 222. 223.

224. 225. 226.

227. 228.

229.

230.

231. 232.

91

Gs-alpha gene, the possible role of iodine deficiency and secondary and TSH-independent molecular mechanisms. Exp Clin Endocrinol Diabetes 1998; 106:S6–S9. Krohn K, Fuhrer D, Holzapfel HP, Paschke R. Clonal origin of toxic thyroid nodules with constitutively activating thyrotropin receptor mutations. J Clin Endocrinol Metab 1998; 83:130–134. Paschke R. Constitutively activating TSH receptor mutations as the cause of toxic thyroid adenoma, multinodular toxic goiter and autosomal dominant non autoimmune hyperthyroidism. Exp Clin Endocrinol Diabetes 1996; 104:129–132. Blum M, Shenkman L, Hollander CS. The autonomous nodule of the thyroid: correlation of patient age, nodule size and functional status. Am J Med Sci 1975; 269: 43–50. Silverstein GE, Burke G, Cogan R. The natural history of the autonomous hyperfunctioning thyroid nodule. Ann Intern Med 1967; 67:539–548. Burman KD, Earll JM, Johnson MC, Wartofsky L. Clinical observations on the solitary autonomous thyroid nodule. Arch Intern Med 1974; 134:915–919. Woeber KA. Iodine and thyroid disease. Med Clin North Am 1991; 75:169–178. Burman KD, Adler R, Wartofsky L. Hemiagenesis of the thyroid gland. Am J Med 1975; 58:143–146. Goldstein R, Hart M. Follow-up of solitary autonomous thyroid nodules treated with 1311. N Engl J Med 1983; 309:1473–1476. Clerc J, Dagousset F, Izembart M, et al. Radioiodine therapy of the autonomous thyroid nodule in patients with or without visible extranodular activity. J Nucl Med 1995; 36:217–223. O’Brien T, Gharib H, Suman VJ, Van Heerden JA. Treatment of toxic solitary thyroid nodules: surgery versus radioactive iodine. Surgery 1992; 112:1166–1170. Wiener JD, de Vries AA. On the natural history of Plummer’s disease. Clin Nucl Med 1979; 4:181–190. Ross D, Ridgway E, Daniels G. Successful treatment of solitary toxic thyroid nodules with relatively low-dose iodine-131 with low prevalence of hypothyroidism. Ann Intern Med 1984; 101:488–490. Thomas CG, Jr., Croom RD. Current management of the patient with autonomously functioning nodular goiter. Surg Clin North Am 1987; 67:315–328. Hedman I, Jansson S, Lindberg S. Need for thyroxine in patients lobectomised for benign thyroid disease as assessed by follow-up on average fifteen years after surgery. Acta Chir Scand 1986; 152:481–486. Lippi F, Ferrari C, Manetti L, et al. Treatment of solitary autonomous thyroid nodules by percutaneous ethanol injection: results of an Italian multicenter study. The Multicenter Study Group. J Clin Endocrinol Metab 1996; 81:3261–3264. Monzani F, Caraccio N, Goletti O, et al. Five-year follow-up of percutaneous ethanol injection for the treatment of hyperfunctioning thyroid nodules: a study of 117 patients. Clin Endocrinol (Oxf) 1997; 46:9–15. Siegel RD, Lee SL. Toxic nodular goiter. Endocrinol Metab Clin North Am 1998; 27:151–168. Morris JC. Hyperthyroidism from toxic nodules and other causes. Surks MI, ed. Atlas of Clinical Endocrinology, Vol 1, Current Medicine, Philadelphia, PA. 1999, pp 104–112.

92

Burman and Cooper

233. Joba W, Spitzweg C, Schriever K, Heufelder AE. 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. 234. 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. 235. 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. 236. 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. 237. Gabriel EM, Bergert ER, Grant CS, van Heerden JA, Thompson GB, Morris JC. 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. 238. Holzapfel HP, Fuhrer D, Wonerow P, Weinland G, Scherbaum WA, Paschke R. Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiters. J Clin Endocrinol Metab 1997; 82:4229– 4233. 239. 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. 240. Hurley DL, Gharib H. Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996; 29:527–540. 241. Franklyn JA, Daykin J, Holder R, Sheppard MC. Radioiodine therapy compared in patients with toxic nodular or Graves’ hyperthyroidism. QJM 1995; 88:175– 180. 242. Erickson D, Gharib H, Li H, van Heerden JA. Treatment of patients with toxic multinodular goiter. Thyroid 1998; 8:277–282. 243. Jensen MD, Gharib H, Naessens JM, van Heerden JA, Mayberry WE. Treatment of toxic multinodular goiter (Plummer’s disease): surgery or radioiodine? World J Surg 1986; 10:673–680. 244. Fogelfeld L, Wiviott MB, Shore-Freedman E, et al. Recurrence of thyroid nodules after surgical removal in patients irradiated in childhood for benign conditions. N Engl J Med 1989; 320:835–840.

3 Diagnosis and Treatment of Thyroiditis and Other More Unusual Forms of Hyperthyroidism Shon E. Meek and Robert C. Smallridge Mayo Clinic, Jacksonville, Florida

1

THYROIDITIS AND HYPERTHYROIDISM

1.1 Subacute Thyroiditis 1.1.1

Introduction

Subacute thyroiditis is a painful inflammatory condition of the thyroid that is associated with thyrotoxicosis. In the past it has also been called granulomatous thyroiditis, giant-cell thyroiditis, noninfectious thyroiditis, acute nonsuppurative thyroiditis, and de Quervain’s thyroiditis. 1.1.2

Epidemiology

Subacute thyroiditis is not as common as Graves’ disease but is more common than silent thyroiditis. It has been reported to occur at the rate of one case in five to eight cases of Graves’ disease (1). 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 (2). Whether the lack 93

94

Meek and Smallridge

of occurrence in the tropical and subtropical areas is due to actual frequency or ascertainment bias is not known. However, despite the possible geographical variation, subacute thyroiditis is recognized more frequently during the summer months (3,4). Subacute thyroiditis has been reported in all age groups, although it is most common in the third to sixth decades of life, and is rare in children. Female patients outnumber male patients in a ratio of 3 to 6:1 (1,5–7). 1.1.3

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 (8–14). Subacute thyroiditis is associated with HLA-B35 about 72% of the time (13,15). Infiltrative diseases such as amyloid have also been reported to cause a subacute thyroiditis–like picture (16). 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. The most distinctive feature is the granuloma, consisting of groups of giant cells (17,18). 1.1.4

Diagnosis

Patients with subacute thyroiditis usually present with the 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. About one-third of patients can have pain that is migratory throughout the thyroid. Approximately one-third of cases may present with diffuse pain in the thyroid (1,14,19). Some biopsy-proven cases of subacute thyroiditis have been reported to be painless (18,20,21). Many patients may have systemic symptoms of malaise, myalgia, fever, and anorexia. About 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 may include heat intolerance, palpitations, tremor, and nervousness. Physical examination shows an uncomfortable patient with a tender, enlarged, firm thyroid gland. The process is often asymmetrical. Lymphadenopathy is usually not present. Symptoms of thyrotoxicosis may last 4 to 10 weeks, but the inflammation with a painful tender thyroid may last for 8 weeks and rarely up to a year. Pain and tenderness resolve first, followed by resolution of the

Diagnosis and Treatment of Hyperthyroidism

95

FIG. 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. (This figure was first published in the Western Journal of Medicine 1991 155:61–63 and is reproduced by permission of the Western Journal of Medicine)

palpable thyroid abnormalities, as shown in Fig. 1 (2). If the patient is not seen until late in the course of the disease after pain resolves, the discovery of a thyroid nodule may lead to unnecessary surgery unless a FNA is performed. Laboratory evaluation shows increased thyroid hormones and thyroglobulin due to follicular disruption, which releases 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 (22). The white blood cell count is usually normal but may be moderately increased, and the erythrocyte sedimentation rate is virtually always increased, often to as high as 100 mm/h (14,19). Thyroid antibodies are usually absent or in low titer; if present, they are usually transient. The radioactive iodine uptake is low. As the course of subacute thyroiditis progresses, the serum concentration of thyroid hormones returns to normal. In more severe cases, hypothyroidism develops (23). Thyroid function usually returns to normal and permanent hypothyroidism occurs in ⬍5% of cases. Recurrent bouts of subacute thyroiditis have been described but are rare. Figure 2 shows the typical phases of thyroid function during subacute thyroiditis.

96

Meek and Smallridge

FIG. 2 Natural history of subacute thyroiditis

1.1.5

Treatment

Nonsteroidal anti-inflammatory drugs or salicylates (2 g/day) are used initially to treat subacute thyroiditis (24,25). However, corticosteroids are used for more severe cases and result in rapid improvement (26). Corticosteroids produce partial or near complete relief in pain and neck tenderness within 24 to 48 h. 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/week and withdrawal by 4 weeks. As the drug is tapered, exacerbation of pain may occur in about 20% of patients (7,25). If this occurs, treatment can be continued for another month. In extremely rare cases, neck pain and malaise may be prolonged. In these cases thyroidectomy or ablation of the thyroid with radioactive iodine 131 ( 131 I) may be needed. Beta-adrenergic antagonist drugs may be helpful in controlling symptoms of thyrotoxicosis, but they are usually not needed, since steroids or anti-inflammatory drugs usually alleviate thyrotoxicosis as well as the thyroid pain. 1.2 Silent Thyroiditis 1.2.1

Introduction

Silent thyroiditis is often a painless inflammation of the thyroid that produces a transient hyperthyroid state. 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

Diagnosis and Treatment of Hyperthyroidism

97

subacute thyroiditis, lymphocytic thyroiditis, spontaneously resolving lymphocytic thyroiditis, and transient thyrotoxicosis with lymphocytic thyroiditis. Silent thyroiditis may also occur in the postpartum period, in which case it is called postpartum thyroiditis. 1.2.2

Epidemiology

The incidence of painless thyroiditis was reported in increasing frequency in the late 1970s and early 1980s in the Great Lakes region of the United States and in 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 (27). 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 (28). 1.2.3

Pathophysiology

In many cases, silent thyroiditis is an autoimmune disease and may be a variant of Hashimoto’s thyroiditis. Histologically, silent thyroiditis is characterized by a lymphocytic infiltration of the thyroid and is sometimes associated with lymphoid follicles (29,30). It is associated with other autoimmune diseases, such as autoimmune adrenal insufficiency, lupus erythematosus, idiopathic thrombocytopenic purpura, and rheumatoid arthritis (31–34). Silent thyroiditis has been associated with HLA DR3 (35). Thyroid antibodies are present in the serum in up to 50% of patients, which suggests an autoimmune process. No association with a viral infection has been found. However, the lack of antibodies in some patients and lack of clear female predominance suggest that silent thyroiditis is a heterogeneous disorder. 1.2.4

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 usually lasts about 3 months. Approximately one-half of patients present with a goiter. The thyroid is 1.5 to 3 times the normal size, is diffusely enlarged, and symmetrical; it is firm and nontender (36). The course of the disease may follow four different phases. The first phase is characterized by hyperthyroidism, which is usually followed by euthyroidism in the second phase. Many but not all patients will go on to develop hypothyroidism as a third stage of silent thyroiditis. Most patients will then become euthyroid in the fourth stage, but permanent hypothyroidism may develop months to years later.

98

Meek and Smallridge

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 thyrotoxicosis factitia. Serum thyroglobulin concentrations may remain slightly increased even 1 to 2 years after recovery of normal thyroid function (37). Thyroid antibody levels are increased approximately 30% to 50% of the time. However, about 50% of the positive antibody titers become negative within 6 months after thyroid recovery (28,36). The white cell count is usually normal. The sedimentation rate is normal in ⬎50% of cases, with only mild elevation in the remaining cases (28). FNA of the thyroid shows lymphocytic infiltration, but aspiration is rarely needed to make the diagnosis. Biopsy lacks some of the features of chronic lymphocytic thyroiditis, such as no Hu¨rthle cells or germinal centers. 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, thyroid hormone, and other druginduced thyrotoxic conditions. In addition, struma ovarii tumor can cause a low radioactive iodine uptake over the thyroid, but uptake over the pelvic tumor will be increased. Thyroid hormone levels decrease during the euthyroid and hypothyroid phases 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. 1.2.5

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, since the thyrotoxic phase is due to the discharge of thyroid hormones from thyroid cellular destruction. If severe thyrotoxicosis is present, corticosteroids can be administered to decrease the inflammatory process (28). Sodium ipodate has been used successfully in one patient with silent thyroiditis to treat the thyrotoxic phase (38). The rapid improvement in symptoms and lowering of T3 levels may have been due to the inhibition of 5′ monodeiodination by ipodate. Patients have rarely been treated with thyroidectomy when they have had frequent debilitating episodes of silent thyroiditis (30,39). Radioactive iodine ablation of the thyroid could also be considered, after the thyroid has returned to normal function with a normal uptake, for patients with recurrent episodes of silent thyroiditis.

Diagnosis and Treatment of Hyperthyroidism

99

The hypothyroid phase of silent thyroiditis usually does not need to be treated, since 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. However, thyroid function should be monitored yearly, since approximately 50% of patients with silent thyroiditis will ultimately develop hypothyroidism in the future (28). 1.3 Postpartum Thyroiditis 1.3.1

Introduction

Postpartum thyroiditis is a syndrome of thyroid dysfunction that occurs within the first year following parturition. It is usually characterized by transient painless thyrotoxicosis with a low radioactive iodine uptake. The thyrotoxic phase is often followed by a hypothyroid phase that is then followed by thyroid recovery. However, many patients with postpartum thyroiditis will ultimately develop permanent hypothyroidism within a few years after the episode of postpartum thyroiditis (40). 1.3.2

Epidemiology

Postpartum thyroiditis has been reported to occur in North America, South America, Europe, and Asia. An average prevalence figure of about 5% has been generally accepted (41–47). The lower frequency of 1.1% in Asia may be related to variations in regional dietary iodine intake or genetic differences in susceptibility (48). 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% to 25%) is found among patients with type 1 diabetes mellitus, reflecting the underlying autoimmune diathesis (49–51). Postpartum thyroid dysfunction has also been reported to occur after a miscarriage, although this case was found to have postmiscarriage hypothyroidism only (52). 1.3.3

Pathophysiology

Women who are prone to developing postpartum thyroiditis most likely have a preexisting, asymptomatic autoimmune thyroiditis. During pregnancy, the maternal immune system is partially suppressed, with a subsequent rise in thyroid antibodies after delivery. Studies have shown that higher thyroid antibody levels are associated with a higher risk of thyroid dysfunction and clinical symptoms (53–56). Postpartum thyroiditis has also been related to HLA type. HLA-DR3, -DR4, and -DR5 are increased in patients with postpartum thyroiditis (57–60). Biopsy specimens of thyroid tissue during postpartum thyroiditis have shown a lymphocytic infiltration (45). Smoking was associated with postpartum thyroidi-

100

Meek and Smallridge

tis in two studies (41,61) but was not associated with smoking in three other studies (46,62,63). Several studies have shown postpartum thyroiditis is associated with the presence of goiter during pregnancy (43,53,64). One study using ultrasound has shown a significant increase in thyroid volume between 8 and 20 weeks’ gestation in women who went on to develop postpartum thyroiditis (65). However, a prospective study using ultrasound found that thyroid size before, during, or after pregnancy is not a useful indicator for the development of postpartum thyroiditis (62). Therefore, even though postpartum thyroiditis may be associated with a goiter, the presence of a goiter is not a predictive indicator for postpartum thyroiditis. 1.3.4

Diagnosis

Patients with postpartum thyroiditis may present with fatigue, palpitations, memory impairment, or emotional liability. Many patients will have some enlargement in the thyroid. Postpartum thyroiditis is almost universally painless, although one case of painful disease has been reported (67). Antithyroid antibodies are almost always increased. Patients may present at a time when thyroid hormones are high, normal, or low. There is an absence of exophthalmos. Since the hyperthyroid phase is a destructive type of thyroiditis, a low radioactive iodine uptake is found. Figure 3 shows the frequency of hyperthyroidism, hypothyroidism, or both in postpartum thyroid dysfunction. The classical 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 1 to 6 months postpartum. Frequently, a period of hypothyroidism develops over the next 3 to 4 months, and then thyroid

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

Diagnosis and Treatment of Hyperthyroidism

FIG. 4

101

Natural history of postpartum thyroiditis

function returns to normal. Some patients with postpartum thyroiditis develop only transient hyperthyroidism that is not followed by hypothyroidism. About 24% of patients with postpartum thyroid dysfunction have hyperthyroidism caused by thyroiditis. About 11% of patients have hyperthyroidism caused by Graves’ disease. Some patients (40%) with postpartum thyroiditis present only with hypothyroidism that is subsequently followed by thyroid recovery. 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. About a quarter of patients with transient thyroid disease postpartum become hypothyroid within about four years (54,57,58,66). Factors that are associated with the development of hypothyroidism include higher titer of thyroid antibodies during gestation, severity of the hypothyroid phase of postpartum thyroiditis, and a previous history of spontaneous abortion (66,67). 1.3.5

Treatment

Treatment of the thyrotoxic phase of postpartum thyroiditis is often not needed, since the symptoms are usually mild. Beta-blocker therapy can be used in patients who are symptomatic; it can then be tapered as the thyrotoxic phase resolves. The hypothyroid phase can also be observed without treatment if symptoms are mild and transient. If the hypothyroid stage is severe or prolonged, thyroxine should be administered for 6 to 12 months. Thyroid hormone can subsequently be withdrawn and serum TSH measured several months later, to see if the patient is euthyroid. Even if full thyroid recovery occurs, patients with a history of post-

102

Meek and Smallridge

partum thyroiditis should be followed over the long term for the subsequent development of permanent hypothyroidism. Since postpartum thyroiditis tends to recur in up to 80% of subsequent pregnancies, future pregnancies should also be monitored (68). 1.4 Acute Infectious Thyroiditis 1.4.1

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. 1.4.2

Epidemiology

Infectious thyroiditis is a rare disorder. The thyroid is felt to be 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. 1.4.3

Pathophysiology

Many different bacteria can infect the thyroid including Streptococcus, Staphylococcus, Pneumococcus, Salmonella, Bacteroides, and Treponema pallidum (69). Mycobacterium tuberculosis (70) and several fungi, including Coccidioides immitis, Aspergillus, and Candida albicans (71), have been associated with thyroiditis. Pneumocystis carinii may also cause infectious thyroiditis (72). Patients who are immunocompromised or have acquired immunodeficiency syndrome may be at particular risk for infectious thyroiditis. Most often, infection is due to direct extension from an internal fistula from the pyriform sinus (73,74). This tract is more common in children and may represent the course of migration of the ultimo branchial body from the site of its embryonic origin in the fifth pharyngeal pouch. This tends to develop in the left thyroid lobe more commonly than the right. However, infection in the thyroid may occur in a normal thyroid, multinodular goiter, or in a degenerative thyroid nodule also. 1.4.4

Diagnosis

Patients with infectious thyroiditis usually present with pain and may have a hot, tender thyroid (94%). They may avoid extension of their neck due to pain, swallowing may be painful, and dysphagia may be present (91%). There may be signs of infection in adjacent tissues and lymphadenopathy may be present. The patient may have systemic signs of fever and chills (92%) (69).

Diagnosis and Treatment of Hyperthyroidism

103

Laboratory data include an increased white blood cell count and increased sedimentation rate. The patient may have increased thyroid hormone levels and present with thyrotoxicosis due to thyroid hormone release from the thyroid (75). In one review, 12 of 56 cases had laboratory data suggesting hyperthyroidism (69). However, most patients are euthyroid and the radioactive iodine uptake will usually be normal. Thyroid ultrasound or computed tomography (CT) of the neck may show a local abscess that can be aspirated and cultured to make the diagnosis (76). A barium swallow can be obtained to evaluate for the presence of a fistula tract between the pyriform sinus and the thyroid that may have been a predisposing factor. 1.4.5

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 are administered which are tailored to the specific infectious agent. An abscess will require surgical exploration and drainage, and fistula tracts also require surgery to prevent recurrent infection. 1.5 Radiation Thyroiditis 1.5.1

Introduction

Radiation in the form of 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. 1.5.2

Epidemiology

Radiation thyroiditis from 131 I occurs in approximately 20% of patients receiving ⱖ50,000 rads (50 Gy) to ablate residual normal thyroid tissue (77). It is more common with larger thyroid remnants. 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, 8 of 22 patients developed a TSH below the normal range after receiving 40 Gy of external beam radiation over 2 weeks. Levels of T4 and T3 tended to rise after 40 Gy of radiation but did not reach statistical significance (78). Several case reports of external beam radiation–induced thyrotoxicosis have been reported (79,80). 1.5.3

Pathophysiology

Radiation presumably causes a destructive thyroiditis with release of preformed thyroid hormone into the bloodstream. The thyrotoxicosis is transient. The radia-

104

Meek and Smallridge

tion dose that has been reported to cause external beam radiation–induced thyrotoxicosis varies between 37 and 50 Gy (79,81). It is likely that the greater the external beam radiation dose, the more frequently thyrotoxic thyroiditis and subsequent hypothyroidism occur. 1.5.4

Diagnosis

External beam radiation–induced thyrotoxic thyroiditis usually occurs within a few weeks of radiation exposure. It is characterized by increased levels of thyroid hormones and suppressed levels of TSH. Serum antithyroid autoantibodies are often negative. The 24-h radioactive iodine uptake is low. In radioactive iodine–induced thyrotoxic thyroiditis, manifestations usually occur within about 4 days after radioactive iodine is administered. Symptoms, if present, consist of neck and ear pain, dysphagia, thyroid tenderness, and/or transient thyrotoxicosis. 1.5.5

Treatment

Since the thyrotoxicosis from radiation thyroiditis is transient, observation may be all that is needed. Treatment with beta blockers can be used to control tachycardia and tremor. Patients with 131 I-induced thyrotoxic thyroiditis may have significant neck pain requiring treatment with corticosteroids. All patients treated with radioactive iodine or external beam radiation therapy should be monitored for subsequent hypothyroidism months to years after the radiation exposure. 1.6 Trauma-Induced Thyroiditis Several reports of trauma-induced thyroiditis have been described; 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 (82–84). The thyroid may be tender due to the trauma. The thyrotoxicosis is transient and associated with a low uptake of radioactive iodine.

2

DRUG INDUCED HYPERTHYROIDISM

2.1 Iodine-Induced Hyperthyroidism 2.1.1

Introduction

Iodine-induced hyperthyroidism was first described in 1821 by Coindet (85). 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.

Diagnosis and Treatment of Hyperthyroidism

2.1.2

105

Epidemiology

The incidence of iodine-induced hyperthyroidism has varied according to the underlying thyroid abnormality, the geographical region, and the particular time in history. The highest incidence has been in areas of iodine deficiency and in individuals with multinodular goiters at times when iodine supplementation was introduced into the diet. In four different iodine-deficient countries, the incidence of iodine-induced hyperthyroidism was determined before and after iodinization of salt. In a region of Holland, the average yearly incidence of iodine-induced hyperthyroidism was calculated at 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%. These data were based on observations of the incidence of hyperthyroidism before and after iodinization of salt with iodide. In general, the incidence of hyperthyroidism rose within about 6 months after iodinization and reached a peak at 1 to 3 years. The incidence of hyperthyroidism returned to baseline about 3 to 10 years after iodinization was begun (86). The best-documented epidemic of iodine-induced hyperthyroidism occurred in Tasmania and is shown in Fig. 5. The increased incidence of hyperthyroidism occurred after the introduction of iodophors for sanitation in the dairy industry in 1963. Potassium iodate was also introduced as a bread conditioner. Patients with endemic goiters who were older than 40 years were primarily affected by the thyrotoxicosis (85). 2.1.3

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 pharmacological doses of iodine in iodine-sufficient or deficient regions. However, iodine-induced thyrotoxicosis occurs more commonly in iodine-deficient areas. The term Jod-Basedow phenomenon has been used to describe the condition of thyrotoxicosis produced by iodine exposure. Some studies have suggested that the dose of iodine may influence the development of iodine-induced hyperthyroidism. Doses of iodine that are ⬍50 µg/day are generally considered safe, whereas doses of 200 to 500 µg/day are capable of causing hyperthyroidism in patients with abnormal thyroid physiology (87). However, even large doses of iodine (1 g/day) usually do not cause hyperthyroidism. Many different iodine sources have been reported to cause iodineinduced hyperthyroidism. Compounds such as potassium iodide and iodoquino-

106

Meek and Smallridge

FIG. 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.) (This figure was first published in Thyroid 1998; 8:83–100 and is reproduced by permission of the journal Thyroid.)

lones, 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 (88). A large number of different iodine-containing substances and drugs have been reported to cause hyperthyroidism. These iodinated substances include seaweed (89), iodinated glycerol (90,91), and topical povidone iodine (92,93). Many cases of hyperthyroidism induced by iodinated contrast agents have also been described (94). In general, it is prudent to avoid administering large doses of iodine to patients with nontoxic goiter, since doing so can induce hyperthyroidism (95). Table 1 lists various drugs that contain iodine. 2.1.4

Diagnosis

Iodine-induced hyperthyroidism occurs in older patients more commonly than in children. Men can be affected as often as women can. Exophthalmos is usually absent. The thyroid may be nodular, diffusely enlarged, or normal. TSH levels are suppressed and thyroid hormone levels are increased. Thyroid antibodies are

Diagnosis and Treatment of Hyperthyroidism

107

TABLE 1 Iodine-Containing Drugs and Their Brand Names Radiological 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 Iodinated glycerol (Organidin, Tuss Organidin, Iophen)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.

usually absent. The 24-h 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. 2.1.5

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 are not uniformly effective. Steroids can be effective in promptly lowering thyroid

108

Meek and Smallridge

hormone levels (86,88). Radioactive iodine has been used, but high doses may be needed, since uptake is usually low. Thyroidectomy has occasionally been used to treat iodine-induced hyperthyroidism. 2.2 Amiodarone-Induced Hyperthyroidism 2.2.1

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 (96). Amiodarone, therefore, can have dramatic effects on thyroid function and has been associated with hypothyroidism as well as hyperthyroidism. 2.2.3

Epidemiology

The prevalence of amiodarone-induced hyperthyroidism and hypothyroidism varies geographically and seems to correlate with dietary intake of iodine. The incidence of amiodarone-induced thyrotoxicosis has been reported to be 1% to 23% (97). In West Tuscany, Italy, where iodine intake is low, the incidence of amiodarone-induced hyperthyroidism was reported at 9.6%, while hypothyroidism was reported at 5%. On the other hand, in Worcester, Massachusetts, where iodine intake is sufficient, amiodarone-induced hyperthyroidism was reported in only 2% of patients, while hypothyroidism was reported in 22% (98). In Los Angeles, California, hyperthyroidism associated with amiodarone was found in 3% of patients, while hypothyroidism was found in 8% (99). In a retrospective review, amiodarone-induced hyperthyroidism was found in 4.2% of patients seen at the Cleveland Clinic (100). However, this geographic variance with iodine intake is not supported by all studies (101). 2.2.4

Pathophysiology

Two major forms of amiodarone-induced thyrotoxicosis (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 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 (102–104). This has also been suggested by FNA biopsy (105). In patients with type 1 AIT, the radioactive iodine uptake is inappropriately normal or even increased in the presence of high levels of iodine. In 12 patients with type 1 AIT, 24-h radioactive iodine uptake ranged from 6% to 50% (mean 17%) (106). In another study, 9 of 11 patients with diffuse goiter and 8 of 12 patients with nodular goiters and AIT had 24-h radioactive iodine uptake of ⬎8%

Diagnosis and Treatment of Hyperthyroidism

109

TABLE 2 Amiodarone-Induced Thyrotoxicosis Feature

Type 1

Thyroid abnormality

Pathogenesis Thyroid exam Radioactive iodine uptake Thyroid antibodies Interleukin-6 Thyroid ultrasound Doppler flow Therapy options

Type 2

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

Destructive thyroiditis

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

Negative High (⬎250 fmol/L)

Stop amiodarone, ATD, KC1O4, RAI thyroidectomy

Stop amiodarone, ATD, Steroids

Thyroid hormone release Normal or small goiter Very low

Decreased

Key: ATD, antithyroid drugs; KC1O4, potassium perchlorate; RAI, radioactive iodine.

(107). In patients with type 2 AIT, 24-h radioactive iodine uptakes are very low (106–108). Twelve patients with type 2 AIT had 24-h radioactive iodine uptakes of 0.5% to 2%, with a mean of 1% (106). Interleukin-6 (IL-6) levels have also been used to distinguish type 1 from type 2 AIT. IL-6 levels are only mildly increased in patients with type 1 AIT as compared with those in patients with spontaneous hyperthyroidism (102). IL-6 levels in patients with type 2 AIT are markedly increased due to the release of IL-6 produced by destroyed thyrocytes (102). However, the utility of IL-6 levels have not been confirmed by other authors (109). Recently, 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 (110). 2.2.5

Diagnosis

The presentation of amiodarone-induced hyperthyroidism may be subtle, with relatively few clinical signs (111). However, patients typically present with tachycardia, tremor, weight loss, nervousness, or irritability. One review found weight

110

Meek and Smallridge

loss as the most common presenting symptom, with goiter and tremor being the most common presenting signs (100). Some patients may present with recurrence of arrhythmia that was once controlled with the use of amiodarone (99,112). However, tachycardia in AIT may not always be present, due to the beta-blocking properties of amiodarone. Amiodarone treatment itself increases T4 levels and decreases T3 levels by inhibiting type 1 iodothyronine deiodinase. After therapy commences, serum TSH levels increase due to inhibition of T4 to T3 deiodination in the pituitary, but subsequently serum TSH levels usually return to normal. When thyrotoxicosis develops, there is a further increase in T4 levels and an increase in T3 levels in most patients (103). Serum T3 levels may be in the upper range of normal but higher than prior to onset of hyperthyroidism. TSH levels are decreased (100). 2.2.6

Treatment

The treatment of amiodarone-induced hyperthyroidism is often difficult and protracted because of the long half-life of amiodarone and the high intrathyroidal and tissue concentration of iodine. If amiodarone is discontinued, it may take up to 8 months for thyrotoxicosis to subside (88). Medical treatment of AIT has consisted of antithyroid drugs, potassium perchlorate, and steroids, sometimes in combination. Radioactive iodine is not a treatment option for type 2 AIT, since the high concentration of iodine in amiodarone and the thyroiditis lead to a suppressed uptake of radioactive iodine. It has been recommended that medical therapy is best accomplished when taking the type of AIT into account. Patients with type 1 AIT may respond to a combination of an antithyroid drug (to decrease thyroxine synthesis) and potassium perchlorate (to decrease intrathyroidal iodine content). A decrease in intrathyroidal iodine content reduces the substrate for thyroid hormone production, thereby decreasing systemic thyroid hormone levels. Patients given methimazole 30 mg/day and potassium perchlorate (0.5 g twice daily) achieved normal T3 levels after an average of 4 weeks. Potassium perchlorate was withdrawn after 19 to 40 days. Methimazole was continued at the lowest dose required to maintain a euthyroid state and a normal urinary iodide excretion (106). Patients with type 2 AIT were treated with prednisone 40 mg/day for 7 to 14 days with subsequent tapering of the prednisone over 3 months. These patients achieved normal free T3 levels after an average of 8 days. If patients had an exacerbation of thyrotoxicosis with tapering of the steroids, the prednisone dose was increased again (106). Lithium in combination with antithyroid drugs has been reported to help control thyrotoxicosis faster than treatment with antithyroid drugs alone (113). If patients do not respond to steroids alone or if the pathogenesis is unclear, a combination of steroids and antithyroid drugs would be reason-

Diagnosis and Treatment of Hyperthyroidism

111

able. These patients are often poor operative candidates because of their underlying cardiovascular disease, and the surgical risks and benefits must be weighed against the risks and benefits of medical therapy. Near total thyroidectomy is an alternative for patients with AIT. Thyroidectomy rapidly resolves the hyperthyroidism and allows continued treatment with amiodarone (114,115). 2.3 Cytokine-Induced Hyperthyroidism 2.3.1

Introduction

Interferon therapy has been used to treat chronic viral hepatitis with promising results. However, the immune-mediated effects of interferon have been shown to increase the incidence of thyroid diseases and other immune-mediated disorders. Alpha interferon has been most often shown to cause hypothyroidism; however, the incidence of hyperthyroidism is also increased with the use of alpha interferon. 2.3.2

Epidemiology

Alpha interferon has been shown to induce thyroid dysfunction in about 6% of patients. The majority of cases (4%) develop hypothyroidism, but 2% develop hyperthyroidism (116). Females seem to be more susceptible to interferoninduced hyperthyroidism than males. Hyperthyroidism has been reported from as early as 6 weeks after the onset of interferon therapy (117) to as late as 6 months after interferon therapy was completed (118). Hyperthyroidism tends to be more often transient (70%) than permanent (116). Interleukin-2 (IL-2) therapy has also been reported to cause hypothyroidism and transient hyperthyroidism (119). 2.3.3

Pathophysiology

Thyroid dysfunction, including hyperthyroidism, is more common among patients who had increased titers of thyroid antibodies prior to treatment. Thyroid dysfunction occurred in 46% of patients with baseline elevation in thyroid antibodies. Only 5% of thyroid antibody–negative patients develop thyroid dysfunction (116). Approximately 10% of thyroid antibody–negative patients develop thyroid antibodies during interferon therapy, and about half of these patients develop thyroid dysfunction, suggesting that the thyroid dysfunction is mediated through an immune mechanism. However, some patients with thyroid dysfunction had no evidence of thyroid antibodies, raising the question of a direct toxic effect of interferon on the thyroid. Patients with either hepatitis C or malignancy have been found to have

112

Meek and Smallridge

a higher frequency of thyroid abnormalities in the absence of interferon therapy, which may contribute to the higher rate of thyroid dysfunction when interferon is used in these conditions (120). 2.3.4

Diagnosis

Hyperthyroidism associated with interferon therapy presents with the usual signs and symptoms. The thyroid may be normal in size or enlarged, and serum thyroid hormone levels are increased, with a suppressed serum TSH concentration. In addition to thyroid peroxidase and thyroglobulin antibodies, some patients develop thyroid-stimulating immunoglobulins 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. 2.3.5

Treatment

Hyperthyroidism associated with the use of interferon therapy, 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. Patients with interferon-induced destructive thyroiditis with low radioactive iodine uptake have been successfully treated with glucocorticoids. However, transient thyrotoxicosis may give rise to hypothyroidism that 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 (121).

2.4 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 (122). 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 have also concluded that the association was not coincidental (123). The majority of cases of lithium-associated thyrotoxicosis and increased radioactive iodine uptakes have been treated successfully with antithyroid drugs even while lithium therapy is continued.

Diagnosis and Treatment of Hyperthyroidism

113

2.5 Hyperthyroidism Due to Exogenous Thyroid Hormone 2.5.1

Introduction

Thyrotoxicosis factitia describes a condition due to the excess use of thyroid hormone, leading to symptoms and signs of thyrotoxicosis. The term is used most commonly when the use of thyroid hormone is surreptitious. 2.5.2

Epidemiology

Thyroid hormone has been used for a variety of nonthyroid conditions in the past, ranging from obesity to depression to infertility. When the dose is escalated to supraphysiological doses, thyrotoxicosis results. The secretive use of thyroid hormone by psychiatrically disturbed patients is another common cause of thyrotoxicosis factitia. Occasionally patients such as children will present with thyrotoxicosis due to accidental ingestion of thyroid hormone (124). 2.5.3

Pathophysiology

The thyrotoxicosis caused by thyrotoxicosis factitia is due to the excess 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 (125,126). 2.5.4

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. Thyroglobulin measurements are low, a finding that is useful in distinguishing thyrotoxicosis factitia from other forms of hyperthyroidism with low uptake of radioactive iodine (127). 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 (128). 2.5.5

Treatment

The treatment of thyrotoxicosis factitia is putting a stop to the use of exogenous thyroid hormone. This can sometimes be difficult in the psychiatrically disturbed

114

Meek and Smallridge

patient who is taking thyroid hormone secretly; psychiatric consultation may be helpful here. Beta-blocking agents may be needed temporarily while thyroid hormone levels are decreasing. 3

THYROTROPHIN-INDUCED HYPERTHYROIDISM

3.1 TSH-Secreting Pituitary Adenomas 3.1.1

Introduction

Since the advent of radioimmunoassays for measurement of TSH, pituitary tumors that produce TSH have become recognized. Inappropriate secretion of TSH can give rise to hyperthyroidism. Earlier reports described large pituitary tumors, but microadenomas are being recognized more frequently in more recent case series. 3.1.2

Epidemiology

TSH-producing pituitary tumors (TSHomas) are rare, occurring in about 1 in 1 million persons. However, the number of cases being reported has increased, along with the introduction of second- and third-generation TSH assays. TSHproducing pituitary tumors may account for 0.5% to 3% of pituitary tumors (129– 131). TSH-producing pituitary tumors may occur at any age, with males and females affected about equally (132,133). 3.1.3

Pathophysiology

TSHomas are macroadenomas about 90% of the time. Approximately 30% of TSH-producing pituitary tumors are mixed tumors secreting other pituitary hormones. Growth hormone and prolactin are the most common hormones cosecreted, but tumors that cosecrete LH and FSH have also been described (132,133). Alpha subunit may also be produced in TSH-producing pituitary adenomas. One case of an ectopic TSH-secreting pituitary tumor has also been reported (134). 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 (135). No activating mutation in the gene coding for G proteins has been found in TSH-producing pituitary tumors (132). 3.1.4

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 case it was due to orbit invasion by tumor, while Graves’ disease has been present in several patients with coexisting TSHomas. Dermopathy and acropachy are not found. If the tumor is large, headache (23%) and visual field disturbance (40%) may be present. Features of cosecreted hormones may be present, such as acro-

Diagnosis and Treatment of Hyperthyroidism

115

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. 132.

megaly (15%) or the galactorrhea/amenorrhea (10%) syndrome (132). Hypopituitarism may also be present, most commonly hypogonadism. Laboratory evaluation shows increased levels of thyroid hormones in the presence of an inappropriately normal or increased 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 TSH-producing pituitary adenomas and thyroid hormone resistance. Antithyroid antibodies are usually not present. The radioactive iodine uptake is increased. Circulating levels of alpha subunit are increased. The alpha subunit/TSH molar ratio, which is the moles of serum alpha subunit divided by the moles of serum TSH, is usually ⬎1 [molar ratio ⫽ (α-SU ng/mL/TSH mU/mL) ⫻ 10]. However, the alpha subunit/TSH molar ratio is not reliable in postmenopausal women and in men with primary hypogonadism, since increased levels of alpha subunit are present in these conditions due to increased gonadotrophins (132,133,136–138). In vivo and in vitro parameters of thyrotoxicosis are usually present in patients with TSH-producing adenomas. An increased level of sex hormone–binding globulin has been proposed to help differentiate patients with TSH-producing adenomas from those with thyroid hormone resistance (139). 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. Imaging of the sella with CT or magnetic resonance imaging (MRI) will usually reveal a pituitary tumor. For patients previously treated with thyroid ablation, 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 MRI has not detected microadenomas. In one case, inferior petrosal sinus sampling disclosed a gradient consistent with a TSH-producing pituitary adenoma (140). In another case, dynamic MRI imaging identified the tumor (141).

116

3.1.5

Meek and Smallridge

Treatment

Transsphenoidal surgical resection of the pituitary tumor is the treatment of choice for TSH producing pituitary tumors. Approximately 35% of patients can be cured with surgery alone, and earlier diagnosis improves the prognosis (132,133). 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 include euthyroidism with a normalized TRH test and absence of residual tumor on MRI (129,142). Antithyroid drugs and beta blockers should be used to restore the euthyroid state before surgery. Radiation therapy is used for incompletely resected pituitary tumor. Octreotide, 50 to 100 µg subcutaneously two to three times daily, has been successfully used to treat patients with TSH-producing pituitary tumors (143,144). The longacting somatostatin analogue lanreotide has also been used successfully to treat patients with TSH-producing tumors (145). Octreotide produces normalization of TSH in about 79% of cases, and in about one-half of cases there is tumor regression. In addition, octreotide alters the glycosylation pattern (and presumably the bioactivity) of serum TSH (146). Tachyphylaxis may develop in approximately one-quarter of patients, necessitating an increased octreotide dose (143). Approximately 10% of patients may escape from octreotide’s inhibitory effects on TSH suppression. Octreotide has also been used to restore euthyroidism in pregnancy without apparent effects on fetal development and thyroid function (147). Ablation of the thyroid with radioactive iodine or surgery should be avoided. 3.2 Thyroid Hormone Resistance 3.2.1

Introduction

Resistance to thyroid hormone is a heterogeneous syndrome in which there is a reduced response of tissues to thyroid hormone. Generalized thyroid hormone resistance is at one end of the spectrum of thyroid hormone resistance. These patients have a normal metabolism due to increased thyroid hormone levels maintained by TSH stimulation of thyroid hormone production. 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 but near normal peripheral tissue responsiveness to thyroid hormone. In these patients, there are clinical signs and symptoms of thyrotoxicosis that are TSH-mediated. 3.2.2

Epidemiology

The prevalence of generalized thyroid hormone resistance is unclear, but it is a rare disease. It was first described in 1967 (148). Pituitary resistance to thy-

Diagnosis and Treatment of Hyperthyroidism

117

roid hormone was first described in 1975 (149). Since that time, ⬎400 cases of thyroid hormone resistance have been reported. It occurs in males and females and has been reported in all races. The majority of cases of thyroid hormone resistance have generalized tissue resistance to thyroid hormone. Most cases of thyroid hormone resistance are familial, and inheritance is usually autosomal dominant. 3.2.3

Pathophysiology

Thyroid hormone resistance is most often due to a mutation in the thyroid hormone receptor–beta gene (TR-β) found on chromosome 3. Patients with thyroid hormone resistance are usually heterozygous for mutations that cluster within three areas of the thyroid hormone–binding domain (150,151). The ability of the mutant receptor proteins to bind thyroid hormone is reduced, and therefore the ability to effect gene expression is reduced. Analysis of patients with only pituitary resistance to thyroid hormone with consequent hyperthyroidism indicates that these individuals also are heterozygous for mutations in the hormone-binding region of the TR-β receptor (151,152). The same mutations in the TR-β gene in patients with pituitary resistance have 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 that is suggestive of pituitary thyroid hormone resistance. These observations suggest that pituitary and generalized thyroid hormone resistance may be a single genetic disorder with variable clinical or phenotypic expression. 3.2.4

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 in patients classified as having generalized resistance versus those thought to have pituitary thyroid hormone resistance. Attention deficit disorder, delayed speech development, lower IQ, shorter stature and lower weight, delayed bone age, and hearing loss have been found with higher frequency in patients with thyroid hormone resistance. There may be a higher frequency of ear, nose, and throat infections (150,153,154). A goiter is found commonly (65% to 90%) in patients with thyroid hormone resistance (150,151). Tachycardia and an increased frequency of arrhythmia have been found in some patients with thyroid hormone resistance. Increased levels of thyroid hormones, including T4 and T3, are found with inappropriately normal or increased levels of TSH. The 24-h 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 supraphysiological doses of thyroid hormone are suggestive of a TSH-producing pituitary adenoma. An increased

118

Meek and Smallridge

molar ratio of alpha subunit to TSH and a pituitary adenoma on MRI of the brain are diagnostic of a TSH-producing pituitary adenoma (155). 3.2.5

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. Supraphysiological doses of thyroid hormone caused regression of the pituitary gland back to normal size (156). Patients with pituitary resistance to thyroid hormone who have mildly symptomatic hyperthyroidism may be treated with beta-blocker therapy. Antithyroid drugs or radioactive iodine ablation of the thyroid have been used, but TSH levels rise dramatically and imaging studies of the pituitary may be needed periodically to monitor for the possibility of pituitary enlargement. Moderate doses of T3 (25 to 50 µg daily) over a period of several months can decrease TSH secretion, thyroid hormone levels, and clinical thyrotoxicosis (157) but are not often successful. d-Thyroxine has also been reported to be beneficial (158,159). Triiodothyroacetic acid (Triac) appears to be able to suppress TSH with minimal peripheral thyromimetic actions (160–162). Bromocriptine and octreotide have been used in a few cases to suppress TSH production (161,163,164). In 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. 4

HYPERTHYROIDISM OF EXTRATHYROID ORIGIN

4.1 Struma Ovarii Tumor 4.1.1

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 ⬎50% thyroid tissue or functioning thyroid tissue causing thyrotoxicosis is called a struma ovarii (165). 4.1.2

Epidemiology

Struma ovarii represents ⬍2% of ovarian teratomas, with peak frequency during the fifth decade of life. A recent review found struma ovarii in 5 of 1390 (0.4%) ovarian tumors (166). Struma ovarii tumors usually do not cause hyperthyroidism. One review reported that 3 of 41 patients (7%) with struma ovarii had clinical

Diagnosis and Treatment of Hyperthyroidism

119

symptoms and laboratory signs of hyperthyroidism found preoperatively (165). Hyperthyroidism was found in 8 of 25 patients with struma ovarii tumor in another review (167). 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% (168). 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 (169). 4.1.3

Pathophysiology

Struma ovarii and associated thyrotoxicosis is due to the presence of autonomous hyperfunctioning thyroid tissue within a teratoma. Struma ovarii tumors are unilateral in 90% of cases, with the left ovary more frequently involved (170). Most struma ovarii tumors are benign (167). However, it is sometimes difficult to determine if the thyroid tissue in the tumor is benign or malignant (165). Follicular carcinomas are more commonly reported than papillary carcinoma. Metastatic struma ovarii may spread to the peritoneum, intraabdominal nodes, bone, liver, lung, mediastinum and brain (167,169). Struma ovarii can be mixed with a carcinoid tumor and has been reported to occur in association with multiple endocrine neoplasia type IIA (171). 4.1.4

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 iodine. However, the thyroid has been reported to be enlarged in several reports (167,172,173). Some patients may present with a pelvic mass, and ascites may be present even in the absence of malignant struma ovarii (167). 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 (172). However, radioactive iodine uptake has been reported in a hemorrhagic ovarian cyst, which did not contain thyroid tissue (174). 4.1.5

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 (175), 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

120

Meek and Smallridge

radioactive iodine after thyroidectomy. Thyroid hormone treatment with TSH suppression is also recommended for metastatic struma ovarii. 4.2 Trophoblastic Tumors 4.2.1

Introduction

Molar pregnancy and trophoblastic tumors in males and females 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 (176). 4.2.2

Epidemiology

The prevalence of thyrotoxicosis in patients with trophoblastic tumors is unknown. One study involving 20 patients evaluated at a referral center during 1 year found that 5 of the patients had thyrotoxicosis (177). Another study found that 30 of 52 patients with gestational trophoblastic tumors had thyrotoxicosis (178). It has been estimated that 20% of women with hydatidiform moles have hyperthyroidism (179). Hydatiform mole occurs in about 1 in 1500 pregnancies in the United States and is about 10 times more common in Asian and Latin American countries (180). Choriocarcinoma occurs in 1 of 60,000 pregnancies. 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 (181–183). 4.2.3

Pathophysiology

Human chorionic gonadotrophin 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 human chorionic gonadotrophin 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 human chorionic gonadotrophin 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 that are secreted by trophoblastic tumors have greater thyrotrophic activity than hCG secreted by normal placental tissue. Removal of the tumor, and therefore the hCG, is associated with rapid resolution of the hyperthyroidism. 4.2.4

Diagnosis

Women with trophoblastic tumors may or may not have clinical evidence of hyperthyroidism. The nausea, vomiting, and toxemia that occur in molar preg-

Diagnosis and Treatment of Hyperthyroidism

121

nancy may obscure hyperthyroidism. The thyroid gland is either normal in size or slightly enlarged. Chorionic gonadotrophin is secreted in large amounts by trophoblastic tissue and serves as a marker for the tumor. The hCG levels exceed 100 U/mL in patients with hyperthyroidism and often exceed 300 U/mL (184–187). 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 (188). The uptake of radioactive iodine is increased (189). 4.2.5

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 can be used to achieve remission of metastatic choriocarcinoma with associated hyperthyroidism. The prognosis for men with testicular choriocarcinoma and hyperthyroidism is usually poor. Medical therapy for hyperthyroidism due to trophoblastic disease may include iodine, 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. 4.3 Metastatic Thyroid Cancer and Hyperthyroidism 4.3.1

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. 4.3.2

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 (190,191). Eightyfive percent of patients with hyperfunctioning thyroid cancer are older than 40 years. The female-to-male ratio is about 3–5 to 1. 4.3.3

Pathophysiology

Malignant thyroid tissue is functionally less efficient than normal thyroid tissue (192). The estimated efficacy of the iodine-concentrating ability of functioning

122

Meek and Smallridge

metastases is about 10% of normal thyroid tissue (193,194). The inefficient thyroid hormone production is due in part to lower iodine trapping by tumor tissue and in part to abnormal thyroglobulin synthesis. There is evidence that expression of the TSH receptor in malignant thyroid tissue may be absent or low (195). Therefore, many of the cases of thyrotoxicosis caused by thyroid cancer are due to large, bulky metastatic tumors, often weighing 2 to 3 kg (191). Follicular thyroid cancer is the most common thyroid malignancy reported to cause hyperthyroidism (190,191,196), but papillary thyroid cancer may also cause hyperthyroidism. Patients with functioning metastases more commonly come from areas of low iodine intake. Thyroglobulin levels have been reported to be higher in patients with functioning metastases, but this finding did not reach statistical significance (190). Finally, the time to metastasis and the 10-year survival rate appear to be equal for metastatic follicular carcinoma with or without thyrotoxicosis (190,191,196). The discovery of metastases precedes or occurs simultaneously with the onset of hyperthyroidism (196). Anaplastic thyroid cancer and thyroid lymphoma have been reported to cause thyrotoxicosis with a low uptake of radioactive iodine (197,198). 4.3.4

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 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 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 (191,199,200). 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. 4.3.5

Treatment

Treatment of metastatic functioning thyroid cancer usually consists of radioactive I therapy. The usual dose of radioactive iodine ranges from 100 to 200 mCi. Treatment with radioactive iodine may exacerbate the thyrotoxicosis (201). Therefore, radioactive iodine should be administered with caution, and patients are often treated prophylactically with beta-adrenergic blocking agents. If normal

131

Diagnosis and Treatment of Hyperthyroidism

123

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, isolated metastases are producing the thyrotoxicosis, surgical resection may be the best treatment option. REFERENCES 1. Woolner JB, McConahey WM, Beahrs OH. Granulomatous thyroiditis (de Quervain’s thyroiditis). J Clin Endocrinol Metab 1957; 17:1202–1221. 2. Nordyke RA, Gilbert FI Jr, Lew C. Painful subacute thyroiditis in Hawaii. West J Med 1991; 155:61–63. 3. Martino E, Buratti L, Bartalena L, Mariotti S, Cupini C, Aghini-Lombardi F, Pinchera A. High prevalence of subacute thyroiditis during summer season in Italy. J Endocrinol Invest 1987; 10:321–323. 4. Saito S, Sakurada T, Yamamoto M, Yamaguchi T, Yoshida K. Subacute thyroiditis: observations on 98 cases for the last 14 years. Tohoku J Exp Med 1974; 113:141– 147. 5. Hay ID. Thyroiditis: a clinical update. Mayo Clin Proc 1985; 60:836–843. 6. Hamburger JI. The various presentations of thyroiditis. Diagnostic considerations. Ann Intern Med 1986; 104:219–224. 7. Singer PA. Thyroiditis: acute, subacute, and chronic. Med Clin North Am 1991; 75:61–77. 8. Hung W. Mumps thyroiditis and hypothyroidism. J Pediatr 1969; 74:611–613. 9. Robertson WS. Acute inflammation of the thyroid gland. Lancet 1911; 1:930–931. 10. Hintze F, Fortelius P, Railo J. Epidemic thyroiditis. Acta Endocrinol 1964; 45: 381–401. 11. Swann N. Acute thyroiditis: five cases associated with adenovirus infection. Metabolism 1964; 13:908–910. 12. Shumway M, Davis P. Cat-scratch thyroiditis treated with thyrotrophic hormone. J Clin Endocrinol Metab 1954; 14:742–743. 13. Bech K, Nerup J, Thomsen M, Platz P, Ryder LP, Svejgaard A, Sierbaek-Nielsen K, Molholm Hansen JE. Subacute thyroiditis de Quervain: a disease associated with HLA-B antigen. Acta Endocrinol 1977; 86:504–509. 14. Volpe R, Johnston MW. Subacute thyroiditis: a disease commonly mistaken for pharyngitis. Can Med Assoc J 1957; 77:297–307. 15. Nyulassy S, Hnilica P, Buc M, Guman M, Hirschova V, Stefanovic J. Subacute (de Quervain’s) thyroiditis: association with HLA-Bw35 antigen and abnormalities of the complement system, immunoglobulins and other serum proteins. J Clin Endocrinol Metab 1977; 45:270–274. 16. Ikenoue H, Okamura K, Kuroda T, Sato K, Yoshinari M, Fujishima M. Thyroid amyloidosis with recurrent subacute thyroiditis-like syndrome. J Clin Endocrinol Metab 1988; 67:41–45. 17. Mizukami Y, Michigishi T, Kawato M, Matsubara F. Immunohistochemical and ultrastructural study of subacute thyroiditis, with special reference to multinucleated giant cells. Hum Pathol 1987; 18:929–935.

124

Meek and Smallridge

18. Sanders LR, Moreno AJ, Pittman DL, Jones JD, Spicer MJ, Tracy KP. Painless giant cell thyroiditis diagnosed by fine needle aspiration and associated with intense thyroidal uptake of gallium. Am J Med 1986; 80:971–975. 19. Greene JN. Subacute thyroiditis. Am J Med 1971; 51:97–108. 20. Rotenberg Z, Weinberger I, Fuchs J, Maller S, Agmon J. Euthyroid atypical subacute thyroiditis simulating systemic or malignant disease. Arch Intern Med 1986; 146:105–107. 21. de Bruin TW, Riekhoff FP, de Boer JJ. An outbreak of thyrotoxicosis due to atypical subacute thyroiditis. J Clin Endocrinol Metab 1990; 70:396–402. 22. Weihl AC, Daniels GH, Ridgway EC, Maloof F. Thyroid function tests during the early phase of subacute thyroiditis. J Clin Endocrinol Metab 1977; 44:1107–1114. 23. Larsen PR. Serum triiodothyronine, thyroxine, and thyrotropin during hyperthyroid, hypothyroid, and recovery phases of subacute nonsuppurative thyroiditis. Metabolism 1974; 23:467–471. 24. Van Herle AJ, Vassart G, Dumont JE. Control of thyroglobulin synthesis and secretion (first of two parts). N Engl J Med 1979; 301:239–249. 25. Volpe R. The management of subacute (de Quervain’s) thyroiditis. Thyroid 1993; 3:253–255. 26. Yamamoto M, Saito S, Sakurada T, Fukazawa H, Yoshida K, Kaise K, Kaise N, Nomura T, Itagaki Y, Yonemitsu K. Effect of prednisolone and salicylate on serum thyroglobulin level in patients with subacute thyroiditis. Clin Endocrinol (Oxf) 1987; 27:339–344. 27. Schneeberg NG. Silent thyroiditis (letter). Arch Intern Med 1983; 143:2214. 28. Nikolai TF, Coombs GJ, McKenzie AK. Lymphocytic thyroiditis with spontaneously resolving hyperthyroidism and subacute thyroiditis: long-term follow-up. Arch Intern Med 1981; 141:1455–1458. 29. Nikolai TF, Brosseau J, Kettrick MA, Roberts R, Beltaos E. Lymphocytic thyroiditis with spontaneously resolving hyperthyroidism (silent thyroiditis). Arch Intern Med 1980; 140:478–482. 30. Gorman CA, Duick DS, Woolner LB, Wahner HW. Transient hyperthyroidism in patients with lymphocytic thyroiditis. Mayo Clin Proc 1978; 53:359–365. 31. Parker M, Klein I, Fishman LM, Levey GS. Silent thyrotoxic thyroiditis in association with chronic adrenocortical insufficiency. Arch Intern Med 1980; 140:1108– 1109. 32. Nagai K, Sakata S, Takuno H, Tanabashi S, Kametani M, Tokimitsu N, Miura K. A case of silent thyroiditis associated with idiopathic thrombocytopenic purpura. Endocrinol Jpn 1988; 35:791–794. 33. Sakata S, Nagai K, Shibata T, Kamikubo K, Tokimitsu N. A case of rheumatoid arthritis associated with silent thyroiditis. J Endocrinol Invest 1992; 15:377–380. 34. Magaro M, Zoli A, Altomonte L, Mirone L, La Sala L, Barini A, Scuderi F. The association of silent thyroiditis with active systemic lupus erythematosus. Clin Exp Rheumatol 1992; 10:67–70. 35. Farid NR, Hawe BS, Walfish PG. Increased frequency of HLA-DR3 and 5 in the syndromes of painless thyroiditis with transient thyrotoxicosis: evidence for an autoimmune aetiology. Clin Endocrinol (Oxf) 1983; 19:699–704.

Diagnosis and Treatment of Hyperthyroidism

125

36. Woolf PD. Transient painless thyroiditis with hyperthyroidism: a variant of lymphocytic thyroiditis? Endocr Rev 1980; 1:411–420. 37. Smallridge RC, De Keyser FM, Van Herle AJ, Butkus NE, Wartofsky L. Thyroid iodine content and serum thyroglobulin: cues to the natural history of destructioninduced thyroiditis. J Clin Endocrinol Metab 1986; 62:1213–1219. 38. Arem R, Munipalli B. Ipodate therapy in patients with severe destruction-induced thyrotoxicosis. Arch Intern Med 1996; 156:1752–1757. 39. Nikolai TF, Coombs GJ, McKenzie AK, Miller RW, Weir GJ Jr. Treatment of lymphocytic thyroiditis with spontaneously resolving hyperthyroidism (silent thyroiditis). Arch Intern Med 1982; 142:2281–2283. 40. Smallridge RC. Postpartum thyroid dysfunction: a frequently undiagnosed endocrine disorder. Endocrinologist 1996; 1:44–50. 41. Fung HY, Kologlu M, Collison K, John R, Richards CJ, Hall R, McGregor AM. Postpartum thyroid dysfunction in Mid Glamorgan. Br Med J (Clin Res Ed) 1988; 296:241–244. 42. Walfish PG, Meyerson J, Provias JP, Vargas MT, Papsin FR. Prevalence and characteristics of post-partum thyroid dysfunction: results of a survey from Toronto, Canada. J Endocrinol Invest 1992; 15:265–272. 43. Amino N, Mori H, Iwatani Y, Tanizawa O, Kawashima M, Tsuge I, Ibaragi K, Kumahara Y, Miyai K. High prevalence of transient post-partum thyrotoxicosis and hypothyroidism. N Engl J Med 1982; 306:849–852. 44. Gerstein HC. How common is postpartum thyroiditis? A methodologic overview of the literature. Arch Intern Med 1990; 150:1397–1400. 45. Nikolai TF, Turney SL, Roberts RC. Postpartum lymphocytic thyroiditis: prevalence, clinical course, and long-term follow-up. Arch Intern Med 1987; 147:221– 224. 46. Jansson R, Bernander S, Karlsson A, Levin K, Nilsson G. Autoimmune thyroid dysfunction in the postpartum period. J Clin Endocrinol Metab 1984; 58:681–687. 47. Freeman R, Rosen H, Thysen B. Incidence of thyroid dysfunction in an unselected postpartum population. Arch Intern Med 1986; 146:1361–1364. 48. Rajatanavin R, Chailurkit LO, Tirarungsikul K, Chalayondeja W, Jittivanich U, Puapradit W. Postpartum thyroid dysfunction in Bangkok: a geographical variation in the prevalence. Acta Endocrinol (Copenh) 1990; 122:283–287. 49. Gerstein HC. Incidence of postpartum thyroid dysfunction in patients with type I diabetes mellitus. Ann Intern Med 1993; 118:419–423. 50. Alvarez-Marfany M, Roman SH, Drexler AJ, Robertson C, Stagnaro-Green A. Long-term prospective study of postpartum thyroid dysfunction in women with insulin dependent diabetes mellitus. J Clin Endocrinol Metab 1994; 79:10–16. 51. Bech K, Hoier-Madsen M, Feldt-Rasmussen U, Jensen BM, Molsted-Pedersen L, Kuhl C. Thyroid function and autoimmune manifestations in insulin-dependent diabetes mellitus during and after pregnancy. Acta Endocrinol (Copenh) 1991; 124: 534–539. 52. Stagnaro-Green A. Post-miscarriage thyroid dysfunction. Obstet Gynecol 1992; 80: 490–492. 53. Hayslip CC, Fein HG, O’Donnell VM, Friedman DS, Klein TA, Smallridge RC.

126

54.

55.

56.

57.

58.

59. 60.

61. 62.

63. 64. 65.

66.

67. 68. 69.

Meek and Smallridge The value of serum antimicrosomal antibody testing in screening for symptomatic postpartum thyroid dysfunction. Am J Obstet Gynecol 1988; 159:203–209. Solomon BL, Fein HG, Smallridge RC. Usefulness of antimicrosomal antibody titers in the diagnosis and treatment of postpartum thyroiditis. J Fam Pract 1993; 36:177–182. Harris B, Othman S, Davies JA, Weppner GJ, Richards CJ, Newcombe RG, Lazarus JH, Parkes AB, Hall R, Phillips DI. Association between postpartum thyroid dysfunction and thyroid antibodies and depression. Br Med J 1992; 305:152–156. Stagnaro-Green A, Roman SH, Cobin RH, el-Harazy E, Wallenstein S, Davies TF. A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction. J Clin Endocrinol Metab 1992; 74:645–653. Tachi J, Amino N, Tamaki H, Aozasa M, Iwatani Y, Miyai K. Long term followup and HLA association in patients with postpartum hypothyroidism. J Clin Endocrinol Metab 1988; 66:480–484. Vargas MT, Briones-Urbina R, Gladman D, Papsin FR, Walfish PG. Antithyroid microsomal autoantibodies and HLA-DR5 are associated with postpartum thyroid dysfunction: evidence supporting an autoimmune pathogenesis. J Clin Endocrinol Metab 1988; 67:327–333. Kologlu M, Fung H, Darke C, Richards CJ, Hall R, McGregor AM. Postpartum thyroid dysfunction and HLA status. Eur J Clin Invest 1990; 20:56–60. Jansson R, Safwenberg J, Dahlberg PA. Influence of the HLA-DR4 antigen and iodine status on the development of autoimmune postpartum thyroiditis. J Clin Endocrinol Metab 1985; 60:168–173. Kuijpens JL, Pop VJ, Vader HL, Drexhage HA, Wiersinga WM. Prediction of postpartum thyroid dysfunction: can it be improved? Eur J Endocrinol 1998; 139:36–43. Rasmussen NG, Hornnes PJ, Hoier-Madsen M, Feldt-Rasmussen U, Hegedus L. Thyroid size and function in healthy pregnant women with thyroid autoantibodies: relation to development of postpartum thyroiditis. Acta Endocrinol (Copenh) 1990; 123:395–401. Lazarus JH, Hall R, Othman S, Parkes AB, Richards CJ, McCulloch B, Harris B. The clinical spectrum of postpartum thyroid disease. Q J Med 1996; 89:429–435. Lervang HH, Pryds O, Ostergaard Kristensen HP. Thyroid dysfunction after delivery: incidence and clinical course. Acta Med Scand 1987; 222:369–374. Adams H, Jones MC, Othman S, Lazarus JH, Parkes AB, Hall R, Phillips DI, Richards CJ. The sonographic appearances in postpartum thyroiditis. Clin Radiol 1992; 45:311–315. Othman S, Phillips DI, Parkes AB, Richards CJ, Harris B, Fung H, Darke C, John R, Hall R, Lazarus JH. A long-term follow-up of postpartum thyroiditis. Clin Endocrinol (Oxf) 1990; 32:559–564. Lazarus JH, Othman S. Thyroid disease in relation to pregnancy. Clin Endocrinol (Oxf) 1991; 34:91–98. Smallridge RC. Postpartum thyroid disease. A model of immunologic dysfunction. Clin Appl Immunol Rev 2000; 1:89–103. Berger SA, Zonszein J, Villamena P, Mittman N. Infectious diseases of the thyroid gland. Rev Infect Dis 1983; 5:108–122.

Diagnosis and Treatment of Hyperthyroidism

127

70. Das DK, Pant CS, Chachra KL, Gupta AK. Fine needle aspiration cytology diagnosis of tuberculous thyroiditis: a report of eight cases. Acta Cytol 1992; 36:517– 522. 71. Gandhi RT, Tollin SR, Seely EW. Diagnosis of Candida thyroiditis by fine needle aspiration. J Infect 1994; 28:77–81. 72. Guttler R, Singer PA, Axline SG, Greaves TS, McGill JJ. Pneumocystis carinii thyroiditis: report of three cases and review of the literature. Arch Intern Med 1993; 153:393–396. 73. Hatabu H, Kasagi K, Yamamoto K, Iida Y, Misaki T, Hidaka A, Endo K, Konishi J. Acute suppurative thyroiditis associated with piriform sinus fistula: sonographic findings. Am J Roentgenol 1990; 155:845–847. 74. Miyauchi A, Matsuzuka F, Kuma K, Takai S. Piriform sinus fistula: an underlying abnormality common in patients with acute suppurative thyroiditis. World J Surg 1990; 14:400–405. 75. Nieuwland Y, Tan KY, Elte JW. Miliary tuberculosis presenting with thyrotoxicosis. Postgrad Med J 1992; 68:677–679. 76. Bernard PJ, Som PM, Urken ML, Lawson W, Biller HF. The CT findings of acute thyroiditis and acute suppurative thyroiditis. Otolaryngol Head Neck Surg 1988; 99:489–493. 77. Maxon HR, Thomas SR, Saenger EL, Buncher CR, Kereiakes JG. Ionizing irradiation and the induction of clinically significant disease in the human thyroid gland. Am J Med 1977; 63:967–978. 78. Nishiyama K, Kozuka T, Higashihara T, Miyauchi K, Okagawa K. Acute radiation thyroiditis. Int J Radiat Oncol Biol Phys 1996; 36:1221–1224. 79. Blitzer JB, Paolozzi FP, Gottlieb AJ, Zamkoff KW, Chung CT. Thyrotoxic thyroiditis after radiotherapy for Hodgkin’s disease. Arch Intern Med 1985; 145:1734– 1735. 80. Aizawa T, Watanabe T, Suzuki N, Suzuki S, Miyamoto T, Ichikawa K, Oguchi M, Hashizume K. Radiation-induced painless thyrotoxic thyroiditis followed by hypothyroidism: a case report and literature review. Thyroid 1998; 8:273–275. 81. Petersen M, Keeling CA, McDougall IR. Hyperthyroidism with low radioiodine uptake after head and neck irradiation for Hodgkin’s disease. J Nucl Med 1989; 30:255–257. 82. Kobayashi A, Kuma K, Matsuzuka F, Hirai K, Fukata S, Sugawara M. Thyrotoxicosis after needle aspiration of thyroid cyst. J Clin Endocrinol Metab 1992; 75:21– 24. 83. Calle RA, Cohen KL. Transient thyroiditis due to surgical trauma. Am J Med 1993; 95:546–548. 84. Leckie RG, Buckner AB, Bornemann M. Seat belt-related thyroiditis documented with thyroid Tc-99m pertechnetate scans. Clin Nucl Med 1992; 17:859–860. 85. Stanbury JB, Ermans AE, Bourdoux P, Todd C, Oken E, Tonglet R, Vidor G, Braverman LE, Medeiros-Neto G. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998; 8:83–100. 86. Fradkin JE, Wolff J. Iodide-induced thyrotoxicosis. Medicine (Baltimore) 1983; 62:1–20. 87. Livadas DP, Koutras DA, Souvatzoglou A, Beckers C. The toxic effect of small

128

88.

89. 90. 91. 92. 93.

94. 95. 96. 97. 98.

99.

100. 101.

102.

103. 104.

105.

Meek and Smallridge iodine supplements in patients with autonomous thyroid nodules. Clin Endocrinol (Oxf) 1977; 7:121–127. Leger AF, Massin JP, Laurent MF, Vincens M, Auriol M, Helal OB, Chomette G, Savoie JC. Iodine-induced thyrotoxicosis: analysis of eighty-five consecutive cases. Eur J Clin Invest 1984; 14:449–455. Shilo S, Hirsch HJ. Iodine-induced hyperthyroidism in a patient with a normal thyroid gland. Postgrad Med J 1986; 62:661–662. Becker CB, Gordon JM. Iodinated glycerol and thyroid dysfunction: four cases and a review of the literature. Chest 1993; 103:188–192. Huseby JS, Bennett SW, Hagensee ME. Hyperthyroidism induced by iodinated glycerol. Am Rev Respir Dis 1991; 144:1403. Bryant WP, Zimmerman D. Iodine-induced hyperthyroidism in a newborn. Pediatrics 1995; 95:434–436. Jacobson JM, Hankins GV, Murray JM, Young RL. Self-limited hyperthyroidism following intravaginal iodine administration. Am J Obstet Gynecol 1981; 140:472– 473. Martin FI, Tress BW, Colman PG, Deam DR. Iodine-induced hyperthyroidism due to nonionic contrast radiography in the elderly. Am J Med 1993; 95:78–82. Vagenakis AG, Wang CA, Burger A, Maloof F, Braverman LE, Ingbar SH. Iodideinduced thyrotoxicosis in Boston. N Engl J Med 1972; 287:523–527. Rao RH, McCready VR, Spathis GS. Iodine kinetic studies during amiodarone treatment. J Clin Endocrinol Metab 1986; 62:563–568. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997; 126:63–73. Martino E, Safran M, Aghini-Lombardi F, Rajatanavin R, Lenziardi M, Fay M, Pacchiarotti A, Aronin N, Macchia E, Haffajee C. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984; 101: 28–34. Nademanee K, Singh BN, Callahan B, Hendrickson JA, Hershman JM. Amiodarone, thyroid hormone indexes, and altered thyroid function: long-term serial effects in patients with cardiac arrhythmias. Am J Cardiol 1986; 58:981–986. Harjai KJ, Licata AA. Amiodarone induced hyperthyroidism: a case series and brief review of literature. Pacing Clin Electrophysiol 1996; 19:1548–1554. Trip MD, Wiersinga W, Plomp TA. Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med 1991; 91:507– 511. Bartalena L, Grasso L, Brogioni S, Aghini-Lombardi F, Braverman LE, Martino E. Serum interleukin-6 in amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 1994; 78:423–427. Seminara S, Daniels G. Amiodarone and the thyroid. Endoc Pract 1998; 4:48–57. Chiovato L, Martino E, Tonacchera M, Santini F, Lapi P, Mammoli C, Braverman LE, Pinchera A. Studies on the in vitro cytotoxic effect of amiodarone. Endocrinology 1994; 134:2277–2282. Roti E, Minelli R, Gardini E, Bianconi L, Braverman LE. Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone: a possible consequence of a destructive process in the thyroid. Arch Intern Med 1993; 153:886–892.

Diagnosis and Treatment of Hyperthyroidism

129

106. Bartalena L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996; 81:2930–2933. 107. Martino E, Aghini-Lombardi F, Lippi F, Baschieri L, Safran M, Braverman LE, Pinchera A. Twenty-four hour radioactive iodine uptake in 35 patients with amiodarone associated thyrotoxicosis. J Nucl Med 1985; 26:1402–1407. 108. Martino E, Bartalena L, Mariotti S, Aghini-Lombardi F, Ceccarelli C, Lippi F, Piga M, Loviselli A, Braverman L, Safran M. Radioactive iodine thyroid uptake in patients with amiodarone-iodine-induced thyroid dysfunction. Acta Endocrinol (Copenh) 1988; 119:167–173. 109. Bauters C, D’Herbomez M, Nocaudie M, Decoulx M, Marchandise X, Wemeau JL. Interleukin-6 and thyroid radioactive iodine uptake in patients with amiodaroneinduced thyrotoxicosis. J Endocrinol Invest 1999; 22(Suppl to No 6):94. 110. Bogazzi F, Bartalena L, Brogioni S, Mazzeo S, Vitti P, Burelli A, Bartolozzi C, Martino E. Color flow doppler sonography rapidly differentiates type I and type II amiodarone-induced thyrotoxicosis. Thyroid 1997; 7:541–545. 111. Jonckheer MH, Blockx P, Broeckaert I, Cornette C, Beckers C. ‘‘Low T3 syndrome’’ in patients chronically treated with an iodine-containing drug, amiodarone. Clin Endocrinol (Oxf) 1978; 9:27–35. 112. Singh BN, Nademanee K. Amiodarone and thyroid function: clinical implications during antiarrhythmic therapy. Am Heart J 1983; 106:857–869. 113. Dickstein G, Shechner C, Adawi F, Kaplan J, Baron E, Ish-Shalom S. Lithium treatment in amiodarone-induced thyrotoxicosis. Am J Med 1997; 102:454–458. 114. Brennan MD, van Heerden JA, Carney JA. Amiodarone-associated thyrotoxicosis (AAT): experience with surgical management. Surgery 1987; 102:1062–1067. 115. Farwell AP, Abend SL, Huang SK, Patwardhan NA, Braverman LE. Thyroidectomy for amiodarone-induced thyrotoxicosis. JAMA 1990; 263:1526–1528. 116. Koh LK, Greenspan FS, Yeo PP. Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature. Thyroid 1997; 7:891– 896. 117. Lisker-Melman M, Di Bisceglie AM, Usala SJ, Weintraub B, Murray LM, Hoofnagle JH. Development of thyroid disease during therapy of chronic viral hepatitis with interferon alfa. Gastroenterology 1992; 102:2155–2160. 118. Preziati D, La Rosa L, Covini G, Marcelli R, Rescalli S, Persani L, Del Ninno E, Meroni PL, Colombo M, Beck-Peccoz P. Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a. Eur J Endocrinol 1995; 132:587–593. 119. Vialettes B, Guillerand MA, Viens P, Stoppa AM, Baume D, Sauvan R, Pasquier J, San Marco M, Olive D, Maraninchi D. Incidence rate and risk factors for thyroid dysfunction during recombinant interleukin-2 therapy in advanced malignancies. Acta Endocrinol (Copenh) 1993; 129:31–38. 120. Tran A, Quaranta JF, Benzaken S, Thiers V, Chau HT, Hastier P, Regnier D, Dreyfus G, Pradier C, Sadoul JL. High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy. Hepatology 1993; 18:253–257. 121. Baudin E, Marcellin P, Pouteau M, Colas-Linhart N, Le Floch JP, Lemmonier C,

130

122.

123. 124. 125.

126.

127.

128.

129.

130. 131. 132. 133. 134. 135.

136. 137.

138.

Meek and Smallridge Benhamou JP, Bok B. Reversibility of thyroid dysfunction induced by recombinant alpha interferon in chronic hepatitis C. Clin Endocrinol (Oxf) 1993; 39:657–661. Barclay ML, Brownlie BE, Turner JG, Wells JE. Lithium associated thyrotoxicosis: a report of 14 cases, with statistical analysis of incidence. Clin Endocrinol (Oxf) 1994; 40:759–764. McDermott MT, Burman KD, Hofeldt FD, Kidd GS. Lithium-associated thyrotoxicosis. Am J Med 1986; 80:1245–1248. Cohen JHD, Ingbar SH, Braverman LE. Thyrotoxicosis due to ingestion of excess thyroid hormone. Endocr Rev 1989; 10:113–124. Kinney JS, Hurwitz ES, Fishbein DB, Woolf PD, Pinsky PF, Lawrence DN, Anderson LJ, Holmes GP, Wilson CK, Loschen DJ. Community outbreak of thyrotoxicosis: epidemiology, immunogenetic characteristics, and long-term outcome. Am J Med 1988; 84:10–18. Hedberg CW, Fishbein DB, Janssen RS, Meyers B, McMillen JM, MacDonald KL, White KE, Huss LJ, Hurwitz ES, Farhie JR. An outbreak of thyrotoxicosis caused by the consumption of bovine thyroid gland in ground beef. N Engl J Med 1987; 316:993–998. Mariotti S, Martino E, Cupini C, Lari R, Giani C, Baschieri L, Pinchera A. Low serum thyroglobulin as a clue to the diagnosis of thyrotoxicosis factitia. N Engl J Med 1982; 307:410–412. Bouillon R, Verresen L, Staels F, Bex M, De Vos P, De Roo M. The measurement of fecal thyroxine in the diagnosis of thyrotoxicosis factitia. Thyroid 1993; 3:101– 103. Losa M, Giovanelli M, Persani L, Mortini P, Faglia G, Beck-Peccoz P. Criteria of cure and follow-up of central hyperthyroidism due to thyrotropin-secreting pituitary adenomas. J Clin Endocrinol Metab 1996; 81:3084–3090. Wilson CB. A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J Neurosurg 1984; 61:814–833. Mindermann T, Wilson CB. Thyrotropin-producing pituitary adenomas. J Neurosurg 1993; 79:521–527. Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC, Weintraub BD. Thyrotropin-secreting pituitary tumors. Endocr Rev 1996; 17:610–638. Smallridge RC. Thyrotropin-secreting pituitary tumors. Endocrinol Metab Clin North Am 1987; 16:765–792. Cooper DS, Wenig BM. Hyperthyroidism caused by an ectopic TSH-secreting pituitary tumor. Thyroid 1996; 6:337–343. Gesundheit N, Petrick PA, Nissim M, Dahlberg PA, Doppman JL, Emerson CH, Braverman LE, Oldfield EH, Weintraub BD. Thyrotropin-secreting pituitary adenomas: clinical and biochemical heterogeneity: case reports and follow-up of nine patients. Ann Intern Med 1989; 111:827–835. Weintraub B, Gershengorn M, Kourides E, Fein H. Inappropriate secretion of thyroid-stimulating hormone. Ann Intern Med 1981; 95:339–351. Kourides IA, Ridgway EC, Weintraub BD, Bigos ST, Gershengorn MC, Maloof F. Thyrotropin-induced hyperthyroidism: use of alpha and beta subunit levels to identify patients with pituitary tumors. J Clin Endocrinol Metab 1977; 45:534–543. Smallridge RC, Smith CE. Hyperthyroidism due to thyrotropin-secreting pituitary

Diagnosis and Treatment of Hyperthyroidism

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150. 151.

131

tumors: diagnostic and therapeutic considerations. Arch Intern Med 1983; 143: 503–507. Beck-Peccoz P, Roncoroni R, Mariotti S, Medri G, Marcocci C, Brabant G, Forloni F, Pinchera A, Faglia G. Sex hormone-binding globulin measurement in patients with inappropriate secretion of thyrotropin (IST): evidence against selective pituitary thyroid hormone resistance in nonneoplastic IST. J Clin Endocrinol Metab 1990; 71:19–25. Frank SJ, Gesundheit N, Doppman JL, Miller DL, Merriam GR, Oldfield EH, Weintraub BD. Preoperative lateralization of pituitary microadenomas by petrosal sinus sampling: utility in two patients with non-ACTH-secreting tumors. Am J Med 1989; 87:679–682. Smallridge RC, Czervionke LF, Fellows D, Bernet VF. Corticotropin- and thyrotropin-secreting microadenomas: identification by dynamic magnetic resonance imaging. Mayo Clinic Proc 2000; 75:521–528. Brucker-Davis F, Oldfield EH, Skarulis MC, Doppman JL, Weintraub BD. Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab 1999; 84:476–486. 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; 119:236–240. Comi RJ, Gesundheit N, Murray L, Gorden P, Weintraub BD. Response of thyrotropin-secreting pituitary adenomas to a long-acting somatostatin analogue. N Engl J Med 1987; 317:12–17. Gancel A, Vuillermet P, Legrand A, Catus F, Thomas F, Kuhn JM. Effects of a slow-release formulation of the new somatostatin analogue lanreotide in TSHsecreting pituitary adenomas. Clin Endocrinol (Oxf) 1994; 40:421–428. Francis TB, Smallridge RC, Kane J, Magner JA. Octreotide changes serum thyrotropin (TSH) glycoisomer distribution as assessed by lectin chromatography in a TSH macroadenoma patient. J Clin Endocrinol Metab 1993; 77:183–187. Caron P, Gerbeau C, Pradayrol L, Simonetta C, Bayard F. Successful pregnancy in an infertile woman with a thyrotropin-secreting macroadenoma treated with somatostatin analog (octreotide). J Clin Endocrinol Metab 1996; 81:1164– 1168. 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; 27:279–294. 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; 56:633–642. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993; 14:348–399. Adams M, Matthews C, Collingwood TN, Tone Y, Beck-Peccoz P, Chatterjee KK. Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone: identification of thirteen novel mutations in the thyroid hormone receptor beta gene. J Clin Invest 1994; 94:506–515.

132

Meek and Smallridge

152. Mixson AJ, Renault JC, Ransom S, Bodenner DL, Weintraub BD. Identification of a novel mutation in the gene encoding the beta-triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone. Clin Endocrinol (Oxf) 1993; 38:227–234. 153. Brucker-Davis F, Skarulis MC, Grace MB, Benichou J, Hauser P, Wiggs E, Weintraub BD. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone: the National Institutes of Health Prospective Study. Ann Intern Med 1995; 123:572–583. 154. Brucker-Davis F, Skarulis MC, Pikus A, Ishizawar D, Mastroianni MA, Koby M, Weintraub BD. Prevalence and mechanisms of hearing loss in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 1996; 81:2768–2772. 155. Beck-Peccoz P, Persani L, Faglia G. Glycoprotein hormone alpha subunit in pituitary adenomas. Trends Endocrinol Metab 1992; 3:41–45. 156. Gurnell M, Rajanayagam O, Barbar I, Jones MK, Chatterjee VK. Reversible pituitary enlargement in the syndrome of resistance to thyroid hormone. Thyroid 1998; 8:679–682. 157. Rosler A, Litvin Y, Hage C, Gross J, Cerasi E. Familial hyperthyroidism due to inappropriate thyrotropin secretion successfully treated with triiodothyronine. J Clin Endocrinol Metab 1982; 54:76–82. 158. Hamon P, Bovier-Lapierre M, Robert M, Peynaud D, Pugeat M, Orgiazzi J. Hyperthyroidism due to selective pituitary resistance to thyroid hormones in a 15-monthold boy: efficacy of d-thyroxine therapy. J Clin Endocrinol Metab 1988; 67:1089– 1093. 159. Dorey F, Strauch G, Gayno JP. Thyrotoxicosis due to pituitary resistance to thyroid hormones: successful control with D thyroxine: a study in three patients. Clin Endocrinol (Oxf) 1990; 32:221–228. 160. Beck-Peccoz P, Piscitelli G, Cattaneo MG, Faglia G. Successful treatment of hyperthyroidism due to nonneoplastic pituitary TSH hypersecretion with 3,5,3′triiodothyroacetic acid (TRIAC). J Endocrinol Invest 1983; 6:217–223. 161. Salmela PI, Wide L, Juustila H, Ruokonen A. Effects of thyroid hormones (T4, T3), bromocriptine and Triac on inappropriate TSH hypersecretion. Clin Endocrinol (Oxf) 1988; 28:497–507. 162. Darendeliler F, Bas F. Successful therapy with 3,5,3′-triiodothyroacetic acid (TRIAC) in pituitary resistance to thyroid hormone. J Pediatr Endocrinol Metab 1997; 10:535–538. 163. Beck-Peccoz P, Mariotti S, Guillausseau PJ, Medri G, Piscitelli G, Bertoli A, Barbarino A, Rondena M, Chanson P, Pinchera A. Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with the somatostatin analog SMS 201– 995. J Clin Endocrinol Metab 1989; 68:208–214. 164. Connell JM, McCruden DC, Davies DL, Alexander WD. Bromocriptine for inappropriate thyrotropin secretion (letter). Ann Intern Med 1982; 96:251–252. 165. Devaney K, Snyder R, Norris HJ, Tavassoli FA. Proliferative and histologically malignant struma ovarii: a clinicopathologic study of 54 cases. Int J Gynecol Pathol 1993; 12:333–343. 166. Dunzendorfer T, deLas Morenas A, Kalir T, Levin RM. Struma ovarii and hyperthyroidism. Thyroid 1999; 9:499–502.

Diagnosis and Treatment of Hyperthyroidism

133

167. Kempers RD, Dockerty MB, Hoffman DL, Bartholomew LG. Struma ovarii— ascitic, hyperthyroid, and asymptomatic syndromes. Ann Intern Med 1970; 72: 883–893. 168. Gould SF, Lopez RL, Speers WC. Malignant struma ovarii: a case report and literature review. J Reprod Med 1983; 28:415–419. 169. Pardo-Mindan FJ, Vazquez JJ. Malignant struma ovarii: light and electron microscopic study. Cancer 1983; 51:337–343. 170. Scully RE. Recent progress in ovarian cancer. Hum Pathol 1970; 1:73–98. 171. Tamsen A, Mazur MT. Ovarian strumal carcinoid in association with multiple endocrine neoplasia, type IIA. Arch Pathol Lab Med 1992; 116:200–203. 172. Brown WW, Shetty KR, Rosenfeld PS. Hyperthyroidism due to struma ovarii: demonstration by radioiodine scan. Acta Endocrinol (Copenh) 1973; 73:266–272. 173. Smith FG. Pathology and physiology of struma ovarii. Arch Surg 1946; 53:603– 626. 174. Nodine J, Maldia G. Pseudostruma ovarii. Obstet Gynecol 1961; 17:460–463. 175. Rosenblum NG, LiVolsi VA, Edmonds PR, Mikuta JJ. Malignant struma ovarii. Gynecol Oncol 1989; 32:224–227. 176. Hershman JM. Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors. Thyroid 1999; 9:653–657. 177. Rajatanavin R, Chailurkit LO, Srisupandit S, Tungtrakul S, Bunyaratvej S. Trophoblastic hyperthyroidism: clinical and biochemical features of five cases. Am J Med 1988; 85:237–241. 178. Desai RK, Norman RJ, Jialal I, Joubert SM. Spectrum of thyroid function abnormalities in gestational trophoblastic neoplasia. Clin Endocrinol (Oxf) 1988; 29: 583–592. 179. Goodwin TM, Hershman JM. Hyperthyroidism due to inappropriate production of human chorionic gonadotropin. Clin Obstet Gynecol 1997; 40:32–44. 180. Fisher PM, Hancock BW. Gestational trophoblastic diseases and their treatment. Cancer Treat Rev 1997; 23:1–16. 181. Karp PJ, Hershman JM, Richmond S, Goldstein DP, Selenkow HA. Thyrotoxicosis from molar thyrotropin. Arch Intern Med 1973; 132:432–436. 182. Giralt SA, Dexeus F, Amato R, Sella A, Logothetis C. Hyperthyroidism in men with germ cell tumors and high levels of beta-human chorionic gonadotropin. Cancer 1992; 69:1286–1290. 183. Schimke RN, Madigan CM, Silver BJ, Fabian CJ, Stephens RL. Choriocarcinoma, thyrotoxicosis, and the Klinefelter syndrome. Cancer Genet Cytogenet 1983; 9:1–8. 184. Higgins HP, Hershman JM, Kenimer JG, Patillo RA, Bayley TA, Walfish P. The thyrotoxicosis of hydatidiform mole. Ann Intern Med 1975; 83:307–311. 185. Morley JE, Jacobson RJ, Melamed J, Hershman JM. Choriocarcinoma as a cause of thyrotoxicosis. Am J Med 1976; 60:1036–1040. 186. Nisula BC, Taliadouros GS. Thyroid function in gestational trophoblastic neoplasia: evidence that the thyrotropic activity of chorionic gonadotropin mediates the thyrotoxicosis of choriocarcinoma. Am J Obstet Gynecol 1980; 138:77–85. 187. Norman RJ, Green-Thompson RW, Jialal I, Soutter WP, Pillay NL, Joubert SM. Hyperthyroidism in gestational trophoblastic neoplasia. Clin Endocrinol (Oxf) 1981; 15:395–401.

134

Meek and Smallridge

188. Cohen JD, Utiger RD. Metastatic choriocarcinoma associated with hyperthyroidism. J Clin Endocrinol Metab 1970; 30:423–429. 189. Galton VA, Inggar SH, Jimenez-Fonseca J, Hershman JM. Alterations in thyroid hormone economy in patients with hydatidiform mole. J Clin Invest 1971; 50: 1345–1354. 190. Gross JL, Vasques Moraes I. Thyroid hormone-producing metastases in differentiated thyroid cancer. J Endocrinol Invest 1996; 19:21–24. 191. Paul SJ, Sisson JC. Thyrotoxicosis caused by thyroid cancer. Endocrinol Metab Clin North Am 1990; 19:593–612. 192. Ober KP, Cowan RJ, Sevier RE, Poole GJ. Thyrotoxicosis caused by functioning metastatic thyroid carcinoma: a rare and elusive cause of hyperthyroidism with low radioactive iodine uptake. Clin Nucl Med 1987; 12:345–348. 193. Hunt WB, Crispell KR, McKee J. Functioning metastatic carcinoma of the thyroid producing clinical hyperthyroidism. Am J Med 1960; 28:995–1001. 194. Studer H, Veraguth P, Wyss F. Thyrotoxicosis due to a solitary hepatic metastasis of thyroid carcinoma. J Clin Endocrinol Metab 1961; 21:1334–1338. 195. Verschueren CP, Rutteman GR, Vos JH, Van Dijk JE, de Bruin TW. Thyrotrophin receptors in normal and neoplastic (primary and metastatic) canine thyroid tissue. J Endocrinol 1992; 132:461–468. 196. Bowden WD, Jones RE. Thyrotoxicosis associated with distant metastatic follicular carcinoma of the thyroid. South Med J 1986; 79:483–486. 197. Oppenheim A, Miller M, Anderson GH Jr, Davis B, Slagle T. Anaplastic thyroid cancer presenting with hyperthyroidism. Am J Med 1983; 75:702–704. 198. Shimaoka K, VanHerle AJ, Dindogru A. Thyrotoxicosis secondary to involvement of the thyroid with malignant lymphoma. J Clin Endocrinol Metab 1976; 43:64– 68. 199. Nakashima T, Inoue K, Shiro-ozu A, Yoshinari M, Okamura K, Itoh M. Predominant T3 synthesis in the metastatic thyroid carcinoma in a patient with T3-toxicosis. Metabolism 1981; 30:327–330. 200. Sung LC, Cavalieri RR. T3 thyrotoxicosis due to metastatic thyroid carcinoma. J Clin Endocrinol Metab 1973; 36:215–217. 201. Cerletty JM, Listwan WJ. Hyperthyroidism due to functioning metastatic thyroid carcinoma: precipitation of thyroid storm with therapeutic radioactive iodine. JAMA 1979; 242:269–270.

4 Diagnosis and Treatment of Hypothyroidism Michael T. McDermott and E. Chester Ridgway University of Colorado Health Sciences Center, Denver, Colorado

1

INTRODUCTION

Hypothyroidism is a condition in which the thyroid gland produces insufficient amounts of thyroid hormones 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 readily cross targetcell 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. 135

136

McDermott and Ridgway

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 briefly discuss the epidemiology, etiology, clinical manifestations, and diagnosis of hypothyroidism, but it will focus primarily on practical issues in the management of patients with thyroid hormone deficiency. 2

EPIDEMIOLOGY

Hypothyroidism is the most common functional disorder of the thyroid gland. The condition is distinctly more common in women than men and increases in frequency with age. Statistics regarding prevalence and incidence are difficult to interpret because existing published 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 4.1 in 1000 population per year in women and 0.6 in 1000 per year in men (8). The prevalence of overt hypothyroidism has been reported to be approximately 1% to 2% in women and 0.1% in men in several large population-based screening studies (9–11). The overall prevalence of thyroid gland failure, however, is significantly higher. Subclinical hypothyroidism, defined as an increased serum TSH level associated with normal total T4 or free T4 values, has been consistently found in 4% to 10% of multiple populations (9–17). The Colorado Thyroid Disease Prevalence Study of over 25,000 state residents reported an increased serum TSH concentration in 9.5% of all subjects and in 8.9% of those individuals who were not already taking thyroid hormone; nearly 75% of these individuals had serum TSH values between 5 and 10 mU/L and over 95% had normal serum total T4 levels (18). The National Health and Nutrition Examination Survey III (NHANES III) screened 31,000 adults and children throughout the United States and found increased serum TSH levels (⬎4.5 mU/L) in 1.4% to 8.1% of subjects in all age brackets ⬍60 years old (19). This study and others have reported significantly higher prevalence rates in the elderly population, varying from 7% to over 17% in subjects ⬎60 years of age (9,13–19). Progression from subclinical to overt hypothyroidism has been reported to occur in 5% to 18% of patients per year (8,16,17,20,21). Individuals most likely to undergo progression are those with positive antithyroid antibodies, basal serum TSH levels ⬎20 mU/L, a prior history of radioiodine or external beam radiation therapy, and a history of long-term lithium treatment (12).

Diagnosis and Treatment of Hypothyroidism

3

137

ETIOLOGY AND PATHOPHYSIOLOGY

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 TRH production from the hypothalamus (tertiary hypothyroidism). The latter two scenarios are more generally referred to as ‘‘central hypothyroidism’’ (22,23). Primary hypothyroidism accounts for ⬎99.5% of all diagnosed cases of hypothyroidism, whereas central hypothyroidism is responsible for ⬍0.5% (23), although some sources suggest this value may be as high as 5% (24). Conditions that cause primary and central hypothyroidism, including several recently described rare genetic disorders (25– 32), are listed in Table 1.

4

CLINICAL MANIFESTATIONS

4.1 Overt Hypothyroidism 4.1.1

Common Features

As noted above, thyroid hormones have important physiological actions in multiple tissues and organ systems throughout the body. Thyroid hormone deficiency may therefore result in a broad spectrum of symptoms, signs, and laboratory abnormalities (33–37). Furthermore, thyroid gland failure is usually an insidious process that produces features of variable severity that progress gradually over time. Affected patients often experience fatigue, weakness, weight gain (mild, usually ⬍10 lb), cold intolerance, dry skin, facial puffiness, hair loss, constipation, arthralgias, myalgias, decreased libido, menstrual irregularities, difficulty concentrating, and depression. Common physical findings include bradycardia, hypertension, cool skin with a yellowish discoloration, periorbital edema, coarse hair, thinning of the hair in 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 (35) versus the 1990s (36) are shown in Table 2. Depending upon the underlying etiology, the thyroid gland may be visibly or palpably enlarged, normal, or absent. In our experience, patients whose hypothyroidism occurs acutely (e.g., 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. Hypothyroid patients may also exhibit a number of general laboratory abnormalities such as anemia (macrocytic, normocytic, or microcytic), hyponatremia, hypercholesterolemia, increased liver-associated enzymes, and increased

138

McDermott and Ridgway

TABLE 1 Etiology of Hypothyroidism Primary hypothyroidism Chronic lymphocytic thyroiditis (Hashimoto’s disease) Thyroidectomy Radioiodine therapy External radiation therapy (⬎2000 R) Infiltrative/infectious diseases Iodine deficiency Thyroid agenesis/dysgenesis Disruptive thyroiditis (usually transient) Postpartum thyroiditis Silent (painless) thyroiditis Subacute (granulomatous) thyroiditis Drug-induced hypothyroidism Thionamides Iodine excess Amiodarone Lithium Sertraline Interferon alpha Genetic disorders TSH receptor gene mutations (25) Sodium-iodide symporter gene mutations (26) Thyroperoxidase gene mutations (27) Thyroglobulin gene mutations (28) Central hypothyroidism Mass (tumor, aneurysm) Hypophysectomy Radiation therapy Infiltrative/infectious diseases Genetic disorders TSHβ gene mutations (29) TRH receptor gene mutations (30) Pit-1 gene mutations (31) Prop-1 gene mutations (32)

creatine 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 below). Pleural and pericardial effusions may be seen on chest radiographs, while electrocardiograms are frequently characterized by bradycardia, diffuse low voltage, and nonspecific ST- and T-wave abnormalities. Symptoms of central hypothyroidism are similar to those seen in patients

Diagnosis and Treatment of Hypothyroidism

139

TABLE 2 Clinical Symptoms in Patients with Overt Hypothyroidism Symptom Early studies, 1930sa 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 Recent studies, 1990sb Dry skin Cold intolerance Coarse skin Periorbital puffiness Diminished sweating Weight gain a b

Percent of cases

Symptom

Percent of cases

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

76 64 60 60 54 54

Paresthesias Cold skin Constipation Slow movements Hoarseness Impaired learning

52 50 48 36 34 22

Adapted from Ref. 35. Adapted from Ref. 36.

with primary hypothyroidism but tend to be milder. 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, deficiencies of other anterior pituitary hormones and, less commonly, diabetes insipidus. These features often overshadow the manifestations of hypothyroidism (22,23). 4.1.2

Less Common Features

4.1.2.1 Infections Hypothyroid patients have an increased propensity to develop infections, particularly those of the upper and lower respiratory tracts, 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

140

McDermott and Ridgway

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 (38–40). 4.1.2.2 Pulmonary Abnormalities Hypothyroidism is commonly associated with fatigue and decreased exercise tolerance, symptoms that may be related, at least partly, to disorders of pulmonary function. Some of the more prominent pathophysiological features that have been described in patients with thyroid failure, particularly more severe degrees of thyroid failure, include CO2 retention, hypoxemia, decreased diffusing capacity of carbon monoxide (DlCO), and increased alveolar-arterial (A-a) oxygen gradients (41–45). Mechanisms for these effects include upper airway obstruction from goiter and soft tissue enlargement, decreased compliance of the chest wall, respiratory muscle weakness (46–48), increased capillary permeability (49–50), pleural effusions (51,52), and impairment of both hypoxic and hypercapneic ventilatory drives (53–55). This combination of aberrations may also predispose the patient to peripheral or central sleep apnea (56–60). Respiratory muscle weakness and impaired ventilatory drives may also profoundly impair the ability of acutely ill hypothyroid patients to be weaned from assisted ventilation devices (61). 4.1.2.3 Cardiovascular Abnormalities Pericardial effusion is a well-recognized complication of hypothyroidism (51,62,63), occurring in up to 50% of patients with overt thyroid failure (63). The effusions are usually small and have little clinical significance (64), although pericardial tamponade has been reported (65). Myocardial dysfunction—manifest by prolongation of the preejection period, abnormal systolic time intervals, and disordered diastolic relaxation—is readily demonstrable in overt hypothyroidism (66–74) and, to a lesser extent, in some patients with subclinical hypothyroidism (75–82); reversible asymmetrical septal hypertrophy has been reported as well (83). Thyroid hormone deficiency also increases systemic vascular resistance (67,84), which may further impair left ventricular performance. Despite these pathophysiological effects, hypothyroidism alone rarely causes congestive heart failure (24,85). However, a severe dilated cardiomyopathy was found in one young man with profound hypothyroidism and was completely reversible with thyroid hormone replacement therapy (86). Hypothyroidism may additionally predispose to the development of coronary artery disease; implicated mechanisms include lipid disorders and elevations of the arterial blood pressure (87,88). Transient myocardial ischemia, due to regional myocardial perfusion abnormalities, has also been demonstrated in patients with severe thyroid failure (89). Serum CK levels may be increased in both over (90–93) and subclinical (93) hypothyroidism. Although the CK is generally of the MM (skeletal muscle) fraction, there may also be a component of the MB

Diagnosis and Treatment of Hypothyroidism

141

(myocardial) fraction in some patients (94). Increased CK levels may occasionally lead to a mistaken diagnosis of acute myocardial infarction (MI) in hypothyroid patients experiencing atypical chest pain (95). 4.1.2.4 Endocrine Abnormalities Hypothyroidism may be associated with hyperprolactinemia, usually of a mild degree (96,97). Patients with long-standing hypothyroidism may rarely develop more marked prolactin elevations associated with pituitary pseudotumors due to thyrotrope hyperplasia (98–100). Reported patients have presented with high serum prolactin levels and significant pituitary enlargement on imaging studies, suggesting the presence of pituitary prolactinomas (Fig. 1). Upon discovery of increased serum TSH levels and institution of thyroid hormone replacement therapy, the increased 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 polyendocrinopathy (Schmidt’s syndrome), an HLA-DR3/DR4–related condition in which circulating organ-specific autoantibodies cause thyroid failure, adrenal failure, and, less often, type 1 diabetes mellitus (101). The two disorders may also coexist in patients with tumors or infiltrative disorders of the pituitary gland or hypothalamus, resulting in central hypothyroidism and central adrenal insufficiency (102); such patients often have evidence of pituitary mass effects, other anterior pituitary hormone deficiencies, and, less frequently, diabetes insipidus (22,23). Since thyroid hormone replacement may acutely lower serum cortisol levels by increasing the cortisol metabolic clearance rate (103–105), initiating thyroid hormone replacement without recognizing and treating coexisting adrenal disease may precipitate an acute adrenal crisis (102). Therefore, in our opinion, adrenal function should be assessed with an ACTH stimulation test, metyrapone test, or insulin tolerance test in any 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 (106–109). Both delayed puberty (101,111) and precocious pseudopuberty (112,113) have been described in hypothyroid children; the mechanism for the latter is uncertain but may result from a type of hormonal crosstalk involving the effects of increased TRH and TSH on the gonadal axis (113). In adult women, hypothyroidism may cause infertility, anovulation, irregular or heavy menses, amenorrhea, and galactorrhea (111), while in men it may cause infertility, defective spermatogenesis, and erectile dysfunction (114,115).

142

McDermott and Ridgway

FIG. 1 Pituitary pseudotumor in primary hypothyroidism. A 15- year-old girl presented with primary amenorrhea, galactorrhea, increased serum prolactin (prolactin 52.9 ng/mL; nl, 5-25) and enlargement of the pituitary gland (A). She was subsequently discovered to have primary hypothyroidism (TSH ⬎ 100 mU/L). Her symptoms, laboratory abnormalities, and pituitary enlargement resolved (B) following institution of appropriate thyroid hormone therapy. (From Ref. 100.)

4.1.2.5 Psychiatric Disorders Depression and other psychiatric disturbances in patients with hypothyroidism were initially reported in the late nineteenth century (116–119). The term myxedema madness was coined in 1949, referring to the not infrequent discovery of hypothyroidism in patients who were residents of mental hospitals (120). The neuropsychiatric alterations that have since been described in association with hypothyroidism span a wide spectrum of conditions, including irritability, poor

Diagnosis and Treatment of Hypothyroidism

143

concentration, impaired memory, cognitive dysfunction, depression, paranoia, hallucinations, and schizophrenia (121–123). 4.1.2.6 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 (124). Recently it has been demonstrated that euthyroid children whose mothers had untreated or inadequately treated hypothyroidism during pregnancy have lower full-scale IQ scores than do children whose mothers were euthyroid during pregnancy (125). Hypothyroid adults may, as discussed above, exhibit a variety of psychiatric disorders (121–123). Peripheral metabolic polyneuropathies and multiple entrapment neuropathies, including but not limited to carpal tunnel syndrome, are also well described (126–129). Rarely, hypothyroidism has been reported to cause a central focal neurological disorder such as cerebellar ataxia (130). 4.1.2.7 Musculoskeletal Disorders Arthralgias, myalgias, and variable degrees of proximal myopathy are well recognized features of thyroid hormone deficiency (90,92,131–134). Moderate to marked elevations of serum muscle enzymes are also well described (90–95) and even acute exertional rhabdomyolysis has been reported (135). Less commonly, a peculiar myopathy characterized by muscle hypertrophy, stiffness, weakness, and slowness of movement has been described in association with hypothyroidism; this myopathy has been referred to as Hoffman’s syndrome in adults (136,137) and as the Kocher-Debre-Semelaigne syndrome in children (138). 4.2 Subclinical Hypothyroidism Subclinical hypothyroidism (Table 3) is more common than overt hypothyroidism (12–21). Although the disorder is often asymptomatic, it may be associated with a variety of nonspecific but potentially thyroid-related symptoms (18,79,80,139,140). In the Colorado Thyroid Disease Prevalence Study (18), patients with subclinical hypothyroidism had slightly but statistically significantly

TABLE 3 Subclinical Hypothyroidism/Mild Thyroid Failure—Definition Few or no clinical symptoms Few or no clinical signs Increased basal TSH Normal free T4 and free T3

144

McDermott and Ridgway

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

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.01 ⬍0.001 ⬍0.001 ⬍0.05 ⬍0.05 ⬍0.05

Dry skin Poor memory Slow thinking Muscle weakness Fatigue Muscle cramps Cold intolerance Puffy eyes Constipation Hoarseness Source: Adapted from Ref. 18.

higher frequencies of multiple symptoms on a thyroid health survey than did the euthyroid controls (Table 4). Other investigators (140–143) have found a higher prevalence of depression and anxiety disorders. Symptomatic improvement following institution of thyroid hormone replacement has been reported in most (79,80,139) but not all (144) studies of these patients. Mild thyroid failure may also be associated with indices of subtle cardiac dysfunction, such as abnormal systolic time intervals (75,76,79,80), myocardial contractility (77,78), and diastolic relaxation (81,82), all of which improve with thyroid hormone replacement therapy (76–82). Disorders of skeletal muscle (93,145), peripheral nerves (146), and the stapedial reflex (147) have also been reported. The effects of subclinical hypothyroidism on serum lipids and lipoproteins has been another active area of investigation. Mild elevations of serum total cholesterol and low-density-lipoprotein (LDL) cholesterol as well as reductions of serum high-density-lipoprotein (HDL) cholesterol have been reported in several studies of patients with mild thyroid failure (148–150). The Colorado Thyroid Disease Prevalence Study found that patients had higher levels of both total cholesterol and LDL cholesterol than did euthyroid controls and that these values correlated positively with the severity of hypothyroidism (18). Furthermore, lipid profiles have been shown to improve in these patients after institution of thyroid hormone replacement therapy in some (148,150–152) but not all studies (12).

Diagnosis and Treatment of Hypothyroidism

145

4.3 Myxedema Coma Myxedema coma is a life-threatening condition that represents the extreme end of the spectrum of thyroid hormone deficiency (153,154). 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 below, must be instituted promptly because of the very high mortality rate in this condition when appropriate therapy is delayed or neglected. 5

DIAGNOSIS

5.1 Hormone Assays The key to the accurate diagnosis of hypothyroidism is measurement and appropriate interpretation of serum thyrotropin (TSH) and thyroid hormone levels. Currently, the most sensitive and accurate TSH measurements are performed with immunometric assays (155–158). The main difference between second- and third-generation TSH assays is the ability of the latter to detect TSH accurately below the normal range. This is usually not an important consideration in the diagnosis of primary hypothyroidism where serum TSH levels are increased; however, accurate and sensitive TSH assays are helpful in diagnosing central hypothyroidism, where TSH levels tend to be inappropriately normal or low (22,23,159). Serum total T4 and T3 may be measured by radioimmunoassay or related nonisotope methods; free thyroid hormone levels may be assessed using equilibrium dialysis or competitive binding assays. Free hormone measurements avoid the pitfalls encountered with medications and disorders that affect thyroid hormone binding proteins. Thyroid gland failure is a gradual but generally progressive process. Although it exists on a continuum, it is convenient to characterize the disorder according to grades of severity as being mild, moderate, or severe (Fig. 2, 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

146

McDermott and Ridgway

FIG. 2 Development of primary hypothyroidism. In the earliest stage, mild hypothyroidism, the only detectable abnormality is an increased 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.

TSH secretion. TSH then stimulates the secretory activity of the damaged thyroid gland, achieving serum T4 and T3 levels within the population normal range but still low for the individual patient. The only detectable abnormality at this early stage, therefore, is a mildly or moderately increased serum TSH concentration, usually ⬍20 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 (160–162). Moderate hypothyroidism is thus characterized by a high serum TSH level and low T4 but a normal or low-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. 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. Progressively more severe

Diagnosis and Treatment of Hypothyroidism

147

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, ↑

degrees of central hypothyroidism are characterized by declining serum T4 and T3 profiles similar to those seen with primary hypothyroidism (Fig. 3, Table 5) with the exception that the serum TSH level remains normal or low (22,23,159). In some cases, however, mildly increased serum TSH concentrations have been observed; such patients apparently produce a TSH molecule with normal immunological but reduced biological activity due to altered glycosylation (163,164). 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 6 to 8 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 (157). 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 (165). Approximately 15% of patients, however, may later recover thyroid function and return to a euthyroid state (166). 5.2 Increased Serum TSH Levels in Conditions Other Than Hypothyroidism Patients with nonthyroidal illnesses may present with hormone profiles that initially suggest hypothyroidism (167,168). The distinction between the two disor-

148

McDermott and Ridgway

FIG. 3 Development of central hypothyroidism. This disorder results from impaired pituitary TSH secretion; 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 lownormal range.

ders (Table 5) is important, particularly in critically ill patients in whom the differential diagnosis may include severe myxedema. Patients with nonthyroidal illnesses first develop low serum T3 levels due to decreased peripheral conversion of T4 to T3. As the nonthyroidal illness becomes more severe, T4 levels also decline because of reduced hepatic synthesis of thyroid-binding proteins; free T4 levels, however, do not change. Complicating the situation, severely ill patients often receive multiple medications that can have confounding effects on pituitary–thyroid function. For example, the administration of dopamine suppresses TSH secretion from the pituitary gland and lowers serum TSH levels (169), glucocorticoids similarly suppress serum TSH levels and also inhibit peripheral T4to-T3 conversion by 5′ deiodinase (169). When a patient begins to recover, hepatic protein synthesis is restored, resulting in improvement in the total T4 concentration but a transient, slight drop in the free-T4 level with consequent mild elevation of the serum TSH. Throughout the course of a nonthyroidal illness, however, serum T3 levels are proportionately lower than T4 levels and TSH is rarely ⬎20

Diagnosis and Treatment of Hypothyroidism

149

mU/L. In contrast, T4 tends to decrease first in hypothyroidism and is usually relatively more depressed than is the T3 level; this is because of enhanced T4-toT3 conversion (160–162), which tends to preserve serum T3 levels in the normal range until hypothyroidism is severe. Accordingly, hypothyroid patients with low T3 levels generally have very high serum TSH concentrations unless there is coexisting pituitary disease. The syndrome of generalized resistance to thyroid hormone (GRTH) may also be confused with hypothyroidism, particularly subclinical hypothyroidism. GRTH most often results from dominant negative mutations in the thyroid hormone receptor beta (TRβ) gene (170). Affected patients may be clinically hyperthyroid, euthyroid, or hypothyroid and their serum TSH levels are normal or frankly increased. The key to the diagnosis of GRTH, however, is the association of inappropriately normal or increased serum TSH levels with increased total and free thyroid hormone concentrations. The rare TSH-secreting pituitary tumors produce a hormone profile similar to that seen with GRTH (171). In contrast, the appropriately increased serum TSH in hypothyroidism is associated with low or low-normal thyroid hormone levels. 5.3 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 appear to be the best marker for this disorder (172). 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 antithyroid antibodies (8,16,17,20,21). Hypothyroidism may occasionally result from the production of TSH receptor–blocking antibodies (173–175) without evidence of anti-TG and anti-TPO antibodies. 5.4 Screening for Hypothyroidism Screening for hypothyroidism among asymptomatic persons is an issue that continues to spark significant controversy. Based on disease prevalence data and cost-effectiveness estimates, the American College of Physicians (ACP) has recommended screening women over age 50 years with a serum TSH determination; a free T4 measurement should be obtained only if the TSH value is undetectable

150

McDermott and Ridgway

FIG. 4 Cost-effectiveness of TSH screening according to age and gender. (Adapted from Ref. 177; Copyright American Medical Association.)

or ⬎10 mU/L. Routine testing in younger women and in men is not considered to be cost-effective (11,176). In contrast, a recent comprehensive cost-utility analysis (177) has estimated that screening for hypothyroidism at age 35 years and every 5 years thereafter would cost $9223 per quality-adjusted life year (QALY) for women and $22,595 per QALY for men. Furthermore, the cost-effectiveness improved when screening started at an older age, dropping progressively to $829 per QALY for women and $3182 per QALY for men at age 65 years (Fig. 4). They concluded 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 (Fig. 5). An awareness that the probability of finding hypothyroidism may be higher in certain individuals (178) can facilitate case finding. Conditions associated with a high risk (prevalence ⬎10%), a moderate risk (prevalence 3% to 10%), and low risk (prevalence ⬍2%) of associated hypothyroidism are shown in Table 6. We believe a more aggressive approach to screening should be adopted than that previously recommended by the ACP (11,176). This recommendation is based on the relatively high prevalence of undiagnosed subclinical hypothyroidism (9–19), the frequency of associated nonspecific symptoms (18,79,80, 139–143), subtle cardiac dysfunction (75–82) and lipid abnormalities (79,80, 148–150), and the finding that children born to women with untreated or inadequately treated hypothyroidism have suboptimal IQ scores (125). In our opinion,

Diagnosis and Treatment of Hypothyroidism

151

FIG. 5 Cost-effectiveness of TSH screening every 5 years compared with other generally accepted prevention strategies. (Adapted from Ref. 177; Copyright American Medical Association.)

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

152

McDermott and Ridgway

TABLE 7 Mild Thyroid Failure—Benefits and Costs of Early Detection and Therapy Benefits Treat symptoms related to mild thyroid hormone deficiency Control associated hypercholesterolemia Prevent progression to overt hypothyroidism Costs Serum TSH assays Levothyroxine therapy Follow-up visits

TSH testing is indicated for all patients who have symptoms compatible with thyroid hormone deficiency, palpably enlarged thyroid glands, or conditions associated with an increased prevalence of associated hypothyroidism (Table 6) and for all women planning pregnancy or early in their first trimester. For otherwise low-risk individuals who are completely asymptomatic, screening should be conducted every 5 years starting at age 35 years in women and 45 years in men. A free T4 determination should follow in any patient whose serum TSH is undetectable or greater than the upper limit of the normal range (usually 4 to 5 mU/L). Measurement of anti-TPO antibodies in patients with subclinical hypothyroidism (high TSH, normal free T4) may help the provider predict the likelihood of progression to overt hypothyroidism. Various cost–benefit issues involved in screening for mild thyroid failure are outlined in Table 7. 6

TREATMENT

6.1 Thyroid Hormone Preparations Thyroid hormone replacement therapy was introduced in 1891, when George Murray reported on his studies in treating myxedema with injections of an extract of sheep thyroid glands (179). Subsequently, Hector MacKenzie demonstrated similar beneficial effects from an oral preparation of whole sheep thyroid and later from a desiccated extract of ovine thyroid (180). Following these reports, desiccated extracts 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

Diagnosis and Treatment of Hypothyroidism

153

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 (181,182) and that serum TSH measurements were a superior tool for monitoring LT4 dosage requirements (183,184). Multiple thyroid hormone preparations are currently in use as thyroid hormone replacement therapy. Pure LT4 is available in various oral brand-name (Synthroid, Levothroid, Levoxyl) and generic products as well as a parenteral formulation (Synthroid). The United States Pharmacopeia (USP) currently requires that LT4 preparations contain between 90% and 110% of the stated amount of LT4. Pure LT3 is also available as an oral preparation (Cytomel) and a parenteral product (Triostat). Mixtures of LT4 and LT3 (Liotrix, Thyrolar) and several brands of desiccated thyroid are also in use. In the past, desiccated preparations were standardized by their iodine contents, but the USP now requires standardization of both their T4 and T3 contents. The use of Liotrix and desiccated thyroid is nevertheless discouraged because these products contain a higher T3 /T4 ratio (1 :4)(185,186) than is present in human thyroid secretions (⬃1:8 to 10). 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, 2 to 6 h after ingestion of these medications (187). Most experts in the field today consider LT4 to be the treatment of choice for hypothyroidism (182,188), based on the principle that T4 is converted to T3 in peripheral tissues at a regulated rate 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. 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. Except in rare instances, 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 generally recommended, because previous studies have suggested that different LT4 brands are not equal in potency (189–192). When generic LT4 is prescribed, pharmacies are free to dispense whatever preparation is on hand, potentially resulting in significant variation in T4 delivery when brands are interchanged. A more recent study has called this assumption into question, however, reporting that four generic and brand-name preparations were bioequivalent and could be used interchangeably as thyroid hormone replacement therapy (193). This report raised a maelstrom of controversy over study design, interpretation of results, and conflicts of interest (194–

154

McDermott and Ridgway

196). Clearly, carefully designed prospective studies will be needed to resolve this ongoing controversy. At present, considering their demonstrated long-term reliability and overall low cost, we continue to recommend the use of brandname LT4 preparations for thyroid hormone replacement. The absorption of oral LT4 is approximately 80%, whereas that of LT3 is 85% to 100% (197–199). Absorption of LT4 occurs at multiple sites throughout the length of the small intestine, but nearly two-thirds occurs in the proximal small bowel (197,198). The presence of food decreases LT4 absorption by about 10% (200). Administered LT4 accumulates slowly and has a serum half-life of about 7 days. It requires approximately 5 to 6 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 5 to 6 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. (201). In addition, hypothyroid patients have small decreases in serum TSH levels (202,203) and increases in serum total and free T4 concentrations (202) several hours after exogenous LT4 administration. We therefore recommend obtaining TSH measurements prior to LT4 ingestion whenever possible. 6.2 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 µg/kg/day (199,204); in one small study, this translated into a mean LT4 dose of 112 µg/day (199). Alternatively, the initial LT4 dose can be estimated based on the magnitude of the TSH elevation (205). 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. 6.2.1

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 µg/kg/ day. After 6 weeks, the serum TSH level should be measured and the results used to guide dosage titration until the serum TSH is normal (206) (Table 8, Fig. 6). 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 3 months and then on an annual basis.

Diagnosis and Treatment of Hypothyroidism

155

TABLE 8 Fine Tuning LT4 Dosages If serum TSH is:

Then:

⬎5.0 mU/L 0.5 to 5.0 mU/L ⬍0.5 mU/L

Increase daily LT4 dose by 12.5–25 µg/day Continue dose; recheck annually Decrease daily LT4 dose by 12.5–25 µg/day

When a hypothyroid patient is ⬎60 years old, it is prudent to adopt a more cautious approach to LT4 replacement therapy. Such patients are more likely to 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 µg/day and an increment of 25 µg/day 6 weeks later is recommended. Once a dose of 75 µg/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 µg/day and increase the dose in 12.5 to 25 µg increments every 6 to 8 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. 6.2.2

Subclinical Hypothyroidism

When a patient is first discovered to have a mildly increased serum TSH level, it is always wise to confirm this finding, since some individuals will have a normal TSH value upon retesting. Once a diagnosis of subclinical hypothyroidism is confirmed (increased TSH, normal free or total T4), the first decision to make is whether thyroid hormone replacement therapy is warranted. Since many of these patients have few convincing symptoms of thyroid hormone deficiency, the costeffectiveness of such treatment has been brought into question (11). However, as discussed above, patients with subclinical hypothyroidism have been shown by numerous investigators to have a variety of nonspecific symptoms (18,79,80,139,140), neuropsychiatric conditions (140–143), subtle abnormalities of myocardial and skeletal muscle function (75–82,93,145), and suboptimal lipid profiles (12,18,148–150). Furthermore, these patients have been shown to experience mild but statistically significant improvement of multiple measured vari-

156

McDermott and Ridgway

(a) FIG. 6 Fine adjustment of levothyroxine (LT4) dosage in patients with hypothyroidism. TSH levels are shown in (a) and free T4 levels in (b). (From Ref. 206.)

ables (Fig. 7) when treated with thyroid hormone replacement (76–80,140,149, 150,152). Finally, approximately 5% to 18% of patients may progress to overt hypothyroidism each year (8,16,17,20,21); progression is particularly likely in those patients with circulating antithyroid antibodies or basal TSH levels ⬎20 mU/L. Given these data, it is our opinion that most if not all patients with mild

Diagnosis and Treatment of Hypothyroidism

157

(b)

thyroid failure should be treated with LT4 in doses sufficient to reduce the serum TSH levels to 0.5 to 2.0 mU/L. 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 µg/day, recheck the serum TSH in 6 weeks, and adjust the dose in 25-µg 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 25-µg increments to the next level that normalizes the serum TSH. This method is intended to avoid initial overtreatment in patients who

158

McDermott and Ridgway

FIG. 7 Improvement in myocardial function after institution of levothyroxine (LT4) therapy in patients with subclinical hypothyroidism. PEP⫽ preejection period; LVET ⫽ left ventricular ejection time; QKd ⫽ the interval between the onset of the QRS complex on the electrocardiogram and the onset of diastolic Korotkoff sounds detected by a sphygmomanometer with a microphone over the brachial artery. (Adapted from Ref. 76.)

may have significant residual thyroid function and possibly autonomous activity (207). An alternative approach is to start patients directly on an estimated full LT4 replacement dose of 1.6 to 1.7 µg/kg/day. The serum TSH is then checked 6 weeks later and the LT4 dose adjusted to bring the TSH level into the range of 0.5 to 2.0 mU/L. Once there, the patient should be monitored on an annual basis. The rationale for this method is that these patients are likely eventually to develop overt hypothyroidism 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 ⬎60 years of age should be treated cautiously, again because overtreatment can be hazardous in this group. The recommended approach is to start them on 25 to 50 µg/day of LT4 and to increase the dose, as described above for young patients, until the first dose that lowers the serum TSH into the desired range of 0.5 to 2.0 mU/L is reached.

Diagnosis and Treatment of Hypothyroidism

159

Mild thyroid failure in patients with known or suspected coronary artery disease should be treated carefully, using the more gradual approach described above 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. 6.2.3

Postradioiodine Hypothyroidism

Since an increased serum TSH level often occurs relatively late in the development of postradioiodine hypothyroidism (165), 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 (208). 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 we advise an initial LT4 replacement dose of 1.2 to 1.3 µg/kg/day in these patients, with careful monitoring of their clinical status, free T4, and TSH levels. About 3 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. 6.2.4

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 (22,23,159). 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 must be determined with consideration given to the patient’s age, severity of hypothyroidism, and 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 (159). The goal of treatment should be amelioration of pertinent symptoms and maintenance of serum free T4 levels in the mid-normal range (159). 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.

160

6.2.5

McDermott and Ridgway

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 (209). Nonetheless, the serum TSH concentration remains the most accurate guide to the proper LT4 dosage (183,184). 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 0.1 and 0.5 mU/L is satisfactory for all patients with thyroid cancer (209). Others believe that full suppression of TSH levels to below the detection limits of third-generation TSH assays (⬍0.01 mU/L) is ideal (210–212). Our practice is to suppress TSH levels to 0.1 to 0.5 mU/L for the majority of lowrisk patients in whom primary treatment of the thyroid cancer (surgery ⫹/⫺ radioiodine) has likely cured the disease. For patients with high-risk metastatic disease, we use greater degrees of suppression, reducing TSH levels to 0.05 to 0.01 mU/L. 6.2.6

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 (213–215). 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 µg/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 3 to 6 months of therapy, LT4 should be tapered in 25-µg decrements until eventual discontinuation, provided serum TSH concentrations remain within the normal range. 6.2.7

Drug-Induced Hypothyroidism

Amiodarone is a highly lipophilic antiarrhythmic agent with a long half-life of ⬃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

Diagnosis and Treatment of Hypothyroidism

161

of iodine into the circulation. This medication significantly inhibits peripheral T4-to-T3 conversion and thereby commonly alters circulating thyroid hormone concentrations (high T4, low T3, high TSH). It may also precipitate overt symptomatic hypothyroidism or hyperthyroidism (216), particularly in patients with underlying goiters or antithyroid antibodies. 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 (217,218); 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 µg/day and increased carefully in 12.5 to 25-µg increments every 6 to 8 weeks in order to bring the TSH into the normal range. If arrhythmias appear to be exacerbated with LT4 therapy, mildly increased 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 (219). 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 (169). Lithium administration is known to increase the intrathyroidal iodine concentration (220); 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 (221–223). If lithium withdrawal is not practical, we recommend LT4 treatment for all patients who have goiters or increased serum TSH levels. The goal TSH should be 0.5 to 2.0 mU/L. Patients with chronic inflammatory conditions or tumors are being treated with increasing frequency using cytokines and cytokine receptors. Administration of interferon alpha 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 (169,224–226). Interleukin-2 has also been implicated as a possible cause of silent (painless) thyroiditis (169,227). Although these thyroid disorders can be transient and may resolve when the inciting drugs are discontinued, we recommend treatment if patients are symptomatic, if their

162

McDermott and Ridgway

TSH levels are ⬎20 mU/L, or if TSH elevations of any degree persist for more than 3 months. The goal TSH levels on treatment should be 0.5 to 2.0 mU/L. 6.2.8

Myxedema Coma

Patients suspected of having myxedema coma should be managed in an intensive care unit (153,154). The cornerstone of treatment is rapid restoration of the thyroid hormone deficit. Intravenous LT4, 300–500 µg, should be given as soon as the diagnosis is made (228,229); this should be followed by 50–100 µg of LT4 intravenously each day until the patient is able to take food and medications orally. At that point, they can be given oral LT4 50 to 100 µg/day. The initial loading dose of 300 to 500 µg approximates the normal total body pool of T4; since the volume of distribution of LT4 is approximately 10 L, a 300 to 500-µg dose will raise the serum T4 concentration by 3 to 5 µg/dL (300 to 500 µg in 10 L ⫽ 3–5 µg/dL). The subsequent administration of 50 to 100 µg/day is similar to the normal daily rate of T4 production. The administration of LT3 in this condition is controversial but has theoretical advantages (230,231). T3 is more metabolically active than is T4 and T4-toT3 conversion is almost certainly impaired, both because these patients are critically ill (167,168) and because they are often treated with glucocorticoids (169). Therefore, some practitioners prefer to treat with LT3 or combinations of LT4 and LT3 (153,154). When this approach is used, the initial LT3 loading dose to replenish the total body pool is 50 to 100 µg intravenously, followed by 10 to 20 µg every 8 to 12 h until oral therapy is possible; at that point, oral administration of LT4 50 to 100 µg/day should be initiated. However, since there is no substantial evidence to indicate that LT3 is superior to LT4 in terms of outcomes in these patients, we currently recommend that LT4 be used initially, as described above, and that LT3 be added only in patients who do not respond rapidly and adequately to LT4. Myxedema coma is a syndrome in which severe thyroid hormone deficiency is complicated by one or more precipitating events, as discussed previously. It is therefore critical to identify and treat these precipitating events just as aggressively as the thyroid hormone deficiency (153,154). Ventilatory and circulatory monitoring and support are essential. Hypothermia should be corrected by slow rewarming with blankets or by central rewarming when extreme. 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 µg intravenously every 6 to 8 h, should also be started without delay, because thyroid hormone administration acutely increases the metabolic clearance rate of cortisol in these patients (103–105), who may have limited adrenal reserve or frank adrenal insufficiency.

Diagnosis and Treatment of Hypothyroidism

163

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%. 6.3 Pitfalls in the Management of Hypothyroidism 6.3.1

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; 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, endogenous depression, anemia, electrolyte and mineral abnormalities, diabetes mellitus, and other systemic disorders—should be evaluated and managed appropriately. Theoretically, utilizing an LT4 /LT3 combination that approximates the normal thyroidal secretion ratio might be beneficial, particularly in patients whose initial symptoms persist. It has recently been reported that replacing 50 µg of the total LT4 dose with 12.5 µg of LT3 for a 5-week period resulted in significantly improved neuropsychiatric function, memory, mood, and overall sense of wellbeing compared to full replacement doses of LT4 alone (232). This information must be considered preliminary and clearly needs to be reproduced in larger longterm studies before this type of therapy can be generally recommended (233). The future use of combination LT4 /LT3 therapy will ultimately depend on the development of slow-release T3 preparations and careful comparative studies testing their efficacy, safety, and optimal dosing regimens. However, this report does raise the possibility that some patients with suboptimal clinical responses to LT4 treatment might benefit from the addition of a small dose of LT3, either transiently or permanently. 6.3.2

Changing Thyroid Hormone Requirements

Certain conditions or situations are commonly associated with increased LT4 dose requirements (Table 9 and 10). Pregnancy, for example, may result in as much as a 40% to 100% increase in the LT4 dose needed to maintain normal serum TSH levels (234,235); this is particularly important to recognize, since inadequately treated maternal hypothyroidism may impair intellectual development of the fetus in utero (125). Medications–such as iron, calcium, antacids, bile acid resins, and fiber supplements—can bind LT4 in the intestine and thereby reduce its absorption (236–238). Taking these products at a time of day that is separated by at least 4 to 8 h from the LT4 dose will often bring about resolution of this problem. Other

164

TABLE 9 Conditions Associated with Altered LT4 Dose Requirements Reasons for increased LT4 dose requirements Pregnancy Use of drugs that decrease LT4 absorption Use of drugs that increase LT4 metabolism Use of drugs that decrease T4 to T3 conversion Noncompliance Malabsorption Progression of endogenous thyroid disease Reasons for decreased LT4 dose requirements Aging Androgen use Self-administration of excess LT4 Reactivation of Graves’ disease Development of autonomous thyroid nodules

TABLE 10 Drugs That May Increase Exogenous LT4 Dose Requirements Drugs that decrease LT4 absorption Ferrous sulfate Calcium carbonate Aluminum hydroxide Sucralfate Cholestyramine/colestipol Fiber supplements Drugs that increase LT4 metabolism Phenytoin Phenobarbital Carbamazepine Rifampin Drugs that inhibit T4 to T3 conversion Amiodarone Glucocorticoids Propranolol Propylthiouracil Ipodate

McDermott and Ridgway

Diagnosis and Treatment of Hypothyroidism

165

medications, predominantly the antiseizure and antituberculous agents, can significantly enhance hepatic T4 metabolism, resulting in lower circulating serum T4 concentrations (239); discontinuation of these drugs, however, is often not feasible. An apparent increase in LT4 requirements can also result from patient noncompliance (240). There may be a finding of an increased serum TSH level associated with a high normal or increased 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 compliance should be specifically discussed with such patients. An alternative solution to noncompliance is weekly, rather than daily, ingestion of the calculated 7-day requirement (1.6 to 1.7 µg/kg ⫻ 7) under the supervision of a health care provider (241). Intestinal disease causing LT4 malabsorption can also result in escalating LT4 requirements and should be pursued when other causes are not apparent. 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 6-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 (242–244). Prescribed or surreptitious androgen use may also be responsible for this occurrence (245). Regardless of age, 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 6-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 sometimes slightly outside the normal range (199). We have occasionally seen patients with highly variable or ‘‘erratic’’ serum TSH levels (low, normal, and high) while on the same or minimally adjusted doses of LT4. In these circumstances, poor or variable compliance must again be strongly suspected. Such patients might also be intermittently using iron, calcium, antacids, bile acid resins, or fiber supplements without knowing their effects on thyroid medication. 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

166

McDermott and Ridgway

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 him or her to take the medications at the same time each day, to separate their LT4 dose time by at least 4 to 8 h from food and drugs that may interfere with LT4 absorption, and to consistently have blood drawn for TSH monitoring before the daily LT4 dose. 6.3.3

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 missed doses should be discouraged, patients can be assured that LT4 has a long half-life in the serum (7 days) and that virtually no harm results from the occasional missed dose. However, the long serum half-life and slow absorption of LT4 also give 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. 6.3.4

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 thyroid secretion (⬃1:8 to 10) (185,186), because of the rapid absorption of T3 from the gastrointestinal tract, serum T3 levels are often supraphysiological 2 to 6 h following ingestion of these products (187). For this reason, most experts discourage their use and recommend that patients who are taking them 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 1 gr (60 mg) of desiccated thyroid is approximately equal to 100 µg of LT4 (24,185,186). Accordingly, recommended LT4 doses to be used in patients on various desiccated products are shown in Table 11. Once these changes are made, LT4doses should be titrated by 12.5 to 25 µg every 6 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 concentration 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 µg of LT4 and substituting 6.25 to 12.5 µg 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 above, firm recommendations regarding LT4 / LT3 combinations must await the future development and careful testing of slowrelease T3 preparations.

Diagnosis and Treatment of Hypothyroidism

167

TABLE 11 Conversion from a Dessicated Thyroid Preparation to Levothyroxine Therapy Dessicated thyroid Dose, gr 1.0 1.5 2.0 2.5 3.0 3.5 4.0

T4 content, µg

T3 content, µg

Levothyroxine equivalent initial dose, µg

38 57 76 95 114 133 152

9 13.5 18 22.5 27 31.5 36

100 150 200 250 300 350 400

Source: Adapted from Ref. 24.

6.3.5

Patients Who Are Sensitive to Thyroid Hormone Tablets

Patients occasionally complain of being ‘‘allergic’’ to thyroid hormone preparations. Provided that the dose is correct, it is unlikely that a patient would have an adverse reaction to a hormone that is normally present in his or her body. However, a patient may have sensitivity to a component of the pill, such as coloring dye or a filler substance. When this is suspected, the 50-µg size of LT4, which in most preparations is white, 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. 6.3.6

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 3 days, no LT4 replacement during this brief interval is necessary. However, if the period of abstinence is anticipated to be longer than 3 days, the patient should be treated with intravenous LT4 in a daily dose that is 80% of the usual oral dose; this amount is based on the determination that about 80% of an oral dose is absorbed into the circulation (197–199). 6.3.7

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

168

McDermott and Ridgway

studies indicate that hypothyroid patients tolerate surgery well and heal appropriately (246–248). 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, and neuropsychiatric symptoms (249). 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 (247,248,250), can proceed directly to surgery without LT4 replacement until the postoperative period, at which time dose schedules should be initiated, as discussed previously, according to the patient’s age, severity of hypothyroidism, and underlying general health. 6.3.8

Treatment of Nonthyroid Conditions with Thyroid Hormone

6.3.8.1 Obesity Hypothyroidism is commonly associated with mild weight gain, while thyrotoxicosis usually causes weight loss. These observations prompted the use of highdose thyroid hormone therapy to induce weight loss in the past (251,252), 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 (253–256). High-dose T3 given during the study period has been shown to prevent the drop in resting metabolic rate and to promote weight loss; however, this occurs at the expense of increased nitrogen loss, suggesting protein catabolism (257–259). In contrast, lower-dose T3 therapy (40 µg/ day) has been shown in two small studies to promote weight loss in subjects on very low calorie diets without negatively affecting nitrogen balance (260,261). 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 above will hopefully stimulate further study into the potential use of T3 and other thyroid hormone analogues as an adjunct in the management of obesity. 6.3.8.2 Depression Depression has been clearly identified as a symptom that may result from both overt and subclinical hypothyroidism (121–123,140–143) and that improves or resolves with LT4 replacement therapy (123). 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

Diagnosis and Treatment of Hypothyroidism

169

administration of intravenous TRH (123). It is not surprising, then, that thyroid hormone therapy has been utilized in the treatment of depression, even in patients with normal thyroid function (262,263). LT4 has been used more commonly in bipolar affective disorders, while LT3 has been given more often in depression (263). 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 (262,263). Further research into this area is currently ongoing. 6.3.8.3 Premenstrual Syndrome Disorders of the thyroid axis have been postulated to play a role in at least a subset of patients with premenstrual syndrome (264). 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 (265–267). Based on existing data, therefore, there does not appear to be a role for thyroid hormone therapy in the management of premenstrual syndrome. 6.3.9

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 (268). Low TSH levels in elderly subjects have clearly been demonstrated to be associated with an increased risk of developing atrial fibrillation (269) (Fig. 8). More subtle abnormalities of cardiac function—including increased heart rate, atrial premature beats, increased left ventricular mass, increased left ventricular contractility, diastolic dysfunction, and impaired cardiac reserve—have been demonstrated in some studies during periods of even mild thyroid hormone excess (270–273). 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 osteoporosis, particularly in postmenopausal women (274–277). 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 (268).

170

McDermott and Ridgway

FIG. 8 Increased risk of developing atrial fibrillation in patients with subclinical thyrotoxicosis. (Adapted from Ref. 269.)

7

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 but appears to 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 which, without the initiation of prompt thyroid hormone administration and appropriate treatment of precipitating causes, has a potentially high mortality rate. 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 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. Brand-name LT4 preparations are recommended in most instances because of their purity, reliability, and known hormone content. 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

Diagnosis and Treatment of Hypothyroidism

171

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. 2. Braverman LE, Ingbar SH, Sterling K. Conversion of thyroxine to triiodothyronine in athyrotic human subjects. J Clin Invest 1970; 49:855–864. 3. Pittman CS, Chambers JB, Read VH. The extrathyroidal conversion rate of thyroxine to triiodothyronine in normal man. J Clin Invest 1971; 50:1187–1196. 4. Chin WW. Molecular mechanisms of thyroid hormone action. Thyroid 1994; 4: 389–393. 5. Brent GA. The molecular basis of thyroid hormone action. Mech Dis 1994; 331: 847–853. 6. Oppenheimer JH, Schwartz HL, Sterling K. Thyroid hormone action 1994: the plot thickens. Eur J Endocrinol 1994; 130:15–24. 7. Motomura K, Brent GA. Mechanisms of thyroid hormone action: implications for the clinical manifestation of thyrotoxicosis. Endocrinol Metab Clin North Am 1998; 27:1–23. 8. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Clin Endocrinol (Oxf) 1995; 43:55–68. 9. Tunbridge F, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. The spectrum of thyroid disease in a community: The Whickham survey. Clin Endocrinol (Oxf) 1977; 7:481–493. 10. Vanderpump MP, Tunbridge WM. The epidemiology of thyroid disease. In: Braverman LE, Utiger RD, eds. The Thyroid, 9th ed. Philadelphia: Lippincott-Raven, 1996, pp 474–482. 11. Helfand M, Redfern CC. Clinical Guideline Part 2: Screening for thyroid disease: an update. Ann Intern Med 1998; 129:144–158. 12. Ross DS. Subclinical hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: Lippincott-Raven, 1996, pp 1010– 1015. 13. Bagachi N, Brown TR, Parish RF. Thyroid dysfunction in adults over age 55 years: a study in an urban U.S. community. Arch Intern Med 1990; 150:785–787. 14. Guel KW, van Sluisveld IL, Grobbee DE, Docter R, de Bruyn AM, Hooykaas H, et al. The importance of thyroid microsomal antibodies in the development of elevated serum TSH in middle-aged women: associations with serum lipids. Clin Endocrinol (Oxf) 1993; 39:275–280. 15. Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach P. The aging thyroid: increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA 1979; 242:247–250.

172

McDermott and Ridgway

16. Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly: microsomal antibodies as discriminant for therapy. JAMA 1987; 258:209–213. 17. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and followup of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991; 34:77–83. 18. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160:526–534. 19. Hollowell J, Braverman L, Spencer CA, Staehling N, Flanders D, Hannon H. Serum TSH, T4, and thyroid antibodies in the United States population: NHANES III. 72nd Annual Meeting of the American Thyroid Association, Palm Beach, FL, September 29–October 3, 1999, abstract #213. 20. Tunbridge F, Brewis M, French JM, Appleton D, Bird T, Clark F, et al. Natural history of autoimmune thyroiditis. Br Med J 1981; 282:258–262. 21. Kabadi UM. ‘‘Subclinical hypothyroidism’’: natural course of the syndrome during a prolonged follow-up study. Arch Intern Med 1993; 153:957–961. 22. Samuels MH, Ridgway EC. Central hypothyroidism. Endocrinol Metab Clin North Am 1992; 21:903–919. 23. Martino E, Bartalena L, Faglia G, Pinchera A. Central hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: Lippincott-Raven, 1996, pp 779–791. 24. Larsen PR, Davies TF, Hay IL. Thyroid hormone deficiency. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. William’s Textbook of Endocrinology, 9th ed. Philadelphia: Saunders, 1998, pp 460–475. 25. Nogueira CR, Nguyen LQ, Coelho-Neto JR, Arseven OK, Jameson JL, Kopp P, Medeiros-Neto GA. Structural analysis of the thyrotropin receptor in four patients with congenital hypothyroidism due to thyroid hypoplasia. Thyroid 1999; 9:523– 529. 26. Kosugi S, Bhayana S, Dean HJ. A novel mutation in the sodium/iodide symporter gene in the largest family with iodide transport defect. J Clin Endocrinol Metab 1999; 84:3248–3253. 27. Pannain S, Weiss RE, Jackson CE, Dian D, Beck JC, Sheffield VC, Cox N, Refetoff S. Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping. J Clin Endocrinol Metab 1999; 84:1061–1071. 28. Targovnik HM, Frechtel GD, Mendive FM, Vono J, Cochaux P, Vassart G, Medeiros-Neto G. Evidence for the segregation of three different mutated alleles of the thyroglobulin gene in a Brazilian family with congenital goiter and hypothyroidism. Thyroid 1998; 8:291–297. 29. Medeiros-Neto G, Herodotou DT, Rajan S, Kommareddi S, de Lacerda L, Sandrini R, Boguszewski MC, Hollenberg AN, Radovick S, Wondisford FE. A circulating biologically inactive thyrotropin caused by a mutation in the beta subunit gene. J Clin Invest 1996; 97:1250–1256. 30. Collu R, Tang J, Castagne J, Lagace G, Masson N, Huot C, Deal C, Delvin E, Faccenda E, Eidne KA, Van Vliet G. A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab 1997; 82:1561–1565.

Diagnosis and Treatment of Hypothyroidism

173

31. Cohen LE, Wondisford FE, Salvatoni A, Maghnie M, Brucker-Davis F, Weintraub BD, Radovick S. A ‘‘hot spot’’ in the Pit-1 gene responsible for combined pituitary hormone deficiency: clinical and molecular correlates. J Clin Endocrinol Metab 1995; 80:679–684. 32. Deladoey J, Fluck C, Buyukgebiz A, Kuhlmann BV, Eble A, Hindmarsh PC, Wu W, Mullis PE. ‘‘Hot spot’’ in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1999; 84:1645–1650. 33. Billewicz W, Chapman RS, Crooks J, Day ME, Gossage J, Wayne E, et al. Statistical methods applied to the diagnosis of hypothyroidism. Q J Med 1969; 38:255– 266. 34. Oddie TH, Boyd CM, Fisher DA, Hales IR. Incidence of signs and symptoms in thyroid disease. Med J Aust 1972; 2:981–986. 35. Means JH. Relative frequency of the several symptoms and signs of myxedema. In: Means JH, ed. The Thyroid and Its Diseases, 2nd ed. Philadelphia: Lippincott 1948, pp 232–234. 36. Zulewski HK, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997; 82:771–776. 37. Canaris GJ, Steiner JF, Ridgway EC. Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med 1997; 12:544–550. 38. Gupta OP, Bhatia PL, Agarwal MK, Mehrotra ML, Mishr SK. Nasal, pharyngeal, and laryngeal manifestations of hypothyroidism. Ear Nose Throat J 1977; 56:349–356. 39. Moley JR, Ohkawa M, Chaudry IH, Clemens MG, Baue AE. Hypothyroidism abolishes the hyperdynamic phase and increases susceptibility to sepsis. J Surg Res 1984; 36:265–273. 40. Schoenfeld PS, Myers JW, Myers L, LaRocque JC. Suppression of cell-mediated immunity in hypothyroidism. South Med J 1995; 88:347–349. 41. Wilson WR, Bedell GN. The pulmonary abnormalities in myxedema. J Clin Invest 1960; 39:42–55. 42. Nordqvist P, Dhuner KG, Stenberg K, Orndahl G. Myxedema coma and CO2 retention. Acta Med Scand 1960; 166:189–194. 43. Massumi RA, Winnacker JL. Severe depression of the respiratory center in myxedema. Am J Med 1964; 36:876–882. 44. Weg JG, Calverly JR, Johnson C. Hypothyroidism and alveolar hypoventilation. Arch Intern Med 1965; 115:302–306. 45. Burack R, Edwards RH, Green M, Jones NL. The response to exercise before and after treatment of myxedema with thyroxine. J Pharmacol Exp Ther 1971; 176: 212–219. 46. Laroche CM, Cairns T, Moxham J, Green M. Hypothyroidism presenting with respiratory muscle weakness. Am Rev Respir Dis 1988; 138:472–474. 47. Martinez FJ, Bermudez-Gomez M, Celli BR. Hypothyroidism: a reversible cause of diaphragmatic dysfunction. Chest 1989; 96:1059–1063. 48. Siafakas NM, Salesiotou V, Filaditaki V, Tzanakis N, Thalassinos N, Bouros D. Respiratory muscle strength in hypothyroidism. Chest 1992; 102:189–194. 49. Zondek H, Michael M, Kaatz A. The capillaries in myxedema. Am J Med Sci 1941; 202:435–440.

174

McDermott and Ridgway

50. Lange K. Capillary permeability in myxedema. Am J Med Sci 1944; 208:5–15. 51. Sachdev Y, Hall R. Effusions into body cavities in hypothyroidism. Lancet 1975; 1:564–566. 52. Gottehrer A, Roa J, Stanford GG, Chernow B, Sahn SA. Hypothyroidism and pleural effusions. Chest 1990; 98:1130–1132. 53. Zwillich CW, Pierson DJ, Hofeldt FD, Lufkin EG, Weil JV. Ventilatory control in myxedema and hypothyroidism. N Engl J Med 1975; 292:662–665. 54. Ladenson PW, Goldenheim PD, Ridgway EC. Prediction and reversal of blunted ventilatory responsiveness in patients with hypothyroidism. Am J Med 1988; 84: 877–883. 55. Duranti R, Gheri RG, Gorini M, Gigliotti F, Spinelli A, Fanelli A, et al. Control of breathing in patients with severe hypothyroidism. Am J Med 1993; 95:29–37. 56. Orr WC, Males JL, Imes NK. Myxedema and obstructive sleep apnea. Am J Med 1981; 70:1061–1066. 57. Skatrud J, Iber C, Ewart R, Thomas G, Rasmussen H, Schultze B. Disordered breathing during sleep in hypothyroidism. Am Rev Respir Dis 1981; 124:325–329. 58. Rajagopal KR, Abbrecht PH, Derderian SS, Pickett C, Hofeldt F, Tellis CJ, et al. Obstructive sleep apnea in hypothyroidism. Ann Intern Med 1984; 101:491– 494. 59. Pelttari L, Rauhala E, Polo O, Hyyppa MT, Kronholm E, Viikari J, et al. Upper airway obstruction in hypothyroidism. J Intern Med 1994; 236:177–181. 60. Millman RP, Bevilacqua J, Peterson DD, Pack AI. Central sleep apnea in hypothyroidism. Am Rev Respir Dis 1983; 127:504–507. 61. Pandya K, Lal C, Scheinhorn D, Day IK, Sharma OP. Hypothyroidism and ventilator dependency. Arch Intern Med 1989; 149:2115–2116. 62. Klein I, Levey GS. Unusual manifestations of hypothyroidism. Arch Intern Med 1984; 144:123–128. 63. Kabadi UM, Kumar SP. Pericardial effusion in primary hypothyroidism. Am Heart J 1990; 120:1393–1395. 64. Kerber RE, Sherman B. Echocardiographic evaluation of pericardial effusion in myxedema: incidence and biochemical and clinical correlations. Circulation 1975; 52:823–827. 65. Manolis AS, Varriale P, Ostrowski RM. Hypothyroid cardiac tamponade. Arch Intern Med 1987; 147:1167–1169. 66. Klein I, Ojamaa K. Clinical review 36: cardiovascular manifestations of endocrine disease. J Clin Endocrinol Metab 1992; 75:339–342. 67. Polikar R, Burger AG, Scherrer U, Nicod P. The thyroid and the heart. Circulation 1993; 87:1435–1441. 68. Amidi M, Leon DF, DeGroot WJ, Kroetz FW, Leonard JJ. Effect of the thyroid state on myocardial contractility and ventricular ejection rate in man. Circulation 1968; 38:229–239. 69. Crowley WF, Jr., Ridgway EC, Bough EW, Francis GS, Daniels GH, Kourides IA, et al. Noninvasive evaluation of cardiac function in hypothyroidism. Response to gradual thyroxine replacement. N Engl J Med 1977; 296:1–6. 70. Tseng KH, Walfish PG, Persaud JA, Gilbert BW. Concurrent aortic and mitral valve echocardiography permits measurement of systolic time intervals as an index of

Diagnosis and Treatment of Hypothyroidism

71. 72.

73.

74.

75.

76.

77.

78.

79. 80.

81.

82.

83.

84.

85.

86.

175

peripheral tissue thyroid functional status. J Clin Endocrinol Metab 1989; 633– 638. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system: from theory to practice. J Clin Endocrinol Metab 1994; 78:1026–1027. Wieshammer S, Keck FS, Waitsinger J, Henze E, Loos U, Hombach V, et al. Acute hypothyroidism slows the rate of left ventricular diastolic relaxation. Can J Physiol Pharmacol 1989; 67:1007–1010. Vora J, O’Malley BP, Petersen S, McCullough A, Rosenthal FD, Barnett DB. Reversible abnormalities of myocardial relaxation in hypothyroidism. J Clin Endocrinol Metab 1985; 61:269–272. Tielens ET, Pillay M, Storm C, Berghout A. Cardiac function at rest in hypothyroidism evaluated by equilibrium radionuclide angiography. Clin Endocrinol 1999; 50: 497–502. Ooi TC, Whitlock RM, Frengley PA, Ibbertson HK. Systolic time intervals and ankle reflex time in patients with minimal serum TSH elevation: response to triiodothyronine therapy. Clin Endocrinol (Oxf) 1999; 13:621–627. Ridgway EC, Cooper DS, Walker H, Rodbard D, Maloof F. Peripheral responses to thyroid hormone before and after l-thyroxine therapy in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1981; 53:1238–1242. Bell GM, Todd WT, Forfar JC, Martyn C, Wathen CG, Gow S, et al. End-organ responses to thyroxine therapy in subclinical hypothyroidism. Clin Endocrinol (Oxf) 1985; 22:83–89. Forfar JC, Wathen CG, Todd WT, Bell GM, Hannan WJ, Muir AL, et al. Left ventricular performance in subclinical hypothyroidism. Q J Med 1985; 224:857– 865. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. l-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med 1984; 101:18–24. Nystrom E, Caidahl K, Fager G, Wikkelso C, Lundberg P-A, Lindstedt G. A double-blind cross-over 12-month study of l-thyroxine treatment of women with ‘‘subclinical’’ hypothyroidism. Clin Endocrinol 1988; 29:63–76. Arem R, Rokey R, Kiefe C, Escalante DA, Rodriquez A. Cardiac systolic and diastolic function at rest and exercise in subclinical hypothyroidism: effect of thyroid hormone therapy. Thyroid 1996; 6:397–402. Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A, et al. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1999; 84:2064–2067. Santos AD, Miller RP, Mathew PK, Wallace WA, Cave WT Jr, Hinojosa L. Echocardiographic characterization of the reversible cardiomyopathy of hypothyroidism. Am J Med 1980; 68:675–682. Anthonisen P, Holst E, Thomsen AA. Determination of cardiac output and other hemodynamic data in patients with hyper- and hypothyroidism, using dye dilution technique. Scand J Clin Lab Invest 1960; 12:472–480. Klein I, Ojamaa K. The cardiovascular system in hypothyroidism. In: Braverman LE, Utiger RD, ed. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: Lippincott-Raven, 1996, pp 799–804. Ladenson PW, Sherman SI, Baughman KL, Ray PE, Feldman AM. Reversible alter-

176

87.

88.

89. 90.

91. 92.

93. 94.

95. 96.

97. 98.

99. 100. 101.

102. 103.

McDermott and Ridgway ations in myocardial gene expression in a young man with dilated cardiomyopathy and hypothyroidism. Proc Natl Acad Sci USA 1992; 89:5251–5255. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure. Clin Endocrinol (Oxf) 1977; 7:495–508. Streeten DHP, Anderson GH, Jr., Howland T, et al. Effects of thyroid function on blood pressure: recognition of hypothyroid hypertension. Hypertension 1988; 11: 78–83. Bernstein R, Muller C, Midtbo K, Smith G, Haug E, Hertzenberg L. Silent myocardial ischemia in hypothyroidism. Thyroid 1995; 5:443–447. del Palacio A, Trueba JL, Cabello A, Gutierrez E, Moya I, Fernandez Miranda C, et al. Hypothyroid myopathy: clinicopathologic study of 20 cases. Ann Med Interna 1990; 7:115–119. Burnett JR, Crooke MJ, Delahunt JW, Feek CM. Serum enzymes in hypothyroidism. N Z Med J 1994; 107:355–356. Khaleeli AA, Griffith DG, Edwards RH. The clinical presentation of hypothyroid myopathy and its relationship to abnormalities in structure and function of skeletal muscle. Clin Endocrinol (Oxf) 1983; 19:365–376. Beyer IW, Karmali R, DeMeester-Mirkine N, Cogan E, Fuss MJ. Serum creatine kinase levels in overt and subclinical hypothyroidism. Thyroid 1998; 8:1029–1031. Miyamoto T, Nagasaka A, Kato K, Masunaga R, Kotake M, Kawabe T, et al. Immunoreactive creatine kinase-MB and creatine kinase isozyme concentrations during treatment of hypothyroid patients. Eur J Clin Chem Clin Biochem 1994; 32:589– 593. LeMar HJ, Jr., West SG, Garrett CR, Hofeldt FD. Covert hypothyroidism presenting as a cardiovascular event. Am J Med 1991; 91:549–552. Contreras P, Generini G, Michelsen H, Pumarino H, Campino C. Hyperprolactinemia and galactorrhea: spontaneous versus iatrogenic hypothyroidism. J Clin Endocrinol Metab 1981; 53:1036–1039. Honbo KS, van Herle AJ, Kellett KA. Serum prolactin levels in untreated primary hypothyroidism. Am J Med 1978; 64:782–787. Groff TR, Shulkin BL, Utiger RD, Ralbert LM. Amenorrhea-galactorrhea, hyperprolactinemia, and suprasellar pituitary enlargement as presenting features of primary hypothyroidism. Obstet Gynecol 1984; 63:86S–89S. Grubb MR, Chakeres D, Malarkey WB. Patients with primary hypothyroidism presenting as prolactinomas. Am J Med 1987; 83:765–769. Poretsky L, Garber J, Kleefield J. Primary amenorrhea and pseudoprolactinoma in a patient with primary hypothyroidism. Am J Med 1986; 81:180–182. Eisenbarth GS, Verge CF. Immunoendocrinopathy syndromes. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, ed. William’s Textbook of Endocrinology, 9th ed. Philadelphia: Saunders, 1998, pp 1651–1662. Means JH, Hertz S, Lerman J. The pituitary type of myxedema or Simmonds’ disease masquerading as myxedema. Trans Assoc Am Physicians 1940; 55:32–53. Peterson RE. The influence of the thyroid on adrenal cortical function. J Clin Invest 1958; 37:736–743.

Diagnosis and Treatment of Hypothyroidism

177

104. Peterson RE. The miscible pool and turnover rate of adrenocortical steroids in man. Recent Prog Horm Res 1959; 15:231–274. 105. Iranmanesh A, Lizarralde G, Johnson ML, Veldhuis JD. Dynamics of 24-hour endogenous cortisol secretion and clearance in primary hypothyroidism assessed before and after partial thyroid hormone replacement. J Clin Endocrinol Metab 1990; 70:155–161. 106. Root AW, Rosenfield RL, Bongiovanni AM, Eberlein WR. The plasma growth hormone response to insulin-induced hypoglycemia in children with retardation of growth. Pediatrics 1999; 39:844–852. 107. MacGillivray MH, Aceto T, Jr., Frohman LA. Plasma growth hormone responses and growth retardation of hypothyroidism. Am J Dis Child 1968; 115:273–276. 108. Katz HP, Youlton R, Kaplan SL, Grumbach MM. Growth and growth hormone: III. Growth hormone release in children with primary hypothyroidism and thyrotoxicosis. J Clin Endocrinol Metab 1969; 29:346–351. 109. Rivkees SA, Bode HH, Crawford JD. Long-term growth in juvenile acquired hypothyroidism. N Engl J Med 1988; 318:599–602. 110. Hayles AB, Cloutier MD. Clinical hypothyroidism in the young—a second look. Med Clin North Am 1972; 56:871–884. 111. Thomas R, Reid RL. Thyroid disease and reproductive dysfunction: a review. Obstet Gynecol 1987; 70:789–798. 112. Kendle F. Case of precocious puberty in a female cretin. Br Med J 1905; 1:246. 113. Van Wyk J, Grumbach MM. Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap pituitary feedback. J Pediatr 1960; 57:416–435. 114. Wortsman J, Rosner W, Dufau ML. Abnormal testicular function in men with primary hypothyroidism. Am J Med 1987; 82:207–212. 115. De La Balze FA. Male hypogonadism in hypothyroidism: A study of six cases. J Clin Endocrinol Metab 1962; 22:212–222. 116. Gull WW. On a cretinoid state supervening in adult life in women. Trans Clin Soc (Lond) 1873; 7:180–185. 117. Inglis T. Two cases of myxoedema. Lancet 1880; 2:496–497. 118. Report of a committee of the Clinical Society of London. Report on myxedema. Trans Clin Soc (Lond)(Suppl) 1888; 21:1–215. 119. Savage GH. Myxoedema and its nervous symptoms. J Ment Sci 1880; 25:417. 120. Asher R. Myxoedematous madness. Br Med J 1949; 2:555–562. 121. Whybrow PC. Behavioral and psychiatric aspects of hypothyroidism. In: Braverman LE, ed. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: LippincottRaven, 1996, pp 866–870. 122. Pop VJ, Maartens LH, Leusink G, van Son MJ, Knottnerus AA, Ward AM, et al. Are autoimmune thyroid dysfunction and depression related? J Clin Endocrinol Metab 1998; 83:3194–3197. 123. Jackson I. The thyroid axis and depression. Thyroid 1998; 8:951–956. 124. Oppenheimer JH, Schwartz HL. Molecular basis of thyroid hormone-dependent brain development. Endocr Rev 1997; 18:462–475. 125. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir

178

126.

127. 128. 129. 130. 131.

132. 133.

134.

135. 136. 137. 138. 139.

140.

141.

142. 143.

McDermott and Ridgway CE, Mitchell ML, Herms RJ, Waisbren SE, Faik JD, Klein RZ. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341:549–555. Phalen GS. The carpal-tunnel syndrome: seventeen years’ experience in diagnosis and treatment of six hundred fifty-four hands. J Bone Joint Surg [Am] 1966; 48: 211–228. Earll JM, Kolb FO. Facial paralysis occurring with hypothyroidism: a report of two cases. Calif Med 1967; 106:56–58. Moosa A, Dubowitz V. Slow nerve conduction velocity in cretins. Arch Dis Child 1971; 46:852–854. Beghi E, Delodovici ML, Boglium G, Crespi V, Paleari F, Gamba P, et al. Hypothyroidism and polyneuropathy. J Neurol Neurosurg Psychiatry 1989; 52:1420–1423. Barnard RO, Campbell MJ, McDonald WI. Pathological findings in a case of hypothyroidism with ataxia. J Neurol Neurosurg Psychiatry 1971; 34:755–760. Khaleeli AA, Gohil K, McPhail G, Round JM, Edwards RH. Muscle morphology and metabolism in hypothyroid myopathy: effects of treatment. J Clin Pathol 1983; 36:519–526. Mastaglia FL, Ojeda VJ, Sarnat HB, Kakulas BA. Myopathies associated with hypothyroidism: a review based upon 13 cases. Aust N Z J Med 1988; 18:799–806. DeLong GR. The neuromuscular system and brain in hypothyroidism. In: Braverman LE, ed. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: LippincottRaven, 1996, pp 826–835. Rodolico C, Toscano A, Benvenga S, Mazzeo A, Bartolone S, Bartolone L, et al. Myopathy as the persistently isolated symptomatology of primary autoimmune hypothyroidism. Thyroid 1998; 8:1033–1038. Riggs JE. Acute exertional rhabdomyolysis in hypothyroidism: the result of a reversible defect in glycogenolysis. Mil Med 1990; 155:171–172. Hoffman J. Weiteger beitrag zur lehr von tetanie. Deutsch Z Nervenheilk 1897; 9:278. Hetzel BS, Potter BJ, Dulberg EM. The iodine deficiency disorders: nature, pathogenesis and epidemiology. World Rev Nutr Diet 1990; 62:59–119. Debre R, Semelaigne G. Syndrome of diffuse muscular hypertrophy in infants causing athletic appearance. Am J Dis Child 1935; 50:1351–1361. Staub JJ, Althaus BU, Engler H, Ryff AS, Trabucco P, Marquardt K, et al. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target issues. Am J Med 1992; 92:631–642. Monzani F, Del Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, et al. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of l-thyroxine treatment. Clin Invest 1993; 71:367–371. Tappy L, Randin JP, Schwed P, Wertheimer J, Lemarchand-Beraud T. Prevalence of thyroid disorders in psychogeriatric inpatients: a possible relationship of hypothyroidism with neurotic depression but not dementia. J Am Geriatr Soc 1987; 35: 526–531. Joffe RT, Levitt AJ. Major depression and subclinical (grade 2) hypothyroidism. Psychoneuroendocrinology 1992; 17:215–221. Haggerty JJ Jr., Stern RA, Mason GA, Beckwith J, Morey CE, Prange AJ Jr. Sub-

Diagnosis and Treatment of Hypothyroidism

144.

145.

146. 147.

148.

149.

150.

151.

152.

153. 154. 155. 156. 157. 158. 159.

160.

179

clinical hypothyroidism: a modifiable risk factor for depression? Am J Psychiatry 1993; 150:508–510. Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, et al. Does treatment with l-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med 1996; 11:744–749. Monzani F, Caraccio N, Siciliano G, Manca L, Murri L, Ferrannini E. Clinical and biochemical features of muscle dysfunction in subclinical hypothyroidism. J Clin Endocrinol Metab 1997; 82:3315–3318. Misiunas A, Ravera HN, Faraj G, Faure E. Peripheral neuropathy in subclinical hypothyroidism. Thyroid 1995; 5:283–286. Goulis DG, Tsimpiris N, Delaroudis S, Maltas B, Tzoiti M, Dagilas A, et al. Stapedial reflex: a biological index found to be abnormal in clinical and subclinical hypothyroidism. Thyroid 1998; 8:583–587. Tanis BC, Westendorp GJ, Smelt AHM. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol 1996; 44:643–649. Althaus BU, Staub JJ, Ryff-De Leche A, Oberhansli A, Stahelin HB. LDL/HDL changes in subclinical hypothyroidism: possible link factors for coronary heart disease. Clin Endocrinol 1988; 28:157–163. Caron P, Calazel C, Parra HJ, Hoff M, Louvet JP. Decreased HDL cholesterol in subclinical hypothyroidism: the effect of l-thyroxine therapy. Clin Endocrinol 1990; 33:519–523. Bogner U, Arntz HR, Peters H, Schleusener H. Subclinical hypothyroidism and hyperlipoproteinaemia: indiscriminate l-thyroxine treatment not justified. Acta Endocrinol (Copenh) 1993; 128:202–206. Arem R, Patsch W. Lipoprotein and apolipoprotein levels in subclinical hypothyroidism: effect of levothyroxine therapy in patients with subclinical hypothyroidism. Arch Intern Med 1981; 150:2097–2100. Nicoloff JT, LoPresti JS. Myxedema coma: a form of decompensated hypothyroidism. Endocrinol Metab Clin North Am 1993; 22:279–290. Wartofsky L. Myxedema coma. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: Lippincott-Raven, 1996, pp 871–877. Toft AD. Use of sensitive immunoradiometric assay for thyrotropin in clinical practice. Mayo Clin Proc 1988; 63:1035–1042. Hershman JM, Pekary AE, Smith VP, Hershman JD. Evaluation of five highsensitivity American thyrotropin assays. Mayo Clin Proc 1988; 63:1133–1139. Spencer CA. Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and hospitalized patients. Mayo Clin Proc 1988; 63:1214–1222. Nicoloff JT, Spencer CA. The use and misuse of the sensitive thyrotropin assays. J Clin Endocrinol Metab 1990; 71:553–558. Ferretti E, Persani L, Jaffrain-Rea M-L, Giambona S, Tamburrano G, Beck-Peccoz P. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999; 84:924–929. Lum SM, Nicoloff JT, Spencer CA. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest 1984; 73:570–575.

180

McDermott and Ridgway

161. Croteau W, Davey JC, Galton VA, Jermain DL. Cloning of the mammalian type II iodothyronine deiodinase: a selenoprotein differentially expressed and regulated in human and rat brain and other tissues. J Clin Invest 1996; 98:405–417. 162. Salvatore D, Tu H, Harney JW, Larsen PR. Type 2 iodothyronine deiodinase is highly expressed in human thyroid. J Clin Invest 1996; 98:962–968. 163. Faglia G, Bitensky L, Pinchera A, Ferrari C, Paracchi A, Beck-Peccoz P, et al. Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin. J Clin Endocrinol Metab 1979; 48:989–998. 164. Beck-Peccoz P, Amr S, Menezes-Ferreira MM, Faglia G, Weintraub BD. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism: effect of treatment with thyrotropin-releasing hormone. N Engl J Med 1985; 312:1085–1090. 165. Uy HL, Reasner CA, Samuels MH. Pattern of recovery of hypothalamic-pituitarythyroid axis following radioactive iodine therapy in patients with Graves’ disease. Am J Med 1995; 99:173–179. 166. Sawers JSA, Toft AD, Irvine WJ, Brown NS, Seth J. Transient hypothyroidism after iodine-131 treatment of thyrotoxicosis. J Clin Endocrinol Metab 1980; 50: 226–229. 167. Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: the ‘‘euthyroid sick syndrome.’’ Endocr Rev 1982; 3:164–217. 168. DeGroot LJ. Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 1999; 84:151–164. 169. Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995; 333:1688– 1694. 170. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993; 14:348–399. 171. McDermott MT, Ridgway EC. Central hyperthyroidism. Endocrinol Metab Clin North Am 1998; 27:187–203. 172. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996; 335:99–107. 173. Steel NR, Weightman DR, Taylor JJ, Kendall-Taylor P. Blocking activity to action of thyroid stimulating hormone in serum from patients with primary hypothyroidism. Br Med J 1984; 288:1559–1562. 174. Konishi J, Iida Y, Kasagi K, Misaki T, Nakashima T, Endo K, et al. Primary myxedema with thyrotrophin-binding inhibitor immunoglobulins. Ann Intern Med 1985; 103:26–31. 175. Takasu N, Yamada T, Takasu M, Komiya I, Nagasawa Y, Asawa T, et al. Disappearance of thyrotropin-blocking antibodies and spontaneous recovery from hypothyroidism in autoimmune thyroiditis. N Engl J Med 1992; 326:513–518. 176. American College of Physicians. Screening for thyroid disease. Ann Intern Med 1998; 129:141–143. 177. Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild thyroid failure at the periodic health examination. JAMA 1996; 276:285–292. 178. Ladenson PW. Diagnosis of hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: Lippincott-Raven, 1996, pp 878–882.

Diagnosis and Treatment of Hypothyroidism

181

179. Murray GR. Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. Br Med J 1891; 2:796–797. 180. MacKenzie HWG. A case of myxoedema treated with great benefit by feeding with fresh thyroid glands. Br Med J 1892; 2:940–941. 181. Toft AD. Thyroxine therapy. N Engl J Med 1994; 331:174–181. 182. Oppenheimer JH, Braverman LE, Toft AD, Jackson I, Ladenson PW. A therapeutic controversy. Thyroid hormone treatment: when and what? J Clin Endocrinol Metab 1995; 80:2873–2882. 183. Helfand M, Crapo LM. Monitoring therapy in patients taking levothyroxine. Ann Intern Med 1990; 113:450–454. 184. Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993; 119:492–502. 185. Rees-Jones RW, Larsen PR. Triiodothyronine and thyroxine content of desiccated thyroid tablets. Metabolism 1977; 26:1213–1218. 186. Rees-Jones RW, Rolla AR, Larsen PR. Hormonal content of thyroid replacement preparations. JAMA 1980; 243:549–550. 187. LeBoff MS, Kaplan MM, Silva JE, Larsen PR. Bioavailability of thyroid hormones from oral replacement preparations. Metabolism 1982; 31:900–905. 188. Singer PA, Cooper DS, Levy EG, Ladenson PW, Braverman LE, Daniels G, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA 1995; 273:808–812. 189. Stoffer SS, Szpunar WE. Potency of brand name and generic levothyroxine. JAMA 1980; 244:1704–1705. 190. Sawin CT, Surks MI, London M, Ranganathan C, Larsen PR. Oral thyroxine: variation in biologic action and tablet content. Ann Intern Med 1984; 100:641–645. 191. Hennessey JV, Burman KD, Wartofsky L. The equivalency of two l-thyroxine preparations. Ann Intern Med 1985; 102:770–773. 192. Dong BJ, Young VR, Rapoport B. The nonequivalence of levothyroxine products. Drug Intell Clin Pharm 1986; 20:77–78. 193. Dong BJ, Hauck WW, Gambertoglio JG, Gee L, White JR, Bubp JL, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997; 277:1205–1213. 194. Rennie D. Thyroid storm. JAMA 1997; 277:1238–1243. 195. Spiegelman MK. Bioequivalence of levothyroxine preparations for treatment of hypothyroidism. JAMA 1997; 277:1199. 196. Eckert CH. Bioequivalence of levothyroxine preparations: industry sponsorship and academic freedom. JAMA 1997; 277:1200–1201. 197. Hays MT. Thyroid hormone and the gut. Endocr Res 1988; 14:203–224. 198. Hays MT. Localization of human thyroxine absorption. Thyroid 1991; 1:241– 248. 199. Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. N Engl J Med 1987; 316:764–770. 200. Wenzel KW, Kirschsieper HE. Aspects of the absorption of oral l-thyroxine in normal man. Metabolism 1977; 26:1–8. 201. Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC. Pulsatile secretion of thyrotropin in man. J Clin Endocrinol Metab 1986; 63:661–668.

182

McDermott and Ridgway

202. Ain KB, Pucino F, Shiver TM, Banks SM. Thyroid hormone levels affected by time of blood sampling in thyroxine-treated patients. Thyroid 1993; 3:81–85. 203. Wennlund A. Variation in serum levels of T3, T4, FT4 and TSH during thyroxine replacement therapy. Acta Endocrinol (Copenh) 1999; 113:47–49. 204. Hennessey JV, Evaul JE, Tseng Y-C, Burman KD, Wartofsky L. l-thyroxine dosage: a reevaluation of therapy with contemporary preparations. Ann Intern Med 1986; 105:11–15. 205. Kabadi UM. Optimal daily levothyroxine dose in primary hypothyroidism. Arch Intern Med 1989; 149:2209–2212. 206. Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol 1988; 28:325–333. 207. Tibaldi J, Barzel US. Thyroxine supplementation: method for the prevention of clinical hypothyroidism. Am J Med 1985; 79:241–244. 208. Tallstedt L, Lundell G, Blomgren H. Does early administration of thyroxine reduce the development of Graves’ ophthalmopathy after radioiodine treatment? Eur J Endocrinol 1994; 130:494–497. 209. Burmeister LA, Goumaz MO, Mariash CN, Oppenheimer JH. Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab 1992; 75:344–350. 210. Wartofsky L. Use of sensitive TSH assay to determine optimal thyroid hormone therapy and avoid osteoporosis. Annu Rev Med 1991; 42:341–345. 211. Spencer CA, LoPresti JS, Nicoloff JT, Dlott R, Schwarzbein D. Multiphasic thyrotropin responses to thyroid hormone administration in man. J Clin Endocrinol Metab 1995; 80:854–859. 212. Pujol P, Daures J-P, Nsakala N, Baldet L, Bringer J, Jaffiol C. Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab 1996; 81:4318–4323. 213. Othman S, Phillips DIW, Parkes AB, Richards CJ, Harris B, Lazarus JH. A longterm follow-up of postpartum thyroiditis. Clin Endocrinol 1990; 32:559–564. 214. Burrow GN. Thyroid dysfunction in the recently pregnant: postpartum thyroiditis. Thyroid 1994; 4:363–365. 215. Lazarus JH. Clinical manifestations of postpartum thyroid disease. Thyroid 1999; 9:685–689. 216. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997; 126:63–73. 217. Wolff J, Chaikoff IL. Plasma inorganic iodide as a homeostatic regulator of thyroid function. J Biol Chem 1948; 174:555–564. 218. Raben MS. The paradoxical effects of thiocyanate and of thyrotropin on the organic binding of iodine by the thyroid in the presence of large amounts of iodide. Endocrinology 1949; 45:304. 219. Figge J, Dluhy RG. Amiodarone-induced elevation of thyroid stimulating hormone in patients receiving levothyroxine for primary hypothyroidism. Ann Intern Med 1990; 113:553–555. 220. Berens SC, Berstein RS, Robbins J, Wolff J. Antithyroid effects of lithium. J Clin Invest 1970; 49:1357–1367.

Diagnosis and Treatment of Hypothyroidism

183

221. Deniker P, Eyquem A, Bernheim R, Loo H, Delarue P. Thyroid autoantibody levels during lithium therapy. Neuropsychobiology 1978; 4:270–275. 222. Gelfand EW, Dosch HM, Hastings B, Shore A. Lithium: a modulator of cyclic AMP–dependent events in lymphocytes? Science 1979; 203:365–367. 223. Dosch HM, Matheson D, Schuurman RK, Gelfand EW. Anti-suppressor cell effects of lithium in vitro and in vivo. Adv Exp Med Biol 1980; 127:447–462. 224. Roti E, Minelli R, Giuberti T, Marchelli S, Schianchi C, Gardini E, et al. Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon-alpha. Am J Med 1996; 172:482–487. 225. Schuppert F, Rambusch E, Kirchner H, Atzpodien J, Kohn LD, von zur Muhlen A. Patients treated with interferon-alpha, interferon-beta, and interleukin-2 have a different thyroid autoantibody pattern than patients suffering from endogenous autoimmune thyroid disease. Thyroid 1997; 7:837–842. 226. Koh L, Greenspan FS, Yeo P. Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature. Thyroid 1997; 7:891–896. 227. Atkins MB, Mier JW, Parkinson DR, Gould JA, Berkman EM, Kaplan MM. Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 1988; 318:1557–1563. 228. Holvey DN, Goodner CJ, Nicoloff JT, Dowding JT. Treatment of myxedema coma with intravenous thyroxine. Arch Intern Med 1964; 113:89. 229. Ridgway EC, McCammon JA, Benotti J, Maloof F. Acute metabolic responses in myxedema to large doses of intravenous l-thyroxine. Ann Intern Med 1972; 77: 549–555. 230. Chernow B, Burman KD, Johnson DL, McGuire RA, O’Brian JT, Wartofsky L, et al. T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model. Crit Care Med 1983; 11:99–104. 231. Ladenson PW, Goldenheim PD, Ridgway EC. Rapid pituitary and peripheral tissue responses to intravenous l-triiodothyronine in hypothyroidism. J Clin Endocrinol Metab 1983; 56:1252–1259. 232. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999; 340:424–429. 233. Toft AD. Thyroid hormone replacement—one hormone or two? N Engl J Med 1999; 340:469–470. 234. Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990; 323:91– 96. 235. Kaplan MM. Monitoring thyroxine treatment during pregnancy. Thyroid 1992; 2: 147–152. 236. Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong N. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med 1992; 117: 1010–1013. 237. Schneyer CR. Calcium carbonate and reduction of levothyroxine efficacy. JAMA 1998; 279:750. 238. Chiu AC, Sherman SI. Effects of pharmacological fiber supplements on levothyroxine absorption. Thyroid 1998; 8:667–671.

184

McDermott and Ridgway

239. Blackshear JL, Schultz AL, Napier JS, Stuart DD. Thyroxine replacement requirements in hypothyroid patients receiving phenytoin. Ann Intern Med 1983; 99:341– 342. 240. Ain KB, Refetoff S, Fein HG, Weintraub BD. Pseudomalabsorption of levothyroxine. JAMA 1991; 266:2118–2120. 241. Grebe S, Cooke RR, Ford HC, Fagerstrom JN, Cordwell DP, Lever NA, et al. Treatment of hypothyroidism with once weekly thyroxine. J Clin Endocrinol Metab 1997; 82:870–875. 242. Rosenbaum RL, Barzel US. Levothyroxine replacement dose for primary hypothyroidism decreases with age. Ann Intern Med 1982; 96:53–55. 243. Sawin CT, Herman T, Moltich ME, London M, Kramer SM. Aging and the thyroid: decreased requirement for thyroid hormone in older hypothyroid patients. Am J Med 1983; 75:206–209. 244. Robuschi G, Safran M, Braverman LE, Gnudi A, Roti E. Hypothyroidism in the elderly. Endocr Rev 1987; 8:142–153. 245. Arafah BM. Decreased levothyroxine requirement in women with hypothyroidism during androgen therapy for breast cancer. Ann Intern Med 1994; 121:247–251. 246. Weinberg AD, Brennan MD, Gorman CA, Marsh HM, Fallon WM. Outcome of anesthesia and surgery in hypothyroid patients. Arch Intern Med 1983; 143:893– 897. 247. Drucker DJ, Burrows GN. Cardiovascular surgery in the hypothyroid patient. Arch Intern Med 1985; 145:1585–1587. 248. Becker C. Hypothyroidism and atherosclerotic heart disease: pathogenesis, medical management, and role of coronary artery bypass surgery. Endocr Rev 1985; 6:432– 440. 249. Ladenson PW, Levin AA, Ridgway EC, Daniels G. Complications of surgery in hypothyroid patients. Am J Med 1984; 77:261–266. 250. Sherman SI, Ladenson PW. Percutaneous transluminal coronary angioplasty in hypothyroidism. Am J Med 1991; 90:367–370. 251. Gwinup G, Poucher R. A controlled study of thyroid analogs in the therapy of obesity. Am J Med Sci 1967; 254:416–420. 252. Rivilin RS. Drug therapy: therapy of obesity with hormones. N Engl J Med 1975; 292:26–29. 253. Sorbris R, Petersson BG, Nilsson-Ehle P. The variability of weight reduction during fasting: predictive value of thyroid hormone measurements. Int J Obes 1982; 6: 101–111. 254. Stokholm KH, Hansen MS. Lowering of serum total T3 during a conventional slimming regime. Int J Obes 1983; 7:195–199. 255. Welle SL, Amatruda JM, Forbes GB, Lockwood DH. Resting metabolic rates of obese women after rapid weight loss. J Clin Endocrinol Metab 1984; 59:41–44. 256. Cavallo E, Armellini F, Zamboni M, Vicentini R, Milani MP, Bosello O. Resting metabolic rate, body composition, and thyroid hormones: short term effects of very low calorie diet. Horm Metab Res 1990; 22:632–635. 257. Moore R, Grant AM, Howard AN, Mills IH. Treatment of obesity with triiodothyronine and a very-low-calorie liquid-formula diet. Lancet 1980; 1:223–226. 258. Wilson JH, Lamberts SW. The effect of triiodothyronine on weight loss and nitro-

Diagnosis and Treatment of Hypothyroidism

259. 260.

261.

262. 263. 264.

265.

266.

267. 268.

269.

270.

271.

272.

273.

185

gen balance of obese patients on a very-low-calorie liquid-formula diet. Int J Obes 1981; 5:279–282. Wolman SI, Sheppard H, Fern M, Waterlow JC. The effect of triiodothyronine (T3) on protein turnover and metabolic rate. Int J Obes 1985; 9:459–463. Pasquali R, Baraldi G, Biso P, Piazzi S, Patrono D, Capelli M, et al. Effect of ‘‘physiological’’ doses of triiodothyronine replacement on the hormonal and metabolic adaptation to short-term semistarvation and to low-calorie diet in obese patients. Clin Endocrinol (Oxf) 1984; 21:357–367. Rosen R, Abraham G, Falcou R, Apfelbaum M. Effects of a ‘‘physiological’’ dose of triiodothyronine on obese subjects during a protein-sparing diet. Int J Obes 1986; 10:303–312. Joffe RT, Sokolov S, Singer W. Thyroid hormone treatment of depression. Thyroid 1995; 5:235–239. Prange AJ, Jr. Novel uses of thyroid hormones in patients with affective disorders. Thyroid 1996; 6:537–543. Girdler SS, Pedersen CA, Light KC. Thyroid axis function during the menstrual cycle in women with premenstrual syndrome. Psychoneuroendocrinology 1995; 20: 395–403. Casper RF, Patel-Christopher A, Powell AM. Thyrotropin and prolactin responses to thyrotropin-releasing hormone in premenstrual syndrome. J Clin Endocrinol Metab 1989; 68:608–612. Nikolai TF, Molligan GM, Gribble RK, Harkins PG, Meier PR, Roberts RC. Thyroid function and treatment in premenstrual syndrome. J Clin Endocrinol Metab 1990; 70:1108–1113. Schmidt PJ, Grover GN, Roy-Byrne PP, Rubinow DR. Thyroid function in women with premenstrual syndrome. J Clin Endocrinol Metab 1993; 76:671–674. Ross DS. Subclinical thyrotoxicosis. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: Lippincott-Raven, 1996, pp 1016– 1020. Sawin CT, Geller A,Wolf PA, Belanger AJ, Baker E, Bacharach P, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331:1249–1252. Bell GM, Sawers JSA, Forfar JC, Doig A, Toft AD. The effect of minor increments in plasma thyroxine on heart rate and urinary sodium excretion. Clin Endocrinol 1983; 18:511–516. Biondi B, Fazio S, Carella C, Amato G, Cittadini A, Lupoli G, et al. Cardiac effects of long-term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1993; 77:334–338. Fazio S, Biondi B, Carella C, Sabatini D, Cittadini A, Panza N, et al. Diastolic dysfunction in patients on thyroid-stimulating hormone suppressive therapy with levothyroxine: beneficial effect of beta-blockade. J Clin Endocrinol Metab 1995; 80:2222–2226. Biondi B, Fazio S, Cuocolo A, Sabatini D, Nicolai E, Lombardi G, et al. Impaired cardiac reserve and exercise capacity in patients receiving long-term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1996; 81:4224– 4228.

186

McDermott and Ridgway

274. Stall GM, Harris S, Sokoll LJ, Dawson-Hughes B. Accelerated bone loss in hypothyroid patients overtreated with l-thyroxine. Ann Intern Med 1990; 113:265–269. 275. Adlin EV, Maurer AH, Marks AD, Channick BJ. Bone mineral density in postmenopausal women treated with l-thyroxine. Am J Med 1991; 90:360–366. 276. Schneider DL, Barrett-Connor EL, Morton DJ. Thyroid hormone use and bone mineral density in elderly women. JAMA 1994; 271:1245–1249. 277. Faber J, Galloe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to l-thyroxine treatment: A meta-analysis. Eur J Endocrinol 1994; 130: 350–356.

5 Thyroid Nodules and Multinodular Goiter Hossein Gharib Mayo Medical School, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

1

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—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 toxic, nontoxic, benign, or malignant. Each patient is evaluated for structural or functional abnormalities or both. It is difficult to overstate the influence of recent technological developments on examination and treatment of the thyroid nodule. The introduction of highly sensitive thyrotropin (TSH) assays, the widespread application of fine-needle aspiration (FNA) biopsy, and the availability of high-resolution ultrasonography have significantly improved thyroid nodule management. 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 187

188

Gharib

discovery of subclinical nodules in the thyroid gland, creating difficult treatment decisions for the clinician and patient. This chapter on nodular thyroid disease includes a discussion of the classification and prevalence of thyroid nodules; the pathogenesis of thyroid nodules; laboratory diagnosis, with a review of the use and limitations of FNA biopsy, thyroid scanning, and ultrasonography; approaches to management of clinically solitary nodules and multinodular glands; thyroid incidentalomas; ultrasonographically guided FNA biopsy (US-FNA) with a brief review of percutaneous alcohol injection; routine calcitonin testing in nodular thyroid disease; and the impact of FNA on thyroid practice. 2

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, nonendemic, or sporadic, goiter affects more than 5% of the adult population (1). With declining iodine intake in this country, goiter incidence may increase. Additionally, nonendemic goiter may be caused by excessive iodine intake (e.g., from amiodarone or kelp). Epidemiological studies suggest that nodular thyroid disease occurs in the United States with an annual incidence of 0.09% (2). 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 between 30 and 59 years old (2–5). The prevalence of nodules increases throughout life, in women, and in persons exposed to ionizing

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

Thyroid Nodules and Multinodular Goiter

189

radiation in infancy or childhood. The data provided by the Framingham, Massachusetts, population study suggest an incidence of 0.1% per year, or approximately 275,000 new nodules in the United States in 1998–1999, with a 10% lifetime expectancy of a nodule developing (2,6). However, these figures substantially underestimate the problem. For example, in an autopsy series, Mortensen and colleagues (7) reported that in patients whose glands appeared clinically normal, one or more thyroid nodules were detected in approximately 50%. Furthermore, 35% of patients had nodules ⬎2 cm that had escaped clinical detection. More recent ultrasonographic data support earlier autopsy results. Brander and associates (8) found that 30% of asymptomatic adults had occult thyroid nodules detected with ultrasonography, and Horlocker and colleagues (9) reported that 41% of 1000 patients with primary hyperparathyroidism had one or more thyroid nodules detected ultrasonographically and later confirmed by surgery. Overall, most ultrasonographic studies suggest that unsuspected thyroid nodules are present in 20% to 50% of adult women and 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 (4,6). The presence of multiple nodules, either on palpation or ultrasonographic examination, in a normal or an enlarged gland is consistent with multinodular goiter (MNG). Recent imaging data have shown that in patients with clinical solitary thyroid nodules, high-resolution ultrasonography identifies one or more nodules in approximately 50% (10). 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 tiny nodules. Furthermore, the frequency of malignancy in both groups, single nodules and multinodular glands, seems to be almost identical. In a study of 5637 patients, Belfiore and colleagues (11) reported thyroid cancer in 4.1% of clinically solitary nodules versus 4.7% of clinically multinodular glands. 3

PATHOGENESIS

Currently, the molecular mechanisms that stimulate the formation and growth of only a few follicular cells within a thyroid follicle and lead to thyroid nodule formation and growth are poorly understood (12,13). 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 (cAMP), which in turn activates protein kinase A, thus leading to biochemical events that stimulate the growth of follicular cells (14). Extrathyroidal factors may also act on the intrinsic and abnormal growth potential of thyroid follicular cells, resulting in accelerated nodular growth and development.

190

Gharib

Another possible mechanism is that the formation of fibrous tissue, due to follicular necrosis and hemorrhage, may promote thyroid nodularity in MNG. Nodule formation has also been attributed to somatic mutations (12). It is now believed that benign and malignant thyroid tumors are monoclonal neoplasms arising from a single precursor cell that presumably has gained growth advantage through somatic mutations of genes critical for growth regulation. The most widely held theory is that chronic TSH stimulation leads initially to the development of a diffuse enlargement, which results in thyroid nodule development and ends with the formation of multiple nodules, typically creating an MNG. However, it is important to emphasize that the exact role of TSH as a thyroid growth factor remains a matter of controversy (15). In recent years, growth factors other than TSH have been identified that can stimulate thyroid cell growth: growth-stimulating immunoglobulin(s), epidermal growth factor, insulin-like growth factors (IGF), interleukin-1, interferon-γ, and transforming growth factor-β (16). It is also noteworthy that growth-promoting effects of TSH in vitro depend largely on the presence of IGF. Additionally, somatic mutations known to occur in thyroid follicular cells include ras oncogenes, G proteins, and mutations in the TSH receptor gene, resulting in hyperfunctioning adenomas (12). In summary, the exact cause(s) or molecular mechanism(s) stimulating the 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, TSH stimulation, stimulation by other growth factors, and the development of follicular necrosis, hemorrhage, and fibrous tissue. 4

HISTORY AND EXAMINATION

Thyroid nodules are usually asymptomatic and often noted by a patient or a physician with careful palpation of the neck (Fig. 1). MNGs are also often asymptomatic, and 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 (1,17,18). Nodules are more common in women but are more likely to be malignant in men (1,4). On physical examination, 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 these findings lack the sensitivity and specificity sufficient for diagnosing thyroid cancer.

Thyroid Nodules and Multinodular Goiter

191

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

TABLE 2 Causes of Thyroid Nodules Colloid Cyst Thyroiditis Lymphocytic Granulomatous Benign neoplasms Hu¨rthle cell Follicular adenoma Malignancy Primary—papillary, follicular, medullary, anaplastic Metastatic Lymphoma Miscellaneous—infections, Graves’ disease, Riedel thyroiditis

192

5

Gharib

LABORATORY DIAGNOSIS

Serum TSH should be measured in all patients with nodular thyroid disease. Further thyroid function testing depends on the level of TSH. In most instances, serum TSH is normal and further diagnostic evaluation is by FNA biopsy, thyroid scanning, or thyroid ultrasonography (reviewed below). 5.1 FNA Biopsy FNA biopsy—now considered the most accurate test for the diagnosis of thyroid nodules—has emerged as a safe, accurate, and cost-effective test (1,4,5,19–25). 5.1.1

Indications

These are summarized in Table 3. Biopsy is performed under direct palpation for clinically solitary thyroid nodules or dominant (largest) nodule in an MNG. US-FNA can be performed on patients with impalpable nodules that are often discovered incidentally on thyroid ultrasonography (incidentalomas). Patients with diffuse goiters—for example, Hashimoto’s thyroiditis, subacute (granulomatous) thyroiditis, or amyloid goiters—can undergo diagnostic FNA biopsy. Primary or metastatic malignancy of the thyroid can be diagnosed by FNA bi-

TABLE 3 Indications for Diagnostic Biopsy in Patients with Thyroid Disease Nodular goiter Palpable, solitary nodule Impalpable nodule (incidentaloma) Dominant nodule in MNG Diffuse goiter Hashimoto’s thyroiditis Subacute thyroiditis Amyloid goiter Malignancy Lymphoma Anaplastic cancer Metastatic cancer Adenopathy Patient with PTC Patient with MTC Key: MNG, multinodular goiter; PTC, papillary thyroid carcinoma; MTC, medullary thyroid carcinoma.

Thyroid Nodules and Multinodular Goiter

193

opsy, and adenopathy due to thyroid malignancy can be examined successfully by FNA biopsy (20). 5.1.2

Technique

Biopsy can be performed on the examining table in the office or on a hospital bed, with the patient supine; the neck is hyperextended by placing a pillow under the shoulders. This position allows maximal exposure (26–28). The area for biopsy is clearly identified and the skin cleansed with alcohol. The operator should be on the side opposite the nodule. Although some physicians use 1% lidocaine for local anesthesia (29) and others apply ice cubes contained in a plastic bag (27), some argue that biopsy can be done without any such preparation (24). 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 immediately applied. 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 sucked into the syringe, the needle is replaced in the syringe, and the aspirated material is forced out onto glass slides. A drop of aspirate is placed on each of several slides, and with an additional glass slide, smears are prepared in a manner similar to that for 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 two to four aspirations are prepared per nodule; some physicians advocate at least six separate aspirations per nodule. For larger nodules, aspirates are obtained from the center and circumferentially from the periphery. Slides are then taken to the laboratory, where wet-fixed slides are stained with a modified Papanicolaou stain and air-dried smears are stained with Diff-Quik or other stains (20,28). After the procedure has been completed, local pressure is applied to the biopsy sites. The patient is observed for a few minutes and is then allowed to leave. 5.1.3

Results

Results of FNA are usually categorized into four diagnostic groups: benign (negative), suspicious (indeterminate), malignant (positive), and unsatisfactory (nondiagnostic) (3,24,28,30,31). The most common benign cytodiagnosis is that of colloid or benign thyroid nodule. The adenomatoid, or ‘‘colloid,’’ nodule shows abundant colloid, normal follicular cells, and some foam cells. Other benign diagnoses include cystic lesions, lymphocytic thyroiditis, and subacute (granulomatous) thyroiditis. The suspicious or indeterminate category consists of specimens that have features ‘‘suggestive of but not diagnostic for malignancy.’’ This group includes cytological specimens that require histological evaluation for a conclu-

194

Gharib

sive diagnosis. Included in this category are follicular neoplasms, Hu¨rthle cell neoplasms, and other specimens with varying degrees of cellular atypia (3,20,26). Characteristically, these nodules produce hypercellular aspirates with microfollicular patterns, or Hu¨rthle 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 (24,26). Common thyroid cytological findings are shown in Fig. 2. Hypocellular smears, accounting for 5% to 15% of specimens, are considered nondiagnostic or unsatisfactory (32). 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, each group composed of at least 10 cells from separate aspirates (5,26). Unsatisfactory smears usually result from poor technique and, less often, from cystic lesions yielding fluid and foam cells, vascular lesions yielding too much blood, excessive air-drying, or poorly prepared smears. Approximately half of the FNAs that are repeated are adequate. Published FNA series from many centers in various countries confirm its utility and accuracy (29,32–34). For example, in a 1995 review by Giuffrida and Gharib (23), who combined the results from more than 16,500 specimens from two institutions, diagnostic results were as follows: benign, 69%; malignant, 4%; and suspicious or nondiagnostic, 27%. In another review, Caruso and Mazzaferri (35) reported on more than 9000 biopsies from nine centers, with the following results: benign, 70%; malignant, 4%; and suspicious, 22%. Analysis of the data 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 cytological result is from 50% to 75%. 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 10% (mean, 3%) (28,32). Limitations of FNA biopsy include unsatisfactory or nondiagnostic results, suspicious or indeterminate cytological findings, and false-negative diagnosis (36–43). Although nondiagnostic results can be as high as 20%, rebiopsy yields satisfactory results in half the cases. US-FNA further reduces nondiagnostic rates. Nevertheless, there may be a residual 5% to 10% frequency of nondiagnostic results. Surgical excision is sometimes necessary in patients with persistently nondiagnostic results because the probability of malignancy may be as high as 10% in nondiagnostic specimens (5,17). Cellular, follicular, and Hu¨rthle cell neoplasms pose a difficult problem because benign nodules cannot be separated from malignant lesions by FNA cytology alone. Because approximately 20% of cytologically suspicious results are malignant, the current recommendation is to ex-

Thyroid Nodules and Multinodular Goiter

195

FIG. 2 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’s thyroiditis. Lymphocytes and Hu¨rthle 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.)

196

Gharib

cise these nodules surgically (3,4,6). False-negative results mean missed malignancy and are typically the result of sampling errors and errors of interpretation (29,38). The adequacy of sampling can be increased by carefully sampling different portions of a nodule, using US-FNA for nodules ⬍1 cm in diameter and obtaining multiple FNA samples from large tumors (44). Cytological examination has proved to be both safe and accurate and is now recommended for the primary diagnosis of benign and malignant thyroid lesions. Complications are very minor, transient, and never serious. Bruising or hematoma is infrequent and mild; seeding in the needle tract is extremely rare with FNA. Probably 5 to 10 biopsies with supervision plus another 10 are necessary to acquire adequate experience, and at least 20 FNAs should be done annually to maintain and upgrade the biopsy technique. There is evidence that aspiration experience has a direct effect on the insufficiency rate (45). 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. 5.2 Scintigraphy 5.2.1

Indications

With increasing use of FNA biopsy in the diagnosis of thyroid nodules, the role of thyroid scintigraphy has progressively declined (46). The current role of radioisotope scanning is summarized in Table 4. In a patient with a palpable nodule and suppressed serum TSH, the next appropriate test is a thyroid scan to determine whether the nodule is hot. Thyroid scanning is also useful in determining goiter size, because the extent of goiter may influence clinical management. Furthermore, radioisotope scans can evaluate nodule function in MNGs, determine the extent and size of substernal goiter, identify ectopic thyroid tissue, and determine function in a nodule in a patient with Graves’ disease.

TABLE 4 Indications for Radioisotope Scan Diagnose hot nodule Determine goiter size Assess nodule functions in MNGa Evaluate substernal goiter Identify ectopic thyroid tissue (sublingual thyroid, struma ovarii) Nodule in Graves’ gland a

MNG, multinodular goiter.

Thyroid Nodules and Multinodular Goiter

5.2.2

197

Technique

The gamma scintillation camera with a pinhole collimator is the instrument generally used for thyroid scanning; it has replaced the rectilinear scanner. The two most commonly used radioisotopes are technetium (99mTc) and radioiodine (123 I) (46). Both isotopes are transported into thyroid follicular cells, but only iodine is organified. Theoretically, a rare nodule may exhibit ‘‘discordance’’ between 123 I and 99mTc scans. Because 99mTc is trapped but not organified, a nodule may appear to be functioning on pertechnetate imaging and appear cold on 123 I imaging; conversely, cold nodules on 99mTc may be hot with 123 I. In practice, this has not proved to be an important problem. For studies with 99mTc, 1 to 10 mCi is administered intravenously and imaging is performed 20 min later. For studies with 123 I, the tracer is administered orally in capsule form and images obtained at 6 and 24 h. 131 I is administered orally in a dose of 2 to 10 mCi, and imaging is performed 24 h or later. This isotope is reserved mainly for imaging of thyroid carcinoma. 5.2.3

Results

The radionuclide scan may demonstrate 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 normal subject, radioisotope appears homogeneous and uniform in distribution. Characteristically, the salivary glands are visualized with 99mTc, whereas they are not visualized with 123 I because images are obtained 6 to 24 h later (Fig. 3A). A hypofunctioning (cold) nodule means no or subnormal isotope concentration in the nodular tissue (Fig. 3C). The likelihood of carcinoma in cold thyroid nodules is reported to vary from approximately 5% to 15% (1,5,24,25). 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 (Fig. 3D). In MNG, the pattern has an inhomogeneous, irregular, or ‘‘patchy’’ appearance, with functioning and nonfunctioning areas within an often enlarged gland (Fig. 4A and B). Patchy uptake may also be seen in Hashimoto’s thyroiditis. 5.3 Ultrasonography 5.3.1

Indications

The current indications for thyroid ultrasonography include an adjunct to physical examination when neck palpation is difficult in patients with short fat necks, to evaluate goiter size in a patient with MNG, to perform US-FNA, and to evaluate

198

Gharib

FIG. 3 Four different 99mTc 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 radioactive iodine 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 radioactive iodine uptake was 22%.

Thyroid Nodules and Multinodular Goiter

199

FIG. 4 Scan patterns of multinodular goiter (MNG). A. Evolution of toxicity in an MNG. A 40-year-old woman initially evaluated in 1980 with an asymmetrical MNG and normal findings on thyroid function studies. In 1990, the goiter was increasing in size; serum level of thyroid-stimulating hormone was 0.005 mIU/L (normal, 0.5 to 5.0), T3 was 332 ng/dL (normal, 80 to 180), and total T4 was 14.4 µg/dL (normal, 5 to 12.5). Radioactive iodine uptake was 40%. The patient was treated surgically. B. A 75-year-old woman with a large MNG and local compressive symptoms. Thyroid scan shows the typical irregular, patchy uptake of an enlarged MNG. Thyroidectomy revealed 248 g of benign thyroid tissue.

thyroid structure in a member of a kindred with familial medullary thyroid carcinoma (MTC) syndrome or in a patient with a history of childhood neck irradiation. 5.3.2

Technique

High-resolution ultrasonography uses sound frequencies between 5 and 10 million Hz, called ‘‘megahertz’’ (MHz), which allow measurement of the volume of the gland as well as the number, size, and characteristics of the nodules within it (46,47). The sound waves are produced and received by the transducer. Current transducers can identify cystic or solid lesions as small as 1 to 2 mm in the gland. Images are obtained in both the longitudinal and transverse planes. Highresolution ultrasonography equipment has become less expensive and more userfriendly; many endocrinologists use it in the office for careful evaluation and description of a broad spectrum of thyroid abnormalities. 5.3.3

Results

Thyroid high-resolution ultrasonography patterns include consistency, echogenicity, and patterns of calcification (46,47). On the basis of consistency, thyroid nodules are divided into solid, cystic, and mixed solid-cystic. Simple or pure cystic lesions are extremely rare, and most cystic lesions are considered ‘‘mixed’’

200

Gharib

FIG. 5 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. C. Carotid artery; T, trachea.

or ‘‘complex,’’ consisting of both solid and cystic components (Fig. 5A). Benign nodules are hyperechoic and may have a sonolucent rim, or ‘‘halo,’’ surrounding the nodule (Fig. 5B). A malignant thyroid nodule is typically an irregular, solid, hypoechoic mass. Calcification occurs in 13% of nodules. Types of calcifications are important; peripheral eggshell calcifications are seen in benign, degenerating adenomas, whereas microcalcifications (seen as punctate deposits) suggest papillary carcinoma, corresponding to psammoma bodies (Fig. 5C) (46). Ultrasonographic features do not regularly and reliably differentiate benign from malignant nodules. However, ultrasonography can and should be used to assist thyroid pal-

Thyroid Nodules and Multinodular Goiter

201

TABLE 5 Indications for Ultrasonography Difficult thyroid palpation Determine extent of goiter Perform US-FNA when initial cytologic results are nondiagnostic for incidentaloma At-risk family member with hereditary MTC syndromes History of radiation exposure Follow-up of patients with thyroid cancer Key: US-FNA, ultrasonographically guided fine-needle aspiration; MTC, medullary thyroid carcinoma.

pation when this is difficult, to determine multinodularity in a patient with a clinically single nodule, and to follow up thyroid lesions (Table 5). 5.4 Other Imaging Techniques Magnetic resonance imaging (MRI) or computed tomography (CT) is used occasionally to evaluate the size and extent of an MNG (Fig. 6). CT or MRI can be particularly helpful in evaluating substernal goiters and defining the relationship of the goiter to surrounding structures. Neither of these imaging techniques sepa-

FIG. 6 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.

202

Gharib

TABLE 6 Operating Characteristics of Tests in the Diagnosis of Thyroid Cancer Diagnostic Test

Sensitivity, %

Specificity, %

93 95 85 87

15 18 25 75

Radioisotope scan Ultrasonography Thyroxine suppression FNAa biopsy a

FNA, fine-needle aspiration. Source: Modified from Ref. 48. Copyright 1991, American College of Physicians.

rates benign from malignant thyroid growths, and because of their relatively high cost, they are used less frequently than ultrasonography and scintigraphy (46). 5.5 Conclusions Recent FNA studies have provided compelling evidence for clinicians to preferentially use FNA biopsy in the management of thyroid nodules. Dolan (48) compared diagnostic strategies using FNA, scintigraphy, and ultrasonography and concluded that the specificity of thyroid scintigraphy is very low, and because more than 80% of thyroid nodules are cold, a large proportion of positive scans will be falsely positive. The sensitivity of high-resolution ultrasonography for detecting malignancy is 95%, but the specificity is only 18%, which reflects the fact that although most thyroid cancers are noncystic lesions, most noncystic nodules are benign. Because approximately 80% of thyroid nodules are noncystic, ultrasonography’s diagnostic utility is similar to that of radioisotope scanning (48). FNA cytology discriminates well if the aspirate is interpreted as definitely benign or definitely malignant. If both malignant and suspicious cytological findings are considered positive, the sensitivity of FNA is about 87%, with a specificity at about 75%. These results are summarized in Table 6. Dolan (48) recommends performing FNA of the nodule in a patient with an isolated solitary thyroid nodule. He states that since patients with a solitary nodule have a low likelihood of malignancy and most thyroid nodules are benign, the best test in this situation is an FNA. 6

MANAGEMENT

6.1 Clinically Solitary Nodule Evaluation of nodular thyroid disease begins with determining the serum level of TSH. If serum TSH is suppressed, the next test should be a radioisotope scan to rule out toxic adenoma. The serum level of TSH is usually normal, and man-

Thyroid Nodules and Multinodular Goiter

203

FIG. 7 Management of a clinically solitary nodule. With a normal serum value of thyroid-stimulating hormone (TSH), findings on fine-needle aspiration (FNA) cytological results dictate management; 70% of nodules are benign and managed medically. Malignant and suspicious nodules (15%) are treated surgically. One-half of nondiagnostic nodules (15%) are diagnostic on reaspiration; the rest are evaluated further by ultrasonographically guided FNA (US-FNA). A residual 5% to 10% of nondiagnostic nodules are managed on the basis of clinical assessment and risk factor analysis. When the initial serum level of TSH is suppressed, no FNA is necessary and radioisotope (99mTc) scan is the next test to evaluate nodule function. (Adapted from Gharib H. Thyroid FNA biopsy. In: Baskin HJ, ed. Thyroid ultrasound and ultrasoundguided FNA biopsy. Boston: Kluwer Academic Publishers, 2000 pp 103–123. By permission of the publisher.)

agement rests on cytological results (Fig. 7). Almost 70% of satisfactory aspirates are benign, with the majority being from colloid nodules and requiring no further workup. If the initial biopsy findings are benign, some authorities recommend reaspiration of all thyroid nodules 1 year later (49). However, in experienced centers, reaspiration seldom changes the initial diagnosis, and several reports have demonstrated the reliability and consistency of sequential aspirations in patients with a benign diagnosis on FNA (50). For patients with malignant cytological findings, surgical exploration is indicated. The extent of thyroid surgery depends on the histological type of malignant disease: near-total thyroidectomy for papillary thyroid carcinoma (PTC)/

204

Gharib

follicular thyroid carcinoma (FTC) and total thyroidectomy for MTC. For falsepositive diagnosis, primary lobectomy is adequate. Approximately 10% of patients have a cytologic diagnosis of ‘‘suspicious for malignancy,’’ a difficult diagnostic dilemma for clinicians. Because about 20% of these nodules are malignant, most physicians prefer surgical removal. Attempts have been made to stratify patients with suspicious cytological findings. For example, Schlinkert and colleagues (41) studied 219 patients with suspicious follicular neoplasm and reported that younger age, nodule size ⬎4 cm, solitary nodule pathologically, and fixed primary nodule were predictive of malignancy in the nodule. Similarly, Tuttle et al. (43) reported a 21% incidence of malignancy in 103 patients with follicular neoplasia; the risk of malignancy was significantly higher in males, nodules ⬎4 cm, and solitary nodule by palpation. Biochemical and cytological studies—such as flow cytometric nuclear DNA analysis (51), silver-staining nuclear organizer regions (52), proton magnetic resonance (53), and antiperoxidase and JT-95 antibodies (54)—have been assessed as potential predictors of a malignant tumor. Some authors have suggested radioisotope scanning for a cytologically suspicious nodule, with surgical treatment for cold nodules and medical treatment for functioning nodules (25,55). This author believes that thyroid scintigraphy has a limited—and, occasionally, a misleading—role in this setting and is best avoided. Two recent cases illustrate the point. 1.

2.

A 46-year-old woman had a 3-cm right thyroid nodule. The FNA diagnosis was suspicious for follicular neoplasm (Fig. 8A). Thyroid scintigraphy showed the nodule was hypofunctioning (Fig. 8B); at thyroidectomy, the gross specimen incidentally had a focus of bleeding at the site of FNA biopsy (Fig. 8C). Histological examination revealed a benign follicular adenoma with an intact capsule (Fig. 8D). A 26-year-old woman was evaluated for a 1-cm left thyroid nodule; FNA showed a suspicious ‘‘hypercellular specimen with Hu¨rthle cell features’’ (Fig. 9A), and thyroid scintigraphy showed a functioning, ‘‘warm’’ nodule that corresponded to the palpable small left thyroid mass (Fig. 9B). Surgery revealed a ‘‘0.7-cm left lobe Hu¨rthle cell carcinoma with capsular invasion’’ (Fig. 9C). In this case, relying on the scan (which showed the nodule to be functioning) would have been a mistake, and a curable cancer would not have been treated.

Similar cases have reinforced the author’s skepticism about the usefulness of scanning cytologically suspicious lesions and have led to our management proposition that most suspicious lesions are cold on isotope scanning and that, therefore, scanning results do not alter surgical treatment in most cases. Also, evidence of function on a radionuclide scan does not exclude malignant disease, and a rare functional nodule may be malignant, as illustrated by the case in Fig. 9. Recently, McHenry and colleagues (56) showed that scanning with normal

Thyroid Nodules and Multinodular Goiter

205

FIG. 8 Suspicious thyroid cytology in a 46-year-old woman with a right thyroid nodule 3 by 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 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. (H&E; ⫻50.)

FIG. 9 Suspicious thyroid cytology in a 26-year-old woman with a recent 1cm left thyroid nodule. A. Fine-needle aspiration biopsy showed hypercellular specimen with Hu¨rthle cells suspicious for Hu¨rthle cell tumor. (PAP; ⫻400.) B. Thyroid technetium scan showed left thyroid nodule was a functioning ‘‘warm’’ nodule. C. Thyroidectomy revealed a 0.7-cm left lobe Hu¨rthle cell carcinoma with capsular invasion (arrow). (H&E; ⫻50.)

206

Gharib

TSH is very unlikely to be useful; they suggest a 123 I scan only in patients with a cellular aspirate when the serum TSH level is low. In the author’s experience, scanning a cytologically suspicious nodule is rarely helpful and not cost-effective (3). Approximately 15% of nodules are nondiagnostic on initial biopsy (4,22,32,57,58). A nondiagnostic result should be pursued by reaspiration, which may be satisfactory in half the cases; however, in some cases, US-FNA may be necessary for diagnosis (Fig. 7). The routine removal of all nondiagnostic nodules is not recommended; however, the author favors surgical treatment for recurrent cysts ⬎4 cm in diameter or solid and ‘‘clinically suspicious’’ nodules or when other clinical criteria increase the risk of malignancy (6). 6.1.1

Thyroid Hormone Therapy

For the past 50 years, thyroid hormones have been used to suppress thyroid nodules. The rationale for suppressive therapy is based on the assumption that TSH stimulates nodule growth and its suppression will shrink or at least arrest nodule growth (16). By definition, suppressive therapy requires that T4 doses used are sufficient to suppress pituitary TSH secretion. The practice of T4 suppressive therapy for nodular thyroid disease is a matter of controversy and is intensely debated (16,17). Several recent randomized trials have failed to consistently prove the efficacy of suppressive therapy. In fact, current evidence seems to suggest that most benign (colloid) thyroid nodules do not regress significantly with T4 suppression (59–71). Recently, Zelmanovitz and colleagues (72) reported their experience with suppressive therapy, reviewed the literature, and performed a meta-analysis on some of the recent prospective controlled trials. These authors concluded that, as calculated by cumulative meta-analysis, the number of patients who actually benefited from this treatment was relatively small and that T4 treatment was associated with decreased nodule volume in only 17% of patients. Data analysis suggested to the authors that even if there is no decrease in nodule volume, treatment may be beneficial in preventing further nodule growth (Fig. 10). In 1998, Gharib and Mazzaferri (73) reviewed recent data on suppressive trials, evolving concepts, and controversies on suppressive therapy and offered their recommendations. They concluded that in ⬍20% of patients nodules shrink in response to T4 therapy; the nodules that do are usually the smallest ones (⬍2.5 cm in diameter). Data did not demonstrate that T4 therapy prevents either further growth of existing nodules or the emergence of new nodules. Furthermore, T4 therapy in doses sufficient to suppress TSH may have adverse effects. It is now established that long-term T4 suppressive therapy results in a state of subclinical hyperthyroidism that may be associated with osteopenia/osteoporosis and altered cardiac function (5,6,73–75). A low serum level of TSH in persons 60 years or older is associated with a threefold increase in the risk of atrial fibrillation (75).

Thyroid Nodules and Multinodular Goiter

207

FIG. 10 Cumulative meta-analysis of studies on the capacity of thyroxine suppressive therapy to decrease a nodule volume to ⬍50% of baseline value (left) and to arrest expansion of a solitary thyroid nodule volume to ⬍50% of baseline value (right). Each study was presented as risk difference and 95% confidence intervals of cumulative clinical effect size. (From Ref. 72. By permission of the Endocrine Society.)

In addition, suppressive therapy may be associated with decreased bone mineral density in postmenopausal women (74). Very little information is available about the outcome of untreated asymptomatic benign thyroid nodules. In reports from Japan, Kuma and associates (76,77) examined the long-term outcome of untreated cytologically benign thyroid nodules in 134 patients followed for 10 to 30 years (average, 15 years) and found 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%. In the group in whom nodules completely disappeared, nodules were predominantly cystic on ultrasonography. Gharib and Mazzaferri (73) offered the following conclusions and recommendations. Long-term follow-up of untreated thyroid nodules shows that 50% of nodules spontaneously decrease in size or disappear, 30% remain the same, and ⬍20% increase in size. Nodules that decrease in size are often cystic; those that increase in size should be evaluated by rebiopsy or excision for the possibility of malignancy. Patients with cytologically benign nodules can be followed by palpation and reaspiration without T4 suppression. Adverse effects of suppressive therapy include osteoporosis and cardiac arrhythmias, which can be significant

208

Gharib

potential risks in postmenopausal women or elderly patients. Although routine suppressive therapy is no longer recommended, Gharib and Mazzaferri (73) offered the following guidelines for physicians who choose suppressive therapy: Serum levels of TSH should be maintained from 0.1 to 0.5 mIU/L and not be totally suppressed to ⬍0.1 mIU/L. In postmenopausal women, T4 suppressive therapy should be accompanied by estrogen therapy if peak bone mineral density is more than two standard deviations below that of age-matched controls (78). Also, bisphosphonate therapy may be useful when estrogen is contraindicated or not tolerated, but there are no long-term data yet to support its use. Furthermore, T4 suppression therapy is not recommended for nodules ⬎3.0 cm in diameter or for patients in whom pretreatment serum levels of TSH are ⬍0.5 mIU/L. 6.1.2

Conclusions

Cytologically benign nodules should be observed, preferentially without therapy. With T4 therapy, ⬍20% of clinically solitary colloid nodules are expected to shrink. Target serum TSH treatment levels should be 0.1 to 0.5 mIU/L; complete TSH suppression is not necessary and should be avoided. The duration of treatment is not well defined: a 1-year trial of suppressive doses of T4 for premenopausal women and men without cardiac disease seems reasonable. In postmenopausal women or elderly patients, antiresorptive treatment should complement T4 therapy. The author offers the following advice to patients or colleagues who seek advice on suppressing benign nodules: nodule shrinkage for its own sake is an outcome that may not be of clinical value to patient or physician. The potential risks of long-term T4 therapy outweigh the potential benefits in most patients, particularly postmenopausal women (73). One study (79) suggested benefit from T4 therapy in previously irradiated patients who had undergone subtotal thyroidectomy for benign nodules. It seems reasonable to treat this group of patients with T4. 6.2 Multinodular Goiter Evaluation of patients with MNG includes determination of thyroid function, estimation of goiter size, exclusion of malignancy, and assessment of local symptoms (80). Evaluation should begin with serum TSH determination; if TSH is suppressed, serum levels of thyroid hormone (FT4 and T3) are determined, followed by a radioactive iodine uptake (RAIU) test. 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 suggests the presence of a nontoxic MNG. Cytologic evaluation by FNA biopsy helps management strategy (Fig. 11). In patients with benign goiters, periodic evaluation—including thyroid palpation, determination of serum levels of TSH, and

Thyroid Nodules and Multinodular Goiter

209

FIG. 11 Management of patient with a multinodular gland (MNG). Evaluation begins with determining thyroid-stimulating hormone (TSH) level; suppressed TSH (⬍0.1 mIU/L) suggests subclinical or clinical hyperthyroidism and 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. FT4, free thyroxine; N, normal; RAIU, radioactive iodine uptake; Rx, therapy; T3, triiodothyronine.

imaging studies—is helpful in management. Cytologically suspicious or malignant MNGs should be treated surgically. Surgical excision is preferred in patients with nontoxic MNG with 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 (73). In patients with primary lobectomy, T4 therapy is advised only if hypothyroidism develops.

210

Gharib

In recent years, radioiodine therapy has been advocated for patients with large nontoxic MNGs (81–88). Nygaard and associates (85,86) reported that total thyroid volume decreased by 60%, 2 years after radioiodine treatment. In several studies, Huysmans and colleagues (82–84) reported results of successful treatment with radioiodine in nontoxic goiters: symptomatic improvement in 71% of patients, decrease in tracheal deviation in 20%, and increase in tracheal lumen in 36%. Radioiodine (131 I) therapeutic doses have ranged from 50 to 200 mCi, depending on the uptake and goiter size. Reported adverse effects of radioiodine therapy in this group of patients included posttherapy hyperthyroidism, posttherapy hypothyroidism, radiation-induced thyroiditis, and potential risks for cancer and/or leukemia. So far, no follow-up data are available on the risk of radioiodine-induced malignancy in euthyroid patients treated with high doses of 131 I (88). 6.2.1

Conclusions

Serum TSH level, FNA biopsy, and imaging with radioisotope scanning, ultrasonography, CT, or MRI help delineate function, morphology, and extent of an MNG. Indications for treatment include tracheal compression, cosmetic reasons, and concern about malignancy based on growth and/or cytologic findings. The efficacy of T4 suppressive therapy in reducing goiter size remains controversial (73). However, T4 should not be used in patients who already have 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 in elderly patients and those considered high risk for surgery. 7

INCIDENTALOMA

Nonpalpable thyroid nodules discovered incidentally on imaging examination are referred to as ‘‘incidentalomas.’’ They are usually ⬍1.5 cm in diameter, are a common clinical problem, and constitute a management dilemma for clinicians (10,23,89,90). Most of them are discovered when high-resolution ultrasonography 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 thyroid disease who undergo neck ultrasonography. The incidence of incidentalomas appears higher in the elderly and in persons with iodine deficiency or radiation exposure (91). The results of older autopsy (7) and more recent US-FNA studies (92) suggest that fewer than 5% of asymptomatic nodules may be malignant. Schneider and coworkers (18) studied the results of ultrasonography in patients with a history of upper-body irradiation. They reported that 87% of the patients had one or more discrete nodules on ultrasonography and 75% of the nodules were ⬍1 cm in diameter. These authors concluded that thyroid ultrasonography is more sensitive than physical examination and scanning and patients with no history of radiation exposure should not have ultrasonography

Thyroid Nodules and Multinodular Goiter

211

FIG. 12 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 ⬍1.5 cm in diameter, observation and follow-up palpation are sufficient. FNA, fine-needle aspiration. (Modified from Ref. 91. By permission of the American College of Physicians.)

when thyroid palpation is normal. Those with radiation exposure may undergo periodic ultrasonography and US-FNA whenever indicated. However, because ultrasonography is so sensitive, great caution must be used in interpreting the results. We recently reviewed the clinical importance of thyroid incidentalomas and proposed practical management guidelines (Fig. 12) (91). If incidentalomas do not have imaging features of malignancy and are ⬍1.5 cm in diameter and if the clinical history is not suggestive of increased risk for thyroid cancer, followup neck palpation at 6 months and annually thereafter is a practical, cost-effective approach. However, for patients with nodules ⬎1.5 cm in diameter or with neck irradiation or with imaging characteristics suspicious for malignancy, US-FNA is performed. Suspicious imaging features include a solid, hypoechoic nodule with irregular borders, sometimes containing punctate microcalcifications. Nonpalpable nodules that are predominately cystic are most likely benign.

212

Gharib

FIG. 13 Thyroid incidentaloma. A 79-year-old woman was evaluated after carotid endarterectomy for arteriosclerosis, with carotid ultrasonography, which showed an unexpected mixed solid/cystic nodule, 1.2 by 1.1 cm, in the right thyroid lobe. Neck palpation was normal. Serum level of thyroidstimulating hormone was 1.8 mIU/L. Observation was suggested.

In conclusion, incidental thyroid micronodules are common and are commonly benign and can be followed up by neck palpation only. US-FNA should be performed in high-risk patients. A typical patient with a thyroid incidentaloma discovered during carotid ultrasonography is shown in Fig. 13. In view of the patient’s age, benign ultrasonographic features, and nodule size, follow-up palpation without biopsy, T4 therapy, or ultrasonography was recommended. 8

US-FNA

In recent years, US-FNA has been used with increasing frequency in clinical practice (93–96). The diagnostic and therapeutic indications for US-FNA are listed in Table 7. US-FNA can be used when the initial biopsy results are nondiagnostic, for nodules that are difficult to palpate, for thyroid incidentalomas, and for impalpable adenopathy in patients with a history of thyroid cancer. Recent studies have shown that US-FNA results in a significantly lower percentage of inadequate samples compared with direct (palpation-guided) FNA (95,96). With US-FNA, the biopsy sites can be precisely selected and the needle correctly positioned, allowing sampling of the cyst walls or solid components. As a result, the rate of satisfactory aspirates has increased. Color Doppler imaging can also be used as an aid in obtaining adequate aspirates (47). The application of US-FNA has resulted in fewer thyroidectomies because of the increased yield of satisfactory aspirates (96).

Thyroid Nodules and Multinodular Goiter

213

TABLE 7 Diagnostic and Therapeutic Indications for US-FNA a Diagnosis Nondiagnostic palpation—FNA Difficult-to-palpate nodule

Treatment Evacuate cyst Alcohol ablation of thyroid cyst; solid, cold thyroid nodule; toxic hot nodule; nontoxic hot nodule; inoperable thyroid cancer; parathyroid adenoma; inoperable parathyroid cancer

Palpable nodule ⱕ1 cm Impalpable nodule (incidentaloma) Impalpable adenopathy a

US-FNA, ultrasonographically guided fine-needle aspiration.

Therapeutic uses of US-FNA, outlined in Table 7, include cyst evacuation and alcohol ablative therapy of various types of thyroid nodules (97–101). Cystic evacuation can be assisted by US-FNA, and a significant number of cysts can be cured after simple aspiration. The reported success rate varies from 30% to 50% (102). Larger cysts are more likely to recur. Alcohol ablative therapy has been applied to thyroid nodules. Percutaneous ethanol injection (PEI) has been used successfully in the treatment of different kinds of thyroid nodules. In 1995, Papini and colleagues (100) reviewed the indications for and results of PEI for thyroid nodules. Patients treated successfully included those with thyroid cysts, toxic hot nodules, nontoxic hot nodules, and solid (cold) nodules in clinically solitary nodules or MNGs. The usual treatment protocol consists of the administration of ethanol as a single bolus via a 20- to 22-gauge needle during 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, ethanol is injected slowly in the amounts of 1 to 10 mL on the basis of the aspirated fluid volume. Generally, PEI is given once or twice weekly, and treatment is usually completed in four to eight procedures. Complications include transient dysphonia, local pain, hematoma, and mild fever. In experienced hands, side effects are transient and minimal, and treatment is generally well accepted by most patients (100). Lippi and coworkers (103) reported the results of a large Italian multicenter study in patients with toxic thyroid nodules. The cure rate was 90% if nodules were small, with a nodule volume ⬍15 mL; there were no recurrences of hyperthyroidism. On the contrary, only a minority of patients with large nodules responded favorably to treatment. More recently, Zingrillo and colleagues (104)

214

Gharib

treated large, cold, benign thyroid nodules in patients not considered eligible for surgical excision. Ethanol was injected at weekly intervals, divided into 2- to 7mL doses, with a range of two to eight sessions per patient. No significant side effects were reported. Nodule volume measured ultrasonographically decreased significantly after PEI treatment. Zingrillo et al. propose PEI as a safe, effective, and alternative treatment for symptomatic large, cold, benign nodules in patients considered poor surgical risks. PEI is now considered an effective therapeutic tool in the management of thyroid nodules. Although experience with this treatment is limited in the United States, it may be a treatment option in an occasional patient with a benign recurrent cyst or a toxic nodule who either refuses surgery or cannot be treated with radioiodine. The author recently has successfully treated a hyperthyroid young woman with end-stage renal disease, a 3-cm hot nodule, and suppressed TSH. Renal failure made treatment with 131 I difficult, and the patient refused surgery. PEI, completed in four sessions, resulted in a decrease in nodule size and the restoration of a normal TSH level. 9

CALCITONIN TESTING

According to current data, sporadic MTC accounts for 5% of all thyroid cancers. Several recent studies have suggested that the prevalence of MTC in nodular thyroid disease is common, ranging from 0.5% to 1.37%, and that routine measurement of plasma calcitonin levels in patients with thyroid nodules will result in the detection of unsuspected MTC (105–110). Routine screening with calcitonin in combination with careful, meticulous pathologic examination has resulted in a higher detection of MTC in patients with nodular thyroid disease. For example, Vierhapper et al. (107) showed MTC in 0.5% and Henry et al. (108) in 0.71% of patients with nodular goiters. In a prospective study, Niccoli et al. (109) measured basal calcitonin concentrations in patients undergoing surgery for nodular goiters and reported that 1.37% had MTC. The authors stated that measurement of plasma levels of calcitonin is more sensitive than FNA biopsy in detecting sporadic MTC in nodular thyroid disease. Niederle and Scheuba (111) have proposed routine determination of plasma calcitonin in the initial diagnostic evaluation of all patients with morphological and functional thyroid disorders. If the basal calcitonin concentration is ⬎10 pg/mL, it should be followed by a calcium stimulation test, since pentagastrin is no longer available in the United States. Patients with abnormal stimulated calcitonin results (plasma calcitonin ⬎100 pg/mL 10 min after 2 mg/kg calcium in 50 mL normal saline IV infused over 1 min) should be further evaluated by ultrasonography and biopsy when indicated. Our recommendation is to follow these cases carefully and repeat provocative CT tests. If the abnormality persists, thyroidectomy is appropriate because of a substantially increased risk of sporadic MTC or C-cell hyperplasia.

Thyroid Nodules and Multinodular Goiter

215

Current data suggest that routine measurements of plasma concentrations of calcitonin will unmask unsuspected MTC. What is not known is how significant chief cell hyperplasia or microscopic MTC is and whether these lesions would become clinically significant if left untreated. Finally, is routine determination of calcitonin concentrations a cost-effective approach to diagnose MTC? These are unanswered questions, and it is premature to offer definite suggestions. In the meantime, we continue to rely on FNA to detect MTC in patients with nodular thyroid disease. 10 FNA IMPACT ON PRACTICE 10.1

Cost Considerations

Cost-effectiveness analysis takes into account medical outcome as well as procedure costs. It has been clearly established that FNA biopsy is both efficient and cost-effective (3,6). The cost-saving impact of FNA is particularly impressive when FNA is used as the initial diagnostic test. There seems to be unanimity among endocrinologists that FNA biopsy should be used in the diagnostic evaluation of thyroid nodules. It is fair to say that FNA biopsy has significantly influenced thyroid practice by being more efficacious as well as cost-saving in nodule management. Several publications have shown that with FNA biopsy the number of thyroid operations has decreased and the incidence of carcinoma in patients undergoing surgery has increased (112–118). In 1981, Miller and colleagues (112) reported that the availability of biopsy decreased the percentage of patients undergoing thyroid surgery from 37% to 11%, while increasing the yield of thyroid cancer from 33% to 67%. Others have reported similar results, some of which are listed in Table 8. After the introduction of FNA at the Mayo Clinic, the percentage of patients who TABLE 8 Impact of Fine-Needle Aspiration on Thyroid Surgery and Cancer Frequency Thyroidectomy, % a Study Miller et al. (112) Reeve et al. (113) Baskin and Guarda (114) Caplan et al. (115) Garcia-Mayor et al. (116) Hadi et al. (117) a

Cancer, % b

Pre-FNAc

Post-FNA

Pre-FNA

Post-FNA

37 74 — 61 90 67

11 57 17 37 47 43

33 10 9 18 15 18

67 22 54 35 33 40

Percentage of patients with nodular goiters undergoing thyroidectomy. Percentage of patients with cancer found at thyroidectomy. c FNA, fine-needle aspiration. b

216

Gharib

had surgery decreased from 67% to 43% and the percentage of carcinomas in operated patients more than doubled, from 18% to 40% (117,118). Clearly, this outcome represents improved surgical selection and indicates that few, if any, thyroid cancers are missed. The recently published guidelines of the American Association of Clinical Endocrinologists and the American Thyroid Association recommend referral to an endocrinologist for FNA as a primary approach (19,119). Recently, Ortiz and colleagues (120) showed that early referral of patients with suspected thyroid nodules to an endocrinologist results in significant savings in both cost and patient inconvenience. They compared the practice patterns of a primary care physician with those of an endocrinologist; evaluation pursued by a primary care physician resulted in an average unnecessary loss of $390 per patient. In several patients, advice to have surgery was reversed after consultation with the endocrinologist. This study suggests that not only are evaluations performed by primary care physicians more costly and more time-consuming than if the patients were referred to endocrinologists early during the evaluation but also that they are more likely to lead to unnecessary surgery. The issues of cost-effectiveness have been addressed previously by our group and others (6,25). FNA biopsy reduces the need for scanning or ultrasonography, decreasing the cost per nodule evaluated. Furthermore, the cost of management is significantly reduced by eliminating unnecessary thyroid surgery. Hamberger and colleagues (118) reported in 1982 that FNA biopsy decreased costs by about $400 to $700 per patient evaluated. In a similar analysis in 1991, Caplan and colleagues (115) found that the mean cost of care per patient decreased approximately $1300 after the introduction of FNA into their practice, by eliminating costly testing and reducing thyroid surgery for benign disease. 10.2

Practice Patterns

Current management of thyroid nodules rests on cytological diagnosis, using FNA as the screening test (Fig. 7). Some suggest scanning first, in part because of the premise that hot nodules yield hypercellular (‘‘suspicious’’) aspirates on FNA and would be treated surgically if FNA were used first (55). In fact, the author’s experience is similar to that of others (121)—namely, that most hyperfunctioning (hot) thyroid nodules are benign (colloid) nodules on FNA. Another issue is selecting the appropriate sequence of tests. For example, a 49-year-old woman was discovered to have a 3-cm right-lobe thyroid nodule during a recent routine examination (Fig. 14). The first test was ultrasonography, which showed a solitary solid nodule. Next, FNA biopsy was performed to rule out malignancy; the cytological results were benign, showing a colloid nodule. At this point, the patient was referred to an endocrinologist, who measured the serum level of TSH; this test was diagnostic because it showed TSH was sup-

Thyroid Nodules and Multinodular Goiter

217

FIG. 14 Inappropriate sequence of thyroid testing. A 49-year-old woman was found to have a firm, single right thyroid nodule. Ultrasonography confirmed the presence of a solitary solid right nodule 3 by 2 cm. Fine-needle aspiration biopsy results were benign, colloid. Serum level of thyroid-stimulating hormone was suppressed at 0.12 mIU/L (normal, 0.3 to 5). Thyroid scan showed palpable right nodule was hyperfunctioning; 131 I uptake was 37%. Treatment with 25 mCi of radioiodine was successful.

pressed. The diagnosis of a hot nodule was confirmed by a radioisotope scan that showed a solitary hot nodule in the right lobe of the thyroid. The patient was then treated with radioiodine. This is an example of an inappropriate test sequence, because both ultrasonography and FNA could have been avoided if the serum level of TSH had been determined during the initial evaluation. Such an approach would have been less costly and time-consuming and less of an inconvenience for the patient. Solomon and colleagues (122) published a survey of clinical members of the American Thyroid Association about their diagnostic assessment of thyroid nodules and cancer. Most (96%) of the respondents would perform FNA biopsy for diagnosis of thyroid nodules. Unexpectedly, approximately only 36% of respondents preferred performing the biopsy before getting a thyroid scan. In fact, 56% of respondents would get a thyroid scan, and—yet more unexpectedly— 28% would also determine the uptake. This practice appears to be at variance with the current increased emphasis on avoidance of unnecessary tests. As illustrated in the case in Fig. 8, such a practice pattern leads to increasing costs without improving care. A scan is indicated only if the initial TSH level is suppressed. Solomon and colleagues (122) concluded that even if there is consensus in practice patterns among specialists, the practice patterns should not necessarily be construed as model guidelines for management.

218

Gharib

11 CONCLUSIONS Thyroid nodules are very common and carry a ⬍5% risk of malignancy. FNA biopsy is now established as a safe, reliable, and accurate diagnostic test and should be performed on all patients with palpable nodules, either solitary or dominant nodules in MNGs. Biopsy with ultrasonographic guidance should be performed on incidentalomas in a patient with a high risk of malignancy or if the nodule is ⬎1.5 cm in diameter. Patients with cytologically benign nodules (75%) can be followed by palpation and have reaspiration in 1 to 2 years. Patients with cytologically suspicious or malignant nodules should have surgical excision. Cytologically benign colloid nodules should be followed carefully, either with or without suppressive therapy. Suppressive therapy is controversial. Currently, most endocrinologists follow nodules without T4 therapy because (a) treatment has not been convincingly demonstrated to be effective and (b) treatment has significant potential adverse effects. Thyroxine therapy is indicated for those who have had partial thyroidectomy or external irradiation or for those who have postoperative hypothyroidism. New treatment modalities include large radioiodine doses for large symptomatic MNGs and PEI for thyroid cysts, cold nodules, or hot nodules. These approaches are effective and, in the future, probably will be used increasingly for patients who either refuse surgery or are not candidates for surgical treatment. US-FNA is gaining increasing popularity because new high-resolution ultrasonography equipment is easy to operate, is less costly, and has been shown to increase biopsy yield. US-FNA is recommended for nondiagnostic nodules, nodules ⬍1 cm, and small nodules discovered incidentally in high-risk patients. The routine measurement of plasma calcitonin concentrations in patients with nodular disease is not recommended. Current information suggests that discovery of unsuspected MTC may lead to curative treatment. We await further studies in this area. Finally, FNA biopsy has dramatically affected thyroid practice and is accepted to be truly cost-effective. The application of FNA results in fewer thyroidectomies for benign disease and an increased rate of cancer in surgical specimens. Currently, it is believed that FNA should be performed by endocrinologists and that early referral of patients with nodular thyroid disease to endocrinologists will result in more money saved and less time spent by the patient. REFERENCES 1. Rojeski MT, Gharib H. Nodular thyroid disease. Evaluation and management. N Engl J Med 1985; 313:428–436. 2. Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med 1968; 69:537–540.

Thyroid Nodules and Multinodular Goiter

219

3. Gharib H. Fine-needle aspiration biopsy of thyroid nodules: advantages, limitations, and effect. Mayo Clin Proc 1994; 69:44–49. 4. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993; 328: 553–559. 5. Burch HB. Evaluation and management of the solid thyroid nodule. Endocrinol Metab Clin North Am 1995; 24:663–710. 6. Gharib H. Changing concepts in the diagnosis and management of thyroid nodules. Endocrinol Metab Clin North Am 1997; 26:777–800. 7. Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol 1955; 15:1270–1280. 8. Brander A, Viikinkoski P, Nickels J, Kivisaari L. Thyroid gland: US screening in a random adult population. Radiology 1991; 181:683–687. 9. Horlocker TT, Hay JE, James EM, Reading CC, Charboneau JW. Prevalence of incidental nodular thyroid disease detected during high-resolution parathyroid ultrasonography. In: Medeiros-Neto G, Gaitan E, eds. Frontiers in Thyroidology. Vol. 2. New York: Plenum Press, 1986, pp 1309–1312. 10. Tan GH, Gharib H, Reading CC. Solitary thyroid nodule: comparison between palpation and ultrasonography. Arch Intern Med 1995; 155:2418–2423. 11. Belfiore A, La Rosa GL, La Porta GA, Giuffrida D, Milazzo G, Lupo L, Regalbuto C, Vigneri R. Cancer risk in patients with cold thyroid nodules: relevance of iodine intake, sex, age, and multinodularity. Am J Med 1992; 93:363–369. 12. Fagin JA, ed. Thyroid Cancer. Boston: Kluwer, 1998, pp 59–83. 13. Derwahl M, Studes H. Pathogenesis and treatment of multinodular goiter. In: Fagin JA, ed. Thyroid Cancer. Boston: Kluwer, 1998, pp 155–186. 14. Fagin JA. Molecular pathogenesis of human thyroid neoplasm. Thyroid Today 1994; 3:1–7. 15. Derwahl M, Broecker M, Kraiem Z. Clinical review 101: thyrotropin may not be the dominant growth factor in benign and malignant thyroid tumors. J Clin Endocrinol Metab 1999; 84:829–834. 16. Smith SA, Gharib H. Thyroid nodule suppression. Adv Endocrinol Metab 1991; 2:107–124. 17. Daniels GH. Thyroid nodules and nodular thyroids: a clinical overview. Compr Ther 1996; 22:239–250. 18. Schneider AB, Bekerman C, Leland J, Rosengarten J, Hyun H, Collins B, ShoreFreedman E, Gierlowski TC. Thyroid nodules in the follow-up of irradiated individuals: comparison of thyroid ultrasound with scanning and palpation. J Clin Endocrinol Metab 1997; 82:4020–4027. 19. AACE Clinical Practice Guidelines for the diagnosis and management of thyroid nodules. Endocr Pract 1996; 2:78–84. 20. Atkinson BF. Fine needle aspiration of the thyroid. Monogr Pathol 1993; 35:166–199. 21. Gharib H. Diagnosis of thyroid nodules by fine-needle aspiration biopsy. Curr Opin Endocrinol 1996; 3:433–438. 22. Gharib H. Management of thyroid nodules: another look. Thyroid Today 1997; 20: 1–11. 23. Giuffrida D, Gharib H. Controversies in the management of cold, hot, and occult thyroid nodules. Am J Med 1995; 99:642–650.

220

Gharib

24. Singer PA. Evaluation and management of the solitary thyroid nodule. Otolaryngol Clin North Am 1996; 29:577–591. 25. Van Herle AJ, Rich P, Ljung B-ME, Ashcraft MW, Solomon DH, Keeler EB. The thyroid nodule. Ann Intern Med 1982; 96:221–232. 26. Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid nodules. Endocr Pract 1995; 1:410–417. 27. Oertel YC. Find-needle aspiration and the diagnosis of thyroid cancer. Endocrinol Metab Clin North Am 1996; 25:69–91. 28. Jeffrey PB, Miller TR. Fine-needle aspiration cytology of the thyroid. Pathology (Phila) 1996; 4:319–335. 29. Hamburger JI. Diagnosis of thyroid nodules by fine needle biopsy: use and abuse. Clin Endocrinol Metab 1994; 79:335–339. 30. Gharib H, Goellner JR. Evaluation of nodular thyroid disease. Endocrinol Metab Clin North Am 1988; 17:511–526. 31. Gharib H, Goellner JR, Johnson DA. Fine-needle aspiration cytology of the thyroid: a 12-year experience with 11,000 biopsies. Clin Lab Med 1993; 13:699–709. 32. Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Intern Med 1993; 118:282–289. 33. Bisi H, de Camargo RY, Longatto Filho A. Role of fine-needle aspiration cytology in the management of thyroid nodules: a review of experience with 1,925 cases. Diagn Cytopathol 1992; 8:504–510. 34. Goellner JR, Gharib H, Grant CS, Johnson DA. Fine needle aspiration cytology of the thyroid, 1980 to 1986. Acta Cytol 1987; 31:587–590. 35. Caruso D, Mazzaferri EL. Fine needle aspiration biopsy in the management of thyroid nodules. Endocrinologist 1991; 1:194–202. 36. Caraway NP, Sneige N, Samaan NA. Diagnostic pitfalls in thyroid fine-needle aspiration: a review of 394 cases. Diagn Cytopathol 1993; 9:345–350. 37. Cersosimo E, Gharib H, Suman VJ, Goellner JR. ‘‘Suspicious’’ thyroid cytologic findings: outcome in patients without immediate surgical treatment. Mayo Clin Proc 1993; 68:343–348. 38. Hall TL, Layfield LJ, Philippe A, Rosenthal DL. Sources of diagnostic error in fine needle aspiration of the thyroid. Cancer 1989; 63:718–725. 39. MacDonald L, Yazdi HM. Nondiagnostic fine needle aspiration biopsy of the thyroid gland: a diagnostic dilemma. Acta Cytol 1996; 40:423–428. 40. Powers CN, Frable WJ. Fine Needle Aspiration Biopsy of the Head and Neck. Boston: Butterworth-Heinemann, 1996. 41. Schlinkert RT, van Heerden JA, Goellner JR, Gharib H, Smith SL, Rosales RF, Weaver AL. Factors that predict malignant thyroid lesions when fine-needle aspiration is ‘‘suspicious for follicular neoplasm.’’ Mayo Clin Proc 1997; 72:913– 916. 42. Schmidt T, Riggs MW, Speights VO Jr. Significance of nondiagnostic fine-needle aspiration of the thyroid. South Med J 1997; 90:1183–1186. 43. Tuttle RM, Lemar H, Burch HB. Clinical features associated with an increased risk of thyroid malignancy in patients with follicular neoplasia by fine-needle aspiration. Thyroid 1998; 8:377–383. 44. Musgrave YM, Davey DD, Weeks JA, Banks ER, Rayens MK, Ain KB. Assess-

Thyroid Nodules and Multinodular Goiter

45.

46. 47. 48.

49. 50.

51. 52. 53.

54.

55. 56.

57. 58. 59.

60. 61.

221

ment of fine-needle aspiration sampling technique in thyroid nodules. Diagn Cytopathol 1998; 18:76–80. Burch HB, Burman KD, Reed HL, Buckner L, Raber T, Ownbey JL. Fine needle aspiration of thyroid nodules: determinants of insufficiency rate and malignancy yield at thyroidectomy. Acta Cytol 1996; 40:1176–1183. Reading CC, Gorman CA. Thyroid imaging techniques. Clin Lab Med 1993; 13: 711–724. Blum M, Yee J. Advances in thyroid imaging: thyroid sonography—when and how should it be used? Thyroid Today 1997; 20:1–13. Dolan JG. Thyroid nodules. In: Panzer RJ, Black ER, Griner PF, eds. Diagnostic Strategies for Common Medical Problems. Philadelphia: American College of Physicians, 1991, pp 385–393. Wiersinga WM. Is repeated fine-needle aspiration cytology indicated in (benign) thyroid nodules? Eur J Endocrinol 1995; 132:661–662. Lucas A, Llatjos M, Salinas I, Reverter J, Pizarro E, Sanmarti A. Fine-needle aspiration cytology of benign nodular thyroid disease: value of re-aspiration. Eur J Endocrinol 1995; 132:677–680. Komatsu M, Kuroda T. Flow cytometric nuclear DNA analysis of follicular thyroid nodules. Res Surg 1995; 7:36–41. Karmakar T, Dey P. Role of AgNOR in diagnosis of thyroid follicular neoplasms on fine-needle aspiration smears. Diagn Cytopathol 1995; 12:148–149. Delbridge L, Lean CL, Russell P, May GL, Roman S, Dowd S, Reeve TS, Mountford CE. Proton magnetic resonance and human thyroid neoplasia. II: Potential avoidance of surgery for benign follicular neoplasms. World J Surg 1994; 18:512– 516. Yamashita H, Noguchi S, Murakami N, Adachi M, Maruta J. Immunohistological differentiation of benign thyroid follicular cell tumors from malignant ones: usefulness of anti-peroxidase and JT-95 antibodies. Acta Pathol Jpn 1993; 43:670– 673. Ridgway EC. Clinical review 30: clinician’s evaluation of a solitary thyroid nodule. J Clin Endocrinol Metab 1992; 74:231–235. McHenry CR, Slusarczyk SJ, Askari AT, Lange RL, Smith CM, Nekl K, Murphy TA. Refined use of scintigraphy in the evaluation of nodular thyroid disease. Surgery 1998; 124:656–661. McHenry CR, Walfish PG, Rosen IB. Non-diagnostic fine needle aspiration biopsy: a dilemma in management of nodular thyroid disease. Am Surg 1993; 59:415–419. Baloch ZW, Sack MJ, Yu GH, Livolsi VA, Gupta PK. Fine-needle aspiration of thyroid: an institutional experience. Thyroid 1998; 8:565–569. Gharib H, James EM, Charboneau JW, Naessens JM, Offord KP, Gorman CA. Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study. N Engl J Med 1987; 317:70–75. Cheung PS, Lee JM, Boey JH. Thyroxine suppressive therapy of benign solitary thyroid nodules: a prospective randomized study. World J Surg 1989; 13:818–821. Reverter JL, Lucas A, Salinas I, Audi L, Foz M, Sanmarti A. Suppressive therapy with levothyroxine for solitary thyroid nodules. Clin Endocrinol (Oxf) 1992; 36: 25–28.

222

Gharib

62. Berghout A, Wiersinga WM, Drexhage HA, Smits NJ, Touber JL. Comparison of placebo with l-thyroxine alone or with carbimazole for treatment of sporadic nontoxic goitre. Lancet 1990; 336:193–197. 63. Celani MF. Levothyroxine suppressive therapy in the medical management of nontoxic benign multinodular goiter. Exp Clin Endocrinol 1993; 101:326–332. 64. Celani MF, Mariani M, Mariani G. On the usefulness of levothyroxine suppressive therapy in the medical treatment of benign solitary, solid or predominantly solid, thyroid nodules. Acta Endocrinol (Copenh) 1990; 123:603–608. 65. Diacinti D, Salabe GB, Olivieri A, D’Erasmo E, Tomei E, Lotz-Salabe H, De Martinis C. Suppressive therapy with levothyroxine for euthyroid nodular goiter. Minerva Med 1992; 83:745–751. 66. LaRosa GL, Ippolito AM, Lupo L, Cercabene G, Santonocito MG, Vigneri R, Belfiore A. Cold thyroid nodule reduction with l-thyroxine can be predicted by initial nodule volume and cytological characteristics. J Clin Endocrinol Metab 1996; 81: 4385–4387. 67. La Rosa GL, Lupo L, Giuffrida D, Gullo D, Vigneri R, Belfiore A. Levothyroxine and potassium iodide are both effective in treating benign solitary solid cold nodules of the thyroid. Ann Intern Med 1995; 122:1–8. 68. Mainini E, Martinelli I, Morandi G, Villa S, Stefani I, Mazzi C. Levothyroxine suppressive therapy for solitary thyroid nodule. J Endocrinol Invest 1995; 18:796–799. 69. Kuo SW, Hu CA, Pei D, Ni KB, Shian LR. Efficacy of thyroxine-suppressive therapy and its relation to serum thyroglobulin levels in solitary nontoxic thyroid nodules. J Formos Med Assoc 1993; 92:55–60. 70. Ross DS. Thyroid hormone suppressive therapy of sporadic nontoxic goiter. Thyroid 1992; 2:263–269. 71. Cooper DS. Thyroxine suppression therapy for benign nodular disease. J Clin Endocrinol Metab 1995; 80:331–334. 72. Zelmanovitz F, Genro S, Gross JL. Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study and cumulative meta-analyses. J Clin Endocrinol Metab 1998; 83:3881–3885. 73. Gharib H, Mazzaferri EL. Thyroxine suppressive therapy in patients with nodular thyroid disease. Ann Intern Med 1998; 128:386–394. 74. Faber J, Galloe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to l-thyroxine treatment: a meta-analysis. Eur J Endocrinol 1994; 130: 350–356. 75. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW, Benjamin EJ, D’Agostino RB. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331:1249–1252. 76. Kuma K, Matsuzuka F, Kobayashi A, Hirai K, Morita S, Miyauchi A, Katayama S, Sugawara M. Outcome of long standing solitary thyroid nodules. World J Surg 1992; 16:583–587. 77. Kuma K, Matsuzuka F, Yokozawa T, Miyauchi A, Sugawara M. Fate of untreated benign thyroid nodules: results of long-term follow-up. World J Surg 1994; 18: 495–498. 78. Schneider DL, Barrett-Connor EL, Morton DJ. Thyroid hormone use and bone

Thyroid Nodules and Multinodular Goiter

79.

80. 81.

82. 83.

84. 85.

86.

87.

88. 89. 90.

91.

92. 93.

223

mineral density in elderly women: effects of estrogen. JAMA 1994; 271:1245– 1249. Fogelfeld L, Wiviott MB, Shore-Freedman E, Blend M, Bekerman C, Pinsky S, Schneider AB. Recurrence of thyroid nodules after surgical removal in patients irradiated in childhood for benign conditions. N Engl J Med 1989; 320:835–840. Hurley DL, Gharib H. Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996; 29:527–540. Huysmans DA, Buijs WC, van de Ven MT, van den Broek WJ, Kloppenborg PW, Hermus AR, Corstens FH. Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters. J Nucl Med 1996; 37:2072–2079. Huysmans DA, Hermus AR, Corstens FH, Barentsz JO, Kloppenborg PW. Large, compressive goiters treated with radioiodine. Ann Intern Med 1994; 121:757–762. Huysmans DAKC, Hermus ARMM, Edelbroek MAL, Tjabbes T, Oostdijk A, Ross HA, Corstens FHM, Kloppenborg PWC. Autoimmune hyperthyroidism occurring late after radioiodine treatment for volume reduction of large multinodular goiters. Thyroid 1997; 7:535–539. Huysmans D, Hermus A, Edelbroek M, Barentsz J, Corstens F, Kloppenborg P. Radioiodine for nontoxic multinodular goiter. Thyroid 1997; 7:235–239. Nygaard B, Faber J, Hegedus L. Acute changes in thyroid volume and function following 131 I therapy of multinodular goitre. Clin Endocrinol (Oxf) 1994; 41:715– 718. Nygaard B, Soes-Petersen U, Hoilund-Carlsen PF, Veje A, Holst PE, Vestergaard A, Solling K. Improvement of upper airway obstruction after 131 I-treatment of multinodular nontoxic goiter evaluated by flow volume loop curves. J Endocrinol Invest 1996; 19:71–75. Wesche MF, Tiel-v-Buul MM, Smits NJ, Wiersinga WM. Reduction in goiter size by 131 I therapy in patients with non-toxic multinodular goiter. Eur J Endocrinol 1995; 132:86–87. Hermus AR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med 1998; 338:1438–1447. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas: prevalence by palpation and ultrasonography. Arch Intern Med 1994; 154:1838–1840. Tomimori E, Pedrinola F, Cavaliere H, Knobel M, Medeiros-Neto G. Prevalence of incidental thyroid disease in a relatively low iodine intake area. Thyroid 1995; 5:273–276. Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 1997; 126: 226–231. Hagag P, Strauss S, Weiss M. Role of ultrasound-guided fine-needle aspiration biopsy in evaluation of nonpalpable thyroid nodules. Thyroid 1998; 8:989–995. Cochand-Priollet B, Guillausseau PJ, Chagnon S, Hoang C, Guillausseau-Scholer C, Chanson P, Dahan H, Warnet A, Tran Ba Huy PT, Valleur P. The diagnostic value of fine-needle aspiration biopsy under ultrasonography in nonfunctional thyroid nodules: a prospective study comparing cytologic and histologic findings. Am J Med 1994; 97:152–157.

224

Gharib

94. Carmeci C, Jeffrey RB, McDougall IR, Nowels KW, Weigel RJ. Ultrasound-guided fine-needle aspiration biopsy of thyroid masses. Thyroid 1998; 8:283–289. 95. Danese D, Sciacchitano S, Farsetti A, Andreoli M, Pontecorvi A. Diagnostic accuracy of conventional versus sonography-guided fine-needle aspiration biopsy of thyroid nodules. Thyroid 1998; 8:15–21. 96. Sabel MS, Haque D, Velasco JM, Staren ED. Use of ultrasound-guided fine needle aspiration biopsy in the management of thyroid disease. Am Surg 1998; 64:738– 741. 97. Papini E, Bacci V, Panunzi C, Pacella CM, Fabbrini R, Bizzarri G, Petrucci L, Giammarco V, La Medica P, Masala M, Pitaro M, Nardi F. A prospective randomized trial of levothyroxine suppressive therapy for solitary thyroid nodules. Clin Endocrinol (Oxf) 1993; 38:507–513. 98. Monzani F, Lippi F, Goletti O, Del Guerra P, Caracio N, Lippolis PV, Baschieri L, Pinchera A. Percutaneous aspiration and ethanol sclerotherapy for thyroid cysts. J Clin Endocrinol Metab 1994; 78:800–802. 99. Monzani F, Caraccio N, Goletti O, Lippolis PV, Casolaro A, Del Guerra P, Cavina E, Miccoli P. Five-year follow-up of percutaneous ethanol injection for the treatment of hyperfunctioning thyroid nodules: a study of 117 patients. Clin Endocrinol (Oxf) 1997; 46:9–15. 100. Papini E, Pacella CM, Verde G. Percutaneous ethanol injection (PEI): what is its role in the treatment of benign thyroid nodules? Thyroid 1995; 5:147–150. 101. Zingrillo M, Torlontano M, Ghiggi MR, D’Aloiso L, Nirchio V, Bisceglia M, Liuzzi A. Percutaneous ethanol injection of large thyroid cystic nodules. Thyroid 1996; 6:403–408. 102. Sidawy MK, Del Vecchio DM, Knoll SM. Fine-needle aspiration of thyroid nodules: correlation between cytology and histology and evaluation of discrepant cases. Cancer 1997; 81:253–259. 103. Lippi F, Ferrari C, Manetti L, Rago T, Santini F, Monzani F, Bellitti P, Papini E, Busnardo B, Angelini F, Pinchera A, Verde G, Martino E, Andreoli M, Fenzi G, Andreani M, Giordano G, Monaco F, Ianni A, Pontecorvi A, Caraccio N, Paracchi A, Portioli I. Treatment of solitary autonomous thyroid nodules by percutaneous ethanol injection: results of an Italian multicenter study. J Clin Endocrinol Metab 1996; 81:3261–3264. 104. Zingrillo M, Collura D, Ghiggi MR, Nirchio V, Trischitta V. Treatment of large cold benign thyroid nodules not eligible for surgery with percutaneous ethanol injection. J Clin Endocrinol Metab 1998; 83:3905–3907. 105. Pacini F, Fontanelli M, Fugazzola L, Elisei R, Romei C, Di Coscio G, Miccoli P, Pinchera A. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1994; 78:826–829. 106. Rieu M, Lame MC, Richard A, Lissak B, Sambort B, Vuong-Ngoc P, Berrod JL, Fombeur JP. Prevalence of sporadic medullary thyroid carcinoma: the importance of routine measurement of serum calcitonin in the diagnostic evaluation of thyroid nodules. Clin Endocrinol (Oxf) 1995; 42:453–460. 107. Vierhapper H, Raber W, Bieglmayer C, Kaserer K, Weinhausl A, Niederle B. Rou-

Thyroid Nodules and Multinodular Goiter

108.

109.

110.

111. 112. 113. 114. 115. 116.

117. 118.

119.

120.

121. 122.

225

tine measurement of plasma calcitonin in nodular thyroid diseases. J Clin Endocrinol Metab 1997; 82:1589–1593. Henry JF, Denizot A, Puccini M, Gramatica L, Kvachenyuk A, Conte Devolx B, De Micco C. Latent subclinical medullary thyroid carcinoma: diagnosis and treatment. World J Surg 1998; 22:752–756. Niccoli P, Wion-Barbot N, Caron P, Henry JF, de Micco C, Saint Andre JP, Bigorgne JC, Modigliani E, Conte-Devolx B. Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group. J Clin Endocrinol Metab 1997; 82:338–341. Kudva YC, Gharib H. Thyroid nodules: approaches to diagnosis and management. In: Fagin JA, ed. Thyroid Cancer. Boston: Kluwer Academic Publishers, 1998, pp 139–154. Niederle B, Scheuba C. Invited commentary. World J Surg 1998; 22:756–757. Miller JM, Hamburger JI, Kini SR. The needle biopsy diagnosis of papillary thyroid carcinoma. Cancer 1981; 48:989–993. Reeve TS, Delbridge L, Sloan D, Crummer P. The impact of fine-needle aspiration biopsy on surgery for single thyroid nodules. Med J Aust 1986; 145:308–311. Baskin HJ, Guarda LA. Influence of needle biopsy on management of thyroid nodules: reasons to expand its use. South Med J 1987; 80:702–705. Caplan RH, Strutt PJ, Kisken WA, Wester SM. Fine needle aspiration biopsy of thyroid nodules. Wis Med J 1991; 90:285–288. Garcia-Mayor RV, Perez Mendez LF, Paramo C, Luna Cano R, Rego Iraeta A, Regal M, Sierra JM, Fluiters E. Fine-needle aspiration biopsy of thyroid nodules: impact on clinical practice. J Endocrinol Invest 1997; 20:482–487. Hadi M, Gharib H, Goellner JR, van Heerden JA. Has fine-needle aspiration biopsy changed thyroid practice? Endocrinol Pract 1997; 3:9–13. Hamberger B, Gharib H, Melton LJ III, Goellner JR, Zinsmeister AR. Fine-needle aspiration biopsy of thyroid nodules. Impact on thyroid practice and cost of care. Am J Med 1982; 73:381–384. Singer PA, Cooper DS, Daniels GH, Ladenson PW, Greenspan FS, Levy EG, Braverman LE, Clark OH, McDougall IR, Ain KV, Dorfman SG. Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. Arch Intern Med 1996; 156:2165–2172. Ortiz R, Hupart KH, DeFesi CR, Surks MI. Effect of early referral to an endocrinologist on efficiency and cost of evaluation and development of treatment plan in patients with thyroid nodules. J Clin Endocrinol Metab 1998; 83:3803–3807. Liel Y, Zirkin HJ, Sobel RJ. Fine needle aspiration of the hot thyroid nodule. Acta Cytol 1988; 32:866–867. Solomon BL, Wartofsky L, Burman KD. Current trends in the management of well differentiated papillary thyroid carcinoma. J Clin Endocrinol Metab 1996; 81:333– 339.

6 Thyroid Carcinoma Richard T. Kloos and Ernest L. Mazzaferri The Ohio State University, Columbus, Ohio

1

INTRODUCTION

Thyroid carcinoma comprises a spectrum of malignancies ranging from rarely lethal, slow-growing neoplasms to among the most deadly aggressive cancers to afflict humanity. Fortunately, most cases are well-differentiated tumors that can be treated successfully. However, therapy remains controversial because definitive prospective clinical studies are confounded by low disease incidence, prolonged disease time course, and relatively good outcome in the majority of patients. Further, while staging systems predict outcome reasonably well, they remain inexact. Thus, while the majority of patients can be reassured that they are likely to do well, this outcome cannot be absolutely guaranteed. As a result, therapy has remained relatively dogmatic, as the ideal strategy that prevents unnecessary overtreatment while avoiding detrimental undertreatment is not a current reality, leading physicians to essentially choose on which side to err. The goals of patient management are to minimize morbidity and mortality from cancer (tumor recurrence, metastases, and death) as well as from therapy [surgery, hypothyroidism, iodine-131 (131I) therapy, thyroid stimulating hormone (TSH) suppression, and cost]. This chapter emphasizes features that predict outcome and current management paradigms. 227

228

2

Kloos and Mazzaferri

EPIDEMIOLOGY

Approximately 17,000 new cases of thyroid carcinoma have been diagnosed annually in the United States in recent years, ranking it 14th among internal organ malignancies (1). It occurs at all ages but is most common among middle-aged and postmenopausal women and in older men (Fig. 1). The lifetime risk of clinically apparent thyroid carcinoma is 0.65% for women and 0.25% for men (2). However, according to reproductive status, the female-to-male incidence ratio varies, from being almost 1 in childhood, increasing to 3 from puberty to menopause, and declining to 1.5 by age 65 years. Overall death rates are ⬍10% (there were 1200 deaths among 135,000 persons living with thyroid carcinoma in 1998) (1). Importantly, both the incidence and mortality rates vary substantially among the different forms of thyroid carcinoma (Table 1) (3). Between 1973 and 1992 the incidence of thyroid carcinoma rose almost 28%, while its mortality rates dropped more than 23% (2). This improved survival is due to effective therapy of differentiated (papillary and follicular) thyroid carci-

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

Thyroid Carcinoma

229

TABLE 1 Incidence and 10-Year Relative Survival Rates of the Major Histological Types of Thyroid Carcinoma Among 31,513 Cases Diagnosed Between 1985 And 1995 a Thyroid Carcinoma Type

Frequency (%)

Survival (%)

80 11 3 4 2

93 85 76 75 14

Papillary Follicular Hu¨rthle Medullary Anaplastic a

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

nomas detected at an earlier tumor stage, when the disease is most amenable to surgery and 131 I therapy (4). 2.1 Classification Thyroid carcinomas are classified into four major types, which, in decreasing order of frequency, are papillary (PTC), follicular (FTC), medullary (MTC) and anaplastic thyroid carcinoma (ATC) (Table 1). PTC and FTC—often termed well-differentiated thyroid carcinomas—arise from follicular cells, synthesize thyroglobulin (Tg), and tend to be sporadic tumors, although occasionally PTC is familial. MTC, which originates from thyroidal C cells that secrete calcitonin, may be sporadic or familial. ATC usually arises from well-differentiated thyroid carcinomas. 3

PAPILLARY AND FOLLICULAR THYROID CARCINOMA

3.1 Prevalence and Inheritance 3.1.1

Papillary Thyroid Carcinoma (PTC)

This tumor accounts for about 80% of all thyroid carcinomas in the United States (3,5). PTC is three times more frequent in women than in men. Incidence is highest in women in midlife, but it occurs at all ages. Often considered a separate disease, occult microscopic PTC (⬍1 cm) is found in 10% or more of autopsy and surgical thyroid specimens obtained from men and women throughout adult life (6).

230

Kloos and Mazzaferri

3.1.2

Familial Papillary Carcinoma

About 5% of PTCs are familial tumors inherited as an autosomal dominant trait without other associated pathology. The gene responsible for its transmission has not been identified (7,8). Familial PTC seems to have a poorer prognosis than sporadic PTC (9). PTC can also be inherited with other diseases, such as familial adenomatous polyposis, Cowden disease, and Carney complex. PTCs inherited as a component of familial adenomatous polyposis (Gardner’s syndrome) occur at a young age and are bilateral, multicentric tumors that have an excellent prognosis, particularly those with RET/PTC activation (10,11). Cowden disease is an autosomal dominant syndrome characterized by multiple mucocutaneous hamartomas, keratoses, fibrocystic breast disease or breast cancer, and well-differentiated thyroid cancer (12,13). Carney complex, a syndrome with spotty skin pigmentation, myxomas, schwannomas, and multiple neoplasia that affects multiple glands also includes thyroid carcinoma (14). 3.1.3

Follicular Thyroid Carcinoma (FTC)

This tumor occurs sporadically and accounts for about 10% of all thyroid cancers in the United States, although it is more common in countries with low dietary iodine (5). It usually occurs at a slightly older age than PTC (15), but in some studies almost half the patients are ⬍40 years old at diagnosis (16). This tumor is rare in children, occurs infrequently after head and neck irradiation, and is not commonly found incidentally. 4

RADIATION-INDUCED THYROID CARCINOMA

4.1 Epidemiology Exposure to ionizing radiation during childhood is the best understood cause of thyroid carcinoma. Nevertheless, such a history usually is now elicited in only about 5% of patients (5). Some radiation exposure events have been associated with an increased risk of thyroid cancer, while others have not. Possible explanations of this difference may include the different sources of radiation involved, which delivered different thyroid doses and different thyroid dose rates. 4.1.1

External Radiation

The risk of developing PTC after therapeutic external radiation, used in the past for children with benign head and neck conditions and today for childhood cancer, is well known (17). The cancers tend to be multifocal and behave similarly to sporadic PTC. Adults exposed to external beam radiation have low or no increased risk of thyroid cancer. Exposure before the age of 15 years poses a major risk that progressively increases with increasing doses of radiation between 0.10 Gy (10 rads) and 10 Gy (1000 rad). Above 15 Gy the risk of thyroid cancer is

Thyroid Carcinoma

231

increased, but the risk per gray decreases, presumably due to cell destruction consistent with the rise in hypothyroidism risk. The incidence of thyroid carcinoma begins to increase within 5 years of exposure and continues unabated for 30 years, after which it begins to decline, with significant risk still present after 40 years (17). Over this period of time, the risk of developing a benign thyroid nodule is 60%, and 15% for thyroid cancer (18). Often the predominant nodule is benign, while smaller malignant tumors are present in the background. This fact does not imply that all radiated patients with a thyroid nodule should have an operation; but it does suggest that if an operation is performed, it should be a total thyroidectomy. Female gender, radiation for childhood cancer (as opposed to benign conditions), and family history of thyroid cancer increase the risk of developing thyroid cancer after external beam radiation therapy (17). Children radiated for neuroblastoma have a fivefold greater risk of thyroid cancer than do children radiated for other cancers. 4.1.2

Radioiodine-Induced Thyroid Carcinoma

131

I is less effective than external radiation in inducing thyroid cancer (19). A recent large study reported a slight elevation of thyroid cancer mortality following treatment of hyperthyroidism with 131 I, but the absolute risk was small and the underlying thyroid disease probably played a significant role (20). Most other studies of thyroid cancer risk following exposure to diagnostic or therapeutic 131 I in children and adults suggest no increased risk (21–24). 4.1.3

Fallout from Nuclear Weapons and Reactor Accidents

Atomic bombing of Hiroshima and Nagasaki occurred in 1945. Radiation exposure was mainly from external x-rays and neutrons. The first solid tumor found to be significantly increased among A-bomb survivors was thyroid carcinoma, which occurred only among those under age 20 at the time of exposure (19). The Bravo nuclear test occurred on the Bikini atoll in 1954, exposing individuals to external beta and gamma radiation and internal radionuclides. Most of the thyroid radiation was from short-lived isotopes that delivered their radiation dose in about half the time as 131 I does and theoretically would allow less time for DNA repair. Follow-up studies have demonstrated increased risk for thyroid nodules (22%) and thyroid carcinomas (7%). Nuclear weapons tested above ground in Nevada between 1951 and 1963 released radioactive particles into the atmosphere that exposed individuals across the continental United States mainly to radiation from 131 I. The chance of a significant exposure was highest in the 1950s for children who routinely drank milk from a ‘‘backyard’’ cow or goat that had ingested grass contaminated with radioactive iodine fallout. This situation resulted in an average cumulative thyroid

232

Kloos and Mazzaferri

dose of 0.02 Gy (2 rad) for the American population collectively and 0.1 Gy (10 rad) for those under age 20 at time of exposure, which, when delivered by external beam radiation, is in the range known to cause thyroid carcinoma in children. One study established an association between thyroid carcinoma and radioiodine fallout from nuclear tests in Nevada among children exposed at ⬍1 year of age and those born between 1950 and 1959 (25). However, others (26), like the Hanford Thyroid Disease Study which focused on the Hanford Nuclear Site in Washington (which released almost exclusively 131 I), found no increased risk. Mass screening for potential thyroid disease from radioactive fallout is not recommended for the general population, but physicians should discuss the potential risk with concerned patients and palpate the neck annually as part of routine care (27). Thyroid carcinoma developed after exposure to radioactive fallout from the Chernobyl nuclear reactor accident in 1986, with a 75-fold increased incidence in children, 10-fold in adolescents, 4-fold in young adults, and 3-fold in adults after 10 years. Most of the thyroid carcinomas occurred in children who were exposed under the age of 10 years, and it occurred with a nearly equal sex ratio (28). Radionuclides released included 131 I, 132I, and 133I. These carcinomas harbor a high frequency (55% to 85%) of RET/PTC gene rearrangements (PTC1 and PTC3). PTC3 has been associated with aggressive tumor behavior (29). The Chernobyl data support the etiological role of radioactive iodine isotopes in the development of thyroid carcinoma. However, the specific role of 131 I by itself has not been clearly established. Potassium iodide prophylaxis is indicated in the setting of nuclear fallout to diminish thyroid uptake of radioiodines, especially in pregnant women and children.

5

PAPILLARY THYROID CARCINOMA

5.1 Pathology Papillary thyroid carcinoma (PTC) is typically an unencapsulated invasive tumor with ill-defined margins. In about 10% of cases, the thyroid capsule is penetrated by tumor that may invade surrounding tissues, while another 10% are fully encapsulated (30). The tumor is typically firm and solid but may develop chronic hemorrhagic necrosis, making it soft, and yielding a thick brownish fluid on needle biopsy that may cause it to be mistaken for a benign cyst (31). Small tumors ⱕ1.0 cm in diameter, termed microcarcinomas, often have a stellate appearance and are usually found by serendipity. Although they generally pose no risk to the patient, microcarcinomas are rarely locally invasive and metastatic (32). Most PTCs have a typical appearance, with complex, branching papillae and a fibrovascular core covered by a single layer of tumor cells intermingled with follicular structures; but some PTCs have a pure follicular or trabecular

Thyroid Carcinoma

233

appearance (33). The term mixed papillary-follicular carcinoma has no clinical value because the follicular component does not alter 131 I uptake or prognosis: thus such tumors are considered to be PTCs (34). Nuclear features are more important than architectural appearance in establishing a PTC diagnosis. Tumors with a pure follicular pattern but typical cellular features of PTC are termed follicular variant of PTC, which some pathologists argue comprises most of the tumors diagnosed as FTC (35). Multiple foci of PTC are common within the thyroid gland. They are generally thought to be intraglandular metastases and are present in up to 80% of cases when the gland is examined in detail but are found in 20% to 45% of specimens on routine examination and usually are bilateral (5). Focal areas of infiltration with lymphocytes or plasma cells or classic Hashimoto’s disease is usually present in or around the tumor and is intense in up to 20% of cases (36). The presence of neoplastic cell phagocytosis by macrophages and lymphocytic infiltration has been associated with a more favorable clinical outcome (37). The cellular features of PTC distinguish it from other tumors, regardless of its architecture, permitting an accurate diagnosis by fine-needle aspiration (FNA) cytology (Fig. 2A). The large cells contain pink to amphophilic finely granular cytoplasm and large pale nuclei sometimes called ‘‘Orphan Annie eye’’ nuclei, with inclusion bodies and nuclear grooves that identify it as PTC (Fig. 2A). Psammoma bodies—the ‘‘ghosts’’ of infarcted papillae that are virtually pathognomonic of PTC—are calcified, concentric lamellated spheres found in about half the cases (Fig. 2A) (38). Multiple histological subtypes or variants of PTC have been described (Table 2) (33,39,40). 5.1.1

Lymph Node Metastases

PTC metastasizes to lymph nodes in the lateral and central neck and mediastinum. Lymph node metastases are found in almost half the cases at the time of diagnosis, while even more—up to 85% in some studies (41,42)—have microscopic nodal metastases found on more careful histological study (34). The number and size of lymph node metastases increase as the primary tumor size enlarges (5). When the isthmus or both lobes are involved with tumor, nodal metastases are often bilateral or extend into the mediastinum; in other cases tumor penetrates the lymph node capsule and invades the soft tissues. All of these are poor prognostic signs (34,43). 5.1.2

Distant Metastases

Fewer than 5% of patients have distant metastases at the time of diagnosis and another 5% develop them over the next two or three decades (5). The lung is the most common site of distant metastases and is the most common disease-specific cause of death from PTC. In a review of 1231 patients with distant metastases,

234

a

b

Kloos and Mazzaferri

Thyroid Carcinoma

235

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

236

Kloos and Mazzaferri

TABLE 2 Main Histological Variants a of Papillary and Follicular Thyroid Carcinoma Better

Worse

Papillary thyroid carcinoma (PTC) Encapsulated Tall cell Cystic Columnar cell Microcarcinoma Diffuse sclerosis Macrocarcinoma Diffuse follicular

Possibly Worse Follicular Solid Oncocytic (Hu¨rthle cell) Associated with Graves’ disease

Insular cell PTC with dedifferentiation Follicular thyroid carcinoma (FTC) Oncocytic (Hu¨rthle cell) Insular cell a

Other histological variants—such as PTC with lipomatous stroma or fascitis-like stroma or myxoid and cribriform variant PTC—have been reported too rarely to be certain about prognosis. Source: Adapted from Ref. 39.

49% were in the lung alone and another 15% were in lung and bone, 25% were in bone alone, and 12% were in the central nervous system or in multiple organs (5). Lung metastases may be large and discrete (Fig. 3A) or may have a ‘‘snowflake’’ appearance from diffuse lymphangitic spread (Fig. 3B); they may concentrate sufficient 131 I to be detected on whole-body scan (Fig. 3C and 3D). Some lung metastases are not seen on radiographs but are visible on 131 I whole-body scans, sometimes only after administration of therapeutic doses (44–47). 5.1.3

Papillary Microcarcinoma

Papillary microcarcinomas are tumors ⱕ1.0 cm in diameter that are almost always clinically unapparent. Histologically malignant, they are usually clinically benign in their behavior and are generally found by serendipity during surgery for benign thyroid disease. However, about 20% are multifocal tumors that metastasize to cervical lymph nodes in up to 60% of the cases (42), which signals more aggressive tumor behavior (32). Lung metastases from microcarcinomas are rare but may occur with multifocal microcarcinomas that have bulky cervical metastases (32,40). Otherwise, the recurrence and cancer-specific mortality rates of papillary microcarcinoma are near zero (6,32). 5.1.4

Thyroglossal Duct

PTC within a thyroglossal duct is almost always small and usually has a benign course (48).

Thyroid Carcinoma

237

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

238

5.1.5

Kloos and Mazzaferri

Encapsulated Papillary Carcinoma

This variant accounts for about 10% of PTCs. Completely surrounded by a fibrous capsule but otherwise a typical PTC, it is about half as likely as usual to metastasize, rarely recurs after initial therapy, and almost never causes death (38,40). 5.1.6

Follicular Variant Papillary Carcinoma

Ten percent of PTCs are unencapsulated, with microfollicular architecture otherwise indistinguishable from FTC but with nuclear features of PTC that can be identified by routine histological sections and by FNA cytology (38,40). Some physicians claim that the prognosis of this lesion is similar to that of typical PTC; others suggest that distant metastases are more likely and long-term outcome is less favorable (39,40,49). 5.1.7

Diffuse Follicular Variant Papillary Carcinoma

This uncommon tumor may be confused with typical multinodular goiter or macrofollicular adenoma on frozen section (39). It occurs mainly in women with goiter, about one-third of whom have hyperthyroidism. Most have distant metastases with very high mortality rates (39). 5.1.8

Tall Cell Variant

Ten percent of PTCs have papillae with cells twice as tall as they are wide that constitute at least 30% of the tumor (39). Compared with typical PTC, tall cell variants tend to be diagnosed about two decades later (in the mid-50s), are larger, and are more often associated with invasion into local soft tissues and with distant metastases (12,39,40). The tumor can be identified by FNA cytology. It often expresses the p53 oncogene, loses or lacks 131 I uptake, and has long-term mortality rates two to threefold those of typical PTC (12,40). 5.1.9

Columnar Cell Variant

This rare variant, which is possibly related to tall cell carcinoma, is found mainly in males and is composed of rectangular cells with clear cytoplasm (39). Distant metastases develop in 90% and are usually unresponsive to 131 I therapy or chemotherapy, resulting in death in most patients (39,40). When it is encapsulated, it has a much better prognosis (30). 5.1.10

Diffuse Sclerosing Variant

About 5% of spontaneously occurring PTC and about 10% of those found among the children of Chernobyl are of this type (39,40,50). The tumor is usually bilateral, presenting as a goiter with extensive squamous metaplasia, sclerosis, psammoma bodies, and abundant lymphatic invasion involving the whole thyroid gland. Almost all have lymph metastases and about 25% have lung metastases

Thyroid Carcinoma

239

(39,40). FNA cytology reveals squamous metaplasia, inflammatory cells, and psammoma bodies, but this tumor may be difficult to differentiate from thyroiditis. Although local and pulmonary metastases are more frequent than usual, there is some disagreement about whether its long-term prognosis is worse than that of typical PTC (39,40). 5.1.11

Solid or Trabecular Variant

This tumor has a predominantly (⬎75%) solid architectural pattern but maintains the typical nuclear features of PTC. It has a propensity for extrathyroidal spread and lung metastases that impart a poor prognosis (39,40), but some find it to be more common in children, in whom its prognosis is the same as that of typical PTC (51). 5.1.12

Oxyphilic (Hu¨rthle Cell) Variant

About 2% of PTCs have cellular features resembling those of Hu¨rthle cell (oxyphilic) FTCs (52). Some cases have multiple oxyphilic thyroid tumors and a familial occurrence (53). This tumor cannot be identified as PTC by FNA cytology but is recognized by its papillary architecture on the final histological sections. Compared with typical PTC, oxyphilic PTC has fewer neck nodal metastases at diagnosis but has higher recurrence and mortality rates and in this respect resembles oxyphilic FTC (40,52). 5.1.13

Insular Carcinoma

About 5% of all thyroid carcinomas show solid clusters of cells with small follicles that resemble pancreatic islet cells but contain Tg. Often categorized as a variant of FTC, some tumors show papillary differentiation. LiVolsi believes that this tumor should be considered as a separate entity derived from follicular epithelium (54). These are unusually large and invasive tumors that grow through the tumor capsule and into tumor blood vessels. Compared with PTC, insular carcinoma presents at an older age (54 versus 36 years) with larger tumors (4.7 versus 2.5 cm), fewer neck metastases (36% versus 50%) but more distant metastases (26% versus 2%), and has a worse 30-year cancer-specific mortality rate (25% versus 8%) (12). Insular carcinoma also displays aggressive behavior in children but is usually responsive to thyroidectomy and 131 I therapy (55). 6

FOLLICULAR THYROID CARCINOMA

6.1 Pathology Follicular thyroid carcinomas (FTCs) are solid invasive tumors which, unlike PTCs, do not show necrotic degeneration but tend to be solitary and encapsulated, even when they are biologically aggressive (5). Minimally invasive tumors show

240

Kloos and Mazzaferri

just enough evidence—usually invasion into the tumor capsule without penetration through it (and no vascular invasion)—to make a diagnosis of carcinoma. Others have multiple foci of tumor capsule and vascular penetration but remain fairly discrete masses, while a few are highly invasive tumors with satellite nodules. Large, aggressive tumors may extend into the opposite lobe or adjacent cervical tissue. Most FTCs cannot be differentiated from follicular adenomas on gross tumor inspection, FNA, or frozen section and must be differential from follicular variant PTC and follicular adenoma based on final histological sections (5). FTCs typically are compact, highly cellular tumors composed of microfollicles, trabeculae, and solid masses of cells. Less often, they contain mediumsized or large follicles and such low invasive characteristics that they are difficult to differentiate from benign adenomas even on the final histological sections— a finding associated with an excellent prognosis (5). FTC has compact cells with small, dark-staining, round nuclei that are more uniform in shape, size, and location than the nuclei of PTCs and are difficult to identify as carcinoma by FNA (Fig. 2B) (5,56). 6.1.1

Hu¨rthle Cell Carcinoma (HTC)

Oxyphilic cells, termed Hu¨rthle or Askanazy cells, contain increased amounts of acidophilic cytoplasm that contains numerous mitochondria on electron microscopy. Greater than 75% of cells must be Hu¨rthle cells to constitute HTC. Some consider this to be a distinct clinicopathological entity; others consider it to be a variant of FTC (35). HTCs demonstrate lymph node metastases more frequently than typical FTC and metastases rarely respond to 131 I therapy. Regardless of its classification, HTC has a less favorable prognosis than nonoxyphilic FTC, even though the former may not initially appear less differentiated or more invasive (5). 6.1.2

Lymph Node Metastases

Compared to PTC, FTC metastasizes less often to regional lymph nodes, occurring in about 10% of cases, and is usually caused by the more aggressive tumors that often have distant metastases. 6.1.3

Distant Metastases

FTC tends to metastasize to lung, bone, central nervous system, and other soft tissues with greater frequency than does PTC, and the metastases often avidly concentrate 131 I. Distant metastases at the time of diagnosis are about twice as common with FTC compared to PTC (5). Unlike small PTCs that rarely metastasize to distant sites, small FTCs can metastasize widely, and tumors larger than 3 cm are associated with a much higher mortality rate (57).

Thyroid Carcinoma

7

241

DIAGNOSIS OF PAPILLARY AND FOLLICULAR THYROID CARCINOMA

7.1 Presentation PTCs were often diagnosed in the past at a late stage, when the tumor was large and invasive. Now, however, most are identified earlier by FNA of small asymptomatic thyroid nodules—usually in the range of 2 cm—found on routine neck palpation (5). A few come to attention as the result of pain, hoarseness, dysphagia, hemoptysis, or other signs of tissue infiltration or rapid tumor growth. These findings are associated with a high probability of carcinoma in a nodule (58) and greater than usual mortality rates (4). Sometimes palpably enlarged cervical lymph nodes are the only clue to the diagnosis. A history of exposure to head or neck radiation is important, but only about one-third of such nodules are malignant (18,59). A nodule in the setting of a family history of PTC should be regarded with higher than usual suspicion. Nevertheless, the evaluation of familial or radiation-induced tumors is similar to that of sporadic nodules. Most FTCs present as an asymptomatic neck mass without palpable cervical lymphadenopathy. Less often, a distant metastasis is the first manifestation, appearing as large discrete lung nodules, osteolytic bone lesion, or pathological fracture or as a central nervous system tumor with neurological sequelae. Rarely, distant metastases are seen in the absence of a palpable thyroid lesion (5). Bulky metastatic lesions may be functional and cause thyrotoxicosis. Differentiated thyroid carcinoma usually manifests as a palpably firm thyroid nodule that moves upward when the patient swallows. PTC, however, may be cystic and soft or may diffusely infiltrate one lobe or the entire thyroid gland; or its first manifestation may be a palpable cervical lymph node metastasis. A midline mass above the thyroid isthmus may be a metastatic (Delphian) lymph node or carcinoma within a thyroglossal duct—the latter is suggested by upward movement with tongue protrusion. Distant metastases are found less often at the time of diagnosis of PTC than FTC; but when they are present, the primary tumor is usually large and invasive. Only 10% of thyroid nodules have clear evidence of malignancy, such as vocal cord paralysis or signs of invasion or metastases, at the time of diagnosis. Most appear benign and are associated with few or no symptoms. Thus neither the history nor physical examination offers enough evidence of a nodule’s benign nature that further testing can be deferred. 7.2 Fine-Needle Aspiration (FNA) FNA is the first test that should be done to evaluate a thyroid nodule in a clinically euthyroid patient, whether the patient has a single nodule or a multinodular goiter (56). Other tests—especially imaging studies—are too nonspecific to be used as the first test.

242

Kloos and Mazzaferri

FIG. 4 Diagnostic paradigm for evaluating a thyroid nodule. (Adapted from Ref. 56.)

FNA yields cytology that can be categorized as malignant, benign, indeterminate (suspicious), or inadequate for diagnosis (Fig. 4). FNA is highly effective in obtaining sufficient cytology to identify the distinctive features of PTC, including most of its variants as well as most other malignant lesions (56). Benign Hu¨rthle cell tumors and follicular adenomas may be difficult to differentiate from their malignant counterparts by FNA and surgically obtained frozen tissue sections. Large-needle aspiration biopsies and cutting-needle biopsies usually yield results similar to those of FNA but cause more complications (56). FNA cytology specimens showing normal or atypical follicular or Hu¨rthle cells are often simply designated as follicular or Hu¨rthle cell neoplasms because their benign or malignant character cannot be determined with certainty until the final histological sections are available (and even then there may be difficulty separating malignant and benign tumors) (56). Cytological material sufficient for diagnosis can be obtained in most palpable nodules, but the accuracy of FNA may be enhanced by ultrasonographically guided FNA, especially for small solid and hypoechoic nodules (60). Nodules that yield malignant cytology should be excised (Fig. 4). Before performing surgery on nodules with indeterminate cytology (highly cellular specimens with nor-

Thyroid Carcinoma

243

mal or atypical follicular cells without colloid), an 123 I thyroid scan should be done to identify hot nodules, which are usually not malignant. Thyroxine therapy should not be used as a diagnostic test to identify thyroid carcinoma because some malignant nodules may temporarily shrink (56). When there is a history of head-and-neck irradiation, FNA is the first test recommended for a palpable thyroid nodule. However, controversy arises regarding an asymptomatic person with a palpably normal thyroid gland. Schneider et al. (61) found that 55% of such patients had a thyroid noduleⱖ1.5 cm that was not palpable. As a result, they suggested routine ultrasound every 3 to 5 years. Others argue that routine ultrasonography is too sensitive, as it identifies thyroid nodules in about half of the healthy middle-aged population and in most people exposed to thyroid irradiation (27,61–63). Regardless, most authorities agree that the majority of thyroid nodules ⬍1 cm discovered by serendipity are benign and that ⬍1 cm nodules can be followed by ultrasonography for 1 to 2 years without FNA (provided that they do not grow) after detailed discussion with the patient (27,61–63). Larger thyroid nodules or those associated with suspicious ultrasonographic characteristics (invasion or microcalcifications) or physical findings (cervical lymph nodes, etc.) should be biopsied regardless of how they are discovered. Thyroid hormone therapy does not prevent the appearance of thyroid nodules or cancer in a previously irradiated patient with a palpably normal thyroid gland (59). It does, however, reduce the recurrence of nodules in irradiated patients who have undergone thyroid surgery for benign thyroid nodules (64). 8

FACTORS INFLUENCING PROGNOSIS AND AFFECTING OUTCOME

The prognosis of differentiated thyroid carcinoma is determined by an interaction of three variables—tumor stage, patient age, and therapy—and ranges from excellent to dismal. The overall mortality rate attributable to differentiated thyroid cancer is low (⬍10% over three decades), but recurrence rates are high (and often not addressed by prognosis scoring systems), and distant metastases or serious local recurrences can occur many years after initial therapy (Fig. 5) (4,5). 8.1 Patient Variables Influencing Prognosis Age over 40 years at the time of initial therapy is the most important adverse prognostic factor, which becomes progressively worse thereafter, increasing at a particularly steep rate after age 60 years (Fig. 6) (4,5). The best responses to therapy are in younger patients whose tumors concentrate 131 I (65–67). Survival rates are most favorable in children, although at the time of diagnosis their tumors are typically more advanced, with more local and distant metastases than those of adults (65,67–69). However, tumor recurrence rates over

244

Kloos and Mazzaferri

FIG. 5 Cancer-specific mortality rates and recurrence rates following initial therapy of differentiated thyroid carcinoma (mean and standard error). (Adapted from Ref. 4.)

several decades are about 40% in children compared with 20% in adults (4,67). Moreover, their rate of pulmonary metastases is over 20% in some series, which is almost twice the rate in adults (4,5,68). The prognosis for survival in children is nonetheless excellent, with or without a history of irradiation, except for those children under age 10, who have very high mortality rates (65–67). Thyroid cancer recurrence and mortality rates are higher in men than in women (2,40). The 30-year cancer-specific mortality rate for males with PTC is nearly twice that of women (7.8% versus 4%, p ⬍ 0.01), and gender is an independent prognostic factor (4). Although estrogen and progesterone receptors are expressed in up to 50% of PTCs, this does not explain the risk imposed by male gender. Serum from patients with Graves’ disease stimulates thyroid follicular cells in vitro that can produce progression of thyroid carcinoma (70). One study of PTC

Thyroid Carcinoma

245

FIG. 6 Cancer mortality and recurrence rates according to age at the time of diagnosis. See Fig. 5 for legend. (Adapted from Ref. 4.)

associated with Graves’ disease found the tumors were more often multifocal and the rate of distant metastases was four times higher than usual (71). Other studies have failed to show this effect (72). 8.2 Tumor Variables Influencing Prognosis Outcome is more favorable with PTC than with FTC. In a review of 9744 patients of mean age 47 years with differentiated thyroid carcinoma, the 10-year mortality rates were 12% for those with PTC and 29% for those with FTC (5). The 30year cancer-specific mortality rates for a somewhat younger group of patients with PTC (aged 35.8 ⫾ 0.4 years) and FTC (aged 40.0 ⫾ 0.9 years) were 5% and 13%, respectively. Other recent studies report a 10-year mortality from FTC of about 10% (73), but the rate ranges up to 50%, depending on the degree of vascular invasion and capsular penetration by the tumor and the age of the patient at the time of diagnosis (5,15,73,74). HTCs have a worse prognosis than FTCs (74). Patients with FTC are more likely to have distant metastases at the time of diagnosis than are those with PTC (2.2% versus 5.3%) (4). Also, tumor recurrence

246

Kloos and Mazzaferri

in distant sites is seen more often with FTC than with PTC and occurs most frequently with highly invasive tumors, when the primary lesions are larger than 4.5 cm, and in HTCs (5,16,57,74). Marked cellular atypia or frank anaplastic transformation is associated with a poor prognosis. PTC primary tumors smaller than 1.5 cm in diameter rarely recur or cause death, while those larger than 4.5 cm are associated with high mortality rates (4,5). Collectively, PTCs and FTCs smaller than 1.5 cm, 1.5 to 4.4 cm, and 4.5 cm or larger caused distant metastases, respectively, in 4%, 10%, and 17% of patients, and 30-year cancer-specific mortality rates of, respectively, 0.5%, 8%, and 22% (4). The 20-year cause-specific mortality rates in the large Mayo Clinic series for tumors 2 to 3.9 cm, 4 to 6.9 cm, and 7 cm or larger were 6%, 16%, and 50%, respectively (72). Multifocal disease in one thyroid lobe is almost always associated with bilateral thyroid cancer when completion thyroidectomy is performed (75). Accordingly, the rates of recurrence or locally persistent disease are significantly higher following less than near-total thyroidectomy (76–80), although some report almost no recurrences in the thyroid remnant (81,82). One study found a 1.7-fold higher risk of recurrence in multifocal compared with unifocal tumors (83). Another study found that the only two parameters significantly influencing tumor recurrence of PTC microcarcinomas were the number of histological foci and the extent of initial thyroid surgery (32). 8.2.1

Lymph Node Metastases

Up to 85% of meticulously examined cervical lymph nodes contain metastatic PTCs (5), which reflect aggressive tumor behavior and correlate with primary tumor size and tumor multicentricity (40). Some report that metastatic lymph nodes have no effect on recurrence or survival (81,84), while others find an increased risk for local tumor recurrence when cervical lymph node metastases are present (4,77,85,86). Higher than usual cancer-specific mortality rates are seen with bilateral cervical or mediastinal lymph node metastases or when tumor penetrates the lymph node capsule and invades surrounding tissues (4,43,87–90). FTC is less often metastatic to regional lymph nodes, but when it occurs the prognosis is less favorable (5). 8.2.2

Thyroid Capsular Invasion and Extrathyroidal Extension

Up to one-third of PTCs penetrate the thyroid capsule, which may result in deep tissue invasion, including tracheal or spinal cord invasion and penetration of the major vessels. When this occurs, the mortality rate is about 20% at 5 years, a rate 10-fold greater than that of noninvasive PTC (4,5). Aggressive FTCs also invade local tissues.

Thyroid Carcinoma

8.2.3

247

Distant Metastases

The main cause of death from differentiated thyroid carcinoma, distant metastases were associated with a 5-year mortality rate of 47% among 1231 patients with metastatic PTC or FTC (5). Children and young adults with pulmonary metastases have a more favorable prognosis when their distant metastases are discovered early, are small, and concentrate 131 I (68,91). For example, 10-year survival rates are about 20% in adults with macronodular lung or bone metastases compared with about 80% in children and young adults with micronodular pulmonary metastases that concentrate 131 I (92). The most important elements in prolonging disease-free survival and improving the survival rate are early radionuclide scintigraphic diagnosis before the metastases are apparent on chest roentgenograms (Fig. 3) and early treatment with 131 I (93). 8.2.4

Irradiation-Induced Papillary Thyroid Carcinoma

Cancer mortality rates are typically similar between radiation-induced and spontaneously-occurring PTCs, although those associated with radiation are often large, multicentric tumors with high recurrence rates (59,94). Recent data have suggested more aggressive behavior by tumors from Chernobyl victims demonstrating RET/PTC3 mutations. 8.2.5

Other Tumor Factors

The histological variants of PTC and FTC affect prognosis (12,39). Also, coexistent Hashimoto’s thyroiditis (usually with PTC) is associated with a lower tumor stage and may be an independent predictor of a favorable prognosis (36,95). Anaplastic tumor transformation that occurs in well-differentiated thyroid carcinoma dramatically alters its course and results in aggressive local tumor invasion and widespread, rapidly fatal metastases that do not concentrate 131 I (40). 8.2.6

Oncogenes

To date, no convincing evidence exists to suggest that prognosis can be adequately predicted by tumor genetics. The most frequent genetic alterations in differentiated thyroid carcinoma are somatic rearrangements of the RET protooncogene, which generate several chimeric RET/PTC oncogenes in PTC (96– 98). Transgenic mice expressing the thyroid-targeted RET/PTC-1 develop PTC (99,100). Although RET/PTC rearrangements are present in about 40% of PTCs and may play a role in metastatic behavior (101,102), their clinical role is uncertain. The RET/PTC oncogenes, especially RET/PTC3, have frequently been found among the PTCs of the Chernobyl children (103), and PTC3 may be associated with more aggressive tumors. However, the significance of this association remains controversial.

248

Kloos and Mazzaferri

8.3 Treatment Variables Influencing Prognosis Treatment of differentiated thyroid carcinoma has a major impact on long-term outcome, as discussed below in sections dealing with surgical and medical therapy. In our cohort of patients, we found that the median time from the first manifestation of thyroid cancer—nearly always a neck mass—to initial therapy was 4 months in patients who survived and 18 months in those who died of thyroid cancer ( p ⬍ 0.001) (4). The 30-year cancer mortality rate was nearly doubled when therapy was delayed longer than a year (13% versus 6%, p ⬍ 0.0001) (4).

9

TUMOR STAGING SYSTEMS AND PROGNOSTIC SCORING SYSTEMS

Several staging and prognostic scoring systems have been devised to discriminate between low-risk patients anticipated to have a good outcome, thus requiring less aggressive therapy, and higher-risk patients who require the most aggressive therapy to avoid morbidity and mortality from thyroid carcinoma (104). However, most systems fail to distinguish the variants of PTC and FTC that substantially affect outcome. All but a few use patient age at the time of diagnosis to stage the tumor in a unimodal rather than a bimodal fashion, which is problematic to predict recurrence, because recurrence rates are very high in both young and old patients. Further, relatively little importance is assigned to tumor recurrence or disease-free survival. The greatest utility of staging systems is in epidemiological studies and as tools to stratify patients for prospective therapy trials (40). They may be less useful in determining treatment for individual patients unless a reproducible group of patients can be identified with a very low risk of recurrence and cancer-specific mortality. Because the TNM classification of the American Joint Commission on Cancer (AJCC) and International Union Against Cancer (UICC) is universally available and widely accepted for other disease sites, it is often recommended for thyroid carcinoma (105). Most patients are classified as stage I with this system (Table 3), which de facto categorizes most patients as being at low risk (83). However, stage I TNM patients had a 15% recurrence rate after a median of 11 years of follow-up (83), which many would argue suggests that less aggressive therapy for this group is not appropriate. The numerous staging and prognostic scoring systems that have been proposed underscore the fact that none fully provides information to guide therapy. In our view, low-risk tumors are small, noninvasive tumors confined to the thyroid—classical unifocal PTCs or FTCs smaller than 1 to 1.5 cm and FTCs smaller than 4 cm with minimal tumor capsular invasion (without penetration

Thyroid Carcinoma

249

TABLE 3 TNMa classification of the American Joint Commission on Cancer (AJCC) and International Union Against Cancer (UICC) Papillary or Follicular Stage I II III IV

⬍45 years

ⱖ45 years

Medullary

M0 M1

T1 T 2–3 T 4 or N 1 M1

T1 T 2–4 N1 M1

T is primary tumor: T 1, ⬍ 1 cm; T 2, ⱖ 1 cm to 4 cm; T 3, ⬎ 4 cm; T 4, extension beyond thyroid capsule. N is regional lymph nodes: N 1, regional lymph node metastases (cervical and upper mediastinal nodes). M is distant metastases: M 0, no distant metastases; M 1, distant metastases present. All undifferentiated (anaplastic) carcinomas are stage IV. Source: From Ref. 104. a

through the capsule or vascular invasion)—without metastases. All others pose a risk of tumor recurrence or death and should be treated accordingly. 10 TREATMENT OF PAPILLARY AND FOLLICULAR THYROID CARCINOMA There continues to be debate about the treatment of differentiated thyroid carcinoma. Three studies shed light upon the current practice. In 1987, at an international symposium, 160 specialists from 13 countries recommended total thyroidectomy and postoperative 131 I thyroid remnant ablation for most patients with differentiated thyroid carcinoma regardless of their age (106). Another study published in 1989 was based upon a questionnaire completed by 157 thyroid experts regarding the management of a hypothetical patient with a solitary thyroid nodule (107). The majority recommended total or near total thyroidectomy followed by 131 I ablation of the thyroid remnant. Most did not recommend altering this treatment for different tumor histological types. A third study published in 1996 was based upon a survey of the clinical members of the American Thyroid Association who were queried about their long-term management recommendations of a hypothetical patient with PTC (108). Most opted for near total thyroidectomy and 131 I ablation and almost everyone preferred long-term levothyroxine therapy in doses sufficient to lower the TSH levels ranging from 0.01 to 0.5 µU/mL. The majority did not alter therapy for patients with a history of radiation, at the ex-

250

Kloos and Mazzaferri

tremes of age, in the presence of a nodule ⬍1 cm or multiple foci in the contralateral lobe, or with capsular invasion of the nodule. 10.1 10.1.1

Thyroidectomy Frozen Section (FS) Studies of Tumor at Surgery

Because FNA has a high specificity for PTC, total thyroidectomy can be done without FS when it is diagnosed by preoperative FNA (109). The test characteristics of FNA and FS in one study (110) were equal: the sensitivity of both was 67%, the specificity was 99%, and the accuracy was 89%. The positive predictive value in this study was 96% for FNA and 98% for FS; the negative predictive values were 88% and 87%, respectively. When FNA cytology is interpreted as ‘‘follicular neoplasm,’’ frozen section is unlikely to change the diagnosis (111). Thus, when FNA yields a cytology specimen adequate for diagnosis, FS examination rarely changes intraoperative decision making and its routine use is not costeffective (112). If the FNA is suspicious but not diagnostic of PTC, FS studies should be done; if either the gross findings or FS studies suggest malignancy, total thyroidectomy can be performed, because nearly all such cases have cancer. If the FS is not diagnostic of malignancy, a thyroid lobectomy with or without isthmusectomy is recommended, as about three-fourths are benign lesions (113). 10.1.2

Subtotal Lobectomy

Resection of less than a thyroid lobe, sometimes done as a nodulectomy, is inadequate therapy for thyroid carcinoma and is not the current standard of practice (40,114). Even microscopic thyroid carcinoma requires more surgery than subtotal lobectomy (6,32,115). 10.1.3

Ipsilateral Lobectomy and Isthmusectomy

A few surgeons prefer lobectomy, often referred to as subtotal thyroidectomy, and regional lymph node dissection as the initial therapy for nearly all patients with differentiated thyroid carcinoma (116). When the diagnosis of thyroid carcinoma is known preoperatively, however, most advise total or near total thyroidectomy for all patients (117) because it improves disease-free survival, even in children and adults with low-risk tumors (118–121). Patients treated with lobectomy alone have a 5% to 10% recurrence rate in the opposite thyroid lobe (5), an overall long-term recurrence rate over 30% (5), and the highest frequency (11%) of subsequent pulmonary metastases (80), compared with recurrence rates of only 1% after total thyroidectomy and 131 I therapy (5). Higher recurrence rates are also observed with cervical node metastases. Multicentric tumors—often found on study of the final histological sections—also justifying more complete initial thyroid resection (4). Lobectomy may be adequate surgery for microcarcinoma discovered serendipitously on the final pathology studies of surgery done

Thyroid Carcinoma

251

for benign disease provided that the patient has not been exposed to radiation, has no other risk factors, and has a truly low-risk carcinoma—a tumor smaller than 1 to 1.5 cm that is unifocal and confined to the thyroid without vascular invasion (4,6,32,115). Complications with lobectomy are few, and survival in this latter group is virtually assured (4,6,32,115). Nonetheless, the thyroid remnant tissue hampers long-term follow-up with serum Tg determinations and whole-body 131 I scans; therefore the decision to forgo complete thyroidectomy must be discussed with the patient. 10.1.4

Total or Near Total Thyroidectomy

Total or near total thyroidectomy (ipsilateral total lobectomy, isthmusectomy, and nearly total contralateral lobectomy) is preferred for tumors that are ⱖ1 to 1.5 cm in diameter, multicentric (any size), or metastatic or that penetrate the thyroid capsule; this should also be done for histological variants with aggressive behavior. Complete or nearly complete thyroid resection removes multifocal and bilateral carcinoma and provides the opportunity to ablate residual thyroid bed uptake with small doses of 131 I, which substantially facilitates long-term followup. Modified neck dissection (levels II to VI) that preserves the sternocleidomastoid muscle is done for involved cervical lymph nodes. Radical neck dissection is done only for tumors that extensively invade the strap muscles (34). 10.1.5

Completion Thyroidectomy

When subtotal thyroidectomy has been performed, it is best to consider completion thyroidectomy for lesions that are anticipated to have the potential for recurrence and because large thyroid remnants are difficult to ablate with 131 I (122). This surgery has a low complication rate and is appropriate to perform routinely for aggressive thyroid cancer variants, metastatic disease, PTC ⬎ 1 to 1.5 cm, FTC ⬎ 1 to 1.5 cm with more than minimal capsular invasion, or multifocal carcinomas of any size, because about half the patients have residual carcinoma in the contralateral thyroid lobe (Table 4) (75,123–129). When there has been a

TABLE 4 Residual Carcinoma in Contralateral Thyroid Lobe Found with Completion Thyroidectomy Number of Patients (Percent with Residual Disease in Contralateral Lobe)

Total number of patients from seven studies a

Papillary

Follicular

Hu¨rthle

Total Residual Cancer

545

327 (58%)

206 (38%)

12 (57%)

244 (45%)

Sources: Refs. 75, 125–129, and 286.

252

Kloos and Mazzaferri

local or distant tumor recurrence following subtotal thyroidectomy, carcinoma is found in over 60% of the excised contralateral lobes (75). A study of children from Chernobyl found that completion thyroidectomy allowed for the diagnosis and treatment of recurrent cancer and lung or lymph node metastases in 61% of patients in whom residual carcinoma was not preoperatively recognized (120). In another study, patients who underwent completion thyroidectomy within 6 months of their primary operation developed significantly fewer lymph node and hematogenous recurrences and survived significantly longer than those in whom the second operation was delayed for longer than 6 months (128). 10.1.6

Radioiodine-Assisted Surgery

It has recently been reported that the completeness of surgical excision of recurrent or persistent thyroid carcinoma can be improved by giving 100 mCi 131 I to patients with functioning lymph node metastases and locating the tumor with the aid of an intraoperative probe (130). This method detected both suspected and unsuspected lesions in 56% of patients, although about 25% had nodal metastases that were undetected by this and other techniques (130). 10.1.7

Surgical Complications

The main complications of thyroidectomy are hypoparathyroidism and recurrent laryngeal nerve damage, which are most common after total thyroidectomy. The rates of hypoparathyroidism immediately after surgery are as high as 5% in adults131 and even higher in children (120,132) undergoing total thyroidectomy. However, the rates of persistent hypocalcemia are much lower. For example, one study reported a 5.4% rate of hypocalcemia after total thyroidectomy that persisted in only 0.5% of the patients 1 year after surgery (133). In a review of seven published surgical series, the average rates of permanent recurrent laryngeal nerve injury and hypoparathyroidism, respectively, were 3% and 2.6% after total thyroidectomy and 1.9% and 0.2% after subtotal thyroidectomy (134). When experienced surgeons perform the surgery and the posterior thyroid capsule is left intact on the contralateral side, hypoparathyroidism occurs at a lower rate. A study of 5860 patients treated in the state of Maryland found that surgeons who performed more than 100 thyroidectomies a year had the lowest overall complication rates (4.3%), which were fourfold lower than those of surgeons who performed ⬍10 cases annually (135). 10.1.8

Thyroidectomy During Pregnancy

Thyroid carcinoma may occasionally progress rapidly during pregnancy, perhaps due to high maternal β-hCG levels, which have a TSH-like effect (136). Nonetheless, most differentiated thyroid carcinomas are slow-growing and have an excel-

Thyroid Carcinoma

253

lent prognosis during pregnancy; therefore surgery can usually be delayed until after delivery (137). 10.2 10.2.1

Radioiodine (131 I) Therapy Sodium Iodide Symporter

Differentiated thyroid carcinomas concentrate iodide much less avidly than does normal thyroid tissue, perhaps due to abnormalities in the sodium-iodide symporter. Increased sodium-iodide symporter activity in PTC was reported in one study (138), while others find reduced sodium-iodide symporter activity and heterogeneous immunohistochemical sodium-iodide symporter staining in differentiated thyroid carcinoma (139,140). 10.2.2

Preparation for

131

I Therapy

Females with childbearing potential must have a negative pregnancy test documented shortly before receiving diagnostic imaging or therapeutic doses of 131 I. Ideally, 131 I therapy is given about 6 weeks after surgery. Serum TSH levels must be high enough (⬎30 µU/mL) to sufficiently stimulate neoplastic and normal thyroid tissues to concentrate 131 I before whole-body scans or 131 I treatment can be done. However, the optimal magnitude of TSH elevation is not known. Adequate TSH elevation can be accomplished with recombinant human TSH (rh TSH) injections, but the FDA to date has not approved its use for therapy (Fig. 7). To raise the TSH level for 131 I treatment, levothyroxine therapy is discontinued for 4 to 6 weeks and triiodothyronine (Cytomel), 1 µg/kg/day (about 25 µg orally, two or three times daily), may be given until the final 2 weeks (Fig. 7) (141). During the 4 to 6 weeks prior to therapy (and preferably longer), longlasting sources of iodine, such as intravenous CT contrast, must be carefully avoided. During the final 2 weeks, a low-iodine diet should be ingested (142) with avoidance of iodine-rich drugs. Serum TSH and Tg levels should be measured before diagnostic or therapeutic 131 I dosing. Inability to obtain adequate TSH elevation should raise suspicion of insufficient thyroidectomy, functioning metastases, continued thyroid hormone ingestion, or, rarely, hypopituitarism. 10.2.3

Lithium

This drug inhibits iodine release from the thyroid without impairing iodine uptake, thus enhancing 131 I retention in normal thyroid and tumor cells (143). Given at a dosage of 400 to 800 mg daily (10 mg/kg) for 7 days, it increases 131 I uptake in metastatic lesions while only slightly increasing uptake in normal tissue (143). A more recent study (144) showed that the mean increase in the biological or retention half-life was 50% in tumors and 90% in thyroid remnants. The effect

254

Kloos and Mazzaferri

FIG. 7 Preparation for

131

I imaging and/or therapy.

was greater in lesions with poor 131 I retention, such that when the biological halflife was ⬍3 days, lithium prolonged the effective half-life of 131 I by ⬎50%. The increase in the accumulated 131 I and the lengthening of the effective half-life together increased the estimated 131 I radiation dose in metastatic tumors an average of more than twofold (144). Blood lithium levels should be measured frequently if not daily and maintained between 0.8 and 1.2 nmol/L. 10.2.4

Whole-Body

131

I Scan and the Stunning Effect

A diagnostic whole-body scan is obtained 24 to 72 h after giving 2 to 4 mCi of I (Fig. 7). Larger scanning doses should not be given because focal abnormalities not seen with 2 to 4 mCi are less likely to be ablated successfully (145), and 131 I doses as small as 3 mCi diminish the subsequent uptake of therapeutic 131 I, which is termed the ‘‘stunning effect’’ (146–148). To avoid stunning, doses of 1 to 3 mCi doses of 131 I have been recommended; however, these doses are slightly less sensitive than larger scanning doses of 131 I in identifying thyroid remnants, and they require longer imaging times (147,148). Administration of the therapeutic dose as soon as possible after the diagnostic dose of 131 I helps to minimize stunning. Although 123 I in doses of ⱖ1.5 mCi has been reported to yield 131

Thyroid Carcinoma

255

excellent images without stunning, its use to date has been limited by issues of cost and availability. 10.2.5

False-Positive

131

I Scans

Many things can infrequently cause false-positive 131 I scans, including body secretions, transudates, inflammation, nonspecific mediastinal uptake (e.g., blood pool), and neoplasms of nonthyroidal origin, which may uncommonly concentrate 131 I (149). False-positive scans can also be seen with physiological secretion of 131 I from the nasopharynx, salivary and sweat glands, stomach, and genitourinary tract and from skin and hair contamination with sputum or tears (150). Diffuse hepatic uptake of 131 I is rarely due to occult liver metastases but more commonly due to hepatic clearance of Tg labeled with 131 I by functioning thyroid remnants or extrahepatic thyroid cancer metastases. The more 131 I uptake by residual thyroid tissue, the more 131 I appears in the liver. In one large study (151), 12% of all diagnostic scans showed uptake in the liver. The frequency of hepatic uptake in posttherapy scans was related to the dose of 131 I, being 39% with 30 mCi, 61.5% with 75 to 100 mCi, and 71.3% with 150 to 200 mCi (151). On the other hand, occult liver metastases should be suspected when there is focal hepatic uptake or diffuse hepatic uptake of 131 I without 131 I uptake elsewhere (151). 10.2.6

Rationale for Thyroid Remnant Ablation

Because it is nearly impossible to remove all thyroid tissue with routine surgery, I uptake is almost always seen postoperatively in the thyroid bed (including normal tissue of thyroglossal duct remnants). These foci must be ablated before 131 I will optimally detect and be concentrated in metastatic deposits (120,152). Although there continues to be debate concerning 131 I ablation of thyroid bed uptake after near total thyroidectomy (72,79), there are four compelling reasons to do this. First, a thyroid remnant with high radioiodine uptake can obscure cervical or lung metastases when their contribution to the total radioiodine uptake is low (120,152). Second, high levels of circulating TSH, necessary to enhance tumor 131 I uptake, cannot be achieved in the presence of a large thyroid remnant (141). Patients with large amounts of residual tissue in the neck (e.g., an entire lobe) prohibiting adequate hypothyroidism should be strongly considered for completion thyroidectomy, and only under unusual circumstances should 131 I be used to primarily ablate this tissue. Third, serum Tg measurement (and its trend) is the most sensitive test for carcinoma when measured during hypothyroidism after thyroid bed uptake ablation (153). Fourth, ablative doses may destroy undocumented micrometastases, microscopic thyroid bed foci of malignancy, or eliminate ‘‘normal’’ residual tissue otherwise destined to become malignant. These arguments would be consistent with decreased rates of thyroid bed recurrence and metastases in patients treated with 131 I remnant ablation in the absence of residual malignancy. 131

256

Kloos and Mazzaferri

FIG. 8 Recurrence rates of differentiated thyroid carcinoma after various forms of medical therapy. The differences are statistically significant between all for treatments shown. (Derived from Ref. 4.)

10.2.7

Recurrence After 131

131

I Ablation

Postoperative I remnant ablation is done in patients at risk for disease recurrence (79). There is a large and growing number of studies demonstrating decreased recurrence and disease-specific mortality rates from differentiated thyroid carcinoma attributable to 131 I therapy (Fig. 8) (4,78,79,85,154–157). The lowest incidence of pulmonary metastases occurs after total thyroidectomy and 131 I. For example, recurrences of differentiated thyroid carcinoma (in the form of pulmonary metastases) when analyzed as a function of initial therapy were reported as follows: thyroidectomy plus 131 I (ablation dose of 100 mCi), 1.3%; thyroidectomy alone, 3%; partial thyroidectomy plus 131 I, 5%; partial thyroidectomy alone, 11% (80). We compared outcome in 1004 patients with differentiated thyroid carcinoma who underwent thyroid remnant ablation with 131 I and subsequent thyroid hormone (n ⫽ 151) or thyroid hormone alone (n ⫽ 755) or no postoperative medial therapy (n ⫽ 89) (79). Tumor recurrence was about threefold lower ( p ⬍ 0.001) and fewer patients developed distant metastases ( p ⬍ 0.002) after thyroid remnant ablation than after other forms of postoperative treatment—an effect

Thyroid Carcinoma

257

observed only in patients with primary tumors ⱖ1.5 cm in diameter. The doses of 131 I were stratified into two groups: 29 to 50 mCi (mean 45 mCi) in 43% and 51 to 200 mCi (mean 111mCi) in 57% of patients. Both groups experienced similar recurrence rates (7% and 9%, respectively, p ⫽ 0.7). There were fewer cancer deaths after thyroid remnant ablation than after the other treatment strategies ( p ⬍ 0.001), differences that occurred only in patients aged 40 years or older at the time of initial treatment and with primary tumors ⱖ1.5 cm. The variables that influenced cancer recurrence in a Cox proportional hazards model were absence of cervical lymph node metastases [hazards ratio (HR) 0.8], tumor stage (HR 1.8), and thyroid remnant ablation (HR 0.8). Variables that independently affected cancer-specific death rates were age (HR 13.3), cancer recurrence (HR 16.6), time to treatment (HR 3.5), thyroid remnant ablation (HR 0.5), and tumor stage (HR 2.3). This study suggests that thyroid remnant ablation is effective in reducing recurrence of differentiated thyroid carcinoma in patients of all ages and reduces the risk of death from thyroid carcinoma in patients over age 40 at the time of diagnosis. These effects were not apparent in patients with isolated tumors ⬍1.5 cm that were not metastatic to regional lymph nodes or invading the thyroid capsule. 10.2.8

131

I Dose for Thyroid Remnant Ablation

Usually remnant ablation can be achieved with 30 to 50 mCi of 131 I, which is as effective as larger doses in preventing tumor recurrence (4,154,158). This has been a popular way to avoid hospitalization but is no longer necessary in most states because of changes in federal regulations permitting outpatient use of much larger 131 I doses (159). Even so, considering the differences in cost and radiation exposure and the fact that doses to the thyroid remnant above 30,000 rad do not substantially improve the rate of successful ablation, it may be reasonable to use a relatively low dose for remnant ablation (158). Successful thyroid remnant ablation with doses of ⬃30 and ⬃51 mCi of 131 I were reported as 63% and 78%, respectively, in one study from India (158). However, this optimal dose of ⬃51 mCi was reported to deliver ⬃30,000 rad to the thyroid remnant. In comparison, in one American study, 30,000 rad was achieved with a mean 131 I dose of almost 87 mCi and completely ablated the remnant in 86% of cases (122). Increasing the dose to deliver more than 30,000 rad does not increase the success rate (122,158). The rate of successful ablation is significantly lower when patients have less than a total or near total thyroidectomy or have a thyroid remnant calculated to be ⬎2 g (122). 10.2.9

Treatment of Residual or Recurrent Carcinoma with 131 I

Thyroid carcinoma (especially macroscopic disease) should be treated surgically whenever possible. Only about 50% to 75% of differentiated thyroid carcinomas

258

Kloos and Mazzaferri

and their metastases and up to about one-third of Hu¨rthle cell carcinomas concentrate 131 I (160–162). Moreover, the larger the tumor mass, the less likely that 131 I therapy will successfully ablate the tumor. There are three approaches to therapy: empirical fixed doses, therapy determined by the upper bound limit of blood and body dosimetry, and quantitative tumor dosimetry (159). Dosimetric methods are often reserved for distant metastases or unusual cases, as when renal failure is present or therapy with recombinant human TSH stimulation is deemed necessary. 10.2.10

Empirical Fixed Doses

With empirical doses, a fixed amount of 131 I is given based on tumor stage. Generally, about 30 to 125 mCi are given to ablate thyroid remnants, 150 to 200 mCi for residual carcinoma in cervical nodes or neck tissues, and ⱖ200 mCi for distant metastases. Tumor 131 I uptake in amounts adequate for imaging with 4-mCi diagnostic doses is usually sufficient for 131 I therapy, using empirical doses from 30 to 200 mCi. (163) 10.2.11

Upper-Bound Limits Set by Blood Dosimetry

This approach establishes an upper limit on the amount of 131 I in a single dose that can be given safely, which is generally considered to be 200 rad to the whole blood (164). This limit may be increased to 300 rad in unusual circumstances. In patients with diffuse pulmonary metastases, the dose is also limited, so that ⬍80 mCi of 131 I remains in the lungs after 48 h to avoid pulmonary fibrosis. Without diffuse pulmonary metastases, most authors suggest that the whole-body retention be ⬍120 mCi at 48 h; however, this limit is usually greater than that of the blood dosimetry and thus not a limiting factor. Based on these calculations, therapy doses of 450 to 600⫹ mCi are not uncommon in our experience. 10.2.12

Quantitative Tumor Dosimetry

This approach calculates the dose of 131 I that is required to deliver 30,000 rad to ablate the thyroid remnant or 8000 to 12,000 rad to treat nodal or discrete soft tissue metastases (159). Diffuse pulmonary metastases are treated according to the upper-bound limit described above. The mass of residual tissue and the effective half-time of 131 I in that tissue are the two most important factors in determining success (159). In one study, an 80% response was found in tumor deposits that received at least 8000 rad (122). Lesions calculated to receive ⬍3000 to 4000 rad despite reaching the upper-bound radiation limit describe above should be considered for alternative therapy. 10.2.13

Repeat 131

131

I Treatments

Treatment with I should be continued every 6 to 12 months, as long as metastatic deposits are present and continue to concentrate 131 I and a favorable re-

Thyroid Carcinoma

259

sponse to previous therapy has been demonstrated, such as a decreasing Tg level or decreasing tumor mass. Repeat 131 I doses should not be given until the bone marrow has fully recovered from the previous dose. Few adverse effects occur with this approach to 131 I therapy (165). Before large cumulative doses of 131 I are given over an extended period to treat neck metastases or well-localized disease, especially in the central nervous system (CNS) or spine, serious consideration should be given to excising the tumor surgically. 10.2.14

Immediate Complications of

131

I Therapy

There are few immediate serious risks of 131 I therapy except when metastases are in critical locations that will not tolerate enlargement from TSH stimulation or posttherapeutic swelling from radiation injury. For example, brain or spinal cord metastases can undergo serious edema and hemorrhage 12 h to 2 weeks after 131 I treatment (166). Significant radiation thyroiditis can occur within a week of administering a large dose of 131 I to a patient with inadequate thyroidectomy (e.g., lobectomy), causing thyrotoxicosis (and possibly atrial fibrillation), pain, swelling, and rarely airway compromise that may require prednisone therapy (167). Thyroid storm may rarely occur about 2 to 10 days after a therapeutic dose of 131 I is administered, especially when there is a large burden of functioning tissue (159). Acute bone pain is sometimes experienced after 131 I treatment. Radiation sickness—characterized by headache, nausea, and occasional vomiting— is experienced by about two-thirds of patients about 4 to 12 h after the oral administration of ⱖ200 mCi of 131 I, which resolves in about 24 h; this almost never occurs with smaller doses (159). Vomiting occurs more frequently in children and with increasing 131 I doses. Patients with extensive neck tumors may rarely develop transient vocal cord paralysis, and facial nerve paralysis has been reported after very high doses of 131 I (159). Radiation cystitis does not occur if the patient is well hydrated. Radiation sialadenitis, leukopenia, and thrombocytopenia often occur about 6 weeks after therapy but ordinarily are mild and transient unless very large doses of 131 I are administered (168). 10.2.15

Parotid Dysfunction

Transient parotid swelling reminiscent of Stensen’s duct obstruction may occur after 131 I therapy. Hydration and salivary stimulation around the time of 131 I therapy (consuming sour candy, lemon drops, or chewing gum) increases salivary flow and decreases salivary radiation but does completely eliminate radiation injury. Salivary pseudoobstruction from radiation injury occurs more frequently after large 131 I doses and usually presents within the first few months as acute salivary gland enlargement following food stimulation. Repeated bouts are transient; they are easily managed by the patient with manual ‘‘milking’’ of the gland or salivary stimulation (biting one quarter of a lemon) and occur with decreasing frequency, but the patient is often left with xerostomia. In one study of 131 I therapy

260

Kloos and Mazzaferri

complications, about 60% of patients reported side effects lasting longer than 3 months, which included sialoadenitis (33%) and transient loss of taste or smell (27%) (169). More than a year after the last 131 I treatment, 43% suffered from reduced salivary gland function and over 4% had complete xerostomia; nearly 23% reported chronic or recurrent conjunctivitis—complications that were related to the cumulative dose of 131 I (169). Another study found that pretreatment with reserpine reduced parotid 131 I activity for at least 7 days (170). Amifostine has been successfully used as a free radical scavenger to prevent salivary injury, exploiting its high concentration in the salivary glands with low levels of drug accumulation in thyroid tissue. Complications of amifostine include hypotension. Thus, combined therapy with chewing gum, lemon candies, and hydration—and perhaps some pharmaceuticals—may help to prevent or reduce the sialadenitis and xerostomia due to large doses of 131 I. 10.2.16

Radiation Pneumonitis

Pulmonary fibrosis is a potential complication of 131 I therapy for diffuse pulmonary metastases when the lung retention of 131 I is ⬎80 mCi 48 h after treatment. Some reports suggest that diffuse pulmonary metastases can be treated with 150 mCi of 131 I without risking pulmonary fibrosis (171) and smaller 131 I doses of ⬃100 mCi are often given when there is diffuse and intense uptake of the scanning dose in the lungs. However, a randomized controlled study to investigate outcome of distant metastases treated with these relatively low doses versus dosimetrically determined much higher doses (often 200 to 800 mCi) has not been conducted, so optimal therapy is not known. 10.2.17

Leukemia and Other Bone Marrow Effects

There is a slightly increased risk of developing acute myelogenous leukemia after I therapy, which is estimated to range from 3 to 22 excess cases per 1000 patients treated with 131 I, depending upon the cumulative dose (159,165). The lower estimate seems more likely according to a Swedish study that found two cases of leukemia among 834 thyroid carcinoma patients treated with 131 I, which was not a statistically significant increase over the general population rate (172). When 131 I doses are given at 12-month intervals and total cumulative doses are limited to 500 mCi in children and 600 to 800 mCi in adults, long-term effects on the bone marrow are minimal and few cases of leukemia occur (165,173– 175). Limiting the cumulative dose is usually not a problem unless large single doses of 131 I are given, because tumor tissue that concentrates 131 I is likely to be ablated by a few 131 I treatments, leaving either no residual tumor or metastases that do not concentrate 131 I. For example, all patients cured of pulmonary metastases by 131 I in one study (176) did so with a cumulative dose of ⱕ1500 mCi. It is reasonable to give high cumulative doses of 131 I to patients with extensive 131

Thyroid Carcinoma

261

metastatic disease responsive to therapy, as the risk posed by the known thyroid cancer outweighs the risk of a potential second cancer from radiation. 10.2.18

Cancer Caused by

131

I Therapy

The incidences of colon, breast, bladdder, and salivary cancer are increased in some studies of 131 I therapy for thyroid carcinoma but not in others (159,172). The possibly increased incidence of these cancers following 131 I underscores the need for laxatives, hydration, and salivary stimulation following 131 I treatment. 10.2.19

Infertility and Gonadal Failure

Gonadal damage may be caused by large doses of 131 I, but it is observed infrequently (159,177). A large European study of 2113 pregnancies in women treated with surgery and 131 I for thyroid carcinoma found that the baseline miscarriage rate was 11%. This rate increased to 20% after surgery alone, remained at this level with 131 I therapy of ⬍100 mCi, but increased to 40% with ⬎100 mCi 131 I within the preceding 12 months of pregnancy, possibly due to gonadal irradiation (178). The incidences of stillbirth, preterm birth, low birth weight, congenital malformation, and death during the first year of life were not significantly different before or after 131 I therapy. Further, the incidence of thyroid disease and nonthyroidal malignancy was similar in children born either before or after their mothers were exposed to 131 I. Testicular germinal cell function may be transiently impaired when men are given 131 I therapy for thyroid carcinoma, although the damage may become permanent when large doses of 131 I are delivered repeatedly (179). Since this might pose a significant risk of infertility, it seems prudent to selectively advise young men to bank their sperm before 131 I therapy. 10.3 10.3.1

Thyroid Hormone Therapy Levothyroxine (T4) Suppression of TSH

Differentiated thyroid carcinomas express TSH receptors, and TSH stimulates their growth and uptake of iodine (70). Thyroid hormone therapy significantly reduces recurrence rates and cancer-specific mortality rates (Fig. 8) (4,79). However, the degree of TSH suppression required for this benefit is debated. The levothyroxine dosage needed to maintain serum TSH levels in the euthyroid range is greater among thyroid cancer patients (2.11 µg/kg/day) than among those with primary hypothyroidism caused by nonmalignant disease (1.62 µg/kg/day) (180). An Italian study found that patients who had undergone total thyroid ablation for thyroid carcinoma required 2.7 ⫾ 0.4 (SD) µg/kg/day of levothyroxine to achieve an undetectable basal serum TSH level that did not increase after TRH administration (181). A French study found that a constantly suppressed TSH (ⱕ0.05 µU/mL) was associated with a longer relapse-free survival than when

262

Kloos and Mazzaferri

serum TSH levels were always ⱖ 1 µU/mL, and that the degree of TSH suppression was an independent predictor of recurrence (182). However, a prospective U.S. study of 617 patients in the National Thyroid Cancer Treatment Cooperative Study found that disease stage, patient age, and 131 I therapy independently predicted disease progression, but that the degree of TSH suppression did not (183). 10.3.2

Complications of Levothyroxine Therapy

Potential problems associated with subclinical thyrotoxicosis are an increased risk of atrial fibrillation (184), a higher 24-h heart rate, more atrial premature contractions per day, ventricular hypertrophy, diastolic dysfunction, and impaired cardiac reserve (185–187). Patients with thyroid carcinoma treated with suppressive doses of levothyroxine have a high rate of bone turnover that decreases acutely after withdrawing treatment (188), which is of most concern in postmenopausal women not receiving estrogen-like or bisphosphonate therapy (189). However, others have not demonstrated bone loss despite exogenous levothyroxineinduced TSH suppression (190). Further, unlike endogenous hyperthyroidism, exogenous subclinical hyperthyroidism has not been associated with an increased fracture risk (191). 10.4 10.4.1

Other Therapy Retinoic Acid

This drug, which partly redifferentiates follicular thyroid carcinoma in vitro, may benefit a few patients. In one study, retinoic acid given orally (1.18 ⫾ 0.37 mg/ kg) for at least 2 months induced significant 131 I uptake in two of 12 patients with differentiated carcinoma untreatable by other modalities (192). This response was associated with a rise in serum Tg concentration, suggesting tumor redifferentiation. However, its beneficial effects have not been widely reproduced by others. Potential adverse consequences of retinoic acid therapy include severe birth defects, liver function test abnormalities, and hypertriglyceridemia. 10.4.2

External Beam Radiation Therapy

This therapy is generally considered third-line therapy for localized well-differentiated thyroid cancer after surgical resection and 131 I therapy. Typical candidate sites of disease for external beam radiation therapy include the neck, upper mediastinum, or bone lesions that are symptomatic or in critical locations to prevent fracture. External beam radiation therapy is frequently reserved for inoperable, non-iodine-avid disease; however, in some iodine-avid situations, it is considered for adjuvant therapy following 131 I therapy such as in patients with T4N1 disease and over age 45, aerodigestive invasion, nonresectable local bulk disease, or selected osseous metastases (85).

Thyroid Carcinoma

10.4.3

263

Gamma Knife

Brain metastases from thyroid carcinoma are an extremely poor prognostic sign. Surgical resection of brain metastases may be associated with a limited prolongation of survival and rarely with apparent cure (193). While controlled studies are lacking, inoperable CNS metastases should probably be treated with gamma knife rather than external beam radiation therapy if possible (193). 10.4.4

Chemotherapy

The benefit of chemotherapy for well-differentiated thyroid carcinoma is limited and at best provides palliation (194,195). 10.5

Follow-up

In our view, low-risk tumors are small, noninvasive tumors confined to the thyroid—classical unifocal PTCs or FTCs smaller than 1 to 1.5 cm and FTCs smaller than 4 cm with minimal tumor capsular invasion (without penetration through the capsule or vascular invasion)—without metastases. Following complete surgical resection of these tumors, these patients usually have an excellent outcome, yet they may benefit from a general annual history and physical examination with attention to the neck and symptoms suggestive of metastases. The TSH should be kept in the normal range. Tumors that are not low-risk pose a greater threat of tumor recurrence or death and should be evaluated every 6 to 12 months for 10 years, during which time two-thirds of recurrences are expected to appear. After 10 to 20 years of following a patient believed to be disease-free, it may be reasonable to follow less actively (e.g., every 2 years). Follow-up consists of history and physical examinations, and if postoperative thyroid 131 I ablation has been performed, whole-body 131 I or 123 I scans and serum Tg determinations (Fig. 9). Periodic neck ultrasonography and/or chest radiography should be considered. Within a year after initial therapy, many patients have complete absence of tumor when they are evaluated by whole-body radioiodine imaging and TSHstimulated Tg measurements. One study found, however, that the predictive value for relapse-free survival of one negative diagnostic 131 I whole-body scan was 91% and for two consecutive annual negative 131 I scans was 97%, differences that were statistically significantly ( p ⬍ 0.02) (196). A stepwise logistic regression analysis was performed in this study to identify risk factors for disease recurrence after complete thyroid ablation. None of the variables assessed—including age, gender, tumor histology, tumor size, vascular or capsular invasion, surgical margin status, or lymph node status—was predictive of recurrence. These authors recommended annual 131 I imaging for surveillance until two consecutive negative studies are obtained, after which repeat imaging at 3 to 5 years may be satisfactory unless there is a change in the examination, a rise in serum Tg concentration, or other clinical suspicion of disease recurrence.

264

Kloos and Mazzaferri

FIG. 9 Follow-up paradigms for papillary and follicular thyroid carcinoma.

10.6

Recombinant Human TSH (rh TSH)

During follow-up, periodic withdrawal of thyroid hormone therapy is required to raise the serum TSH concentration sufficiently to stimulate thyroid tissue so that serum Tg measurement and radioiodine scanning can be performed, which causes symptomatic hypothyroidism. Intramuscular administration of rhTSH stimulates thyroidal 131 I uptake and Tg release while the patient continues thyroid hormone suppression therapy, thus avoiding symptomatic hypothyroidism (197,198). The drug has been approved for diagnostic use and has been tested in two large international multicenter studies. Although not yet approved for preparation of patients for 131 I therapy, rhTSH has been used successfully for this purpose (199). 10.6.1

Clinical Studies

The first study found that the results of whole-body 131 I scan after two 0.9-mg doses of rhTSH, given while thyroid hormone TSH suppression therapy was continued, were of good quality and were equivalent to the scans obtained after thyroid hormone withdrawal in 66% of patients, superior in 5%, and inferior in 29% (198). A second multicenter, international study was done to test the effects of two dosing schedules of rhTSH on whole-body 131 I scans and serum Tg levels compared with those obtained after thyroid hormone withdrawal. The scanning

Thyroid Carcinoma

265

method was more carefully standardized and took into account the fact that 131 I retention was higher in subjects rendered hypothyroid than in those given rhTSH (200). In this study, the scans were concordant in 89% of the patients and superior in 4% after rhTSH and in 8% after thyroid hormone withdrawal, differences that were not statistically significant. The main finding was that the combination of rhTSH whole-body scanning and serum Tg measurements detected 100% of the patients with metastatic carcinoma (200). Recombinant human TSH, 0.9 mg, is given intramuscularly every day for 2 days followed by 4 mCi of 131 I orally on the third day and a whole-body scan and Tg measurement on the fifth day (Fig. 7). Whole-body 131 I images are acquired after 30 min of scanning or after obtaining 140,000 counts, because a 4-mCi dose of 131 I may have the same body retention as a 2-mCi dose given to a hypothyroid patient. When a large- or small-field-ofview camera is used, a minimum of 60,000 and 35,000 counts per view, respectively, are required. 10.6.2

Paradigm for rhTSH Use

A serum Tg of ⱖ2.0 to 5.0 ng/mL obtained 72 h after the last rhTSH injection indicates that thyroid tissue or thyroid carcinoma is present, which almost always can be identified on the rhTSH-stimulated whole-body scan provided that one follows the scanning procedure noted above (Fig. 7) (200). The drug is well tolerated, with transient mild headache (7.3%) and nausea (10.5%) being its main adverse effects (200). Under the current conditions, rhTSH is probably best utilized in the follow-up of patients suspected to be free of disease. It may also be helpful in a limited number of other well-thought-out scenarios in which the findings will guide other therapies (such as surgery) without generating the needless expense of rhTSH, only to proceed to conventional hypothyroid 131 I therapy. 10.7 10.7.1

Serum Thyroglobulin (Tg) Tg and Whole-Body

131

I Scans

Serum Tg determinations and whole-body 131 I imaging can almost always detect residual thyroid tissue, whether benign or malignant, in patients who have undergone thyroidectomy. The serum Tg concentration correlates with the mass of normal or malignant thyroid tissue, the amount of thyroid physical damage or inflammation, and the level of TSH receptor stimulation (201). Tg measurement is more sensitive when thyroid hormone has been stopped or rhTSH is given to elevate the serum TSH (44,200) and, under these conditions, has a lower falsenegative rate than whole-body 131 I scanning (44). 10.7.2

Serum Anti-Tg Antibodies

Serum antithyroglobulin antibodies must be measured in the serum sample obtained for Tg assay because they are present in up to 25% patients with thyroid carcinoma and almost always invalidate serum Tg measurement (153,202). The

266

Kloos and Mazzaferri

presence of thyroid tissue or cancer can be inferred by a newly introduced Tg mRNA method, which is an even more sensitive marker than measuring Tg by immunometric assay, particularly during levothyroxine treatment (203). This assay, while not yet commercially available, can reliably detect serum Tg mRNA in patients with circulating antithyroglobulin antibodies (203). It has been suggested that an increasing antibody titer correlates with increasing tumor burden. 10.7.3

Serum Tg Cutoff Levels

A serum Tg above the lower detection limit (usually 0.5 to 1.0 ng/mL in newer assays) during levothyroxine therapy in a patient who has undergone total or near total thyroidectomy and 131 I ablation is a sign of persistent normal tissue (thyroid remnant) or thyroid carcinoma, which is an indication for repeat 131 I scanning when there is no other evidence of disease (Fig. 9). If serum Tg rises above 10 ng/mL after levothyroxine is discontinued or rises above 2 to 5 ng/mL after rhTSH is administered, normal or malignant thyroid tissue is usually present, even if the 2 to 4 mCi (74 to 148 MBq) 131 I diagnostic scan is negative (117,200,201). Other imaging studies—such as neck ultrasonography, CT, MRI, fluorodeoxyglucose positron emission tomography (FDG-PET), or other modalities—should be performed to detect occult tumor that might be amenable to surgical excision or external beam radiation therapy. 10.8

Imaging Studies

Although imaging with 131 I is the ‘‘gold standard’’ in detecting thyroid tissue, several other scanning techniques are available. Some are particularly useful in identifying the location of tumor in patients with high serum Tg levels and negative diagnostic 131 I scans and negative neck ultrasonography. 10.8.1

Thallium 201 (201TI)

Scintigraphy with this isotope may identify metastases or uptake in the thyroid bed when the serum Tg is elevated and the diagnostic whole-body 131 I scan is negative (204). Studies comparing the sensitivity of 201TI and 131 I scans are controversial, with reports of 201TI sensitivity being superior (205), comparable (206), and inferior (207,208). Most agree that 131 I scintigraphy is highly specific. There is some evidence that 201TI uptake predicts the response to 131 I therapy: all the patients in one study in whom 131 I therapy was effective had low 201TI uptake and 86% of 29 patients in whom radioiodine was ineffective had high 201TI uptake (204). 10.8.2

Technetium 99m (99mTc)

Scintigraphy with this isotope may localize differentiated thyroid carcinoma; however, as for 201 TI, results and opinions are conflicting. One study found that

Thyroid Carcinoma

267

the sensitivities of 201 TI, 99m Tc-tetrofosmin, and 131 I in identifying distant metastases were nearly the same (85%, 85%, and 78%, respectively); however 131 I was much more sensitive than 99m Tc-tetrofosmin for demonstrating remnant thyroid tissue after surgery (100% and 33%, respectively) (207). Scanning with 99m Tcmethoxyisobutyl isonitrile ( 99m Tc-MIBI) also detects metastases of thyroid carcinoma. One large study found increased accumulation of 99m Tc-MIBI in 75% of the patients with lung metastases, in 100% of those with lymph node metastases, and in 94% of the patients with bone metastases. These results were compared to those of 201 TI and 131 I, which, respectively, were positive in 80% and 85% of patients with lung metastases, in 100% and 42% of patients with lymph node metastases, and in 90% and 87% of patients with bone metastases (209). Another study found that the sensitivity of 99m Tc-furifosmin SPECT scans was poor, being 33% on a patient-by-patient basis and 34% on a lesion-by-lesion basis, compared to whole-body PET fluoride-18 (18F) fluorodeoxyglucose, which yielded a sensitivity of 72% on a patient-by-patient basis and 91% on a lesion-by-lesion basis (210). 10.8.3

Whole-Body Positron Emission Tomography (PET)

Scanning with 18F fluorodeoxyglucose may identify thyroid carcinoma metastasis that cannot be identified by scintigraphy with 131 I. Uptake of 18F-FDG seems to be an indicator of poor functional differentiation (211), and these tumors appear more likely to behave aggressively. Although PET has better sensitivity, resolution imaging, and spatial localization, this must be balanced against its higher cost and lower availability when compared with 201 Tl or 99m Tc scintigraphy (212). False-positive 18F-FDG uptake may occur with benign lung disease, inflammatory conditions, and other malignancies (213). FDG-PET may be of most value in the setting of high serum Tg levels and negative 131 I scans and other imaging studies. 10.9

Treatment of High Serum Tg levels and Negative Imaging Studies

When the serum Tg level is elevated and a tumor cannot be found by localizing techniques—including 131 I diagnostic scans, neck ultrasonography, and CT or MRI scans—metastases are sometimes found only after administrating therapeutic doses of 131 I (Fig. 3) (47,214). 10.9.1

Tg Cutoffs for Treatment with

131

I

The Tg level used for treating patients with large doses of 131 I whose only evidence of disease is an elevated serum Tg has been coming down. It was about 30 or 40 ng/mL about a decade ago but now is about 10 ng/mL after thyroid hormone withdrawal (47). If tumor is not found and the serum Tg is above 10 ng/mL, it is reasonable to give a therapeutic dose of 131 I, usually 100 to 150 mCi

268

Kloos and Mazzaferri

(3700 to 5550 MBq) up to 300⫹ mCi, and perform a posttreatment scan. In our experience, about 20% of patients with elevated serum Tg levels and negative diagnostic 131 I scans have lung metastases. 10.9.2

Rationale for

131

I Therapy

Although some skepticism has been voiced about this therapeutic maneuver, there is increasing evidence that this approach is beneficial. Multivariate analysis has shown the independent prognostic significance of the size of pulmonary metastases at the time of therapy (175). Another multivariate analysis of prognostic factors in 134 patients with pulmonary metastases showed that an early diagnosis (a normal chest roentgenogram with pulmonary metastases found only on 131 I scintigraphy) and treatment with 131 I were the most important factors to significantly improve the survival rate and prolong the disease-free time interval (93). Two studies (45,46) found clearly beneficial effects of 131 I therapy for such patients: 80% achieved a negative whole-body 131 I posttherapy scan, 60% had a serum Tg ⬍5 ng/mL off thyroid hormone, 6 of 8 patients had normalization of the CT scan, and 2 patients had negative lung biopsies. Improvement sometimes occurs with one or two 131 I treatments, but complete resolution of pulmonary metastases after 131 I therapy is often difficult to achieve (68). When a partial reduction of metastatic disease is achieved, patients usually have a good quality of life with no further disease progression and a low mortality rate (68). It seems intuitively wrong to withhold therapy in this group of patients, who are usually young and have a small tumor burden. Withholding of therapy seems especially discordant given the fact that 131 I treatment directly targets the metastatic deposits and is effective in reducing tumor burden. Early diagnosis and treatment of cancer is a desirable and effective therapeutic goal, especially when the treatment has relatively few serious side effects. Although administering 100⫹ mCi of 131 I to some patients without distant metastases on the basis of an elevated serum Tg level may not be desirable, many of them are found in retrospect to have regional lymph node metastases or a thyroid remnant to account for the high serum Tg level, and these foci may be eliminated by the therapy or at least identified for further potential intervention. 11 MEDULLARY THYROID CARCINOMA 11.1

Classification

Medullary thyroid carcinoma (MTC) was first recognized in 1959 as a pleomorphic neoplasm with amyloid struma. A few years later it became apparent that the tumor arises from the calcitonin-secreting C cells of the thyroid. MTC typically occurs in one of two settings: sporadic disease accounts for 70% to 80%

Thyroid Carcinoma

269

of cases, while 20% to 30% of cases are part of one of three familial autosomal dominant syndromes that are often associated with other endocrine neoplasms. 11.2 11.2.1

Multiple Endocrine Neoplasia (MEN) Type 2 Syndromes MEN Type 2A (MEN-2A)

This syndrome is familial, comprising bilateral MTC associated with hyperparathyroidism and bilateral pheochromocytoma. 11.2.2

MEN Type 2B (MEN-2B)

This syndrome comprises bilateral MTC, bilateral pheochromocytoma, an abnormal phenotype with multiple mucosal ganglioneuromas, and musculoskeletal abnormalities suggestive of the marfanoid habitus. Ganglioneuromas may occur in the lips, causing them to appear lumpy and patulous, and in the alimentary tract, which may be associated with constipation, diarrhea, and megacolon. The marfanoid characteristics include long limbs, hyperextensible joints, scoliosis, and anterior chest deformities, but not with the ectopic lens or cardiovascular abnormalities seen in Marfan’s syndrome (215). 11.2.3

Familial Non-MEN Medullary Thyroid Carcinoma (FMTC)

This syndrome consists of bilateral MTC with no other endocrine tumors or somatic abnormalities (216). It is transmitted as an autosomal dominant trait and is the least common form of MTC, manifest at a later age than the other familial syndromes (216). 11.2.4

Medullary Thyroid Carcinoma Tumor Location

MTC in the familial syndromes is generally bilateral and multicentric, as opposed to sporadic MTC, which is usually unilateral. The C cells, which are normally located in the upper and middle thirds of the lateral thyroid lobes, initially undergo hyperplasia in the familial syndromes before developing into MTC. 11.2.5

Parathyroid Disease

Hyperparathyroidism develops in one-third to half of the patients with the MEN2A syndrome, most of whom (85%) develop parathyroid hyperplasia, which (217) almost never occurs in MEN-2B (215). MEN-2A patients seldom present with symptoms of hypercalcemia but often form renal stones. When MTC develops in MEN-2A patients, parathyroid hyperplasia is often discovered during thyroidectomy even when there is no clinical or biochemical evidence of hyperparathyroidism (215).

270

11.2.6

Kloos and Mazzaferri

Pheochromocytoma

Adrenal medullary disease occurs in both MEN-2 syndromes. Its manifestations range from diffuse or nodular adrenal hyperplasia to large bilateral multilobular pheochromocytomas. These abnormalities are typically bilateral and occur in about 40% of affected family members, although this ranges widely from 6% to 100% in different kindreds (217). Pheochromocytoma symptoms are typically subtler than those encountered with sporadic pheochromocytoma (218). Demonstration of high urinary or plasma catecholamine levels or their metabolites typically establishes the diagnosis. 11.2.6.1 Genetic Alterations in MEN 2 and FMTC Syndromes Point mutations of the RET proto-oncogene occur in germ-line and tumor DNA of unrelated patients from kindreds with MEN-2A, MEN-2B, and FMTC (219– 221). Several different and independent point mutations in the genomic sequence of the RET proto-oncogene have been identified, all involving codons for cysteine residues, which provides an important direct means of identifying affected kindreds. Nonetheless, the normal function of RET is not yet known and its role in the development of these inherited syndromes remains unclear. There is, however, a relationship between specific RET proto-oncogene mutations and the MEN-2 phenotypes (221). 11.2.6.2 Genetic Alterations in Sporadic Medullary Thyroid Carcinoma Approximately 3% of apparently sporadic MTC cases are familial, with typical genomic RET proto-oncogene mutations. It is recommended that all MTC cases be tested, given the potential of pheochromocytoma and family-wide implications. About 50% of sporadic MTC tumors harbor a somatic mutation at codon 918 of the RET proto-oncogene without showing a similar mutation in other tissues (222). This may be useful information. In one study (223), a RET somatic mutation at codon 918 was detected in FNA cytology specimens obtained from both a thyroid nodule and two enlarged neck lymph nodes but not in the peripheral blood, thus establishing a diagnosis of sporadic MTC before surgery. This is important, because excluding MEN-2 preoperatively permits immediate thyroidectomy without a search for pheochromocytoma (223). 11.3

Prevalence and Demographics

MTC accounts for about 4% of all thyroid malignancies (3). Inherited MTC occurs with equal frequency in both sexes, while sporadic MTC has a female/male ratio of 1.5 to 1. Only about 20% of MTC cases occur as familial tumors. The other 80% are sporadic and may occur at any age but are usually detected later in life than inherited MTC. For instance, the median age of patients with sporadic

Thyroid Carcinoma

271

MTC seen at the Mayo Clinic was 51 years, compared with 21 years for those with familial tumors (218). Familial FMTC is usually detected later, around age 40 to 50 years, as compared with an average age of 20 to 30 years for MEN-2A when detected by calcitonin screening of affected kindreds. The diagnosis is made even earlier now that genetic testing is available. 11.4 11.4.1

Pathology Primary Tumor

Ranging from large bulky tumors to microscopic lesions, sporadic and familial tumors are nonetheless histologically similar. However, the widest spectrum is encountered in familial tumors, which range from isolated hypertrophied C cells to large bilateral multicentric tumors that are usually in the superior portions of the thyroid lobes. Sporadic MTC is typically unilateral. MTC is typically composed of fusiform or polygonal cells surrounded by irregular masses of amyloid and abundant collagen. About half the tumors have calcifications, which occasionally appear as trabecular bone formation. Calcitonin can usually be demonstrated in the tumors by immunohistochemical studies. 11.4.2

Metastases

Cervical lymph node metastases occur early in the disease and can be seen with primary lesions as small as several millimeters. Tumors larger than 1.5 cm in diameter are more likely to metastasize to distant sites, especially to lung, bone, and liver but also to the CNS. Metastatic deposits usually contain calcitonin and stain for amyloid. 11.4.3

Tumor Calcitonin

Immunohistochemical staining for calcitonin serves not only to identify MTC but also, by the staining pattern, to differentiate virulent from less aggressive tumors. In one study, patients with primary tumors that showed intense homogeneous calcitonin staining were all clinically well on follow-up examination, while those with tumors that showed patchy localization of calcitonin either developed metastatic disease or died of cancer within 6 months to 5 years of initial surgery (224). 11.5 11.5.1

Diagnosis Clinical Features

Patients with sporadic disease or unrecognized inherited MTC usually present with one or more painless thyroid nodules in an otherwise normal gland, although some experience pain, dysphagia, and hoarseness. The presenting feature may

272

Kloos and Mazzaferri

be enlarged cervical lymph nodes or occasionally distant metastases, most commonly to the lung, followed in frequency by metastases to the liver, bone (osteolytic or osteoblastic lesions), and brain. Cervical lymph node metastases are present at the time of diagnosis in about half the patients with sporadic MTC. The thyroid nodule is usually solid on echography and malignant of FNA, and may be cold or warm on 123 I imaging. Radiographs may show dense, irregular calcifications of the primary tumor and cervical nodes and mediastinal widening due to metastases. The abnormal phenotype of MEN 2B may lead to the clinical diagnosis. Rarely, a paraneoplastic syndrome such as diarrhea or flushing may be the presenting manifestation. 11.5.2

Hormonal Features

In addition to calcitonin, MTC may synthesize calcitonin gene–related peptide, l-dopa decarboxylase, serotonin, prostaglandins, adrenocorticotropin, histaminase, carcinoembryonic antigen (CEA), nerve growth factor, and substance P (218). Elevated serum levels of calcitonin, histaminase, l-dopa decarboxylase, and CEA are frequently found in MTC patients. About 10% have episodes of flushing, often induced by alcohol ingestion, calcium infusion, and pentagastrin injection; these episodes may be due to tumor release of prostaglandins and serotonin (218). The only clinical manifestation of high circulating calcitonin levels is a secretory diarrhea that occurs in about 30% of patients and is usually seen only with advanced tumors. Because of the indolent course of MTC, ectopic adrenocorticotropic hormone (ACTH) produced by the tumor may cause typical Cushing’s syndrome. 11.5.3

Calcitonin and Tumor Mass

Elevated basal plasma calcitonin levels, which are almost always found once the MTC becomes palpable, correlate directly with tumor mass (218). As a result, basal calcitonin often is not elevated with small tumors and is almost invariably normal in those with C-cell hyperplasia; however, after stimulation with pentagastrin and/or calcium, serum calcitonin levels increase to abnormally high levels. 11.5.4

Calcitonin in the Evaluation of Thyroid Nodules

Some clinicians advise routine measurement of basal serum calcitonin in those with nodular thyroid disease, finding that it allows early preoperative diagnosis of subclinical MTC and improves the results or surgery (225). Most of the studies that advocate this approach are from European countries where the incidence of multinodular goiter is high. This has not been the practice among U.S. thyroidologists (108), perhaps because it is viewed as not being cost-effective, since FNA usually yields malignant cytology with MTC.

Thyroid Carcinoma

11.5.5

273

Stimulation Tests

Some patients with small MTC tumors have normal basal calcitonin levels, which rise to supranomal levels with stimulation (218). The combination of intravenous pentagastrin and calcium is a more potent stimulus to calcitonin release than either agent alone. Unfortunately, pentagastrin is no longer available in the United States. In the calcium stimulation test, elemental calcium (2 g/kg) in 50 mL of 0.9% saline is given intravenously over 1 min and plasma is collected for calcitonin determination every 10 min for 30 min. Patients with C-cell hyperplasia and MTC generally have plasma calcitonin levels that rise fivefold above than baseline. Basal and stimulated levels are higher in men than in women and decline with age. Of course, the diagnosis of inherited MTC is now possible with genetic screening long before the thyroid tumor is clinically manifest or calcitonin levels are elevated, rendering stimulation testing obsolete in most situations. 11.5.6

Omeprazole Stimulation Test

Omeprazole stimulates intrinsic gastrin release, which may stimulate calcitonin and be useful in the diagnosis and follow-up of MTC (226). 11.5.7

Differential Diagnosis of Hypercalcitoninemia

An elevated serum calcitonin level is not absolutely diagnostic of MTC because it occurs in other conditions (218). When the differential diagnosis of a high plasma calcitonin value is between MTC and another malignancy, a higher calcitonin value and a palpable thyroid tumor usually identify patients with MTC. In addition, calcitonin secretion by other cancers is poorly stimulated by pentagastrin (218). 11.6 11.6.1

Factors Influencing Prognosis Age and Tumor Stage

MTC is more aggressive than PTC and FTC, having a cancer-specific mortality rate of about 10% to 20% at 10 years (73,73). However, pheochromocytoma causes a number of deaths among those with MEN-2 (227). The mortality rate is substantially worse with sporadic tumors, when metastases are found at the time of diagnosis, with the MEN-2B phenotype, and among patients older than 50 years of age at diagnosis. Patients with familial disease operated on during the first decade of life generally have no evidence of residual disease postoperatively (218). However, persistent or recurrent disease occurs in about one-third of patients operated on in the second decade, and it gradually increases in frequency until the seventh decade, when about two-thirds of patients have persistent disease after surgery (218). This is largely due to the patient’s age and the clinical

274

Kloos and Mazzaferri

stage of disease at the time of surgery; these are the most powerful prognostic factors predicting outcome (228,229). 11.6.2

Inherited Medullary Thyroid Carcinoma

Prognosis is best with non-MEN familial MTC (FMTC) and MEN-2A. Early detection and treatment have a profound impact on the clinical course of MTC. When nodal metastases are not present, the 10-year survival rates are nearly similar to those in unaffected subjects, but they fall to about 45% when nodal metastases are present (218). Before 1970, MTC was usually diagnosed in the fifth or sixth decade. For the next 20 years, biological markers assumed a preeminent role in diagnosis. With periodic calcitonin screening, patients from MEN kindreds were diagnosed at a much earlier age, usually in the second decade or earlier, when they had C-cell hyperplasia or microscopic carcinoma confined to the thyroid (230). Nonetheless, the results of long-term studies using this approach are somewhat disappointing. One large study comparing calcitonin with genetic testing found 14 young gene carriers (18% of the 80 known gene carriers in the study) who had normal plasma calcitonin tests, 8 of whom had undergone thyroidectomy at the time of the report and were found to have foci of MTC (231). Another study (232) reported long-term follow-up of 22 children in whom biological screening studies were routinely performed once a year and thyroidectomy was recommended for any elevation in serum calcitonin levels. MTC had already developed in 17 children (77%), and only 5 had C-cell hyperplasia (CCH). Of the 17 with MTC, 13 had macroscopic tumors, and recurrent disease developed in four children (24%) (232). 11.6.3

Genetic Screening

Now, with the availability of genetic testing, affected patients can be identified at birth, which will hopefully result in prevention of disease when operated in the first few years of life (see below) (233). 11.7 11.7.1

Therapy Initial Surgery

This offers the only chance for cure and should be performed as soon as disease is detected (228,229). However, pheochromocytoma must be rigorously searched for and excised before thyroidectomy is performed. The treatment of MTC confined to the neck is total thyroidectomy because the disease is often bilateral, even with a negative family history, and patients are often unsuspected relatives of affected MEN-2 kindreds (228,229). All patients with palpable MTC or clinically occult disease that is visible on cut section of the thyroid should undergo routine dissection of lymph nodes in the central neck compartment because nodal metastases occur early and adversely influence survival. The lateral cervical

Thyroid Carcinoma

275

lymph nodes should be dissected when they contain tumor, and they are frequently involved by the time the tumor becomes palpable, so that most advocate routine ipsilateral modified radical neck dissection and bilateral neck dissections in the setting of bilateral disease. Radical neck dissection is not recommended unless the jugular vein, accessory nerve, or sternocleidomastoid muscle is invaded by tumor (132). 11.7.2

Residual or Recurrent Medullary Thyroid Carcinoma

Persistent or recurrent disease, which is ordinarily manifest by elevated calcitonin levels postoperatively, occurs commonly following primary treatment of the tumor. Nonetheless, survival is often good. For example, a French study reported that 57% of 899 patients were not cured, but that survival was 80% at 5 years and 70% at 10 years (228). Reopertion in appropriately selected patients is reasonable, as it is the only treatment that consistently and reliably reduces calcitonin levels and often results in excellent local disease control. There is no curative therapy for widely metastatic disease, but reoperative neck ‘‘microdissections’’ may normalize calcitonin levels when metastatic MTC is confined to regional lymph nodes. Improved results have been reported in recent years with the surgical management of recurrent MTC, mainly through better preoperative selection of patients and the use of routine laparoscopic liver examination preoperatively, which identifies hepatic metastases in MTC patients with normal CT and MRI imaging (234). Although patients with widely metastatic MTC often live for years, many develop symptoms from disease progression. Despite the presence of widespread incurable tumor, patients with metastatic MTC causing significant symptoms or physical compromise may respond to palliative reoperative resection (235). Judicious palliative reoperative resection of discrete symptomatic lesions provides substantial long-term relief of symptoms with minimal operative mortality and morbidity (235). 11.7.3

Inoperable Disease

Patients with inoperable disease are often given palliative treatment with external radiation for localized disease or with doxorubicin or other chemotherapy combinations for widespread, life-threatening disease, which is of limited benefit. Radiolabeled metaiodobenzylguanidine (MIBG) or somatostatin analogues and 131 I or yttrium-90 (90Y)–labeled humanized anti-CEA monoclonal antibodies are potentially useful toward tumor debulking. Nonradioactive somatostatin analogues may importantly control the paraneoplastic symptoms of flushing or diarrhea, but they do not improve the natural course of advanced stages of MTC (236). 11.8

Follow-Up

The success of surgery is assessed postoperatively by measuring plasma calcitonin levels. Although it may take up to 6 months for calcitonin to normalize,

276

Kloos and Mazzaferri

normal basal and stimulated calcitonin levels usually indicate a cure (237). Persistent modest basal calcitonin elevations are often seen after surgery in patients who often remain well for many years, particularly those from an MEN-2A kindred, who should be followed without further aggressive therapy. If postoperative plasma calcitonin levels are extremely high or diarrhea occurs, metastases can be localized by neck palpation, and imaging of the neck, chest, and abdomen, isotope bone (but not liver) scans, laparoscopic liver biopsy, angiography, and venous catheterization with calcitonin measurement. Both 99m Tc dimercaptosuccinic acid (DMSA) and indium-111 (111In)–octreotide studies have similar sensitivity in localizing MTC metastases; however, like other imaging techniques, these scans do not reliably detect small metastatic foci (238) and have no clinical utility for preoperative MTC staging. 11.9 11.9.1

Family Screening Genetic Screening

All first-degree relatives of a patient who tests positive for a MEN-2 or FMTC mutation should be screened. One study found that without genetic testing, even when the mean age at the time of thyroidectomy was about 10 years, a significant number of patients (21%) with MEN-2A or 2B developed persistent or recurrent MTC over a follow-up of about a decade (239). However, the sensitivity of genetic screening for MEN-2A offered by diagnostic laboratories that limit RET analysis to exons 10 and 11 is about 83% (240). Genetic testing that includes RET exon 14 results in a more complete and accurate analysis with a sensitivity of nearly 95% (240). It is recommend that clinicians conform the comprehensiveness of a laboratory’s genetic screening approach for MEN-2A to ensure thoroughness of sample analysis and recognize that new mutations continue to be discovered, so that periodic retesting of mutation-negative patients may be prudent as our knowledge evolves. 11.9.2

Prophylactic Total Thyroidectomy

In 1993, when mutations of the RET proto-oncogene were identified in hereditary MTC, surgeons obtained the opportunity to operate on patients prophylactically before the disease is clinically manifest. Nonetheless, microscopic or grossly evident MTC is often present in the excised thyroid glands but almost none are metastatic to regional lymph nodes at the time of surgery (233). Many clinicians advocate routine central lymph node dissection at the time of prophylactic total thyroidectomy and ipsilateral neck dissection in MEN-2A if thyroid tumors⬎1 cm are present and in MEN-2B if tumors⬎0.5 cm are present. Others recommend central neck lymph node dissection when calcitonin levels are elevated or if patients are older than 10 years (132). Almost all patients are biochemically cured

Thyroid Carcinoma

277

with prophylactic total thyroidectomy, which can be performed safely in experienced centers (132). Prophylactic total thyroidectomy is recommended by age 5 or 6 (132) years for patients who test genetically positive for MEN-2A. Thyroidectomy should be done at an earlier age (e.g., first year of life) for children who test positive for MEN-2B, because its behavior is so aggressive (239,241). 12 ANAPLASTIC THYROID CARCINOMA (ATC) Its extremely aggressive behavior and poor prognosis distinguish this exceptionally virulent and invasive neoplasm. Occurring in an older population, ATC demonstrates a biological behavior that is among the worst encountered in humans. 12.1

Incidence and Demographics

The frequency of ATC relative to other thyroid cancers was about 5% to 10% in the past (242), but more recently it has been about 2% in the United States (3). In a review of 475 patients with ATC from six large studies, the mean age was 65 years, with only a slight female predominance (242). It is almost never seen before age 20. The incidence of ATC is influenced by dietary iodine. In one study (243) there was a threefold greater frequency of FTC and ATC in an iodine-deficient area compared with an iodine-rich area. This finding may account for differences in disease frequency reported from around the world, which were especially evident several decades ago. 12.2

Origin

Although some ATCs appear to arise de novo (244), there are many examples in laboratory animals and humans of well-differentiated tumors transforming into ATCs, events that may evolve over many years (242,245,246). One large study (247) demonstrated elements of differentiated thyroid carcinoma in almost 90% of ATC specimens, which, in over 20% of the cases, came from persons previously diagnosed and treated for well-differentiated thyroid carcinoma. 12.3

Pathology

These tumors are composed wholly or in part of undifferentiated cells and tend to behave according to their most aggressive tumor element. 12.3.1

Small Cell Carcinoma

In the past, ATCs or undifferentiated thyroid carcinomas were divided into two broad categories: spindle- and giant-cell carcinomas and small cell carcinoma.

278

Kloos and Mazzaferri

Now, however, almost all small cell carcinomas are recognized both by electron microscopy and immunohistochemical study as primary thyroid lymphomas, MTCs, insular variants of thyroid carcinoma, or occasionally a small cell metastasis from lung cancer (242). The World Health Organization (WHO) classification of thyroid tumors (33) recommends against using the term. 12.3.2

Large-Cell Carcinoma

The three major cell types of ATC are spindle cells, giant cells, and squamoid patterns. Subdivision based upon these cellular features is not clinically helpful and is not recommended in the current WHO classification. For example, one large study (248) found spindle cells in 53%, giant cells in 50%, and a squamoid element in 19% of the tumors, but outcome was similar regardless of these features. 12.3.3

Gross Features

ATCs often involve both thyroid lobes and are typically invasive and poorly demarcated from surrounding neck tissues. Extensive local invasion into the soft tissues and other structures of the neck is common at the time of presentation. On gross examination, the tumors are gray-white, fibrous, calcified, or even ossified, and they frequently show areas of necrosis. 12.3.4

Histological Features

ATCS exhibit the three distinct morphological patterns—spindle cell, giant cell, and squamoid features—often with frequent mitotic figures. The tumors are very pleomorphic and may resemble a fibrosarcoma or rhabdomyosarcoma, or they may contain multinucleated giant cells that resemble osteoclasts and, very rarely, malignant osteoid or cartilage may be seen simulating an osteogenic sarcoma or chondrosarcoma. 12.3.5

Immunohistochemical Studies

The immunohistochemical proof of the follicular origin of ATC is its staining with epithelial markers, the most useful of which is low-molecular-weight keratin (cytokeratin), expressed in up to 80% of the cases (249). Other markers may be detected, but some studies (250) show that 30% of ATCs express none of the tumor markers examined. Less than one-third react with epithelial membrane antigen or CEA and some (0% to 70%) stain for Tg (242). An occasional case of anaplastic MTC occurs (242). 12.3.6

p53 Suppressor Gene

Mutations in this gene occur in thyroid carcinoma almost exclusively in the poorly differentiated tumors and thyroid cancer cell lines, suggesting that inacti-

Thyroid Carcinoma

279

vation of p53 may confer aggressive properties and further loss of differentiated function. For example, one study found the frequency of p53 mutations to be zero in normal thyroid, follicular adenomas, PTCs, and MTCs; however, it was about 9% in FTCs and 83% in ATCs (251). 12.4 12.4.1

Diagnosis Clinical Presentation

12.4.1.1 History A study (249) from M.D. Anderson found that almost two-thirds of patients presented with a rapidly enlarging neck mass and about one-third had symptoms due to tracheal compression and invasion. Another study (252) from the Mayo Clinic also found that about two-thirds had a rapidly enlarging neck mass, either with (37%) or without (32%) a preexisting goiter, and about half had dyspnea at the time of diagnosis. In this series, symptoms had been present for less than 3 months in almost half the patients, while 20% had them for a year before diagnosis. Rapid tumor enlargement often causes neck pain that may mimic subacute thyroiditis, probably due to tumor necrosis and invasion of neck tissues. Hoarseness and cough, with systemic symptoms such as fever or weight loss, are often present. Most patients have normal thyroid function, although thyrotoxicosis rarely occurs, probably from rapid thyroid tissue necrosis releasing thyroid hormone (242). 12.4.1.2 Physical Examination The tumor is typically hard, poorly circumscribed, and fixed to surrounding structures. In the Mayo Clinic series (252), 60% presented as a multinodular goiter and 38% presented as an apparently isolated thyroid nodule, while only 2% caused diffuse thyroid enlargement. The tumors are characteristically quite large and may be associated with palpable cervical lymph nodes. In the Mayo series, about 80% were⬎5 cm, half the patients had palpably enlarged cervical lymph nodes, and one-third of the patients had vocal cord paralysis (252). Stridor that occurs when the patient’s neck is extended portends serious airway obstruction and should raise the question of elective tracheostomy to protect the airway. The tumor may cause a superior mediastinal syndrome with venous distention and edema of the face, arms, and neck. 12.4.2

Distant Metastases

Only about one-third of patients have distant metastases, mostly to the lung, recognized at the time of diagnosis, but about half the patients eventually developed them (242,249,252). The lung is the most common site of distant metastases, comprising 75% to 90% of all distant metastases reported in large series

280

Kloos and Mazzaferri

(242,249,252). They are typically manifest as large isolated metastases that do not concentrate 131 I. Skeletal metastases are the second most frequent but only account for about 5% of the distant metastases at the time of diagnosis and about 15% of all distant metastases that eventually develop (242,249,252). Uncommonly patients with ATC have distant metastases to other sites, such as the CNS (242,249,252). The diagnosis of malignancy is usually quite evident with ATC because of the ominous symptoms and physical findings suggesting an aggressive tumor. The main diagnostic problems are differentiating ATC from less aggressive undifferentiated thyroid tumors and delineating the extent of the neck disease. 12.4.3

Fine-Needle Aspiration

Most cases of ATC diagnosed by FNA should at least have open biopsy with immunohistochemical staining to confirm the diagnosis. Although a diagnosis of thyroid malignancy is almost always possible by FNA cytology, ATC may be difficult to distinguish from thyroid lymphoma, MTC, and other forms of poorly differentiated thyroid carcinoma or cancers metastatic to the thyroid gland. Nonetheless, the giant- and spindle-cell patterns of ATC usually predominate, sometimes with multinucleated giant cells, suggesting the correct diagnosis. Although MTC often shows a spindle-cell population, it can usually be correctly identified by FNA cytology that may stain for amyloid or calcitonin (242). Non-Hodgkin’s thyroid lymphoma can be identified by FNA, usually by its small cells, but open biopsy and histochemical staining are often necessary to differentiate it from ATC, especially when the lymphoma is composed of large cells. 12.4.4

Radionuclide Studies

Thyroid scanning with radioiodine usually discloses one or more cold nodules in ATC, which is a nonspecific finding. However, gallium-67 (67Ga) uptake is low in well-differentiated thyroid carcinomas but high in anaplastic carcinomas and malignant lymphomas and may detect distant metastases (253). 12.4.5

Thyroid Ultrasonography

The majority of differentiated carcinomas and all anaplastic tumors present as hypoechoic masses by ultrasonography. Tumor clearly extending beyond the thyroid capsule or infiltrating adjacent tissues strongly suggests a malignant diagnosis. 12.4.6

Computed Tomography (CT)

CT is indispensable preoperatively since it may alter surgical planning, especially when the tumor extends into the thorax or invades the larynx, esophagus, or other neck structures. ATC appears as a large mass of low attenuation accompanied

Thyroid Carcinoma

281

by dense calcification in over half the patients in most of whom there is also evidence of tumor necrosis (254). CT usually identifies tumor infiltrating neck structures, including the carotid artery, internal jugular vein, larynx, trachea, esophagus, mediastinum, and regional lymph nodes. CT identifies lymph nodes, which are often necrotic, more consistently than palpation (254). 12.5

Natural History and Mortality Rates

ATC has a dismal prognosis. In 1961, Woolner and associates (255) reported from the Mayo Clinic that 61% of ATC patients were dead within 6 months and 77% died within a year of diagnosis. Almost 30 years later, a study from M.D. Anderson (249) reported a mean survival of 7 months. Only 8% (20 of 240 patients) from both series survived longer than 1 year. Median survival in a later Mayo Clinic series was only 4 months (252), which is similar to that reported in most series in the past two decades (242). This is why lymphomas and MTCs—which histologically resemble ATC but have a substantially better prognosis—must be carefully identified by immunohistochemical studies. 12.5.1

Cause of Death

Death occurs most commonly from the effects of local tumor invasion, particularly asphyxiation. In one large study (256) over half the patients died of suffocation, while the others died of a combination of effects from the primary tumor and metastases. 12.6

Prognostic Factors

Although prognosis with ATC is very poor, certain features predict a more favorable response to therapy. Like differentiated thyroid carcinoma, patient age (249) and tumor stage at the time of diagnosis are the most important variables influencing prognosis. In one large study (249), mean survival was 8.1 months if the disease was confined to the neck, compared with 3.3 months when it was distantly metastatic. The Mayo Clinic (252) reported that relatively favorable prognostic features were unilateral tumors, a tumor diameter ⬍5 cm, no invasion of adjacent tissue, and absence of cervical node involvement. Cox multivariate analysis showed that extent of disease, tumor size, histological cell type, and surgical treatment were the most significant variables. In a recent report spanning 1985– 1995, with 893 cases (3), the 10-year relative survival in the United States was 14%, with 77% of deaths within 1 year and 100% of all deaths by year 4. Age ⬍ 45 years at diagnosis demonstrated dramatically better 5-year survival at 55%. Small tumor size and absent extrathyroidal extension were more common in patients surviving more than 5 years.

282

12.7

Kloos and Mazzaferri

Treatment

ATCs are very resistant to any form of therapy and are rarely cured. Surgery, chemotherapy, or radiotherapy used separately generally has not been effective (257–259). The best survival rates occur with combined surgery, accelerated and hyperfractionated external irradiation, and chemotherapy (260). 12.8 12.8.1

Surgical Therapy Thyroid Surgery

Less than total thyroidectomy, with resection of the involved adjacent neck tissues and cervical lymph nodes, should be done if possible, without resorting to radical surgery in surgically noncurable patients. In the Mayo Clinic series (252), 41% of the patients had surgical resection—mostly total lobectomy with subtotal resection of the contralateral lobe—in an attempt to cure the patient. In the M.D. Anderson series (249), about 45% of patients underwent total thyroidectomy. However, in neither series did the surgical extent influence the survival. Total thyroidectomy and radical neck dissection result in an increased complication rate without conferring a clear advantage over a more conservative approach. When the tumor is resectable, an appropriately aggressive and safe surgical approach is to resect the tumor with wide margins of adjacent soft tissue on the involved side. When the tumor is not resectable, attention is directed toward airway management. 12.8.2

Airway Management

Tumor may compromise the airway by compression, displacement, infiltration, and less often as the result of neurogenic dysfunction. Management involves thyroid gland resection with decompression of the airway and tracheostomy when the airway is infiltrated with tumor. Many patients require tracheostomy during their course, mainly to relieve airway obstruction but also as a precautionary measure before initiating external radiation therapy. External irradiation may cause tumor edema that acutely exacerbates airway obstruction. More than half the patients in the Mayo Clinic series required tracheostomy at some time during the course of their disease (252). 12.9 12.9.1

Medical Therapy External Radiotherapy

After treatment with surgery and conventional radiotherapy, ⬍5% of patients with ATC survive 5 years, although survivors who are disease-free at 2 years may live for longer periods (242). Because conventional external irradiation fails to eradicate local disease, larger doses of radiation have been given at closer

Thyroid Carcinoma

283

intervals with limited success in controlling local disease, but the toxicity is very high, resulting in severe esophagitis, dysphagia, spinal cord necrosis, and death (259,261). 12.9.2

Chemotherapy

There is no consensus regarding the selection of chemotherapeutic agents for ATC, mainly because this tumor is so resistant to chemotherapy. None provides clearly superior therapeutic efficacy, and the selection is often based as much upon the side-effect profiles of the drugs as its potential efficacy. Doxorubicin is perhaps the most commonly used, administered either alone or in combination with other drugs. There is a dose-response relationship such that patients receiving lower doxorubicin doses, in the range of 45 mg/m2, show little or no response, while those treated with larger doses demonstrate therapeutic responses more consistently (242). The most frequently applied doxorubicin dosage has been between 60 and 90 mg/m2 body surface (242). With this dosage, one study (195) found the response rate (complete or partial remission) to be almost 40% in patients with advanced thyroid carcinoma of all types, although the response rate was only 22% for ATC treated with doxorubicin monotherapy. Even when remission does occur, its duration is relatively short, with a median period of 90 (range 33 to 560) days in the 20% to 30% who responded to doxorubicin (242). Others believe that doxorubicin alone does not improve the extremely poor prognosis of ATC. When there is a response to doxorubicin, pulmonary metastases most frequently respond, followed by bone metastases and local tumor growth; however, the drug may not control local disease (242). 12.9.3

Doxorubicin and Hyperfractionated Radiation Therapy

In 1983, a new treatment regimen consisting of combination doxorubicin and hyperfractionated radiation therapy was reported for the treatment of ATC (262,263). The protocol consisted of once-weekly administration of low-dose doxorubicin (10 mg/m2) and hyperfractionated radiation therapy carried out with a fractional dose of 160 cGy per treatment twice a day for 3 days per week. The total tumor dose was 5760 cGy delivered in 40 days. The protocol was well tolerated with little morbidity. Complete tumor response was observed in 84% of the patients and rate of local tumor control was 68% at 2 years. Median survival was 1 year, but most patients developed distant metastases and died from the disease. In 1990, a Swedish group (264) reported prospectively treating 16 patients with a protocol of hyperfractionated radiotherapy, doxorubicin, and debulking surgery. The radiotherapy was administered preoperatively to a target dose of 30 Gy in 3 weeks and postoperatively to an additional dose of 16 Gy in 1.5 weeks. Radiotherapy was administered twice daily, 5 days a week, with a target dose

284

Kloos and Mazzaferri

of 1 Gy per fraction and with a minimum interval of 6 h. Doxorubicin (20 mg) was administered intravenously 1 to 2 h before the first radiotherapy session every week. Debulking surgery was feasible in 9 patients. Complete remission of local disease was achieved in 5 of 16, of whom 3 were alive and disease-free at 10, 30, and 30 months after diagnosis. Only 6 patients died of local disease. This combination regimen was well tolerated despite the patients’ advanced age and disease stage. In 1994, the same group (260) reported prospectively treating 33 consecutive patients with ATC according to the above protocol except that the daily fraction of radiotherapy was increased to 1.3 Gy per fraction after 1988. No patient failed to complete the protocol because of toxicity. There were no local recurrences in 16 patients (48%). Death was attributed to local failure in only eight patients (24%). In four patients, survival with no evidence of disease exceeded 2 years. Local tumor control was marginally improved in patients treated in the latter part of the study. The authors concluded that combination-modality treatment of ATC is feasible and effective despite the patients’ advanced age and locally advanced disease. In 1991, a French group (265) reported their results in 20 ATC patients treated prospectively according to a combination protocol of chemotherapy and external radiation therapy. Depending on the patient’s age, two types of chemotherapy were used every 4 weeks. For those younger than 65 years, a combination of doxorubicin (60 mg/m2) and cisplatin (90 mg/m2) was employed; for older patients, mitoxantrone (14 mg/m2) alone was used. Between days 10 and 20 of the first four chemotherapy cycles, radiotherapy (17.5 Gy) was given in seven fractions to the neck and superior mediastinum. Of the total, 3 patients (15%) survived longer than 20 months. Complete tumor response in the neck was observed in 5 (25%) patients, among who four had undergone previous thyroidectomy. No response was seen in distant metastases, which were the cause of death in 70% of the patients in this series. Toxicity was the main limiting factor—all patients developed pharyngoesophagitis and tracheitis after the first or second cycle of radiotherapy. It was severe in 60% of the patients, requiring 1 to 2 weeks’ rest before resuming treatment. Hematological toxicity occurred in 40% of the patients, while cardiotoxicity was seen in 25% of those treated with doxorubicin. 13 PRIMARY THYROID LYMPHOMA (PTL) Primary thyroid lymphoma (PTL) is an uncommon but potentially life-threatening disorder that often poses a major diagnostic and therapeutic dilemma because most clinicians rarely see these tumors. PTL typically arises in the setting of chronic thyroiditis, sometimes in patients with long-standing hypothyroidism. The true character of the neoplasm may go unrecognized for several months,

Thyroid Carcinoma

285

until the development of airway obstruction symptoms; then, unfortunately, an erroneous diagnosis of ATC is sometimes made. It is important to identify the tumor correctly as a PTL, since treatments and prognoses differ, and diagnosis at an early stage is associated with an excellent prognosis. 13.1

Incidence

The annual incidence of PTL in the United States is less than one in 2 million persons (266). It is tenfold less frequent than gastrointestinal lymphoma, the most common extranodal non-Hodgkin’s lymphoma, and only slightly more common than breast lymphoma (266). The likelihood that a thyroid nodule is a lymphoma is ⬍1 per 1000, whereas secondary involvement of the thyroid with lymphoma occurs in about 10% of patients who die of the disease (266). Despite the relative rarity of PTL, its incidence has been rising, and it now constitutes about 5% of all thyroid malignancies, with estimates ranging from 2% to 8% (266). Its frequency may be increasing for several reasons. Many PTLs were incorrectly diagnosed in the past as anaplastic small cell thyroid carcinoma (266). Also, pathologists now have become more adept at separating lymphoma from advanced Hashimoto’s thyroiditis, which is important, since PTL typically develops in the setting of preexisting lymphocytic thyroiditis (266). Some of the increase seems related to more aggressive diagnostic evaluation of thyroid nodules. Finally, the increasing frequency of PTL has paralleled the rising incidence of Hashimoto’s thyroiditis in the United States. 13.2

Age and Sex Distribution

Contrary to other lymphomas in which males predominate, female preponderance is the rule for PTL (266), probably because it originates from active lymphoid cells in chronic lymphocytic thyroiditis, which occurs more often in women. Among 812 PTL patients, females outnumbered males almost 3 to 1, and the mean age was 62.7 years (266). However, the female-to-male ratio under age 60 was 1.5 to 1 compared with 5 to 1 over age 60 (266). Although primarily a disease of older women, about one-third of these patients are under 60 years of age (266). 13.3

Hashimoto’s Thyroiditis (Chronic Lymphocytic Thyroiditis) and Thyroid Lymphoma

An association exists between PTL and Hashimoto’s thyroiditis, but how this occurs is unclear. In one study, the relative risk of PTL among people in Sweden with Hashimoto’s thyroiditis, after an average follow-up of 8.5 years, was 67fold greater than expected (267). Another study (268) from Japan found an 80-

286

Kloos and Mazzaferri

fold increased frequency of PTL among 5592 women aged 25 years or older with chronic thyroiditis. The average interval between the diagnosis of chronic thyroiditis and PTL was 9.2 years. 13.4 13.4.1

Pathology Lymphoma Cell Types

Virtually all PTLs are B-cell types, which can be identified by monoclonal antibodies (266). Many extranodal lymphomas, including those in the thyroid, arise from mucosa-associated lymphoid tissue (MALT); they are a special group of B-cell lymphomas (266). Most are diffuse (as opposed to nodular) lymphomas, with variable cellular features typical of low-grade malignancies. Cases classified as immunoblastic B-cell lymphoma are uncommon but are typically quite aggressive. 13.4.2

Histological Features of Hashimoto’s Disease

The histological features of Hashimoto’s disease and PTL are often difficult to differentiate. Hashimoto’s features include well-differentiated lymphocytes, plasma cells, macrophages, and lymphoid follicles with germinal centers and scattered Langhans-type giant cells. The reactive lymphoid follicles are largely composed of B lymphocytes that mainly produce polyclonal IgG. The inflammatory cells are associated with both damage and stimulation of the thyroid follicular cells, causing atrophy, metaplasia, and hyperplasia, which leads to considerable loss of thyroid colloid. Most of the inflammatory cells lie in the interstitial tissue between thyroid follicles and are typically confined to the thyroid parenchyma, with minimal infiltration of the thyroid capsule. 13.4.3

Histological Features of Lymphoma

The normal thyroid tissue is extensively infiltrated with abnormal lymphoid cells that often penetrate the thyroid capsule, extending into adjacent soft tissues. The lymphoma is usually composed of small cells monotonously similar to one another, which represents a distinct difference from those seen in autoimmune thyroiditis. The border between the two may be sharply defined, or there may be a transitional zone in which elements of both are mixed. The lymphoma cells tend to displace, distort, and replace the thyroid epithelium. Most thyroid follicles are packed and distended with lymphoma cells and loose colloid (266). Lymphoma cells infiltrate blood vessel walls in at least one-fourth of the cases and lymphoma cells may undergo necrosis. Leukocyte common antigen can usually be found and substantial proportions of lymphomas contain both monoclonal heavy and light chain immunoglobulins, characteristics that allow their differentiation from

Thyroid Carcinoma

287

small cell carcinomas. Also, identification of monoclonal light chains usually allows differentiation of a malignant proliferation from a polyclonal benign lymphocyte inflammation, although monoclonal gammopathy occasionally can be demonstrated in Hashimoto’s disease. 13.5 13.5.1

Clinical Features Symptoms and Signs

13.5.1.1 Duration of Symptoms Most patients with PTL have impressive symptoms caused by a rapidly expanding goiter that is invading and compressing neck structures. Symptoms typically are short in duration, averaging less than 5 months (266), which contrasts sharply with the indolent course of Hashimoto’s thyroiditis. 13.5.1.2 Compression Symptoms Patients characteristically have a subacute onset of symptoms caused by tumor pressing and growing into vital neck organs, particularly the trachea, laryngeal nerve, esophagus, and neck muscles. The most common complaints are hoarseness (21%); dysphagia, dyspnea, and stridor (19%); neck pressure (5%); and neck pain (5%) (266). These are important signals of extrathyroidal tumor extension that should alert the clinician to the malignant nature of the goiter. Stridor and hoarseness often occur together, and when they do, laryngeal nerve paralysis is almost invariably seen on laryngoscopy. Symptoms of invasion, particularly dyspnea and dysphagia, are ominous and portend a poor outcome. 13.5.1.3 Goiter The most common presenting feature is recent growth of goiter, which is experienced by about half the patients (266). A rapidly enlarging goiter typically becomes apparent to the patient over several weeks to a few months before the diagnosis of lymphoma is established, although longer periods have been reported. A goiter was present for a year or more in 16% of 556 patients reported in nine large studies (266). Only one thyroid lobe may enlarge or a discrete nodule may be palpable within the gland, or there may be diffuse thyromegaly. The goiter is nearly always firm or hard, is usually nontender and is often fixed to adjacent tissues, a sign that tumor is invading neck structures. Other signs of extrathyroidal spread include ill-defined thyroid borders with extension laterally or retrosternally. 13.5.1.4 Lymph Node Involvement and Retrosternal Extension Large (⬎2 cm), nontender, and matted cervical lymph nodes are found on physical examination in up to half the patients (266). The chest roentgenogram may

288

Kloos and Mazzaferri

show retrosternal involvement or mediastinal widening, although lymph nodes elsewhere are seldom enlarged. 13.5.1.5 Coexisting Hashimoto’s Thyroiditis Almost all patients with PTL have clinical or histological evidence of lymphocytic thyroiditis at the time of diagnosis (266). In 10 large series (266), antithyroglobulin and antimicrosomal antibodies are found in almost 75% of 539 patients, and 83% had histological evidence of Hashimoto’s thyroiditis. 13.5.1.6 Thyroid Dysfunction Although laboratory evidence of autoimmune thyroiditis is common, few patients have overt hypothyroidism. Most are euthyroid or only mildly hypothyroid, showing minimal elevation in serum thyroid-stimulating hormone (TSH) and otherwise normal thyroid function tests at the time PTL is discovered. When lymphoma was diagnosed, overt hypothyroidism was seen in only about 8% of 366 patients from seven large studies (266). However, despite its relative infrequency, a goiter that suddenly enlarges during appropriate long-term levothyroxine therapy is an important clinical clue to the diagnosis of lymphoma. Thyrotoxicosis is extremely uncommon but can occur in patients with lymphoma. 13.6 13.6.1

Diagnosis Differential Diagnosis

The diagnoses that should be considered in a patient with a rapidly enlarging thyroid mass are PTL, ATC, MTC, multinodular goiter or colloid nodule with acute hemorrhage, and various inflammatory disorders including acute, subacute, and Hashimoto’s thyroiditis. 13.6.2

Early Diagnosis

It is important to diagnose PTL at an early stage. A German study showed that non-Hodgkin’s lymphomas with low-grade histology can, over time, undergo transformation into high-grade tumors (266). In one large study from Japan (269), the frequency of high-grade PTLs decreased significantly after 1982, which the authors attributed to early diagnosis and therapy. Although the diagnosis is usually made in response to a rapidly enlarging and symptomatic thyroid mass, PTL can sometimes be discovered at an earlier stage by investigating more subtle clues in patients with known Hashimoto’s thyroiditis. PTL should be considered in a patient with Hashimoto’s thyroiditis with a discrete hypofunctional area on 123 I scanning, whether or not there is a palpable nodule (266). PTL also should be suspected when the entire thyroid gland with Hashimoto’s disease or any portion of it enlarges during thyroid hormone therapy or when palpable cervical or supraclavicular lymph nodes develop.

Thyroid Carcinoma

289

TABLE 5 Indications for Fine-Needle Aspiration or Open Surgical Biopsy in Patients Suspected of Having Thyroid Lymphoma Thyroid mass with Rapid enlargement Hoarseness Laryngeal paralysis Dysphagia Stridor Dyspnea Pain Hashimoto’s thyroiditis Hypofunctional (cold) nodule Hypofunctional area on scan without nodule Goiter or nodule enlargement despite thyroid hormone therapy Monoclonal gammopathy Source: Adapted from Ref. 266.

13.6.3

Routine Laboratory Studies

13.6.3.1 Serum Chemistries and Immunoglobulins Routine serum chemistries and hematological studies are usually normal. The serum immunoglobulins are occasionally abnormal, showing a monoclonal gammopathy, and—very rarely—the bone marrow is involved by lymphoma (266). 13.6.4

Thyroid Tests

Thyroid function testing may disclose subclinical or overt hypothyroidism, and serum antimicrosomal and antithyroglobulin antibodies are often positive. 13.6.5

Fine-Needle Aspiration Biopsy

13.6.5.1 Selection of Patients FNA should be considered in patients with features summarized in Table 5 (266). A diagnosis of lymphoma may be established by FNA cytology or by open surgical biopsy. Immunophenotyping with flow cytometry or Southern blot analysis for lymphocytic clones may also be helpful (270). 13.7 13.7.1

Imaging Studies Timing of Studies

Thyroid imaging done with radionuclides, CT, MRI, and ultrasonography usually demonstrate nonspecific abnormalities and are not first-line tests. However, once

290

Kloos and Mazzaferri

the diagnosis is established by FNA, imaging is useful in defining the extent of disease. 13.7.2

Ultrasonography

PTL usually appears as a well-delineated hypoechoic solid mass intermingled with echogenic structures. It is easily distinguishable from the surrounding thyroid tissue even though the latter often shows low echogenicity and nodularity due to coexisting Hashimoto’s thyroiditis. Most PTLs are discrete solid nodules, but some appear as diffuse goiters or multiple irregular nodules in a diffuse goiter. Ultrasonography may disclose contiguous tumor spread into both thyroid lobes and is sensitive in detecting cervical lymph nodes. It is an important adjunct to physical examination that is useful both on initial evaluation with FNA and in follow-up. 13.7.3

Computed Tomography (CT)

PTL usually is manifest as one or more areas of low thyroid density. CT appearances are of three types: solitary nodule (80%), multiple nodules (13%), and diffuse goiter (7%) (266). Both lobes are usually involved with advanced disease. The tumors have a strong tendency to compress (80%) or infiltrate (53%) surrounding structures and less often show calcification (7%) and necrosis (7%) (266). Lymphomas often completely encircle the trachea, which is a characteristic feature of malignancy sometimes termed the ‘‘donut sign.’’ Although CT and ultrasonography are both highly sensitive in detecting thyroidal abnormalities caused by lymphoma, CT is better at demarcating intrathoracic tumor extension and laryngeal invasion and is the preferred radiological technique for staging (266). 13.7.4

Magnetic Resonance Imaging (MRI)

Lymphomas appear as homogeneous iso- or high-intensity areas on T1-weighted images compared with uninvolved thyroid tissue, which appears homogeneously high-intensity on T2-weighted images (266). The distinction between tumor and uninvolved thyroid gland is sometimes more apparent by MRI than CT, but the two are comparable in identifying extrathyroidal extension, and cervical lymphadenopathy and in the staging of lymphoma (271). Hashimoto’s thyroiditis often shows homogeneous signal intensities on MRI that are indistinguishable from those of lymphoma. 13.7.5

Radionuclide Scanning

Various radionuclides, including compounds labeled with radioactive iodine, 201 Tl, 67Ga, 111In-octreotide, FDG-PET, MIBG, and 99m Tc may be used to study patients with PTL, but none is specific for the diagnosis. Lymphoma appears as a hypofunctional lesion with 123 I or 99m Tc-pertechnetate thyroid scanning. Like 99m Tc-labeled compounds, 201 TI may demonstrate uptake in PTL. Perhaps the

Thyroid Carcinoma

291

best-studied agent is 67Ga, which demonstrates uptake not only in malignant lymphoma (86%) but also in anaplastic carcinoma (90%) and other high-grade malignancies (266). 13.8 13.8.1

Staging Initial Disease Stage

The disease is confined to the thyroid gland (stage IE) in almost half the patients and within regional lymph nodes (stage IIE) in 43% at the time of diagnosis (266). In a study of 245 patients (272), ⬍2% had disease outside of regional lymph nodes when they presented, but 10 eventually developed involvements of bone marrow, retroperitoneal nodes, and other tissues outside the neck. 13.8.2

Gastrointestinal Lymphoma

Although opinions differ, some suggest that there is an association between PTL and gastrointestinal lymphomas. Among the approximately 500 cases of PTL reported from the mid-1930s to 1986, gastrointestinal involvement was found in 62% of those dying with metastatic PTL—a frequency more than twofold greater than that reported for all non-Hodgkin’s lymphomas (273). Accordingly, gastrointestinal infiltration by PTL does not appear to occur by serendipity. 13.8.3

Staging Workup

Since site-directed radiation alone is often used for lymphoma, accurate staging of the disease is important, although there is little agreement regarding the extent of staging evaluation (266,271). We believe that all patients should have a complete blood count, blood chemistries, and chest roentgenogram in addition to studies to investigate the extent of local disease, including regional lymph node involvement and tumor extension into surrounding neck structures and disease in the chest and abdomen. Thyroid ultrasonography may be helpful but CT or MRI of the neck, chest, and abdomen should be done routinely. Whether a bone marrow examination should be done in every patient is even less certain. Several studies suggest that almost no patients with PTC have bone marrow involvement, and they conclude that such an examination is usually unnecessary (266,274). There also is lack of consensus about gastrointestinal evaluation, and at our institution dedicated gastrointestinal studies are not done routinely. Others routinely examine the gastrointestinal tract in almost all patients with PTL, although when this was done in one study only 2.5% had stage IV disease (275). 13.9 13.9.1

Prognostic Features Long-Term Survival

Five-year survival with PTL was almost 60% in 368 patients reported in seven large series (266). However, survival is dependent upon several variables, particularly tumor stage and grade.

292

13.9.2

Kloos and Mazzaferri

Stage

In a large study in 1966 from the Mayo Clinic (276), when tumor was limited to the thyroid (stage IE), only one death occurred; however, involvement of local lymph nodes (stage IIE) or infiltration of adjacent soft tissues reduced average survival rate to only 18 months. A more recent study (277) found 5-year survival rates were 91% in stage IE and only 62% in stage IIE patients. Over the past several decades, 5-year survival rates have been at least 75% to 100% when tumor is confined to the thyroid compared with only 35% to 60% when it is outside the gland (266,278,279). 13.9.3

Tumor Grade

In one study (275), 5-year survival rates were 92% for patients with low-grade lymphomas, 79% for intermediate-grade lymphomas, and 13% for immunoblastic type (high-grade) tumors. 13.9.4

Other Prognostic Factors

Reported favorable prognostic factors include longer duration (⬎6 months) of goiter, age ⬍60 years at the time of diagnosis, goiter smaller than 10 cm, and preexisting Hashimoto’s thyroiditis (275,280,281). Reported negative prognostic factors include large tumor size and fixation, extracapsular extension, retrosternal involvement, large cell lymphoma, unresectable tumor, possibly male sex, advanced age (⬎65), hoarseness, stridor, hepatosplenomegaly, and axillary lymph nodes (274,278,280,281). 13.10 Therapy Treatment is not standard because large, randomized, multicenter trials for this uncommon disorder have not yet been done. Although external radiation has become the treatment of choice in many centers, controversy exists about the optimal extent of surgery and the use of chemotherapy. Although survival has improved over the past few decades, it is not clear which factors are responsible. There are indications that PTL is being diagnosed at an earlier stage and at a lower grade, that adequate staging is being performed more regularly, and that radiation therapy is being used in nearly all cases (266). 13.10.1

Surgery

Some (274) report that patients undergoing total macroscopic tumor removal fare considerably better than those with persistent tumor after surgery; 5-year survival rates in the two groups, respectively, were about 65% and 22%. Similar results were reported from the Mayo Clinic (280), where 5-year survival rates were lower (49% versus 75%) when patients had obvious residual disease postoperatively. Perhaps the least controversial reasons for surgery are for diagnosis and tumor

Thyroid Carcinoma

293

staging and to relieve airway obstruction. Since the cytological diagnosis of lymphoma may be difficult to establish with certainty by FNA, open biopsy may be necessary. In our institution, this is frequently the case, and surgeons excise as much malignant tissue as possible without performing radical surgery. In addition, a tracheostomy is done if there is any question about the integrity of the airway. 13.10.2

Airway Protection

Patients commonly present with a rapidly enlarging thyroid mass. On occasion— and sometimes with striking swiftness—this leads to severe tracheal compression with respiratory distress that may necessitate emergency surgery (266). This complication should be anticipated and an elective tracheostomy performed whenever airway compromise is a possibility, because death from laryngeal obstruction can occur in the immediate postoperative period or later with uncontrolled disease (266). Almost 25% of the patients in a large series from the Mayo Clinic (282) required an elective tracheostomy; however, there was a 10% rate of infection, sepsis, or bleeding. 13.10.3

Radiotherapy

Radiotherapy is employed in most centers, especially for patients with stage IE or IIE disease. Control of neck disease is related both to radiation dosage and selection of radiation fields and may also be dependent upon the degree of surgical debulking prior to radiotherapy. The thyroid, bilateral neck, and mediastinum are treated with at least 40 Gy (4000 rad) given in divided doses over 4 to 5 weeks (266). There are differences of opinion, however, concerning the radiation fields, with some (274) recommending radiation only to the neck and others (280) advocating irradiation of the axilla and mediastinum. Despite important differences in patient cohorts and radiation techniques, overall 5-year survival rates range from 55% to 70% following external radiation given either alone or with surgery (266). Results are best for patients with stage IE and IIE disease. For example, one group (277) reported 5-year survival rates of 91% in patients with stage IE disease who were treated with 40 Gy. 13.10.4

Chemotherapy

Although chemotherapy is often used as salvage therapy, PTL recurrence rates as high as 50% and the predominance of diffuse histiocytic lymphoma (which responds particularly well to chemotherapy) have led some to propose using chemotherapy either alone or as an adjuvant to surgery or radiotherapy in most patients (266). Others recommend chemotherapy only for patients with poor prognostic factors (266). Most chemotherapy regimens consist of cyclophosphamide, Adriamycin, vincristine, and prednisone, with or without bleomycin (CHOP ⫾ bleomycin) or minor alterations of this combination (266). A review of the pub-

294

Kloos and Mazzaferri

lished literature suggests that the addition of chemotherapy to radiation significantly lowered distant and overall recurrence (283). 13.10.5

Failure Patterns

Recurrence rates vary dramatically among various series because authors do not always explicitly distinguish between persistent and recurrent disease, but most (75%) recurrences are detected within the first year following therapy and commonly involve lymph nodes (272,280,284). The gastrointestinal tract, lung, liver, pancreas, and kidney are much less frequently involved. 13.10.6

Local Disease Failure

Local disease failure usually occurs in 25% to 35% of patients after 40 Gy, although results vary (266,274,277,283). The rate of local failure is related to the amount of residual disease after initial thyroidectomy and to the placement of the radiation fields and the use of chemotherapy. One study (280) reported no failures within the treatment fields in patients without residual disease when radiation therapy was started, but otherwise there were twice as many failures following radiotherapy to the neck alone compared with radiotherapy to both the neck and mediastinum (60% versus 36%). 13.10.7

Distant Recurrence

Distant recurrences occur to lung, gastrointestinal tract, liver, CNS, and kidneys. One study (272) of 245 patients found that the gastrointestinal tract was infrequently involved, but others (273) reported its involvement in 62% of patients dying with metastatic PTL. An autopsy study (285) found the most common sites of involvement were the gastrointestinal tract (100%), lung and kidney (each 63%), and liver and pancreas (each 50%). 13.10.8

Survival Following Relapse

Salvage therapy has little impact upon the disease once relapse occurs (266). One group (274) reported that disease-free survival was almost identical to overall actual survival, emphasizing the poor response of recurrent disease to therapy. Another study (284) reported an 8-month (range 1 to 21 months) mean survival in six patients following relapse. REFERENCES 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA 1998; 48: 6–30. 2. Kosary CL, Ries LAG, Miller BA, Hankey BF, Harras A, Edwards BK. SEER Cancer Statistic Review, 1973–1992: Tables and Graphs. NIH Pub. No. 96-2789, Bethesda, MD: National Cancer Institute, 1995.

Thyroid Carcinoma

295

3. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A national cancer data base report on 53,856 cases of thyroid carcinoma treated in the US, 1985–1995. Cancer 1998; 83:2638–2648. 4. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994; 97:418–428. 5. Mazzaferri EL. Thyroid carcinoma: Papillary and follicular. In: Mazzaferri EL, Samaan N, eds. Endocrine Tumors. Cambridge, MA: Blackwell, 1993, pp 278– 333. 6. Moosa M, Mazzaferri EL. Occult thyroid carcinoma. Cancer J 1997; 10:180–188. 7. Burgess JR, Duffield A, Wilkinson SJ, Ware R, Greenaway TM, Percival J, et al. Two families with an autosomal dominant inheritance pattern for papillary carcinoma of the thyroid. J Clin Endocrinol Metab 1997; 82:345–348. 8. Stoffer SS, Van Dyke DL, Bach JV, Szpunar W, Weiss L. Familial papillary carcinoma of the thyroid. Am J Med Genet 1986; 25:775–782. 9. Lupoli G, Vitale G, Caraglia M, Fittipaldi MR, Abbruzzese A, Tagliaferri P, Bianco AR. Familial papillary thyroid microcarcinoma: a new clinical entity. Lancet 1999; 353:637–639. 10. Bell B, Mazzaferri EL. Familial adenomatous polyposis (Gardner’s syndrome) and thyroid carcinoma: a case report and review of the literature. Dig Dis Sci 1993; 38:185–190. 11. Cetta F, Olschwang S, Petracci M, Montalto G, Baldi C, Zuckermann M, Costantini RM, Fusco A. Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection. World J Surg 1998; 22:1231–1236. 12. Burman KD, Ringel MD, Wartofsky L. Unusual types of thyroid neoplasms. Endocrinol Metab Clin North Am 1996; 25:49–68. 13. Dahia PLM, Marsh DJ, Zheng ZM, Zedenius J, Komminoth P, Frisk T, Wallin G, Parsons R, Longy M, Larsson C, Eng C. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res 1997; 57: 4710–4713. 14. Stratakis CA, Courcoutsakis NA, Abati A, Filie A, Doppman JL, Carney JA, Shawker T. Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex). J Clin Endocrinol Metab 1997; 82:2037–2043. 15. Brennan MD, Bergstralh EJ, van Heerden JA, McConahey WM. Follicular thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 1991; 66:11–22. 16. Young RL, Mazzaferri EL, Rahe AJ, Dorfman SG. Pure follicular thyroid carcinoma: impact of therapy in 214 patients. J Nucl Med 1980; 21:733–737. 17. Ron E, Lubin JH, Shore RE, Mabuchi K, Modan B, Pottern LM, Schneider AB, Tucker MA, Boice JD, Jr. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res 1995; 141:259–277. 18. Schneider AB, Ron E, Lubin J, Stovall M, Gierlowski TC. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab 1993; 77: 362–369.

296

Kloos and Mazzaferri

19. Hall P, Holm LE. Radiation-associated thyroid cancer—facts and fiction. Acta Oncol 1998; 37:325–330. 20. Ron E, Doddy MM, Becker DV, Brill AB, Curtis RE, Goldman MB, Harris BSH, III, Hoffman DA, McConahey WM, Maxon HR, Preston-Martin S, Warshauer ME, Wong FL, Boice JD, Jr., Coop Thyrotoxicos Therap Fellow Stud. Cancer mortality following treatment for adult hyperthyroidism. JAMA 1998; 280:347–355. 21. Hall P, Fu¨rst CJ, Mattsson A, Holm LE, Boice JD Jr, Inskip PD. Thyroid nodularity after diagnostic administration of iodine-131. Radiat Res 1996; 146:673–682. 22. Holm LE, Wiklund KE, Lundell GE, Bergman NA, Bjelkengren G, Ericsson UB, Larsson LG, Lidberg ME, Lindberg RS, et al. Cancer risk in population examined with diagnostic doses of 131 I. J Natl Cancer Inst 1989; 81:302–306. 23. Holm LE, Wiklund KE, Lundell GE, Bergman NA, Bjelkengren G, Cederquist ES, et al. Thyroid cancer after diagnostic doses of iodine-131: a retrospective cohort study. J Natl Cancer Inst 1988; 80:113–118. 24. Hall P, Mattsson A, Boice JD Jr. Thyroid cancer after diagnostic administration of iodine-131. Radiat Res 1996; 145:86–92. 25. Gilbert ES, Tarone R, Bouville A, Ron E. Thyroid cancer rates and 131 I doses from Nevada atmospheric nuclear bomb tests. J Natl Cancer Inst 1998; 90:1654–1660. 26. Kerber RA, Till JE, Simon SL, Lyon JL, Thomas DC, Preston-Martin S, Rallison ML, Lloyd RD, Stevens W. A cohort study of thyroid disease in relation to fallout from nuclear weapons testing. JAMA 1993; 270:2076–2082. 27. Anonymous: Committee on Exposure of the American People to I-131 from the Nevada Atomic-Bomb Test: Implications for Public Health. Washington, DC: Institute of Medicine, National Academy of Sciences, 1999. 28. Jacob P, Goulko G, Heidenreich WF, Likhtarev I, Kairo I, Tronko ND, Bogdanova TI, Kenigsberg J, Buglova E, Drozdovitch V, Golovneva A, Demidchik EP, Balonov M, Zvonova I, Beral V. Thyroid cancer risk to children calculated. Nature 1998; 392:31–32. 29. Powell DJ Jr, Russell J, Nibu K, Li GQ, Rhee E, Liao M, et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res 1998; 58:5523–5528. 30. Evans HL. Encapsulated columnar-cell neoplasms of the thyroid—a report of four cases suggesting a favorable prognosis. Am J Surg Pathol 1996; 20:1205–1211. 31. de los Santos ET, Keyhani-Rofagha S, Cunningham JJ, Mazzaferri EL. Cystic thyroid nodules: the dilemma of malignant lesions. Arch Intern Med 1990; 150:1422– 1427. 32. Baudin E, Travagli JP, Ropers J, Mancusi F, Bruno-Bossio G, Caillou B, Cailleux AF, Lumbroso JD, Parmentier C, Schlumberger M. Microcarcinoma of the thyroid gland—the Gustave-Roussy Institute Experience. Cancer 1998; 83:553–559. 33. Hedinger C, Williams ED, Sobin LH. The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 1989; 63:908–911. 34. Mazzaferri EL, Young RL, Oertel JE, Kemmerer WT, Page CP. Papillary thyroid carcinoma: the impact of therapy in 576 patients. Medicine (Baltimore) 1977; 56: 171–196. 35. LiVolsi V, Asa SL. The demise of follicular carcinoma of the thyroid gland. Thyroid 1994; 4:233–236.

Thyroid Carcinoma

297

36. Scha¨ffler A, Palitzsch KD, Seiffarth C, Ho¨hne HM, Riedhammer FJ, Hofsta¨dter F, Scho¨lmerich J, Ru¨schoff J. Coexistent thyroiditis is associated with lower tumour stage in thyroid carcinoma. Eur J Clin Invest 1998; 28:838–844. 37. Fiumara A, Belfiore A, Russo G, Salomone E, Santonocito GM, Ippolito O, Vigneri R, Gangemi P. In situ evidence of neoplastic cell phagocytosis by macrophages in papillary thyroid cancer. J Clin Endocrinol Metab 1997; 82:1615–1620. 38. LiVolsi VA. Papillary lesions of the thyroid. In: LiVolsi VA, ed. Surgical Pathology of the Thyroid. Philadelphia: Saunders, 1990, pp 136–172. 39. LiVolsi VA. Unusual variants of papillary thyroid carcinoma. In: Mazzaferri EL, Kreisberg RA, Bar RS, eds. Advances in Endocrinology and Metabolism, 6th ed. St. Louis: Mosby-Year Book, 1995, pp 39–54. 40. Ain KB. Papillary thyroid carcinoma etiology, assessment, and therapy. Endocrinol Metab Clin North Am 1995; 24:711–760. 41. Noguchi M, Yamada H, Ohta N, Ishida T, Tajiri K, Fujii H, Miyazaki I. Regional lymph node metastases in well-differentiated thyroid carcinoma. Int Surg 1987; 72: 100–103. 42. Sugino K, Ito K, Jr., Ozaki O, Mimura T, Iwasaki H, Ito K. Papillary microcarcinoma of the thyroid. J Endocrinol Invest 1998; 21:445–448. 43. Yamashita H, Noguchi S, Murakami N, Kawamoto H, Watanabe S. Extracapsular invasion of lymph node metastasis is an indicator of distant metastasis and poor prognosis in patients with thyroid papillary carcinoma. Cancer 1997; 80:2268– 2272. 44. Pacini F, Lari R, Mazzeo S, Grasso L, Taddei D, Pinchera A. Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer. Clin Endocrinol 1985; 23:405–411. 45. Pineda JD, Lee T, Ain K, Reynolds J, Robbins J. Iodine-131 therapy for thyroid cancer patients with elevated thyroglobulin and negative diagnostic scan. J Clin Endocrinol Metab 1995; 80:1488–1492. 46. Schlumberger M, Arcangioli O, Piekarski JD, Tubiana M, Parmentier C. Detection and treatment of lung metastases of differentiated thyroid carcinoma in patients with normal chest x-rays. J Nucl Med 1988; 29:1790–1794. 47. Schlumberger M, Mancusi F, Baudin E, Pacini F. 131-I Therapy for elevated thyroglobulin levels. Thyroid 1997; 7:273–276. 48. Yoo KS, Chengazi VU, O’Mara RE. Thyroglossal duct cyst with papillary carcinoma in an 11-year-old girl. J Pediatr Surg 1998; 33:745–746. 49. Sobrinho-Simoes M, Soares J, Carneiro F. Diffuse follicular variant of papillary carcinoma of the thyroid: report of eight cases of a distinct aggressive type of tumor. Surg Pathol 1990; 3:189–203. 50. Nikiforov Y, Gnepp DR. Pediatric thyroid cancer after the Chernobyl disaster: pathomorphologic study of 84 cases (1991–1992) from the Republic of Belarus. Cancer 1994; 74:748–766. 51. Rosai J. Papillary carcinoma. Monogr Pathol 1993; 138–165. 52. Herrera MF, Hay ID, Wu PS, Goellner JR, Ryan JJ, Ebersold JR, Bergstralh EJ, Grant CS. Hurthle cell (oxyphyilic) papillary thyroid carcinoma: a variant with more aggressive biologic behavior. World J Surg 1994; 16:669–674.

298

Kloos and Mazzaferri

53. Katoh R, Harach HR, Williams ED. Solitary, multiple, and familial oxyphil tumours of the thyroid gland. J Pathol 1998; 186:292–299. 54. LiVolsi VA. Follicular lesions of the thyroid. In: LiVolsi VA, ed. Surgical Pathology of the Thyroid. Philadelphia: Saunders, 1990, pp 173–212. 55. Hassoun AAK, Hay ID, Goellner JR, Zimmerman D. Insular thyroid carcinoma in adolescents—a potentially lethal endocrine malignancy. Cancer 1997; 79:1044– 1048. 56. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993; 328: 553–559. 57. Lin JD, Chao TC, Ho J, Weng H-F, See LC. Poor prognosis of 56 follicular thyroid carcinomas with distant metastases at the time of diagnosis. Cancer J 1998; 11: 190–195. 58. Hamming JF, Goslings BM, vanSteenis GJ, Claasen H, Hermans J, Velde JH. The value of fine-needle aspiration biopsy in patients with nodular thyroid disease divided into groups of suspicion of malignant neoplasms on clinical grounds. Arch Intern Med 1990; 150:113–116. 59. Schneider AB, Shore Freedman E, Ryo UY, Bekerman C, Favus M, Pinsky S. Radiation-induced tumors of the head and neck following childhood irradiation: prospective studies. Medicine (Baltimore) 1985; 64:1–15. 60. Leenhardt L, Hejblum G, Franc B, Fediaevsky LD, Delbot T, Le Guillouzic D, et al. Indications and limits of ultrasound-guided cytology in the management of nonpalpable thyroid nodules. J Clin Endocrinol Metab 1999; 84:24–28. 61. Schneider AB, Bekerman C, Leland J, Rosengarten J, Hyyppa¨ MT, Collins B, Shore-Freedman E, Gierlowski TC. Thyroid nodules in the follow-up of irradiated individuals: comparison of thyroid ultrasound with scanning and palpation. J Clin Endocrinol Metab 1997; 82:4020–4027. 62. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas: prevalence by palpation and ultrasonography. Arch Intern Med 1994; 154:1838–1840. 63. Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 1997; 126: 226–231. 64. Fogelfeld L, Wiviott MBT, Shore-Freedman E, Blend M, Bekerman C, Pinsky S, Schneider AB. Recurrence of thyroid nodules after surgical removal in patients irradiated in childhood for benign conditions. N Engl J Med 1989; 320:835–840. 65. Dottorini ME, Vignati A, Mazzucchelli L, Lomuscio G, Colombo L. Differentiated thyroid carcinoma in children and adolescents: a 37-year experience in 85 patients. J Nucl Med 1997; 38:669–675. 66. Harach HR, Williams ED. Childhood thyroid cancer in England and Wales. Br J Cancer 1995; 72:777–783. 67. Hung W. Well-differentiated thyroid carcinomas in children and adolescents: a review. Endocrinologist 1994; 4:117–126. 68. Samuel AM, Rajashekharrao B, Shah DH. Pulmonary metastases in children and adolescents with well-differentiated thyroid cancer. J Nucl Med 1998; 39:1531– 1536. 69. Zimmerman D, Hay ID, Gough IR, Goellner JR, Ryan JJ, Grant CS, McConahey WM. Papillary thyroid carcinoma in children and adults: long-term follow-up of

Thyroid Carcinoma

70.

71.

72. 73.

74.

75.

76. 77. 78.

79. 80.

81. 82. 83.

84. 85.

299

1039 patients conservatively treated at one institution during three decades. Surgery 1988; 104:1157–1166. Filetti S, Belfiore A, Amir SM, Daniels GH, Ippolito O, Vigneri R, Ingbar SH. The role of thyroid-stimulating antibodies of Graves’ disease in differentiated thyroid cancer. N Engl J Med 1988; 318:753–779. Belfiore A, Garofalo MR, Giuffrida D, Runello F, Filetti S, Fiumara A, et al. Increased aggressiveness of thyroid cancer in patients with Graves’ disease. J Clin Endocrinol Metab 1990; 70:830–835. Hay ID. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 1990; 19: 545–576. Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma—a population-based study of 15,698 cases from the surveillance, epidemiology and end results (SEER) program 1973–1991. Cancer 1997; 79:564–573. Samaan NA, Schultz PN, Hickey RC, Haynie TP, Johnston DA, Ordonez NG. Welldifferentiated thyroid carcinoma and the results of various modalities of treatment: a retrospective review of 1599 patients. J Clin Endocrinol Metab 1992; 75:714– 720. Pasieka JL, Thompson NW, McLeod MK, Burney RE, Macha M. The incidence of bilateral well-differentiated thyroid cancer found at completion thyroidectomy. World J Surg 1992; 16:711–716. Sarda AK, Bal S, Kapur MM. Near-total thyroidectomy for carcinoma of the thyroid. Br J Surg 1989; 76:90–92. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990; 71:414–424. Taylor T, Specker B, Robbins J, Sperling M, Ho M, Ain K, Bigos ST, Brierley J, Cooper D, Haugen B, Hay I, Hertzberg V, Klein I, Klein H, Ladenson P, Nishiyama R, Ross D, Sherman S, Maxon HR. Outcome after treatment of high-risk papillary and non-Hurthle-cell follicular thyroid carcinoma. Ann Intern Med 1998; 129:622– 627. Mazzaferri EL. Thyroid remnant 131 I ablation for papillary and follicular thyroid carcinoma. Thyroid 1997; 7:265–271. Massin JP, Savoie JC, Garnier H, Guiraudon G, Leger FA, Bacourt F. Pulmonary metastases in differentiated thyroid carcinoma: study of 58 cases with implications for the primary tumor treatment. Cancer 1984; 53:982–992. Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery 1995; 118:1131–1138. Sanders LE, Cady B. Differentiated thyroid cancer—reexamination of risk groups and outcome of treatment. Arch Surg 1998; 133:419–424. Loh KC, Greenspan FS, Gee L, Miller TR, Yeo PPB. Pathological tumor-nodemetastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients. J Clin Endocrinol Metab 1997; 82:3553–3562. Cady B. Staging in thyroid carcinoma. Cancer 1998; 83:844–847. Tsang TW, Brierley JD, Simpson WJ, Panzarella T, Gospodarowicz MK, Sutcliffe SB. The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer 1998; 82: 375–388.

300

Kloos and Mazzaferri

86. Simpson WJ, McKinney SE, Carruthers JS, Gospodarowicz MK, Sutcliffe SB, Panzarella T. Papillary and follicular thyroid cancer. Prognostic factors in 1,578 patients. Am J Med 1987; 83:479–488. 87. Kurozumi K, Nakao I, Nishida T, Nakahara M, Ogino N, Tsujimoto M. Significance of biologic aggressiveness and proliferating activity in papillary thyroid carcinoma. World J Surg 1998; 22:1237–1242. 88. Sugitani I, Yanagisawa A, Shimizu A, Kato M, Fujimoto Y. Clinicopathologic and immunohistochemical studies of papillary thyroid microcarcinoma presenting with cervical lymphadenopathy. World J Surg 1998; 22:731–737. 89. Akslen LA, Varhaug JE. Oncoproteins and tumor progression in papillary thyroid carcinoma—presence of epidermal growth factor receptor, c-erbB-2 protein, estrogen receptor related protein, p21-ras protein, and proliferation indicators in relation to tumor recurrences and patient survival. Cancer 1995; 76:1643–1654. 90. Sellers M, Beenken S, Blankenship A, Soong S, Turbat-Herrera E, Urist M, Maddox W. Prognostic significance of cervical lymph node metastases in differentiated thyroid cancer. Am J Surg 1992; 164:578–581. 91. Sisson JC, Giordano TJ, Jamadar DA, Kazerooni EA, Shapiro B, Gross MD, Zempel SA, Spaulding SA. 131-I treatment of micronodular pulmonary metastases from papillary thyroid carcinoma. Cancer 1996; 78:2184–2192. 92. Neˆmec J, Zamrazil V, Pohunkova´ D, Ro¨hling S. Radioiodide treatment of pulmonary metastases of differentiated thyroid cancer: results and prognostic factors. Nuklearmedizin 1979; 18:86–90. 93. Casara D, Rubello D, Saladini G, Masarotto G, Favero A, Girelli ME, et al. Different features of pulmonary metastases in differentiated thyroid cancer: natural history and multivariate statistical analysis of prognostic variables. J Nucl Med 1993; 34:1626–1631. 94. Viswanathan K, Gierlowski TC, Schneider AB. Childhood thyroid cancer: characteristics and long-term outcome in children irradiated for benign conditions of the head and neck. Am J Dis Child 1994; 148:260–265. 95. Kashima K, Yokoyama S, Noguchi S, Murakami N, Yamashita H, Watanabe S, et al. Chronic thyroiditis as a favorable prognostic factor in papillary thyroid carcinoma. Thyroid 1998; 8:197–202. 96. Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, Pierotti MA, Della Porta G, Vecchio G. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 1987; 328:170–172. 97. Donghi R, Sozzi G, Pierotti MA, Biunno I, Miozzo M, Fusco A, Grieco M, Santoro M, Vecchio G, Spurr NK. The oncogene associated with human papillary thyroid carcinoma (PTC) is assigned to chromosome 10 q11-q12 in the same region as multiple endocrine neoplasia type 2A (MEN2A). Oncogene 1989; 4:521–523. 98. Smanik PA, Furminger TL, Mazzaferri EL, Jhiang SM. Breakpoint characterization of the ret/PTC oncogene in human papillary thyroid carcinoma. Hum Mol Genet 1995; 4:2313–2318. 99. Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY, Xing S, Ledent C. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 1996; 137:375–378. 100. Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, et al. Devel-

Thyroid Carcinoma

101.

102. 103. 104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114. 115.

301

opment of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 1996; 12:1821– 1826. Jhiang SM, Caruso DR, Gilmore E, Ishizaka Y, Tahira T, Nagao M, Chiu IM, Mazzaferi EL. Detection of the PTC/retTPC oncogene in human thyroid cancers. Oncogene 1992; 7:1331–1337. Sugg SL, Ezzat S, Zheng L, Freeman JL, Rosen IB, Asa SL. Oncogene profile of papillary thyroid carcinoma. Surgery 1999; 125:46–52. Nikiforov YE, Nikiforova M, Fagin JA. Radiation-induced post-Chernobyl pediatric thyroid carcinomas. Oncogene 1998; 17:1983–1988. American Joint Committee on Cancer. Head and neck tumors—thyroid gland. In: Beahrs OH, Henson DE, Hutter RVP, Myers MH, eds. Manual for Staging of Cancer, 4th ed. Philadelphia: Lippincott, 1992, pp 53–54. Brierley JD, Panzarella T, Tsang RW, Gospodarowicz MK, O’Sullivan B. A comparison of different staging systems predictability of patient outcome—thyroid carcinoma as an example. Cancer 1997; 79:2414–2423. Van De Velde CJH, Hamming JF, Goslings BM, Schelfhout LJDM, Clark OH, Smeds S, Bruining HA, Krenning EP, Cady B. Report of the consensus development conference on the management of differentiated thyroid cancer in the Netherlands. Eur J Cancer Clin Oncol 1988; 24:287–292. Baldet L, Manderscheid JC, Glinoer D, Jaffiol C, Coste Seignovert B, Percheron C. The management of differentiated thyroid cancer in Europe in 1988: results of an international survey. Acta Endocrinol (Copenh) 1989; 120:547–558. Solomon BL, Wartofsky L, Burman KD. Current trends in the management of well differentiated papillary thyroid carcinoma. J Clin Endocrinol Metab 1996; 81:333– 339. Boyd LA, Earnhardt RC, Dunn JT, Frierson HF, Hanks JB. Preoperative evaluation and predictive value of fine-needle aspiration and frozen section of thyroid nodules. J Am Coll Surg 1998; 187:494–502. Hamming JF, Vriens MR, Goslings BM, Songun I, Fleuren GJ, Van De Velde CJH. Role of fine-needle aspiration biopsy and frozen section examination in determining the extent of thyroidectomy. World J Surg 1998; 22:575–580. Mulcahy MM, Cohen JI, Anderson PE, Ditamasso J, Schmidt W. Relative accuracy of fine-needle aspiration and frozen section in the diagnosis of well-differentiated thyroid cancer. Laryngoscope 1998; 108:494–496. McHenry CR, Raeburn C, Strickland T, Marty JJ. The utility of routine frozen section examination for intraoperative diagnosis of thyroid cancer. Am J Surg 1996; 172:658–661. Chen H, Zeiger MA, Clark DP, Westra WH, Udelsman R. Papillary carcinoma of the thyroid: can operative management be based solely on fine-needle aspiration? J Am Coll Surg 1997; 184:605–610. Pasieka JL, Rotstein LE. Consensus conference on well-differentiated thyroid cancer: a summary. Can J Surg 1999; 36:298–301. Tourniaire J, Bernard MH, Bizollon-Roblin MH, Bertholon-Gregoire M, BergerDutrieux N. Thyroid papillary microcarcinoma: 179 cases since 1973. Presse Med 1998; 27:1467–1469.

302

Kloos and Mazzaferri

116. Cady B. Our AMES is true: How an old concept still hits the mark: or, risk group assignment points the arrow to rational therapy selection in differentiated thyroid cancer. Am J Surg 1997; 174:462–468. 117. Schlumberger MJ. Medical progress—papillary and follicular thyroid carcinoma. N Engl J Med 1998; 338:297–306. 118. Mazzaferri EL. Treating differentiated thyroid carcinoma: where do we draw the line? Mayo Clin Proc 1991; 66:105–111. 119. Newman KD, Black T, Heller G, Azizkhan RG, Holcomb GW, III, Sklar C, Vlamis V, Haase GM, La Quaglia MP. Differentiated thyroid cancer: determinants of disease progression in patients ⬍21 years of age at diagnosis—a report from the Surgical Discipline Committee of the Children’s Cancer Group. Ann Surg 1998; 227: 533–541. 120. Miccoli P, Antonelli A, Spinelli C, Ferdeghini M, Fallahi P, Baschieri L. Completion total thyroidectomy in children with thyroid cancer secondary to the Chernobyl accident. Arch Surg 1998; 133:89–93. 121. Hay ID, Grant CS, Bergstralh EJ,Thompson GB, van Heerden JA. Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery 1998; 124:958–966. 122. Maxon HR, Englaro EE, Thomas SR, Hertzberg VS, Hinnefeld JD, Chen LS, et al. Radioiodine-131 therapy for well-differentiated thyroid cancer—a quantitative radiation dosimetric approach: outcome and validation in 85 patients. J Nucl Med 1992; 33:1132–1136. 123. Chao TC, Jeng LB, Lin JD, Chen MF. Completion thyroidectomy for differentiated thyroid carcinoma. Otolaryngol Head Neck Surg 1998; 118:896–899. 124. DeGroot LJ, Kaplan EL. Second operations for ‘‘completion’’ of thyroidectomy in treatment of differentiated thyroid cancer. Surgery 1991; 110:936–940. 125. Emerick GT, Duh Q-Y, Siperstein AE, Burrow GN, Clark OH. Diagnosis, treatment, and outcome of follicular thyroid carcinoma. Cancer 1993; 72:3287–3295. 126. Rao RS, Fakih AR, Mehta AR, Agarwal R, Raghavan A, Shrikhande SS. Completion Thyroidectomy for thyroid carcinoma. Head Neck Surg 1987; 9:284–286. 127. Auguste LJ, Attie JN. Completion thyroidectomy for initially misdiagnosed thyroid cancer. Otolaryngol Clin North Am 1990; 23:429–439. 128. Scheumann GFW, Seeliger H, Musholt TJ, Gimm O, Wegener G, Dralle H, Hundeshagen H, Pichlmayr R. Completion thyroidectomy in 131 patients with differentiated thyroid carcinoma. Eur J Surg 1996; 162:677–684. 129. De Jong SA, Demeter JG, Lawrence AM, Paloyan E. Necessity and safety of completion thyroidectomy for differentiated thyroid carcinoma. Surgery 1992; 112: 734–737. 130. Travagli JP, Cailleux AF, Ricard M, Baudin E, Caillou B, Parmentier C, Schlumberger M. Combination of radioiodine (131 I) and probe-guided surgery for persistent or recurrent thyroid carcinoma. J Clin Endocrinol Metab 1998; 83:2675–2680. 131. Burge MR, Zeise TM, Johnsen MW,Conway MJ, Qualls CR. Risks of complication following thyroidectomy. J Gen Intern Med 1998; 13:24–31. 132. Dralle H, Gimm O, Simon D, Frank-Raue K, Go¨rtz G, Niederle B, Wahl RA, Koch B, Walgenbach S, Hampel R, Ritter MM, Spelsberg F, Heiss A, Hinze R, Ho¨ppner W. Prophylactic thyroidectomy in 75 children and adolescents with hereditary med-

Thyroid Carcinoma

133.

134. 135.

136. 137. 138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

303

ullary thyroid carcinoma: German and Austrian experience. World J Surg 1998; 22:744–751. Pattou F, Combemale F, Fabre S, Carnaille B, Decoulx M, Wemeau JL, Racadot A, Proye C. Hypocalcemia following thyroid surgery: incidence and prediction of outcome. World J Surg 1998; 22:718–724. Udelsman R, Lakatos E, Ladenson P. Optimal surgery for papillary thyroid carcinoma. World J Surg 1996; 20:88–93. Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R. The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg 1998; 228:320–328. Driggers RW, Kopelman JN, Satin AJ. Delaying surgery for thyroid cancer in pregnancy—a case report. J Reprod Med 1998; 43:909–912. Moosa M, Mazzaferri EL. Outcome of differentiated thyroid cancer diagnosed in pregnant women. J Clin Endocrinol Metab 1997; 82:2862–2866. Saito T, Endo T, Kawaguchi A, Ikeda M, Katoh R, Kawaoi A, Muramatsu A, Onaya T. Increased expression of the sodium/iodide symporter in papillary thyroid carcinomas. J Clin Invest 1998; 101:1296–1300. Arturi F, Russo D, Schlumberger M, Du Villard JA, Caillou B, Vigneri P, Wicker R, Chiefari E, Suarez HG, Filetti S. Iodide symporter gene expression in human thyroid tumors. J Clin Endocrinol Metab 1998; 83:2493–2496. Jhiang SM, Cho JY, Ryu K-Y, DeYoung B, Smanik PA, McGaughy VR, Fischer AH, Mazzaferri EL. An immunohistochemical study of Na⫹/I-symporter in human thyroid tissues and salivary gland tissues. Endocrinology 1998; 139:4416– 4419. Goldman JM, Line BR, Aamodt RL, Robbins J. Influence of triiodothyronine withdrawal time on 131-I uptake postthyroidectomy for thyroid cancer. J Clin Endocrinol Metab 1980; 50:734–739. Lakshmanan M, Schaffer A, Robbins J, Reynolds J, Norton J. A simplified low iodine diet in I-131 scanning and therapy of thyroid cancer. Clin Nucl Med 1988; 2:866–868. Pons F, Carrio I, Estorch M, Ginjuame M, Pons J, Milian R. Lithium as an adjuvant of iodine-131 uptake when treating patients with well-differentiated thyroid carcinoma. Clin Nucl Med 1987; 8:644–647. Koong SS, Reynolds JC, Movius EG, Keenan AM, Ain KB, Lakshmanan MC, Robbins J. Lithium as a potential adjuvant to 131 I therapy of metastatic, well differentiated thyroid carcinoma. J Clin Endocrinol Metab 1999; 84:912–916. Maxon HR, Thomas SR, Hertzberg VS, Kereiakes JG, Chen IW, Sperling MI, Saenger EL. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N Engl J Med 1983; 309:937–941. Park HM, Perkins OW, Edmondson JW, Schnute RB, Manatunga A. Influence of diagnostic radioiodines on the uptake of ablative dose of iodine-131. Thyroid 1994; 4:49–54. Leger FA, Izembart M, Dagousset F, Barritault L, Baillet G, Chevalier A, Clerc J. Decreased uptake of therapeutic doses of iodine-131 after 185- MBq iodine-131 diagnostic imaging for thyroid remnants in differentiated thyroid carcinoma. Eur J Nucl Med 1998; 25:242–246.

304

Kloos and Mazzaferri

148. Muratet JP, Giraud P, Daver A, Minier JF, Gamelin E, Larra F. Predicting the efficacy of first iodine-131 treatment in differentiated thyroid carcinoma. J Nucl Med 1997; 38:1362–1368. 149. Greenler DP, Klein HA. The scope of false-positive iodine-131 images for thyroid carcinoma. Clin Nucl Med 1989; 14:111–117. 150. Bakheet SMB, Hammami MM, Hemidan A, Powe JE, Bajaafar F. Radioiodine secretion in tears. J Nucl Med 1998; 39:1452–1454. 151. Chung JK, Lee YJ, Jeong JM, Lee DS, Lee MC, Cho BY, Koh CS. Clinical significance of hepatic visualization on iodine-131 whole-body scan in patients with thyroid carcinoma. J Nucl Med 1997; 38:1191–1195. 152. Vassilopoulou-Sellin R, Klein MJ, Smith TH, Samaan NA, Frankenthaler RA, Goepfert H, Cangir A, Haynie TP. Pulmonary metastases in children and young adults with differentiated thyroid cancer. Cancer 1993; 71:1348–1352. 153. Spencer CA, Takeuchi M, Kazarosyan M, Wang CC, Guttler RB, Singer PA, Fatemi S, LoPresti JS, Nicoloff JT. Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998; 83: 1121–1127. 154. Hodgson DC, Brierley JD, Tsang RW, Panzarella T. Prescribing 131iodine based on neck uptake produces effective thyroid ablation and reduced hospital stay. Radiother Oncol 1998; 47:325–330. 155. Cunningham MP, Duda RB, Recant W, Chmiel JS, Sylvester JA, Fremgen A. Survival discriminants for differentiated thyroid cancer. Am J Surg 1990; 160:344– 347. 156. DeGroot LJ, Kaplan EL, Straus FH, Shukla MS. Does the method of management of papillary thyroid carcinoma make a difference in outcome? World J Surg 1994; 18:123–130. 157. Samaan NA, Maheshwari YK, Nader S, Hill CS Jr, Schultz PN, Haynie TP, Hickey RC, Clark RL, Goepfert H, Ibanez ML, Litton CE. Impact of therapy for differentiated carcinoma of the thyroid: an analysis of 706 cases. J Clin Endocrinol Metab 1983; 56:1131–1138. 158. Bal C, Padhy AK, Jana S, Pant GS, Basu AK. Prospective randomized clinical trial to evaluate the optimal dose of 131 I for remnant ablation in patients with differentiated thyroid carcinoma. Cancer 1996; 77:2574–2580. 159. Brierley J, Maxon HR. Radioiodine and external radiation therapy. In: Fagin JA, ed. Thyroid Cancer. Boston/Dordrecht/London: Kluwer, 1998, pp 285–317. 160. Simpson WJ, Panzarella T, Carruthers JS, Gospodarowicz MK, Sutcliffe SB. Papillary and follicular thyroid cancer: impact of treatment in 1578 patients. Int J Radiat Oncol Biol Phys 1988; 14:1063–1075. 161. Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary metastasis of differentiated thyroid carcinoma: treatment results in 101 patients. J Clin Endocrinol Metab 1985; 60:376–380. 162. Ruegemer JJ, Hay ID, Bergstralh EJ, Ryan JJ, Offord KP, Gorman CA. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab 1988; 67:501–558. 163. Mazzaferri EL. Carcinoma of follicular epithelium: radioiodine and other treatment

Thyroid Carcinoma

164.

165.

166. 167. 168.

169.

170. 171.

172. 173.

174.

175.

176.

177.

178.

305

outcomes. In: Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text, 7th ed. Philadelphia: Lippincott-Raven, 1996, pp 922–945. Benua RS, Cicale NR, Sonenberg M. The relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer. AJR 1962; 87:171–178. Maxon H III, Smith HS. Radioiodine-131 in the diagnosis and treatment of metastatic well differentiated thyroid cancer. Endocrinol Metab Clin North Am 1990; 19:685–718. Datz FL. Cerebral edema following iodine-131 therapy for thyroid carcinoma metastatic to the brain. J Nucl Med 1986; 27:637–640. DiRusso G, Kern KA. Comparative analysis of complications from I-131 radioablation for well-differentiated thyroid cancer. Surgery 1994; 116:1024–1030. Allweiss P, Braunstein GD, Katz A, Waxman A. Sialadenitis following I-131 therapy for thyroid carcinoma: concise communication. J Nucl Med 1984; 25:755– 758. Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and longterm side effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl Med 1998; 39:1551–1554. Levy HA, Park CH. Effect of reserpine on salivary gland radioiodine uptake in thyroid cancer. Clin Nucl Med 1987; 12:303–307. Brown AP, Greening WP, McCready VR, Shaw HJ, Harmer CL. Radioiodine treatment of metastatic thyroid carcinoma: the Royal Marsden Hospital experience. Br J Radiol 1984; 57:323–327. Hall P, Holm L-E. Cancer in iodine-131 exposed patients. J Endocrinol Invest 1995; 18:147–149. Van Nostrand D, Neutze J, Atkins F. Side effects of ‘‘rational dose’’ iodine-131 therapy for metastatic well-differentiated thyroid carcinoma. J Nucl Med 1986; 27: 1519–1527. De Vathaire F, Schlumberger M, Delisle MJ, Francese C, Challeton C, De la Genardie`re E, Meunier F, Parmentier C, Hill C, Sancho-Garnier H. Leukaemias and cancers following iodine-131 administration for thyroid cancer. Br J Cancer 1997; 75: 734–739. Schlumberger M, Challeton C, De Vathaire F, Travagli JP, Gardet P, Lumbroso JD, Francese C, Fontaine F, Ricard M, Parmentier C. Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med 1996; 37:598–605. Menzel C, Gru¨nwald F, Schomburg A, Palmedo H, Bender H, Spa¨th G, Biersack HJ. ‘‘High-dose’’ radioiodine therapy in advanced differentiated thyroid carcinoma. J Nucl Med 1996; 37:1496–1503. Schlumberger M, De Vathaire F, Ceccarelli C, Francese C, Pinchera A, Parmentier C. Outcome of pregnancy in women with thyroid carcinoma. J Endocrinol Invest 1995; 18:150–151. Schlumberger M, De Vathaire F, Ceccarelli C, Delisle MJ, Francese C, Couette JE, Pinchera A, Parmentier C. Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients. J Nucl Med 1996; 37:606–612.

306

Kloos and Mazzaferri

179. Pacini F, Gasperi M, Fugazzola L, Ceccarelli C, Lippi F, Centoni R, Martino E, Pinchera A. Testicular function in patients with differentiated thyroid carcinoma treated with radioiodine. J Nucl Med 1994; 35:1418–1422. 180. Burmeister LA, Goumaz MO, Mariash CN, Oppenheimer JH. Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab 1992; 75:344–350. 181. Bartalena L, Martino E, Pacchiarotti A, Grasso L, Aghini Lombardi F, Buratti L, Bambini G, Breccia M, Pinchera A. Factors affecting suppression of endogenous thyrotropin secretion by thyroxine treatment: retrospective analysis in athyreotic and goitrous patients. J Clin Endocrinol Metab 1987; 64:849–855. 182. Pujol P, Daures JP, Nsakala N, Baldet L, Bringer J, Jaffiol C. Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab 1996; 81:4318–4323. 183. Cooper DS, Specker B, Ho M, Sperling M, Ladenson PW, Ross D, Ain KB, Bigos ST, Brierley JD, Haugen BR, Klein I, Robbins J, Sherman SI, Taylor T, Maxon HR, III. Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry. Thyroid 1999; 8:737–744. 184. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331:1249–1252. 185. Biondi B, Fazio S, Carella C, Amato G, Cittadini A, Lupoli G, et al. Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1993; 77:334–338. 186. Fazio S, Biondi B, Carella C, Sabatini D, Cittadini A, Panza N, Lombardi G, Sacca` L. Diastolic dysfunction in patients on thyroid-stimulating hormone suppressive therapy with levothyroxine: beneficial effect of β-blockade. J Clin Endocrinol Metab 1995; 80:2222–2226. 187. Shapiro LE, Sievert R, Ong L, Ocampo EL, Chance RA, Lee M, Nanna M, Ferrick K, Surks MI. Minimal cardiac effects in asymptomatic athyreotic patients chronically treated with thyrotropin-suppressive doses of l-thyroxine. J Clin Endocrinol Metab 1997; 82:2592–2595. 188. Toivonen J, Tahtela R, Laitinen K, Risteli J, Valimaki MJ. Markers of bone turnover in patients with differentiated thyroid cancer with and following withdrawal of thyroxine suppressive therapy. Eur J Endocrinol 1998; 138:667–673. 189. Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 1996; 81:4278–4289. 190. Marcocci C, Golia F, Vignali E, Pinchera A. Skeletal integrity in men chronically treated with suppressive doses of l-thyroxine. J Bone Miner Res 1997; 12:72–77. 191. Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM. Risk factors for hip fracture in white women. N Engl J Med 1995; 332:767–773. 192. Gru¨nwald F, Menzel C, Bender H, Palmedo H, Otte R, Fimmers R, Risse J, Biersack HJ. Redifferentiation therapy-induced radioiodine uptake in thyroid cancer. J Nucl Med 1998; 39:1903–1906.

Thyroid Carcinoma

307

193. Chiu AC, Delpassand ES, Sherman SI. Prognosis and treatment of brain metastases in thyroid carcinoma. J Clin Endocrinol Metab 1997; 82:3637–3642. 194. Schlumberger M, Baudin E, Travagli JP. Papillary and follicular cancer of the thyroid. Presse Med 1998; 27:1479–1481. 195. Ahuja S, Ernst H. Chemotherapy of thyroid carcinoma. J Endocrinol Invest 1987; 10:303–310. 196. Grigsby PW, Baglan K, Siegel BA. Surveillance of patients to detect recurrent thyroid carcinoma. Cancer 1999; 85:945–951. 197. Meier CA, Braverman LE, Ebner SA, Veronikis I, Daniels GH, Ross DS, Deraska DJ, Davies TF, Valentine M, DeGroot LJ, Curran P, McEllin K, Reynolds J, Robbins J, Weintraub BD. Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase I/II study). J Clin Endocrinol Metab 1994; 78:188– 196. 198. Ladenson PW, Braverman LE, Mazzaferri EL, Brucker-Davis F, Cooper DS, Garber JR, Wondisford FE, Davies TF, DeGroot LJ, Daniels GH, Ross DS, Weintraub BD. Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma. N Engl J Med 1997; 337:888–896. 199. Rudavsky AZ, Freeman LM. Treatment of scan-negative, thyroglobulin-positive metastatic thyroid cancer using radioiodine 131 I and recombinant human thyroid stimulating hormone. J Clin Endocrinol Metab 1997; 82:11–14. 200. Haugen B, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, Cooper DS, Graham KE, Braverman LE, Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri EL, Daniels GH, Ross DS, Luster M, Samuels MH, Becker DV, Maxon HR, III, Cavalieri RR, Spencer CA, McEllin K, Weintraub BD, Ridgway EC. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999; 84:3877–3885. 201. Spencer CA, Wang CC. Thyroglobulin measurement—techniques, clinical benefits, and pitfalls. Endocrinol Metabol Clin North Am 1995; 24:841–863. 202. Spencer CA. Recoveries cannot be used to authenticate thyroglobulin (Tg) measurements when sera contain Tg autoantibodies. Clin Chem 1996; 42:661–663. 203. Ringel M, Ladenson P, Levine MA. Molecular diagnosis of residual and recurrent thyroid cancer by amplification of thyroglobulin messenger ribonucleic acid in peripheral blood. J Clin Endocrinol Metab 1998; 83:4435–4442. 204. Nakada K, Katoh C, Kanegae K, Tsukamoto E, Shiga T, Mochizuki T, Itoh K, Tamaki N. Thallium-201 scintigraphy to predict therapeutic outcome of iodine-131 therapy of metastatic thyroid carcinoma. J Nucl Med 1998; 39:807–810. 205. Carril JM, Quirce R, Serrano J, Banzo I, Jime´nez-Bonilla JF, Tabuenca O, Barquin RG. Total-body scintigraphy with thallium-201 and iodine-131 in the follow-up of differentiated thyroid cancer. J Nucl Med 1997; 38:686–692. 206. Lin JD, Kao PF, Weng HF, Lu WT, Huang MJ. Relative value of thallium-201 and iodine-131 scans in the detection of recurrence or distant metastasis of well differentiated thyroid carcinoma. Eur J Nucl Med 1998; 25:695–700. ¨ zbey N, Alago¨l F, Cantez S. Thallium¨ nal S, Menda Y, Adalet I, Boztepe H, O 207. U 201, technetium-99m-tetrofosmin and iodine-131 in detecting differentiated thyroid carcinoma metastases. J Nucl Med 1998; 39:1897–1902.

308

Kloos and Mazzaferri

208. Lorberboym M, Murthy S, Mechanick JI, Bergman D, Morris JC, Kim CK. Thallium-201 and iodine-131 scintigraphy in differentiated thyroid carcinoma. J Nucl Med 1996; 37:1487–1491. 209. Miyamoto S, Kasagi K, Misaki T, Alam MS, Konishi J. Evaluation of technetium99m-MIBI scintigraphy in metastatic differentiated thyroid carcinoma. J Nucl Med 1997; 38:352–356. 210. Brandt-Mainz K, Mu¨ller SP, Sonnenschein W, Bockisch A. Technetium-99m-furifosmin in the follow-up of differentiated thyroid carcinoma. J Nucl Med 1998; 39: 1536–1541. 211. Feine U, Lietzenmayer R, Hanke JP, Held J, Wo¨hrle H, Mu¨ller-Schauenburg W. Fluorine-18-FDG and iodine-131-iodide uptake in thyroid cancer. J Nucl Med 1996; 37:1468–1472. 212. Huang TS, Chieng PU, Chang CC, Yen RF. Positron emission tomography for detecting iodine-131 nonvisualized metastasis of well-differentiated thyroid carcinoma: two case reports. J Endocrinol Invest 1998; 21:392–398. 213. Bakheet SMB, Powe J. Fluorine-18-fluorodeoxyglucose uptake in rheumatoid arthritis-associated lung disease in a patient with thyroid cancer. J Nucl Med 1998; 39:234–236. 214. Mazzaferri EL. Treating high thyroglobulins with radioiodine: a magic bullet or a shot in the dark? J Clin Endocrinol Metab 1995; 80:1485–1487. 215. Raue F, Zink A. Clinical features of multiple endocrine neoplasia type 1 and type 2. Horm Res 1992; 38(suppl 2):31–35. 216. Gagel RF, Robinson MF, Donovan DT, Alford BR. Medullary thyroid carcinoma: recent progress. J Clin Endocrinol Metab 1993; 76:809–814. 217. Howe JR, Norton JA, Wells SA, Jr. Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery 1993; 114:1070–1077. 218. Sizemore GW. Medullary carcinoma of the thyroid gland. Semin Oncol 1987; 14: 306–314. 219. Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993; 363:458–460. 220. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA Jr. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993; 2:851–856. 221. Eng C, Clayton D, Schufenecker I, Lenoir G, Cote G, Gagel RF, Van Amstel HKP, Lips CJM, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET mutation consortium analysis. JAMA 1996; 276:1575–1579. 222. Gimm O, Neuberg DS, Marsh DJ, Dahia PLM, Cuong HV, Raue F, Hinze R, Dralle H, Eng C. Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene 1999; 18:1369–1373.

Thyroid Carcinoma

309

223. Russo D, Arturi F, Chiefari E, Meringolo D, Bianchi D, Bellanova B, Filetti S. A case of metastatic medullary thyroid carcinoma: early identification before surgery of an RET proto-oncogene somatic mutation in fine-needle aspirate specimens. J Clin Endocrinol Metab 1997; 82:3378–3382. 224. Mendelsohn G. Markers as prognostic indicators in medullary thyroid carcinoma. Am J Clin Pathol 1991; 95:297–298. 225. Henry JF, Denizot A, Puccini M, Gramatica L, Kvachenyuk A, Devolx BC, de Micco C. Latent subclinical medullary thyroid carcinoma: diagnosis and treatment. World J Surg 1998; 22:752–757. 226. Erdogan MF, Gu¨llu¨ S, Baskal N, Uysal AR, Kamel N, Erdogan G. Omeprazole: calcitonin stimulation test for the diagnosis follow-up and family screening in medullary thyroid carcinoma. J Clin Endocrinol Metab 1997; 82:897–899. 227. Cohen R, Buchsenschutz B, Estrade P, Gardet P, Modigliani E. Causes of death in patients suffering from medullary thyroid carcinoma: report of 119 cases. Presse Med 1996; 25:1819–1822. 228. Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A, Schlumberger M, Bigorgne JC, Dumontier P, Leclerc L, Corcuff B, Guilhem I, The GETC Study Grp. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. Clin Endocrinol (Oxf) 1998; 48:265– 273. 229. Dottorini ME, Assi A, Sironi M, Sangalli G, Spreafico G, Colombo L. Multivariate analysis of patients with medullary thyroid carcinoma—prognostic significance and impact on treatment of clinical and pathologic variables. Cancer 1996; 77:1556– 1565. 230. Wells SA, Baylin SB, Leight G. The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Ann Surg 1982; 195:204. 231. Lips CJM, Landsvater RM, Ho¨ppener JWM, Geerdink RA, Blijham G, JansenSchillhorn van Veen JM, Van Gils APG, De Wit MJ, Zewald RA, Berends MJH, Beemer FA, Brouwers-Smalbraak J, Jansen RPM, Van Amstel HKP, Van Vroonhoven TJMV, Vroom TM. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994; 331:828– 835. 232. Iler MA, King DR, Ginn-Pease ME, O’Dorisio TM, Sotos JF. Multiple endocrine neoplasia type 2A: a 25-year review. J Pediatr Surg 1999; 34:92–96. 233. Wells SA Jr, Skinner MA. Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Exp Clin Endocrinol Diabetes 1998; 106:29–34. 234. Moley JF, DeBenedetti MK, Dilley WG, Tisell LE, Wells SA. Surgical management of patients with persistent or recurrent medullary thyroid cancer. J Intern Med 1998; 243:521–526. 235. Chen HB, Roberts JR, Ball DW, Eisele DW, Baylin SB, Udelsman R, Bulkley GB. Effective long-term palliation of symptomatic, incurable metastatic medullary thyroid cancer by operative resection. Ann Surg 1998; 227:887–893. 236. Frank-Raue K, Ziegler R, Raue F. The use of octreotide in the treatment of medullary thyroid carcinoma. Horm Metab Res 1993; 27(suppl):44–47. 237. Fugazzola L, Pinchera A, Luchetti F, Iacconi P, Miccoli P, Romei C, Puccini M,

310

238.

239.

240.

241.

242.

243.

244.

245.

246. 247.

248. 249.

250. 251.

252.

253.

Kloos and Mazzaferri Pacini F. Disappearance rate of serum calcitonin after total thyroidectomy for medullary thyroid carcinoma. Int J Biol Markers 1994; 9:21–24. Kurtaran A, Scheuba C, Kaserer K, Schima W, Czerny C, Angelberger P, Niederle B, Virgolini I. Indium-111-DTPA-D-Phe-1-octreotide and technetium-99m-(V)dimercaptosuccinic acid scanning in the preoperative staging of medullary thyroid carcinoma. J Nucl Med 1998; 39:1907–1909. Skinner MA, DeBenedetti MK, Moley JF, Norton JA, Wells SA Jr. Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 1996; 31:177–182. Decker RA, Peacock ML. Update on the profile of multiple endocrine neoplasia type 2a RET mutations—practical issues and implications for genetic testing. Cancer 1997; 80:557–568. O’Riordain DS, O’Brien T, Weaver AL, Gharib H, Hay ID, Grant CS, van Heerden JA. Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surgery 1994; 116:1017–1023. Mazzaferri EL. Undifferentiated thyroid carcinoma and unusual thyroid malignancies. In: Mezzaferri EL, Samaan N, eds. Endocrine Tumors. Boston: Blackwell, 1993, pp 378–398. Belfiore A, La Rosa GL, Padova G, Sava L, Ippolito O, Vigneri R. The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine-deficient area. Cancer 1987; 60:3096–3102. Wallin G, Backdahl M, Tallroth E, Lundell G, Auer G, Lowhagen T. Co-existent anaplastic and well differentiated thyroid carcinomas: a nuclear DNA study. Eur J Surg Oncol 1989; 15:43–48. Mooradian AD, Allam CK, Khalil MF, Salti I, Salem PA. Anaplastic transformation of thyroid cancer: report of two cases and review of the literature. J Surg Oncol 1983; 23:95–98. Moore JH Jr, Bacharach B, Choi HY. Anaplastic transformation of metastatic follicular carcinoma of the thyroid. J Surg Oncol 1985; 29:216–221. Aldinger KA, Samaan NA, Ibanez ML, Hill CS Jr. Anaplastic carcinoma of the thyroid: a review of 84 cases of spindle and giant cell carcinoma of the thyroid. Cancer 1978; 41:2267–2275. Carcangiu ML, Steeper T, Zampi G, Rosai J. Anaplastic thyroid carcinoma: a study of 70 cases. Am J Clin Pathol 1985; 83:135–158. Venkatesh YS, Ordonez NG, Schultz PN, Hickey RC, Goepfert H, Samaan NA. Anaplastic carcinoma of the thyroid: a clinicopathologic study of 121 cases. Cancer 1990; 66:321–330. LiVolsi VA, Brooks JJ, Arendash Durand B. Anaplastic thyroid tumors: immunohistology. Am J Clin Pathol 1987; 87:434–442. Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang S-H, Koeffler HP. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 1993; 91:179–184. Nel CJ, van Heerden JA, Goellner JR, Gharib H, McConahey WM, Taylor WF, Grant CS. Anaplastic carcinoma of the thyroid: a clinicopathologic study of 82 cases. Mayo Clin Proc 1985; 60:51–58. Higashi T, Ito K, Mimura T, Ohi T, Nishikawa Y, Wilcox JR Jr. Clinical evaluation

Thyroid Carcinoma

254.

255. 256. 257.

258.

259. 260.

261. 262.

263. 264.

265.

266.

267. 268. 269. 270. 271.

311

of 67-Ga scanning in the diagnosis of anaplastic carcinoma and malignant lymphoma of the thyroid. Radiology 1981; 141:491–497. Takashima S, Morimoto S, Ikezoe J, Takai S, Kobayashi T, Koyama H, Nishiyama K, Kozuka T. CT evaluation of anaplastic thyroid carcinoma. AJNR 1990; 11:361– 367. Woolner LB, Beahrs OH, Black BM, McConahey WM, Keating RE Jr. Classification and prognosis of thyroid carcinoma. Am J Surg 1961; 102:354–387. Tallroth E, Wallin G, Lundell G, Lowhagen T, Einhorn J. Multimodality treatment in anaplastic giant cell thyroid carcinoma. Cancer 1987; 60:1428–1431. Lu WT, Lin JD, Huang HS, Chao TC. Does surgery improve the survival of patients with advanced anaplastic thyroid carcinoma? Otolaryngol Head Neck Surg 1998; 118:728–731. Asakawa H, Kobayashi T, Komoike Y, Maruyama H, Nakano Y, Tamaki Y, Matsuzawa Y, Monden M. Chemosensitivity of anaplastic thyroid carcinoma and poorly differentiated thyroid carcinoma. Anticancer Res 1997; 17:2757–2762. Mitchell G, Huddart R, Harmer C. Phase II evaluation of high dose accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 1999; 50:33–38. Tennvall J, Lundell G, Hallquist A, Wahlberg P, Wallin G, Tibblin S, Swedish Anaplast Thyroid Cancer Grp. Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma: report on two protocols. Cancer 1994; 74:1348–1354. Simpson WJ. Anaplastic thyroid carcinoma: a new approach. Can J Surg 1980; 23: 25–27. Kim JH, Leeper RD. Treatment of anaplastic giant and spindle cell carcinoma of the thyroid gland with combination Adriamycin and radiation therapy: a new approach. Cancer 1983; 52:954–957. Kim JH, Leeper RD. Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 1987; 60:2372–2375. Tennvall J, Tallroth E, el Hassan A, Lundell G, Akerman M, Biorklund A, et al. Anaplastic thyroid carcinoma: doxorubicin, hyperfractionated radiotherapy and surgery. Acta Oncol 1990; 29:1025–1028. Schlumberger M, Parmentier C, Delisle MJ, Couette JE, Droz JP, Sarrazin D. Combination therapy for anaplastic giant cell thyroid carcinoma. Cancer 1991; 67:564– 566. Mazzaferri EL, Oertel YC. Primary malignant lymphoma and related lymphoproliferative disorders. In: Mazzaferri EL, Samaan N, eds. Endocrine Tumors. Boston: Blackwell, 1993, pp 348–377. Holm LE, Blomgren H, Lowenhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med 1985; 312:601–606. Kato I, Tajima K, Suchi T. Chronic thyroiditis as a risk factor of B-cell lymphoma in the thyroid gland. Jpn J Cancer Res (Amsterdam) 1985; 76:1085–1090. Aozasa K. Hashimoto’s thyroiditis as a risk factor of thyroid lymphoma. Acta Pathol Jpn 1990; 40:459–468. Wozniak R, Beckwith L, Ratech H, Surks MI. Maltoma of the thyroid in a man with Hashimoto’s thyroiditis. J Clin Endocrinol Metab 1999; 84:1206–1209. Takashima S, Nomura N, Noguchi Y, Matsuzuka F, Inoue T. Primary thyroid

312

272.

273.

274.

275.

276. 277.

278. 279.

280.

281. 282. 283. 284. 285. 286.

Kloos and Mazzaferri lymphoma: evaluation with US, CT,and MRI. J Comput Assist Tomogr 1995; 19: 282–288. Compagno J, Oertel JE. Malignant lymphoma and other lymphoproliferative disorders of the thyroid gland. A clinicopathologic study of 245 cases. Am J Clin Pathol 1980; 74:1–11. Stone CW, Slease RB, Brubaker D, Fabian C, Grozea PN. Thyroid lymphoma with gastrointestinal involvement: report of three cases. Am J Hematol 1986; 21:357– 365. Tupchong L, Hughes F, Harmer CL. Primary lymphoma of the thyroid: clinical features, prognostic factors, and results of treatment. Int J Radiat Oncol Biol Phys 1986; 12:1813–1821. Aozasa K, Inoue A, Tajima K, Miyauchi A, Matsuzuka F, Kuma K. Malignant lymphomas of the thyroid gland: analysis of 79 patients with emphasis on histologic prognostic factors. Cancer 1986; 58:100–104. Woolner LB, McConahey WM, Beahrs OH, Black BM. Primary malignant lymphoma of the thyroid: review of forty-six cases. Am J Surg 1966; 111:502–523. Vigliotti A, Kong JS, Fuller LM, Velasquez WS. Thyroid lymphomas stages IE and IIE: comparative results for radiotherapy only, combination chemotherapy only, and multimodality treatment. Int J Radiat Oncol Biol Phys 1986; 12:1807– 1812. Pedersen RK, Pedersen NT. Primary non-Hodgkin’s lymphoma of the thyroid gland: a population based study. Histopathology 1996; 28:25–32. Sasai K, Yamabe H, Haga H, Tsutsui K, Dodo Y, Ishigaki T, Shibamoto Y, Abe M. Non-Hodgkin’s lymphoma of the thyroid—a clinical study of twenty-two cases. Acta Oncol 1996; 35:457–462. Blair TJ, Evans RG, Buskirk SJ, Banks PM, Earle JD. Radiotherapeutic management of primary thyroid lymphoma. Int J Radiat Oncol Biol Phys 1985; 11:365– 370. Shaw JH, Dodds P. Carcinoma of the thyroid gland in Auckland, New Zealand. Surg Gynecol Obstet 1990; 171:27–32. Devine RM, Edis AJ, Banks PM. Primary lymphoma of the thyroid: a review of the Mayo Clinic experience through 1978. World J Surg 1981; 5:33–38. Doria R, Jekel JF, Cooper DL. Thyroid lymphoma: the case for combined modality therapy. Cancer 1994; 73:200–206. Makepeace AR, Fermont DC, Bennett MH. Non-Hodgkin’s lymphoma of the thyroid. Clin Radiol 1987; 38:277–281. Souhami L, Simpson J, Carruthers JS. Malignant lymphoma of the thyroid gland. Int J Radiat Oncol Biol Phys 1980; 6:1143–1147. Rao RS, Fakih AR, Mehta AR, Agarwal R, Raghavan A, Shrikhande SS. Completion thyroidectomy for thyroid carcinoma. Head Neck Surg 1987; 9:284–286.

7 Pediatric Thyroid Disorders Thomas P. Foley University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

1

THYROID ONTOGENESIS AND FUNCTION

1.1 Ontogenesis The human thyroid originates primarily from the median anlage in close contact with the endothelial tubes of the embryonic heart. The median anlage arises from the pharyngeal floor and is seen in the 17-day-old embryo (1,2). After the descent of the heart, the rapidly growing median thyroid progressively descends caudally until reaching its definitive level anterior to the second to sixth tracheal ring by 45 to 50 days’ gestation (2). The embryonic growth and descent of the thyroid are regulated by transcription factors, and mutations in the genes that code for these transcription factors cause thyroid dysgenesis. When the pharyngeal region of the anlage contracts, a narrow stalk, known as the thyroglossal duct, remains and subsequently atrophies. Probably because of its topographical contact, the descent of the heart may influence the downward movement of thyroid. Usually the median anlage grows caudally, so that no lumen is left in the tract of its descent. An ectopic thyroid and persistent thyroglossal duct or cyst form as a consequence of abnormalities of the thyroid descent. The lateral parts of the descending median anlage expand to form the thyroid lobes and the isthmus (1,2). A second anlage of the thyroid, composed of a pair of ultimobranchial bodies, arises from the caudal extension of the fourth pharyngeal pouch and ini313

314

Foley

tially is connected to the pharynx by the ductus pharyngobranchialis IV late in the seventh week. The pharyngeal connection is later lost and the ductal lumen becomes obliterated. The ultimobranchial bodies are incorporated into the expanding lateral lobes of the median anlage and contribute little to future thyroid tissue, though differentiation appears to require the influence of the median anlage. Parafollicular or C cells that in mammals arise from ultimobranchial bodies are the source of calcitonin. The histogenesis of the thyroid is virtually complete by the 10th week of gestation even though at this age the follicles do not contain colloid (1,2). Then, a single layer of endothelial cells surrounds the follicular lumen. Thyroxine (T4) appears in serum around 11 weeks when the fetal thyroid is capable of trapping and oxidizing iodide (3), begins to secrete iodothyronines, and contributes along with maternal T4 to the fetal requirement of thyroid hormones (4). During the first month of gestation, the hypothalamus develops from the ventral portion of the diencephalon; thyrotropin-releasing hormone (TRH) appears as early as 30 days and is found in the hypothalamus by 9 weeks of gestation (5). The anterior pituitary gland is derived from Rathke’s pouch. The various pituitary cells begin to differentiate by 7 to 10 weeks’ gestation, and thyroidstimulating hormone (TSH) is secreted by 10 to 12 weeks (6). 1.2 Fetal Thyroid Function The hypothalamic-pituitary-thyroid axis of the mother and the fetus function independently (Fig. 1) (7). Once T4 appears in fetal serum, levels increase linearly with gestational age. Mean cord T4 concentrations between 20 and 30 weeks’ gestation are 5.5 ⫾ 1.6 µg/dL, which increase to mean cord levels of 12.6 ⫾ 4.0 (SD) µg/dL at term and are 10% to 20% lower than corresponding values in maternal serum (4). Cord serum free T4 (FT4) is equal to or higher than maternal levels (7). Fetal T4 metabolism differs markedly from that of postnatal life, for T4 in the fetus is metabolized primarily to reverse T3 (rT3), 3,3′, 5′-triiodothyronine, rather than T3. Reverse T3 concentrations exceed 250 ng/dL early in the third trimester, progressively decrease to levels between 150 to 200 ng/dL at term, and rapidly decrease after the first 3 to 5 days of life to adult levels by 1 to 2 months of age (4,7,8). Therefore, serum concentrations and production rates of rT3 are much greater in the fetus, whereas T3 and free T3 (FT3) concentrations in the fetus are lower than in adults. The T3 and FT3 levels in the cord serum at term are 30% to 50% of the maternal concentrations. TSH is present in the 12-week-old fetus and rapidly increases thereafter, paralleling the increasing levels of FT4 (9), but does not correlate with fetal T4 levels or maternal FT4. Fetal TSH levels are higher than maternal levels and more than twice maternal levels at term, suggesting that fetal TSH regulates fetal thyroid function.

Pediatric Thyroid Disorders

315

FIG. 1 Fetal-neonatal concentrations of thyroid hormones and TSH. The mean serum concentrations of TSH and the iodothyronines vary with maturation of the hypothalamic-pituitary-thyroid axis during gestation and the first five days of postnatal life. From Fisher and Klein, 1981, reprinted with permission from The New England Journal of Medicine, 304:702, 1981.

T4-binding proteins are detected in the 12-week-old fetus when T4 is bound primarily to transthyretin (TTR) and albumin (10). Fetal concentrations of thyroxine-binding globulin (TBG) increase rapidly to reach levels approaching those of full-term infants by midgestation. The fetal TBG increase parallels the increase in total T4. The binding capacity of TBG in premature and full-term infants approximates 1.5 times the normal adult capacity but is lower than maternal binding capacity. High neonatal TBG levels are caused primarily by the transplacental transport of maternal estrogens to the fetus. Serum TBG levels remain unchanged during the first 5 days of life (11). TTR is low in newborn and maternal sera and seem to play a minor role after midgestation. 1.3 Neonatal Thyroid Function Within minutes after birth, a dramatic release of TSH occurs in the newborn infant, reaching peak levels around 100 mU/L at 30 min of age that persist with decreasing intensity for the next 6 to 24 h (7,9). The acute increase of TSH may be stimulated in part by the drop in body temperature of the fetus at birth. In response to the early postnatal TSH surge, T4, FT4, T3, and T3U levels increase progressively during the first hours of extrauterine life and peak by 48 h (7,11,12). Because there is increased peripheral conversion of T4 to T3, serum molar concen-

316

Foley

trations of T3 and FT3 are greater than T4 and FT4. Thus newborn infants experience a physiological hyperthyroid state during the first 2 to 3 days of life, and absence of the biochemical hyperthyroid state suggests congenital hypothyroidism. Thyroid hormones remain elevated during the first 2 weeks of life and gradually decrease thereafter, reaching high normal adult values by 4 to 6 weeks of age (13); adult levels are not attained until puberty (14). The postnatal TSH surge occurs in preterm and small-for-gestational-age neonates, although the magnitude of the increases in serum TSH and iodothyronines is less than in healthy term infants, and preterm T4 levels may remain lower than levels in full-term infants during 1 to 2 months of life. FT4 levels in preterm infants are generally in the normal adult range, although low compared with healthy term infants. The TSH levels approximate adult normal values after 3 to 5 days of postnatal life regardless of gestational age. In the fetus, infant, and small child, iodine kinetics differ from those of the adult. Thyroid gland weight approximates 2 g at birth, or 10% of the adult thyroid weight. The 24-h thryoidal 123I uptake is much greater in the neonate though similar to adult values after the first month. Thus, concentrations of 123I per gram of thyroid tissue in the infant is much greater than in the adult. Until approximately 3 to 5 years of age, the thyroid of the fetus is more susceptible than that of the older child and adult to mitogenic effects of radiation (15) and blocking effects of iodine (16) and other goitrogens. The T4 turnover rate and serum half-life are also higher in infants and children compared to adults, but the precise mechanisms that account for the higher turnover rate are not fully understood. 1.3.1

The Role of the Placenta

The placenta (Fig. 2) has a major influence on fetal-maternal thyroid function (17). TSH does not cross the placental barrier, whereas TRH does. There is some maternal-to-fetal transport of T4, which is especially important during the first trimester as the only source of T4 for the developing fetal brain (18,19). Maternal hypothyroidism during early gestation may lead to intellectual deficiency in the fetus (19,20). Transplacental transfer of maternal T4 in late pregnancy is limited, for the placenta rapidly deiodinates T4 into biologically inactive rT3 and diiodothyronines. Nevertheless, maternal T4 contributes 25% to 50% of the T4 concentration in those fetuses who are unable to synthesize any T4 (21). Iodides easily cross the placenta (17), and when given in large quantities to the mother or neonate produce transient inhibition of T4 synthesis by inhibiting the iodination process, probably through its effect on thyroidal autoregulation (22). Maternal iodide causes fetal goiter, and iodine applied topically to the mother (such as vaginal application of povidone-iodine) may cause transient primary neonatal hypothyroidism (16). The antithyroid drugs, environmental goitrogens, and thyroid antibodies cross the placenta from mother to fetus and can affect fetal thyroid function

Pediatric Thyroid Disorders

317

FIG. 2 Hypothalamic-pituitary-thyroid control of thyroid hormone secretion in the maternal, placental and fetal compartments is indicated. The maternal and fetal compartments are independently regulated, although maternal drugs and immunoglobulins may have a profound effect upon fetal and early neonatal thyroid function.

318

Foley

(17,23–25). Iodine, propylthiouracil (PTU), methimazole, and carbimazole are antithyroid drugs that can cause fetal goiter with or without hypothyroidism (17). AntiTSH receptor antibodies that stimulate the thyroid cross the placenta and may cause transient neonatal thyrotoxicosis (24), and those that block the TSH receptor may cause transient neonatal hypothyroidism (26). Though thyroid hormones are present in amniotic fluid, T4, FT4, T3, and TSH levels in the amniotic fluids may not reflect maternal or fetal serum levels (27). In human milk, T4 is present in very small amounts, and concentrations of T3 and rT3 in human milk vary considerably. However, the concentrations in breast milk are insufficient to normalize thyroid function in infants with congenital hypothyroidism (except in very mild disease) and do not prevent the detrimental effects of hypothyroidism, although they may alleviate or attenuate symptoms and signs (28). 2

THYROID DISORDERS OF TERM AND PRETERM NEONATES AND INFANTS

2.1 Congenital Hypothyroidism (Cretinism) Congenital hypothyroidism, or cretinism, is caused by thyroid hormone deficiency before birth (11,28–30). Prompt diagnosis is critical because delay in treatment can lead to irreversible brain damage (31); however, the overt signs of hypothyroidism are rarely present at birth, and 95% of patients are asymptomatic (32). The dynamic changes in thyroid function after birth, the limited thyroid hormone dependence of peripheral tissues until late in fetal life, and the deprivation of maternal hormones and factors acquired by transplacental transfer contribute to the difficulty in establishing a diagnosis. 2.1.1

Epidemiology

The frequency of congenital hypothyroidism appears to be about 1 in 3500 to 4000 births (30,32). In the United States, the incidence among racial groups differs: 1 in 4000 to 5000 births in Caucasians, 1 in 32,000 in blacks, and 1 in 3000 in Hispanics. The prevalence is increased in Down’s syndrome (33), occurring in 1 in 140 cases, although most have mildly elevated TSH (5 to 15 mU/L) and normal FT4 values that are often transient. This may not require therapy if no thyroid dysgenesis or dyshormonogenesis is present (3,30,33). There is a femaleto-male preponderance of 2 to 1 (32). An aplastic or hypoplastic thyroid gland is responsible for congenital hypothyroidism in approximately one-third of cases; familial dyshormonogenesis occurs in 10% to 20% of infants with primary hypothyroidism; ectopic thyroid tissue occurs in one-third to one-half of cases, and a few infants have thyroid hypoplasia with thyroid tissue in the normal location in the neck. Infants with secondary (TSH deficiency) or tertiary (TRH deficiency)

Pediatric Thyroid Disorders

319

hypothyroidism make up ⬍5% of the detected cases. In the United States, the combined incidence of secondary and tertiary hypothyroidism is about 1 in 80,000 to 100,000 births. As a cause of euthyroid hypothyroxinemia, TBG deficiency is an X-linked trait that occurs in 1 in 5000 to 10,000 births (30,34). The prevalence of transient hypothyroidism varies geographically, depending on iodine intake. In areas with adequate iodine supply, most infants with transient hypothyroidism are born to mothers who received goitrogens during pregnancy; however, occasional infants have idiopathic transient primary hypothyroidism (28–30). As many as 25% of premature infants have low levels of total T4, but normal FT4 and TSH values when compared with the normal range for full-term infants (35,36). As seen in older children and adults, serious illness is associated with low total T4 values. With gestational age ⬍30 weeks, TBG levels may be low; but after 30 weeks, TBG has reached the level present at term and therefore does not account for the low levels of total T4. By 6 months’ gestation, the thyroid function of preterm infants was in the normal range, thus documenting the transient nature of the defect. Developmental attainment at 1 year of age was equal to that of a matched control group that did not have low T4 levels. 2.1.2

Management

The management of the neonate with thyroid disease usually begins with the results of mandatory screening tests for hypothyroidism. These tests are collected before discharge from the nursery or during the first week of life for small infants who remain in the nursery. Blood is collected by heel prick, placed on special filter paper, and allowed to air-dry at room temperature. Screening programs test by using one of three strategies: only test TSH, initially test T4 and subsequently measure TSH on the lowest 3% to 20% of the T4 values, or measure both TSH and T4 simultaneously (37,38). An elevated TSH value with either a low or normal T4 value requires serum confirmation tests of thyroid function that should be performed by the next working day after the physician has been notified. These tests should include serum TSH and FT4 (39). A history of material thyroid disease, familial thyroid disease, exposure to excess iodine, or iodine deficiency provides important information in determining whether hypothyroidism is transient or permanent and whether familial versus sporadic disease is present. Additional tests may be indicated to define the etiology and determine if the hypothyroidism is transient. When the TSH is elevated on the newborn screen, and particularly when the T4 is low, it is useful to obtain a thyroid radionuclide scan or ultrasound at the same time that serum for confirmation tests is drawn. Since an anatomic abnormality is the most common cause, a technetium scan is the most cost-effective method to promptly define the diagnosis of athyreosis, ectopic thyroid dysgenesis, or a eutopic gland that is small (hypoplastic), normal, or enlarged (goiter). For infants with severe hypothyroidism, a bone age radio-

320

Foley

graph may be useful to estimate the fetal age of onset of hypothyroidism. If the skeletal maturation is comparable to that of a newborn infant, no fetal hypothyroidism of significant duration occurred and there is an excellent prognosis for normal intellectual, neurobehavioral, and physical development. Conversely, skeletal maturation of ⬍36 fetal weeks for a full-term infant indicates fetal hypothyroidism with an onset before age 8 months of gestation for an undermined duration. Fetal hypothyroidism of several weeks’ or months’ duration has a guarded prognosis and poses an increased risk for abnormal intellectual and neurobehavioral development (40). In newborn screening programs that include total T4 determinations, other conditions may be identified when the T4 is low, such as deficiencies of thyroxinebinding protein which do not require therapy, and hypothalamic or pituitary hypothyroidism, which require further investigation and therapy (37). In these instances, the differential diagnosis depends on the FT4 value, and the equilibrium dialysis method is the most accurate and definitive FT4 method (41). A diagnosis in the neonate should not be dependent upon indirect determinations of FT4 unless those methods have been validated against the equilibrium dialysis FT4 method in healthy and ill preterm and term infants (41). Once the diagnosis of congenital primary hypothyroidism is suspected and specimens have been collected for confirmation of the diagnosis, l-thyroxine therapy should be started promptly, even before the results of confirmatory confirmation tests are obtained (39,42). Therapy is not harmful and can be stopped at any time should the confirmatory tests be normal. The usual starting dose of l-thyroxine is 10 to 15 µg/kg given once daily (39,42). Infants with athyreosis and very low or undetectable FT4 and elevated TSH values should start with 13 to 15 µg/kg per day. In children with an elevated TSH ⬎20 mU/L and normal thyroxine values, a thyroxine dose of 37.5 µg per day for term infants of normal weight should be sufficient. Since the absorption of thyroxine varies from patient to patient, the correct dose for each child should be determined by serial measurements of FT4 and TSH (37,38). The TSH value should be suppressed below 10 mU/L by 2 weeks of therapy and kept above 0.1 mU/L to prevent excessive thyroid hormone effect. Blood specimens for TSH and FT4 should be collected at weekly intervals for the first month, at monthly intervals until age 6 months, and at 3-monthly intervals until age 2 years (37,38). In Switzerland, to monitor therapy, TSH and T4 are measured in eluates from dried blood specimens spotted on filter paper which are collected and mailed to the screening laboratory, thus avoiding venipuncture and enabling families to have their primary care physician collect the specimens at a convenient location. The medication is available for infants in tablets of 25, 50, 75 µg and higher. During infancy, 25-µg tablets should be prescribed; 1.5-µg tablets will provide a dose of 37.5 µg/day, and 2.5-µg tablets will provide a dose of 62.5 µg/day. Adjustments in dosage can be achieved by an increase or decrease in

Pediatric Thyroid Disorders

321

the thyroxine dose by one tablet per week, or by 12.5-µg increments daily. The addition of one 25-µg tablet per week provides approximately 3.5 µg daily, and one 50-µg tablet increase per week provides approximately 7 µg of thyroxine daily. Minor dose adjustments can be achieved by the addition or omission of one dose per week. Medication should be administered at least 30 min to 1 h before feeding and never with substances that may interfere with its absorption, such as medications containing iron, possibly calcium, and some soy-containing formulas or fiber-containing foods (42). Liquid preparations of thyroxine have not been developed because they are not stable on storage. If the medication cannot be swallowed as a tablet, the tablet should be crushed in a spoon and mixed with water or another liquid. Thyroxine only needs to be administered once daily. If a dose is missed or thought to be missed, a double dose should be given the next day. Substances that affect thyroxine metabolism or absorption need to be eliminated or higher doses prescribed (Table 1) (43). Occasionally, especially during infancy, there are abnormalities in thyroid function that require additional studies or dose alterations (39,42). These are least likely to occur when the child is monitored with serum concentrations of TSH and FT4 performed by a method validated for accuracy and reliability in infancy. Examples of occasionally encountered problems, summarized by the abnormality of thyroid function, are described in the following paragraphs. 2.1.1.1 Persistently Elevated Serum TSH and Normal Serum FT4 Concentrations Usually a persistent elevation in serum TSH indicates the need for an increase in the l-thyroxine dose followed by repeat thyroid function tests in 4 to 6 weeks. In most laboratories the expected upper limit of normal for serum TSH between the ages of 2 and 20 weeks should not exceed 9 mU/L; from 5 months to 2 years, 8 mU/L; and between ages 2 and 7 years, 6 mU/L. Often the thyroxine dose must be increased even when the FT4 value is in the upper range of normal if factors that influence the absorption or metabolism of thyroxine are excluded (Table 1). It is important to remember that normal values for total and FT4 are highest during the first 9 months of life. The serum TSH is usually the best indicator of normal thyroid function at this age. 2.1.1.2 Intermittent Elevations of Serum TSH on the Same Thyroxine Dose Fluctuations in serum TSH while the child receives the same dose of l-thyroxine are usually caused by inconsistent compliance with medication, inconsistent absorption, or—least likely—variable potency of the medication. Parents who forget to give the medication or do not supervise their child while he or she is taking medication may decide to give their child excessive amounts of thyroxine just prior to blood testing. Doing so will cause the serum TSH to remain elevated,

322

Foley

TABLE 1 Medications, Foods, and Chemicals That Interfere with Thyroid Function Tests, Thyroid Hormone Metabolism, or Thyroid Hormone Absorption Medications that alter the binding of T4 and T3 in serum Decreased total T4 and/or T3 Androgens Anabolic steroids Glucocorticoids Nicotinic acid Salicylates Furosemide Phenytoin Increased total T4 and T3 Estrogens (oral, not transdermal) Medications that increase the metabolism of T4 and T3 Rifampin Phenobarbital Carbamazepine Phenytoin Medications, foods, and chemicals that decrease absorption of ingested thyroid hormones Iron salts High dietary fiber Soy milk formulas Calcium salts Cholestyramine Activated charcoal Sucralfate Aluminum hydroxide–containing preparations

but the FT4 will be normal or mildly elevated. At other times, when the child is tested and compliance is satisfactory, TSH and FT4 values will be normal. Similarly, when thyroxine is given with substances that interfere with absorption— such as iron, possibly calcium, or with foods that prevent complete absorption, such as fiber-containing foods—inconsistent thyroid function tests are observed (Table 1). In these circumstances, when education fails, it may be necessary to increase the dose, realizing that there may be episodes of better compliance and/ or improved absorption associated with mild thyrotoxicosis. 2.1.1.3 An Increase in the Serum TSH, FT4, and T3 Children with these test results are rare and are the most difficult to manage. Data in experimental animals indicate that intrauterine hypothyroidism may be

Pediatric Thyroid Disorders

323

associated with abnormal feedback control of pituitary TSH secretion. When this occurs in the experimental animal or in the child, excessive amounts of thyroid hormone are necessary to normalize serum TSH values. Elevated serum FT4 and T3 levels are required to reduce serum TSH to normal, and the patient may have clinical signs and symptoms of thyrotoxicosis. Once this situation can be documented clinically, the dose of l-thyroxine should be reduced until the patient is clinically euthyroid and FT4 and T3 levels are normal regardless of the concentration of serum TSH. During childhood, this abnormality in the feedback control of TSH usually subsides. Chronic thyrotoxicosis in the infant may cause deleterious effects on intellectual development and skeletal maturation. 2.1.1.4 Undetectable TSH Concentrations with Consistently Normal FT4 and T3 Values If the child has clinical thyrotoxicosis, the dose of l-thyroxine should be reduced until the TSH is measurable and the clinical symptoms subside. If the child is clinically euthyroid and the serum TSH value is unmeasurable, it is advisable to decrease the dose of l-thyroxine slightly, by one-half to one tablet per week, in order to retain normal FT4 and T3 values with a normal, measurable serum TSH value. In children who are clinically euthyroid with a normal linear growth rate and normal serum TSH and FT4 values, there is no need for additional laboratory tests. After the age of 3 years, only an annual evaluation of these parameters is needed in euthyroid children with normal growth and thyroid function tests unless other clinical conditions develop that potentially could interfere with the oral administration and absorption of thyroxine (42,43). If the diagnosis of hypothyroidism was not clearly established at initiation of thyroxine therapy and if serum TSH values have remained normal or suppressed on the same dose of thyroxine since age 3 months, thyroxine therapy should be discontinued or decreased at age 3 and repeat serum TSH and FT4 measured to establish the diagnosis of permanent primary hypothyroidism and confirm the need for lifelong thyroxine therapy. 2.1.2

Other Considerations

In very low birth-weight (VLBW) infants, infants with intrauterine growth retardation (IUGR), or those who are small for gestational age (SGA) and some preterm infants, thyroid function may be abnormal without any other evidence of thyroid disease. Often these infants are tested for thyroid function because of inexplicable clinical signs or have abnormal newborn screening and confirmatory screening test results. Infants with a persistently elevated serum TSH should be treated as if they had congenital hypothyroidism, as already described. Problems arise with infants who have persistently low total T4 results and normal or low serum TSH levels. If a validated FT4 determination indicates a normal value for

324

Foley

age, no further evaluation or treatment is necessary. In recent studies based on psychomotor and neurological outcome measures, those infants ⱖ27 weeks of gestational age did not seem to benefit from l-thyroxine therapy, whereas there was a suggestion of benefit for the infants ⬍27 weeks of gestation, although the sample size was too small for definitive conclusions (44). These infants may have hypothalamic hypothyroidism as a consequence of their extreme immaturity and may benefit from small doses of thyroxine that raise the FT4 values into the normal range. An occasional infant, often with Down’s syndrome, has mildly elevated TSH values (⬍20 mU/L), persistently normal FT4 values, negative thyroid antibodies, and, if measured, normal FT3 levels. During infancy and childhood the TSH values do not further increase, often decrease, and eventually normalize. There is no evidence that thyroxine therapy is beneficial as long as the free hormone values do not decrease. Treatment, however, certainly would not cause harm if thyroid function were carefully monitored to avoid iatrogenic thyrotoxicosis. The cause of the abnormality in TSH feedback control is unknown. There are specific management issues for infants with familial inborn errors of thyroid hormone synthesis and metabolism, a group of disorders known collectively as familial thyroid dyshormonogenesis (45). These autosomal recessive conditions are usually detected on newborn screening with elevations in TSH and comprise approximately 10% to 15% of newborns who are hypothyroid, depending upon the frequency of the mutation in the population. They are suspected in the newborn period by palpable or enlarged thyroid glands. Thyromegaly can be documented with thyroid ultrasound or scan. The parents should be advised about the possibility of a 25% chance of the disease in subsequent children. In those infants with partially reduced enzymatic activities, the dose of lthyroxine replacement therapy often is less than is usually prescribed for infants with athyreosis. The definitive diagnosis of an oxidation or organification defect can be confirmed with a perchlorate discharge test. Radioiodine is administered by nasogastric tube and an image is obtained 2 h later. Then a radioiodine uptake is obtained, followed by the perchlorate discharge test, as follows: 10 mg/kg of potassium perchlorate (KClO4) is given by nasogastric tube and radioiodine uptake by the thyroid is determined every 15 min for 1 h. The test is positive (abnormal) if there is a ⱖ50% decrease, or discharge, of radioiodine from the gland following KClO4 administration. Pendred’s syndrome is the association of congenital hypothyroidism caused by an oxidation or organification defect and neurosensory hearing loss (45). This disease is associated with mutations in the gene that codes for the protein known as pendrin (46). The pathophysiology of the abnormality of pendrin and the thyroid and hearing defect has not been clarified (47). Infants and children proven to have an oxidation defect causing congenital hypothyroidism or infants diag-

Pediatric Thyroid Disorders

325

nosed with congenital hypothyroidism on newborn screening and found to have a palpable thyroid gland in the normal anterior cervical location (normal in size or enlarged) should have a neurosensory hearing test, such as auditory evoked potential, as soon as the diagnosis of hypothyroidism is established. Thyroid function may normalize in those patients who have two inherited defects (iodide trapping and dehalogenase) if they are exposed to or treated with iodine. Infants with these defects may be missed on newborn screening tests if the mother receives a moderate to high iodine intake during pregnancy, since the iodine that crosses the placenta can provide sufficient substrate to transiently affect thyroid function in the fetus (48). 2.2 Acquired Hypothyroidism of Infancy Infants with acquired hypothyroidism caused by autoimmune thyroiditis may present with symptoms and signs of congenital hypothyroidism that develop after 6 months of age (49). These infants are asymptomatic during the first 6 months of life; however, at diagnosis, they have symptoms and signs similar to those of infants with congenital hypothyroidism not detected by screening. The important clinical features are similar to those seen in infants with untreated congenital hypothyroidism: dry skin and constipation, deceleration in linear growth beginning late in the first year or early in the second year of life, and a delay or arrest in developmental milestones. If hypothyroidism begins at about 2 years of age, there may be some symptoms and signs characteristic of hypothyroidism in older children, such as muscular pseudohypertrophy. There may be no delay in skeletal maturation or in eruption of primary teeth when the child is first seen, because hypothyroidism often develops rapidly in these young infants. If the duration of untreated hypothyroidism is not prolonged, any delay in developmental milestones should not be permanent. 2.3 Congenital Hyperthyroidism Neonatal thyrotoxicosis is usually caused by transplacental transfer of TSH receptor–stimulating immunoglobulins (TSI) from the mother (Table 2) (24,50). The disease occurs in approximately 1 of every 70 infants born to mothers known to have active Graves’ disease either before or during pregnancy, Graves’ disease previously treated with thyroidectomy or radioiodine ablation, or Hashimoto’s disease (51). However, mothers with detectable TSI usually give birth to normal infants, especially when maternal serum TSI activity is only mildly elevated (52). Neonatal thyrotoxicosis may occur in infants without detectable TSI (Table 2). In these infants the disorder is caused either by the syndrome of generalized resistance to thyroid hormone with mild thyrotoxicosis (autosomal dominant inheritance) (45) or germ-line mutations in the TSH receptor gene that cause consti-

326

Foley

TABLE 2 Causes of Thyromegaly Diffuse thyromegaly Autoimmune (Hashimoto’s) thyroiditis Thyrotoxicosis Graves’ disease Toxic autoimmune thyroiditis McCune-Albright syndrome Iodine-induced hyperthyroidism TSH secreting pituitary adenoma Resistance to thyroid hormone Goitrogen ingestion Antithyroid drugs Antithyroid agents and foods Iodine deficiency (endemic goiter and cretinism) Familial dyshormonogenesis Acute and subacute thyroiditis Idiopathic (simple) thyromegaly Nodular thyromegaly Autoimmune (Hashimoto’s) thyroiditis Thyroid cyst Thyroid tumors Adenoma Hyperfunctioning (hot): hyperthyroid or euthyroid Non-functioning (cold): follicular adenoma Adenomatous hyperplasia Carcinoma: papillary, follicular, medullary Other tumors: lymphoma, histiocytoma Nonthyroidal masses: Lymphadenopathy Branchial cleft cyst Thyroglossal duct cyst

tutive activation of the TSH receptor (53,54). The mutations in the transmembrane domains of the receptor keep the receptor in the activated state, so that adenylate cyclase is continuously produced, causing goiter and hyperthyroidism (54). In this situation, TSI does not play a role, serum FT4 and FT3 are elevated, and serum TSH is unmeasurable. The clinical manifestations of hyperthyroidism may become apparent within the first 24 h of life (55). Infants may be born prematurely when a mother is thyrotoxic. Irritability, excessive movement, tremor, flushing of the cheeks, sweating, increased appetite, weight loss or lack of weight gain, supraventricular tachycardia, goiter, and exophthalmos may be observed. Unique to the neonate

Pediatric Thyroid Disorders

327

with severe Graves’ disease is generalized enlargement of the reticuloendothelial system, causing lymphadenopathy, hepatosplenomegaly, thrombocytopenia, and hypoprothrombinemia. Although a goiter is inevitably present in neonatal thyrotoxicosis, its size varies considerably; it may be small and escape notice on cursory examination, or it may be large enough to cause tracheal compression. Furthermore, the goiter may increase in size during the early neonatal period. Exophthalmos is usually mild when present. In severe neonatal thyrotoxicosis, hyperthermia, arrhythmias, and high output cardiac failure may occur; if the condition is untreated, death may ensue (50,55). The course of TSI-induced disease is self-limited because of the gradual metabolism of transplacentally acquired TSI (24). The signs and symptoms gradually subside in a few weeks, depending on the severity of the disease and the titer of TSI in the plasma of the mother and neonate. Goiter, however, may persist after the signs of hyperthyroidism disappear, but it gradually subsides. Rarely, neonatal thyrotoxicosis may not be a transient disorder and may persist for months or years. The onset of clinical manifestations in the infant may be modified by transplacental passage of antithyroid medications prescribed for an affected mother with Graves’ disease during the later months of pregnancy. An infant may be euthyroid or even hypothyroid at birth, and the presence of a goiter may be the only abnormal clinical sign. Since the duration of action of antithyroid medications is short, the typical manifestations of neonatal thyrotoxicosis may then appear several days after birth (50). If born hypothyroid, an infant may become euthyroid within a few days, and thyrotoxicosis may not occur until a week or more after birth. The immunoglobulins that cause neonatal Graves’ disease are usually purely stimulatory. However, an atypical form of the disease can occur if different antibody populations exist in the maternal serum. For example, late-onset hyperthyroidism may occur at 1 to 2 months of age if a high-affinity TSH receptor– blocking antibody in low concentrations predominates initially; once this is metabolized, a second population of TSH receptor-stimulating antibodies, which are then present in greater concentrations but have lower binding affinity, then predominate to cause late-onset hyperthyroidism (24). 2.3.1

The Diagnosis of Congenital Hyperthyroidism

The diagnosis and differential diagnosis of neonatal hyperthyroidism may be difficult unless the maternal history of Graves’ disease before or during pregnancy is known in advance (50,52,55). Information concerning previous and current treatment of maternal hyperthyroidism also is important. The antenatal diagnosis is suspected by poor fetal growth, fetal tachycardia (pulse ⬎160 per minute), and fetal goiter on ultrasound. Maternal antithyroid drug therapy should provide adequate treatment if fetal thyrotoxicosis is diagnosed before birth.

328

Foley

Congenital thyrotoxicosis can be confused with various neurological disorders, narcotic withdrawal in an infant of an addicted mother, congenital heart disease, or sepsis, but a positive maternal history of Graves’ disease and the presence of a goiter should readily alert one to the correct diagnosis (24,51). The thyroid gland of normal neonates and infants may be difficult to palpate, so an easily palpable thyroid at this stage of life should be considered to be a goiter. Rare cases of hyperthyroxinemia are characterized by elevated serum levels of FT4 but measurable TSH levels within the normal range (i.e., not suppressed as expected) (45). Affected individuals probably have a variant of thyroid hormone resistance with variable expression of the mutant thyroid hormone receptor. These patients have the clinical manifestations of mild hyperthyroidism that usually present later in infancy or childhood and are distinguishable by measurable rather than suppressed levels of TSH in the presence of high levels of serum free iodothyronines and absence of TSI. The rare patient with congenital hyperthyroidism due to an activating mutation of the TSH receptor will have clinical features suggesting Graves’ disease but no eye disease or circulating TSI. An infant born to a mother with Graves’ disease should be examined repeatedly for signs of thyrotoxicosis, and the neck should be palpated carefully to detect a goiter. Determination of FT4 and TSH should be obtained as soon as the diagnosis is suspected. An unmeasurable TSH supports the presence of thyrotoxicosis. However, if there has been fetal hyperthyroidism, the basal TSH level in the neonate may be undetectable for several weeks, and the TSH response to a TRH infusion may be diminished for several months. A radioiodine uptake test has little value during the neonatal period, for the uptake in normal infants is very high for several days after birth and provides no needed additional diagnostic information. A very high maternal titer of TSI (e.g., ⬎200% of control) will strongly support the diagnosis of neonatal thyrotoxicosis. Serial determinations of TSI by methods that need only a very small volume of serum are helpful to monitor disease activity and influence the decision to decrease or terminate antithyroid drug therapy (24). 2.3.2

Therapy of Congenital Thyrotoxicosis

Most signs and symptoms of hyperthyroidism, including the cardiovascular manifestations, are closely related to increased adrenergic response. Beta-adrenergic blocking drugs, therefore, can alleviate many of the potentially life-threatening manifestations of neonatal thyrotoxicosis (55). In contrast to antithyroid drugs, these agents can rapidly diminish the severity of thyrotoxicosis, and their effects are evident within a few hours. Thus, propranolol or atenolol, together with iodine and PTU, should be used in the treatment of severe neonatal thyrotoxicosis. Propranolol is given orally in a dosage of 2 mg/kg/day in two or more divided doses. Therapy with digoxin may be necessary in neonates with cardiac failure. A large goiter compressing the trachea and causing asphyxia may have to be treated surgically by splitting the thyroid isthmus.

Pediatric Thyroid Disorders

329

Most infants with neonatal thyrotoxicosis have mild disease that does not require specific antithyroid therapy (24). A neonate with mild symptomatic disease may require only short-term therapy with iodine (Lugol’s solution containing approximately 7 mg of iodine per day) and usually will not need an antithyroid medication. Lugol’s solution can be given in doses of 1 drop three times daily. Although iodine rapidly inhibits the release of T4 from the thyroid, its effect tends to disappear after several weeks. Care should be exercised not to induce hypothyroidism with excessive medication. Neonates with moderate to severe thyrotoxicosis are started on both iodine and antithyroid medications, either PTU or methimazole (Tapazole). PTU is given orally in amounts of 5 to 10 mg/kg/ day in three divided doses at 8-h intervals. Methimazole is given in amounts of 0.5 to 1 mg/kg/day initially in three divided doses; after euthyroidism is achieved, methimazole can be given once daily as the dose is tapered and TSI disappear from the circulation over 1 to 4 weeks. Circulating T4 has a half-life of 3.6 days in neonates and 6.9 days in adults. Therefore, little or no clinical response to antithyroid drugs can be expected during the first few days of therapy. The expected increase in serum TSH in a few weeks may be delayed despite low free T4 values, and the dose of iodine and antithyroid drug should be reduced or the drugs discontinued to determine whether the disease has abated. The euthyroid or hypothyroid infant born to a mother who received antithyroid medications during pregnancy should be managed as described in the section on congenital hypothyroidism. If the infant has already received thyroid hormone, it should be discontinued if thyrotoxic manifestations occur and appropriate management of hyperthyroidism should be initiated. The prognosis usually is good when the diagnosis is known before delivery (50,51). Prior to the use of beta-adrenergic blocking medications, neonatal thyrotoxicosis carried a mortality of more than 15% when it was not recognized and treated properly. In most instances the syndrome has a self-limited course and no sequelae have been recognized. The goiter resolves slowly over several months. Premature closure of cranial sutures occasionally occurs that only rarely requires surgical therapy. It is advisable to obtain a roentgenogram of the skull at 6 to 12 months of age. Toxicity to the antithyroid medications rarely occur in infancy, but must be remembered when unexplained illnesses develop (Table 3). 3

ACQUIRED THYROID DISORDERS OF CHILDHOOD AND ADOLESCENCE

3.1 Goiter, Autoimmune Thyroiditis, and Hypothyroidism 3.1.2

Introduction

Thyromegaly is a common clinical disorder during childhood and adolescence and very prevalent in endemic goiter regions of the world (Table 2) (56,57). The differential diagnosis and initial evaluation of the child depends upon the clinical

330

Foley

presentation (hypothyroid, euthyroid, hyperthyroid) and the physical examination of the thyroid gland (diffuse or nodular, symmetrical or asymmetrical). The initial laboratory investigation should be tailored to the physical characteristics of the gland and the surrounding structures in the neck. 3.1.3

Autoimmune thyroid disease

For the child with a symmetrical, firm, irregular or smooth thyroid gland, the evaluation should be directed toward the diagnosis of autoimmune thyroiditis. Serum thyroid antibodies, TSH, and free T4 should be assessed (56). Positive thyroperoxidase (TPO) antibodies or thyroglobulin antibodies confirm the diagnosis of autoimmune thyroiditis (56). When both parents have a history of autoimmune thyroid disease, their children should have an annual examination of the thyroid gland; the measurement of thyroid antibodies would be appropriate to screen for thyroiditis in the preclinical stage of the disease. The frequency of repeat thyroid antibody measurements when the initial tests are normal is not known, but determinations once every 1 to 3 years with decreasing frequency as negative values are reported would seem to be an appropriate screening plan. Approximately 20% of children with autoimmune thyroiditis present with primary hypothyroidism (58–60). Most patients with euthyroid goiter secondary to autoimmune thyroiditis remain euthyroid (58–60). However, approximately 10% of young patients will subsequently develop hypothyroidism (60). Once hypothyroidism develops in a previously euthyroid child, the disease is usually permanent rather than transient. Although children with goiter may rarely present with mild thyrotoxicosis, known as toxic thyroiditis (see below), the more common presentation is hypothyroidism, which may develop at any time during the course of the disease (58,60). The most sensitive test to diagnose primary hypothyroidism is the serum TSH. It should be monitored annually in children with thyroiditis. When the serum TSH value is slightly elevated, a second specimen should be tested and, if this is again elevated, the patient started on l-thyroxine therapy. Mild primary hypothyroidism may be transient or permanent, especially if the disease initially presents with toxic thyroiditis. On occasion, children and adolescents with primary hypothyroidism present with linear growth deceleration and no enlargement of the thyroid gland; usually the thyroid is nonpalpable or a small remanent of firm thyroid tissue is present (60). Hypothyroidism may cause complete cessation of linear growth once clinical myxedema develops. Prepubertal girls with severe, chronic hypothyroidism rarely present with isosexual precocity without sexual hair. Adolescents with primary hypothyroidism usually have delayed onset of puberty; hypothyroidism of any cause should be excluded in an initial evaluation of delayed puberty or delayed menarche, especially if it is associated with growth deceleration (61). Other than iatrogenic causes of primary hypothyroidism (radiation-induced postsurgical thyroidectomy), the chronic fibrous variant of autoimmune thyroidi-

Pediatric Thyroid Disorders

331

tis is the usual cause. When the onset of hypothyroidism occurs after 3 years of age, treatment should be instituted slowly, beginning with a 25-µg daily dose for 2 to 4 weeks and increasing every 2 to 4 weeks by 12.5 to 25 µg daily until thyroid function tests are normal (60). Patients corrected more rapidly experience very disturbing and uncomfortable symptoms of thyrotoxicosis that interfere with schoolwork, sleep, and daily activities. The reason is unknown, but the metabolic correction toward euthyroidism is recognized systemically as hyperthyroidism, possibly mediated in part through hypersensitive adrenergic receptors. Small doses of beta-adrenergic blocking drugs, if not otherwise contraindicated, may provide some relief until readjustment occurs, usually within 6 to 12 months. lthyroxine should be given at least 30 min before a meal because of the impaired absorption of thyroxine by certain foods and infant formulas. It should not be given at the same time of day as iron medications, probably calcium-containing drugs, and foods that contain fiber. Serum TSH is the only test needed to monitor adequacy and compliance of therapy unless symptoms of hyperthyroidism develop, and in this situation, measurements of FT4 and T3 may be useful. 3.2 Other Causes of Thyromegaly (Table 2) 3.2.1

Toxic Thyroiditis

This condition represents the transient thyrotoxic phase of autoimmune thyroiditis; it may be difficult, initially, to differentiate this from Graves’ disease (60). The radioiodine uptake is elevated, and it therefore differs from the hyperthyroid phase of ‘‘silent’’ thyroiditis seen in adults. The presence of TSI in serum favors the diagnosis of early Graves’ disease (62). The rare patient who presents with autoimmune toxic thyroiditis is expected to return gradually to euthyroidism within 1 to 2 months and subsequently may experience mild hypothyroidism that persists or recovers (56,60). The duration of the hypothyroid phase of toxic thyroiditis is variable; it may last for a few weeks to several months or may be permanent—i.e., actual Graves’ disease. Patients usually experience only mild symptoms during the thyrotoxic phase and require no treatment. Low doses of propranolol (10 mg three or four times daily) or atenolol can relieve symptoms in patients with more symptomatic thyrotoxicosis. Antithyroid drugs are not indicated in the treatment of toxic thyroiditis. It is important to monitor serum thyroid function tests during the recovery phase of toxic thyroiditis. If is also hypothyroidism develops, the child should be treated with l-thyroxine. Since this phase usually transient, the child can discontinue medication after 3 to 6 months of treatment and be reevaluated 4 to 6 weeks later. If serum TSH is elevated, lthyroxine replacement therapy should be resumed. 3.2.2

Idiopathic Thyromegaly (Simple Goiter)

An occasional child will present with diffuse thyromegaly, normal thyroid function tests, and negative thyroid antibodies. This clinical presentation was

332

Foley

known for years as ‘‘simple goiter’’ and is most often seen during adolescence. Autoimmune thyroiditis is the suspected diagnosis, and thyroid antibodies should be repeated if the goiter persists, since children may have negative thyroid antibodies early in the course of autoimmune thyroiditis that later become positive. 3.2.3

Iodine Deficiency

Iodine deficiency remains the most common cause of thyromegaly worldwide and is especially prevalent in the mountainous regions of South America and Central Asia (57). It has been virtually eradicated in the United States since the introduction of iodized salt in the 1920s. Iodine deficiency rarely occurs in infants with congenital nephrosis from excessive urinary losses of iodothyronines and iodide (63,64), nutritional diseases, or the consumption of iodine-deficient diets (⬍50 µg iodine daily). The optimal daily iodine requirement is estimated to be between 150 and 300 µg, but a nutritional intake of iodine between 50 and 1000 µg/day is satisfactory (57). A diagnosis of iodine deficiency is confirmed if urinary excretion of iodine is less than 50 µg/g of creatinine excretion. Presumably, because of the normal to high salt and milk intake of children and adolescents, iodine deficiency has not been seen in the United States or Canada over the past five decades. However, recent data suggest that mild iodine deficiency may once again exist in young women in the United States (65). 3.2.4

Goitrogens

These rarely cause thyroid enlargement alone; usually underlying mild thyroid diseases such as autoimmune thyroiditis or iodine deficiency or excess are present (57). A variety of chemicals, drugs, and foods can interfere with thyroid gland function, inhibit thyroid hormone synthesis, and cause decreased serum thyroid hormone levels, a compensatory increase in TSH secretion, and thyromegaly. In addition to goitrogenic drugs, such as antithyroid agents (propylthiouracil, methimazole), carbimazole, iodine, sulfisoxazole, and lithium, foods such as cassava, cabbage, cauliflower, brussels sprouts, turnips, and maize contain goitrogenic compounds (57). The chronic ingestion of large amounts of these foods should not cause thyroid disease or hypothyroidism except possibly in association with iodine deficiency. Therefore, complete dietary and medication histories should be included in the clinical evaluation of thyromegaly. Avoidance of exposure to goitrogens or starting thyroxine therapy will restore euthyroidism and normal thyroid gland size. 3.2.5

Acute Suppurative Thyroiditis

This rare disease is easy to recognize but difficult to manage (66). The disease is a perithyroidal inflammation, usually due to a persistent left-sided embryonic

Pediatric Thyroid Disorders

333

perilymphatic fistulous tract that becomes infected with oral pathogens (67). The thyroid is very tender and the child appears toxic from the infection but is not thyrotoxic. Serial thyroid ultrasound examinations are very important to perform to detect abscess formation early, so that proper incision and drainage can be performed (67). Intravenous antibiotics and fluids are essential. No residual thyroid disease is expected. Once the infection has subsided, to prevent recurrence, imaging studies are needed to identify the fistula so that it can be excised (67). 3.2.6

Subacute Thyroiditis

This condition also is rarely diagnosed during childhood and adolescence, either because it rarely occurs or is so mild that the underlying upper respiratory infection will mask its clinical presentation. The disease presumably results from a viral infection of the thyroid gland which typically but not always is tender. During the early phase of the disease, the child may have mild hyperthyroidism, and one finds normal to elevated levels of total and free T4 and T3, normal or undetectable levels of TSH, either negative or low titers of thyroid antibodies, and a low or absent uptake of radioactive iodine (68). The erythrocyte sedimentation rate is usually markedly elevated but may be normal to slightly elevated whenever the thyroid is not tender. Mild thyrotoxicosis is controlled with lowdose beta-adrenergic blockade. The clinical course of subacute thyroiditis is variable, but it often progresses through three phases (mild hypothyroidism, euthyroid goiter, and mild hypothyroidism) before the patient finally recovers with completely normal thyroid function (68). The transient phase of hypothyroidism during recovery will vary in length and severity that may require a course of thyroxine therapy. Full recovery is expected; after complete recovery, late recurrences may occur but are rare. 3.3 Juvenile Thyrotoxicosis 3.3.1

Introduction

Thyrotoxicosis in children and adolescents is difficult for the primary care physician to recognize and for the endocrinologist to manage (50,69,70). Graves’ disease is the most common cause of thyrotoxicosis, for other causes in children are rare and only suspected when the clinical presentation is atypical. The thyrotoxic state is tolerated much better by children than adults, although school performance and the ability to compete is athletics and interact socially are often adversely affected. Thyrotoxicosis results in a catabolic state except for the unusual child who maintains a very high caloric intake to match the exaggerated caloric expenditure. With a constant increased metabolic activity, the patient experiences fatigue during the day from exhaustion and insomnia at night. Treatment is dependent upon the severity of the hypermetabolic state and not entirely judged by the free thyroid hormone levels. Often behavioral manifestations predominate the clinical presentation, espe-

334

Foley

cially in interactions with family and friends. Unpredictable and explosive outbursts or mood swings often create stress and difficult interpersonal relations until the diagnosis is established and the patient rendered euthyroid. 3.3.2

Epidemiology and Demographics

Graves’ disease is rare before the age of 5 years and increases in frequency through childhood into adolescence, when it is seen most often during the first two decades of life (50,69). The disease in childhood and adolescence is more common in girls than boys; the female-to-male ratio ranges from 3.5 to 6:1 except in the neonate, when the ratio is unity because there is equal frequency of exposure to transplacental TSI that causes transient neonatal Graves’ disease. The prevalence in children is estimated to be 0.02%, and the disease is more frequent in patients with trisomy 21 (50). In most instances there is a positive family history of autoimmune thyroid diseases as well as other autoimmune diseases: insulin-dependent diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, vitiligo, Addison’s disease, pernicious anemia, and idiopathic thrombocytopenic purpura. The pathogenesis for Graves’ disease in the child is the same as for adults. 3.3.3

Diagnosis

The determination of serum TSI is important if the diagnosis of Graves’ disease is uncertain. The most sensitive test for hyperthyroidism is the serum T3; however, this test is not usually necessary if the patient has obvious exophthalmic goiter, elevated serum FT4, suppressed serum TSH levels, and hyperthyroidism. Additional tests are indicated only in the presence of mild or equivocal thyrotoxicosis or when the cause is obscure. 3.3.4

Management

Managing hyperthyroidism in childhood is challenging and difficult. Factors such as age and severity of disease influence the mode and duration of therapy (70). For most children and adolescents, methimazole or PTU is prescribed to bring the disease under control. Beta-adrenergic blocking drugs such as propranolol or atenolol promptly exert effective control of clinical symptoms in moderately to severely affected patients, and reduce the risk of thyroid storm should another serious intervening illness occur. Doses as low as 10 mg every 6 to 8 h of propranolol or once daily doses of atenolol for older children and adolescents quickly provide symptomatic relief. For mildly affected children, beta-adrenergic blockade is not needed unless school performance is affected or sleeping habits are disturbed; a single morning dose could improve an adjustment in school, or an evening dose could improve problems with restless sleeping. The major contraindication is asthma.

Pediatric Thyroid Disorders

335

TABLE 3 Side Effects of Antithyroid Drugs Granulocytopenia Dermatitis, urticaria Arthralgia, arthritis Edema Hepatitis Thrombocytopenia Lupus-like syndrome Hypoprothrombinemia Lymphadenopathy Peripheral neuritis Disseminated intravascular coagulation Fever Loss of taste sensation

Methimazole (Tapazole) and PTU are the antithyroid medications available in North America (50,69,70). They are equally effective and probably have comparable frequency and severity of side effects. PTU is prescribed initially in divided doses three or four times daily for patients with moderate to severe thyrotoxicosis. Methimazole may be given once daily (69). The PTU dose is 5 to 10 mg/kg/day and methimazole 0.5 to 1 mg/kg/day with a starting dose for children usually 50 mg tid for PTU and 5 mg tid for methimazole. For older children and adolescents, the starting doses are 20 mg to 40 mg daily for methimazole and 100 to 150 mg three times daily for PTU. Serious side effects from methimazole and PTU are uncommon (Table 3). Approximately 5% of children will experience mild and reversible side effects—such as rashes, arthralgia, and neutropenia— that disappear on discontinuation of therapy. If the side effect is not serious, the other available antithyroid medication can be tried; however, very close monitoring is most important, since rarely the same problem may recur with the other drug (50,69). If higher doses are used, hypothyroxinemia will be induced in many patients within the first 4 to 12 weeks of therapy, depending upon the severity and duration of the disease at diagnosis. The serum TSH in most children, however, will remain undetectable even when the free T4 has decreased into the hypothyroid range (71). Serum T3 should be monitored, since some patients have normal or low free T4 but persistently elevated serum T3 levels. Once there is measurable or elevated serum TSH, either thyroxine therapy can be initiated or the dose of methimazole or PTU decreased. If not given as a single dose

336

Foley

initially, methimazole therapy can be changed to a once-daily regimen. The activity of Graves’ disease can be judged by serum TSI activity and clinically by a reduction in size of the thyroid gland (62). A return of the thyroid gland to normal is the most reliable indicator of remission. Even if gland size is normal, however, continual presence of TSI in the serum would indicate a high likelihood of relapse, and antithyroid drugs should be continued. If the thyroid gland size remains normal and TSI titers are negative, a trial off medication is indicated, although a negative TSI titer has a relatively low predictive value for remission (50%). However, a normal or small gland with persistently detectable TSI by thyrotropin binding inhibitory immunoglobulin (TBII) methods may suggest the presence of TSH-receptor blocking antibodies (72); in this situation a trial of antithyroid drugs would be worthwhile. In general, antithyroid drugs are given for at least 1 to 2 years before stopping them to see if a remission has been achieved. After cessation of antithyroid therapy, relapses usually occurs within 6 months. In this situation, the patient and family have two options: either another course of methimazole or PTU or an alternate form of therapy such as radioiodine ablation or subtotal thyroidectomy. In prepubertal children, most endocrinologists prefer to continue methimazole or PTU therapy to the adolescent age unless there has been a serious idiosyncratic reaction with one of the medications. This preference results from the limited experience with radioiodine therapy in young children and the concern about the potential carcinogenesis of radioiodine therapy during the growth phase of the thyroid gland. However, it should be acknowledged that large studies in the United States and Europe have failed to document any increased risk for thyroid malignancy after radioiodine therapy in adults with Graves’ disease (73). Since there are risks for serious complications of thyroidectomy in children in the hands of inexperienced surgeons, radioiodine ablation therapy is the second treatment of choice after antithyroid drug therapy for older children and adolescents, and for any child with an idiosyncratic reaction to medication. The morbidity, cost and mortality of radioiodine therapy are lower than surgery. Within 6 to 12 months permanent hypothyroidism usually develops, necessitating thyroxine replacement therapy. For the rare patient with thyrotoxicosis caused by a hypersecreting thyroid adenoma, surgical excision of the tumor will cure the disease. The surgery is not associated with the usual risks of thyroidectomy since only resection of the tumor or a lobectomy is performed. The indications for surgery are clinical thyrotoxicosis associated with elevated levels of serum free T4 and/or T3 and undetectable levels of TSH, an enlarging mass, and lack of homogeneity on ultrasound or radionuclide imaging. Because this cause of thyrotoxicosis is rare, other forms of therapy (e.g., radioiodine, ethanol injections) have not been advocated, since there is no experience with their use in children.

Pediatric Thyroid Disorders

337

3.4 Nodular Thyroid Disease Localized enlargement of the thyroid gland may occur in a lobe or in the isthmus of the thyroid gland. Although a localized enlargement in the form of a single nodule may be seen in autoimmune thyroiditis, a mass in the thyroid must always be evaluated to determine if it represents a benign or a malignant lesion, since malignancy is found in approximately 30% of children with thyroid nodules (74). There are a number of benign lesions, both thyroidal and nonthyroidal, which may present as a thyroid nodule (Table 2). These include cysts, follicular adenomas, and adenomatous hyperplasia. Nonthyroidal masses include teratomas, branchial cleft and thyroglossal duct cysts, lymphadenopathy, hemangiomas, lymphangiomas, and neurofibromas. Hemiagenesis of the thyroid may present as a nodule, usually on the left side. It should be remembered that the first clinical sign of metastatic thyroid carcinoma may be persistent enlargement of one or more firm anterior cervical lymph nodes. The clinician should strongly suspect a malignant lesion whenever a patient presents with a solitary firm, painless nodule in an otherwise normal gland, especially when there is a history of prior irradiation to the head or neck for childhood malignancies or a family history of thyroid malignancy (75). Likewise, a rapidly enlarging solid mass in the region of the thyroid, especially in association with hoarseness and/or dysphagia, is indicative of thyroid carcinoma. Though most malignancies of the thyroid are carcinomas, other malignant tumors, such as lymphoma and sarcoma, may rarely occur. Thyroid carcinoma is rare in children, with an incidence of 0.5 to 1 case per million children per year (76) except for children exposed to ionizing radiation. Papillary thyroid carcinoma is the most common cancer reported in children and adolescents. Follicular thyroid carcinoma is seen less often, and the oxyphil (Hu¨rthle cell) variants are rarely seen. Medullary thyroid carcinoma is rare and usually seen as part of the multiple endocrine neoplasia syndromes (MEN IIa and IIb). Anaplastic thyroid carcinoma is not seen during the first two decades of life. As children exposed to high levels of radiation from the Chernobyl nuclear power plant accident in 1986 have recently immigrated to North America, clinicians must be aware of the dramatic rise in papillary carcinoma of the thyroid among this population, who are now adolescents and young adults (77–79). Those children who were very young or in utero after the first trimester of pregnancy at the time of the accident are at risk for the development of thyroid cancer. Therefore, the thyroid of these individuals should be carefully examined annually. Ultrasound and thyroid function are usually the initial tests performed whenever a nodule is detected on palpation. The ultrasound excludes embryonic cysts that often present as thyroid nodules in children. The unusual susceptibility of the

338

Foley

thyroid of very young children to the mutagenic effects of radiation may be related to residual growth potential of the thyroid follicular cell in very young children, in contrast to older children and adults (15). Furthermore, iodine deficiency that was prevalent in Belarus and Ukraine at the time of the accident probably increased the radiation dose from iodine radioisotopes taken up by the thyroid. The management of the nodule or nodules in children differs from the recommendations for adults for these reasons: nodules are uncommon, they often are embryonic cysts (thyroglossal and brachial cleft), and the percentage of cancer in nodules that do not accumulate radioisotope are higher (approximately 30% in most reported series). The most important studies for the patient with a thyroid nodule are those designed to determine the structure and consistency of the thyroid gland, namely, ultrasonography to distinguish between solid and cystic lesions, and a radionuclide (123I iodide or 99mTc technetium) scan to determine whether the nodule is functioning or nonfunctioning. Almost all malignant thyroid tumors will appear as a solid or complex, non-functioning mass. In contrast, small cystic lesions (⬍2 cm in diameter) without a solid component, and hyperfunctioning nodules are almost always benign. Malignancy of the thyroid gland usually is not associated with abnormalities of thyroid function. The child with a solitary nodule, symptoms of hyperthyroidism, and a suppressed serum TSH with an elevated serum free T4 or T3 level usually has a functioning, benign follicular adenoma. Hyperfunctioning thyroid carcinomas are exceedingly rare. Likewise, primary hypothyroidism and elevated titers of thyroid antibodies are strong evidence against the diagnosis of thyroid malignancy and are very suggestive of autoimmune thyroiditis as the cause of nodular goiter. However, an enlarging mass in a patient with positive thyroid antibodies and clinical thyroiditis may have thyroid cancer and needs an evaluation of the mass. If ultrasound and radionuclide scan studies cannot rule out a malignancy, fine-needle aspiration (FNA) biopsy should be performed as a preoperative diagnostic test to guide the surgeon: if it is malignant, the surgeon should perform a total thyroidectomy and excision of affected lymph nodes; if it is a follicular neoplasm (indeterminant or suspicious), the mass should be excised. If it proves to be malignant on permanent section, a completion thyroidectomy is performed. FNA biopsy in patients during the first two decades of life is associated with an unacceptable 10% to 20% false-negative result, and there is need for more experience and lower false negative rates before it can be considered a definitive diagnostic procedure for children (80–82). However, if the result of the FNA biopsy is unequivocally benign and there is no evidence of recent growth, the patient should be followed often and examined carefully and a repeat FNA performed if there is evidence of growth on physical examination and/or ultrasound.

Pediatric Thyroid Disorders

339

Within weeks to months after total thyroidectomy, patients with papillary or follicular thyroid carcinoma are withdrawn from thyroxine therapy and evaluated with radioiodine imaging. Treatment with radioiodine to ablate residual normal thyroid and possible microscopic cancer in the remnant is usually advised (83). Subsequently, treatment with suppressive doses of thyroxine should maintain serum TSH levels around 0.1 mU/L. Serum thyroglobulin is measured every 4 to 6 months, and radioiodine imaging are performed at decreasing time intervals if the results are negative. The postoperative management for children and adolescents is similar to the management in adults (83). In those individuals ⬍20 years of age with an isolated papillary thyroid carcinoma and no evidence of metastatic or multifocal disease, some advocate only lobectomy and isthmusectomy (84). They argue that the prognosis of papillary thyroid carcinoma in this age group is excellent and that there is no need for more extensive surgery and radioiodine therapy unless a recurrence is found. Such patients are placed on suppressive thyroxine therapy and monitored with serum thyroglobulin every 6 to 12 months and thyroid ultrasound annually. However, the serum thyroglobulin may not be as specific in detecting recurrent disease if a total thyroidectomy has not been performed. The clinical presentation, diagnostic evaluation, and management of children and adolescents with medullary thyroid carcinoma (MTC) is the same as described for adults (85) (see Chap. 6). Where there is a family history of familial MTC or MEN IIa or IIb syndromes, every member of the family is tested for the RET proto-oncogene mutations, including infants (86). If the mutation is present, children should have a total thyroidectomy as early as 2 years of age, since there are reports of MTC occurring at this age. The opportunity for a cure is best achieved by total thyroidectomy during the preclinical stage of the disease when C-cell hyperplasia without tumors is seen. REFERENCES 1. Pintar JE, Toran-Allerand CD. Normal development of the hypothalamic-pituitarythyroid axis. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid 6th ed. Philadelphia: Lippincott, 1991, pp 7–21. 2. Shepard TH. Onset of function in the human fetal thyroid: biochemical and radioautographic studies from organ culture. J Clin Endocrinol Metab 1967; 27:945– 958. 3. Foley TP Jr, Malvaux P, Blizzard RM. Thyroid Disease. In: Kappy MS, Blizzard RM, Migeon CJ, eds. Wilkins the Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, 4th ed. Springfield, IL: Charles C Thomas, 1994, pp 457–533. 4. Thorpe-Beeston JG, Nicolaides KH, Felton CV, et al. Maturation of the secretion of thyroid hormone and thyroid stimulating hormone in the fetus. N Engl J Med 1991; 324:532–536.

340

Foley

5. Winters AJ, Eskay RL, Porter JC. Concentration and distribution of TRH and LRH in the human fetal brain. J Clin Endocrinol Metab 1974; 39:960–963. 6. Rosen F, Ezrin C. Embryology of the thyrotroph. J Clin Endocrinol Metab 1966; 26:1343–1345. 7. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J Med 1994; 331:1072–1078. 8. Fisher DA, Dussault JH, Sack J, Chopra IJ. Ontogenesis of hypothalamic-pituitarythyroid function and metabolism in man, sheep and rat. Rec Prog Horm Res 1977; 33:59–116. 9. Ballabio M, Nicolini U, Jowett T, et al. Maturation of thyroid function in normal human fetuses. Clin Endocrinol 1989; 31:565–571. 10. Greenberg AH, Czernichow P, Reba RC, Tyson J, Blizzard RM. Observations on the maturation of thyroid function in early fetal life, J Clin Invest 1970; 49:1790– 1803. 11. Fisher DA, Klein AH. Thyroid development and disorders of thyroid function in the newborn. N Engl J Med 1981; 304:702–712. 12. Abuid J, Stinson DA, Larsen PR. Serum triiodothyronine and thyroxine in the neonate and the acute increases in these hormones following delivery. J Clin Invest 1973; 52:1195–1199. 13. Abuid J, Klein AH, Foley TP, Larsen PR. Total and free triiodothyronine and thyroxine in early infancy, J Clin Endocrinol Metab 1974; 39:263–268. 14. Fisher DA, Sack J, Oddie TH, et al. Serum T4, TBG, T3 uptake, T3, reverse T3 and TSH concentrations in children 1 to 15 years of age. J Clin Endocrinol Metab 1977; 45:191–198. 15. Williams ED. Radiation-induced thyroid cancer. Histopathology 1993; 23:387–389. 16. Gru¨ters A, L’Allemand D, Heidemann PH, et al. Incidence of iodine contamination in neonatal transient hyper-thyrotropinemia. Eur J Pediatr 1983; 140:299–300. 17. Roti E, Gnudi A, Braverman LE. The placental transport, synthesis and metabolism of hormones and drugs which affect thyroid function. Endocr Rev 1983; 4:131–149. 18. Morreale de Escobar G, Obregon MJ, Calvo R, Escobar del Rey F. Effects of iodine deficiency on thyroid hormone metabolism and the brain in fetal rats: the role of the maternal transfer of thyroxine. Am J Clin Nutr Suppl 1993; 57:280S–285S. 19. Xue-Yi C, Xin-Min J, Zhi-Hong D, Rakeman MA, Ming-Li Z, O’Donnell K, Tai M, Amette K, DeLong N, DeLong GR. Timing of vulnerability of the brain to iodine deficiency in endemic cretinism. N Engl J Med 1994; 331: 1739–1744. 20. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341:549–555. Utiger RD. Maternal hypothyroidism and fetal development (editorial). N Engl J Med 1999; 341:601–602. 21. Vulsma T, Gons MH, and de Vijlder JJM. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to total organification defect or thyroid agenesis. N Engl J Med 1989; 321:13–16. 22. Pisarev MA. Thyroid autoregulation. J Endocrinol Invest 1985; 8:475–484. 23. Drexhage HA. Autoimmunity and thyroid diseases. In: Monaco F, Satta MA, Shapiro B, Troncone L, eds. Thyroid Diseases. Boca Raton, FL: CRC Press, 1993:491– 505.

Pediatric Thyroid Disorders

341

24. Foley TP Jr. Maternally transferred thyroid disease in the infant: recognition and treatment. In: Bercu BB, Shulman DI, eds. Advances in Perinatal Thyroidology. New York: Plenum Press, 1991, pp 209–226. 25. Matsura N, Yamada Y, Nohara Y, et al. Familial, neonatal transient hypothyroidism due to maternal TSH-binding inhibitor immunoglobulins. N Engl J Med 1980; 303: 738–741. 26. Iseki M, Shimizu M, Oikawa T, et al. Sequential serum measurements of thyrotropin binding inhibitor immunoglobulin G in transient familial neonatal hypothyroidism. J Clin Endocrinol Metab 1983; 57:384–387. 27. Kourides IA, Berkowitz RL, Pang S, Van Natta FC, Barone CM, Ginsberg-Fellner F. Antepartum diagnosis of goitrous hypothyroidism by fetal ultrasonography and amniotic fluid thyrotropin concentration, J Clin Endocrinol Metab 1984; 59:1016– 1018. 28. Gru¨ters A. Congenital hypothyroidism. Pediatr Ann 1992; 15:18–21. 29. Foley TP Jr. Congenital hypothyroidism and screening. In: Monaco F, Satta MA, Shapiro B, Troncone L, eds. Thyroid Diseases. Boca Raton, FL: CRC Press, 1993, pp 121–129. 30. LaFranchi S. Congenital hypothyroidism: a newborn screening success story? Endocrinologist 1994; 4:477–480. 31. Klein AH, Meltzer S, Kenny FM. Improved prognosis in congenital hypothyroidism treated before age three months. J Pediatr 1972; 81:912–915. 32. Fisher DA, Dussault JH, Foley TP Jr, Klein AH, LaFranchi S, Larsen PR, Mitchell ML, Murphey WH, Walfish PG. Screening for congenital hypothyroidism: results of screening one million North American infants. J Pediatr 1979; 94:700–705. 33. Lione D, Neri G. Thyroid disorders in genetic diseases. In: Monaco F, Satta MA, Shapiro B, Troncone L, eds. Thyroid Diseases. Boca Raton, FL: CRC Press, 1993, pp 579–586. 34. American Academy of Pediatrics. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1993; 91:1203–1209. 35. Delange F, Bourdoux P, Ermans AM. Transient disorders of thyroid function and regulation in preterm infants. In: Delange F, Fisher DA, Malvaux P, eds. Pediatric Thyroidology. Basel: Karger, 1985, pp 369–393. 36. Jacobsen BB, Andersen HJ, Peitersen AB, Dige-Petersen H, Hummer L. Serum levels of thyrotropin, thyroxine and triiodothyronine in full-term, small-for-gestational age and preterm newborn babies, Acta Paediatr Scand 1977; 66:681–687. 37. American Academy of Pediatrics and American Thyroid Association. LaFranchi S, Dussault JH, Fisher DA, Foley TP Jr., Mitchell ML. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1993; 91:1203–1209 and Thyroid 1993; 3:257–263. 38. Gru¨ters A, Delange F, Giovanelli G, et al. Guidelines for neonatal screening programmes for congenital hypothyroidism. Eur J Pediatr 1993; 152:974–975. 39. Fisher DA. Management of congenital hypothyroidism. J Clin Endocrinol Metab 1991; 72:523–527. 40. Rovet JF. Congenital hypothyroidism: long-term outcome. Thyroid 1999; 9:741–748. 41. Nelson JC, Weiss RM, Wilcox RB. Underestimates of serum free thyroxine (T4) concentrations by free T4 immunoassays. J Clin Endocrinol Metab 1994; 79:76–79.

342

Foley

42. Foley TP Jr. Congenital hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 8th ed. Philadelphia: Lippincott-Raven, 2000, Part VIII, Chapter 82, pp 977–983. 43. Sherman SI, Malecha SE. Absorption and malabsorption of levothyroxine sodium. Am J Ther 1995; 2:814–820. 44. Fisher DA. Hypothyroxinemia in premature infants: is thyroxine treatment necessary? Thyroid 1999; 9:715–720. 45. Vassart G, Dumont JE, Refetoff S. Thyroid disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds: The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York: McGraw-Hill, 1995, pp 2883–2928. 46. Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997; 17:411–422. 47. Kopp P. Pendred syndrome: identification of the genetic defect a century after its first clinical description. Thyroid 1999; 9:65–69. 48. Fisher DA. Screening for congenital hypothyroidism: prevalence of missed cases. Pediatr Clin North Am 1987; 34:881–890. 49. Foley TP Jr, Abbassi V, Copeland KC, Draznin MB. Acquired autoimmune mediated infantile hypothyroidism: a pathologic entity distinct from congenital hypothyroidism. N Engl J Med 1994; 330:466–468. 50. LaFranchi SL, Mandel SH. Graves disease in the neonatal period and childhood. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: Lippincott, 1996, pp 1000–1008. 51. Fisher DA. Neonatal thyroid disease in the offspring of women with autoimmune thyroid disease. Thyroid Today 1986; 9:1–7. 52. Matsura N, Konishi J, Fujieda K, et al. TSH-receptor antibodies in mothers with Graves’ disease and outcome in their offspring. Lancet 1988; 1:14–17. 53. Duprez L, Parma J, Van Sande J, et al. Germ line mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet 1994; 7:396–401. 54. Kopp P, van Sande J, Parma J, et al. Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 1995; 332:150–154. 55. Zimmerman D. Fetal and neonatal hyperthyroidism. Thyroid 1999; 9:727–733. 56. Foley TP Jr. Goiters in Adolescents. In: Rosenfield RL, ed. Adolescent Endocrinology. Endocrinol and Metab Clin N A, 1993; 22:593–606. 57. Delange F, Ermans AM. Iodine deficiency. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: Lippincott, Part I, Section E, Chapter 13, 2000, pp 295–316. 58. Rallison M, Dobyns B, Keating F, Rall J, Tyler F. Occurrence and natural history of chronic lymphocytic thyroiditis in children. J Pediatr 1975; 86:675–682. 59. Inoue M, Taketani N, Sato T, Nakajima H. High incidences of chronic lymphocytic thyroiditis in apparently healthy school children: epidemiological and clinical study. Endocrinol Jpn 1975; 22:483–488. 60. Foley TP Jr. Acquired hypothyroidism in infants, children and adolescents. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 8th ed. Philadelphia: Lippincott-Raven, 2000, Part VIII, Chapter 82, pp 983–988. 61. Foley TP Jr. Effects of the thyroid on gonadal and reproductive function. In: San-

Pediatric Thyroid Disorders

62. 63. 64. 65.

66. 67. 68.

69. 70.

71.

72.

73. 74. 75. 76. 77. 78. 79.

343

filippo JS, Muram D, Lee PA, Dewhurst J, eds. Pediatric and Adolescent Gynecology. Philadelphia: WB Saunders Co., 2000. Foley TP Jr, White C, New A. Juvenile Graves’ disease: the usefulness and limitations of thyrotropin receptor antibody determinations. J Pediatr 1987; 110:378–386. Finnegan JT, et al. Congenital nephrotic syndrome detected by hypothyroid screening. Acta Paediatr Scand 1980; 69:705–706. Chadha V, Alon US. Bilateral nephrectomy reverses hypothyroidism in congenital nephrotic syndrome. Pediatr Nephrol 1999; 13:209–211. Hollowell JG, Staehling NW, Hannon WH, Flanders DW, Gunter EW, Maberly GF, Braverman LE, et al. Iodine nutrition in the United States—trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971–1974 and 1988–1994). J Clin Endocrinol Metab 1998; 83: 3401–3408. Abe K, Taguchi T, Okuno A, et al. Acute suppurative thyroiditis in children. J Pediatr 1979; 94:912–914. Abe K, Fujita H, Matsuura N, et al. A fistula from pyriform sinus in recurrent acute suppurative thyroiditis. Am J Dis Child 1981; 135:178. Radfar N, Kenny FM, Larsen PR. Subacute thyroiditis a lateral thyroid gland: evaluation of the pituitary-thyroid axis during the acute destructive and the recovery phases. J Pediatr 1975; 87:34–37. Dallas JS, Foley TP Jr. Hyperthyroidism. In: Lifshitz F, ed. Pediatric Endocrinology: A Clinical Guide. New York: Marcel Dekker, 1995, pp 401–414. Shulman DI, Muhar I, Jorgensen EV, Diamond FB, Bercu BB, Root AW. Autoimmune hyperthyroidism in children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy. Thyroid 1997; 7: 755–760. Sills IN, Horlick MNB, Rapaport R. Inappropriate suppression of thyrotropin during medical treatment of Graves’ disease in childhood. J Pediatr 1992; 121:206– 209. Yamano Y, Takamatsu J, Sakane S, Hirai K, Kuma K, Ohsawa N. 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; 9:769–773. Foley TP Jr, Charron M. Radioiodine treatment of juvenile Graves disease. Exp Clin Endocrinol Diabetes 1997; 105(suppl 4):61–65. Hung W. Nodular thyroid disease and thyroid carcinoma. Pediatr Ann 1992; 21:50– 57. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993; 328: 553–559. Harach HR, Williams ED. Incidence of thyroid cancer in children in England and Wales. Br J Cancer 1995; 72:777–783. Kazakov VS, Demidchik EP, Astakhova LN. Thyroid cancer after Chernobyl. Nature 1992; 359:21. Baverstock K, Egloff B, Pinchera A, Ruchti C, Williams D. Thyroid cancer after Chernobyl. Nature 1992; 359:21–22. Schlumberger M, Pacini F. Consequences of the Chernobyl accident and atmo-

344

80.

81. 82.

83. 84.

85.

86.

Foley spheric contamination by iodine 131. In: Thyroid Tumors. Paris: Editions Nucleon, 1999, pp 237–254. Raab SS, Silverman JF, Elsheikh TM, Thomas PA, Wakely PE. Pediatric thyroid nodules: disease, demographics and clinical management as determined by fine-needle aspiration biopsy. Pediatrics 1995; 95:46–49. Degnan BM, McClellan DR, Francis GL. An analysis of fine-needle aspiration biopsy of the thyroid in children and adolescents. J Pediatr Surg 1996; 31:903–907. Khurana KK, Labrador E, Izquierdo R, Mesonero CE, Pisharodi LR. The role of fine-needle aspiration biopsy in the management of thyroid nodules in children, adolescents, and young adults: a multi-institutional study. Thyroid 1999; 9:383–386. Mazzaferri EL. An overview of the management of papillary and follicular thyroid carcinoma. Thyroid 1999; 9:421–427. Newman KD, Black T, Heller G, Azizhan RG, Holcomb III GW, Sklar C, Vlamis V, Haase GM, LaQuaglia MP. Differentiated thyroid cancer: determinants of disease progression in patients ⬍20 years of age at diagnosis. Ann Surg 1998; 227:533– 541. Ball DW, Baylin SB, De Butros AC. Medullary thyroid carcinoma. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia: Lippincott-Raven, 1996, pp 946–959. Donovan DT, Gagel RF. Medullary thyroid carcinoma and the multiple endocrine neoplasia syndromes. In: Falk A, ed. Thyroid Diseases: Endocrinology, Surgery, Nuclear Medicine and Radiotherapy, 2nd ed. Philadelphia: Lippincott-Raven, 1997, pp 619–644.

8 Practical Management of Thyroid Disease in the Elderly Myron Miller and Steven R. Gambert Sinai Hospital of Baltimore and The Johns Hopkins University School of Medicine, Baltimore, Maryland

1

INTRODUCTION

Although thyroid disorders occur over the entire age range, many are increasingly common with advancing age. It is important to recognize that the clinical features of thyroid disease may be significantly altered in the aged individual, especially in those over the age of 75, so that symptoms and physical findings typical in young persons may be modified, different, or absent in the elderly. The diagnosis of thyroid disorders may be further influenced by the age of the patient as a consequence of normal age-associated changes in thyroid physiology. Of even greater importance, however, is the impact that many age-prevalent nonthyroidal illnesses have on many of the tests used to assess thyroid function (1). 2

NORMAL AGING AND THYROID FUNCTION

2.1 Morphology The normal aging process is accompanied by changes in the gross and microscopic appearance of the thyroid gland. Autopsy data have indicated that overall 345

346

Miller and Gambert

thyroid gland mass declines with age from its normal range of 15 to 25 g; with increasing age, a progressively larger proportion of individuals will have glands weighing ⬍20 g (2). On the other hand, more recent data, obtained by ultrasound in healthy subjects, indicate that aging results in little change in size of the thyroid gland (3). With advancing age, there is progressive fibrosis, the appearance of lymphocytes, a decrease in follicle size, and a reduction in the amount of colloid in the thyroid gland (4). Although these changes are common in the elderly, they are not characteristic of all aged persons. More importantly, there does not appear to be a decline in thyroid function as a result of the morphological changes, and neither weight nor histologic appearance correlates with common measures of thyroid function (5). 2.2 Thyroid Hormone Physiology and Regulation Table 1 details the effect of aging on thyroid hormone physiology. Basal or resting metabolic rate, as measured by oxygen consumption, declines in humans as a function of increasing age. While this observation has implied that the metabolic changes that occur with age may represent a ‘‘relative’’ hypothyroid state, more recent data have correlated this decline in oxygen expenditure with an age-related

TABLE 1 Influence of Aging on Measures of Thyroid Function

Measure

Healthy Elderly (65–96 Years)*

Healthy Centenarians (⬎100 Years)*

TSH TSH response to TRH T4 T3 Free T4 Free T3 rT3 TBG T4 synthesis/secretion T3 synthesis/secretion T4 half-life Antithyroid antibodies Thyroglobulin Radioiodine uptake

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

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

Inc Dec Dec

Dec

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

Thyroid Disease in the Elderly

347

reduction in lean muscle mass rather than with age itself (6). Other data derived from both animal and human models have reported a small but significant decrease in cellular responsiveness to thyroid hormone action (7,8). What clinical significance, if any, this latter phenomenon may have remains controversial. Definite age-related changes have been identified in thyroid hormone economy. The half-life of thyroxine (T4) increases with age. While the mean half-life of T4 is 6.7 days for adults aged 23 to 36 years of age, it is approximately 9 days for those over 80 years (9). Since serum T4 changes little with increasing age, these data suggest that there is a reduction in T4 production by the thyroid gland. In the normal adult, approximately 80 µg of T4 and 30 µg of triiodothyronine (T3) are produced daily (10). In elderly individuals, T4 and T3 production decline to approximately 60 µg and 20 µg per day, respectively. These decreases in production may be related to the decrease in thyroidal iodide accumulation that has been observed with aging or to the morphological changes noted above (11). 2.2.1

TRH-TSH Axis

A study of healthy elderly subjects reported a blunted increase in nocturnal thyroid stimulating hormone (TSH) secretion. This suggested a resetting of the pituitary threshold of TSH feedback suppression leading to a decrease in TSH secretion for a given concentration of circulating thyroid hormone (12). The ability of the pituitary gland to synthesize TSH does not appear to be diminished by the aging process, as reflected by observation that pituitary TSH content undergoes no significant change over the life span (13). The 24-h TSH secretion has been reported to be decreased in healthy elderly men (14), but the secretion rate of TSH has also been reported to be higher in elderly subjects than in young individuals (15). Some have postulated, nevertheless, that TSH secretion may decline slightly with age; the slower clearance of T4 and T3 in older persons implies that less TSH is needed to maintain thyroid secretion. Studies measuring the serum TSH response to thyrotropin-releasing hormone (TRH) in elderly people are conflicting, with some studies showing a decreased response and others showing an increased response (14,16–21). In men aged 30 to 96 years given a continuous TRH infusion instead of bolus TRH administration, the serum TSH response was biphasic, with neither phase being affected by age (18). TSH exerts its effects by binding to the membrane of thyroid follicular cells. The serum T4 response to the TSH secreted after bolus TRH administration does not appear to be altered by age, although the serum T3 response may decrease (22). Administration of large doses of exogenous TSH has been reported to increase serum T4 to a lesser extent in older subjects than in younger subjects (23). 2.2.2

Thyroid Hormone Secretion and Metabolism

The rate of disposal or clearance of T4 decreases with increasing age in both men and women (9). This decrease is consonant with the age-related decrease noted

348

Miller and Gambert

in thyroid radioiodide accumulation and the maintenance of stable serum T4 concentrations throughout life. The decrease in T4 clearance is thought to result from decreases in both the fractional turnover rate and distribution space of T4. The decrease in clearance is thought to be responsible for the lower requirement for exogenous T4 in elderly as compared with younger hypothyroid patients. 2.3 Circulating TSH and Thyroid Hormone over the Age Span Determination of the secretory status of the aging thyroid gland can be accomplished by measurement in blood of TSH, total circulating T4 and T3 concentrations, and free T4 and T3 concentrations through use of radioimmunoassay or immunometric assays (20,24). 2.3.1

TSH

The neuroendocrine mechanisms controlling TSH release may be altered during the normal aging process. There is some disagreement regarding the effect of aging on circulating levels of TSH. Although there are data demonstrating that TSH remains constant with advancing age (25), it has been suggested that the generally accepted value of 5 mIU/L as the upper limit of normal for the adult population may actually be as high as 10 mIU/L in individuals who have reached their eighth decade (26). The current consensus, however, is that serum TSH does not rise in healthy elderly, and that studies which reported a rise did not carefully exclude individuals with illness or with positive antithyroid antibodies (1,18,27). 2.3.2

T4 and T3

Total and free concentrations of T4 and T3 are commonly used to document the status of thyroid secretory activity. The normal range for these hormones is probably unaffected by aging, and deviations from normal must be considered as evidence for thyroid disease or for other illness or states that may affect hormone measurement (22,25–29). A small decline in serum T3 concentration with age has been found, but the decline is more likely attributable to mild nonthyroidal illness than age itself (25,27). While there is little change in mean values for serum T3 as a function of advancing age, fewer persons have values in the ‘‘upper range of normal’’ as derived from data on individuals across the life span. Similarly, the small fraction of T4 and T3 that circulates in the free state (FT4 and FT3) remains constant over the age span, and a decrease in concentration, especially FT3, should be considered a consequence of illness rather than due to normal aging (18,22,25–27). Thyroid binding globulin (TBG) is the primary thyroid hormone transport protein for T4 and T3, carrying about 70% of bound hormone, and its levels do

Thyroid Disease in the Elderly

349

not appear to differ between healthy young and old individuals (18). While a greater T4 binding capacity of TBG has been observed in the elderly, this does not have clinical significance (26,30). Biologically inactive reverse T3(rT3) is generated by 5-monodeiodination of the inner ring of T4 (10,31). A variety of factors—including starvation, febrile illness, elevation of glucocorticoid concentration, and drugs such as high-dose propranolol, amiodarone, and iodinated contrast materials—can result in impaired T4 conversion to T3, with a decline in serum T3 and a parallel increase in rT3 concentration due to decreased rT3 clearance (10,32). Serum rT3 is not affected by normal aging, and an increase must be considered to be a consequence of illness or drug-induced alteration in rT3 degradation (27,28). 2.3.3

Thyroid Function in Advanced Aging

Recent studies in healthy centenarians ranging in age from 100 to 110 years provide further information on the extent to which aging alone contributes to changes in thyroid function. There was no difference in serum FT4 of the centenarians as compared to both healthy elderly (age 65 to 80 years) and healthy younger adults (age 20 to 64 years) but serum FT3 was reduced in the centenarians. Serum TSH was also lower in the centenarians (median 0.97 mU/L versus 1.17 mU/L versus 1.70 mU/L); for the older groups as a whole, there was an inverse relationship between serum TSH and age. Serum rT3 was increased in the centenarians, suggesting that there was reduced outer-ring deiodination. Thus, in healthy aging persons, thyroid function was preserved into the eighth decade, while advanced old age was associated with reduced but clinically insignificant alterations in thyroid activity, likely due to a decrease in TSH secretion and impairment of peripheral 5′-deiodination (1,33). 2.3.4

Antithyroid Antibodies

Many thyroid disorders, including Graves’ disease (34) and Hashimoto’s thyroiditis, are the result of immune dysregulation (20,35). As a consequence, high levels of serum antibodies to both thyroglobulin and to thyroid peroxidase (microsomal) are commonly found in patients with these thyroid problems. However, low levels of antithyroglobulin antibodies (titer ⬍1:100) may be present in people without clinical signs of a thyroid disorder, and moderate to high titers (1 :1600 to 1: 25,600) can be found in patients with nonthyroid autoimmune disorders (20). Thyroid antibodies in the serum increase in incidence progressively with increasing age, reaching a peak incidence of 20% to 25% in women above the age of 50 years and 5% to 10% in similarly aged men (36,37). However, in a highly selected population of healthy elderly ranging in age from 65 to 110 years, the prevalence of antithyroid antibodies was low and did not differ from the prevalence seen in healthy young persons (1). This finding suggests that the high incidence of antithyroid antibodies in certain aging populations is a reflection of

350

Miller and Gambert

disease and not a consequence of normal aging. Thus, the finding of high serum antithyroglobulin and/or antithyroid peroxidase antibody titers, an elevation of basal serum TSH concentration, with or without reduced levels of serum T4, is consistent with autoimmune thyroiditis (38). 2.3.5

Low–Serum T4 States

In addition to the expected reduction in serum T4 concentrations seen in primary or secondary hypothyroidism, serum T4 levels in the elderly may be low for a variety of other reasons. Levels of thyroid binding prealbumin may be acutely lowered in the presence of infectious disease, protein-wasting states, surgery, and malnutrition and may be accompanied by a decline in total T4. More importantly, TBG levels can be depressed as a result of X-linked congenital deficiency, severe catabolic illness, chronic hepatic disease, glucocorticoids, and androgen administration (39). Binding of T4 to TBG can be inhibited by drugs such as high-dose salicylates and furosemide (40). The anticonvulsants carbamazepine and phenytoin can reduce serum T4 by stimulating an increase in hepatic enzyme metabolizing activity (40). 2.3.6

Nonthyroidal Illness

The serum concentration of total T3 is reduced in many nonthyroidal illnesses, giving rise to the ‘‘low T3 syndrome.’’ This consequence of systemic illness is the earliest and most common of the alterations in thyroid hormone levels (22,25,29,32,39,41–43). In response to many acute illnesses, there is decreased peripheral 5′-monodeiodination of T4 to T3, with consequent reduction in serum T3 concentration and an increase in serum rT3. Lowering of thyroid binding prealbumin and TBG in the presence of acute and chronic illness further contributes to the marked decrease in serum T3 that is characteristic of the sick elderly. Although there are limited animal data to suggest that age may alter responses to stressors, such as cold exposure and starvation, human studies are lacking. The finding of a low T4 concentration in the presence of nonthyroidal illness has been termed the ‘‘euthyroid sick syndrome’’ (44). In mild to moderate forms, measurement of free T4 will be normal even though total T4 concentration is reduced (39,45). A putative inhibitor of T4 binding to TBG has been detected in 20% to 74% of hospitalized patients with nonthyroidal illness; this may contribute to the measurement of a low T4 in these patients (39,46). However, severe illness can result in a marked reduction of both total and free T4 concentrations. When this circumstance occurs, the prognosis of the patient is poor, with a mortality rate of approximately 80% having been reported (47). The ability to differentiate these patients from those with frank hypothyroidism is often difficult (41). Although serum TSH is usually in the normal range, in some patients it may be low, raising the question of secondary hypothyroidism. Cytokines such as in-

Thyroid Disease in the Elderly

351

terleukin-1, interleukin-6, and tumor necrosis factor could be involved as intermediaries in the development of low T4 and low T3 states. Many patients with nonthyroidal illnesses and low T4 and/or T3 also have elevated serum concentrations of cytokines (48,49). Experimental increase of tumor necrosis factor-α has been observed to induce low serum concentrations of T4, T3, and TSH (50). Occasionally mild to moderately elevated concentrations of TSH are found, implying the presence of primary hypothyroidism. This is especially true in the recovery phase of the illness, when TSH values can rise to as high as 20 mIU/L. Within 4 to 20 weeks after clinical recovery, all measures of thyroid function will usually have returned to normal (51). 2.3.7

High-T4 States

Although less common than low thyroid hormone states, nonthyroidal factors have also been associated with an elevation of serum T4 concentration (41,52). A euthyroid increase in total T4 can occur as a result of overproduction of TBG, a disorder that may be familial (53). More commonly in the elderly, TBG is increased due to therapy with estrogen or tamoxifen or as an acute-phase reactant during acute hepatocellular injury. In these circumstances, serum free T4 will be normal. Occasionally, with mild to moderate levels of illness, an increase in free T4 is found in the patient with euthyroid sick syndrome as a result of impaired T4 monodeiodination by peripheral tissues (39,42). 2.3.8

Measures of Iodine Uptake

The ability of the thyroid gland to trap iodide and other ions such as technetium (Tc) has been the basis for assessment of both thyroid gland function and morphology. The oral administration of 131 I to normal individuals results in an accumulation of approximately 5% to 25% of the dose in the thyroid gland by 24 h (54). Although a progressive age-related decrease in 131I uptake has been reported, there is little clinical significance in this finding (55). Exposure to increased amounts of iodide in the diet or use of iodine-containing drugs or radiographic contrast media will result in a marked reduction of 131I uptake. While elevated values are useful in supporting a diagnosis of hyperthyroidism, some elderly patients with Graves’ disease or toxic nodular goiter may have 24-h 131I uptake values within the normal range. 2.3.9

Thyroid Imaging

Thyroid scanning with 99mTc is useful in the evaluation of the elderly patient with a palpable single thyroid nodule where demonstration of increased activity within the nodule markedly reduces the likelihood that the nodule represents a malignancy. In the elderly hyperthyroid patient, scanning can also be used to differentiate a diffusely overactive thyroid gland (Graves’ disease) from a gland with single or multiple toxic nodules (56).

352

Miller and Gambert

High-quality anatomic detailing of thyroid structure can be achieved by currently available imaging techniques, including real-time ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). These procedures can be useful in evaluating patients with single and multiple nodules by identifying cysts, areas of hemorrhage, and tissue calcification. Ultrasonography may be of value in determining which regions of the thyroid are most appropriate for fine-needle aspiration. Both CT and MRI are expensive and have few clinical indications at present, but they may be of occasional value in assessing the extent of tracheal compression by a thyroid mass, the substernal extension of goiters, or the extent of local invasion or metastasis by thyroid cancers (57). 2.3.10

Serum Thyroglobulin

Thyroglobulin can gain entry to the circulation, where it can be detected in normal individuals at low levels by means of sensitive radioimmunoassay and immunometric assays (58). Measurement is complicated by the frequent presence in the elderly of antithyroglobulin antibodies, which interfere with accurate quantification of thyroglobulin. Studies to date have not reported differences in serum thyroglobulin due to age. Concentrations can be increased in patients with hyperthyroidism, benign nodules, and inflammatory disorders such as subacute thyroiditis. High levels are found in the majority of patients with thyroid cancer, but serum thyroglobulin is neither sensitive or specific enough to be used as a diagnostic test for cancer. In patients with thyroid cancer previously treated by surgical or radioiodine ablation, measurement of serum thyroglobulin appears to be a sensitive indicator of tumor recurrence, either locally or from metastases. However, caution must be observed in interpreting serum thyroglobulin blood levels, since detectable levels can be found in patients whose ablation has not been complete and have been left with small remnants of nonmalignant thyroid tissue (58). 3

SUBCLINICAL THYROID DISEASE

Controversy remains as to whether subclinical disease of the thyroid is a normal variant of the aging process or represents a disease state. However, it is generally agreed that a subpopulation of elderly persons has either a high or suppressed level of TSH despite normal levels of circulating T4, FT4, and FT3 or T3 alone. Both subclinical hypothyroidism and subclinical hyperthyroidism affect relatively large numbers of persons with advancing age (59,60). The question remains as to whether to screen all elderly persons for thyroid abnormalities, some of which may be subclinical. While many suggest that this practice is cost-effective, others target it only for specific populations. Specifically, the American College of Physicians recommends screening for women

Thyroid Disease in the Elderly

353

who are over age 50 and have one or more general symptoms suggestive of thyroid dysfunction (59). The American Academy of Family Physicians and the American Association of Clinical Endocrinologists suggest that thyroid function be periodically measured in all ‘‘older’’ women. The Canadian Task Force on the Periodic Health Examination asks that physicians ‘‘maintain a high index of suspicion for thyroid disease when evaluating symptoms in perimenopausal and postmenopausal women’’ and does not make any specific recommendation regarding screening. While the U.S. Preventive Services Task Force has concluded that ‘‘little evidence exists to support screening in the absence of suggestive symptoms,’’ the American Thyroid Association recommends screening ‘‘all elderly patients, postpartum women, and patients with autoimmune disease or a strong family history of thyroid disease.’’ It is our recommendation that both women and men over the age of 50 years be screened for thyroid dysfunction using ultrasensitive assays for TSH. 4

HYPOTHYROIDISM IN THE ELDERLY

4.1 Epidemiology The prevalence of hypothyroidism in the elderly has been reported at varying magnitudes depending on the study population and ranges from a prevalence of 0.9% to 17.5% (Fig. 1) (59,61–63). 4.2 Pathophysiology The most common cause of hypothyroidism in the elderly is autoimmune thyroiditis (64). Another major cause of hypothyroidism is the prior treatment of hyperthyroidism with radioiodine or subtotal thyroidectomy (65–67). With both treatments, there is a continuous lifelong risk of development of hypothyroidism. Following radioiodine, the risk is ⱖ50% after the first year of treatment, with an additional annual incidence of 2% to 4% each year thereafter. Thus, any elderly person who has received radioiodine or surgical treatment for hyperthyroidism should have thyroid functional status continuously evaluated at yearly intervals. Hypothyroidism may also be the natural sequel to previous Graves’ disease (68). Medications may also precipitate hypothyroidism, particularly in individuals with autoimmune thyroiditis; these include iodine-containing radiographic contrast agents, amiodarone, and iodine-containing cough medicines (69). Longterm lithium therapy can lead to interference with thyroid hormone synthesis and to inhibition of thyroid hormone release, with up to a 20% prevalence of subclinical hypothyroidism and a similar prevalence of up to 20% of overt hypothyroidism in patients taking this medication (40). Though infrequent, hypothyroidism in the elderly may also result from pituitary or hypothalamic disease.

354

Miller and Gambert

FIG. 1 Pooled prevalence of overt hypothyroidism per 1000 patients. Means and 95% confidence limits of the pooled prevalence of overt hypothyroidism per 1000 patients by patient age and sex categories. Closed circles represent population-based studies; open ovals represent office-based studies. (From Ref. 59.)

4.3 Diagnosis The diagnosis of hypothyroidism in the elderly is often missed, because the presenting complaints are often confused with other age-prevalent disorders. This problem is further compounded by the often insidious onset of illness. Doucet and colleagues reported on the presenting symptoms and signs of hypothyroidism in young (mean age 40.8 ⫾ 9 years) and elderly subjects (mean age 79.3 ⫾ 6.7 years). Statistical differences in presenting findings were noted for weight gain (59% versus 24%); cold intolerance (65% versus 35%); paresthesias (61% versus 18%); and muscle cramps (55% versus 20%). Complaints of fatigue and weakness were present in more than 50% of the elderly patients (70). Many persons who are later discovered to be hypothyroid will be unable to identify when the symptoms actually began. Even patients known to have hypothyroidism may not have classic physical findings, and it often escapes recognition until late in its course, after cognitive changes and functional decline interfere with independent living (Table 2) (71–73). Neurological findings may include dementia, ataxia, and carpal tunnel syndrome. On physical exam, delay

Thyroid Disease in the Elderly

355

TABLE 2 Clinical Features of Elderly Patients (Mean Age 84.5 Years) with Overt Hypothyroidism (N ⫽ 100) and with Subclinical Hypothyroidism (n ⫽ 20) Symptom/sign Presenting Feature Falls/deteriorating mobility/collapse Hypothermia General malaise Confusion Angina Congestive cardiac failure Cerebrovascular accident Other conditions Total Signs Hypothyroid facies Hoarse voice Slow relaxing reflexes Myopathy Cerebellar signs Effusions Total

Overt Hypothyroid

Subclinical Hypothyroid

17 2 2 4 1 6 4 64 100

3

4 1 2 2 2 9 15

17 20

1*

4 5

* Also had myopathy. Source: Modified from Ref. 71.

in the relaxation of deep tendon reflexes may be more difficult to elicit with advancing age, due to other age-prevalent conditions affecting neurological function. Classic signs and symptoms of dry skin, cold intolerance, paresthesias, constipation, and hypothermia, among others, are worth looking for despite the patient’s age, but some of these findings can be due to aging itself. For example, with normal aging, there may be changes in the skin and hair. The hair becomes more coarse and there is a tendency to lose the hair in the lateral aspects of the eyebrows. The skin becomes dry, and scaling may be noted. Hypercholesterolemia may be more common in both circumstances as well. For these reasons, the physician should maintain a high index of suspicion of hypothyroidism when evaluating older persons, especially women and those with prior histories or family histories of some form of thyroid disease. The diagnosis of primary hypothyroidism in the elderly is best made by measuring the serum TSH concentration (26). Changes in protein binding may reduce the level of total T4; T3 may be reduced in persons with significant medical

356

Miller and Gambert

illness or who are malnourished. T4 may be suppressed in individuals with T3 toxicosis. For these reasons, an increase in serum TSH remains the best way to detect primary hypothyroidism regardless of age. However, during the recovery phase after acute nonthyroidal illnesses, an elevated serum TSH level may not represent true clinical hypothyroidism; in this case the serum TSH returns to the normal range within 4 to 6 weeks. While uncommon in the elderly, hypothyroidism can be secondary to pituitary failure or hypothalamic disease. In this case, both serum TSH and T4 levels are low. While antithyroid antibodies are detectable in the circulation of many persons with hypothyroidism, these are not indicated in the workup of every patient suspected of having hypothyroidism. They may be useful and may guide therapy for those found to have subclinical hypothyroidism. Because of the difficulty of factoring out signs and symptoms of hypothyroidism from other age-prevalent illness and normal age-related findings, screening has been recommended for certain high risk populations. While some advocate screening everyone over the age of 50 and periodically thereafter, a relatively higher yield could be expected for elderly persons—and especially women— with cognitive problems, hypercholesterolemia, goiter, family history of thyroid illness, or prior history of thyroid illness (59,74). 4.4 Treatment l-Thyroxine is the preferred medication to treat hypothyroidism. While other preparations are available, elderly persons tolerate the effects of T3 less well due to its ‘‘burst effect’’ on the myocardium, causing an acute increase in oxygen demand as well as the need for more frequent dosing. In general, brand names are suggested to minimize variability that may occur with generic preparations. It is also easier for the elderly person to identify a medication with a consistent color and shape. Elderly patients require a smaller amount of l-thyroxine, on average 110 ⫾ 8 µg/day, as compared with younger subjects, who on average require a weight-related dose of approximately 0.8 µg/lb body weight (1.6 µg/ kg) per day (75–77). Due to the increase in half-life for thyroxine that accompanies the aging process, it will take longer to reach a steady state; therefore, a longer time between dose increases is necessary in order to reduce unwanted side effects. The commonly used adage of ‘‘start low and go slow’’ should be followed. Because many elderly patients with hypothyroidism may have an underlying cardiovascular problem, therapy should start at a dose of 25 µg/day, with gradually increasing increments of 25 µg every 4 to 6 weeks. Individuals with significant cardiac disease may require dose changes as low as 12.5 µg and could even be started at that low level. Once a dose of 75 µg/day is achieved without side effects, increments of 12.5 µg are advised. The final dose required is the amount of lthyroxine that reduces the serum TSH into the range of normal and does not have associated side effects. Not all elderly individuals can be brought to a euthyroid

Thyroid Disease in the Elderly

357

state; this uncommon occurrence is usually seen in those with significant coronary artery disease. In this circumstance, the use of a beta-adrenergic blocking agent may allow a euthyroid state to be reached without induction of symptoms of myocardial ischemia (78,79). Caution is advised to avoid iatrogenic subclinical hyperthyroidism with l-thyroxine, which may lead to increased bone turnover and adverse effects on the cardiovascular system, such as atrial fibrillation. Use of sensitive assays for serum TSH allows for accurate titration of thyroxine. 4.5 Myxedema Coma Myxedema coma is a rare but serious consequence of untreated or inadequately treated hypothyroidism. It occurs almost exclusively in the elderly. While the name implies the presence of coma, the term also encompasses patients with altered cognition, lethargy, seizures, psychotic symptoms, and/or confusion and disorientation thought secondary to hypothyroidism. Most affected persons have experienced a precipitating event such as severe infection, cold exposure, alcoholism, or use of psychoactive medications (80). Exposure to sedatives and/or narcotics has also been associated with this entity. While some patients will have a prior history of being treated for hypothyroidism, many will be diagnosed for the first time. 4.5.1

Diagnosis

Recognition of myxedema coma may be difficult, since its clinical presentation can be attributed to a host of other problems. For those who can provide information, a history of increased fatigue and somnolence is common. A past history of treatment for thyroid illness—including medication, surgery, or radioactive iodine—should raise concern. Use of narcotics, sedatives, or antipsychotic medication may precipitate myxedema coma. Infections such as pneumonia and urosepsis are commonly found at the time of diagnosis; cold exposure, as often occurs in poorly heated residential environments, has also been associated with myxedema coma. Physical examination may demonstrate many of the classic signs and symptoms of a hypothyroid state, such as dry scaly skin, edema, and bradycardia. Profound hypothermia is often present and may be underestimated, because many commonly used thermometers do not read temperatures below 35°C. Patients with myxedema coma may also demonstrate hypoventilation and hypotension. Severe frontal and occipital headaches, psychotic behavior, ataxia, nystagmus, muscle spasms, and sinus bradycardia may be signs of impending coma and must not be dismissed. Other findings of severe hypothyroidism include pericardial effusion, ileus, megacolon, and easy bruising. Laboratory data may not be available early in the diagnostic process, though the classic findings are a markedly reduced total and free serum T4 and elevated

358

Miller and Gambert

serum TSH levels. Hyponatremia and hypoglycemia are not uncommon. Hyponatremia is thought to result from inappropriately increased levels of antidiuretic hormone (ADH) as well as decreased water excretion due to a decrease in glomerular filtration rate. Hypoglycemia is thought to result from impaired gluconeogenesis and, in some patients, from cortisol deficiency. Since hypothyroidism in the elderly is often due to autoimmune thyroiditis, other autoimmune deficiency states must be looked for, including diabetes and adrenal insufficiency. Creatine phosphokinase (CPK) is often elevated and may suggest the presence of a myocardial infarction. Fractionation, however, usually demonstrates a muscle etiology for the elevated CPK. Myocardial infarction can occur in the presence of myxedema coma and may complicate initiation of thyroid hormone therapy. Rarely, associated myoglobinuria and rhabdomyolysis have been reported, though it is unclear if these findings result from circulatory collapse or are directly related to the primary hypothyroid state. Arterial blood gases usually show a decrease in PO2 and an increase in PCO2, indicating acute or impending respiratory failure. Anemia is also a common finding and may range from a normochromic, normocytic variety to a macrocytic form suggestive of B12 and/or folate deficiency. On chest x-ray, cardiomegaly is often reported, which may be due to either a pericardial effusion or dilated myocardium. Evoked potentials may have an abnormal amplitude or latency and the electroencephalogram may demonstrate the presence of triphasic waves that disappear after initiation of thyroid hormone replacement therapy. 4.5.2

Treatment

In patients with severe illness and coma, the decision to initiate thyroid replacement therapy must often be based on clinical evidence prior to obtaining confirming laboratory data (81,82). No controlled, blinded, or randomized studies exist to clearly define the optimal therapeutic regimen at any age. The following principles and guidelines should be followed: 1. 2.

3.

Myxedema coma has a very high mortality rate if left inadequately treated. There is the need to balance the uncertainty of diagnosis prior to receiving laboratory results with empiric treatment and its complications, especially if the individual is later found not to be hypothyroid. Supportive therapy must be provided promptly and includes ventilatory support for respiratory failure, antibiotics for infection as indicated, and management of hypothermia by external rewarming. Hypotension can be treated with fluid replacement or dopamine. Hyponatremia must be treated. Occasionally, severe hypoglycemia and anemia will require prompt therapy. Careful attention should be given to avoid aspiration of secretions, fecal impaction, and urinary retention.

Thyroid Disease in the Elderly

359

4. Prompt initiation of therapy with l-thyroxine is necessary to treat the hypothyroid state. The initial dose is 300 to 500 µg given intravenously. Once there is evidence of a clinical response, usually manifest as a rise in body temperature and in heart rate, the daily dose should be reduced to 50 to 100 µg and can be given orally and then adjusted as necessary (89). T3 or combinations of T4 and T3 are not recommended in the elderly, since the acute metabolic impact of T3 can precipitate cardiac arrhythmia or myocardial infarction. The main principle is that a severely thyroid hormone–deficient individual may require a high initial dose of thyroxine in order to occupy hormone binding sites that have been left free as a result of significant and prolonged hormone deficiency. In addition, problems such as infection may increase the turnover of thyroxine and thus further increase the need for a higher initial replacement dose. The risk, however, is that this high dose can increase myocardial oxygen consumption and increase the potential for a myocardial infarction. Therefore, clinical judgment must prevail, especially in the setting of other comorbidities prevalent in the elderly. 5. Whether or not intravenous glucocorticoids should be administered to all persons with myxedema coma remains controversial. Adrenal insufficiency can coexist with myxedema coma, so that suspicion of cortisol deficiency as based on history, physical examination, or electrolyte abnormalities deserves prompt treatment. In life-threatening situations, blood for measurement of plasma cortisol should be drawn and intravenous stress doses of corticosteroids should be administered and continued until there is laboratory confirmation of status of adrenal function. At that time, the decision can be made either to treat for concomitant adrenal insufficiency or to taper and stop the corticosteroid. In summary, this condition is largely a problem of elderly hypothyroid persons. It requires aggressive supportive therapy and hormone replacement while contributing factors are evaluated and appropriately treated. Close monitoring is required when treatment is initiated to avoid toxicity from large doses of thyroid hormone. 4.6 Subclinical Hypothyroidism While severe primary hypothyroidism is associated with specific symptoms and often changes in physical and mental functioning, subclinical hypothyroidism is characterized by relatively few clinical and biochemical abnormalities (Table 2) (59,71). By definition, the circulating level of TSH is increased, with serum T4 and T3 within the range of normal. In a study of 344 relatively healthy persons over 60 years of age who were part of the Framingham study, serum TSH concentrations of ⬎10 mU/L were

360

Miller and Gambert

found in 5.9%, despite the absence of clinical findings and normal circulating levels of thyroxine. An additional 14.4% had lesser elevations of serum TSH, between 5 to 10 mU/L (61). More recently, a thyroid screening survey of 1149 community-residing women with mean age 69 ⫾ 7.5 years identified 10.8% as having subclinical hypothyroidism (84). These findings have been confirmed in numerous other studies, and it is now generally accepted that with age, a higher percentage of persons will have evidence of a failing thyroid gland. While a few percent will progress to clinical hypothyroidism each year, those patients with high levels of antimicrosomal antibodies will have a faster decline in thyroid function and a higher percentage will become clinically hypothyroid (85). In a group of elderly individuals (mean age 74 years) with subclinical hypothyroidism who were followed for a period of 4 years, 80% of those with antimicrosomal antibody titers ⬎1:1600 developed overt hypothyroidism (86). This association with high levels of autoantibodies suggests that the decline in thyroid function results not from age-related changes but from chronic autoimmune thyroiditis. Since not all persons with subclinical hypothyroidism have high autoantibody levels, however, some other, as yet unknown etiology must be involved. The central, unresolved question is whether individuals with subclinical hypothyroidism warrant replacement therapy with thyroid hormone. Although several studies have observed beneficial effects of thyroxine therapy in patients with subclinical hypothyroidism, no studies have specifically addressed this question in the elderly, in whom this condition is most common. Using a questionnaire to assess symptoms of hypothyroidism, Cooper and colleagues rated symptoms of muscle cramps, dry skin, cold intolerance, constipation, poor energy levels, and easy fatigability in persons with subclinical hypothyroidism. Subsequently, 16 persons were treated with a placebo and 17 with lthyroxine therapy. Symptoms improved in 8 of the 14 patients receiving thyroxine and in 3 of 12 patients receiving the placebo ( p ⬍0.05) (87). In addition, noninvasive indices of myocardial contractility improved with therapy with thyroxine and not with placebo. Jaeschke and coworkers (88) evaluated 37 patients with subclinical hypothyroidism; 19 were treated with a placebo and 18 with thyroid hormone replacement to achieve a normalization of TSH. These patients were reevaluated at various time intervals using a variety of outcome measures, including physical complaints, problems with mood and emotions, energy and well-being, and cognitive function. A disease-specific questionnaire included six items related to the presence and severity of muscle cramps, dry skin, cold intolerance, constipation, energy, and fatigue. A Sickness Impact Profile included 136 items to assess mobility, sleep and rest, emotional feelings, and sensations. Also assessed were memory function and psychomotor speed, bone mineral density, and laboratory tests of thyroid function and lipids. This randomized, doubleblinded study concluded that the group receiving thyroid hormone replacement

Thyroid Disease in the Elderly

361

statistically had higher composite memory scores equating to an approximate increase of 8.7 points on an IQ test and an improvement of 0.9 points in psychomotor speed. No other changes were noted (88). This finding is consonant with a study that reported a positive relationship between circulating levels of T4 and cognitive function in a group of 44 euthyroid men with a mean age of 72 years (89). A study of 883 subjects with a mean age of 74.1 years living in New Mexico found that 12.8% were taking thyroid medication for presumed hypothyroidism. Of these, 33% still had an elevated TSH level, presumably indicating inadequate treatment. Of the remaining subjects, 15.4% had elevated TSH concentrations and were identified as either having subclinical hypothyroidism or mild (TSH ⬎4.7 to 10 mU/L) or moderate (TSH ⬎10 mU/L) degree of true hypothyroidism (1.7%). While Hispanics were noted to have lower rates of hypothyroidism than non-Hispanics, differences reached significance only for women. Women of both groups had higher rates of thyroid disease than did men. While various tests for cognitive (Mini-Mental State Exam, WAIS-R Digits Forward, Fuld Object Memory Evaluation, clock drawing, and Color Trail Making Test) and affective function (Geriatric Depression Scale) were assessed, no differences were noted between groups until TSH concentrations exceeded 10 mU/L, when non-Hispanic women had a significantly lower mean number of correctly connected numbers in the Color Trail Making Test than did participants with normal serum TSH concentrations. Measurements of total cholesterol, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein failed to demonstrate differences between groups other than for a small decrease in HDL levels in the group of individuals with abnormally low levels of free thyroxine. Persons with TSH levels ⬎10 mU/L with normal levels of free thyroxine had a significantly higher prevalence of coronary artery disease than did persons with normal thyroid function tests. No differences were noted for those on thyroid hormone replacement or who had frank hypothyroidism, likely due to the small numbers of individuals in the latter group. No differences were noted in symptoms of fatigue or constipation between groups, though persons with the highest levels of TSH in the subclinical hypothyroid group reported being ‘‘full of energy’’ less frequently than did individuals with normal TSH levels (89). A study of 1200 middle-aged subjects in Holland reported that 10% of women with hypercholesterolemia had coexisting subclinical hypothyroidism, a number higher than expected based on age-corrected prevalence within the community. While the prevalence remained the same for men at 1.6% regardless of the level of plasma cholesterol (e.g., ⬍5mmol/L, 5 to 8 mmol/L, and ⬎8 mmol/ L), the prevalence of subclinical hypothyroidism in women increased from 4% in the low-cholesterol group to 10.3% in those from the highest-cholesterol group (90).

362

Miller and Gambert

Further evidence has been generated indicating that subclinical hypothyroidism is a risk factor for atherosclerosis and coronary artery disease. In a large group of elderly women with evidence of aortic atherosclerosis, 13.9% were found to have subclinical hypothyroidism; in those women with history of myocardial infarction, 21.5% had subclinical hypothyroidism. Similarly, the presence of subclinical hypothyroidism was accompanied by a high prevalence of both aortic atherosclerosis and myocardial infarction, with an even higher prevalence in those patients who also had detectable circulating antiperoxidase (antimicrosomal) antibodies (84). There are no substantive data as yet to indicate that early treatment of subclinical hypothyroidism with thyroid hormone replacement is effective in reducing the risk of subsequent development of atherosclerosis or coronary artery disease. In summary, subclinical hypothyroidism progresses to frank hypothyroidism in approximately 5% to 8% of affected patients each year. This is an even greater problem for those with coexisting high antimicrosomal antibodies, where the rate may be as high as 20%. Abnormal systolic time intervals may be improved by thyroid hormone replacement, though the clinical value of this remains unknown at this time. There may also be improvements in patients’ perceptions of well-being, plasma cholesterol and cholesterol subfractions, and cognitive abilities. While some physicians advocate replacement therapy for all persons with subclinical hypothyroidism, even those with minimally elevated levels of TSH, it is more widely viewed that treatment should be reserved for those individuals with TSH levels ⬎10 mU/L or individuals with serum TSH levels between 5 and 10 mU/L but who have either coexisting high levels of antimicrosomal antibodies, who most certainly will continue to progress to overt hypothyroidism, or symptoms consistent with mild hypothyroidism. Even those persons with minimally elevated levels of TSH and negative antimicrosomal antibodies, however, deserve careful follow-up, as a percentage of these individuals will also develop hypothyroidism each year. The goal of treatment, when initiated, is to normalize serum TSH values as long as the dose of thyroid hormone that is required produces no unwanted side effects. This latter phenomenon is extremely rare with the low doses most commonly required in these patients. Caution is advised in treating patients with significant underlying cardiac disease, as too rapid an increase in thyroid hormone dosage may result in new or worsening symptoms of angina, congestive heart failure, or cardiac arrhythmias. 5

HYPERTHYROIDISM IN THE ELDERLY

Overproduction of thyroid hormone leads to the clinical condition of hyperthyroidism or thyrotoxicosis. This disorder is accompanied by a broad array of symptoms and signs that can differ markedly between young and old patients.

Thyroid Disease in the Elderly

363

5.1 Epidemiology In the past, hyperthyroidism has been regarded as a disorder with preferential expression in young to middle-aged individuals, especially women. It is now clear that this disorder is also common in the elderly population (Fig. 2) (59). The proportion of patients with hyperthyroidism who are over 60 years of age is estimated to be 15% to 20% (91,92). Several studies of prevalence indicate the presence of hyperthyroidism in 1% to 2% of community-residing individuals (60). In a study of the population of Whickham, England, hyperthyroidism was identified in 19 per 1000 women, a prevalance rate 10 times greater than that in men. The mean age at diagnosis was 48 years and the estimate of new cases was 2 to 3 per 1000 women per year (63). Many other studies confirm that hyperthyroidism is far more common in women than in men, with estimates of female preponderance ranging from 4: 1 to as high as 10 :1 (63,91,93). A survey of 968 ambulatory home-residing individuals over the age of 55 years in an urban, midwestern U.S. community identified suppressed serum TSH levels in 2.5%, with a prevalence of 2.7% in women compared to 1.8% in men. Based on suppressed serum TSH and unresponsiveness to TRH stimulation, the calculated prevalence of hyperthyroidism in this population over the age of 55 was 2.0% (62).

FIG. 2 Pooled prevalence of overt hyperthyroidism per 1000 patients. Means and 95% confidence limits of the pooled prevalence of overt hyperthyroidism per 1000 patients by patient age and sex categories. Closed circles represent population-based studies; open ovals represent office-based studies. (From Ref. 59.)

364

Miller and Gambert

5.2 Pathophysiology In young persons, Graves’ disease remains the most common cause of hyperthyroidism (34,94,95). With increasing age, there is a change in etiology, so that more cases are due to multinodular toxic goiter and fewer to Graves’ disease (91,96). Multinodular goiters are common in the elderly and may not be clinically apparent (5). Many clinical observations support the concept that long-standing euthyroid multinodular goiters may evolve to become toxic multinodular thyroid goiters (91). Another less common cause of hyperthyroidism in the elderly is the toxic adenoma, usually identifiable on thyroid scanning by the demonstration of a solitary hyperfunctioning nodule with suppression of activity in the remainder of the thyroid gland (97,98). Hyperthyroidism can also rarely occur in a previously euthyroid elderly person following ingestion of iodide- or iodine-containing substances (99). Most commonly, this occurs following exposure to iodinated radiocontrast agents and to amiodarone. Although up to 40% of patients taking amiodarone will have serum T4 levels above the normal range due to the drug’s effect on T4 metabolism, far fewer (5%) will develop true thyrotoxicosis (100). This form of hyperthyroidism can be of rapid onset and severe in magnitude. Because of amiodarone’s fat-solubility and long half-life, drug-induced thyrotoxicosis can be prolonged and difficult to treat (101,102). The possibility of hyperthyroidism must always be considered in the elderly person who is receiving thyroid hormone, especially if the dose is ⬎0.15 mg of l-thyroxine daily. Patients who have received such doses for many years without evidence for hyperthyroidism may insidiously develop hyperthyroid features as they age past 60 years owing to the age-associated reduction in rate of thyroid hormone metabolism (103). Rare causes of hyperthyroidism in the elderly include TSH-producing pituitary tumors (104,105). These can be recognized by the finding of nonsuppressed levels of serum TSH in the presence of increased amounts of circulating thyroid hormone. An additional uncommon cause of hyperthyroidism is overproduction of thyroid hormone by widespread metastatic follicular carcinoma. Transient hyperthyroidism may occur in patients with silent or subacute thyroiditis as a result of increased discharge of thyroid hormone into the circulation during the inflammatory phase of the illness (106). In a similar fashion, radiation injury to the thyroid can be accompanied by a transient increase in circulating thyroid hormone levels with associated symptoms. 5.3 T3 and T4 Toxicosis In a small proportion of cases of hyperthyroidism, the expected increase in serum T3 is noted, but serum T4 is either within the normal range or at the upper end

Thyroid Disease in the Elderly

365

of normal. This circumstance has been designated as T3 toxicosis and can occur with any type of hyperthyroidism; however, it commonly occurs in older patients with toxic multinodular goiter or solitary toxic adenoma (98). The diagnosis will not be missed if serum T3 is measured in patients with clinically suspected hyperthyroidism or who have suppressed levels of serum TSH. T4 toxicosis, or an isolated increase in serum T4 without an elevation in serum T3, is more commonly noted in the sick elderly patient with hyperthyroidism owing to the higher prevalence of medical conditions and nutritional inadequacies that interfere with T4to-T3 conversion. 5.4 Diagnosis As with other disorders occurring in the elderly person, the clinical presentation of hyperthyroidism often differs from the classical description of the disease in younger individuals (91,92,96,107–109) (Table 3). The presenting feature may be a progressive functional decline including muscle weakness, fatigue, changes in mental status, loss of appetite, weight loss, cardiac arrhythmia, and/or congestive heart failure. A symptom complex peculiar to the geriatric hyperthyroid patient is ‘‘apathetic hyperthyroidism,’’ in which the patient lacks the hyperactivity, irritability, and restlessness common to the young patient with thyrotoxicosis and presents instead with weakness, lethargy, listlessness, depression, and the appearance of a chronic, wasting illness. Often, the initial impression is depression, malignancy, or cardiovascular disease (110,111). TABLE 3 Frequency of Symptoms and Signs of Hyperthyroidism in Elderly Versus Young

Symptom/Sign Palpitation Goiter Tremor Excessive perspiration Weight loss Eye signs Arrhythmias (atrial fibrillation and ventricular premature contraction)

Kawabe et al. (107) Young (n ⫽ 48)

Elderly (n ⫽ 45)

Davis and Davis (91) Elderly (n ⫽ 85)

100% 98% 96% 92%

60% 58% 71% 66%

63% 64% 55% 38%

73% 71% 4.6%

85% 28% 16.4%

69% 57% 62%

Source: Reproduced from Ref. 108.

366

Miller and Gambert

Clinically detectable thyroid enlargement, present in almost all younger patients, is absent in as many as 37% of elderly patients (91). Infiltrative ophthalmopathy with severe proptosis and exophthalmos occurs infrequently in the elderly. Thus, none of the elements of the classic triad of Graves’ disease (clinical hyperthyroidism, diffuse goiter, and infiltrative ophthalmopathy) may be recognizable in the elderly patient, in whom the diagnosis may be suspected only on the basis of laboratory studies (91,107,108). Symptoms less commonly present in the elderly include nervousness, increased sweating, tremor, increased appetite, and increased frequency of bowel movements. Symptoms more common in the elderly include marked weight loss, present in over 80% of patients, poor appetite, worsening angina, edema, agitation, and confusion. There may be correction of previously existing constipation. Similarly, physical findings differ in elderly patients. In addition to the absence of a palpable goiter and eye signs of exophthalmos, the pulse rate tends to be slower, and hyperreflexia may not be present. Lid lag and lid retraction are frequently seen (91,107–111). The spectrum of symptoms and findings due to thyroid hormone excess is broad and can involve almost all body systems. Cardiac manifestations are particularly important in the elderly person who may have coexisting heart disease. An increased heart rate with a related increase in myocardial oxygen demand, stroke volume, cardiac output, and shortened left ventricular ejection time underlie the clinical consequences of palpitations, increased risk of atrial fibrillation—often with slow ventricular response, exacerbation of angina in patients with preexisting coronary artery disease, and precipitation of congestive heart failure that responds less readily to digoxin treatment (79,112). Gastrointestinal consequences of hyperthyroidism in the elderly include weight loss, poor appetite, and occasionally abdominal pain, nausea, and vomiting (91,92). Diarrhea and increased frequency of bowel movements resulting from thyroid hormone action on intestinal motility can occur, but these symptoms are often absent in the elderly, in whom constipation is as likely to be present. Hepatic actions of thyroid hormone can lead to alterations in liver enzymes, including elevation of alkaline phosphatase and gamma glutamyl transpeptidase levels, which return to normal following restoration of thyroid function to euthyroid values. Weakness, especially of the proximal muscles, is a major feature of hyperthyroidism in the elderly and is often accompanied by muscle wasting (91,111). As a consequence, disorders of gait, postural instability and falls can take place. Tremor occurs in over 70% of elderly thyrotoxic patients, but this sign must be distinguished from other causes of tremor that are common in the elderly and are usually more coarse in nature or primarily resting tremors (107,108). A rapid relaxation phase of the deep tendon reflexes is common in young patients but is often difficult to assess in the older patient. Central nervous system manifestations

Thyroid Disease in the Elderly

367

may be prominent in the elderly patient and include confusion, depression, forgetfulness, agitation/anxiety, and a shortened concentration span (96,113). These cognitive impairments may point to a diagnosis of dementia with failure to consider the presence of hyperthyroidism. Other clinical manifestations of hyperthyroidism in the elderly may include glucose intolerance; occasionally, latent diabetes mellitus may be unmasked. Mild elevations of serum calcium can occur, and hyperthyroidism should be ruled out as a secondary cause of osteoporosis in persons with decreased bone mass. Because of the altered clinical presentation of hyperthyroidism in the elderly, suspicion must always be high and the laboratory should be used for any patient with possible symptoms. Many have advocated screening tests for thyroid status in all geriatric patients undergoing initial clinical evaluation (74,114). Serum free T4 or free T4 index and measurement of serum TSH by ultrasensitive methods are the preferable tests for diagnosing thyroid dysfunction (26,115). The findings of a normal or low serum free T4 with suppressed serum TSH raises the possibility of T3 toxicosis and calls for measurement of serum T3 (96,116,117). Demonstration of anti-TSH receptor antibodies can be helpful in making a diagnosis of Graves’ disease, but this is not a routine test (34,94). Thyroid scanning with 99m Tc and measurement of the 24-h 131 I uptake can be useful in distinguishing Graves’ disease from toxic multinodular goiter (54,56,118). Scanning may also demonstrate the presence of a small, diffusely active goiter that could not be detected on physical examination. Very low 131 I uptake in a patient with elevated circulating thyroid hormone levels suggests exogenous thyroid hormone ingestion (factitious or iatrogenic hyperthyroidism), the hyperthyroid phase of painless or subacute thyroiditis, or iodine-induced hyperthyroidism. 5.5 Treatment The first step in the management of the elderly patient with hyperthyroidism is to determine the underlying etiology and exclude the possibility of one of the transient forms, which may require therapy directed toward the primary process (hormone ingestion, iodine exposure, subacute thyroiditis). While the vast majority of patients with either Graves’ disease or multinodular toxic goiter can be treated using antithyroid drugs, radioactive iodine, or surgery, radioactive iodine ablation of the thyroid is the preferred treatment for both in the elderly (119,120). In the older patient with suspected hyperthyroidism who is still undergoing investigation, a useful initial step in treatment is the administration of beta-adrenergic blocking agents such as long-acting propranolol, metoprolol, nadolol, or atenolol. In patients who have palpitations, tachycardia, angina, or agitation, these symptoms of thyrotoxicosis can be quickly controlled with use of the beta blockers, though caution is advised in elderly persons with congestive heart failure,

368

Miller and Gambert

chronic obstructive pulmonary disease (COPD), or diabetes being treated with insulin. Once a diagnosis of Graves’ disease or toxic nodular goiter is established, treatment should be started with one of the antithyroid drugs, propylthiouracil or methimazole (121). These agents impair biosynthesis of thyroid hormone; this will lead to depletion of intrathyroidal hormone stores and ultimately to decreased hormone secretion. A decline in serum T4 concentration is usually seen within 2 to 4 weeks after initiation of antithyroid drug therapy, and the dose should be tapered once thyroid hormone levels reach the normal range in order to avoid hypothyroidism. In 1% to 5% of patients, the antithyroid drugs may cause fever, rash, and arthralgia. Drug-induced agranulocytosis may be more common in the elderly and is most likely to occur within the first 3 months of treatment, especially in those patients who receive more than 30 mg/day of methimazole (122). Some but not all experts recommend periodic monitoring of the white blood cell count and discontinuation of the drugs if there is evidence of the development of neutropenia. Long-term antithyroid drug administration can be an effective therapy in patients above the age of 60 years with Graves’ disease who, in comparison to younger persons, appear to respond more quickly and have a greater likelihood of long-lasting remission (123). In contrast, this approach is rarely successful in elderly patients with a toxic multinodular goiter. The recommended treatment in most elderly persons is ablation of the thyroid with 131 I (119,120). Once the patient has been rendered euthyroid by antithyroid drugs, these agents can be stopped for 3 to 5 days, following which 131 I is given orally. Therapy with beta blockers can be maintained and antithyroid agents can be restarted 5 days after radiotherapy and continued for 1 to 3 months until the major effect of radioiodine is achieved. Some physicians will attempt to calculate a dose that will render the patient euthyroid without subsequent development of hypothyroidism. These calculations are based on a clinical estimate of thyroid gland size, 24-h 131 I uptake, and whether the gland is diffusely overactive or contains toxic nodules. In spite of this approach, many patients will still develop permanent hypothyroidism following 131 I therapy (65). It is not unreasonable, therefore, to treat all elderly patients with a relatively large dose of 131 I to assure ablation of thyroid tissue and avoid the possibility of recurrence of hyperthyroidism. Using this approach, patients are monitored following treatment until their serum thyroid hormone levels reach the hypothyroid range; they are then put on permanent replacement therapy. Hypothyroidism may be evident as early as 4 weeks after treatment but can occur at any time. Regardless of which dosing regimen is used, by 12 months posttherapy, some 40% to 50% of patients will be hypothyroid and hypothyroidism will continue to occur thereafter at the rate of 2% to 3% per year (66). Periodic monitoring of

Thyroid Disease in the Elderly

369

thyroid status is a necessity for any patient treated with 131 I who has not yet become hypothyroid. In some circumstances, when clinical and laboratory features of hyperthyroidism are mild, there are no significant cardiac problems, and the patient is likely to be poorly compliant or unable to follow the regimen of antithyroid drugs and frequent medical visits to monitor thyroid status, it may be appropriate to treat the elderly hyperthyroid patient with 131I without antithyroid drug pretreatment. When this option is chosen, the patient is started on beta-blocker therapy before administering 131I and the beta blocker is continued until there is evidence that thyroid hormone levels have fallen into the normal range. Surgery is not recommended as a primary choice for the treatment of hyperthyroidism in the elderly. The frequent accompaniment of hyperthyroidism by other coexisting illnesses puts the patient at increased operative risk. In addition, postoperative complications of hypoparathyroidism and recurrent laryngeal nerve damage represent significant problems, especially when surgery is performed by surgeons not highly experienced in thyroidectomy (124). Surgery may be of value for the rare patient with tracheal compression secondary to a large goiter. 5.6 Atrial Fibrillation Atrial fibrillation occurs in 10% to 15% of hyperthyroid patients, most of whom are elderly, and raises several management issues regarding cardioversion and anticoagulation. In a retrospective study of 163 thyrotoxic patients with atrial fibrillation, approximately 60% had spontaneous reversion to sinus rhythm after return to a euthyroid state. Most of these reversions took place within 3 weeks of becoming euthyroid; none occurred if the patient still had atrial fibrillation after 4 months of euthyroidism; and none occurred when atrial fibrillation had been present for more than 13 months before becoming euthyroid. Thus, the patient who still has atrial fibrillation beyond 16 weeks of return to euthyroidism is a candidate for cardioversion (125). While in the hyperthyroid state, the patient with atrial fibrillation is more sensitive to the anticoagulant effect of warfarin, which causes a greater lowering of activity of coagulation factors II and VII and greater increase in prothrombin ratio and partial thromboplastin time (126). Many older individuals with hyperthyroidism who develop atrial fibrillation are at increased risk for thromboembolic events, especially those with a prior history of thromboembolism, hypertension, or congestive heart failure or who have evidence of left atrial enlargement or left ventricular dysfunction. In the absence of contraindications, anticoagulant therapy should be given with warfarin in a dose that will increase the International Normalization Ratio (INR) to 2.0 to 3.0. Warfarin should be continued until the patient is euthyroid and there has been restoration of normal sinus rhythm (79).

370

Miller and Gambert

5.7 Thyroid Storm Acute hyperthyroidism or ‘‘thyroid storm’’ can occur in the patient with either known or undiagnosed hyperthyroidism who is subjected to acute stress, such as an operative procedure, trauma, or infection or who is exposed to iodine-containing drugs. It can also occur in the elderly hyperthyroid patient treated with 131 I who did not receive adequate antithyroid medication prior to therapy (127). The features of severe hyperthyroidism can develop over several hours and include fever, tachycardia, arrhythmia, dyspnea, vomiting, diarrhea, dehydration, severe restlessness, and delerium. Acute heart failure can be precipitated. Elderly patients with cardiac disease are at especially high risk for the development of acute myocardial ischemia or congestive heart failure. Thyroid storm is a life-threatening condition and must be treated vigorously and promptly (81,128). Immediate treatment focuses on inhibition of thyroid hormone production and the inhibition of conversion of T4 to T3 in peripheral tissues. This is accomplished by administration of antithyroid drugs, especially propylthiouracil, in an initial dose of 900 to 1200 mg, followed in several hours with sodium iodide or oral Lugol’s solution. High-dose beta blockers such as propranolol and high-dose corticosteroids are also given to blunt peripheral action of thyroid hormone and to inhibit T4-to-T3 conversion. Supportive measures are provided and may include sedation, correction of fluid and electrolyte inbalances, antipyretics (not aspirin), and cooling blankets and antibiotics if infection is present (88). 5.8 Subclinical Hyperthyroidism Subclinical hyperthyroidism has long been recognized as a potential problem in persons on thyroid hormone replacement therapy, but prior to the introduction of the second- or third-generation assays for TSH, it was impossible to differentiate between a normal and a suppressed level of serum TSH. Many persons were maintained on ‘‘excessive’’ amounts of thyroid hormone without hyperthyroid symptoms or obvious clinical sequelae. However, several reports noted significant reductions in bone mineral density and shortened systolic time intervals in such patients. With the advent of newer assays for TSH, however, it became possible to identify individuals with subclinical hyperthyroidism, either on an iatrogenic basis or from mild thyroid dysfunction, usually due to long-standing multinodular goiter. By definition, these individuals have normal circulating levels of free T4 and T3 and levels of TSH below the lower limit of normal (usually 0.3 to 0.5 mU/L), implying that the circulating level of thyroid hormone is more than is required for hormonal balance. Epidemiological data suggest that this problem affects between 4% and 7% of persons aged 60 and over in the general population (129–131). Unfortunately there remains little in the literature to determine

Thyroid Disease in the Elderly

371

whether treatment is indicated in these patients. Although the Wayne score clinical index of thyrotoxicosis in elderly patients with suppressed TSH was noted to be higher than in a group of similarly aged euthyroid persons, there were few or no classic features of hyperthyroidism (132). Most agree that treatment should be initiated if there are any clearly associated symptoms such as a worsening of cardiovascular function or cardiac arrhythmias, excessive muscle wasting, anorexia, or depression. The development of atrial fibrillation has also been described in 10% of these patients, who were followed for up to 10 years (130). There is recent evidence which indicates that treatment of subclinical hyperthyroidism may have a beneficial effect on bone mineral density. Postmenopausal women with subclinical hyperthyroidism and nodular goiter who were treated with 131 I with subsequent restoration of serum TSH into the normal range demonstrated increases in bone mineral density at the spine and hip after 2 years of follow-up, while a similar group of women who were not treated showed progressive decline in bone mineral density (133). Individuals with suppression of serum TSH levels may have a variable course, with some remaining in this state and others becoming either hyperthyroid or euthyroid (130,131). Several studies of large numbers of community-residing persons over the age of 60 years with TSH levels below normal have shown that 47% to 61% had normal TSH levels on retesting within 1 year. The conversion rate to overt hyperthyroidism varies from 1.5% to 13% within 1 year (130–132). It is therefore not clear when to treat subclinical hyperthyroidism, since therapy has the potential for toxicity and expense and the problem may resolve on its own. While most agree that subclinical hyperthyroidism can have effects on the bone and heart, decisions must be made on an individual basis. Patients with underlying cardiovascular disease and significant osteopenia are strong candidates for early treatment. In any case, careful follow-up is advised, since hyperthyroidism in the elderly often presents in a nonspecific manner and may lead to a decline in functional capacity prior to or without presenting with more classic signs and symptoms.

6

NODULAR THYROID DISEASE AND NEOPLASIA

6.1 Epidemiology The development of thyroid nodules is clearly an age-related process that occurs more commonly in women than in men. Autopsy studies have demonstrated that thyroid nodules are frequently found in the elderly even when clinical examination of the neck has failed to reveal abnormality (134). Autopsy data show an increase in frequency of nodules in women and men over age 30, with a progressive increase to a frequency of 90% in women and 50% in men over age 70 years. In the Whickham study, clinically detectable nodules were found in 0.8%

372

Miller and Gambert

of men without a relationship to age. However, 5.3% of women had palpable nodules and the frequency increased from about 4% in those under age 50 years to 9.1% in those aged 75 years or more (63). The Framingham study disclosed a 4.2% overall prevalence of thyroid nodules, with 6.4% in women and 1.5% in men (135). New nodules become clinically recognizable at the rate of 0.1% per year. By means of ultrasonographic study, thyroid nodules have been found in approximately 50% of women beyond the age of 50 years (136). 6.2 Pathophysiology Patients with thyroid nodules should be questioned for a history of external radiation exposure of the head, neck and upper thorax, since it is well established that radiation to this area markedly increases the risk of developing thyroid malignancy. It was common practice from the 1930s to the early 1960s to treat facial acne, tonsillar enlargement, cervical adenitis, and thymic enlargement with external radiation. It is estimated that several million people were irradiated, many of whom are now over 60 years of age. Although a history of irradiation in a patient with nodular thyroid increases the likelihood of malignancy, it is important to note that irradiation also increases the development of benign nodules of the thyroid as well as parathyroid adenomas. Some 16% to 29% of individuals who as children received low-dose head and neck irradiation will develop palpable thyroid nodules, approximately one-third of which will be malignant. Nodules become apparent after a latency of 10 to 20 years, and the incidence of malignant nodules reaches a peak 20 to 30 years after exposure (137). Multinodular thyroid glands occur more commonly in individuals who come from areas of iodine deficiency. Often there is a history of goiter dating back to childhood or young adult years. Very large multinodular goiters, particularly those with a sizable substernal component, may compress the trachea and lead to complaints of dyspnea or wheezing. Disturbances of swallowing may also occur. These compressive symptoms are most common in older women. A large substernal goiter is often first recognized when the patient has had a chest x-ray and is noted to be associated with compression or deviation of the trachea or a superior mediastinal mass (138). 6.3 Diagnosis Thyroid nodules are most commonly asymptomatic. They may be discovered accidentally by the patient or found by the physician during the course of a physical examination. Occasionally, a thyroid nodule will be associated with acute onset of neck pain and tenderness. This circumstance may be the result of acute or subacute thyroiditis but is more likely due to hemorrhage into a preexisting nodule. The finding of a solitary palpable nodule raises the possibility of thyroid malignancy. In many patients, further evaluation will reveal the presence of mul-

Thyroid Disease in the Elderly

373

tiple nodules. Although a single nodule is more likely to harbor a malignancy than a multinodular thyroid, only approximately 5% of clinical solitary nodules will be malignant. Many histological entities can present as a thyroid nodule. The vast majority are benign, including follicular and colloid adenomas, Hashimoto’s thyroiditis, and thyroid cysts. Malignant thyroid neoplasms include papillary, follicular, medullary, and anaplastic carcinomas as well as thyroid lymphoma and metastases to the thyroid. Nonthyroid lesions may also appear to be thyroid nodules; these include lymph nodes, aneurysms, parathyroid adenomas and cysts, and thyroglossal duct cysts (139). The likelihood that a single nodule is malignant is increased if there is a history of radiation exposure, if it occurs in a man over the age of 60 years, has been observed to undergo an increase in size, is accompanied by hoarseness of the voice suggestive of impingement on the recurrent laryngeal nerve, and is stony-hard on palpation. Data derived from the 53,856 patients with thyroid cancer in the National Cancer Data Base indicate that approximately 25% of all thyroid cancers are first diagnosed in individuals above 60 years of age (Fig. 3) (140). Age is a factor in predicting the histological type of malignancy (140,141). The overall histological distribution of thyroid cancer is 79% papillary, 13% follicular, 3% Hu¨rthle cell, 3.5% medullary, and 1.7% anaplastic (140). In patients over the age of 60 years,

FIG. 3

Histological types of thyroid cancer by age. (From Ref. 140.)

374

Miller and Gambert

papillary carcinoma accounts for approximately 67% of thyroid cancers. Follicular carcinoma has a peak frequency of diagnosis in both the fourth and sixth decades of life, with a mean age of 44 years. It, along with related Hu¨rthle cell carcinoma, makes up approximately 23% of the thyroid malignancies in the over60 population. Medullary carcinoma has a peak incidence in the fifth and sixth decades and make up about 5% of thyroid cancers in the elderly (Table 4) (140,142). Anaplastic carcinoma of the thyroid is almost exclusively a disease of older persons and accounts for approximately 10% of thyroid cancers in this age group. It is invariably fatal in a short period of time from its first diagnosis, especially when it is ⬎5 cm in diameter (143). Clinically, it often arises in an area of previous thyroid disease and is recognized by its rapid growth, rock-like consistency, and local invasiveness—with recurrent laryngeal nerve involvement and tracheal compression common consequences. Lymphoma and metastatic cancers make up the remaining thyroid malignancies of the older person. Lymphoma is characterized by a rapidly enlarging painless neck mass, which may cause compressive symptoms. Initially, it may be difficult to differentiate from anaplastic carcinoma on clinical appearance alone. Hashimoto’s thyroiditis, identified by histological or antibody testing, is commonly present in patients with lymphoma (144). The major objective of evaluating an elderly patient with a thyroid nodule, especially an apparently single nodule, is to determine whether the nodule is benign or malignant. A number of diagnostic modalities are available that will then point the way to appropriate treatment. Blood tests of thyroid function will usually give normal results with the exception of the patient with a hyperfunctioning adenoma or toxic multinodular goiter. In some patients with nodular disease due to Hashimoto’s thyroiditis, serum TSH may be increased. Serum thyroglobulin is often elevated in patients with thyroid cancer but cannot reliably differentiate malignancy from benign ade-

TABLE 4 Occurence and Survivorship of Thyroid Malignancy in the Older Patient % of Patients with Type Cancer Type Papillary/mixed Follicular Medullary Anaplastic Lymphoma

⬎Age 40

⬎Age 60

10 Year Survival, Age ⬎ 60, %

79 13 3 2 3

60–67 20–25 5 6 5

⬍65 ⬍57 ⬍63 0 ⱕ100

Thyroid Disease in the Elderly

375

noma or thyroiditis (58). Its major usefulness is in the early recognition of recurrence or metastasis in patients with papillary or follicular carcinoma who had previously undergone total thyroidectomy. Elevation of serum calcitonin concentration is highly supportive of a diagnosis of medullary carcinoma but is not costeffective as a routine test unless there is a family history of multiple endocrine neoplasia (145). At the present time, fine-needle aspiration (FNA) of the thyroid to obtain tissue for cytological or histological examination appears to be the most reliable and accurate method of separating benign from malignant disease (146–148). FNA is indicated in any patient with a solitary nodule and when there is suspicion of thyroid malignancy based on clinical assessment, ultrasound findings, or thyroid scan. In skilled hands, the procedure is safe, inexpensive, and capable of determining presence or absence of malignancy with 95% accuracy. The reliability of FNA can be further increased if it is done in conjunction with real-time sonographic guidance. The cytopathological findings from FNA are assigned to four categories: positive for malignancy, suspicious for malignancy, negative for malignancy, and nondiagnostic. In the case of a nondiagnostic aspirate, a repeat FNA is recommended. If FNA reveals malignant cells, surgery is recommended with little need for further study. The combination of suspicious cytology by FNA and cold appearance on scanning indicates the need for surgical excision. Demonstration of benign cytology in either a solid or cystic nodule indicates that the patient can be managed subsequently by observation. The patient with clinical or FNA features suggestive of lymphoma should have a large-needle or surgical biopsy done to establish the diagnosis (149). Isotopic scanning is no longer considered as an initial diagnostic test because it is not cost-effective. The major role for isotope imaging is in the evaluation of the patient with a thyroid nodule who has had a nondiagnostic result from FNA. Malignant tissue is rarely able to take up iodine, so that identification of a nodule as ‘‘hot’’ by 123I or technetium scanning makes malignancy in the nodule less likely. In addition, scanning may reveal that an apparent single nodule is, in fact, part of a multinodular thyroid, again decreasing the risk of malignancy. The finding of a nonfunctioning or ‘‘cold’’ nodule does not establish a diagnosis of malignancy, since 95% of thyroid nodules are cold, with the frequency of malignancy in cold nodules being 5% (150). Nodules identified as being ‘‘hot’’ and with associated normal thyroid hormone production and no compressive symptoms warrant only observation, with examination at intervals of 6 to 12 months. If evidence of hyperthyroidism is subsequently found, appropriate treatment for this condition should be initiated. High-resolution ultrasonography can detect lesions as small as 2 mm and can permit classification of a nodule as solid, cystic, or mixed solid-cystic (151). The technique will often demonstrate multinodularity in a gland with a single palpable nodule. The value of ultrasonography in establishing a diagnosis of ma-

376

Miller and Gambert

lignancy is limited, since there is considerable overlap in the ultrasound characteristics of benign and malignant nodules. The procedure may be useful in detecting recurrent or residual thyroid cancer and in screening individuals who have had a history of irradiation exposure. It also may be of value in the patient suspected of having lymphoma of the thyroid, since this malignancy often produces a characteristic asymmetrical pseudocystic pattern (149). Computed tomography and magnetic resonance imaging can provide detailed information on thyroid anatomy. These procedures are expensive and appear to add little to the initial clinical assessment of malignancy (57). However, they may be useful in evaluating the extent of disease in patients who are found to have anaplastic carcinoma or lymphoma of the thyroid. They can also provide information about compression of structures in the neck as well as on the size and substernal extent of larger nodules and goiters. 6.4 Treatment In the past, thyroid hormone has been used to suppress TSH on the assumption that benign lesions were more likely to be TSH-dependent and therefore likely to decrease in size. The procedure involves giving l-thyroxine in a dose sufficient to suppress serum TSH and monitoring the size of the thyroid nodule for a period of 3 to 6 months. Because of the subjective nature of assessment of thyroid nodular size and the recent demonstration that suppressive therapy had no significant effect on nodule size during a 6-month, well-controlled, double-blind trial of lthyroxine, there is less enthusiasm for justification for this therapy (152). In addition, the administration of suppressive doses of l-thyroxine to elderly patients carries substantial risk for precipitation or aggravation of ischemic heart disease and for acceleration of bone loss. Detailed discussion of the management of thyroid cancer is beyond the scope of this chapter and is covered elsewhere in this book. Basic principles do not differ significantly between elderly and young patients other than comorbidities that may affect the ability of the older person to undergo surgery. Surgery for thyroid cancer should be performed only by a surgeon experienced in the procedure. If a diagnosis of papillary or follicular carcinoma has been confirmed prior to surgery, near total thyroidectomy should be carried out because of the high frequency of multicentricity of malignancy and the need to remove functional thyroid tissue in order to monitor the patient with total-body radioiodine scanning (153). Thyroid remnants detected postoperatively by scanning should be ablated with 131 I. At 6 months, and subsequently at yearly intervals, scanning should be repeated along with measurement of serum thyroglobulin to determine if residual functional tissue is present. If such is found, large ablative doses of 131 I are administered. This approach reduces the recurrence rate of both papillary and follicular carcinoma and prolongs survival. After surgery and following ra-

Thyroid Disease in the Elderly

377

dioiodine administration, patients are maintained on suppressive doses of l-thyroxine with the desired objective of reducing the serum TSH level to below normal as measured by third-generation TSH assays. The older patient will need to be followed carefully and the dose of l-thyroxine reduced if cardiac symptoms develop. Acceleration of bone loss, particularly in the postmenopausal woman, may also be a limiting factor in maintaining long-term TSH suppression. For medullary carcinoma, the operative procedure of choice is total thyroidectomy, since the disease is often multicentric. The majority of medullary carcinomas do not respond to 131 I therapy, so that patients with inoperable residual or recurrent disease are treated palliatively with external irradiation. The patient with thyroid lymphoma should have clinical staging carried out by means of CT or MRI imaging. The survival rate can approach 100% in response to aggressive therapy with external irradiation in combination with CHOP chemotherapy (149). 6.5 Outcome Age at time of diagnosis is an important factor in predicting cancer aggressiveness and mortality from differentiated thyroid cancer. Individuals who are diagnosed after the age of 50 years have a higher rate of recurrence and death (Table 4) (154). The 10-year survival for patients with papillary carcinoma is estimated to be 97% in those under the age of 45 at the time of diagnosis and ⬍65% in those older than age 60 at the time of diagnosis. Similarly, 10-year survival for patients with follicular carcinoma is estimated to be 98% in those under age 45 years and less than 57% in those older than age 60 years (140,141,154). In patients with follicular carcinoma who are over age 45 years at time of diagnosis, and especially over 60 years, there is a greater risk of recurrence and death. The 10-year survival rate for patients with medullary carcinoma is 84% in patients under 45 years of age. Rate of survival declines with increasing age at time of initial diagnosis, with rates substantially lower for persons over the age of 60 years. In patients in their seventh decade of life, approximately two-thirds will have persistent disease after surgery (155). Efficacy of surgery can be monitored postoperatively by measurement of blood calcitonin concentration, both in the basal state and after stimulation (139). Blood levels of carcinoembryonic antigen may also be elevated in patients with residual or recurrent medullary carcinoma. The outcome of anaplastic carcinoma of the thyroid remains unsatisfactory, with rare survivorship more than 1 year after diagnosis (156). Palliative relief of compression symptoms can sometimes be achieved by surgery followed by highdose (40 to 60 Gy) external irradiation (157). Chemotherapy with doxorubicin and/or cisplatin may be beneficial in combination with surgery and external irradiation (143,158).

378

Miller and Gambert

6.6 Compressive Goiter Subtotal thyroidectomy has traditionally been the recommended therapy for compressive goiter (159). However, in elderly patients, particularly those who may be at operative risk, thyroid ablation with large doses of 131 I (i.e., 25 to 125 mCi) can produce significant shrinkage of the thyroid with accompanying relief of compressive symptoms such as stridor, dyspnea, and dysphagia (138,160). Replacement doses of l-thyroxine should be given following either surgery or radioiodine treatment in order to maintain serum TSH within the normal range and prevent regrowth of thyroid tissue. REFERENCES 1. Mariotti S, Franceschi C, Cossarizza A, Pinchera A. The aging thyroid. Endocr Rev 1995; 16:686–715. 2. Mochizuki Y, Mowafy R, Pasternak B. Weights of human thyroids in New York City. Health Physics 1963; 9:1299–1301. 3. Hegedus L, Perrild H, Poulsen LR, Andersen JR, Holm B, Schnohr P, Jensen G, Hansen JN. The determination of thyroid volume by ultrasound and its relationship to body weight, age and sex in normal subjects. J Clin Endocrinol Metab 1983; 56:260–263. 4. Blumenthal HT, Perlstein IB. The aging thyroid. I. A description of lesions and an analysis of their age and sex distribution. J Am Geriatr Soc 1987; 35:843–854. 5. Denham MJ, Wills EJ. A clinco-pathological survey of thyroid glands in old age. Gerontology 1980; 26:160–166. 6. Tzankoff SP, Norris AH. Effect of muscle mass decrease on age-related BMR changes. J Appl Physiol 1977; 43:1001–1004. 7. Gambert SR, Ingbar SH, Hagen TC. Interaction of age and thyroid hormone status on Na⫹,K⫹-ATPase in rat renal cortex and liver. Endocrinology 1981; 108:27– 30. 8. Gambert SR. Effect of age on basal and 3,5,3′ triiodothyronine (T3) stimulated human mononuclear cell sodium-potassium adenosine-triphosphatase (Na⫹,K⫹-ATPase) activity. Horm Metab Res 1986; 18:649–652. 9. Gregerman RI, Gaffney GW, Shock NW. Thyroxine turnover in euthyroid man with special reference to change with age. J Clin Invest 1962; 41:2065–2074. 10. Chopra IJ, Solomon DH, Chopra U, Wu SY, Fisher DA, Nakamura Y. Pathways of metabolism of thyroid hormones. Recent Prog Horm Res 1978; 34:521–567. 11. Hansen JM, Skovsted L, Siersboek-Nielsen K. Age dependent changes in iodine metabolism and thyroid function. Acta Endocrinol (Copenh) 1975; 79:60–65. 12. Barreca T, Franceschini R, Messina U, Bottaro C, Rolandi E. 24-hour thyroidstimulating hormone secretory pattern in elderly men. Gerontology 1985; 31:119– 123. 13. Ryan M, Kovaks K, Ezrin C. Thyrotrophs in old age: an immunologic study of human pituitary glands. Endokrinologie 1979; 73:191–198. 14. Van Coevorden A, Laurent E, Decoster C, Kerkhofs M, Neve P, van Cauter E,

Thyroid Disease in the Elderly

15.

16. 17. 18.

19.

20. 21. 22.

23. 24.

25.

26.

27. 28.

29.

30.

379

Mockel J. Decreased basal and stimulated thyrotropin secretion in healthy elderly men. J Clin Endocrinol Metab 1989; 69:177–185. Cuttelod S, Lemarchand-Beraud T, Magnenat P, Perret C, Poli S, Vannotti A. Effect of age and role of kidneys and liver on thyrotropin turnover in man. Metabolism 1974; 23:101–113. Snyder PJ, Utiger RD. Response to thyrotropin releasing hormone (TRH) in normal man. J Clin Endocrinol Metab 1972; 34:380–385. Utiger RD. Thyrotropin-releasing hormone and thyrotropin secretion. J Lab Clin Med 1987; 109:327–335. Harman SM, Whemann RE, Blackman MR. Pituitary-thyroid hormone economy in healthy aging men: basal indices of thyroid function and thyrotropin responses to constant infusion of thyrotropin releasing hormone. J Clin Endocrinol Metab 1984; 58:320–326. Targum SD, Marshall LE, Magac-Harris K, Martin D. TRH tests in a healthy elderly population: demonstration of gender differences. J Am Geriatr Soc 1989; 37: 533–536. Hay ID, Klee GG. Thyroid dysfunction. Endocr Metab Clin North Am 1988; 17: 473–509. Snyder PJ, Utiger RD. Thyrotropin response to thyrotropin releasing hormone in normal females over forty. J Clin Endocrinol Metab 1972; 34:1096–1098. Hermann J, Heinen E, Kroll HJ, Rudorff KH, Kruskemper HL. Thyroid function and thyroid hormone metabolism in elderly people: low-T3 syndrome in old age? Klin Wochenschr 1981; 59:315–323. Einhorm J. Studies on the effect of thyrotropic hormone on thyroid function in man. Acta Radiol 1958; 160(suppl):107–110. Franklyn JA, Black EG, Betteridge J, Sheppard MC. Comparison of second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy, and those with nonthyroidal illness. J Clin Endocrinol Metab 1994; 78:1368–1371. Olsen T, Laurberg P, Weeke J. Low serum triiodothyronine and high serum reverse triiodothyronine in old age: an effect of disease not age. J Clin Endocrinol Metab 1978; 47:1111–1115. Klee GG, Hay ID. Assessment of sensitive thyrotropin assays for an expanded role in thyroid function testing: proposed criteria for analytic performance and clinical utility. J Clin Endocrinol Metab 1987; 64:461–471. Kabadi UM, Rosman PM. Thyroid hormone indices in adult healthy subjects: no influence of aging. J Am Geriatr Soc 1988; 36:312–316. Nishikawa M, Inada M, Naito K, Ishii H, Tanaka K, Mashio Y, Imura H. Agerelated changes of serum 3, 3′-diiodothyronine, 3′-5′-diiodothyronine, and 3,5diiodothyronine concentrations in man. J Clin Endocrinol Metab 1981; 52:517– 552. Burrow AW, Shakespear RA, Hesch RD, Cooper E, Aickin CM, Burke CW. Thyroid hormones in the elderly sick: ‘‘T4 euthyroidism.’’ Br Med J 1975; 4:437– 439. Hesch RD, Gatz J, Juppner H, Stubbe P. TBG dependency of age-related variations of thyroxine and triiodothyronine. Horm Metab Res 1977; 9:141–146.

380

Miller and Gambert

31. Engler D, Burger AG. The deiodination of the iodothyronines and of their derivatives in man. Endocr Rev 1984; 5:151–184. 32. Chopra IJ. Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab 1997; 82:329–334. 33. Mariotti S, Barbesino G, Caturegli P, Bartalena L, Sansoni P, Fagnoni F, Monti D, Fagiolo U, Franceschi C, Pinchera A. Complex alteration of thyroid function in healthy centenarians. J Clin Endocrinol Metab 1993; 77:1130–1134. 34. Zakarija M, McKenzie JM. The spectrum and significance of autoantibodies reacting with the thyrotropin receptor. Endocr Metab Clin North Am 1987; 16:343–363. 35. Dussault JH, Rousseau F. Immunologically mediated hypothyroidism. Endocr Metab Clin North Am 1987; 16:417–429. 36. Robuschi G, Safran M, Braverman LE, Gnudi A, Roti E. Hypothyroidism in the elderly. Endocr Rev 1987; 8:142–153. 37. Blumenthal HT, Perlstein IB. The aging thyroid: II. An immunocytochemical analysis of the age-associated lesions. J Am Geriatr Soc 1987; 35:855–863. 38. Spaulding SW. Age and the thyroid. Endocr Metab Clin North Am 1987; 16:1013– 1025. 39. Kaptein EM. Thyroid hormone metabolism in illness. In: Hennemann G, ed. Thyroid Hormone Metabolism. New York: Marcel Dekker, 1986, pp 293–333. 40. Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995; 333:1688– 1694. 41. Gavin LA. The diagnostic dilemmas of hyperthyroxinemia and hypothyroxinemia. Adv Intern Med 1988; 33:185–203. 42. Tibaldi JM, Surks MI: Effects of nonthyroidal illness on thyroid function. Med Clin North Am 1985; 69:899–911. 43. Simmons RJ, Simon JM, Demers LM, Santen RJ. Thyroid dysfunction in elderly hospitalized patients: effect of age and severity of illness. Arch Intern Med 1990; 150:1249– 44. De Groot LJ. Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 1999; 84:151–164. 45. Surks MI, Hupart KH, Pan C, Shapiro LE. Normal free thyroxine in critical nonthyroidal illnesses measured by ultrafiltration of undiluted serum and equilibrium dialysis. J Clin Endocrinol Metab 1988; 67:1031–1039. 46. Chopra IJ, Huang T-S, Beredo A, Solomon DH, Chua Teco GN. Serum thyroid hormone binding inhibitor in nonthyroidal illnesses. Metabolism 1986; 35:152– 159. 47. Slag MF, Morley JE, Elson MK, Crowson TW, Nutall FQ, Schafer RB. Hypothyroxinemia in critically ill patients as a predictor of high mortality. JAMA 1981; 245:43–45. 48. Bartalena L, Brogioni S, Grasso L, Velluzzi F, Martino E. Relationship of the increased serum interleukin-6 concentration to changes of thyroid function in nonthyroidal illness. J Endocrinol Invest 1994; 17:269–274. 49. Rogy MA, Coyle SM, Oldenburg HSA, Rock CS, Barie PS, Vanzee KJ, Smith CG, Moldawer LL, Lowry SF. Persistently elevated soluble tumor necrosis factor receptor and interleukin-receptor antagonist levels in critically ill patients. J Am Coll Surg 1994; 178:132–138.

Thyroid Disease in the Elderly

381

50. Pang XP, Hershman JH, Mirell CJ, Pekary AE. Impairment of hypothalamic-pituitary-thyroid function in rats treated with human recombinant tumor necrosis factorα (cachectin). Endocrinology 1989; 125:76–84. 51. Hamblin PS, Dyer SA, Mohr VS, Le Grand BA, Lim CF, Turpen DV, Topliss DJ, Stockigt JR. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness. J Clin Endocrinol Metab 1986; 62:717–722. 52. Borst CG, Eil C, Burman KD: Euthyroid hyperthyroxinemia. Ann Intern Med 1983; 98:366–378. 53. Ruiz M, Rejatanavin R, Young RA, Taylor C, Brown R, Braverman LE, Ingbar SH. Familial dysalbuminemic hyperthyroxinemia: a syndrome that can be confused with thyrotoxicosis. N Engl J Med 1982; 306:635–639. 54. Khafagi FA, MacFarlane DJ, Shapiro B, Gross MD. Nuclear medicine. In: Moore WT, Eastman RC, eds. Diagnostic Endocrinology, 2nd ed. St. Louis: Mosby–Year Book, 1996; pp 451–492. 55. Hansen JM, Skovsted L, Siersboek-Nielsen K. Age dependent changes in iodine metabolism and thyroid function. Acta Endocrinol (Copenh) 1975; 79:60–65. 56. Sarkar SD, Becker DV. Thyroid uptake and imaging. In: Becker KL, ed. Principles and Practice of Endocrinology and Metabolism. Philadelphia: Lippincott, 1990, pp 284–289. 57. Blum M. Thyroid sonography, computed tomography, and magnetic resonance imaging. In:Becker KL, ed. Principles and Practice of Endocrinology and Metabolism. Philadelphia: Lippincott, 1990, pp 289–293. 58. Spencer CA, Takeuchi M, Kazarosyan M. Current status and performance goals for thyroglobulin assays. Clin Chem 1996; 42:164–173. 59. Helfand M, Redfern CC. Screening for thyroid disease: an update. Ann Intern Med 1998; 129:144–158. 60. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160:526–534. 61. Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P. The aging thyroid: thyroid deficiency in the Framingham study. Arch Intern Med 1985; 145: 1386–1388. 62. Bagchi N, Brown TR, Parish JD. Thyroid dysfunction in adults over age 55 years: a study in an urban US community. Arch Intern Med 1990; 150:785–787. 63. Tunbridge WMG, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Grimley Evans J, Young E, Bird T, Smith PA. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977; 7:481–493. 64. Hurley JR. Thyroid disease in the elderly. Med Clin North Am 1983; 67:497–516. 65. Sridama V, McCormick M, Kaplan EL, Fauchet R, DeGroot LJ. Long-term followup study of compensated low-dose 131 I therapy for Graves’ disease. N Engl J Med 1984; 311:426–432. 66. Holm LE. Changing annual incidence of hypothyrodism after iodine-131 therapy for hyperthyroidism, 1951–1975. J Nucl Med 1982; 23:108–112. 67. Max MH, Scherm M, Bland KI. Early and late complication after thyroid operations. South Med J 1983; 76:977–980. 68. Hirota Y, Tamai H, Hayashi Y, et al. Thyroid function and history in forty-five

382

69. 70. 71. 72. 73. 74. 75. 76.

77.

78. 79. 80. 81. 82. 83. 84.

85.

86. 87.

88.

Miller and Gambert patients with hyperthyroid Graves’ disease in clinical remission more than 10 years after thionamide drug treatment. J Clin Endocrinol Metab 1986; 62:165–169. Roti E, Vagenakis AG. Effect of excess iodide: clinical aspects. In: Braverman LE, Utiger RD, eds. The Thyroid, 6th ed. Philadelphia: Lippincott, 1991, pp 390–402. Doucet J, Menard JF, Bercoff E. Does age play a role in clinical presentations of hypothyroidism. J Am Geriatr Soc 1994; 42:984–986. Rai GS, Gluck T, Luttrell S. Clinical presentation of hypothyroidism in older persons. J Am Geriatr Soc 1995; 43:592–593. Tachman ML, Guthrie GP. Hypothyroidism: diversity of presentation. Endocr Rev 1984; 5:456–465. Bastenie PA, Bonnyns M, Vanhaelst L. Natural history of primary myxedema. Am J Med 1985; 79:91–100. Helfand M, Crapo LM. Screening for thyroid disease. Ann Intern Med 1990; 112: 840–849. Rosenbaum RL, Barzel US. Levothyroxine replacement dose for primary hypothyroidism decreases with age. Ann Intern Med 1982; 96:53–55. Davis FB, LaMantia RS, Spaulding SW, Wehman RE, Davis PJ. Estimation of a physiologic replacement dose of levothyroxine in elderly patients with hypothyroidism. Arch Intern Med 1984; 144:1752–1754. Kabadi UM. Optimal daily levothyroxine dose in primary hypothyroidism. Its relation to pretreatment thyroid hormone indexes. Arch Intern Med 1989; 149:2209– 2212. Levine HD. Compromise therapy in the patient with angina pectoris and hypothyroidism. Am J Med 1980; 69:411–418. Aronow WS. The heart and thyroid disease. Clin Geriatr Med 1995; 11:219–229. Zellman HE. Unusual aspects of myxoedema. Geriatrics 1968; 23:140–148. Gavin LA. Thyroid crises. Med Clin North Am 1991; 75:179–193. Jordan RM. Myxedema coma. Pathophysiology, therapy, and factors affecting prognosis. Med Clin North Am 1995; 79:185–194. Yamamoto T, Fukuyama J, Fujiyoshi A. Factors associated with mortality of myxedema coma: report of eight cases and literature survey. Thyroid 1999; 9:1167–1174. Hak AE, Pols HAP, Visser TJ, Drexhage HA, Hofman A, Witteman JCM. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med 2000; 132:270–278. Sawin CT, Bigos ST, Land S, Bacharach P. The aging thyroid: relationship between elevated serum thyrotropin level and thyroid antibodies in elderly patients. Am J Med 1985; 79:591–595. Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly. Microsomal antibodies as discriminant for therapy. JAMA 1987; 258:209–213. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. l-Thyroxine therapy in subclinical hypothyroidism: a double blind placebo-controlled trial. Ann Intern Med 1984; 101:18–24. Jaeschke R, Guyatt G, Herstein H, Patterson C, Molloy W, Cook D, Harper S, Griffith L, Carbott R. Does treatment with l-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism. J Gen Intern Med 1996; 11:744–749.

Thyroid Disease in the Elderly

383

89. Lindeman RD, Schade DS, LaRue A, Romero LJ, Liang HC, Baumgartner RN, Koehler KM, Garry PJ. Subclinical hypothyrodisim in a biethnic, urban community. J Am Geriatr Soc 1999; 47:703–709. 90. Bindels AJ, Westendorp RG, Frolich M, Seidell JC, Blokstra A, Smelt AH. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding? Clin Endocrinol (Oxf) 1999; 50:217–220. 91. Davis PJ, Davis FB. Hyperthyroidism in patients over the age of 60 years: clinical features in 85 patients. Medicine 1974; 53:161–182. 92. Ronnov-Jessen V, Kirkegaard C. Hyperthyroidism: a disease of old age? Br Med J 1973; 1:41–43. 93. Furszyfer J, Kurland LT, McConahey WM, Woolner LB, Elvebock LR. Epidemiologic aspects of Hashimoto’s thyroiditis and Graves’ disease in Rochester, Minnesota (1935–1967), with special reference to temporal trends. Metabolism 1972; 21: 197–204. 94. Massart C, Hody B, Mouchel L, Eden G, Nicol M. Assay for thyrotropin-receptor binding and thyroid-stimulating antibodies in sera from patients with Graves’ disease. Clin Chem 1986; 32:1332–1335. 95. Rees-Smith B, McLachlan SM, Furmaniak J. Autoantibodies to the thyrotropin receptor. Endocr Rev 1988; 9:106–121. 96. Martin FIR, Deam DR. Hyperthyroidism in elderly hospitalised patients: clinical features and treatment outcomes. Med J Aust 1996; 164:200–203. 97. Ferriman D, Hennebry TM, Tassopoulos CN. True thyroid adenoma. Q J Med 1972; 41:127–139. 98. Marsden P, Facer P, Acosta M, McKerron CG. Serum triidothyronine in solitary autonomous nodules of the thyroid. Clin Endocrinol (Oxf) 1975; 4:327–330. 99. Fradkin JE, Wolff J. Iodine induced thyrotoxicosis. Medicine 1983; 62:1–20. 100. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997; 126:63–73. 101. Bartalana L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996; 81:2930–2933. 102. Dickstein G, Shechner C, Adawi F, Kaplan J, Baron E, Ish-Shalom S. Lithium treatment in amiodarone-induced thyrotoxicosis. Am J Med 1997; 102:454–458. 103. Banovac K, Papic M, Bilsker MS, Zakarija M, McKenzie JM. Evidence of hyperthyroidism in apparently euthyroid patients treated with levothyroxine. Arch Intern Med 1989; 149:809–812. 104. Smallridge RC. Thyrotropin-secreting pituitary tumors. Endocrinol Metab Clin North Am 1987; 16:765–792. 105. Beck-Peccoz P, Mariotti S, Guillausseau PJ, Medri G, Piscitelli G, Bertoli A, Barbarino A, Rondina M, Chanson P, Pinchera A. Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with the somatostatin analog SMS 201995. J Clin Endocrinol Metab 1989; 68:208–214. 106. Hay ID. Thyroiditis: a clinical update. Mayo Clin Proc 1985; 60:836–843. 107. Kawabe T, Komiya I, Endo T, Koizumi Y, Yamada T. Hyperthyroidism in the elderly. J Am Geriatr Soc 1979; 27:152–155.

384

Miller and Gambert

108. Griffin MA, Solomon DH. Hyperthyroidism in the elderly. J Am Geriatr Soc 1986; 34:887–892. 109. Trivalle C, Doucet J, Chassagne P, Landrin I, Kadri N, Menard J-F, Bercoff E. Differences in the signs and symptoms of hyperthyroidism in older and younger patients. J Am Geriatr Soc 1996; 44:50–53. 110. Thomas FB, Mazzaferri EL, Skillman TG. Apathetic thyrotoxicosis: distinctive clinical and laboratory entity. Ann Intern Med 1970; 72:679–685. 111. Tibaldi JM, Barzel US, Alben J, Surks M. Thyrotoxicosis in the very old. Am J Med 1986; 81:619–622. 112. Ladenson PW. Recognition and management of cardiovascular disease related to thyroid dysfunction. Am J Med 1990; 88:638–641. 113. Salzman C, Shader RI. Depression in the elderly: I. Relationship between depression, psychologic defense mechanisms and physical illness. J Am Geriatr Soc 1978; 26:253–260. 114. Livingston EH, Hershman JM, Sawin CT, Yoshikawa TT. Prevalence of thyroid disease and abnormal thyroid tests in older hospitalized and ambulatory persons. J Am Geriatr Soc 1987; 35:109–114. 115. Bayer MF, Macoviak JA, McDougall IR. Diagnostic performance of sensitive measurements of serum thyrotropin during severe nonthyroidal illness: their role in the diagnosis of hyperthyroidism. Clin Chem 1987; 33:2178–2184. 116. Kaptein EM, MacIntyre SS, Weiner JM, Spencer CA, Nicoloff JT. Free thyroxine estimates in nonthyroidal illness: comparison of eight methods. J Clin Endocrinol Metab 1981; 52:1073–1077. 117. Spencer CA. Clinical evaluation of free T4 techniques. J Endocrinol Invest 1986; 9(suppl 4):57–66. 118. Robertson JS, Nolan NG, Wahner HW, McConahey WM. Thyroid radioiodine uptakes and scan in euthyroid patients. Mayo Clinic Proc 1975; 50:79–84. 119. Solomon B, Glinoer D, Lagasse R, Wartofsky L. Current trends in the management of Graves’ disease. J Clin Endocrinol Metab 1990; 70:1518–1524. 120. Orgiazzi J. Management of Graves’ hyperthyroidism. Endocr Metab Clin North Am 1987; 16:365–389. 121. Cooper DS. Antithyroid drugs. N Engl J Med 1984; 311:1353–1362. 122. Cooper DS, Goldminz D, Levin AA, Ladenson PW, Daniels GH, Molitch ME, Ridgway EC. Agranulocytosis associated with antithyroid drugs: effects of patient age and drug dose. Ann Intern Med 1983; 98:26–29. 123. Yamada T, Aizawa T, Koizumi Y, Komiya I, Ichikawa K, Hashizume K. Agerelated therapeutic response to antithyroid drug in patients with hyperthyroid Grave’s disease. J Am Geriatr Soc 1994; 42:513–516. 124. Palestini N, Valori MR, Carlin R, Iannucci P. Mortality, morbidity and long-term results in surgically treated hyperthyroid patients: review of 597 cases. Acta Chir Scand 1985; 151:509–513. 125. Nakazawa HK, Sakurai K, Hamada N, Momotani N, Ito K. Management of atrial fibrillation in the post-thyrotoxic state. Am J Med 1982; 72:903–906. 126. Kellet HA, Sawers JS, Boulton FE, Cholerton S, Park BK, Toft AD. Problems of anticoagulation with warfarin in hyperthyroidism. Q J Med 1986; 58:43– 51.

Thyroid Disease in the Elderly

385

127. McDermott MT, Kidd GS, Dodson LE, Holfeldt FD. Radio-iodine induced thyroid storm. Case report and literature review. Am J Med 1983; 75:353–359. 128. Burch HB, Wartofsky L. Life threatening thyrotoxicosis: thyroid storm. Endocrinol Metab Clin North Am 1993; 22:263–277. 129. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PWF, Hershman JM. Low serum thyrotropin (thyroid stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med 1991; 151:165–168. 130. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PWF, Benjamin EJ, D’Agostino RB. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331:1249–1252. 131. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and followup of abnormal thyrotropin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991; 34:77–83. 132. Stott DJ, McLellan AR, Finlayson J, Chu P, Alexander WD. Elderly persons with suppressed serum TSH but normal free thyroid hormone levels usually have mild thyroid overactivity and are at increased risk of developing overt hyperthyroidism. Q J Med 1991; 78:77–84. 133. Faber J, Jensen IW, Petersen L, Nygaard B, Hegedus L, Siersbaek-Nielsen K. Normalization of serum thyrotrophin by means of radioiodine treatment in subclinical hyperthyroidism: effect on bone loss in postmenopausal women. Clin Endocrinol 1998; 48:285–290. 134. Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 1955; 15:1270–1280. 135. Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules: final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med 1968; 69:537–540. 136. Horlocker TT, Hay JE, James EM, Reading CC, Charboneau JW. Prevalence of incidental nodular thyroid disease detected during high-resolution parathyroid ultrasonography. In: Medeiros-Neto G, Gaitan E, eds. Frontiers in Thyroidology. Vol 2. New York: Plenum Press, 1986, pp 1309–1312. 137. DeGroot LJ. Clinical review 2: diagnostic approach and management of patients exposed to irradiation to the thyroid. J Clin Endocrinol Metab 1989; 69:925–928. 138. Huysmans DAKC, Hermus ARMM, Corstens FHM, Barentsz JO, Kloppenborg PWC. Large, compressive goiters treated with radioiodine. Ann Intern Med 1994; 121:757–762. 139. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 328; 1993: 553–559. 140. Hundahl S, Fleming ID, Fremgen AM, Menck HR. A national cancer data base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995. Cancer 1998; 83:2638–2648. 141. Molitch ME, Beck JR, Dreisman M, Gottlieb JE, Pauker SG. The cold thyroid nodule: an analysis of diagnostic and therapeutic options. Endocr Rev 1984; 5: 185–199. 142. DeGroot LJ, Kaplan EL, Shukla MS, Salti G, Straus FH. Morbidity and mortality in follicular thyroid cancer. J Clin Endocrinol Metab 1995; 80:2846–2953. 143. Kobayashi T, Asakawa H, Umeshita K, Takeda T, Maruyama H, Matsuzuka F,

386

144. 145.

146. 147. 148.

149.

150. 151. 152. 153. 154. 155.

156.

157. 158. 159. 160.

Miller and Gambert Monden M. Treatment of 37 patients with anaplastic carcinoma of the thyroid. Head Neck 1996; 18:36–41. Holm L-E, Blomgren H, Lowhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med 1985; 312:601–604. Rude RK, Singer R. Comparison of serum calcitonin levels after a 1-minute calcium injection and after pentogastrin injection in the diagnosis of medullary thyroid carcinoma. J Clin Endocrinol Metab 1977; 44:980–985. Gharib H, Goellner JR. Evaluation of nodular thyroid disease. Endocr Metab Clin North Am 1988; 17:511–526. Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Intern Med 1993; 118:282–289. Leenhardt L, Hejblum G, Franc B, Fediaevsky LDP, Delbot T, Le Guillouzic D, Menegaux F, Guillausseau G, Hoang C, Turpin G, Aurengo A. Indications and limits of ultrasound-guided cytology in the management of nonpalpable thyroid nodules. J Clin Endocrinol Metab 1999; 84:24–28. Matsuzuka F, Miyauchi A, Katayama S, Narabayashi I, Ikeda H, Kuma K, Sugawara M. Clinical aspects of primary thyroid lymphoma: diagnosis and treatment based on our experience of 119 cases. Thyroid 1993; 3:93–99. Burch HB. Evaluation and management of the solid thyroid nodule. Endocr Metab Clin North Am 1995; 24:663–710. James EM, Charboneau JW. High frequency (10 MHz) thyroid ultrasonography. Semin Ultrasound CT MRI 1985; 6:294–309. Gharib H, Mazzaferri EL. Thyroid suppressive therapy in patients with nodular thyroid disease. Ann Intern Med 1998; 128:386–394. Mazzaferri EL. An overview of the management of papillary and follicular thyroid carcinoma. Thyroid 1999; 9:421–427. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med 1998; 338:297–306. De Bustros AC, Baylin SB. Medullary carcinoma of the thyroid. In: Braverman LE, Utiger RD, eds. The Thyroid, 6th ed. Philadelphia: Lippincott, 1991, pp 1166– 1183. Thoresen SO, Akslen LA, Glattre E, Haldorsen T, Lund EV, Schoultz M. Survival and prognostic factors in differentiated thyroid carcinoma: a multivariate analysis of 1055 cases. Br J Cancer 1989; 59:231–235. Simpson WJ. Anaplastic thyroid carcinoma: a new approach. Can J Surg 1980; 23: 25–27. Kim JH, Leeper RD. Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 1987; 60:2372–2375. Gardiner KR, Russell CFJ. Thyroidectomy for large multinodular colloid goiter. J R Coll Surg Edinb 1995; 40:367–370. Bonnema SJ, Bertelsen H, Mortensen J, Andersen PB, Knudsen DU, Bastholt L, Hegedus L. The feasibility of high dose iodine 131 treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function. J Clin Endocrinol Metab 1999; 84:3636–3641.

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

1

INTRODUCTION

When pregnancy is associated with alterations in maternal thyroid function, the fetus can be affected in two ways: either directly by transplacental passage of maternal thyroid hormone, antithyroid antibodies, or medications or indirectly by adverse influences on maternal physiology. It is important to recognize the expected alterations in thyroid hormone levels during gestation. The clinician must be able to differentiate normal physiological changes from true thyroid disease. Hyperthyroidism and hypothyroidism may first be detected during pregnancy; patients with preexisting thyroid dysfunction require close monitoring and frequently need adjustment of therapy. 2

THYROID HORMONE PHYSIOLOGY DURING GESTATION

During normal gestation, there are changes in thyroid hormone physiology that are reversible after delivery. Serum thyroxine binding globulin (TBG) levels begin to increase within the first weeks after conception, usually more than doubling in concentration, with peak levels reached at the middle of gestation (1). Levels remain increased until delivery and then normalize in the postpartum period. The 387

388

Mandel

increase in serum TBG concentration results from an estrogen-induced increase in the sialylation of the protein, which subsequently decreases its hepatic clearance and prolongs its serum half-life (2). Associated with the rise in TBG are increases in both serum total T4 and T3 levels, which also plateau at the midtrimester or slightly earlier (1,3). Interestingly, it has been observed the serum T4 and T3 concentrations do not increase as much during pregnancy as would be expected given the rise in TBG, and this may be due to decreased TBG saturation (1). The increase in maternal T4 production that occurs in normal gestation is most evident from observations of levothyroxine-replaced hypothyroid women, who require a 25% to 45% dosage increase in order to maintain normal serum TSH levels in pregnancy (4,5). Furthermore, the findings of relative hypothyroxinemia and slightly increased serum TSH levels during pregnancy in women from areas of borderline iodine sufficiency (⬍100 µg/day) support the view that pregnancy constitutes a stress for the maternal thyroid by stimulating thyroidal production (6). There are several possible explanations for this increased T4 requirement. Early in pregnancy, the rise in serum TBG results in expansion of the extrathyroidal T4 pool. In addition, transplacental passage of T4 and placental T4 degradation may contribute to the increased demand on maternal thyroidal production to maintain euthyroid status. Last, renal clearance of iodide increases because of the higher glomerular filtration rate in pregnancy (3). Determination of free T4 (FT4) levels in the first trimester has yielded conflicting results. FT4 levels are variably reported as higher, lower, or the same as prepregnancy values. These discrepancies may relate to the methodology used and dietary iodine intake (7). Relative to first-trimester levels, there is a decline in both serum FT4 and free T3 (FT3) levels throughout gestation, although generally free hormone levels remain within the normal nonpregnant reference range (1). Serum TSH concentration may vary during pregnancy, usually staying within the normal range. First-trimester values are lower compared with either prepregnancy or second- and third-trimester levels. Most recent studies have measured serum TSH levels using dual-antibody sandwich assays that have detection limits of 0.05 mU/L (1,8,9). In these studies, 9% of women without thyrotoxic symptoms have first trimester TSH levels that are subnormal but detectable (⬎0.05 mU/L but ⬍0.2 to 0.4 mU/L, the lower limit of the normal range), and an additional 9% have values that are frankly suppressed (⬍0.05 mU/L). A low serum TSH level has been observed to persist in 5% and 2% of women in the second and third trimesters respectively (9). The nadir in serum TSH levels mirrors the peak in human chorionic gonadotropin (hCG) concentrations (Fig. 1) (1). It has been hypothesized that hCG has thyrotropic activity because of its structural similarity to TSH, and that the high serum hCG levels stimulate the TSH receptor via a hormone specificity ‘‘spillover’’ syndrome (10). In fact, a

Thyroid Disease and Pregnancy

389

FIG. 1 Graph of serum TSH and hCG as a function of gestational age in 606 healthy pregnant women. Between 8 and 14 weeks, there is a significant inverse correlation between individual TSH and hCG levels ( p ⬍0.001). Each point gives the mean values (⫾SE) of individual samples pooled for 2 weeks of gestation. (From Ref. 1.)

positive correlation between individual FT4 and hCG levels in early gestation has been reported, consistent with possible TSH-like activity of hCG (1). In addition, pregnancy is a state of relative iodine deprivation in the mother. Renal iodine clearance increases as a result of an increase in glomerular filtration rate, and there is transplacental passage of iodine and iodothyronines as the fetal-placental unit grows (3). In areas of borderline iodine sufficiency, as in many European countries, this loss of iodine, combined with the increase in thyroid hormone pools from the marked increase in serum TBG levels, may result in goiter formation. In a prospective study from Belgium, thyroid volume increased on average 18% between the first and third trimesters and was associated with the biochemical features of thyroid stimulation, a high T3 /T4 ratio, and elevated thyroglobulin levels (6). In areas where iodine intake is more than sufficient, as the United States, a palpable goiter should not occur during normal gestation; if present, this should direct the clinician to investigate possible thyroid hormone abnormalities (11,12).

390

3

Mandel

THYROID AUTOIMMUNITY AND EUTHYROIDISM

Among euthyroid women in the reproductive years, up to 18% may have detectable antithyroid antibodies (13). These symptomatic euthyroid women with thyroid autoimmunity have been reported to be at risk for three complications of pregnancy: increased rate of spontaneous miscarriage, possible development of subclinical hypothyroidism during gestation, and risk of postpartum thyroiditis (see Sec. 7, below). Several studies have reported a twofold increase in the rate of spontaneous miscarriage early in pregnancy among those euthyroid women who have serum antithyroid antibodies (either antithyroid peroxidase or antithyroglobulin) detected in the first trimester (13–15). The majority of these antibody-positive women who miscarry have normal thyroid function. Furthermore, the presence of antithyroid antibodies either prior to pregnancy or in the first trimester is not correlated with anticardiolipin antibody positivity, which is also known to be associated with pregnancy loss (13,16). On the other hand, the presence of antithyroid antibodies in nonpregnant women with a history of recurrent miscarriage may not be increased when compared to a control group of women (16,17). The mechanism linking thyroid autoimmunity and miscarriage is not known: thyroid autoimmunity may be a marker either for a more generalized activation of the immune system or for subtle changes in maternal/fetal thyroid metabolism. Euthyroid women with detectable antithyroid antibodies may have slightly higher first-trimester serum TSH values, still remaining within the normal range, compared to normal pregnant controls. However, despite the decrease in antithyroid antibody titers with pregnancy progression in these antibody-positive women, thyroid function parameters have been reported in one study to show a progressive deterioration toward hypothyroidism. At term, up to 16% of previously euthyroid women developed mild subclinical hypothyroidism as indicated by an elevated serum TSH level (18). However, this study was conducted in an area of borderline iodine sufficiency, which may have further compromised maternal thyroid gland reserve. There are no data on the possible development of subclinical hypothyroidism in an iodine-replete antibody-positive pregnant population.

4

HYPOTHYROIDISM

Overt hypothyroidism is reported to occur in approximately 1 in 1600 pregnancies (19). However, the prevalence or frequency of subclinical hypothyroidism is reported to be significantly higher, affecting 2.2% of American women screened at 16 to 18 weeks’ gestation (20). Hypothyroxinemia and increased TSH may occur if true hypothyroidism is present or if the mother has been overtreated with antithyroid drugs for hyper-

Thyroid Disease and Pregnancy

391

thyroidism. The obstetrical complications that have been associated with hypothyroidism are linked to the decreased maternal thyroid hormone levels—which provide a less than optimal environment for both fetal and maternal health—and not to the etiology of the biochemical changes in thyroid hormone levels. The majority of cases of hypothyroidism are caused by Hashimoto’s thyroiditis and prior radioiodine or surgical treatment of Graves’ disease. Transient hypothyroidism may occur as part of autoimmune or postpartum thyroiditis, especially if a women has had a recent miscarriage (see Sec. 7, below). 4.1 Diagnosis It is important to diagnose hypothyroidism because of its potential adverse impact on pregnancy (see Sec. 4.2, below); yet most patients are relatively asymptomatic. Only 20% to 30% of women with overt biochemical hypothyroidism (low T4 and high TSH) have symptoms (21,22), and complaints of fatigue and weight gain are often attributed to the pregnancy itself. The majority of patients with subclinical hypothyroidism are asymptomatic as well. The diagnosis of hypothyroidism is confirmed by finding an elevated serum TSH except in the rare instance when hypothyroidism is secondary to pituitary or hypothalamic disease. A cost-effectiveness analysis of universal screening for hypothyroidism during pregnancy has not been done, in part because the true costs with respect to fetal outcome are not known. Several groups are at higher risk for the development of hypothyroidism. These include women with evidence of thyroid autoimmunity because of either a past history of postpartum thyroiditis, prior detection of antithyroid antibodies, or previous treatment for hyperthyroidism, even if they are euthyroid without levothyroxine therapy. In such women, autoimmune damage may not affect basal thyroid hormone output in the nonpregnant state but may impair the thyroid’s ability to compensate for the increased production needed during pregnancy. In addition, 15% of diabetic women with type I diabetes and proteinuria may develop clinical hypothyroidism during pregnancy (23). Because of a recent study examining fetal outcome in women with undiagnosed hypothyroidism during pregnancy (24) (see Sec. 4.2, below), screening for hypothyroidism with TSH measurement should be considered early in gestation. In addition, all levothyroxine-replaced hypothyroid women must be monitored during pregnancy (see Sec. 4.3, below). 4.2 Pregnancy Outcome Overt hypothyroidism can be associated with anovulatory cycles and subsequent infertility. However, hypothyroid women may become pregnant, and several studies have investigated pregnancy outcome in these women (Table 1). The likelihood of complications depends upon the severity of the hypothyroidism and the adequacy of maternal treatment. Gestational hypertension occurs more

392

Mandel

TABLE 1 Complications of Pregnancy Reported in Hypothyroid Women Maternal Gestational hypertension Preeclampsia Pregnancy-induced hypertension Anemia Postpartum hemorrhage Placental abruption Fetal Small for gestational age Stillbirth Transient congenital hypothyroidism due to transplacental passage of maternal thyroid blocking antibodies Possible impairment in cognitive function

frequently in women with overt (22%) compared to subclinical (15%) hypothyroidism, and this is still higher than the prevalence in the general population (7.6%). Low-birth-weight infants are more commonly born to overtly hypothyroid women (22%) compared to either those with subclinical hypothyroidism (9%) or the general population (6.8%) (25). However, this increased incidence in low-birth-weight infants may reflect premature delivery because of gestational hypertension. In addition, compared to women with subclinical hypothyroidism, those with overt disease are more likely to have placental abruption (18% versus 0%), anemia (31% versus 0%), or fetal distress/stillbirth (56% versus 6%) (22,26). The majority of women reported in these studies had less than optimal prenatal care as the average initial antenatal visit occurred between 16 and 20 weeks’ gestation. Levothyroxine therapy may ameliorate some of these complications (21). In addition to pregnancy complications, does maternal hypothyroxinemia pose a threat to fetal development? A recent report documented severe retardation of fetal development, with biparietal diameter and femur length of less than the third centile, in a woman with inadequately treated hypothyroidism and a serum TSH level of 72 mU/L at 29 weeks gestation. With an appropriate increase in her levothyroxine dosage and normalization of her serum TSH level, these fetal parameters normalized by 39 weeks gestation (27). Although the fetus had normal thyroid function, this case illustrates the pivotal role of maternal thyroid hormone for fetal somatic growth. Thyroid hormone is also necessary for normal fetal neurological development and the fetal thyroid does not begin to function until 12 weeks of life. It is now evident that maternal T4 crosses the placenta (28), but the relative contribution of maternal thyroid hormone versus fetal thyroid hormone to fetal neurological development is unknown. In areas of iodine deficiency

Thyroid Disease and Pregnancy

393

where both maternal and fetal thyroid status are compromised, neurological cretinism occurs. In contrast, infants born with congenital hypothyroidism in areas of iodine adequacy have normal neurological function at birth and postnatal levothyroxine therapy is required to continue normal neuronal maturation. Therefore, it is presumed that the transplacental passage of maternal T4 is sufficient to maintain normal fetal neurological development in utero. However, the contribution of maternal thyroid hormone to the brain maturation of a fetus with intact thyroid function is poorly understood. Cognitive function is impaired and brain DNA and protein content are decreased in rats born to thyroidectomized mothers and thereby deprived of maternal thyroid hormone (29). These deficits are not as severe if maternal hypothyroidism occurs only during the second half of gestation, when the rat fetal thyroid gland activity is adequate (30). Data in humans are less secure. Although, early studies of children born to women who were hypothyroxemic during pregnancy reported impaired mental development (31), they have been criticized for their lack of accurate biochemical assessment of hypothyroidism. However, this issue has been addressed by a more recent study. Haddow and colleagues performed neuropsychological testing of 62 children (average age 8 years) born to women who had elevated serum TSH levels at 17 weeks’ gestation and compared these to results for 124 control children matched for maternal educational level and age. Children born to hypothyroid women (partially treated or untreated) scored on average 4 points lower than control children ( p ⫽ 0.06) on the full-scale IQ score of the Wechlser Intelligence Scale for Children. This difference was even more marked, a decrease of 7 IQ points ( p ⫽ 0.005), when the subset of 48 children born to untreated hypothyroid mothers was compared to control children (24). Although differences in the postnatal environment cannot be excluded as etiological factors, this study strongly suggests that untreated or inadequately treated maternal hypothyroidism during pregnancy adversely affects fetal brain development. Based upon these findings, it is worthwhile to consider routine screening for thyroid dysfunction early in gestation. Last, a small percentage of women with atrophic Hashimoto’s thyroiditis may have antibodies that block thyroidal stimulation by TSH. These antibodies may be detected by assays for TSH receptor–binding inhibitory immunoglobulins, which assess the ability of maternal immunoglobulin to block TSH binding to the TSH receptor in vitro. Transient congenital hypothyroidism may be caused by the transplacental passage of these antibodies, which then block TSH stimulation of the neonatal thyroid, analogous but opposite to the situation of neonatal Graves’ disease. The estimated prevalence of this disorder is 1 in 180,000 births, or 2% of infants with congenital hypothyroidism (32). The antibodies can be measured in both the mother and the neonate; if they are present, they may indicate that lifelong levothyroxine therapy may not be necessary for the infant.

394

Mandel

4.3 Treatment Several studies have documented that levothyroxine requirements increase in many hypothyroid women during pregnancy (4,5). There are several possible explanations for this increased requirement and each may have relative importance at different times in gestation. In early pregnancy, the concentration of TBG rapidly increases and more thyroid hormone may be needed to saturate binding sites. The glomerular filtration rate increases, resulting in increased iodide clearance. Later, with placental growth, there is increased metabolism of T4 to its inactive metabolite, reverse T3, by the high levels of placental type III deiodinase (3). In addition, there is transplacental passage of T4. Last, there may be alterations in the volume of distribution of thyroid hormone because of both gravid physiology and the fetal/placental unit. For patients initially diagnosed with overt hypothyroidism during pregnancy, a daily dose of 2 µg/kg per day should be started, which is higher than the full replacement dose in the nonpregnant patient and accounts for the higher requirement in pregnancy (19). If the serum TSH is first found to be only minimally elevated (⬍10 mU/L) in pregnancy, a levothyroxine dose of 0.05 to 0.1 mg/day is often adequate. In those patients with known hypothyroidism taking levothyroxine replacement, the need for dosage adjustment may depend upon the etiology of hypothyroidism, with an increase needed in 76% of women who have undergone prior radioiodine ablation or surgery but in only 47% who have Hashimoto’s thyroiditis (5). Levothyroxine requirements generally increase in the first trimester and persist through gestation. It is important to remember that 25% of those with initial normal serum TSH levels in the first trimester and 37% of those with initial normal serum TSH concentrations in the second trimester will later require dosage increases (5). Women with subclinical hypothyroidism who are taking less than replacement dosages of levothyroxine may not require a dosage increase during gestation because the residual thyroid gland is able to increase synthesis of thyroid hormone. These women may, however, be at increased risk for postpartum thyroiditis (see Sec. 7, below). Levothyroxine-replaced hypothyroid women should have thyroid function monitored as soon as they become pregnant and every 8 to 10 weeks thereafter unless a dosage increase is needed (Table 2). Kaplan has proposed that the increment in levothyroxine dosage can be based upon the initial degree of TSH elevation. For those with serum TSH levels ⬍10 mU/L, the average increase was ⬃50 µg/day; for those with serum TSH values between 10 and 20 mU/L, ⬃75 µg/day; and for those with serum TSH values ⬎20 mU/L, ⬃100 µg/ day (5). Patients should be instructed to separate levothyroxine ingestion from that of prenatal vitamins containing iron and iron supplements, both of which can interfere with levothyroxine absorption (33). Thyroid function should be rechecked 4 weeks after any dose change. The dose may be lowered to pre-

Thyroid Disease and Pregnancy

395

TABLE 2 Guidelines for Clinical Management of Maternal Hypothyroidism During Pregnancy 1. Check serum TSH level early in first trimester. 2. Adjust levothyroxine dosage to maintain a normal serum TSH level. Increment in dosage may depend upon etiology of hypothyroidism. Athyreosis (Graves’ disease after 131I therapy, thyroid cancer) ⬃45% increment Hashimoto’s thyroiditis ⬃25% increment Subclinical hypothyroidism may not require increment 3. TSH should be monitored every 8–10 weeks, or if a dose adjustment is made, it should be checked 4 weeks later. 25% of those with initial normal serum TSH levels in the first trimester and 37% of those with initial normal serum TSH levels in the second trimester will later require dosage increases. 4. Patients should be instructed to separate levothyroxine ingestion and prenatal vitamins containing iron or iron supplements by at least 6 hours. 5. After delivery, the levothyroxine dose should be reduced to the prepregnancy dosage and the serum TSH level should be rechecked at 6 weeks postpartum.

pregnancy levels at delivery and thyroid function should be measured at the 6week postpartum visit. 5

HYPERTHYROIDISM

5.1 hCG-Associated Thyrotoxicosis and Hyperemesis Gravidarum A spectrum of hCG-induced hyperthyroidism occurs during pregnancy, and this entity has recently been referred to as ‘‘gestational thyrotoxicosis’’ (34,35). As previously noted, it is postulated that hCG activates the TSH receptor by a spillover mechanism because of the molecular similarity between these two glycoproteins (10). Findings range from an isolated subnormal serum TSH concentration (up to 18% of pregnancies) to elevations of free thyroid hormone levels in the clinical setting of hyperemesis gravidarum. In women without symptoms of thyrotoxicosis, the serum TSH level may be subnormal but detectable in approximately 9% and undetectable (⬍0.05 mU/L) in an additional 9% (9). Systematic screening of 1900 consecutive pregnant women at their initial antenatal visit demonstrated low serum TSH and elevated FT4 levels in 2.4%, half of whom had weight loss, lack of weight gain, or unexplained tachycardia (35). In all these women, normalization of the FT4 paralleled the decrease in hCG.

396

Mandel

It has been observed that hyperemesis gravidarum, defined as severe nausea and vomiting in pregnancy resulting in weight loss and fluid and electrolyte disturbances, has been associated with abnormal thyroid function tests. Suppressed serum TSH levels may occur in 60% of these patients, with elevated FT4 levels in almost 50% (36). Serum hCG concentrations correlate positively with the FT4 levels and inversely with TSH determinations. The magnitude of the deviation from normal values increases with the severity of nausea and vomiting (8,37). Furthermore, thyroid-stimulating activity as measured by adenylate cyclase activity per international unit of hCG is reported to be greatest in women with hyperemesis gravidarum as compared to those with occasional or no vomiting (34). The vomiting may be related to the elevated hCG-mediated estradiol production, since estradiol levels are higher in hyperemesis subjects than controls, rather than to the thyroid stimulation itself (8). Similar thyroid hormone changes and emetic symptoms may be present with multiple gestations, which are associated with higher peak and more sustained hCG levels (38). In addition, a recent case report further supports the concept of hCG-induced thyrotoxicosis. A woman and her mother with recurrent gestational thyrotoxicosis were found to have a missense mutation in the extracellular domain of their TSH receptor, which caused a two- to threefold increase in activation (cAMP generation) when exposed to hCG compared to wild-type receptor (39). Gestational thyrotoxicosis is transient and usually resolves within 10 weeks of the diagnosis (36). Clinically, this disorder differs from Graves’ disease in several ways: (a) nonautoimmune origin, with negative antithyroid and anti-TSH receptor antibodies; (b) absence of goiter; and (c) resolution in almost all patients after 20 weeks’ gestation (40). Hyperthyroid symptoms—such as weight loss, lack of normal pregnancy weight increase, and tachycardia—are present in 50% of women with gestational thyrotoxicosis (35). However, ophthalmopathy, which is autoimmune in origin, is not seen with this disorder. Treatment with antithyroid drugs is controversial (40) but is generally not recommended. Patients with hyperemesis who remain symptomatic after 20 weeks’ gestation, with elevated thyroid hormone concentrations and suppressed TSH levels, may be considered for antithyroid drug therapy. More than likely, such patients probably have mild Graves’ disease. 5.2 Graves’ Disease Hyperthyroidism is reported to affect 1 in 500 pregnancies, with Graves’ disease accounting for the vast majority of cases (85%). Less common causes are toxic nodular disease in 10% of cases and thyroiditis in 1% to 2% of cases (41). Autoimmune thyroiditis should also be considered as a possible cause, especially if a woman has had a recent miscarriage, which has been reported to trigger ‘‘postpartum’’ thyroiditis (see Sec. 7, below) (42).

Thyroid Disease and Pregnancy

397

The activity of Graves’ disease fluctuates throughout pregnancy, typically with aggravation of hyperthyroidism at 10 to 15 weeks’ gestation followed by subsequent improvement, especially in the third trimester—a time of known immune tolerance (Fig. 2). Often, antithyroid drug dosage can be reduced or even discontinued late in gestation, only to be followed by a worsening of the disease in the postpartum period (43). Graves’ disease may affect a pregnancy in three scenarios. First, women may have active Graves’ disease (either treated or untreated) that can be exacerbated in the first trimester. Second, women in remission may experience a relapse during pregnancy. Third, Graves’ disease may occur for the first time during gestation. In women who have been euthyroid throughout pregnancy but have been treated with antithyroid drugs for Graves’ disease previously, hyperthyroidism may recur in the postpartum period. However, this may represent either the thyro-

FIG. 2 Serum FT4 indices in women with Graves’ disease in remission or near remission during and after pregnancy. Graves’ disease can worsen in early pregnancy, improve in the second half of pregnancy, and relapse postpartum. The normal range for the FT4 index is indicated by the horizontal lines. (From Ref. 107.)

398

Mandel

toxic phase of postpartum thyroiditis in up to 25% or relapse of Graves’ disease. Even in those with postpartum thyroiditis, Graves’ disease often recurs after resolution of postpartum thyroiditis (44). 5.2.1

Diagnosis

The clinical diagnosis of hyperthyroidism may be difficult because pregnancy is itself a hypermetabolic state with symptoms of palpitations and heat intolerance. In addition, patients will usually have increased irritability, decreased exercise tolerance, and fatigue. Patients may describe an inability to control their emotions, with otherwise small irritants culminating in what may be perceived as exaggerated emotional responses. They are aware of increasing shortness of breath climbing stairs. The astute clinician must be cognizant of this constellation of symptoms so that the patient can be appropriately screened for hyperthyroidism. The exam usually reveals the presence of a diffuse goiter, sometimes with a bruit. Other signs may be present as described in Chapter 2. Laboratory studies show a suppressed serum TSH level, usually with elevated serum thyroid hormone concentrations. However, it must be remembered that up to 70% of women with hyperemesis gravidarum may have a suppressed serum TSH level and/or elevated free thyroxine index (8). An elevated FT3 index or FT3 level may be the most clinically useful test to distinguish hyperthyroid patients from those with hyperemesis gravidarum, as less than 15% of hyperemetic women with have elevations in these measures (8). TSH receptor antibodies are usually detectable and may also be of diagnostic utility. 5.2.2

Pregnancy Outcome

Throughout the discussion of the risk and treatment of Graves’ disease during pregnancy, it is important to remember that in reality there are two patients, the mother and the fetus. Maternal hyperthyroidism is associated with increased morbidity for both mother and fetus. Prior to the development of antithyroid drugs, only about 50% of hyperthyroid women were even reported to be able to conceive. Of those women who conceived, spontaneous miscarriage and premature delivery occurred in half (45). The frequency of poor outcomes for both mother and fetus is correlated with the degree and duration of hyperthyroidism, with the highest rates in those women with uncontrolled disease and a decreased risk in those appropriately treated with antithyroid drugs (Table 3). A recent study reported that, among untreated women, 88% had preterm labor, 50% had stillbirths, and 63% had congestive heart failure, whereas for partially treated women, preterm labor occurred in only 25% and stillbirths in 16%. Adequately treated women with biochemical euthyroidism had only a slightly increased risk of preterm labor (8%), without other gestational complications (46). The risk of preeclampsia is also increased in untreated women (14%) compared to those receiving antithyroid drugs (6%)

Thyroid Disease and Pregnancy

399

TABLE 3 Pregnancy Complications Reported in Hyperthyroid Women Maternal Gestational hypertension Preeclampsia Pregnancy-induced hypertension Placental abruption Congestive heart failure Preterm labor Fetal Small for gestational age Intrauterine growth retardation Stillbirth Fetal/neonatal hyperthyroidism

(41), usually leading to premature delivery. Infants born to hyperthyroid women may be small for gestational age, and this may be correlated with the duration of gestational hyperthyroidism (47). In addition, one study reported an increased incidence of congenital malformations (imperforate anus, polydactyl, harelip) if maternal hyperthyroidism is uncontrolled at the time of embryogenesis in the first trimester, although antithyroid drug therapy itself is not associated with a higher incidence of structural anomalies (48). These results highlight the importance of control of maternal hyperthyroidism to ensure optimal pregnancy outcome. 5.2.3

Treatment

5.2.3.1 Antithyroid Drugs Antithyroid drugs are the main treatment for Graves’ disease during pregnancy. Propylthiouracil (PTU) and methimazole (Tapazole) have both been used during gestation. They inhibit thyroid hormone synthesis via reduction in iodine organification and iodotyrosine coupling. Pregnancy itself does not appear to alter the maternal pharmacokinetics of methimazole, although serum PTU levels may be lower in the latter part of gestation compared to the first and second trimesters (49). PTU is more extensively bound to albumen at physiologic pH, whereas methimazole is less bound, which hypothetically might result in increased transplacental passage of methimazole relative to PTU. The standard recommendation of many textbooks and reviews for the preferred use of PTU during pregnancy is based upon a single, often cited report of reduced transplacental passage of PTU compared to methimazole. However, in this study, only six women without a history of thyroid disease received a single injection of either [35 S] methimazole or [35 S] PTU prior to undergoing a therapeutic abortion in the first half of preg-

400

Mandel

nancy (50). A more recent study measuring serum PTU levels in hyperthyroid mothers treated with PTU until term found that the cord PTU concentration was higher than maternal levels (51). No such data evaluating simultaneous maternal and cord levels are available for methimazole. The goals of treatment of Graves’ disease during pregnancy are to control maternal hyperthyroidism with vigilant monitoring of maternal thyroid function and to optimize fetal outcome with careful surveillance of fetal development. Throughout gestation, it is critical that the endocrinologist and obstetrician communicate frequently, so that biochemical and clinical parameters may be correlated. Signs of clinical improvement include maternal weight gain and decrease in pulse rate as well as appropriate fetal growth. For example, if there is concern because of lack of maternal weight gain in conjunction with mild elevations in thyroid hormone levels, the initiation of a low-dose of antithyroid drug should be discussed. 5.2.3.2 Antithyroid Drugs: Effect on the Fetus The clinician must assume that both PTU and methimazole cross the placenta and may decrease fetal thyroid hormone production. For women with Graves’ disease, fetal thyroid status reflects the influence of two maternal factors, both of which cross the placenta: maternal antithyroid drug dosage and maternal TSH receptor antibody activity. TSH receptor antibodies include those that stimulate and those that inhibit thyroid hormone production. Thyroid stimulating immunoglobulins (TSI) are measured functionally by cAMP generation by cultured thyrocytes. Displacement assays of TSH receptor antibodies, TSH receptor inhibitory immunoglobulins, measure displacement of radioloabelled TSH from its receptor by the patient’s serum. This assay does not distinguish between those antibodies that bind to and block the receptor versus those that stimulate the receptor, resulting in increased thyroid production (52). However, in the majority of women with Graves’ disease, levels of TSH-receptor-binding inhibitory immunoglobulins are reported to represent stimulating antibodies and correlate with maternal disease activity (53). Therefore, given these two potential opposing influences on fetal thyroid function, what are the data correlating fetal thyroid function with maternal antithyroid drug dosage? There are seven published studies examining a dose-response relationship between maternal antithyroid drug dose and neonatal thyroid function (Table 4). Three have reported a direct correlation (47,53,54) and four have not demonstrated this relationship (51,55–57). In fact, one study reported that even low daily antithyroid drug dosage (ⱕ100 mg PTU, ⱕ10 mg methimazole) at term may affect the fetal thyroid function; an elevated cord TSH level was found in 23% of babies born to such PTU-treated mothers and in 14% of those treated with methimazole (58). The lack of correlation between maternal

Thyroid Disease and Pregnancy

401

TABLE 4 Relation Between Maternal Antithyroid Drug Dose and Neonatal Thyroid Function No. of Pregnancies

Maternal Antithyroid Rx

Studies demonstrating a dose response between maternal antithyroid drug and neonatal thyroid function Lamberg 1981 (54) 11 CM Mortimer 1990 (53) 16 PTU or CM Mitsuda 1992 (47) 230 Methimazole or PTU Studies demonstrating lack of a dose response between maternal antithyroid drug and neonatal thyroid function Cheron 1981 (55) 11 PTU Gardner 1986 (51) 6 PTU Momotani 1986 (56) 43 Methimazole or PTU Momotani 1997 (57) 77 Methimazole or PTU Key: CM, carbimazole; PTU, propylthiouracil.

dosage and fetal thyroid function may also reflect maternal factors, because there is individual variability in serum PTU levels after a standard oral dose (58). The second factor influencing fetal thyroid function is the transplacental passage of maternal TSH receptor antibodies resulting in excessive fetal thyroid stimulation. Clinically, this becomes relevant at 24 to 26 weeks, and maternal levels reflect the degree of fetal exposure (59). There is a strong correlation between maternal and cord TSH receptor binding inhibitory immunoglobulin levels at term with development of neonatal hyperthyroidism (see Sec. 5.2.5, below). In contrast, the continued use of maternal antithyroid drug therapy at term, in conjunction with low levels of TSH-receptor-binding inhibitory immunoglobulin may result in elevated serum TSH levels in ⬃50% to 60% of infants (53). In this scenario, fetal thyroid function may reflect the relative importance of maternal antithyroid drug dosage when maternal immune thyroid stimulation is low. It is possible that in pregnant women with toxic nodules, a dose relationship may be more likely to be seen, since there is no contribution of fetal thyroid stimulation by the maternal immune system. Therefore, given these varied influences on fetal thyroid function, coupled with maternal individual differences in antithyroid drug pharmacology, it is not surprising that fetal thyroid status is not strictly correlated with maternal antithyroid drug dosage. Based on the literature, current maternal thyroid status, rather than antithyroid drug dose, may be the most reliable marker for titration of antithyroid drug therapy to avoid fetal hypothyroidism (56). If the maternal serum FT4 concentration is either elevated or maintained in the upper third of the normal

402

Mandel

range, serum FT4 levels are normal in more than 90% of neonates. However, if the maternal serum FT4 is in the lower two-third of the normal range, 36% of neonates have a decreased FT4. A decreased FT4 is found in all neonates if the maternal FT4 is below normal. Overdosage with antithyroid drug alone may result in fetal or neonatal goiter, which may cause respiratory distress at birth if the goiter is markedly enlarged. Goiter is reported to have occurred more frequently in older reports where concomitant iodide therapy was used. Because of either transplacental antithyroid drug or iodide-induced inhibition of fetal thyroid hormone production, fetal serum TSH levels increase, resulting in stimulation of thyroid growth. A fetal ultrasound should be obtained for all women who are still taking relatively high antithyroid drug doses at 26 to 28 weeks (PTU ⱖ450 mg/day, methimazole ⱖ30 mg/day). If a fetal goiter is detected on a late-pregnancy ultrasound, the clinician must consider whether this represents fetal hyperthyroidism (see 5.2.5) or fetal ‘‘hypothyroidism’’ because of transplacental passage of maternal antithyroid drug therapy. Intrauterine growth retardation may occur with either condition, but fetal tachycardia (⬎160 to 180 beats per minute) is highly suggestive of hyperthyroidism. In cases where neonatal goiter has occurred because of maternal antithyroid drug use, resolution usually occurs within the first 2 weeks of life with dissipation of the drug (55). Therefore, one option is to stop maternal antithyroid drug therapy and monitor the fetal goiter by ultrasound. There are several case reports of intraamniotic levothyroxine injections for treatment of the fetal goiter due to maternal antithyroid drug exposure. However, in two recent reports (60,61), the injections occurred while the maternal PTU dose was lowered. Therefore, it is difficult to distinguish the relative importance of each factor on the resolution of the fetal goiter. A third recent case report demonstrated that cessation of maternal antithyroid drug therapy alone resulted in decrease in the fetal goiter documented ultrasonographically (62). In cases of fetal goiter where hypothyroidism is suspected because of transplacental antithyroid drugs, it may be prudent to discontinue or substantially decrease the maternal antithyroid drugs and follow the goiter with sequential ultrasounds. If reduction in size does not occur within 2 to 3 weeks, periumbilical blood sampling should be performed to determine fetal thyroid function. If this is still low, intraamniotic levothyroxine therapy should be given. Four studies have reported no defects in either the cognitive and somatic development of children exposed to maternal antithyroid drugs in utero (63–66), even after accounting for higher dosage or first-trimester exposure. These were cross-sectional studies that measured cognitive development by intelligence quotient. Therefore, it is unknown if transient or more subtle developmental changes might have been present. However, maternal thyroid hormone levels were not reported, so it is unknown if maternal hypothyroxinemia, a possible risk factor for cognitive impairment, was present.

Thyroid Disease and Pregnancy

403

There have been reports of an association of maternal methimazole therapy with aplasia cutis, a heterogeneous group of disorders in which localized or widespread areas of skin are absent at birth. The lesions seen in infants born to methimazole treated mothers have all been all localized scalp defects (49). However, the reported frequency of this disorder in infants born to methimazole-treated mothers is not higher than the expected sporadic frequency (49). No cases to date have been reported with PTU therapy despite its more widespread use. For this reason, some clinicians including the author prefer PTU to methimazole for initial therapy of maternal hyperthyroidism. In addition, the rare disorder of absent or hypoplastic nipples associated with choanal atresia has been reported in two infants born to mothers treated with methimazole during the first trimester (67,68). The clinical significance of these reports is unknown. 5.2.3.3 Antithyroid Drugs: Treatment Guidelines Antithyroid drug dosage should be titrated to maintain maternal serum total or FT4 levels in the upper third of the normal range (Table 5) or slightly above it. Maternal serum T3 levels may not be as helpful because there is no correlation with fetal thyroid function (56). Practically, this means that antithyroid drug dosage should be adjusted to maintain a serum total T4 concentration of 12 to 14

TABLE 5 Guidelines for Clinical Management of Maternal Hyperthyroidism During Pregnancy 1. Use the lowest dose of antithyroid drug to maintain maternal thyroid hormone levels in the upper third of the normal range to slightly elevated levels for pregnancy. Because PTU has not been implicated in causing aplasia cutis, therapy may be initiated with PTU. 2. Check maternal thyroid hormone levels monthly, using total or FT4 levels. 3. Measure TSI/TSH receptor binding inhibitory immunoglobulins at 26– 28 weeks. 4. Consider fetal ultrasound at 26–28 weeks if the TSI/TSH receptor binding inhibitory immunoglobulins levels are elevated or if fetal tachycardia is detected by Doppler. 5. If either high doses of maintenance antithyroid drug are required (PTU ⬎600 mg/day, methimazole ⬎40 mg/day) or if a patient is nonadherent or allergic to antithyroid drug therapy, surgery (subtotal thyroidectomy) should be considered. 6. Low doses of iodides may be used transiently, especially preoperatively. 7. Frequent communication between the endocrinologist and obstetrician is essential so that antithyroid drug dose titration is done with monitoring of fetal growth.

404

Mandel

µg/dL or a FT4 of 1.8 to 2.0 ng/L. If a woman has mild Graves’ disease with these values as her initial indices, treatment may be withheld and her thyroid status monitored as long as she has satisfactory clinical progression of pregnancy. The initial antithyroid drug dosage may vary depending upon the degree of hyperthyroidism. I prefer to begin therapy with PTU because there are no reported cases of PTU-associated aplasia cutis. However, if a woman cannot tolerate PTU or finds it difficult to take the prescribed number of pills (PTU usually requires multiple daily dosages whereas methimazole can often be given once daily), methimazole may be substituted. It is my approach generally not to use more than 450 to 600 mg of PTU or 30 mg of methimazole daily. The median time to normalization of the maternal FT4 index is 7 to 8 weeks for both PTU and methimazole (69), although improvement in parameters may be seen earlier at 3 to 4 weeks. One should reassess maternal total T4 or FT4 3 to 4 weeks later and adjust antithyroid drug dosage based upon the decrement in thyroid hormone levels. As in nonpregnant women with Graves’ disease, maternal serum TSH levels may remain suppressed for several weeks after normalization of thyroid hormone levels, and it is not helpful to monitor the serum TSH early in treatment. Graves’ disease may improve in the third trimester and with progressive decreases in antithyroid drug dosage throughout pregnancy, therapy may be stopped by 32 to 34 weeks gestation in 30% of women (70). Of course, the same spectrum of adverse effects related to antithyroid drug therapy in the nonpregnant state applies to use during gestation (see Chapter 2). 5.2.3.4 Beta-Adrenergic Blockers Beta-adrenergic blocking agents may be used transiently to control adrenergic symptoms, until antithyroid drug therapy decreases thyroid hormone levels. There is a recent report of a higher rate of spontaneous first-trimester miscarriages in women who were treated with combined antithyroid drug and propranolol therapy compared to antithyroid drug alone, although both groups had similar levels of thyroid hormone (71). However, this was a small series and propranolol was prescribed for 6 to 12 weeks, which may be longer than would be typically necessary in most patients. 5.2.3.5 Iodides Chronic use of iodides during pregnancy has been associated with hypothyroidism and goiter in neonates, sometimes resulting in asphyxiation because of tracheal obstruction (49). However, a recent report of low-dose potassium iodide (6 to 40 mg/day) administered to selected pregnant hyperthyroid women with maintenance of maternal FT4 levels in the upper half of the normal range did not cause goiter, although 6% of newborns had an elevated serum TSH level (72). Since the experience with iodides is more limited, iodides should not be used as a first line therapy for women with Graves’ disease but could be used transiently if needed in preparation for thyroidectomy.

Thyroid Disease and Pregnancy

405

5.2.3.6 Surgery Subtotal thyroidectomy is usually only considered during pregnancy as therapy for maternal Graves’ disease if consistently high levels of antithyroid drugs (PTU ⬎600 mg/day, methimazole ⬎40 mg/day) are required to control maternal hyperthyroidism, if a patient is nonadherent or allergic to antithyroid drug therapy, or if compressive symptoms exist because of goiter size. If a woman has experienced severe antithyroid drug-related side effects such as agranulocytosis, she should receive transient therapy with supersaturated potassium iodide solution (50 to 100 mg per day) for 10 to 14 days prior to surgery. The timing of surgery is usually in latter half of the second trimester. The rationale for not performing surgery in the first trimester is that this is the time of the highest spontaneous abortion rate and surgery could possibly further increase the risk. However, there are no definitive data supporting an increased miscarriage rate related to the surgical procedure and anesthesia if performed in the first trimester (73) and subtotal thyroidectomy may be done if clinically indicated. 5.2.3.7 131 I Therapy Because of its adverse effects on the fetus, the use of 131I therapy is completely contraindicated in pregnancy, especially after 12 weeks’ gestation, when the fetal thyroid begins to concentrate iodine with an even greater avidity than the maternal thyroid. In addition, other fetal tissues are generally more radiosensitive (74). A pregnancy test should be performed in all women prior to radioiodine therapy. However, inadvertent administration of 131 I in early pregnancy may occur and a survey was sent to endocrinologists regarding their experience with this situation. Of 237 cases, therapeutic abortion was advised and performed for 55 patients. In the remaining 182 pregnancies, the risk of stillbirths, spontaneous abortions, and fetal abnormalities was not higher than in the general population (75), perhaps because the fetal whole-body irradiation from a therapeutic 131 I dose for Graves’ disease at this time is calculated to be below the threshold associated with increased congenital defects (74). However, six infants were hypothyroid at birth, four of whom were mentally retarded. 131 I therapy had been given after 12 weeks in three of the mothers of the hypothyroid infants, at a time when the fetal thyroid had already begun to concentrate iodine (75). Therefore, fetal hypothyroidism is more likely to occur if 131 I treatment is given after 12 weeks, and congenital defects would be the major concern after 131 I therapy in the early first trimester. Dosimetry studies could quantitate the actual fetal exposure, but experts have suggested that the ‘‘relatively low fetal whole-body irradiation is probably not sufficient to justify termination of pregnancy’’ (74). If inadvertent 131 I therapy has been administered to a pregnant woman, PTU therapy may be initiated within 7 days of 131 I, which may reduce 131 I recycling by the fetal thyroid, thereby lowering radiation exposure (74). All infants exposed to maternal 131 I therapy need to be evaluated immediately at birth with institution of levothyrox-

406

Mandel

ine therapy if congenital hypothyroidism is documented. The therapeutic administration of 131 I to a nursing mother is contraindicated and lactation should be stopped immediately if this occurs. 5.2.4

Lactation

Traditionally, many texts have advised against breast-feeding in women treated with antithyroid drugs because of the presumption that the antithyroid drug was present in breast milk in concentrations sufficient to affect the infant’s thyroid. However, over the last two decades, several studies have prospectively monitored thyroid function in infants nursed by mothers taking antithyroid drug therapy. PTU is more tightly protein-bound than methimazole; consequently, the ratio of milk to serum levels is lower for PTU (0.67) (76) than for methimazole (1.0) (77). In addition, the amount of ingested drug secreted in breast milk is approximately six times higher for methimazole than for PTU (0.14% versus 0.025% of the ingested dose) (76,77). Four studies reported no alteration in thyroid function in newborns breastfed by mothers treated with daily doses of PTU (50 to 750 mg), methimazole (5 to 20 mg), or carbimazole (5 to 15 mg) for periods ranging from 3 weeks to 12 months (76,78–80). Even in women who were overtreated and developed elevated serum TSH levels, the babies’ thyroid function tests remained normal. Therefore, antithyroid drug therapy (PTU ⬍450 mg/day, methimazole ⬍20 mg/ day) may be considered during lactation, although the number of reported infants is small. PTU would be preferred because of its decreased appearance in breast milk, and the drug should be taken by the mother after a feeding. Until more studies are available, monitoring the infant’s thyroid function may be prudent. In addition, the theoretical possibility of the infant developing antithyroid drug side effects via antithyroid drug ingestion through lactation has not been reported. 5.2.5

Fetal/Neonatal Hyperthyroidism

In women with either active, radioiodine-ablated, surgically-treated Graves’ disease, fetal or neonatal hyperthyroidism is reported to occur in 1% of pregnancies (81). However, there are no data evaluating whether the incidence rate is higher in those with active versus ‘‘thyrodectomized’’ Graves’ disease. This disorder is caused by the transplacental passage of maternal TSH receptor antibodies, either TSI- or TSH-receptor-binding inhibitory immunoglobulins, that stimulate fetal thyroid hormone production and may cause goiter. Maternal-to-fetal IgG transport becomes clinically significant at the end of the second trimester, which is when fetal hyperthyroidism usually becomes apparent. Measurement of maternal TSI- or TSH-receptor-binding inhibitory immunoglobulins at 26 to 28 weeks provides prognostic information about the development of fetal Graves’ disease

Thyroid Disease and Pregnancy

407

(47). Levels of TSH-receptor-binding inhibitory immunoglobulins ⬎30% (47) or TSI levels ⬎300% (82) are highly suggestive of fetal hyperthyroidism. However, the measurement of these antibody levels is not standardized and may depend upon the individual laboratory’s reference range. Therefore, the clinician should consider the diagnosis of fetal hyperthyroidism if maternal TSI- or TSHreceptor-binding inhibitory immunoglobulins are elevated or if fetal tachycardia (⬎160 beats per minute) and intrauterine growth retardation are present (83). Ultrasound may demonstrate a goiter in some cases and will verify the presence of fetal tachycardia. If necessary, periumbilical blood sampling will confirm the diagnosis. Although there are no established normal ranges for fetal thyroid hormone levels, the serum TSH is ⬎20 mU/L in the published cases of fetal hypothyroidism (60,61) or the serum T4 level is markedly elevated in those of fetal hyperthyroidism (84,85). Periumbilical blood sampling has risks of fetal bleeding, bradycardia, infection, and death (60) and is usually not indicated, as the diagnosis can often be made clinically. Treatment of fetal hyperthyroidism is accomplished by giving the mother antithyroid drug therapy, which then crosses the placenta and inhibits fetal thyroid hormone synthesis. Hypothetically, because methimazole is less protein-bound, it might more readily cross the placenta and have a greater effect on fetal thyroid function. Generally, in the United States, PTU has been used in cases of suspected fetal hyperthyroidism, and can be initiated at doses of 150 mg/day, with subsequent normalization of fetal heart rate within 2 weeks (59). The dose can then be titrated to maintain a normal fetal heart rate. In a woman who has received prior radioablation for Graves’ disease, levothyroxine therapy may have to be initiated or increased if maternal hypothyroxinemia occurs. Since TSI and TSH receptor binding inhibitory immunoglobulin levels usually decline toward term, antithyroid drug dosage can be decreased as fetal heart rate and growth are monitored. If antibody levels remain elevated at term, the risk of neonatal hyperthyroidism is increased (82), and if the mother has been maintained on antithyroid drug until delivery, the clinical manifestations of hyperthyroidism in the newborn may be masked for the first week of life (86). Antithyroid drugs are necessary for treatment of neonatal Graves’ disease, but as maternal antibody levels decrease over the first 3 months of life, therapy can usually be discontinued (86). 6

THYROID NODULES AND THYROID CANCER

Although goiter may occur during pregnancy in areas of borderline iodine deficiency (87), thyroid size does not increase in iodine-replete areas (11,88). The prevalence of nodules has been reported to be higher in middle-aged women with a history of three or more prior pregnancies (89), but solitary thyroid nodules or thyroid cancer does not arise de novo more frequently during pregnancy. The

408

Mandel

detection of thyroid nodules in pregnant women usually reflects the careful examination by an obstetrician of a healthy pregnant woman who had not regularly seen a physician prior to her conception. As in the nonpregnant patient, fine-needle aspiration (FNA) should be performed for diagnosis in nodules identified during pregnancy; the spectrum of cytological results is the same as in the nonpregnant patient (90). Radioactive iodine scanning is generally contraindicated at this time, but ultrasound can be performed either for characterization and monitoring of the nodule or for guidance of the FNA. Nodules with a benign cytology may be observed, and those with a cytology suggestive of follicular neoplasm may require further evaluation and possible surgery after delivery. If the FNA cytology shows evidence of a thyroid cancer, surgery is recommended. However, the timing of surgery, either during or after pregnancy, is debatable, with some recommending surgery during the midtrimester (90) and others advocating waiting until after delivery (91). A recent study has reported no significant difference in recurrence or survival rates between women with malignant nodules who had surgery either during or after pregnancy (92). Furthermore, thyroid cancer discovered during pregnancy is not more aggressive than that found in a similar aged group of nonpregnant women (91,92). For women with previously treated thyroid cancer, most reports confirm that subsequent pregnancy does not increase recurrence rates (93). If a malignant cytology is obtained early in pregnancy, monitoring of nodule size with ultrasound is recommended. If the nodule has grown significantly by the midtrimester, surgery should be strongly considered, with subsequent levothyroxine suppression therapy. Radioactive iodine therapy, if needed, must be delayed until the postpartum period. However, if nodule size is stable or if malignant cytology is detected in the second half of pregnancy, surgery can be delayed until after delivery. In such women, levothyroxine therapy may be considered to maintain the serum TSH level in the subnormal but detectable range (0.1 to 0.3 mU/L), which would theoretically slow TSH-responsive tumor growth and should not be associated with pregnancy complications. 7

POSTPARTUM THYROIDITIS

Postpartum thyroiditis is a painless, destructive inflammation of the thyroid characterized by transient hyperthyroidism and/or hypothyroidism that occurs within the first 6 to 12 months after delivery in women who were euthyroid during pregnancy. It is reported to occur in 2% to 17% of women. The discrepancies in prevalence may reflect differences in diagnostic criteria as well as variable predisposing genetic factors and iodine intake that differ among screened populations (94).

Thyroid Disease and Pregnancy

409

Postpartum thyroiditis is thought to be an autoimmune disorder for several reasons. It is temporally related to the time of immunological ‘‘rebound’’ that occurs in the first months after delivery (95). On cytology, lymphocytic thyroiditis is evident and similar HLA haplotypes are found in patients with postpartum thyroiditis and Hashimoto’s thyroiditis (94). Several studies have documented a correlation between antithyroid antibody positivity and the development of postpartum thyroiditis. The presence of antithyroid peroxidase antibodies in the first trimester is associated with a 33% risk of developing postpartum thyroiditis. Women who develop postpartum thyroiditis have consistently higher titers of antithyroid antibodies throughout gestation than do women who have detectable antibodies but do not develop postpartum thyroiditis (96). If antithyroid antibodies are detectable two days postpartum, postpartum thyroiditis is reported to affect 67% of women (97). There may also be a contribution of cellular immunity to the development of postpartum thyroiditis. The ratio of helper to suppresser T cells declines progressively during pregnancy followed by an increase postpartum. Although women who develop postpartum thyroiditis manifest a decline in the helper/suppresser ratio during pregnancy, the ratio is higher than in unaffected women (96). In addition, women with type I diabetes mellitus, another autoimmune disease, have an increased incidence of postpartum thyroiditis compared to the general population (98). Last, euthyroid patients with a history of Graves’ disease may develop postpartum thyroiditis initially after delivery, which may subsequently be followed by Graves’ hyperthyroidism (44). The thyrotoxic phase of postpartum thyroiditis generally occurs within the first 1 to 4 months after delivery and is transient, lasting for 1 to 2 months. There is release of stored thyroid hormone from the damaged thyroid gland rather than increased thyroidal production of thyroid hormone. Hypothyroidism may follow and last from 2 to 6 months until follicular cell synthetic activity recovers and euthyroidism returns. Not all patients experience both hyper- and hypothyroidism. In fact, either transient hyper- or hypothyroidism alone is observed in the majority of reported patients (99). However, this may reflect differences in screening protocols and the monitoring schedule of postpartum thyroid function. The majority of patients recover from the hypothyroid phase of postpartum thyroiditis. However, up to 10% may have persistent hypothyroidism and 20% may develop permanent hypothyroidism over the next 2 to 10 years (100,101). The risk of permanent hypothyroidism is correlated with the severity of the hypothyroid phase of postpartum thyroiditis and the elevation of the serum TSH level as well as the elevation in antithyroid antibody levels (101). In addition, for those women who recover, there is a 70% risk of developing recurrent postpartum thyroiditis after a subsequent pregnancy (102). There are no data addressing the future risk to these women of developing ‘‘silent’’ autoimmune thyroiditis not associated with pregnancy.

410

Mandel

7.1 Diagnosis The clinical manifestations of the thyrotoxic phase of postpartum thyroiditis are not usually severe. Fatigue and emotional lability may be prominent features, both of which are often attributed to the postpartum state itself. Fatigue is the most consistent finding during the hypothyroid phase but again is a nonspecific symptom. When compared to postpartum euthyroid women, hypothyroid patients with postpartum thyroiditis have significantly increased symptoms of impaired concentration and memory, carelessness, and depression (97). Among women diagnosed with postpartum depression, postpartum thyroiditis is present twice as often as in women without depression (103). In addition, in one study, depressive symptoms in the postpartum period were associated with positive antithyroid antibody status even without thyroid dysfunction (104). On examination, a painless goiter is often detected. The clinician should consider the diagnosis of postpartum thyroiditis in any postpartum woman who presents with a goiter and/or the nonspecific symptoms of fatigue, emotional lability, or palpitations. The serum TSH concentration will be suppressed during the thyrotoxic phase and elevated during the hypothyroid phase. However, in the transition period from thyrotoxicosis to hypothyroidism, changes in the serum TSH level may lag behind the decline in thyroid hormone levels and may therefore be in the normal range when serum thyroid hormone concentrations are low. Consequently, in assessing patients for postpartum thyroiditis, it is important to obtain measurements of both serum TSH and either total or free thyroxine levels. Thyroid receptor antibody levels are usually elevated in patients with Graves’ disease and not in postpartum thyroiditis unless a patient has a prior history of Graves’ disease (44). During the thyrotoxic phase, a radioiodine uptake (contraindicated in pregnant women) is low, differentiating hyperthyroidism in postpartum thyroiditis caused by leakage of stored thyroid hormone from the postpartum presentation of Graves’ disease with increased hormone production. If a patient is nursing and an uptake is considered critical for diagnosis, radiation safety and nuclear medicine should be consulted. 123 I is excreted in breast milk and has an effective half-life of 5 to 8 h. A radioiodine uptake with 123 I (scan is not necessary) can be performed after counseling, and nursing should be stopped for at least 48 h after 123 I administration (105). Afterwards, she may bring in an aliquot of milk for assessment of any residual radioactivity, lactation can usually be resumed at that time. If the patient has entered the recovery phase of postpartum thyroiditis at the time of the uptake evaluation, the uptake may not be low, as the serum TSH has now normalized or become elevated. The clinician should also be aware that postpartum thyroiditis may occur in two other settings. It may develop in women after a miscarriage or therapeutic

Thyroid Disease and Pregnancy

411

abortion, even if the pregnancy loss occurs as early as 5 weeks gestation (42). In addition, women previously diagnosed with subclinical hypothyroidism prior to conception and treated with subreplacement levothyroxine doses (0.025 to 0.075 mg/day) to normalize the serum TSH level may not require a dosage increase in pregnancy, which indicates that the residual thyroid is capable of functioning and synthesizing thyroid hormone. After delivery, the same residual thyroid is subject to the immunological insult that causes postpartum thyroiditis. These women will develop a suppressed serum TSH level during the thyrotoxic phase and levothyroxine should be stopped. However, during the hypothyroid phase, they may require a larger dose than their previous subreplacement dose to restore euthyroidism, since they have transiently lost thyroid hormone secretory capacity from the residual functioning thyroid (106). 7.2 Treatment Treatment is usually not required during the thyrotoxic phase of postpartum thyroiditis. Generally, by the time a patient recognizes the symptoms and seeks medical attention, thyroid function is normalizing. Antithyroid drugs are not beneficial because the increase in circulating thyroid hormone is a result of a destructive process affecting the thyroid gland, not increased thyroidal synthesis. If palpitations are a prominent symptom, beta-adrenergic blocking drugs may be used transiently. Diagnosis of the hyperthyroid phase of postpartum thyroiditis is important because it identifies a group of women who likely will develop hypothyroidism, which has a more prolonged duration. Levothyroxine therapy can be initiated in patients with symptoms or TSH elevation ⱖ10 mU/L. Often, women may be treated with a subreplacement dose (0.05 to 0.075 mg/day) if the serum TSH level is between 10 and 20 mU/L but may require a larger dose if the serum TSH is ⬎20 mU/L. The serum TSH level should be rechecked at 4 to 6 weeks, with dosage adjustment as needed. Since the hypothyroid phase may last up to 6 months, levothyroxine therapy may be continued empirically for several months after a normal serum TSH level is attained. At that point, it may be either discontinued or reduced by half, with monitoring of a serum TSH level 3 to 4 weeks later. If the serum TSH concentration is normal at that time, it should be rechecked an additional time 4 to 6 weeks later if levothyroxine was previously stopped or 4 to 6 weeks after discontinuation of the halved dose. If the serum TSH level increases above normal on a lower dose or off therapy, levothyroxine therapy is still required. Patients who recover from postpartum thyroiditis should have periodic annual monitoring of thyroid function. Consensus recommendations for screening for postpartum thyroiditis are controversial, and universal screening cannot currently be justified (107). However, two populations—women with type I diabetes and those with a prior history

412

Mandel

of postpartum thyroiditis—have a sufficiently high incidence of postpartum thyroiditis that they might benefit from screening with TSH measurements at 6 weeks, 3 months, and 6 months postpartum. REFERENCES 1. Glinoer D, DeNayer P, Bourdoux P, Lemone M., Robyn C, Van Steirteghem A, Kinthaert J, Lejeune B. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 1990; 71:276–287. 2. Ain KB, Mori Y, Refetoff S. Reduced clearance rate of thyroxine-binding globulin (TGB) with increased sialylation: a mechanism for estrogen-induced elevation of serum TBG concentration. J Clin Endocrinol Metab 1987; 65:689–696. 3. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J Med 1994; 331:1071–1078. 4. Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990; 323:91–96. 5. Kaplan, M. Monitoring thyroxine treatment during pregnancy. Thyroid 1992; 2: 147–152. 6. Glinoer D, Delange F, Laboureur I, DeNayer P, Lejeune B, Kinthaert J, Bourdoux P. Maternal and neonatal thyroid function at birth in an area of marginally low iodine intake. J Clin Endocrinol Metab 1992; 75:800–805. 7. Kaplan M. Assessment of thyroid function during pregnancy. Thyroid 1992; 2:57– 61. 8. Goodwin TM, Montoro M, Mestman JH, Pekary AE, Hershman JM. The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum. J Clin Endocrinol Metab 1992; 75:1333–1337. 9. Glinoer D, DeNayer P, Robyn C, Lejeune B, Kinthaert J, Meuris S. Serum levels of intact human chorionic gonadotropin (HCG) and its free a and b subunits, in relation to maternal thyroid stimulation during normal pregnancy. J Endocrinol Invest 1993; 16:881–888. 10. Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonadotropin. Thyroid 1995; 5:425–433. 11. Levy RP, Newman DM, Rejali LS, Barford D. The myth of goiter in pregnancy. Am J Obstet Gynecol 1980; 137:701–703. 12. Nelson M, Wickus GG, Caplan RH, Beguin EA. Thyroid gland size in pregnancy an ultrasound and clinical study. J Reprod Med 1987; 32:888–890. 13. Stagnaro-Green A, Roman SH, Cobin RH, El-Harazy E, Alvarez-Marfany M, Davies TF. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990; 264:1422–1425. 14. Lejeune B, Grun JP, DeNayer P, Servais G, Glinoer D. Antithyroid antibodies underlying thyroid abnormalities and miscarriage or pregnancy induced hypertension. Br J Obstet Gynecol 1993; 100:669–672. 15. Singh A, Dantas Z, Stone S, Asch R. Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies. Fertil Steril 1995; 63:277– 281.

Thyroid Disease and Pregnancy

413

16. Pratt D, Novotny MS, Kaberlein G, Dudkiewicz A, Gleicher, N. Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss. Am J Obstet Gynecol 1993; 168:837–841. 17. Esplin S, Branch DW, Silver R, Stagnaro-Green A. Thyroid autoantibodies are not associated with pregnancy loss. American Thyroid Association, 1997. 18. Glinoer D, Riahi M, Gru¨n J, Kinthaert J. Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 1994; 79:197–204. 19. Montoro M. Management of hypothyroidism during pregnancy. Clin Obstet Gynecol 1997; 40:65–80. 20. Klein RZ, Haddow JE, Faix JD, Brown RS, Hermos RJ, Pulkkinen A, Mitchell ML. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol 1991; 35:41–46. 21. Montoro M, Collea JV, Frasier SD, Mestman JH. Successful outcome of pregnancy in women with hypothyroidism. Ann Intern Med 1981; 94:31–34. 22. Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating pregnancy. Obstet Gynecol 1988; 72:108–112. 23. Jovanovic-Peterson L, Peterson CM. De novo clinical hypothyroidism in pregnancies complicated by type 1 diabetes, subclinical hypothyroidism, and proteinuria: a new syndrome. Am J Obstet Gynecol 1988; 159:442–446. 24. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir E, Mitchell ML, Hemos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341:549–555. 25. Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal outcome in hypothyroid pregnancies. Obstet Gynecol 1993; 81:349–353. 26. Wasserstrum N, Anania CA. Perinantal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement. Clin Endocrinol 1995; 42:353– 358. 27. Rotondi M, Caccavale C, DiSerio C, DelBuono A, Sorvillo F, Glinoer D, Bellastella H, Carella C. Successful outcome of pregnancy in a thyroidectomized parathyroidectomized young woman affected by severe hypothyroidism. Thyroid 1999; 9: 1037–1040. 28. Vulsma T, Gons MH, de Vijlder JJM. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989; 321:13–16. 29. Porterfield SP, Hendrich CE. The role of thyroid hormones in prenatal and neonatal neurological development—current perspectives. Endocr Rev 1993; 14:94–106. 30. Bonet B, Herrera E. Different Response to maternal hypothyroidism during the first and second half of gestation in the rat. Endocrinology 1988; 122:450–455. 31. Man EB, Brown JF, Serunian SA. Maternal hypothyroxinemia: psychoneurological deficits of progeny. Ann Clin Lab Sci 1991; 21:227–239. 32. Brown RS, Bellisario RL, Botero D, Fournier L, Abrams C, Cowger M, David R, Fort P, Richman R. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies. J Clin Endocrinol Metab 1996; 81:1147–1151.

414

Mandel

33. Campbell, NRC, Hasinoff BB, Stalts H. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med 1992; 117:1010–1013. 34. Kimura M, Amino N, Tamaki H, Ito E, Mitsuda N, Miyai K, Tanizawa O. Gestational thyrotoxicosis and hyperemesis gravidarum: possible role of hCG with higher stimulating activity. Clin Endocrinol 1993; 38:345–350. 35. Glinoer D. Thyroid hyperfunction during pregnancy. Thyroid 1998; 8:859–864. 36. Goodwin GM, Montoro M, Mestman JH. Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol 1992; 167:648–652. 37. Mori M, Nobuyuki A, Tamaki H, Miyai K, Tanizawa O. Morning sickness and thyroid function in normal pregnancy. Obstet Gynecol 1988; 72:355–359. 38. Gru¨n, J, Meurist S, DeNayer P, Glinoer D. The thyrotrophic role of human chorionic gonadotrophin (hCG) in the early stages of twin (versus single) pregnancies. Clin Endocrinol 1997; 46:719–725. 39. Rodien P, Bremont C, Sanson M, Parma J, Wan Sande J, Costagliola S, Luton P, Vassart G, Duprez L. Familial Gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 1998; 339:1823–1826. 40. Goodwin T, Hershman J. Hyperthyroidism due to inappropriate production of human chorionic gonadotropin. Clin Obstet Gynecol 1997; 40:32–44. 41. Millar LK, Wing DA, Leung AS, Koonings PP, Montoro MN, Mestman JH. Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 1994; 84:946–949. 42. Marqusee E, Hill JA, Mandel SJ. Thyroiditis after pregnancy loss. J Clin Endocrinol Metab 1997; 82:2455–2457. 43. Amino N, Tanizawa O, Mori H, Iwatani Y, Yamada T, Kurachi K, Kumahara Y, Miyai K. Aggravation of thyrotoxicosis in early pregnancy and after delivery in Graves’ disease. J Clin Endocrinol Metab 1982; 55:108–112. 44. Momotani N, Noh J, Ishikawa N, Ito K. Relationship between silent thyroiditis and recurrent Graves’ disease in the postpartum period. J Clin Endocrinol Metab 1994; 79:285–289. 45. Gardiner-Hill H. Pregnancy complicating simple goitre and Graves’ disease. Lancet 1929; 1:120–124. 46. Davis LE, Lucas MJ, Hankins GDV, Roark MI, Cunningham FG. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989; 160:63–70. 47. Mitsuda, N, Tamaki H, Amino N, Hosono T, Miyai K, Tanizawa O. Risk factors for developmental disorders in infants born to women with Graves’ disease. Obstet Gynecol 1992; 80:359–364. 48. Momotani N, Ito K, Hamada N, Ban Y, Nishikawa Y, Mimura T. Maternal hyperthyroidism and congenital malformation in the offspring. Clin Endocrinol 1984; 20:695–700. 49. Mandel SJ, Brent GA, Larsen PR. Review of antithyroid drug use during pregnancy and report of a case of aplasia cutis. Thyroid 1994; 4:129–133. 50. Marchant B, Brownlie BEW, McKay Hart D, Horton PW, Alexander WD. The placental transfer of propylthiouracil, methimazole and carbimazole. J Clin Endocrinol Metab 1977; 45:1187–1193. 51. Gardner DF, Cruikshank DP, Hays PM, Cooper, D. Pharmacology of propylthio-

Thyroid Disease and Pregnancy

52. 53.

54.

55.

56. 57.

58.

59. 60. 61.

62.

63.

64.

65.

66.

415

uracil (PTU) in pregnant hyperthyroid women: correlation of maternal PTU concentrations with cord serum thyroid function test. J Clin Endocrinol Metab 1986; 62: 217–220. Davies TF, Roti E, Braverman LE, DeGroot LJ. Stimulating antibodies. J Clin Endocrinol Metab 1998; 83:3777–3785. Mortimer RH, Tyack SA, Galligan JP, Perry-Keene DA, Tan YM. Graves’ disease in pregnancy: TSH receptor binding inhibiting immunoglobulins and maternal and neonatal thyroid function. Clin Endocrinol 1990; 32:141–152. ¨ sterbund K, Ma¨kinen T, Pekonen, Lamberg BA, Ikonen E, Teramo K, Wa¨gar G, O F. Treatment of maternal hyperthyroidism with antithyroid agents and changes in thyrotrophin and thyroxine in the newborn. Acta Endocrinol 1981; 97:186– 195. Cheron RG, Kaplan MM, Larsen PR, Selenkow HA, Crigler JF. Neonatal thyroid function after propylthiouracil therapy for maternal Graves’ disease. N Engl J Med 1981; 304:525–528. Momotani N, Noh J, Oyanagi H, Ishikawa N, Ito K. Antithyroid drug therapy for Graves’ disease during pregnancy. N Engl J Med 1986; 315:24–28. Momotoni N, Noh JY, Ishikawa N, Ito K. Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves’ hyperthyroidism. J Clin Endocrinol Metab 1997; 82:3633–3636. Cooper DS, Saxev C, Meskell M., Maloof F, Ridgway EC. Acute effects of propylthiouracil (PTU) on thyroidal iodide organification and peripheral iodothyronine deiodination: correlation with serum PTU level measured by radioimmunoassay. J Clin Endocrinol Metab 1982; 54:101. Fisher DA. Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 1997; 40:16–31. Davidson KM, Richards DS, Schatz DA, Fisher DA. Successful in utero treatment of fetal goiter and hypothyroidism. N Engl J Med 1991; 324:543–561. Van Loon AJ, Derksen J, Bos AF, Rouwe CW. In utero diagnosis and treatment of fetal goitrous hypothyroidism, caused by maternal use of propylthiouracil. Prenatal Diagn 1995; 15:599–604. Ochoa-Maya M, Frates NC, Lee-Parritz A, Seely EW. Resolution of fetal goiter after discontinuation of propylthiouracil in a pregnant woman with Graves’ hyperthyroidism. Thyroid 1999; 9:1111–1114. McCarroll AM, Hutchinson M., McAuley R, Montgomery DAD. Long-term assessment of children exposed in utero to carbimazole. Arch Dis Child 1976; 51:532– 536. Burrow GN, Klatskin EH, Genel M. Intellectual development in children whose mothers received propylthiouracil during pregnancy. Yale J Biol Med 1978; 51: 151–156. Messer PM, Hauffa BP, Olbricht T, Benker G, Kotulla P, Reinwein D. Antithyroid drug treatment of Graves’ disease in pregnancy: long-term effects on somatic growth, intellectual development and thyroid function of the offspring. Acta Endocrinol 1990; 123:311–316. Eisenstein Z, Weiss M, Katz Y, Bank H. Intellectual capacity of subjects exposed to methimazole or propylthiouracil in utero. Eur J Pediatr 1992; 1:558–559.

416

Mandel

67. Greenberg F. Brief clinical report: choanal atresia and athelia: methimazole teratogenicity or a new syndrome? Am J Med Genet 1987; 28:931–934. 68. Wilson LC, Kerr BA, Wilkinson R, Fossard C, Donnai D. Choanal atresia and hypothelia following methimazole exposure in utero: a second report. Am J Med Genet 1998; 75:220–222. 69. Wing DA, Millar LK, Koonings PP, Montoro MN, Mestman JH. A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 1994; 170:90–95. 70. Mestman JH. Hyperthyroidism in pregnancy. Clin Obstet Gynecol 1997; 40:45–64. 71. Sherif IH, Oyan WT, Bosairi S, Carrascal SM. Treatment of hyperthyroidism in pregnancy. Acta Obstet Gynecol Scand 1991; 70:461–463. 72. Momotani N, Hisaoka T, Noh J, Ishikawa N, Ito K. Effects of iodine on thyroid status of fetus versus mother in treatment of Graves’ disease complicated by pregnancy. J Clin Endocrinol Metab 1992; 75:738–744. 73. Brodsky JB, Cohen EN, Brown BW, Wu ML, Whitcher C. Surgery during pregnancy and fetal outcome. Am J Obstet Gynecol 1980; 138:1165–1167. 74. Masiukiewicz US, Burrow GN. Hyperthyroidism in pregnancy; diagnosis and treatment. Thyroid 1999; 9:647–642. 75. Stoffer SS, Hamburger JI. Inadvertent 131 I therapy for hyperthyroidism in the first trimester of pregnancy. J Nucl Med 1976; 17:146–149. 76. Kampmann JP, Hansen JM, Johansen K, Helweg J. Propylthiouracil in human milk. Lancet 1980; 4:736–738. 77. Johansen K, Andersen AN, Kampmann JP, Hansen JM, Mortensen HB. Excretion of methimazole in human milk. Euro J Clin Pharm 1982; 23:339–341. 78. Momotani N, Yamashita R, Yoshimoto M, Noh J, Ishikawa N, Ito K. Recovery from fetal hypothyroidism: evidence for the safety of breast-feeding while taking propylthiouracil. Clin Endocrinol 1989; 31:591–595. 79. Momatani N, Yamashita R, Makino F, Noh J, Iahikawa N, Ito K, Ito K. Thyroid function in wholly breast feeding infants whose mothers take high doses of propylthiouracil. Clin Endocrinol. 2000; 53:177–181. 80. Azizi F, Khoshniat M, Bahrainian M, Hedayati M. Thyroid function and intellectual development of infants nursed by mothers taking methimazole. J Clin Endocrinol Metab. 2000; 85:3233–3238. 81. Burrow GN. Thyroid function and hyperfunction during gestation. Endocr Rev 1993; 14:194–202. 82. Zakarija M, McKenzie M. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves’ disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab 1983; 57:1036–1040. 83. McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid 1992; 2:155–159. 84. Porreco RP, Bloch CA. Fetal blood sampling in the management of intrauterine thyrotoxicosis. Obstet Gynecol 1990; 76:509–512. 85. Wenstrom KD, Weiner CP, Williamson RA, Grant, SS. Prenatal diagnosis of fetal hyperthyroidism using funipuncture. Obstet Gynecol 1990; 76:513–517. 86. Skuza KA, Sills IN, Stene M, Rapaport R. Prediction of neonatal hyperthyroidism in infants born to mothers with Graves’ disease. J Pediatr 1996; 128:264–267.

Thyroid Disease and Pregnancy

417

87. Rasmussen, NG, Hornnes PJ, Hegedu¨s L. Ultrasonographically determined thyroid size in pregnancy and post partum: the goitrogenic effect of pregnancy. Am J Obstet Gynecol 1989; 160:1216–1220. 88. Berghout A, Endert E, Ross A, Hogerzeil HV, Smits NJ, Wiersinga WM. Thyroid function and thyroid size in normal pregnant women living in an iodine replete area. Clin Endocrinol 1994; 41:375–379. 89. Struve CW, Haupt S, Ohlen S. Influence of frequency of previous pregnancies on the prevalence of thyroid nodules in women without clinical evidence of thyroid disease. Thyroid 1993; 3:7–9. 90. Tan GH, Gharib H, Goellner JR, van Heerden JA, Bahn RS. Management of thyroid nodules in pregnancy. Arch Intern Med 1996; 156:2317–2320. 91. Herzon FS, Morris DM, Segal MN, Rauch G, Parnell T. Coexistent thyroid cancer and pregnancy. Arch Otolaryngol Head Neck Surg 1994; 120:1191–1193. 92. Moosa M, Mazzaferri EL. Outcome of differentiated thyroid cancer diagnosed in pregnant women. J Clin Endocrinol Metab 1997; 82:2862–2866. 93. Rosen IB, Korman M, Walfish PG. Thyroid nodular disease in pregnancy: current diagnosis and management. Clin Obstet Gynecol 1997; 40:81–89. 94. Browne-Martin K, Emerson CH. Postpartum thyroid dysfunction. Clin Obstet Gynecol 1997; 40:90–101. 95. Roti E, Emerson CH. Clinical review 92 postpartum thyroiditis. J Clin Endocrinol Metab 1992; 74:3–7. 96. Stagnaro-Green A, Roman SH, Cobin RH, El-Harazy E, Wallenstein S, Davies, TF. A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction. J Clin Endocrinol Metab 1992; 74:645–653. 97. Hayslip CC, Fein HG, O’Donnell VM, Friedman DS, Klein TA, Smallridge RC. The value of serum antimicrosomal antibody testing in screening for symptomatic postpartum thyroid dysfunction. Am J Obstet Gynecol 1988; 159:203–209. 98. Gerstein HC. Incidence of postpartum thyroid dysfunction in patients with type 1 diabetes mellitus. Ann Intern Med 1993; 118:419–423. 99. Solomon B, Fein HG, Smallridge RC. Usefulness of antimicrosomal antibody titers in the diagnosis and treatment of postpartum thyroiditis. J Fam Pract 1993; 36: 177–182. 100. Tachi J, Amino N, Tamaki H, Aozasa M, Iwatani Y, Miyai K. Long term followup and HLA association in patients with postpartum hypothyroidism. J Clin Endocrinol Metab 1988; 66:480–484. 101. Othman S, Phillips DIW, Parkes AB, Richards CJ, Harris B, Fung H, Darke C, John R, Hall R, Lazarus JH. A long-term follow-up of postpartum thyroiditis. Clin Endocrinol 1990; 32:559–564. 102. Lazarus JH, Ammari F, Oretti R, Parkes AB, Richards CJ, Harris B. Clinical aspects of recurrent postpartum thyroiditis. Br J Gen Pract 1997; 5:305–308. 103. Pop VJM, De Rooy HAM, Vader HL, Van Der Heide D, Van Son M, Komproe IH, Essed GGM, De Geus CA. Postpartum thyroid dysfunction and depression in an unselected population. New Engl J Med 1991; 324:1815–1816. 104. Harris B, Othman S, Davies JA, Weppner GJ, Richards CJ, Newcombe RG, Lazarus JH, Parkes AB, Hall R, Phillips DIW. Association between postpartum

418

Mandel

thyroid dysfunction and thyroid antibodies and depression. BMJ 1992; 305:152– 156. 105. Gorman CA. Radioiodine and pregnancy. Thyroid 1999; 9:721–726. 106. Mandel SJ. Postpartum thyroiditis in women with subclinical hypothyroidism. Annual Meeting of the American Thyroid Association 1998. 107. Amino N, Tada H, Hidaka Y, Crapo LM, Stagnaro-Green A. Screening for postpartum thyroiditis. J Clin Endocrinol Metab 1999; 84:1813–1821.

Index

Achilles reflex relaxation time, 18 Achropachy Graves’ disease, 39 Acquired hypothyroidism of infancy, 325 Acute infectious thyroiditis, 102– 103 Acute suppurative thyroiditis children, 333 Adrenal insufficiency overt hypothyroidism, 141 Advanced aging thyroid function, 349 Age Graves’ disease, 41 MTC, 273–274 PTL, 285 thyroid carcinoma, 243–244

Aging advanced thyroid function, 349 antithyroid antibodies, 349–350 circulating T3, 348–349 circulating T4, 348–349 circulating TSH, 348 high-serum T4, 351 low-serum T4, 350 nonthyroidal illness, 350–351 serum thyroglobulin, 352 thyroid hormone physiology, 346–348 thyroid hormone secretion, 347– 348 thyroid imaging, 351–352 thyroid morphology, 345–346 TRH-TSH axis, 347 419

420

Agranulocytosis, 53–54 AIT, 108–111 Albumin, 2 Alcohol ablative therapy, 213 Alpha interferon, 111 American Academy of Family Physicians elderly screening, 353 American Association of Clinical Endocrinologists elderly screening, 353 Amiodarone drug-induced hypothyroidism, 160–161 Amiodarone-induced hyperthyroidism (AIT), 108–111 Analogue free thyroxine (T4) method (see One-step free thyroxine (T4) method) Anaplastic thyroid carcinoma (ATC), 277–281 chemotherapy, 283 clinical presentation, 279 CT, 280–281 distant metastases, 279–280 doxorubicin and hyperfractionated radiation therapy, 283–284 elderly, 374 outcome, 377 external radiotherapy, 282–283 FNA, 280 gross features, 278 histological features, 278 immunohistochemical studies, 278 incidence, 277 large-cell carcinoma, 278 mortality, 281 natural history, 281 origin, 277 p53 suppressor gene, 278–279 pathology, 277–279

Index

[Anaplastic thyroid carcinoma (ATC)] prognostic factors, 281 radionuclide studies, 280 small-cell carcinoma, 277–278 surgery, 282 thyroid ultrasonography, 280 ANCA, 55 Anosmia, 53 Anti-Tg antibodies, 265–266 Anticytoplasmic neutrophil antibodies (ANCA), 55 Antimicrosomal antibodies, 22 Antithyroid antibodies aging, 349–350 hypothyroidism, 149 Antithyroid arthritis syndrome, 54– 55 Antithyroid drugs, 46–49 clinical pharmacology, 46–49 complications, 47 family planning, 50 Graves’ disease pregnancy, 399–404 placenta, 316 side effects, 48, 52–56, 329 Antithyroid microsomal antibodies detection, 16 Antithyroid peroxidase Graves’ disease, 45 Arterial blood gases, 358 ATC (see Anaplastic thyroid carcinoma) Atenolol children, 335 congenital hyperthyroidism, 328 elderly hyperthyroidism, 367 Graves’ disease, 56–57 Atomic bombing, 231 Atrial fibrillation elderly hyperthyroidism, 369 Autoimmune thyroid disease, 9 children, 330–331

Index

Autoimmune thyroiditis diagnosis, 17, 22 elderly, 353 Basal metabolic rate, 17–18 Beta-adrenergic blocking agents elderly hyperthyroidism, 367 Beta-adrenergic blocking agents children, 335 congenital hyperthyroidism, 328 contraindications, 57 Graves’ disease, 56–57 pregnancy, 404 side effects, 57 silent thyroiditis, 98 subacute thyroiditis, 96 Bexarotene TSH effect, 13 Block-replacement regimen, 51 Blood dosimetry radioiodine (131 I) therapy, 258 Bone mineral densitometry, 18 Bravo nuclear test, 231 Breast feeding Graves’ disease pregnancy, 406 C cells, 25 Calcitonin double-antibody immunoassay, 25–26 elderly, 375 MTC, 26–27, 214–215, 272 single-antibody immunoassay, 25–26 Calcium, 36 Calcium channel blockers Graves’ disease, 57 Canadian Task Force of the Periodic Health Examination elderly screening, 353

421

Cancer radioiodine ( 131 I) therapy, 61–62 Cardiac contractility thyroid hormone, 18 Carney complex, 230 Carotid artery pulse tracing, 18 Central hypothyroidism development, 148 treatment, 159 TSH and TH levels in, 147 Central nervous system manifestations Graves’ disease, 37–38 Children acute suppurative thyroiditis, 333 atenolol, 335 autoimmune thyroid disease, 330–331 beta-adrenergic blocking agents, 335 goitrogens, 333 idiopathic thyromegaly, 332 iodine deficiency, 332 methimazole, 335 MTC, 339 nodular thyroid disease, 337–339 overt hypothyroidism, 141 postoperative hypoparathyroidism, 252 propranolol, 335 PTC, 337–338 subacute thyroiditis, 333–334 thyroid carcinoma prognosis, 243–244 toxic thyroiditis, 331–332 Cholestasis, 53 Choriocarcinoma, 121 Circulating thyroid stimulating hormone (TSH) aging, 348 Circulating thyroxine (T4 ) aging, 348–349

422

Circulating triiodothyronine (T3 ) aging, 348–349 Clinically solitary nodule thyroid scintigraphy, 204 Clubbing Graves’ disease, 39 Cold temperature infants TSH levels, 14–15 Colloid thyroid nodule, 193 Colorado Thyroid Disease Prevalence Study, 136, 143– 144 Columnar cell variant PTC, 238 Completion thyroidectomy, 251– 252 Compressive goiter elderly, 378 Computed tomography (CT) ATC, 280–281 elderly, 376 nodular thyroid disease, 201 PTL, 290 Congenital hyperthyroidism, 325– 330 diagnosis, 327–328 therapy, 328–330 Congenital hypothyroidism, 318– 325 epidemiology, 318–319 L-thyroxine, 320–323 management, 319–320 screening tests, 319–320 VLBW, 323–324 Coronary artery disease overt hypothyroidism, 140 Corticosteroids silent thyroiditis, 98 subacute thyroiditis, 96 Cost FNA, 215–218

Index

Cowden disease, 230 Cretinism (see also Congenital hypothyroidism) overt hypothyroidism, 143 CT (see Computed tomography) Cytokine-induced hyperthyroidism, 111–112 Delayed puberty overt hypothyroidism, 141 Dementia, 20 Depression hypothyroidism, 168–169 Dessicated thyroid hypothyroidism, 166 to levothyroxine therapy, 167 Dietary iodine geographical variations, 42 Diffuse follicular variant papillary carcinoma PTC, 238 Diffuse sclerosing variant PTC, 238–239 Digoxin congenital hyperthyroidism, 328 Diltiazem thyrotoxicosis, 57 Distant metastases ATC, 279–280 FTC, 240 PTC, 233–237 thyroid carcinoma prognosis, 247 Double-antibody immunoassay serum calcitonin, 25–26 Down’s syndrome with congenital hypothyroidism, 318, 324 Doxorubicin and hyperfractionated radiation therapy ATC, 283–284

Index

Drug-induced hypothyroidism treatment, 160–162 Drug-induced lupus, 53 Elderly compressive goiter, 378 excess TH replacement hypothyroidism, 169 hyperthyroidism, 362–371 atrial fibrillation, 369 diagnosis, 365–366 epidemiology, 363 pathophysiology, 363 subclinical, 370–371 T3 toxicosis, 364–365 T4 toxicosis, 364–365 thyroid storm, 370 treatment, 367–368 hypothyroidism, 353–362 diagnosis, 354–356 epidemiology, 353 myxedema coma, 357–359 pathophysiology, 353 subclinical, 359–362 treatment, 356–357 LT4, 165 nodular thyroid disease, 371–378 diagnosis, 372–376 epidemiology, 371–372 outcome, 377 pathophysiology, 372 treatment, 376–377 radioiodine (131I) therapy Graves’ disease, 58 screening, 352–353 subclinical thyroid disease, 352 toxic multinodular goiter, 74 Electrocardiography, 18 Elevated serum calcium, 36 Elevated serum thyroglobulin (Tg) negative imaging studies treatment, 267–268

423

Elevated thyroid hormone binding ratio (THBR) euthyroid hypothyroxinemia, 22 ELISA, 3–4 Encapsulated papillary carcinoma PTC, 238 Enzyme-linked immunosorbent assay (ELISA), 3–4 Equilibrium dialysis method, 4 Esmolol Graves’ disease, 56–57 Euthyroid hyperthyroxinemia, 7, 9 diagnosis, 23–24 Euthyroid hypothyroxinemia cause, 10–11 elevated THBR, 22 Euthyroid patients vs. hyperthyroid patients, 13 Euthyroid sick syndrome, 46 aging, 350–351 TSH and TH levels in, 147 Euthyroidism pregnancy, 390 Excess thyroid hormone replacement hypothyroidism, 169 Exogenous thyroid hormone hyperthyroidism from, 113–114 External beam radiation-induced thyrotoxic thyroiditis, 104 External beam radiation therapy, 263 External radiation radiation-induced thyroid carcinoma epidemiology, 230–231 External radiotherapy ATC, 282–283 Familial dysalbuminemic hyperthyroxinemia (FDH), 9 Familial non-MEN medullary thyroid carcinoma (FMTC), 269 genetic alterations, 270

424

Familial papillary carcinoma, 230 Familial thyroid dyshormonogenesis, 324 Family planning antithyroid drugs, 50 FDH, 9 Fertility Graves’ disease, 38 Fetal-maternal thyroid function placenta, 316–317 Fetus brain maturation, 393 goiter, 402 hyperthyroidism, 406–407 thyroid function, 314–315 Fine-needle aspiration (FNA) ATC, 280 cost considerations, 215–218 elderly, 375 follicular adenomas, 242 FTC, 241–243 Hurthle cell tumors, 242 nodular thyroid disease, 192–196 practice patterns, 216–217 PTC, 241–243 PTL, 289 thyroid neoplasia, 25 FMTC, 269 genetic alterations, 270 FNA (see Fine-needle aspiration) Follicular adenomas FNA, 242 Follicular thyroid carcinoma (FTC) distant metastases, 240 epidemiology, 230 FNA, 241–243 follow-up, 263–264 HTC, 240 imaging studies, 266–267 lymph node metastases, 240 pathology, 239–240 presentation, 241

Index

[Follicular thyroid carcinoma (FTC)] radioiodine (131 I) therapy, 253– 261 retinoic acid, 262 rh TSH, 264–265 serum Tg, 265–266 thyroid hormone therapy, 261– 262 thyroidectomy, 250–253 Follicular variant of papillary thyroid carcinoma (PTC), 233, 238 Fractures postmenopausal women, 36 Free thyroxine (T4) determination, 4–7, 21 RIA, 5 Free triiodothyronine (T3) determination, 4–7 FTC (see Follicular thyroid carcinoma) Gamma knife, 264 Gamma scintillation camera, 197 Gender PCT, 229 PTL, 285 thyroid carcinoma prognosis, 243–244 Generalized resistance to thyroid hormone (GRTH) vs. hypothyroidism, 149 Genetic alterations FMTC, 270 MEN 2, 270 sporadic MTC, 270 Genetic screening MTC, 274, 276–277 Gestation thyroid hormone, 387–389 Gestational thyrotoxicosis, 395– 396

Index

Goiter classification, 188–189 PTL, 287 Goitrogens children, 333 Gonadal failure radioiodine (131 I) therapy, 261 Graves’ disease, 23, 33–64 achropachy, 37–38 antithyroid drug therapy, 46–56 beta-adrenergic antagonist drugs, 56–57 bilateral exophthalmos, 39 calcium channel blockers, 57 CNS manifestations, 37–38 diagnosis, 16–17 epidemiology, 34 gynecomastia, 40 with Hashimoto’s thyroiditis, 45 laboratory assessment pitfalls, 45–46 lithium, 57 manifestations age, 41 pathophysiology, 34–35 perchlorate, 57–58 pregnancy, 396–407 complications, 398–399 diagnosis, 398 outcome, 398–399 treatment, 399–407 radioiodine (131 I) therapy, 58–62 dosage, 58–59 radioiodine uptake, 24 remission, 52 serum antithyroid peroxidase, 45 signs and symptoms, 35–36 TH measures, 41–43 therapy choice of, 63–64 thyroglobulin antibody levels, 45 thyroidectomy, 62–63

425

[Graves’ disease] TSH levels, 41–43 TSH receptor antibody measurements, 43–45 Graves’ ophthalmopathy, 37 orbital CT scan, 38 radioiodine (131 I) therapy, 60–61 superior limbal keratopathy, 39 Growth overt hypothyroidism, 141 GRTH vs. hypothyroidism, 149 Gynecomastia Graves’ disease, 38, 40 Hand tremor, 37 Hanford Thyroid Disease Study, 232 Hashimoto’s disease vs. PTL histological features, 286 Hashimoto’s thyroiditis with Graves’ disease, 45 PTL, 285–286, 288 HCG-associated thyrotoxicosis pregnancy, 395–396 Hepatic involvement PTU, 55–56 Hepatitis, 53 Hepatotoxicity methimazole, 56 High-resolution ultrasonography elderly, 375–376 High-thyroxine (T4) aging, 351 Hoffman’s syndrome overt hypothyroidism, 143 Hormone assays hypothyroidism, 145–147 HTC FNA, 242 FTC, 240

426

Human milk thyroid hormone, 318 Hurthle cell carcinoma (HTC) FNA, 242 FTC, 240 Hurthle cell variant PTC, 239 Hydatidiform mole, 120–121 Hydrocortisone thyroid storm, 67 Hypercalcitoninemia MTC differential diagnosis, 273 Hypercapnic ventilatory drives, 18 Hyperdefecation, 35 Hyperemesis gravidarum pregnancy, 395–396 Hyperfractionated radiation therapy and doxorubicin ATC, 283–284 Hyperprolactinemia overt hypothyroidism, 141 Hyperthyroid patients vs. euthyroid patients, 13 Hyperthyroidism, 7 clinical effects, 36 diagnosis, 23–24 elderly, 362–371 from exogenous thyroid hormone, 113–114 iodine-induced, 104–108 and MTC, 121–123 pregnancy, 395–407 Graves’ disease, 396–407 hCG-associated thyrotoxicosis, 395–396 serum alteration, 19 serum TSH level, 24 Tg, 15 thyroid radioisotope scans, 74–75 thyrotrophin-induced, 114–116 treatment, 24

Index

Hyperthyrotropinemia differential diagnosis, 14 TSH levels, 14–15 Hypoglycemia, 358 Hyponatremia, 358 Hypophosphatemia, 37 Hypothalamic-pituitary-thyroid axis mother vs. fetus, 314–315 physiology, 2–3 Hypothyroidism, 6–7 antithyroid antibodies, 149 changing TH requirements, 163– 166 depression, 168–169 dessicated thyroid, 166 diagnosis, 21–23 drug-induced treatment, 160–162 elderly, 353–362 epidemiology, 136 etiology, 137–138 excess TH replacement, 169 vs. GRTH, 149 hormone assays, 145–147 obesity, 168 pathophysiology, 137 patient-oriented treatment, 154–159 pregnancy, 390–395 complications, 392 diagnosis, 391 outcome, 391–393 treatment, 394–395 premenstrual syndrome, 169 radioactive iodine, 71–72 risk factors, 151 screening, 149–152 serum alteration, 19 surgery, 167–168 TH, 152–154 TH tablet sensitivity, 167 thyroid cancer treatment, 160

Index

[Hypothyroidism] thyroid hormone replacement, 22–23 TSH monitoring, 22–23 treatment pitfalls, 163–170 TSH levels, 13 unresolved symptoms, 163 Hypothyrotropinemia TSH radioimmunoassays, 13 Hypothyroxinemia, 11, 21 Hypotriiodothyronemia, 11 Hypoxic ventilatory drives, 18 131

I elderly hyperthyroidism, 368– 369 Graves’ disease pregnancy, 405–406 Idiopathic thyromegaly children, 332 Immunoglobulin PTL, 289 Incidentaloma, 210–212 Indeterminate thyroid nodule, 193– 194 Indirect calorimetry, 17–18 Indirect equilibrium dialysis method, 4 Infants cold temperature TSH levels, 14–15 Infections overt hypothyroidism, 139–140 Infertility overt hypothyroidism, 141 radioiodine (131 I) therapy, 261 Inflammatory thyroiditis thyrotoxicosis, 7 Inherited medullary thyroid carcinoma (MTC), 274 Insular carcinoma PTC, 239

427

Interferon alpha drug-induced hypothyroidism, 166 Interleukin-2 drug-induced hypothyroidism, 166 Intrauterine growth retardation (IUGR) congenital hypothyroidism, 323– 324 Iodides Graves’ disease pregnancy, 404 Iodine congenital hyperthyroidism, 328, 329 deficiency children, 332 dietary geographical variations, 42 insufficiency, 34–35 kinetics pediatric vs. adult, 316 uptake aging, 351 Iodine-containing drugs, 107 Iodine-induced hyperthyroidism, 104–108 diagnosis, 106–107 epidemiology, 105 incidence, 106 pathophysiology, 105–106 therapy, 107–108 Iopanoate thyroid storm, 67 Ipodate silent thyroiditis, 98 thyroid storm, 67 Ipsilateral lobectomy, 250–251 Irradiation-induced papillary thyroid carcinoma (PTC) prognosis, 247

428

Isotopic scanning elderly, 375 Isthmusectomy, 250–251 IUGR congenital hypothyroidism, 323– 324 Juvenile thyrotoxicosis, 334–336 Kocher-Debre-Semeliagne syndrome overt hypothyroidism, 143 Lactation Graves’ disease pregnancy, 406 LATS assay, 16 Left ventricular performance overt hypothyroidism, 140 Leukemia radioiodine (131 I) therapy, 260– 261 Levothyroxine (LT4), 22, 152–166 altered doses conditions associated with, 164 complications, 262 congenital hypothyroidism, 320– 323 drugs increasing requirements for, 164 elderly, 165 hypothyroidism, 356–357 missed doses, 164 pregnancy hypothyroidism, 394–395 TSH suppression, 261–262 Liothyronine (LT3), 152 Lithium drug-induced hypothyroidism, 166 Graves’ disease, 57 radioiodine (131 I) therapy, 253– 254

Index

Lithium-associated thyrotoxicosis, 112 Long-acting thyroid stimulator (LATS) assay, 16 Low-birth-weight infants, 392 Low-serum thyroxine (T4 ) aging, 350 Low triiodothyronine syndrome aging, 350 LT3, 152 LT4 (see Levothyroxine) Lugol’s solution congenital hyperthyroidism, 329 thyroid storm, 67 Lupus drug-induced, 53 Lymph node metastases FTC, 240 PTC, 233 thyroid carcinoma prognosis, 246 Lymphocytic thyroiditis (see Hashimoto’s disease) M-mode echocardiography, 18 Magnetic resonance imaging (MRI) elderly, 376 nodular thyroid disease, 201–202 PTL, 290 Malignant thyroid nodule, 194 Medullary thyroid carcinoma (MTC), 26–28, 268–277 calcitonin, 214–215, 272 children, 339 classification, 268–269 clinical features, 271–272 demographics, 270–271 elderly outcome, 377 family screening, 276–277 follow-up, 275–276 genetic alterations, 270 genetic screening, 274, 276

Index

[Medullary thyroid carcinoma (MTC)] hormonal features, 272 hypercalcitoninemia differential diagnosis, 273 and hyperthyroidism, 121–123 inherited, 274 inoperable, 275 metastases, 271 omeprazole stimulation test, 273 pathology, 271 prevalence, 270–271 prognosis, 273–274 prophylactic total thyroidectomy, 276–277 recurrent, 275 residual, 275 Ret protooncogene mutations, 27 serum calcitonin, 26–27 stimulation tests, 273 surgery, 274–275 tumor calcitonin, 271 tumor location, 269 MEN, 26–28 parathyroid disease, 269 pheochromocytoma, 270 MEN 2 genetic alterations, 270 MEN type 2 syndromes, 269–270 MEN type 2A, 269 Mental retardation overt hypothyroidism, 143 Metastases distant (see Distant metastases) lymph node FTC, 240 PTC, 233 thyroid carcinoma, 246 MTC, 271 Methimazole, 47 AIT, 110 children, 335 congenital hyperthyroidism, 329

429

[Methimazole] elderly hyperthyroidism, 368 fetal effect, 400–403 Graves’ disease pregnancy, 399–404 hepatotoxicity, 56 vs. PTU, 50 side effects, 52–53 subclinical hyperthyroidism, 66 thyroid storm, 67 Metoprolol elderly hyperthyroidism, 367 Graves’ disease, 56–57 Milk thyroid hormone, 318 Miscarriage, 390 Mixed papillary-follicular carcinoma, 233 MNG, 189, 208–210 elderly, 365 toxic (see Toxic multinodular goiter) Molar pregnancy, 120 Monoclonal gammopathies, 9 MRI elderly, 376 nodular thyroid disease, 201–202 PTL, 290 MTC (see Medullary thyroid carcinoma) Multinodular goiter (MNG), 189, 208–210 elderly, 365 toxic (see Toxic multinodular goiter) Multiple endocrine neoplasia syndrome (MEN), 26–28 parathyroid disease, 269 pheochromocytoma, 270 Multiple endocrine neoplasia syndrome (MEN) 2 genetic alterations, 270

430

Multiple endocrine neoplasia syndrome (MEN) type 2 syndromes, 269–270 Multiple endocrine neoplasia syndrome (MEN) type 2A, 269 Multiple entrapment neuropathies overt hypothyroidism, 143 Myocardial dysfunction overt hypothyroidism, 140 Myxedema coma, 145 elderly hypothyroidism, 357–359 treatment, 162–163 Myxedema madness, 142 Nadolol elderly hyperthyroidism, 367 Graves’ disease, 56–57 National Health and Nutrition Examination Survey III (NHANES III), 136 Natural thyroid hypothyroidism, 166 Neonate goiter, 402 hyperthyroidism, 406–407 thyroid function, 315–318 NHANES III, 136 Nodular thyroid disease causes, 191 children, 337–339 classification, 188–189 clinically solitary nodule management, 202–208 CT, 201 cytological examination, 195–196 elderly, 371–378 FNA, 192–196 indications, 192–193 results, 193–196 technique, 193 history, 190 hypocellular smears, 194

Index

[Nodular thyroid disease] MRI, 201–202 pathogenesis, 189–190 physical examination, 190 prevalence, 188–189 scintigraphy, 196–197 thyroid hormone therapy, 206– 208 ultrasonography, 197–201 indications, 197–199, 201 results, 199–201 technique, 199 women, 188–189 Nonsteroidal anti-inflammatory drugs subacute thyroiditis, 96 Nontoxic goiter, 188 Nuclear fallout radiation-induced thyroid carcinoma epidemiology, 231–232 Obesity hypothyroidism, 168 Octreotide TSH-secreting pituitary adenomas, 116 Omeprazole stimulation test MTC, 273 Oncogenes thyroid carcinoma prognosis, 247 One-step free thyroxine (T4 ) method, 4–6 Overt hypothyroidism, 10 cardiovascular abnormalities, 140–141 children, 141 clinical symptoms, 139 common features, 137–139 endocrine abnormalities, 141–142 infections, 139–140

Index

[Overt hypothyroidism] musculoskeletal disorders, 143 neurologic disorders, 143 psychiatric disorders, 142–143 pulmonary abnormalities, 140 Overt primary hypothyroidism treatment, 154–155 Oxyphilic variant PTC, 239 P53 suppressor gene ATC, 278–279 Painless thyroiditis (see Silent thyroiditis) Papillary microcarcinoma PTC, 236 Papillary thyroid carcinoma (PTC) children, 337–338 columnar cell variant, 238 diffuse follicular variant papillary carcinoma, 238 diffuse sclerosing variant, 238– 239 distant metastases, 233–237 encapsulated papillary carcinoma, 238 FNA, 241–243 follicular variant papillary carcinoma, 238 follow-up, 263–264 imaging studies, 266–267 insular carcinoma, 239 irradiation-induced prognosis, 247 lymph node metastases, 233 oxyphilic variant, 239 papillary microcarcinoma, 236 pathology, 232–239 presentation, 241 prevalence, 229 radioiodine (131 I) therapy, 253–261 rh TSH, 264–265

431

[Papillary thyroid carcinoma (PTC)] serum Tg, 265–266 solid variant, 239 tall cell variant, 238 thyroglossal duct, 236 thyroid hormone therapy, 261– 262 thyroidectomy, 250–253 trabecular variant, 239 Parathyroid disease MEN, 269 Parotid dysfunction radioiodine (131 I) therapy, 259–260 PCR Tg, 15 PEI, 213–214 solitary autonomous toxic nodules, 72–73 Pendred’s syndrome, 324–325 Perchlorate AIT, 110 Graves’ disease, 57–58 Perchlorate discharge test, 324 Percutaneous ethanol injection (PEI), 213–214 solitary autonomous toxic nodules, 72–73 Pericardial effusion overt hypothyroidism, 140 Peripheral metabolic polyneuropathies overt hypothyroidism, 143 Persistent subclinical hyperthyroidism, 52 Pheochromocytoma MEN, 270 Phonocardiography, 18 Pituitary pseudotumor primary hypothyroidism, 142 Pituitary tumors radiation therapy, 116 resection, 116

432

Placenta fetal-maternal thyroid function, 316–317 Postmenopausal women fractures, 36 Postoperative hypoparathyroidism, 252 children, 252 Postpartum thyroiditis, 99–102, 408–412 diagnosis, 100–101, 410–411 epidemiology, 99 frequency, 100 natural history, 101 pathophysiology, 99–100 screening, 411–412 thyrotoxic phase, 409 treatment, 101–102, 411–412 Postpartum transient thyroid dysfunction, 20–21 Postradioiodine hypothyroidism treatment, 159 Precocious puberty overt hypothyroidism, 141 Prednisone AIT, 110 subacute thyroiditis, 96 Pregnancy euthyroidism, 390 Graves’ disease fetal hyperthyroidism, 406–407 hyperthyroidism, 395–407 hypothyroidism, 163, 390–395 thyroid autoimmunity, 390 thyroid nodules, 407–408 thyroidectomy, 252–253 Premenstrual syndrome hypothyroidism, 169 Pretibial myxedema, 38–41 Primary hypothyroidism pituitary pseudotumor, 142 TSH and TH levels in, 147

Index

Primary thyroid lymphoma (PTL), 284–294 age, 285 chemotherapy, 293–294 differential diagnosis, 288 distant recurrence, 294 failure patterns, 294 FNA, 289 gender, 285 Hashimoto’s thyroiditis, 285–286, 288 histological features, 286–287 vs. Hashimoto’s disease, 286 imaging studies, 289–291 incidence, 285 long-term survival, 291 lymph nodes, 287–288 lymphoma cell types, 286 prognosis, 291–292 radiotherapy, 293 relapse survival after, 294 serum chemistry, 289 serum immunoglobulin, 289 signs and symptoms, 287–288 staging, 291 surgery, 292–293 thyroid dysfunction, 288 Prophylactic total thyroidectomy MTC, 276–277 Propranolol children, 335 congenital hyperthyroidism, 328 elderly hyperthyroidism, 367 Graves’ disease, 56–57 thyroid storm, 67 Propylthiouracil-induced hepatitis, 55 Propylthiouracil (PTU), 12, 47 breast milk, 406 children, 335 congenital hyperthyroidism, 328, 329

Index

[Propylthiouracil (PTU)] elderly hyperthyroidism, 368 Graves’ disease pregnancy, 399–404 hepatic involvement, 55–56 vs. methimazole, 50 side effects, 52–53 thyroid storm, 67 PTC (see Papillary thyroid carcinoma) PTL (see Primary thyroid lymphoma) Quantitative tumor dosimetry radioiodine (131 I) therapy, 258 Radiation cystitis, 259 Radiation-induced thyroid carcinoma epidemiology, 230–232 external radiation, 230–231 nuclear fallout, 231–232 radioiodine-induced thyroid carcinoma, 231 Radiation pneumonitis, 260 Radiation sialadenitis, 259 Radiation sickness, 259 Radiation thyroiditis, 103–104, 259 Radioactive iodine hypothyroidism, 71–72 MTC, 122 Radioactive iodine ablation silent thyroiditis, 98 toxic adenoma, 71 Radioactive iodine uptake test, 42 radioiodine (131 I) therapy, 58 Radioimmunoassay (RIA), 3 free thyroxine, 5 Radioiodine-assisted surgery, 252 Radioiodine (131 I) therapy blood dosimetry, 258 cancer, 61–62

433

[Radioiodine (131 I) therapy] cancer caused by, 261 empirical fixed doses, 258 false-positive scans, 255 FTC, 253–261 gonadal failure, 261 Graves’ disease, 58–62 dosage, 58–59 Graves’ ophthalmopathy, 60–61 immediate complications, 259 infertility, 261 leukemia, 260–261 lithium, 253–254 parotid dysfunction, 259–260 preparation, 253–254 PTC, 253–261 quantitative tumor dosimetry, 258 rationale, 268 recurrence after, 256–257 recurrent carcinoma, 257–258 repeat treatments, 258–259 residual carcinoma, 257–258 sodium iodide symporter, 253 thyroid remnant ablation, 255, 257 toxic multinodular goiter, 75 whole-body scan stunning effect, 254–255 Radioiodine-induced thyroid carcinoma epidemiology, 231 Radioiodine uptake Graves’ disease, 24 Radionuclide scanning PTL, 290–291 Radionuclide studies ATC, 280 Recombinant human TSH (rh TSH), 264–265 Recurrent carcinoma radioiodine (131 I) therapy, 257–258 Residual carcinoma radioiodine (131 I) therapy, 257–258

434

Resting energy expenditure measurement, 18 Ret protooncogene mutations MTC, 27 Retinoic acid FTC, 262 Reverse triiodothyronine (rT3), 17 Rh TSH, 264–265 RIA, 3 free thyroxine, 5 RT3, 17 Salicylates subacute thyroiditis, 96 Saturated solution of potassium iodide (SSKI) thyroid storm, 67 Schmidt’s syndrome overt hypothyroidism, 141 Scintigraphy nodular thyroid disease, 196–197 Screening congenital hypothyroidism, 319– 320 hypothyroidism, 149–152 MTC, 274, 276–277 postpartum thyroiditis, 411–412 thyroid disease, 19–21 Sense of taste loss of, 53 Serum anti-Tg antibodies, 265–266 Serum antimicrosomal antibodies, 22 Serum antithyroid peroxidase Graves’ disease, 45 Serum calcitonin double-antibody immunoassay, 25–26 elderly, 375 MTC, 26–27 single-antibody immunoassay, 25–26

Index

Serum calcium, 36 Serum chemistry PTL, 289 Serum constituents alteration, 19 Serum immunoglobulin PTL, 289 Serum thyroglobulin (Tg), 15, 265– 266 aging, 352 cutoff levels, 266 elderly, 374–375 thyrotoxicosis, 24 whole-body 131I scans, 265 Serum thyroid stimulating hormone (TSH), 21–22 hyperthyroidism, 24 Serum thyroxine binding globulin (TBG) gestation, 387–388 SGA congenital hypothyroidism, 323– 324 Silent thyroiditis, 96–99 diagnosis, 97–98 epidemiology, 97 pathophysiology, 97 treatment, 98 Simple goiter, 332 Single-antibody immunoassay serum calcitonin, 25–26 Single-antibody immunometric assay, 15 Small for gestational age (SGA) congenital hypothyroidism, 323–324 Sodium iodide symporter radioiodine (131 I) therapy, 253 Solid variant PTC, 239

Index

Solitary autonomous toxic nodules, 68–73 clinical considerations, 69 diagnosis, 69–71 pathogenesis, 68–69 pathology, 68 PEI, 72–73 surgery, 72 treatment, 71–73 Solitary nodule thyroid scintigraphy, 204 Sporadic medullary thyroid carcinoma (MTC) genetic alterations, 270 SSKI thyroid storm, 67 Stapedial reflex, 18 Stimulation tests MTC, 273 Struma ovarii tumor, 118–120 Stunning effect radioiodine (131 I) therapy whole-body scan, 254–255 Subacute thyroiditis, 93–96 children, 333–334 diagnosis, 94–95 epidemiology, 93–94 natural history, 96 pathophysiology, 94 treatment, 96 Subclinical hyperthyroidism, 64– 66 diagnosis, 64–65 treatment, 65–66 Subclinical hypothyroidism, 143– 144 to overt hypothyroidism, 136 treatment, 155–159 Subclinical thyroid disease elderly, 352 Subtotal lobectomy, 250

435

Subtotal thyroidectomy Graves’ disease pregnancy, 405 Synthetic liothyronine (LT3 ), 152 T3 (see Triiodothyronine) T4 (see Thyroxine) Tachyphylaxis, 116 Tall cell variant PTC, 238 TBG, 2 gestation, 387–388 x-linked excess, 7–9 Technetium 99m ( 99m Tc), 266–267 Tg (see Thyroglobulin) Thallium 201 ( 201 Tl), 266 THBR, 6 euthyroid hypothyroxinemia, 22 interpretation pitfalls, 7 Thyroglobulin (Tg), 15, 149, 265– 266 aging, 352 antibody levels Graves’ disease, 45 cutoff levels, 266 elderly, 374–375 negative imaging studies treatment, 267–268 PCR, 15 studies, 15 thyrotoxicosis, 24 whole-body 131 I scans, 265 Thyroglossal duct PTC, 236 Thyroid aging imaging, 351–352 morphology, 345–346 autoantibodies detection, 16–17 autoimmunity pregnancy, 390

436

[Thyroid] function advanced aging, 349 laboratory evaluation of, 3–19 histiogenesis, 314 origin, 313 ultrasonography ATC, 280 Thyroid carcinoma, 227–249 classification, 229 epidemiology, 228–229 hypothyroidism treatment, 160 prognosis, 243–248 distant metastases, 247 irradiation-induced PTC, 247 lymph node metastases, 246 oncogenes, 247 patient variables, 243–245 thyroid capsular invasion, 246 treatment variables, 248 tumor variables, 245–247 radioiodine-induced epidemiology, 231 treatment debates, 249–250 tumor staging systems, 248– 249 Thyroid disease laboratory evaluation, 19–24 screening, 19–21 Thyroid hormone cardiac contractility, 18 gestation, 387–389 measures Graves’ disease, 41–43 neonatal, 316–318 physiology aging, 346–348 resistance, 116–118 TSH and TH levels in, 147

Index

[Thyroid hormone] secretion aging, 347–348 tissue responses to, 19–20 Thyroid hormone assays, 3–12 Thyroid hormone binding ratio (THBR), 6 euthyroid hypothyroxinemia, 22 interpretation pitfalls, 7 Thyroid hormone replacement hypothyroidism, 152–153 TSH monitoring, 22–23 Thyroid hormone therapy nodular thyroid disease, 206–208 Thyroid neoplasms, 24–25 elderly, 373–374 FNA biopsy, 25 Thyroid nodules pregnancy, 407–408 Thyroid ontogenesis, 313–314 Thyroid peroxidase (TPO), 149 Thyroid radioisotope scans hyperthyroidism, 74–75 Thyroid remnant ablation radioiodine (131 I) therapy, 255, 257 Thyroid scintigraphy clinically solitary nodule, 204 Thyroid stimulating hormoneproducing pituitary tumors elderly, 365 Thyroid stimulating hormonesecreting pituitary adenomas, 114–116 Thyroid stimulating hormone (TSH), 2–3, 21–22 aging, 348 assays, 12–15 drug effect on, 13–14 Graves’ disease, 41–43 hyperthyroidism, 24 hyperthyrotropinemia, 14–15

Index

[Thyroid stimulating hormone (TSH)] hypothyroidism, 13 infants cold temperature, 14–15 levothyroxine suppression of, 261–262 placenta, 316 radioimmunoassays hypothyrotropinemia, 13 receptor, 16, 149 receptor antibody measurements Graves’ disease, 43–45 thyroid hormone replacement hypothyroidism, 22–23 Thyroid storm, 66–67, 259 elderly hyperthyroidism, 370 Thyroidectomy, 250–253 AIT, 111 complications, 252 pregnancy, 252–253 silent thyroiditis, 98 toxic multinodular goiter, 76 Thyroiditis acute infectious, 102–103 acute suppurative children, 333 autoimmune diagnosis, 17, 22 elderly, 353 inflammatory thyrotoxicosis, 7 postpartum (see Postpartum thyroiditis) radiation, 103–104, 259 silent (see Silent thyroiditis subacute (see Subactue thyroiditis) Tg, 15 toxic children, 331–332 trauma-induced, 104 Thyromegaly causes, 326, 331–334

437

Thyroperoxidase (TPO) antibodies, 330 Thyrotoxicosis, 6 diltiazem, 57 inflammatory thyroiditis, 7 juvenile, 334–336 lithium-associated, 112 serum thyroglobulin, 24 Thyrotoxicosis factitia, 113–114 Thyrotrophin-induced hyperthyroidism, 114–116 Thyroxine-binding globulin (TBG), 2 gestation, 387–388 x-linked excess, 7–9 Thyroxine-binding prealbumin, 2 Thyroxine (T4 ) aging, 348–349, 351 decreased causes, 10–12 determination, 4–7, 21 gestation, 388–389 increased causes, 7–10 low-serum aging, 350 postpartum thyroiditis, 101– 102 RIA, 5 silent thyroiditis, 99 synthesis, 2 Thyroxine (T4 ) toxicosis elderly hyperthyroidism, 364– 365 TNM classification thyroid carcinoma, 248–249 Total serum iodothyronine concentrations, 3–4 Total thyroidectomy, 251 Toxic adenoma elderly, 365 radioactive iodine ablation, 71

438

Toxic multinodular goiter, 73–77 diagnosis, 75 elderly, 74 pathogenesis, 73–75 treatment, 75–77 Toxic thyroiditis children, 331–332 TPO, 149 TPO antibodies, 330 Trabecular variant PTC, 239 Transient congenital hypothyroidism, 393 Transient hyperthyroidism elderly, 365 Transient hypothyroidism treatment, 160 Transient myocardial ischemia overt hypothyroidism, 140 Transient thyroid dysfunction postpartum, 20–21 Transthyretin, 2 Trauma-induced thyroiditis, 104 Triiodothyronine (T3 ) aging, 348–349 decreased causes, 10–12 determination, 4–7 gestation, 388–389 increased causes, 7–10 synthesis, 2 Triiodothyronine (T3 ) toxicosis elderly hyperthyroidism, 364– 365 Trophoblastic tumors, 120–121 TSH (see Thyroid stimulating hormone)

Index

Tumor calcitonin MTC, 271 Two-antibody immunometric assay, 15 Two-step free thyroxine (T4) method, 6 Type 2 autoimmune polyendocrinopathy overt hypothyroidism, 141 Ultrasonography nodular thyroid disease, 197–201 PTL, 290 US-FNA, 212–214 Vasculitis, 53 Very low birth-weight (VLBW) congenital hypothyroidism, 323– 324 Visual evoked potentials, 18 VLBW congenital hypothyroidism, 323– 324 Whickham study, 20 Whole-body 131 I scans serum Tg, 265 stunning effect, 254–255 Whole-body positron emission tomography (PET), 267 Women nodular thyroid disease, 188–189 postmenopausal fractures, 36 X-linked inherited thyroxine binding globulin excess, 7–9

About the Editor

David S. Cooper is Professor of Medicine and International Health, The Johns Hopkins University School of Medicine, Baltimore, Maryland, Director of the Division of Endocrinology, Sinai Hospital of Baltimore, Maryland, and Director of the Thyroid Clinic, The Johns Hopkins Hospital, Baltimore, Maryland. Dr. Cooper is the author, coauthor, or coeditor of more than 130 peer-reviewed journal articles, abstracts, book chapters, and books; an associate editor of the Journal of Clinical Endocrinology and Metabolism and a contributing editor of the Journal of the American Medical Association; and a Fellow of the American College of Physicians and a member of the American Federation for Clinical Research, the American Thyroid Association, the Endocrine Society, the American Diabetes Association, and the American Association of Clinical Endocrinologists, among others. He received the B.A. degree (1969) from The Johns Hopkins University, Baltimore, Maryland, and the M.D. degree (1973) from Tufts University, Boston, Massachusetts.

439