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Endocrinology

Second Edition
Medical Management of Thyroid Disease
Medical
about the book…
For general practitioners and endocrinologists, the new Second Edition of this
bestselling book offers the most up-to-date and practical guidance to diagnose
and manage common and uncommon thyroid diseases.
New to the Second Edition:
• information on thyroid neoplasia, leading to new effective treatments of
advanced thyroid cancer
• important new research on subclinical thyroid disease in the elderly and
Management
of Thyroid
thyroid disorders in pregnancy
• new research on thyroid physiology, pathophysiology, and therapeutics
The new edition is fully evidence-based and updated to include the most current

Disease
treatment and latest findings:
• the screening and case finding for thyroid disease
• the use of calcitonin in the diagnosis of medullary thyroid cancer
• the diagnosis and management of subclinical hyperthyroidism
(mild hyperthyroidism)

Second Edition
• thyroid disease related to interferon therapy and amiodarone therapy
about the editor...
DAVID S. COOPER is Professor of Medicine, The Johns Hopkins University School
of Medicine; Professor of International Health, Johns Hopkins Bloomberg School
of Public Health; and Physician and Director, the Thyroid Clinic, Johns Hopkins
Hospital, Baltimore, Maryland, USA. Dr. Cooper received his M.D. from Tufts
University, Boston, Massachusetts, USA. He is a member of the Endocrine Society
and is a past president of the American Thyroid Association. Dr. Cooper is currently
Deputy Editor of the Journal of Clinical Endocrinology and Metabolism, Editor–in-
Chief of Endocrinology, Up-to-Date, and Contributing Editor of the Journal of the
American Medical Association (JAMA). Dr. Cooper was also the editor of the first
edition of Informa Healthcare’s Medical Management of Thyroid Disease.
Printed in the United States of America

Cooper
H7064

Edited by
David S. Cooper
Medical
Management
of Thyroid
Disease
Medical
Management
of Thyroid
Disease
Second Edition

Edited by
David S. Cooper
The Johns Hopkins University School
of Medicine, Baltimore, Maryland, USA
Informa Healthcare USA, Inc.
52 Vanderbilt Avenue
New York, NY 10017

C 2008 by Informa Healthcare USA, Inc.
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Library of Congress Cataloging-in-Publication Data


Medical management of thyroid disease / edited by David S. Cooper. – 2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4200-7064-4 (hardcover : alk. paper)
ISBN-10: 1-4200-7064-9 (hardcover : alk. paper)
1. Thyroid gland–Diseases. I. Cooper, David S.
[DNLM: 1. Thyroid Diseases–therapy. 2. Thyroid Diseases–diagnosis.
WK 267 M489 2009]

RC655.M434 2009
616.4’4–dc22
2008042809

For Corporate Sales and Reprint Permission call 212-520-2700 or write to: Sales Department,
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www.informahealthcare.com
Preface to the First Edition

I have been privileged to be a clinical investigator and thyroidologist for almost


25 years. When I was contacted by an editor of Marcel Dekker, Inc., about the
possibility of editing a book on diseases of the thyroid, my first reaction was,
“Why do we need another thyroid book?” There are already several standard
works that exhaustively cover thyroid physiology, pathophysiology, and clinical
thyroid disease. One of these texts is considered to be the “Bible” of thyroidology,
and there are several others that are also notable for their comprehensive treatment
of the subject. Many of them are on my bookshelf, with broken spines and 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 genet-
ics of thyroid neoplasia. While an understanding of molecular mechanisms and
“translational research” is important for optimal patient care, clinicians also need
up-to-date, practical information to help them in the management of common (and
not so common) thyroid problems. In this book, every effort has been made to
cover the universe of thyroidology in as much detail as possible, and yet provide
information that is easily digested and useful. Each chapter considers the epi-
demiology, 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 identi-
fied 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 rep-
utations as authors and thyroid researchers, and who are, most importantly, con-
summate physicians. I thank all of them for their diligence, intellectual approach,
and clinical acumen, without which this volume would not have been possible.
And, although this book was written for clinicians, it is my hope that the millions
of patients with thyroid disease will be the primary beneficiaries.

David S. Cooper

iii
Preface

In deciding whether a second edition of Medical Management of Thyroid Disease


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

v
vi Preface

pregnancy. Furthermore, treatment with thyroid hormone reverses any risk of


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

David S. Cooper, M.D.


Contents

Preface to the First Edition . . . . iii


Preface . . . . v
Contributors . . . . ix

1. The Laboratory Approach to Thyroid Disorders 1


Steven I. Sherman

2. Hyperthyroidism Due to Graves’ Disease, Toxic Nodules and Toxic


Multinodular Goiter 39
Kenneth D. Burman and David S. Cooper

3. Thyroiditis and Other More Unusual


Forms of Hyperthyroidism 101
Shon E. Meek and Robert C. Smallridge

4. Hypothyroidism 145
Michael T. McDermott and E. Chester Ridgway

5. Thyroid Nodules and Multinodular Goiter 203


Hossein Gharib

6. Differentiated Thyroid Carcinoma 237


Jennifer A. Sipos and Ernest L. Mazzaferri

7. Medullary Thyroid Carcinoma, Anaplastic Thyroid Carcinoma, and


Thyroid Lymphoma 297
Jennifer A. Sipos and Ernest L. Mazzaferri

8. Pediatric Thyroid Disorders 331


Rosalind S. Brown

9. Thyroid Disease and Pregnancy 369


Susan J. Mandel

10. Thyroid Disease in the Elderly 401


Anne R. Cappola, Myron Miller and Steven R. Gambert

Index . . . . 439

vii
Contributors

Rosalind S. Brown Harvard Medical School, Boston, Massachusetts, U.S.A.


Kenneth D. Burman Washington Hospital Center, Georgetown University,
and the Uniformed Services of the Health Sciences, Washington, D.C., U.S.A.
Anne R. Cappola University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania, U.S.A.
David S. Cooper The Johns Hopkins University School of Medicine,
Baltimore, Maryland, U.S.A.
Steven R. Gambert Sinai Hospital of Baltimore and The Johns Hopkins
University School of Medicine, Baltimore, Maryland, U.S.A.
Hossein Gharib College of Medicine, Mayo Clinic, Rochester, Minnesota,
U.S.A.
Susan J. Mandel University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania, U.S.A.
Ernest L. Mazzaferri University of Florida, Gainesville, Florida, U.S.A.
Michael T. McDermott University of Colorado Denver, School of Medicine,
Aurora, Colorado, U.S.A.
Shon E. Meek College of Medicine, Mayo Clinic, Jacksonville, Florida,
U.S.A.
Myron Miller Sinai Hospital of Baltimore and The Johns Hopkins University
School of Medicine, Baltimore, Maryland, U.S.A.
E. Chester Ridgway University of Colorado Denver, School of Medicine,
Aurora, Colorado, U.S.A.
Steven I. Sherman The University of Texas, M. D. Anderson Cancer Center,
Houston, Texas, U.S.A.
Jennifer A. Sipos The Ohio State University, Columbus, Ohio, U.S.A.
Robert C. Smallridge College of Medicine, Mayo Clinic, Jacksonville,
Florida, U.S.A.

ix
1
The Laboratory Approach
to Thyroid Disorders

Steven I. Sherman
The University of Texas, M. D. Anderson Cancer Center, Houston,
Texas, U.S.A.

INTRODUCTION
The central role of the thyroid gland in controlling metabolism was recognized
in the 19th century, but evaluation of the function of the thyroid remains an
evolving science. Initial approaches to the assessment of thyroid function cen-
tered 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 sen-
sitive estimation of free hormone levels. With the detection of serum markers
of autoimmune and malignant diseases of the gland has come earlier diagnosis
and improved monitoring of these conditions, often with greater sensitivity than
may be clinically relevant. Limitations to the measurement methods used exist,
however, particularly when underlying assumptions about the comparability of
patient and control specimens are invalid. Nonetheless, the clinician can now
effectively confirm suspected diagnoses of thyroid dysfunction, cost-effectively
screen asymptomatic populations for common diseases, and appropriately monitor
the treatment of patients with disorders of the thyroid.

1
2 Sherman

PHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-THYROID AXIS


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

the nadir occurs in the late afternoon; this nocturnal surge is lost early in the
course of nonthyroidal illness. TSH levels in various populations conform best to
a log-Gaussian rather than Gaussian distribution (5). The hypothalamic tripeptide
thyrotropin-releasing hormone (TRH) stimulates TSH secretion and modulates
thyrotroph response to altered thyroid hormone levels. In conjunction with the
suppressive effects of dopamine, corticosteroids, somatostatin, androgens, and
endogenous opioids, TRH may be responsible for modulating the set point for
the negative feedback loop that controls thyroid hormone levels. Hypothalamic
production of TRH itself is regulated by circulating thyroid hormones as well as
by multiple central nervous system factors.

LABORATORY EVALUATION OF THYROID FUNCTION


Assays of Thyroid Hormones
Total Serum Iodothyronine Concentrations
When concentrations and binding affinities of thyroid hormone-binding proteins
are normal, there exists at physiologic equilibrium a direct relationship between
levels of total hormone and free hormone (6). Thus, measurement of total iodothy-
ronine concentration can provide a reasonable surrogate for estimating the amount
of free iodothyronine present. Either serum or plasma can be used to assay hor-
mone 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” anti-
bodies directed against the specific iodothyronine. To ensure measurement of
bound as well as free hormone, inhibitors of iodothyronine binding are added—for
example, 8-anilino-1-naphthalene sulfonic or salicylic acids for TBG and barbital
for thyroxine-binding prealbumin (TBPA). These agents successfully dissociate
the hormone from binding proteins without interfering with hormone binding to
immunoglobulin.
Radioimmunoassay (RIA) depends upon measurement of the distribution
of a tracer quantity of radiolabeled hormone that competes with the endogenous
hormone in the patient’s specimen for binding to a capture antibody. The higher
the serum hormone concentration, the lower the amount of radiolabel that binds to
the antibody. Following the addition of a limited amount of capture antibody and
the radiolabeled iodothyronine to be measured, the antibody–antigen complexes
are separated from the serum. Separation techniques vary, including ammonium
sulfate or second antibody precipitation. Newer methods that facilitate automated
separation include attachment of the anti-T4 antibody to a solid phase, such as the
wall of the assay tube or magnetizable particles. The concentration of either T4
or T3 is then determined by comparison of the amount of antibody-bound radio-
label with a simultaneously derived standard curve. A fundamental assumption,
therefore, is that there is no difference in the assay conditions (including protein
binding and other constituents found in the serum) between the patient’s sample
and the control standards, an assumption that is often invalid.
4 Sherman

Nonisotopic methods avoid reliance upon radioactive reagents and are now
the most commonly used assays. The heterogeneous enzyme-linked immunosor-
bent assay (ELISA) incorporates colorimetric, fluorescent, or luminescent sub-
strates that create a quantitative signal when interacting with a specific enzyme
bound to the tracer hormone—for example, alkaline phosphatase, horseradish
peroxidase, or glucose-6-phosphate dehydrogenase. As in RIA, numerous phys-
ical 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 assays and to facilitate automation.
Reference ranges vary to some degree, but commonly cited ranges are 4.5
to 12.6 ␮g/dL (58–160 nmol/L) for total T4 and 80 to 180 ng/dL (1.2–2.7 nmol/L)
for total T3 (7).
As developed by their manufacturers, these assay techniques have similar
performance characteristics, although each may be affected by different sources
of interference. In field use, however, a concerning level of inaccuracy exists even
in total thyroxine immunoassays; a survey of nearly 2000 clinical laboratories
employing 19 different automated thyroxine assays identified that approximately
30% of the laboratories failed to meet accuracy standards defined by the Clinical
Laboratory Improvement Amendments of 1988 (8). Testing an identical speci-
men of fresh frozen serum in 1528 laboratories, 13% of the 16 T4 measurement
methods yielded mean results that differed from the overall mean of all meth-
ods by at least 10% (8). For total T3, the degree of inaccuracy is worse; testing
an identical specimen of fresh frozen serum in 926 laboratories, 58% of the 12
T3 measurement methods yielded mean results that differed from the overall
mean of all methods by at least 10% (8). Contributing factors to measurement
error include qualitative differences between the protein constituents of sample
diluents used for calibration and those found in patient sera, leading to differen-
tial dissociation of hormone from binding proteins, and the lack of harmonized
standards (7).
Determination of Free T4 and T3 Concentrations
Because T4 and T3 are highly bound to serum proteins, alterations in either the
levels of these proteins or their binding characteristics can significantly alter the
concentration of total hormone. As it is the free hormone that is biologically
active, however, techniques are required to permit either direct measurement or
estimation of the serum free hormone levels. All methods that have been developed
face the identical problem: distinguishing between the 3 to 4 orders of magnitude
difference in the concentrations of the free and the protein-bound hormones. In all
free hormone assays, the central assumption is that the effectiveness of separating
the free from the bound hormone is identical in both the patient samples and the
standards used to calibrate the assay, an assumption that is difficult to validate in
The Laboratory Approach to Thyroid Disorders 5

all potential clinical situations. As a result, in a study of 1744 clinical laboratories,


using 13 different free T4 measurement methods to assay an identical sample of
fresh frozen serum, 38% of the methods yielded average concentrations of free T4
that were at least 10% different from the overall group mean and 8% differed by
⬎20% (8).
The reference standard for direct measurement of free T4 and T3 is the
equilibrium dialysis method, although even this methodology lacks a univer-
sal reference measurement procedure (9). Undiluted patient serum is dialyzed
overnight across a membrane with pores that allow free but not protein-bound
hormone to partition, allowing equilibration of the free hormone concentration
across the membrane. A highly sensitive RIA, capable of detecting nanogram (or
picomole) quantities of hormone, is then used to measure the hormone content of
the protein-free dialysate, comparing to a standard curve generated with gravimet-
rically determined amounts of hormone (10). Faster turnaround can be achieved
by using ultrafiltration rather than equilibrium dialysis, but greater variability can
result from minimal amounts of serum proteins that leak through the filtration
device as well as hormone that is adsorbed to either the membrane or container
surface. Such direct measurements are generally expensive, time-consuming, and
not widely used commercially except as calibrators for more commonly used
techniques.
By estimating the fraction of hormone that is free or unbound and multi-
plying 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 incor-
porating an anion exchange resin then removes the radioactivity due to labeled
inorganic iodine and other contaminating compounds found in the tracer iodothy-
ronine 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 frac-
tions are approximately 0.02% to 0.04% for T4 and 0.2% to 0.4% for T3. The
free T4 or T3 estimate can then be calculated by multiplying the free fraction
by the total serum hormone concentration obtained using a conventional RIA.
Expected adult values are approximately 0.8 to 2.3 ng/dL for free T4 and 210 to
440 pg/dL for free T3. Although these indirect dialysis methods generally correct
for most protein-binding abnormalities, considerable variability in results still per-
sist, 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 devel-
oped for widespread use. However, a recently developed equilibrium dialysis tech-
nique that utilizes liquid chromatography-tandem mass spectrometry to measure
free T4 levels may permit rapid and cost-effective assessment of multiple blood
samples (11).
6 Sherman

Figure 1 Methods for radioimmunoassay estimation of free thyroxine concentration.

Immunoassay methods for estimation of free hormone concentration are now


widely used (Fig. 1). In the “analogue” or “one-step” free T4 method, a labeled T4
analogue that does not bind to serum-binding proteins is added to serum and the
mixture is either incubated with an anti-T4 antibody or allowed to bind to antibody
attached to a solid phase. At equilibrium, the amount of analogue complexed to the
antibody is inversely proportional to the amount of free T4 that is available. 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.
The Laboratory Approach to Thyroid Disorders 7

Therefore, these methods depend on the assumption that there is no difference in


hormone binding affinity for proteins between the sample to be measured and the
assay controls or calibrators, both for the actual analyte as well as the analogue.
This assumption is particularly at risk when there are circulating inhibitors of
hormone binding in serum, such as renal failure or other nonthyroidal illnesses,
or major alterations in hormone-binding protein concentrations (12). Because the
analogues used generally bind to albumin, although not with the same kinetics as
T4 or T3, this method may not be correct for abnormalities in albumin binding.
In “two-step” assays, serum is exposed to a solid phase containing anti-T4
antibody, binding a certain amount of free hormone to the solid phase. By diluting
the specimen and limiting the duration of incubation, there should be minimal
disruption of endogenous hormone binding to serum proteins (10). After removal
of the serum and its proteins, a tracer quantity of radiolabeled T4 is incubated with
the solid phase, equilibrating with the remaining unoccupied antibody molecules.
The amount of radiolabeled T4 complexed to the solid phase is thus inversely
proportional to the free T4 concentration of the serum. Because the label is unable
to interact with serum-binding proteins or endogenous inhibitors of hormone bind-
ing to protein (due to the physical separation step), the “two-step” method has a
good correlation with the free T4 determined by direct equilibrium dialysis. Non-
radioactive assays have also been developed, and automated two-step procedures
are in common use.
For free T3 measurements, methods that rely upon physical separation of
bound from free hormone, such as dialysis or ultrafiltration, are not generally
commercially available. The same technology for “one-step” assays of free T4 is
used to measure free T3. Interference from serum proteins and difficulty avoiding
stripping T3 from its binding proteins is a greater problem than in free T4 assays
(13). In a study of 404 clinical laboratories, using 11 different free T3 measurement
methods to assay an identical sample of fresh frozen serum, 55% of the methods
yielded average concentrations of free T3 that were at least 10% different from
the overall group mean and 27% differed by ⬎20% (8). New methods that use
tandem mass spectrometry following equilibrium dialysis or ultrafiltration may
allow faster and more reliable assays (14).
The thyroid hormone binding ratio (THBR), another calculated value pro-
portional to the fraction of hormone that is free in circulation, derives from mea-
surement of the availability of protein-binding sites in the patient’s serum. In
the traditional uptake method, a tracer quantity of radiolabeled iodothyronine is
added to the serum and allowed to partition between unoccupied specific protein
binding sites and a nonsaturable adsorbent—for example, talc, charcoal, resin, or
anti-iodothyronine antibodies. T3 is generally preferred as the labeled ligand, as it
has a lower affinity for TBG and therefore does not displace T4 its binding sites.
There is an inverse relationship between the amounts of radiolabel adsorbed by the
inert solid phase and unoccupied serum protein-binding sites. The percent uptake
derives from the ratio of tracer bound by the adsorbent to the tracer bound by
serum proteins; an alternative but less reliable formula expresses the ratio as the
8 Sherman

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 (thy-
rotoxicosis); 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 func-
tion abnormalities produce concordant increases or decreases in the total serum
T4 and THBR, whereas discordant changes in the two tests typically result from
protein-binding abnormalities. Alternate methods use nonisotopic labels, such as
enzyme-linked tracers and light emitters. These all rely on the similar principle of
estimating the partitioning of labeled hormone between serum-binding proteins
and a solid phase. A free hormone index is estimated by multiplying the total
serum hormone concentration by the THBR. In most conditions of endogenous
thyroid function abnormalities or protein-binding alterations, the index corrects
for effects of protein binding on total T4 levels and correlates well with free T4
levels measured by reference methods.
Potential pitfalls in the interpretation of THBR tests occur when there is
a ligand that can interfere with binding to both the solid phase and the serum
proteins, for example, nonthyroidal illness. Falsely elevated free thyroxine index
values can also be present when the protein-binding abnormality is specific for T4
and masked by the use of T3 in the THBR—for example, familial dysalbuminemic
hyperthyroxinemia (FDH), in which an abnormal albumin binds only thyroxine
with high affinity. Similarly derived from the total T3, the “free T3 index” can be
useful in evaluating cases of abnormal serum binding.
Causes of Increased T4 and/or T3 Concentrations
The majority of patients with hyperthyroidism, regardless of the etiology, have
increased total serum concentrations of both T4 and T3, as well as high levels
of the free hormones (Table 1). In a minority of cases, there may be an isolated
elevation of either iodothyronine. T3-toxicosis is especially prominent in patients
with mild and recurrent Graves’ disease or hyperfunctioning adenomas and those
patients overtreated with triiodothyronine-containing thyroid hormone prepara-
tions. The relative magnitude of T3 elevation is often greater than T4 in forms of
hyperthyroidism caused by increased glandular synthesis of hormone; in Graves’
disease, the proportion of circulating T3 that derives from thyroidal production
nearly doubles (15). The opposite—that is, a lower T3:T4 ratio—is true in thyro-
toxicosis due to an inflammatory thyroiditis, in which there is release of previously
formed hormone, iodide-induced hyperthyroidism, and iatrogenic thyrotoxicosis
due to exogenous levothyroxine administration. Mild hyperthyroxinemia can even
be seen in patients being treated with exogenous levothyroxine for hypothyroidism
but whose TSH levels are normal on therapy (16).
The Laboratory Approach to Thyroid Disorders 9

Table 1 Causes of Increased T4 and/or T3 Concentrations


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

Increased total T4 concentrations without thyrotoxicosis, termed euthyroid


hyperthyroxinemia, result from both acquired and congenital etiologies. One com-
monly encountered situation is acquired TBG excess due to hyperestrogenemia.
Elevated hepatic exposure to estrogen leads to increased sialylation of carbohy-
drate 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
10 Sherman

selective estrogen receptor modulators, such as tamoxifen and raloxifene (17,18).


Exogenous estrogen administered transdermally, by avoiding first pass metabolism
in the liver, does not cause elevated TBG levels and hyperthyroxinemia (19).
Acquired TBG excess may also be responsible for the slight increase in T4 levels
reported in male cigarette smokers (20). X-linked inherited TBG excess occurs
with a frequency of 1 in 25,000 newborns, and can cause up to 2.5-fold elevations
in the total serum concentration of T4. Other abnormal serum-binding proteins can
contribute to euthyroid hyperthyroxinemia. In the autosomal dominant condition
FDH, one or more abnormal species of albumin contain a high-affinity binding
site for thyroxine. Because the defect is specific for T4 and does not affect T3
binding, these patients have an elevated total T4; a normal THBR using T3, but a
decreased THBR using T4 as the ligand; a normal total T3; and either a normal
or increased free T4, depending on the type of direct assay used. Equilibrium
dialysis typically yields normal levels of free T4 in this syndrome. The diagnosis
is established by paper or gel electrophoresis of serum enriched with radiolabeled
T4, which permits identification of the abnormal binding proteins.
Elevations of free T4 concentrations can occur as a result of interference
in binding to serum proteins. In vivo, hormone can be displaced from protein by
medications such as furosemide, causing a true, albeit rapidly reversible, minimal
hyperthyroxinemia after rapid intravenous administration of the diuretic. Activa-
tion of lipases by both low– and high–molecular weight heparins leads to increased
levels of free fatty acids that displace thyroid hormones both in vivo and ex vivo,
the latter situation causing an artifactual elevation of measured free hormone (21).
In autoimmune thyroid diseases and monoclonal gammopathies, endoge-
nous serum anti-T4 or anti-T3 antibodies bind thyroid hormones, increasing the
serum concentrations of protein-bound hormones. More commonly, however, anti-
iodothyronine autoantibodies have negligible in vivo effects on hormone binding,
but interfere with immunoassay measurements (22). In a classic RIA for total
hormone concentration, the autoantibody will compete with the capture antibody
for radiolabeled ligand, reducing the amount of signal available to be measured
and leading to a false high value. A similar spuriously increased result can occur
in one-step free T4 assay, in which the autoantibody binds the labeled T4 ana-
logue, preventing it from being measured and yielding a falsely increased free T4
level; this is avoided in a two-step assay in which the labeled ligand is unable to
interact with the serum autoantibodies. Another autoantibody that interferes with
immunoassays is the rheumatoid factor, an IgM directed against the Fc fragment of
human IgG. Because rheumatoid factor is weakly heterophilic, it appears to bind
to the nonhuman capture antibody, preventing interaction with the radiolabeled
ligand and leading to a falsely increased hormone concentration (23). Preincuba-
tion of the serum specimen with a nonspecific animal immunoglobulin, ethanol,
or polyethylene glycol reduces this antibody-mediated interference.
Decreased function of the 5’-monodeiodinase causes impaired conversion
of T4 to T3, decreasing T4 clearance and increasing T4 levels. Iodinated radio-
contrast dyes—for example, sodium ipodate—are potent inhibitors of T4 to T3
The Laboratory Approach to Thyroid Disorders 11

conversion and have been used therapeutically in severely hyperthyroid patients,


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

Table 2 Causes of Decreased T4 and/or T3 Concentrations


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

to decreases in binding protein levels, due to either reduced production (as occurs
in hyperthyroidism) or increased clearance (as from nephrotic syndrome). In most
patients with quantitative or qualitative defects in TBG, direct and indirect esti-
mates of free T4 levels are normal. In the extreme case of complete deficiency, lack
of a linear relationship between free T4 fraction and THBR leads to falsely low
free T4 index results, and values of free T4 can be either normal or underestimated
by two-step and direct measurements.
Hypothyroxinemia and hypotriiodothyroninemia are common findings in
patients with nonthyroidal illness, with more severe reductions in total hormone
levels associated with more severe or critical illness (34,35). Milder degrees of
illness are typically accompanied by reductions in T4 to T3 conversion, resulting
in a low T3 state but preservation of T4 levels. In addition to deficiency of albu-
min and transthyretin, other proposed mechanisms include inhibition of hormone
binding to TBG, perhaps due to certain free fatty acids released from damaged
tissues or cytokines, such as tumor necrosis factor (36). Numerous medications
The Laboratory Approach to Thyroid Disorders 13

interfere with thyroid hormone binding to serum proteins, including diphenyl-


hydantoin, furosemide, heparin, sertraline, and certain nonsteroidal anti-
inflammatory agents (37,38). Inhibition of 5’-monodeiodinase activity in non-
thyroidal tissues accelerates clearance of T4 through nondeiodinative mecha-
nisms, particularly in nonthyroidal illness and starvation, and may be secondary to
increased levels of interleukin-6; the production rate of T3 declines as a result of
this monodeiodinase inhibition, but no change is seen in T3 metabolic clearance
(39). Medications such as glucocorticoids, amiodarone, oral radiocontrast agents,
gold, and high-dose propranolol and propylthiouracil (PTU) also inhibit T4 deio-
dination to T3; however, clinical signs of hypothyroidism are unlikely to develop.
Hypothyroxinemia has been described in patients treated with novel anticancer
agents that inhibit vascular endothelial growth factor receptors, with evidence
of multiple potential mechanisms that include primary thyroid dysfunction, but
also effects on either thyroid hormone absorption or metabolic clearance (40,41).
Pituitary TSH production is suppressed by endogenous and/or exogenous gluco-
corticoids, dopamine, somatostatin, and endorphins and may also be mediated
by reduced hypothalamic TRH secretion (42). Alteration of TSH sialylation and
bioactivity may occur in critical illness as well (43). With increasing severity of
nonthyroidal illness, all of the proposed mechanisms presumably result in a low
T4, low T3 state. Often, the decrease in protein binding is reflected by a decreased
T4 and increased THBR, yielding a normal free thyroxine index. However, in
many instances, the presence of a binding inhibitor (such as heparin or free fatty
acids released in inflammation) interferes with hormone attachment to the solid
phase, leading to a slightly lower value for the THBR and a falsely low estimate
of the free thyroxine index. Most analogue and some two-step procedures for
measuring free T4 are also adversely affected by binding inhibition in nonthy-
roidal illness (6,12). These laboratory abnormalities reverse with recovery from
the nonthyroidal illness or discontinuation of the interfering medication. Although
most of the effects of nonthyroidal illness may represent energy-conserving adap-
tive mechanisms, the traditional view of these patients as being euthyroid is not
universally held (44). However, no benefit from thyroid hormone supplementation
has yet been demonstrated.

Assays of Thyroid-Stimulating Hormone


Early TSH assays used a single polyclonal antibody in a radioimmunoassay and
were capable of detecting elevated levels of TSH in patients who have primary
hypothyroidism. With a sensitivity of approximately 1 mU/L, these tests were
unable to distinguish the low-normal TSH levels in serum of 25% of euthyroid
individuals from subnormal concentrations. With the introduction of immunomet-
ric (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
14 Sherman

high affinity; the second antibody, which may be polyclonal, is labeled, providing
a signal proportional to the amount of ligand bound. With these more sensitive
assays, hyperthyroid patients can be identified on the basis of low or undetectable
levels of TSH in IMAs, analogous to detection of primary hypothyroidism with
elevated TSH levels. Even more sensitive determinations of low TSH values have
been obtained in an assay using a chemiluminescent acridinium ester to gen-
erate the antibody-linked signal. High intra-assay and interassay precision with
chemiluminometric methods may permit routine detection of TSH levels as low as
0.01 mU/L or lower.
The ability of TSH assays to measure accurately low concentrations of
the hormone is termed the “functional sensitivity” of the assay, defined as the
concentration at which the interassay coefficient of variation is 20%. This contrasts
with the “analytical sensitivity,” which is based on intra-assay measurements of the
blank calibrator, and does not reflect a clinically meaningful result (7). Whereas the
original RIA methods have been termed “first generation” assays, the newer, more
sensitive TSH assays, which provide a sufficient separation in serum TSH values
between hyperthyroid and euthyroid patients, are defined as “second generation”
when the functional sensitivity is 0.1 mU/L, and “third generation” when the
functional sensitivity is 0.01 mU/L (45).
Multiple sources contribute to the total variation observed in TSH assay
results (46). Endogenous, biologic variation exists due to heterogeneity of TSH
isoforms, based on posttranslational modifications that can alter the immunoreac-
tivity as well as the bioactivity of the molecule; this potentially may be overcome
with use of variants of recombinant TSH that mimic these individual modifications
(47,48). Circadian and seasonal effects contribute to within-person variation as
well. But, within-person variation during serial measurements is relatively min-
imal compared with between-person variation, raising concern that population
reference standards may be inadequate to distinguish a healthy from diseased
state (46,49,50).
Debate now exists about the optimal reference range for TSH assays. Typi-
cally, the lower and upper limits of a population reference range of the analyte’s
concentrations are the 2.5th and 97.5th percentiles (the 95% confidence interval),
measured in a rigorously defined normal cohort without any evidence of relevant
disease. Applying this criterion to TSH levels, as determined in the recent U.
S. National Health and Nutrition Examination Survey (NHANES III), the pop-
ulation reference range would be 0.45 to 4.12 mU/L (51). Similar ranges have
been reported in other populations, differing to some degree due to variations
in iodine intake, ages, gender, and even the time of day that blood is sampled
(52). As most functional thyroid disorders are due to autoimmune thyroid dis-
ease, the relationship between levels of thyroid autoantibodies and TSH has also
been evaluated, demonstrating a U-shaped curve with the lowest prevalence of
autoantibodies at TSH levels between 0.1 and 1.5 mU/L in women and 0.1 and
2.0 mU/L in men (53). Additionally, the likelihood of eventual development of
overt primary hypothyroidism has been reported to be markedly higher in the
The Laboratory Approach to Thyroid Disorders 15

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

able to classify central hypothyroidism as either hypothalamic or pituitary in origin,


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

subunit of TSH is commonly overproduced. A molar ratio of alpha subunit to


intact TSH that is greater than unity is strongly suggestive of a pituitary adenoma.
Although thyrotoxic with elevated levels of TSH and T4, patients with the rarer
syndrome of isolated pituitary resistance to thyroid hormone do not have radio-
graphic evidence of a pituitary tumor, and their ratio of alpha subunit to intact
TSH is usually ⬍1 (68).
Resistance of the thyroid to TSH, presenting with nongoitrous congenital
hypothyroidism and elevated TSH levels, has been described both in isolated form
and in pseudohypoparathyroidism type Ia (68). In this latter congenital condition,
deficiency of the stimulatory subunit of the guanine nucleotide-binding proteins
that mediate activation of adenylate cyclase can cause resistance to multiple hor-
mones, including TSH and parathyroid hormone.
In infants, exposure to cold temperatures immediately following birth or
during hypothermic surgery causes TSH concentrations to rise as high as 50 to
100 mU/L, which is thought to reflect the immaturity of the hypothalamic-
pituitary-thyroid axis (69). Adults, on the other hand, do not demonstrate altered
TSH levels after brief periods of cold exposure, despite increases in the concen-
trations and fractional clearance rates of circulating free T4 and T3.

Specialized Studies of Thyroid Function


Thyroglobulin
In most forms of thyroid disease, thyroglobulin (Tg) is released from thyroid fol-
licular cells proportional to the synthesis and release of T4 and T3, increasing size
of the gland, and the degree of cytotoxic inflammation. The reference range in
subjects with intact thyroid glands and normal TSH levels is approximately 3 to
40 ng/mL. Markedly elevated levels are seen in most patients with hyperthyroidism
and thyroiditis, but mild increases are also observed in cigarette smokers despite
slightly lower TSH levels (70). In determining the cause of hyperthyroidism, an
undetectable serum thyroglobulin suggests factitious or iatrogenic thyrotoxico-
sis. Undetectable levels are also seen in hypothyroid patients with congenital or
acquired absence of the thyroid. Presently, the primary indication for measurement
of serum Tg concentrations is as a tumor marker for the longitudinal follow-up
of patients with differentiated thyroid carcinoma, which necessitates greater func-
tional sensitivity at lower concentrations than the euthyroid reference range (71).
Although introduced more than 15 years ago, these assays are now being increas-
ingly used to detect Tg in fine-needle aspirations of neck masses or cystic lesions
as an adjunct to cytologic interpretation to diagnose recurrent or metastatic cancer
(72).
Serum Tg is generally measured by either two-antibody immunometric assay
or single-antibody immunoassay. The newer immunometric assays require shorter
incubation times and have greater sensitivity (≤1 ng/mL) than the immunoassays,
but several problems persist. The greatest limitation is the potential for interfer-
ence by anti-Tg autoantibodies, which can be found in up to 25% of differentiated
18 Sherman

thyroid carcinoma patients. In the immunometric assays, the serum Tg concen-


tration can be falsely lowered by autoantibodies that bind Tg and effectively
remove it from the serum, thus making it incapable of binding to the assay’s
reporter antibodies. Attempts to abrogate this effect by use of monoclonal anti-
bodies directed against epitopes of Tg that do not react with the autoantibodies
have been ineffective. Detecting the presence and degree of autoantibody inter-
ference in an immunoassay may also be difficult. Although “recovery tests” that
determine whether the addition of known quantities of exogenous Tg to a serum
specimen that contains anti-Tg antibodies results in an appropriate increase in the
concentration were initially purported to accurately detect the degree of interfer-
ence, subsequent studies have demonstrated that such assessments are unreliable
(73). Conversely, in radioimmunoassays, anti-Tg autoantibodies can cause falsely
high values because they bind radiolabeled Tg; as a result, less is available to
bind to the assay antibody. Thus, in the presence of anti-Tg antibodies, discordant
findings of an undetectable Tg in an immunometric assay and a concentration of
at least 2 ng/dL in a radioimmunoassay may suggest the presence of antibody
interference, but cannot be used to quantify the problem. Measure of serum Tg
should therefore always be preceded by a test for anti-Tg antibodies, and it is rec-
ommended that laboratories withhold reporting low results of Tg immunometric
assays when autoantibodies are identified (7). Of note, recent reports demonstrate
that the presence of anti-Tg antibodies may not preclude identification of the high
concentration of Tg seen in fine-needle aspiration specimens (74).
Despite a trend toward assay standardization, the variability of results using
differing assays remains at least 25%, due to variations in the antithyroglobulin
antibodies used and the molecular heterogeneity of Tg. Occasionally, immuno-
metric assays may fail to detect very high serum Tg concentrations due to the
so-called hook effect, in which the high concentrations of Tg bind to one antibody,
preventing the formation of the two-antibody sandwich upon which the assay
depends. If this effect is suspected, the sample should be reanalyzed after dilu-
tion. Another cause of a false-negative Tg in patients with differentiated thyroid
cancer can be tumor production of variants of Tg that fail to be recognized by the
antibodies used in an assay (75).
The negative predictive value of an undetectable Tg level to identify differ-
entiated thyroid cancer patients who have no remaining evidence of disease has
been markedly improved by the now routine practice of using TSH to try to stim-
ulate Tg production by any remaining tumor cells (76). Whereas higher Tg levels
result from more prolonged endogenous TSH stimulation during withdrawal from
thyroid hormone, quality of life is preserved without significant loss of diagnos-
tic utility when stimulation is provided by exogenous recombinant human TSH
administered to a patient taking thyroid hormone (77,78). Alternatively, the posi-
tive predictive value is limited in the presence of remnant normal thyroid cells left
after thyroidectomy, and thus one indication for postsurgical adjuvant radioiodine
therapy is to eliminate such normal sources of Tg (79). False-positive Tg results
can also be caused by heterophilic antibodies, a problem in many immunometric
The Laboratory Approach to Thyroid Disorders 19

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

reference preparations for standardization of these assays still vary considerably,


and even use of the accepted international standard reference MRC 65/93 has not
resulted in interchangeabilty of assays (84). As with anti-TPO antibody measure-
ments, differences exist in the definitions used for reference ranges. Assays that
report detectable levels of antithyroglobulin antibodies ⬍10 kIU/L as abnormal
may have low specificity both for actual pathology and for antibodies that can
interfere with thyroglobulin assays (86).
No correlation exists between the severity of hypothyroidism and titers of
antithyroid antibodies, and low levels can be seen in patients with no demonstrable
thyroid dysfunction. Anti-TPO and antithyroglobulin antibodies are also present
in Graves’ disease, albeit less frequently (85% and 25%, respectively), and may
predict the subsequent development of hypothyroidism in some patients with this
condition. With appropriate treatment of the thyroid hormone excess or deficiency,
antithyroid antibody titers often decrease but are not clinically useful measures of
disease activity.
Multiple procedures have been developed to measure the TSH-receptor
stimulatory immunoglobulins that are pathogenetic for Graves’ disease, detecting
either stimulation of biochemical functions in thyroid cells (thyroid-stimulating
immunoglobulins) or blockade of receptor binding by TSH (TSH-binding
inhibitors). The original long-acting thyroid stimulator (LATS) assay of Adams
and Purves had been largely replaced by quantitation of cyclic adenosine
monophosphate (AMP) production, iodine uptake, or thymidine incorporation
into DNA in cell lines that derive from a rat thyroid follicular cell. False-negative
results can occur due to human IgG molecules that do not interact with the rat TSH
receptor—an outcome that can be circumvented by use of human thyroid cells in
primary culture or Chinese hamster ovary cells expressing a human TSH receptor
(87). TSH-binding inhibitors can be detected by quantitation of radiolabeled TSH
binding to solubilized porcine thyroid membranes (or more recently recombinant
human TSH receptors) in the presence of serum, followed by polyethylene gly-
col precipitation to separate bound from unbound radiolabel (88). Alternatively,
recombinant TSH receptors can be affinity-immobilized on an antibody-coated
tube, which is then incubated with TSH with an attached radioactive or chemilumi-
nescent label (89). 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,
despite recent adoption of an international standard MRC 90/672 (90). However,
thyroid-stimulating immunoglobulins levels may be more useful for identifying
Graves’ disease as the cause of exophthalmos (91). Blocking antibodies that bind
to but do not stimulate the TSH receptor have also been identified in hypothyroid
and euthyroid patients with autoimmune thyroiditis or Graves’ disease.
The measurement of thyroid autoantibodies is of value in selected clinical
situations. The presence of thyroid-stimulating immunoglobulins in patients in
The Laboratory Approach to Thyroid Disorders 21

whom the etiology of hyperthyroidism is uncertain can lead to a diagnosis of


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

Table 3 How Various Serum Constituents Are Altered in Hyperthyroidism


and Hypothyroidism

Increased Decreased

Hyperthyroidism
Alkaline phosphatase Cholesterol (total, LDL)
Angiotensin converting enzyme Apolipoprotein b, apo (a)
Calcium Corticosteroid-binding globulin
Factor VIII
Ferritin
Osteocalcin
Sex hormone–binding globulin
Urine nitrogen excretion
Urine pyridinoline cross-links
Hypothyroidism
Carcinoembryonic antigen Aldosterone
Cholesterol (LDL and HDL fractions) Angiotensin converting enzyme
Creatine phosphokinase Factor VIII
Creatinine Osmolarity
Lactic dehydrogenase Sex hormone–binding globulin
Myoglobin
Norepinephrine
Prolactin
Corticosteroid-binding globulin

thyroid function tests. Combinations of biophysical and serum parameters of


thyroid hormone action are particularly useful in the evaluation of patients with
possible thyroid hormone resistance states. To characterize the presence and
extent of resistance, parameters of pituitary and peripheral tissue response are
measured before and during administration of increasing doses of T3 (50, 100, and
200 ␮g/day). Among the various tests performed, changes in sex hormone binding
globulin, basal metabolic rate, and body weight provide the strongest distinction
between normal responsiveness and generalized resistance to thyroid hormones
(98).

LABORATORY EVALUATION FOR THYROID DISEASE


Distinct strategies for use of thyroid function tests should be designed to satisfy
four distinct purposes: screening for the presence of clinically unsuspected disease
in an asymptomatic general population, case finding to detect thyroid disease in
patients whose symptoms and signs are sufficiently subtle that the examining
clinician may not suspect thyroid dysfunction as the etiology, diagnosis to prove
the presence of clinically suspected disease, and optimization of management of
proven thyroid disease.
The Laboratory Approach to Thyroid Disorders 23

Screening and Case Finding


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

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 dys-
function, patients hospitalized with acute illnesses should probably not undergo
thyroid testing for case finding (34).
Postpartum women have a high frequency of transient thyroid dysfunc-
tion, especially those with preexisting euthyroid autoimmune thyroiditis. Within
the first three months after delivery, at least 5% of women develop postpartum
thyroiditis, a painless inflammatory condition that can cause thyrotoxicosis and/or
hypothyroidism. More than one-half of these patients require therapeutic interven-
tion. Furthermore, 25% of women with postpartum thyroiditis eventually develop
chronic hypothyroidism, thus requiring lifelong therapy. Case finding with serum
TSH measurements three and six months after delivery is recommended for women
with type I diabetes mellitus, personal history of postpartum thyroiditis, or those
known to have elevated levels of anti-TPO antibodies (110).

Hypothyroidism
Diagnosis
Clinical manifestations, hypothyroxinemia, and an increased serum TSH establish
the diagnosis of primary hypothyroidism. Nonspecific clinical symptoms and signs
alone are a poor predictor of hypothyroidism. Among ambulatory patients evalu-
ated for possible hypothyroidism—with symptoms of weight gain, fatigue, men-
strual irregularities, depression, cold intolerance, constipation, or galactorrhea—
only 4% have increased TSH levels and fewer than half of these have values
⬎5 mU/L above normal (111). The presence of a goiter on examination increases
the likelihood of hypothyroidism sixfold. However, the number and severity of
symptoms are poorly correlated with presence or severity of hypothyroidism.
Given this low prevalence of disease in symptomatic patients, first-line laboratory
testing for suspected hypothyroidism should be a highly sensitive, inexpensive test
capable of excluding patients who would not benefit from therapy.
In patients with hypothyroid symptoms who lack a history of known thy-
roid or pituitary disease, the initial diagnostic test should be the serum TSH,
with confirmation of diagnosis provided by subsequent determination of the
free T4 level. Although rare patients with secondary hypothyroidism may not be
detected, a serum TSH assay will accurately diagnose hypothyroidism in almost
all patients, including those with subclinical hypothyroidism. An alternative strat-
egy 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 diag-
nosis of primary hypothyroidism can then be made with a TSH assay, a test with
specificity and sensitivity for primary hypothyroidism of ⬎95%.
The Laboratory Approach to Thyroid Disorders 25

Other clinical settings present different testing requirements. Hypothyrox-


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

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 hypothy-
roid patient becomes euthyroid, follow-up evaluation should be performed after
several months, given the gradual increase of T4 clearance that occurs in these
patients. Subsequent evaluations generally are recommended annually, although
stable patients may be monitored less frequently (114). To monitor therapy in
patients with secondary or tertiary hypothyroidism, the patient’s clinical status
and serum free T4 levels should be assessed. The goal of therapy should be attain-
ment of a clinically euthyroid state, with normal or high-normal free T4 levels,
since the serum TSH concentration is not a reliable indicator of thyroid hormone
status in this setting (115).
Patients receiving therapy with T3-containing preparations, which are
shorter-acting than levothyroxine sodium alone, may be more difficult to monitor
(116). Individuals who take desiccated thyroid or other formulations containing
triiodothyronine are likely to have variable T3 levels during the day.

Hyperthyroidism
Diagnosis
Clinical manifestations, increased serum thyroid hormone concentrations, and a
subnormal serum TSH level typically establish the diagnosis of thyrotoxicosis. In
the evaluation of the patient with hyperthyroid symptoms, two alternative testing
strategies can be followed. Measurement of free T4, if near or above the upper
range of normal, can detect hyperthyroxinemic patients in whom a low serum
TSH level can then confirm the diagnosis of hyperthyroidism. With this approach,
most patients with euthyroid hyperthyroxinemia due to increased hormone binding
to serum proteins are identified on the basis of a normal free T4. Patients with
FDH, nonthyroidal illness, and generalized resistance to thyroid hormones may be
recognized by their usually normal serum TSH concentrations. However, patients
with T3 toxicosis, due to mild or recurrent Graves’ disease or hyperfunctioning
adenomas, can present with normal or occasionally low serum free T4, and the
diagnosis of hyperthyroidism may be missed using the T4-first strategy.
Alternatively, the serum TSH level, measured in an assay with a detection
limit of ⬍0.1 mU/L, is a more sensitive initial test for the diagnosis of thyro-
toxicosis. In patients with subnormal TSH levels, increased serum T4 and/or T3
levels confirm the diagnosis of thyrotoxicosis, high-normal T4 and/or T3 sug-
gest subclinical thyrotoxicosis, and low-normal or low–thyroid hormone levels
suggest either T3 thyrotoxicosis, nonthyroidal illness, or central hypothyroidism
(58). Patients with the rare causes of TSH-mediated hyperthyroidism who may
have normal or even elevated TSH levels—that is, TSH-secreting pituitary ade-
noma 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
The Laboratory Approach to Thyroid Disorders 27

determinations of serum TSH and thyroid hormone concentrations may be the


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

THYROID NEOPLASIA
Alterations in thyroid function are unusual in the presentation of thyroid neoplasia.
Most neoplastic lesions, both benign and malignant, organify iodine and produce
thyroid hormones inefficiently. Unless most of the nonneoplastic follicular tissue is
destroyed by infiltrating tumor or is ablated during the treatment of the neoplasm,
thyroid hormone levels are normal. Autonomously hyperfunctioning thyroid ade-
nomas can produce hyperthyroidism, thereby suppressing serum TSH levels and
reducing hormone production by nonadenomatous tissue. However, only 5% of
28 Sherman

thyroid nodules are hyperfunctioning, and therefore most patients with thyroid
nodules are euthyroid. Fine-needle aspiration biopsy is the most important diag-
nostic test for the solitary or dominant thyroid nodule, capable of distinguishing
benign from malignant lesions in a majority of patients.
In a patient with differentiated thyroid carcinoma who has undergone total
thyroidectomy or remnant ablation with radioactive iodine, serial thyroglobulin
determinations can assist in the recognition of residual or metastatic disease. In
general, the sensitivity of detecting thyroid carcinoma by measurement of serum
Tg after discontinuation of thyroid hormone therapy is 85% to 95% but may be as
low as 50% during therapy. Levels of thyroglobulin following recombinant human
TSH stimulation may be approximately 50% as high as following endogenous TSH
stimulation after thyroid hormone withdrawal, when performed in conjunction
with diagnostic radioiodine scanning (117). The results are most likely to be
falsely negative in patients with small nodal metastases of papillary carcinoma
and in those with tumor dedifferentiation. In immunometric assays, false-negative
Tg results can also occur due to interference from antithyroglobulin antibodies.
Antithyroglobulin antibodies that persist or are rising beyond the first several
years of follow-up after primary therapy can indicate higher risk for residual
disease (86). However, persistence of antibodies has been reported as long as
18 years after initial treatment without clinical evidence of disease in patients who
had coexistent Hashimoto’s disease in their thyroidectomy specimen (118). It is
difficult to generalize from the results of either Tg or antithyroglobulin antibody
testing in one center because of interlaboratory variations in assay sensitivity
and specificity. With increasing assay sensitivity, Tg levels at least 1 to 2 ng/mL
following TSH stimulation should justify further diagnostic evaluation for possible
residual or metastatic disease (119). Tg levels that are minimally detectable during
TSH suppressive therapy but that do not rise following TSH stimulation may
suggest the presence of heterophilic antibodies causing false elevations of the
assay (81).

C CELLS, CALCITONIN, AND MEDULLARY THYROID CARCINOMA


The 32–amino acid peptide calcitonin is principally produced by the thyroid C
cells; smaller amounts can be found in neuroendocrine cells throughout the body.
Physiological stimuli to calcitonin secretion from the thyroid include hypercal-
cemia, hypergastrinemia, hypermagnesemia, and beta-adrenergic agonists. Sup-
pression 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 hypophos-
phatemia. 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.
The Laboratory Approach to Thyroid Disorders 29

Single- or double-antibody immunoassay techniques are used for the routine


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

Routine measurement of the serum calcitonin concentration is not recom-


mended 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 dis-
ease will have an elevated serum calcitonin level when measured in a sensitive
immunometric assay, many of whom will prove to have MTC at thyroidectomy
(127). The cost-effectiveness of adding a single serum calcitonin determination
to the evaluation of a patient with nodular thyroid disease has been estimated as
nearly $12,000 per life-year saved, and is sensitive to variation in disease preva-
lence, specificity of fine-needle aspiration, and cost of testing (128). Nonetheless,
routine calcitonin measurements have not been recommended in the guidelines
for thyroid nodule evaluation by the American Thyroid Association (129).
For patients in known kindreds with inherited MTC, prospective family
screening increasingly identifies disease carriers long before clinical symptoms or
signs are noted. Using the traditional approach of stimulated secretion of calcitonin
by either pentagastrin or calcium infusion, 65% of MEN 2A gene carriers will have
abnormal calcitonin levels by age 20 years and 95% by age 35 (130). Compared
with sporadic disease, the typical age of presentation for familial disease is the third
decade, without gender preference. In MEN 2A, it is uncommon for the signs or
symptoms of hyperparathyroidism or pheochromocytoma to present before those
of MTC, even in the absence of prospective screening. All familial forms of
MTC and MEN 2 are inherited in an autosomal dominant fashion. In almost all
known kindreds, the disease is caused by a germline mutation in the ret 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 nervous system neurons. Mutations associated with
MEN 2A and familial medullary thyroid carcinoma (FMTC) have been primarily
identified in several codons of the cysteine-rich extracellular domains of exon 8,
10, 11, and 13, whereas MEN 2B and some FMTC mutations are found within the
intracellular exons 15 and 16 (131).
Of note, nearly half of patients with sporadic disease have somatic ret
mutations, typically involving the codon 918 mutation that also causes MEN 2B
when inherited. Further, approximately 6% of patients with clinically sporadic
MTC carry a germline mutation in ret, leading to identification of new kindreds
with multiple previously undiagnosed affected individuals. Genetic testing for
ret proto-oncogene mutations should be offered to all patients newly diagnosed
with clinically apparent sporadic MTC, as well as for screening children and
adults in known kindreds with inherited forms of MTC. Given the frequency of
mutations in certain exons, a sensible strategy for mutational analysis would start
with examination of exon 11, followed sequentially by exons 10, 16, 13, 14, 15,
and 8 (132). Although common mutations can be identified by broadly available
commercial testing sources, only a limited number of sites perform the more
thorough analyses that are required to identify the less common mutations.
Studies of genotype:phenotype correlations of various ret mutations have
demonstrated the presence of three levels of risk, defined as age of earliest
The Laboratory Approach to Thyroid Disorders 31

diagnosis of malignant disease and risk for mortality due to the cancer (131). At the
highest risk are the group 3 mutations, codons 918 and 883 that cause MEN 2B and
metastatic disease as early as age 6 months. At higher risk are the group 2 muta-
tions, which include the common mutations at codons 611, 618, 620, and 634 that
are associated with malignant disease as early as age 5. At high risk are the group
1 mutations, which include those at codons 609, 768, 790, 791, 804, and 891; with
some of the group 1 mutations, fatal MTC has yet to be reported. Recommendations
for the aggressiveness and timing of therapeutic intervention are tied to these risk
levels (132).

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2007; 5(6):568–621.
2
Hyperthyroidism Due to Graves’ Disease,
Toxic Nodules and Toxic Multinodular
Goiter

Kenneth D. Burman
Washington Hospital Center, Georgetown University, and the Uniformed
Services of the Health Sciences, Washington, D.C., U.S.A.

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

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

39
40 Burman and Cooper

etiology of Graves’ hyperthyroidism and ophthalmopathy remains unclear. There


are abnormalities in T-cell function that allow the TSH receptor antibodies to
develop; these antibodies not only stimulate TSH receptor action in thyrocytes
but may cross-react with orbital antigens (e.g., fibroblasts) as well (5,7–13).
The term Graves’ disease commonly refers to patients who manifest clinical
and biochemical hyperthyroidism (1), but in certain circumstances this term may
require further delineation. For example, patients with Graves’ disease and hyper-
thyroidism may become spontaneously euthyroid or hypothyroid because, over
time, the stimulatory TSH receptor antibodies have become blocking antibod-
ies (7,10) or because the chronic inflammatory process has resulted in thyroid
failure.

Epidemiology
Although it may present in patients of any age, Graves’ disease occurs more
commonly in women than in men, especially in women between the ages of
about 20 and 50 years (3). Graves’ disease is rare in young children; when
it occurs in neonates, it is almost always related to transplacental passage of
TSH receptor–stimulating immunoglobulins, a condition that typically persists
for several weeks until the IgG antibodies are cleared from the neonate’s circu-
lation (14–17). In adults, the annual incidence of new cases of Graves’ disease
is 1 to 10 per 100,000, although, of course, these numbers vary depending upon
the method of detection and the iodine content in the geographic area (18–23).
People living in all areas of the world are affected with Graves’ disease. It is
believed that the incidence correlates directly with the amount of iodine in the
diet. Increased iodine intake has been shown to be associated with an increased
frequency of hyperthyroidism, possibly related to enhanced thyroid hormone syn-
thesis and possibly because iodine sufficiency is important for maximal antibody
production (19,20,24–32). Graves’ disease may present more commonly in the
spring and summer months, possibly because warmer weather increases the per-
ception of symptoms rather than a true increased incidence in disease activity.
Cigarette smoking (33) and stressful life events (20) have also been linked to
the etiology of Graves’ disease. The use of certain drugs, especially interferon-
alfa, has been associated with the development of Graves’ disease during
therapy (34).

Pathophysiology
Although much has been learned about the immune dysregulation that character-
izes Graves’ disease, the precise cause is unknown. There are defects in antigen-
specific T cells that result in B-cell production of many antibodies, most notably
stimulatory TSH receptor antibodies. The thyroid glands of patients with Graves’
disease are infiltrated with these antigen-specific T cells. Whether the disease is
caused by abnormal clones of autoreactive T cells or the initial trigger is abnormal
antigen presentation by thyrocytes is not known (35,36).
Hyperthyroidism 41

Table 1 Clinical Effects of Hyperthyroidism


System Effects

General Nervousness, insomnia, fatigue, tremulousness, heat intolerance,


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

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

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

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

Figure 1 (A)Patient with Graves’ ophthalmopathy demonstrating proptosis and severe


exposure keratitis. This patient had received external radiation therapy, which, along with
inability to close the lid completely, contributed to dryness and resultant keratitis (8).
Hyperthyroidism 43

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

postmenopausal women with a history of hyperthyroidism as shown in a recent


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

Figure 3 A patient with Graves’ ophthalmopathy with predominant superior limbal ker-
atopathy (8).
44 Burman and Cooper

A B

Figure 4 A patient with Graves’ disease demonstrating bilateral exophthalmos and


achropachy (clubbing) (left panel). The right panel shows a radiograph of the same patient
demonstrating phalangeal periosteal reaction (arrow) (8).

Hypophosphatemia was present initially in 12 (80%) of 15 episodes. No patient


had a recurrent episode of paralysis after becoming euthyroid. The precise patho-
physiology of these events is unknown, but patients may have a genetic predisposi-
tion to activation of Na/K-ATPase activity, which is enhanced in hyperthyroidism
(53). One suggested treatment regimen is to administer 30 mEq potassium orally
every two hours with close monitoring of serum potassium and cardiac status,
as rebound hyperkalemia occurs commonly (51). Propranolol, given either orally
or intravenously can reverse or prevent attacks (54). Restoration of the euthyroid
state prevents future attacks.
The central nervous system (CNS) manifestations of Graves’ hyperthy-
roidism are varied but include restlessness, irritability, nervousness, and impa-
tience. Some patients may realize that they have a decreased ability to concen-
trate and remember facts; occasionally, they may have demonstrable personality
changes (55). These features are difficult to quantify, but relatives may help to
identify them. After patients are treated and euthyroidism is restored, patients will
frequently comment upon their previous personality changes. Cognitive function
may be more severely impaired, especially in hospitalized elderly patients (56),
and seizures and coma can be the presenting features of “thyroid storm” (see
below). Depression and irrational or even criminal behavior are very unusual. It
is difficult to prove that serious personality disorders or criminal behavior are
directly associated with hyperthyroidism per se, although hyperthyroidism has
been implicated in these circumstances (57). Rarely, hyperthyroid patients may
present with other neurologic findings, such as chorea (58).
Women may have irregular menses and decreased fertility, but amennorhea
is rare (59). Men may have decreased libido and gynecomastia, thought to be
Hyperthyroidism 45

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

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

A B

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

edema may develop, sometimes involving the entire lower leg. In this circum-
stance, the patient may have difficulty wearing shoes and the area may be pruritic
and even painful (Fig. 6). Although the cause of pretibial myxedema is unknown, it
seems to be related to anti-TSH receptor antibody levels (63). Pretibial myxedema
usually does not occur unless a patient has clinical evidence of ophthalmopa-
thy, and pretibial myxedema may occur in other anatomic sites, such as the feet,
face, or preradial area. Topical steroids, usually recommended to be used under
an occlusive dressing is the most effective therapy, but the response is poor in
patients with more severe disease.
The manifestations of Graves’ hyperthyroidism that occur in younger indi-
viduals may be different from those in older subjects (66–68). Younger patients
tend to have more classic findings, such as nervousness, weight loss, anxiousness,
tachycardia, and heat intolerance. Older patients may have none of these manifes-
tations but may only present with weight loss or a cardiac abnormality, especially
atrial fibrillation. The explanation for these differences is unknown, and, of course,
these comments should be taken as generalizations with many exceptions. A more
complete discussion of this topic is found in chapter 10, “Practical Management
of Thyroid Disease in the Elderly.”
Hyperthyroidism 47

Laboratory Diagnosis
Thyroid Hormone and TSH Levels
In the past, common thyroid hormone measures included total T4, total T3, resin
T3 uptake, and TSH. However, recent advances in techniques now allow the direct
measurement of free T4 (FT4). This analysis is preferred to the total T4, as ⬎99%
of T4 is bound to circulating proteins (thyroxine-binding globulin, albumin, and
prealbumin) and ⬍1% is unbound and available to enter cells, and, after conversion
to T3, to bind specific nuclear receptors and mediate biologic activity. Total T4
measurements are affected by factors that influence thyroid hormone–binding
proteins, including drugs (estrogens, birth control pills, and androgens, opiates),
and medical conditions such as hepatitis, cirrhosis, and nephrotic syndrome. FT4
levels remain normal in these situations (3). The resin T3 uptake test was designed
to indirectly assess the quantity of thyroid hormone–binding proteins in serum and
was used as an adjunct to the total T4 concentrations. However, now that we have
the ability to measure FT4 directly, rapidly, and inexpensively, the measurement
of FT4 is preferred. Total T3 is still measured because FT3 cannot yet be measured
in most laboratories in a reliable, precise, cost-effective manner. Approximately
5% of patients will have a normal serum free T4 level and elevated serum T3 level
(“T3 toxicosis”), and some patients, especially the elderly can have “T4 toxicosis”
with normal serum T3 levels. Like total T4, total T3 levels are altered by situations
that change thyroid hormone–binding proteins. TSH assays have also improved,
and “third generation” assays can measure ⬍0.01 mU/L in serum, with the normal
range being approximately 0.5 to 4.5 mU/L (51–57). These improvements in
sensitivity result from utilizing chemiluminescent techniques. All patients with
conventional forms of hyperthyroidism should have an undetectable TSH level in
third-generation assays, although many commercial laboratories only report that
a value is ⬍0.1 mU/L.

24-Hour Radioiodine Uptake


Serum measurements of thyroid hormone and TSH are the cornerstone of the
diagnosis of hyperthyroidism, but they do not assess biologic activity or the tissue
effects of the circulating thyroid hormone levels. The capacity of the thyroid gland
to concentrate radioactive iodine is a physiologic test representing in vivo events.
A normal subject will concentrate approximately 8% to 30% of radioactive
iodine administered when determined at 24 hours. Patients with hyperthyroidism
will usually concentrate higher amounts of radioactive iodine than normal,
reflecting the heightened ability of the gland to concentrate iodine. On the other
hand, patients with thyrotoxicosis and a low radioiodine uptake generally have
a problem associated with increased release into the circulation of preformed
thyroid hormone, for example, the various form of thyroiditis. (see chap. 3,
“Hyperthyroidism.”) Radiocontrast dyes and other sources of exogenous iodine
such as amiodarone will interfere with this test, because the enormous amounts of
48 Burman and Cooper

Table 2 Anti-TSH Receptor Antibody Measurements


Method Nomenclature Frequency Advantage Disadvantage

cAMP TSIa 80–100% Stimulatory Difficult to perform


generation
125
I-TSH TBIIb 70–90% Easy to perform Detects all TSH
binding receptor antibodies
inhibition
a TSI, thyroid stimulating immunoglobulins. This test detects cAMP generation in vitro from thyroid
cells or cells transfected with TSH receptor.
b TBII, thyroid binding inhibitory immunoglobulins. This test detects the ability of serum samples to

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

unlabeled iodine in these compounds dilute out the radioactive tag, resulting in less
radioactive iodine being concentrated by the thyroid gland and a very low 24-hour
uptake (69). An elevated radioactive iodine uptake can also be seen in euthyroid
or even hypothyroid patients with an organification defect, most notably patients
with Hashimoto’s thyroiditis (70,71). Therefore, an elevated radioactive iodine
test is not specific for hyperthyroidism. Since dietary iodine intake has decreased
over time (72), the normal range for the 24-hour uptake may have increased
compared to values obtained 20 or 30 years ago. Variations in geographic and
individual dietary iodine intake of bread, pastry, seafood, salt, and dairy products
may also contribute to changes in the 24-hour uptake. Most institutions have not
reassessed their normal range for this test in many years, mainly because it is
difficult to justify the administration of radioactive materials to normal subjects.
Therefore, the normal range should be considered as a guide and not an absolute
limit. Some clinicians feel that a scan should be performed whenever a radioiodine
uptake is ordered to assess whether an undetected cold nodule also may be present.

TSH Receptor Antibody Measurements


Anti-TSH receptor antibody measurements can be performed with one of two
possible assays (Table 2) (4,10). Stimulatory TSH receptor immunoglobulins (TSI)
are measured in vitro by testing the ability of serum or IgG from a possible
Graves’ patient to stimulate thyroid cells and generate cAMP or enhance T3
and T4 secretion (4,73–75). These responses are compared to those of normal
control serum or IgG. A ⬎30% increase above control serum is considered to
be a positive cAMP response. Usually, sera from Graves’ disease patients will
stimulate cAMP by more than two- or threefold. The advantage of the TSI assay
is that it measures TSH receptor–stimulating antibodies, which are relevant to
hyperthyroidism; but its disadvantages are that it is relatively expensive, and the
sensitivity of commercial assays vary. Another test, called a thyrotropin-binding
Hyperthyroidism 49

inhibitory immunoglobulin assay (TBII assay), measures the total conglomerate


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

Pitfalls

There are several pitfalls that should be avoided in the laboratory assessment
of Graves’ disease patients. The assays for iodothyronines and TSH are specific
and accurate; as a result, there are few reasons for artifactual results except for
mislabeling and rare laboratory errors. Specific antibodies against T3 or T4 may
alter their respective measurements. Although unusual, such antibodies can occur
in patients with autoimmune thyroid disease, in those who work with animals, and
occasionally for no apparent reason. In a study of 115 patients with antithyroid
hormone autoantibodies, approximately 42% of patients had antibodies against
triiodothyronine, 33% against thyroxine, and 25% of patients had both anti-T3
and anti-T4 antibodies (84). Although 44% of these patients were considered to
be euthyroid, 16% were hyperthyroid and almost 40% were hypothyroid. While
the effect of antibodies on T4 and T3 measurements depends upon the method of
measurement, in general, they cause a laboratory result that is incongruent with
the clinical state (84).
It is important to ensure that patients with Graves’ hyperthyroidism have an
undetectable serum TSH level, so that rare individuals with peripheral hormone
resistance or TSH secreting pituitary tumors are not misdiagnosed as having
Graves’ disease. Also, certain patients hay harbor heterophilic antibodies that
can result in falsely elevated serum TSH levels, causing diagnostic confusion in
patients with hyperthyroidism (85). It is also important to exclude other coexistent
autoimmune disorders that may be confusing the clinical picture. For example, a
patient with Graves’ hyperthyroidism who complains of inordinate weakness and
tiredness may, in fact, have coexistent Addison’s disease.
The patient’s clinical assessment and history must be integrated with the
thyroid function tests. Thyroid function tests should ideally be determined twice
prior to treatment and, when possible, measurement of FT4 and T3 is preferred.
In patients with mild hyperthyroidism and no clinical features of Graves’ disease,
it is important to obtain a radioactive iodine uptake test prior to treatment to
confirm high-uptake thyroid disease. Even if the diagnosis of Graves’ disease
seems obvious, at least one TSH measurement should be obtained to rule out the
unlikely TSH-secreting pituitary tumor.
The term euthyroid sick syndrome refers to the thyroid hormone changes that
occur in patients with a wide variety of systemic illnesses (86–88). The presence
of the euthyroid sick syndrome may interfere with the interpretation of thyroid
function tests in a patient being evaluated for possible hyperthyroidism. Early in
the euthyroid sick syndrome, T4 and FT4 remain normal, although occasionally
they may be decreased or even slightly increased. Total and FT3 are decreased
due to diminished T4 to T3 conversion. Serum TSH generally remains within the
normal range but may be decreased slightly or may increase during the recovery
phase of systemic illness. In this circumstance a systemically ill patient with
moderate or severe hyperthyroidism may have few symptoms, and the serum T3
Hyperthyroidism 51

may be inappropriately within the normal range, because of decreased T4-to-T3


conversion (so-called T4 toxicosis).

Treatment
Ideally, the treatment of any medical condition is directed at its cause, but the
cause of the immune dysregulation in Graves’ disease remains obscure (3,36).
Therefore, the available treatments are directed at the thyroid gland rather than the
underlying autoimmunity. The therapies that are available to the clinician in the
21st century are the same as those that were available 50 years ago: Antithyroid
drugs, radioiodine, and surgery. Although some patients, especially those who
are relatively asymptomatic, may wonder whether specific treatment is necessary,
overtly hyperthyroid individuals usually require restoration of a euthyroid state
because of potentially deleterious skeletal, cardiovascular, and psychologic effects.

Antithyroid Drug Therapy


Antithyroid drugs remain the first choice for initial therapy of children, adoles-
cents, and young adults in the United States (89,90) and are the usual treatment
for almost all patients in the rest of the world (91). Antithyroid drugs are generally
safe and effective in controlling the hyperthyroid state. However, they have limi-
tations and toxicities that are important to recognize, and their proper use requires
knowledge of their pharmacology as well as clinical experience.

Clinical Pharmacology of Antithyroid Drugs


Antithyroid drugs do not directly affect iodine uptake or hormone release by the
thyroid; hence, contrary to popular belief, the 24-hour radioiodine uptake is not
affected very much by antithyroid drug therapy. Within the thyroid, both propy-
lthiouracil (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 tis-
sues. Although some feel that this difference confers an advantage of PTU over
methimazole, there are no data to support this supposition; in fact, comparative
studies show that methimazole generally normalizes serum T4 and T3 levels faster
than PTU (92–94). There are also in vitro and in vivo data pointing to possible
beneficial effects of both drugs on the immune system, although it is far from clear
whether this is important clinically in terms of remission rates with antithyroid
drug therapy (89).
Antithyroid agents are well absorbed from the gastrointestinal tract. In the
circulation, PTU is heavily protein-bound, mainly to albumin, while methimazole
binding to proteins is negligible. This characteristic may affect antithyroid drug
choice in pregnancy and lactation, since PTU would be expected to cross the pla-
centa and breast epithelium less readily than methimazole. The serum half-lives
52 Burman and Cooper

of PTU and methimazole are 1 and 4 to 6 hr, respectively. However, the intrathy-
roidal duration of action of both drugs is longer than that, making the determination
of drug blood levels not particularly helpful clinically. Although both drugs are
metabolized in the liver and metabolites are excreted by the kidney, in the absence
of data to the contrary, the doses used to treat hyperthyroidism do not generally
need to be altered in patients with liver or kidney disease.

Antithyroid Drugs in Clinical Practice


Antithyroid drugs are used in two ways in the therapy of hyperthyroidism (89).
They can be employed as primary therapy, and are usually given for one to
two years in the hope that the patient will achieve a remission (a remission is
usually defined arbitrarily as biochemical euthyroidism for one year following
cessation of the antithyroid drug); or, they are used for a few months to “cool the
patient down” prior to ablative therapy with radioiodine or surgery. Unfortunately,
patients are often started on antithyroid drugs without a clear goal in mind and
then remain on them either continuously or intermittently for protracted periods
of time. Antithyroid drugs are also mistakenly used in the long-term treatment of
toxic nodules or toxic multinodular goiter, situations in which remission is highly
unlikely.

Antithyroid Drugs for Primary Therapy of Graves’ Disease


Prior to initiating antithyroid drug therapy, the physician should carefully discuss
the options with patients and their family. Unlike radioiodine and surgery, antithy-
roid drug treatment will not cause permanent hypothyroidism, but the chances of
remission are ⬍50% for an average patient. Even if a remission occurs, the chances
of permanent remission are ⬍50%, and late hypothyroidism may develop in up to
20% (95). Also, the potential for allergic reactions is often underestimated or not
discussed. Patient preferences are important to take into consideration, even if the
decision for or against a particular therapy seems to be based more on emotion
than fact. No therapy has been shown to be superior to any other in terms of effi-
cacy or patient satisfaction (96). However, the physician can help the patient make
an informed choice. Remissions are less likely with large goiters and in severe
disease, especially when the serum T3 concentration is ⬎900 ng/dL (97). In one
report that used a proportional hazards analysis to examine various potential fac-
tors influencing the outcome of antithyroid drug therapy, only the baseline serum
T3 level emerged as an independent risk factor for relapse (97). Some studies have
found that “T3 predominant” disease, in which the unitless serum T3/T4 ⬎20,
also makes remissions less likely (98), but others have not confirmed this obser-
vation (96). A prior history of relapse is another factor that would argue against
antithyroid drug use as first-line therapy. On the other hand, a small gland and
mild biochemical changes would favor a remission, and in some studies the rates
may be as high as 70% to 90%. A negative TSI titer at the beginning of therapy
has been shown to predict a high rate of remission (99), but negative titers occur
in only approximately 10% of patients, so it is probably not cost-effective to order
Hyperthyroidism 53

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

degrees of “T3 predominance,” with serum T3 levels two to three times above the
upper limit of normal and serum T4 values that are subnormal (106). Also, the
serum TSH level can remain suppressed long after the patient has become euthy-
roid or even hypothyroid, which limits its value early in the course of treatment.
In many patients, the drug can be tapered to a lower dose after a few months,
once the patient has become biochemically euthyroid. If this tapering is not done,
hypothyroidism will often ensue (103). In patients who are hyperthyroid on a
low drug dose but hypothyroid on a larger dose, some physicians use a “block-
replacement” regimen. In this method, a dose of antithyroid drug that would cause
hypothyroidism is employed in conjunction with thyroxine supplementation to
maintain a euthyroid state. This method of treating patients may also be useful in
the pediatric population.
The “block-replacement’’ regimen has also been used in the hope that the
combination will yield a higher remission rate than antithyroid drugs alone (107).
This strategy is based on the theory that thyroxine supplementation will suppress
the serum TSH, thereby diminishing the immune system’s exposure to thyroidal
antigens, especially the TSH receptor. While one well-done, randomized, clinical
trial from Japan did show a higher remission rate using combined therapy (107), a
number of equally rigorous trials have failed to confirm these original observations
(108–112). At the present time, most clinicians have abandoned the idea that
combined antithyroid drug–thyroxine therapy enhances the chances of remission.
We prefer simply to taper the antithyroid agent dose as required and not to add
L-thyroxine, which would also make it more difficult to interpret and follow T4
and T3 levels as a measure of endogenous thyroid function.
Once a patient has been placed on long-term therapy with an antithyroid
drug, what is the optimal duration of therapy before a remission has been achieved
and the drug can be discontinued? Older retrospective data suggested that the
longer a person remained on therapy, the more likely a remission would be
achieved once the drug was stopped (113,114). More recently, prospective tri-
als have not shown longer treatment periods (e.g., ⬎12–18 months) to be more
effective (115,116). Therefore, treatment for a year is reasonable, but data sup-
porting longer periods of time are lacking.
After one to two years of therapy, most clinicians discontinue antithyroid
drugs to see whether a remission has occurred. If the goiter has gotten smaller
and the patient’s disease has been controlled on diminishing doses of drug, the
chances of remission are greater. On the other hand, a large goiter, continued
requirement for large doses of drugs, and a persistently high-T3/T4 ratio are all
poor prognostic signs. Although a number of tests have been proposed to predict
the odds that a patient will remain euthyroid off drugs, none has the requisite
sensitivity or specificity to be useful clinically; thyroid-stimulating antibody test-
ing is the most widely studied. If it is positive, the chances of remission are very
low, but even patients with negative titers have a 20% to 50% chance of relapse
(117,118). Practically speaking, it is probably more sensible to taper the antithy-
roid drug rather than to stop it abruptly. Patients should be monitored closely and
Hyperthyroidism 55

thyroid function tests checked monthly, and the drug should be gradually tapered
to discontinuation. Thyroid function tests are then performed every four to six
weeks, but patients are not necessarily seen for an office visit unless they become
hyperthyroid, or at three to four months if they remain normal. T3 thyrotoxicosis
frequently occurs during a relapse, so that serum T3 should be monitored along
with the serum T4 levels. Relapses are most likely to occur within the first six
months after drug discontinuation (119).
Some patients have persistent subclinical hyperthyroidism, with normal
serum T4 and T3 values but suppressed serum TSH concentrations. While the
chances that such patients will have a full-fledged relapse are greater (120), relapse
is not inevitable. Some experts treat patients with subclinical hyperthyroidism (i.e.,
suppressed TSH, normal FT4, and T3) as if they had relapsed and recommend
another trial of antithyroid drug therapy or radioiodine. Others simply observe
them expectantly and only recommend treatment if and when overt hyperthy-
roidism develops.
Remissions are not necessarily lifelong. Older data suggested that eventual
relapse was almost inevitable (121). However, more recent long-term follow-up
studies have shown that some patients have durable remissions that apparently
last for many years (122). A strategy for treatment of relapse should be discussed
with the patient in advance. Some patients will opt for another course of antithy-
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 (123), but this is unusual unless the patient
is highly motivated and the hyperthyroidism relatively mild. As noted above,
some patients eventually develop spontaneous hypothyroidism, so that lifelong
follow-up is necessary.

Antithyroid Drug Side Effects


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

Table 3 Side Effects of Antithyroid Drugs


Overall frequencya Comments

Minor side effects


Skin reactions 4–6% Dose-related for MMI; possibly
more common with MMI
Arthralgias 1–5% Gastrointestinal 1–5%
Hair loss 4% Possibly related to change in
thyroid function
(hypothy-roidism)
Abnormal taste/smell only reported with MMI/CBZ
0.3%
Sialadenitis Very rare
major side effects
Severe polyarthritis 1–2%
Agranulocytosis 0.1–0.5%
Aplastic anemia Rare
Vasculitis Rare May be ANCA + drug-induced
SLE and other immune
syndromes also reported
Severe hepatitis 0.1–0.2%; 1% with Almost exclusively PTU; transient
high-dose PTU (14) increases in transaminases seen
in 30%
Cholestasis Rare Almost exclusively seen with MMI
or CBZ; no deaths reported
Hypoprothrombi Rare No case reports since 1982
nemia
Insulin-autoimmune Rare Seen almost exclusively in Asians
syndrome
a Rate of side effects (minor and major) is greater at high doses of MMI and may approach 30% at
high doses.
Abbreviations: MMI, methimazole; CBZ, carbimazole; PTU, propylthiouracil; ANCA, antineutrophil
cytoplasmic antibody.

possibility, the cross-reaction rate may be as high as 50%. Some patients may
simply elect to stop the offending drug and accept a definitive form of therapy.
Loss of sense of taste, sometimes associated with anosmia, is a rare minor
side effect reported only with methimazole (126). It develops suddenly after one to
two months of therapy and resolves after the drug is stopped. This side effect has
not been reported with PTU, although PTU may cause a metallic taste. A recent
report described the development of arthralgias and elevated serum CPK levels
in four patients treated with methimazole at a time when they were still clearly
hyperthyroid (127). The authors postulated that this side effect was the result of
rapid a decline in serum thyroid hormone levels.
Hyperthyroidism 57

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

been associated with a mortality rate as high as 16% (133). A bone marrow exam-
ination may provide helpful prognostic information; an extreme loss of myeloid
precursors suggests a longer time to recovery (133) as well as the potential for
a poor response to G-CSF therapy (134). The use of G-CSF has become stan-
dard in the management of drug-induced agranulocytosis. However, a randomized
controlled trial of G-CSF in antithyroid drug–induced agranulocytosis found no
statistically significant difference in the mean time to recovery from G-CSF com-
pared to conservative therapy (135). Other retrospective data supporting the use
of G-CSF, however, noted shortened recovery time. In a retrospective review of
109 patients with agranulocytosis related to antithyroid drugs, the mean time to
recovery was 5.5 days compared to 9.2 days in historic controls. There were no
deaths in either group (136). The doses of G-CSF used in the literature range
from 1 to 5 ␮g/kg/day subcutaneously. Common side effects include rashes, bone
pain, myalgias, and headache, all of which respond well to acetaminophen (137).
If thyrotoxicosis requires treatment during the acute episode of agranulocyto-
sis, beta-adrenergic blocking drugs, lithium, or iodinated contrast agents can be
used. Attempting to switch to the other antithyroid drug is not recommended, as
cross-sensitivity has been reported.
Some patients develop a condition that has been termed the “antithyroid
arthritis syndrome” (138). The frequency of this side effect is in the range of 1%
to 2%, and it usually develops within 60 days of initiating therapy. The syndrome
is characterized by hot, swollen, tender joints involving multiple sites. The spe-
cific laboratory studies are not typical of drug-induced lupus. Symptoms usually
resolve after one to two weeks of therapy with nonsteroidal anti-imflammatory
drugs; glucocorticoid therapy may be necessary in severe cases. A more uncom-
mon and potentially significant development is the appearance fever, rash, arthri-
tis, splenomegaly, glomerulonephritis, and other stigmata of drug-induced lupus,
almost always associated with PTU. Patients have elevated sedimentation rates,
positive antibodies for double-stranded DNA, and low serum complement levels.
The syndrome usually resolves in a few weeks after the drug is discontinued,
although it should be remembered that the simultaneous occurrence of other
autoimmune disorders is increased in patients with Graves’ disease.
Recently, an antithyroid drug–related syndrome that includes renal failure,
vasculitic skin changes, pulmonary and respiratory tract involvement, arthritis,
and positive circulating anticytoplasmic neutrophil antibodies (ANCA) has been
described, mainly in Asian patients (139). ANCA have typically been associ-
ated with Wegener’s granulomatosis and polyarteritis nodosa, but they may also
be present in drug allergy. In the antithyroid drug–related cases, the antibod-
ies are of the pericytoplasmic variety (so-called pANCA, with myeloperoxidase
being the putative antigen), and the vast majority have been patients exposed to
PTU (140,141). Although the syndrome usually resolves after a few weeks, some
patients with severe renal dysfunction or pulmonary involvement have required
high-dose glucocorticoid therapy or cyclophosphamide, and several patients have
Hyperthyroidism 59

needed short-term hemodialysis. In some antithyroid drug-treated patients, ANCA


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

Beta-Adrenergic Antagonist Drugs


Beta-adrenergic antagonist drugs play an important role in the management of
thyrotoxicosis (153). Blockade of adrenergic receptors provides patients with
considerable relief from adrenergic symptoms such as tremor, palpitation, anxiety,
and heat intolerance. Small decreases in serum T3 concentrations occur in patients
treated with large doses of selected beta-adrenergic antagonist drugs (propranolol)
because of inhibition of extrathyroidal conversion of T4 to T3 (154), but these are
probably clinically insignificant.
Although beta-blockers improve the negative nitrogen balance (155) and
decrease heart rate (156), cardiac output (157), and oxygen consumption (158)
in thyrotoxic patients, these measurements seldom become normal (159) except
in the mildest cases. Therefore, these drugs are used as primary therapy only in
patients with self-limited forms of thyrotoxicosis (e.g., the various forms of sub-
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 cardiose-
lective (atenolol and metoprolol). The usual starting dose of propranolol is in the
range of 80 to 160 mg/day; similar effects are produced by 50 to 200 mg/day
of atenolol or metoprolol or 40 to 80 mg/day of nadolol. Large doses (e.g.,
360–480 mg/day of propranolol) are sometimes necessary for optimum clini-
cal effects, possibly because of accelerated drug clearance (160). Propranolol and
esmolol can be given intravenously to patients who are acutely ill (see discussion
of thyrotoxic storm).
Beta-adrenergic antagonist drugs are well tolerated. Common side effects
include nausea, headache, fatigue, insomnia, and depression. Rash, fever, agranu-
locytosis, and thrombocytopenia are rare. Undesirable effects related to the beta-
adrenergic antagonist effects are far more common. Patients with a clear history
of asthma should not receive these drugs; a cardioselective drug could be used
cautiously in patients with mild asthma. Patients with a history of congestive
heart failure should not receive a beta-adrenergic blocking drug except when the
heart failure is clearly rate-related or caused by atrial fibrillation (161). Even
then, the drug should be given cautiously, preferably with digoxin. Beta-blockers
are also relatively contraindicated in insulin-treated diabetic patients, in whom
hypoglycemic symptoms may be masked. They should not be given to patients
with bradyarrhythmias or Raynaud’s phenomenon or patients being treated with
a monoamine oxidase inhibitor; they should also probably not be given routinely
to pregnant patients.
The potential usefulness of diltiazem in thyrotoxicosis has been studied
(162). This calcium channel blocking agent reduced resting heart rate by 17%,
Hyperthyroidism 61

comparable to what can be achieved with a beta-adrenergic antagonist drug. Cal-


cium channel blockers should be considered in patients with severe tachycardia in
whom beta-blockers are contraindicated, for example, in patients with both asthma
and thyrotoxicosis.

Lithium
Although lithium has not been extensively used, it is a potential second-line
agent in the treatment of hyperthyroidism. Its mechanism of action is unknown
but is thought to relate to inhibition of thyroid hormone synthesis and secretion
(163,164). Lithium use should be reserved for the unusual patient who has not
responded to or is allergic to more standard antithyroid agents. Lithium is mainly
indicated for short-term use in hospitalized patients with thyroid storm or to
prepare them for surgery. The dose of lithium is usually 300 mg tid, with periodic
monitoring of serum levels to ensure that they are in a therapeutic range. Potential
complications relate to neuromuscular and CNS perturbations, such as ataxia,
tremor, and seizures.

Potassium Perchlorate
Potassium perchlorate is an antithyroid medication that inhibits thyroidal uptake
by the sodium/iodide symporter (165–167), resulting in decreased synthesis and
secretion of T4 and T3. This agent is also a second-line alternative to more standard
therapy. The typical dose is approximately 400 mg bid po. Potential adverse effects
include bone marrow suppression and skin rash. It is unknown if the risk of bone
marrow toxicity increases with concomitant PTU or methimazole use. For several
decades the use of perchlorate had fallen into disrepute due to its potential bone
marrow toxicity. However, interest in employing this medication has resurfaced,
as it was found to be effective for amiodarone-induced hyperthyroidism (168).
In selected circumstances, its use has now extended to all types of high-uptake
hyperthyroidism. Unfortunately, perchlorate is no longer available in the United
States.

Radioiodine (131 I) Therapy for Graves’ Disease


131
I therapy has been utilized for approximately 50 years for patients with Graves’
disease; it is considered safe and effective (169–171). The goal of therapy is to
render the patient permanently hypothyroid, a process that typically takes approx-
imately three months. Radioiodine therapy is considered first-line therapy in most
adults with thyrotoxic Graves’ disease (90). Patients and their families must be
counseled about the advantages and disadvantages of radioiodine therapy and
must participate in the decision process. Elderly or severely thyrotoxic patients
considered too ill to undergo the therapeutic manipulations inherent in the pro-
cess 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.
62 Burman and Cooper

A 24-hour radioactive iodine uptake test is required before administering 131 I


therapy. Measurement of radioactive iodine uptake prior to giving a therapeutic
dose of 131 I is important since it documents that the uptake is sufficiently elevated to
administer 131 I. On rare occasion, a patient will have had exposure to radiocontrast
dye or compounds containing sufficient iodine to suppress the radioactive iodine
uptake. In this circumstance, giving a therapeutic dose of 131 I would fail to treat the
patient and exposure him or her unnecessarily to radiation. 131 I therapy should not
be given to a breast-feeding woman or a patient who may be pregnant. Therefore,
a careful medical history and a serum beta-hCG should be obtained within five to
seven days prior to giving the therapy. A woman of childbearing age should be
counseled not to become pregnant for 6 to 12 months after 131 I therapy. This time
period is chosen based on the biologic half-life of the radioiodine, as well as the
desire for the patient to be euthyroid prior to becoming pregnant. Careful radiation
safety procedures must be followed by the patient and his or her family for about
a week following 131 I therapy. For example, if a patient has young children in
the house, they should not share eating utensils or be kissed or held closely. The
individual instructions vary from institution to institution and with the family
situation.
There are two general approaches to deciding on the appropriate therapeutic
dose of 131 I for a patient with Graves’ disease. The first method attempts to
determine the most appropriate dose for an individual by estimating the size of
the thyroid gland and delivering approximately 100 to 200 ␮C of 131 I per gram
of thyroid tissue. The estimated thyroid gland size is multiplied by the desired
delivered dose per gram of tissue (100–200 ␮C of 131 I), and this number is divided
by the 24-hour uptake expressed as a decimal (e.g., 80% uptake is converted to
0.80). This method appears to be more quantitative than it actually is because
clinicians tend to underestimate the size of large thyroid glands and overestimate
the size of smaller ones, and it is impossible to predict radiation sensitivity of a
specific thyroid gland. Alternatively, a second method of treatment is to use “fixed
doses” of 131 I. With this approach, the physician arbitrarily picks a given 131 I
dose that is used in all patients with hyperthyroid Graves’ disease. A typical fixed
dose would be 10 to 15 mCi 131 I. This practice has the advantage of simplicity—
but, of course, it does not take into effect the size or activity of the thyroid
gland. Retrospective and prospective studies have not shown major differences
in outcomes for the two methods of dose determination (172,173). Some centers
perform dosimetric calculations after a tracer dose of radioiodine in an effort
to deliver a specific dose of radiation to the gland (e.g., 10,000 rads), but this
method is cumbersome and time-consuming and has not gained wide popularity.
The potential complications of radioiodine therapy are listed in Table 4.
The follow-up evaluation of a patient after 131 I therapy varies between
institutions and physicians, and, of course, depends upon the clinical circumstances
and goals of treatment. In the typical patient with Graves’ disease, 131 I is given
in order to induce permanent hypothyroidism. In this circumstance, following a
therapeutic dose of 131 I, serum FT4, and total T3 levels are determined periodically,
Hyperthyroidism 63

Table 4 Complications of Radioiodine Therapy and Surgery


131
I therapy
Exacerbation of hyperthyroidism, especially in elderly patients who are not euthyroid
Transient thyroid gland discomfort or tenderness
Sicca syndrome, taste distortion, sialadenitis
Fetal hypothyroidism if administered during pregnancy
Hypothyroidism (desirable goal)
Carcinogenic effects still being evaluated
Thyroidectomy
Hypothyroidism (desirable goal)
Anesthetic complications
Hypoparathyroidism with hypocalcemia
Transient postoperative hypocalcemia (“hungry bones”)
Recurrent or superior laryngeal nerve injury causing voice changes
Local hemorrhage
Persistent or recurrent hyperthyroidism
Exacerbation of hyperthyroidism
Jugular vein or carotid artery damage
Infection
Thoracic duct or lymph drainage damage

Source: From Ref. 2.

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

older patients with moderate hyperthyroidism or patients with more severe disease
(e.g., presence of coexisting medical conditions, elevated FT4 and total T3 perhaps
two to three times above normal) are commonly given antithyroid agents before
or after radioiodine therapy to maintain normal thyroid hormone levels (178,179).
The drug is tapered as the thyroid function tests normalize, and then stopped when
the tests show hypothyroidism developing. When it is clear the patient is hypothy-
roid 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 exac-
erbation of thyroid function tests following 131 I therapy. Most endocrinologists
provide a window of about two to five days prior to and after 131 I therapy when
the patient does not receive antithyroid drugs.
In a survey of members of the American Thyroid Association, only about
one-third of respondents reported that they pretreat patients prior to administering
radioiodine (90). In meta-analysis of studies that examined outcomes of patients
either pretreated or not pretreated with antithyroid drugs prior to radioiodine (180),
new onset atrial fibrillation was reported in 1/660 (0.2%) patients pretreated with
ATDs versus 3/646 patients without ATDs (0.5%). Death after radioiodine was
reported in 1/660 (0.2%) pretreated with antithyroid agent and in 6/646 (0.9%)
without adjunctive drug therapy. Clearly, the routine use of antithyroid drugs
in this context is unnecessary and potentially exposes patients to drug toxicity.
Antithyroid drug pretreatment may interfere with the efficacy of radioiodine,
perhaps by acting as free radical scavengers within the irradiated gland (181–
184). Recent prospective, randomized studies have shown that PTU has a negative
effect on radioiodine outcome (185), but methimazole did not have such an effect
(186,187). Nevertheless, a meta-analysis of all studies of this question ascertained
that both antithyroid drugs lower the success rate whether if they are used before
or after radioiodine treatment (180). Therefore, if antithyroid drugs are to be used
before or after radioiodine therapy, it is recommended that the radioiodine dose
be increased by 25% to compensate for the potential radioprotective effect of
the drugs. One study has shown that thyroid hormone levels can be normalized
more quickly, and the cure rates with radioiodine-enhanced, with lithium therapy
(300 mg tid for six days beginning on the day of radioiodine therapy) (188).

Radioiodine and Graves’ Ophthalmopathy


131
I therapy is believed to exacerbate existing ophthalmopathy (189,190), at least
when it is more than minimally active on clinical grounds (191); thus it is impor-
tant to take a relevant history and perform a thorough ophthalmologic examination
(5). If there is moderately severe ophthalmopathy or if it seems to be progressive,
it is important to obtain an ophthalmology consultation, and an orbital computed
tomography (CT) scan (without contrast) or magnetic resonance imaging (MRI)
Hyperthyroidism 65

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

disease who smoke should be advised to discontinue. Some endocrinologists avoid


radioiodine therapy in patients with moderate to severe eye disease unless it has
been stable for at least one year.

Radioiodine and Cancer


A number of older studies have failed to show any causal relationship between
radioiodine therapy and the subsequent development of thyroid cancer, leukemia,
or other malignancies. Ron et al. (194) retrospectively analyzed 35,593 hyperthy-
roid patients (91% had Graves’ disease) who had been treated with radioiodine,
antithyroid drugs, or surgery between 1946 and 1954. Some 65% of these patients
were treated with radioactive iodine, thus allowing long-term comparison of
results between various therapeutic modalities. When studied in December 1990,
about half of the patients had died. The total number of cancer deaths in all
hyperthyroid patients was comparable in patients treated with radioactive iodine
and those treated with surgery or antithyroid agents, although there was a slight
excess of cancer-related mortality from lung, breast, kidney, and thyroid. Starting
at least one year after treatment, an enhanced risk of cancer mortality was also
seen in hyperthyroid patients treated with antithyroid drugs. After more than
five years following therapy, radioactive iodine therapy was associated with
an increased risk of thyroid cancer mortality, but only in patients with toxic
multinodular goiter. Overall, the risk of thyroid cancer in patients treated with
radioactive iodine treated resulted in a small, absolute excess in actual patient
deaths.
Franklyn et al. (195) also suggested that 131 I therapy was associated with
a higher incidence of thyroid cancer. They retrospectively studied 7417 patients
treated in Birmingham, England, with radioiodine for Graves’ disease. On ana-
lyzing 72,073 person-years of follow-up, 634 cancer diagnoses were found as
compared with an expected number of 761. The relative risk of cancer mortality
was also decreased. The incidence of cancers of the pancreas, bronchus, trachea,
bladder, and lymphatic and hematopoetic systems was decreased. However, there
were significant increases in incidence and mortality for cancers of the small
bowel and thyroid, although the absolute risk of these cancers was small (195).
In this English study, the goal of radioiodine therapy had been euthyroidism
rather than hypothyroidism. The destruction of all residual thyroid tissue would
be expected to lessen possibility of thyroid cancer. Finally, in one recent pop-
ulation based study of 3888 patients treated for hyperthyroidism, there was no
increase in cancer mortality over eight years of follow up, but the method of treat-
ment was not specified (196). In another similar study of 2973 patients treated
with radioiodine with a nine year follow up, there was an increase in overall and
cancer mortality (adjusted RR 1.36; 95% CI 1.12–1.65), mainly due to cancer
of the stomach and esophagus. However, the increase in total mortality was only
seen in patients with toxic multinodular goiter, but not in patients with Graves’
disease.
Hyperthyroidism 67

Thyroidectomy for Graves’ Disease


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

Choice of Therapy for Graves’ Disease: Summary


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

TREATMENT OF GRAVES’ OPHTHALMOPATHY AND


PRETIBIAL MYXEDEMA
Although almost all patients with Graves’ disease have radiologic evidence of eye
muscle involvement, only approximately 30% of patients have obvious clinical
disease (212). Several different methods for assessing disease severity have been
described, but none of the classifications is perfect. The “NOSPECS” classification
is still in wide use today (Table 5) (213), although it has been criticized for
being overly subjective and not quantitative enough (214). In general, the most
common symptoms are related to soft tissue swelling due to orbital congestion,
with irritation, tearing, burning, and a gritty sensation in the eyes. Diplopia is
a more unusual and debilitating problem, and only rarely is vision threatened
because of corneal exposure or optic nerve involvement. Symptoms and cosmetic
concerns also significantly impact negatively on the quality of life of affected
patients (215).
The symptoms and signs of Graves’ ophthalmopathy are due to orbital
inflammation, with the extraocular muscles and/or retro-orbital fibroblasts being
the target of the autoimmune reaction (6,13,216–218). Glycosaminoglycans pro-
duced by fibroblasts responding to T-cell infiltration cause edema of the extraocular
muscles, and further expansion of the retro orbital tissues is due to increased orbital
fat (214). Ultimately, fibrosis of the extraocular muscles can lead to diplopia, and
severe enlargement of the muscles can cause an ischemic optic neuropathy due to
compression of the optic nerve as it exits the apex of the orbit.
Hyperthyroidism 69

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)

The primary autoimmune target in Graves’ ophthalmopathy is unknown,


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

irradiated patients improved versus 31% of sham irradiated patients. However,


Gorman et al. (225) also performed a prospective, randomized, double-masked,
internally controlled, clinical trial of external beam radiotherapy for patients with
mild to moderate Graves’ ophthalmopathy. When analyzed 6 to 12 months after
orbital radiation, there was no apparent clinical benefit identified. As a result
of these recent studies, the role of external orbital radiation in the treatment of
Graves’ ophthalmopathy is uncertain.
Patients who fail radiation therapy may require surgical decompression of
the orbit if there is rapidly progressive visual loss due to optic neuropathy, steroid
dependence, or continuing ocular motility problems. Surgery is also indicated
to correct self-perceived cosmetic problems, particularly in patients with severe
proptosis or lid retraction. Unfortunately, orbital decompression often results in
more significant ocular motility problems that then require additional strabismus
surgery for correction (226–229).
The cause of pretibial myxedema remains obscure (230), but it probably
shares common features with Graves’ opthahlmopathy, including lymphocytic
infiltration and a response by fibroblasts to the subsequent inflammation. The usual
treatment is topical steroid cream with or without occlusion (231). Intralesional
steroids have also been used. Recently, octreotide has been reported to be of use
(232), but additional data are needed before this therapy can be recommended
outside of a clinical trial. Recent trials have suggested the efficacy of combined
pentoxifylline and intralesional triamcinolone acetonide (233,234).

SUBCLINICAL HYPERTHYROIDISM
Subclinical hyperthyroidism is a term generally utilized to describe patients with
normal serum total and FT4 and T3 levels and a decreased serum TSH level (235–
257). A recent consensus panel has published useful guidelines for approaching
and treating patients with subclinical hyperthyroidism (258). Patients most fre-
quently have undetectable TSH levels, although a TSH that is subnormal but still
detectable also meets the definition assuming that the values are consistent over
time. The serum TSH level should be measured in a third-generation assay that
is capable of discriminating degrees of low values, and the patient must not be
taking or receiving any medications known to alter the hypothalamic-pituitary axis
(such as corticosteroids and dopamine). TSH can be suppressed physiologically
in the first trimester of some pregnant patients, and the patient must have a normal
pituitary-thyroid axis (258). Further, the patient must be relatively healthy, with-
out 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 hyperthy-
roidism are vague and nonspecific and it may be difficult to determine if a patient
is really asymptomatic. In a young patient with subclinical hyperthyroidism due
to Graves’ disease, the thyroid is either not palpable or mildly enlarged, but a
Hyperthyroidism 71

multinodular goiter is often palpable in older patients with multinodular goiters.


Although the frequency of this disorder is not well defined, its recognition has
increased in part due to the advent of more sensitive TSH assays. When patients
with known thyroid disease are excluded, the incidence of subclinical hyperthy-
roidism is estimated to be approximately 2% (258). More details are available in
chapter 10 “Practical Management of Thyroid Disease in the Elderly.”
Sawin et al. (259) determined that low serum thyrotropin concentrations
are a risk factor for subsequent atrial fibrillation. They studied 2007 persons (814
men and 1193 women) older than 60 years during a 10-year follow-up period
to determine how frequently atrial fibrillation would develop. When analyzed
cumulatively over the entire study period, atrial fibrillation occurred in 28% of
the subjects with low serum thyrotropin values (≤0.1 ␮U/mL), as compared
with 11% among those with normal or slightly decreased serum TSH values. The
estimated relative risk for atrial fibrillation was 3.1 in Sawin’s study (259), and this
elevated risk has been confirmed in other studies (255). Although the most frequent
cause of the suppressed TSH levels in the patients in this study was exogenous
thyroid hormone therapy, there is no reason to think that the effects of endogenous
hormone would differ. Some studies have shown that postmenopausal women with
subclinical hyperthyroidism have lower bone mineral density as compared with
age-matched control women (260). However, others have not found this to be the
case (261).

Diagnosis
The evaluation of a patient with subclinical hyperthyroidism may vary among
physicians, but a reasonable approach in a typical asymptomatic patient is to
perform a complete history and physical examination, ensure the thyroid function
tests are measured in appropriately sensitive assays, and repeat the thyroid function
tests monthly for three months. Thyroid function tests should include FT4 and FT3,
since occasionally the free hormone levels may be increased disproportionately
compared to the total hormone levels (258,262). If atrial fibrillation, cardiovascular
disease, or other significant medical illnesses are present, earlier diagnosis and
treatment are appropriate, so it is recommended to repeat thyroid function tests
over a shorter period of time, such as two weeks (258). The suppressed TSH
level may represent the initial manifestations of hyperthyroidism that will evolve
into a more overt form over the ensuing months. Alternatively, the suppressed
TSH may be transient and return to the normal range, as a suppressed TSH
could represent an episode of transient thyroiditis. If this were correct, the TSH
would be expected to return to normal within three months. Therefore, to ensure
stability of the laboratory tests and help exclude the possibility of a laboratory
error, thyroid function tests are determined monthly for three months prior to
further evaluation. If stability in TSH levels is demonstrated, it seems reasonable
to perform a radioactive iodine uptake test and to consider measuring TSH receptor
antibody levels. Frequently, the radioactive iodine uptake is at the upper range of
72 Burman and Cooper

normal or slightly higher, and TSI (and TBII) levels are also minimally elevated
or normal, reflecting the minimal degree of hyperthyroidism. The radioactive
iodine uptake is measured not only to assess the level of thyroidal activity but
also to exclude painless thyroiditis. A thyroid sonogram may be useful in selected
patients to help quantitate thyroid gland size and to determine the presence and
characteristics of thyroid nodules.

Treatment
Once the tests are shown to be consistent with persistent subclinical hyperthy-
roidism, treatment options must be discussed. The first option is simply to continue
to monitor the patient and thyroid levels indefinitely. This is a reasonable option in
some patients, especially young premenopausal women and young men, but—as
noted above—subclinical hyperthyroidism may be associated with a higher risk
of accelerated bone loss and osteoporosis in postmenopausal women. It addition,
as noted above, it may also be associated with a higher risk of atrial fibrillation,
especially in older individuals (259,263,264). The second therapeutic option is to
administer radioactive iodine in an effort to induce permanent hypothyroidism.
Radioactive iodine is considered safe and effective and is the usual treatment
of choice for patients with overt hyperthyroidism. However, this treatment may
appear drastic for most patients with subclinical hyperthyroidism, in part because
they are asymptomatic and often do not desire definitive therapy. Similar comments
apply to the recommendation of a thyroidectomy. Given these considerations, a
6- to 12-month trial of antithyroid agents is a reasonable medical approach. It
normalizes the TSH, FT4, and FT3 levels, and yet also takes into account patients’
natural reluctance to have definitive therapy when they are asymptomatic and
when treatment directives revolve around a single laboratory test abnormality
(i.e., serum TSH). It is uncertain if most patients with subclinical hyperthyroidism
have multinodular goiters or Graves’ disease. Therefore, the remission rates with a
trial of antithyroid agents are unknown. One approach to a patient with subclinical
hyperthyroidism is to treat with low-dose antithyroid medication (e.g., methima-
zole 5–10 mg/day) for an arbitrary time period, such as 6 to 12 months (265). This
course of action might induce a long-lasting remission in a patient with Graves’
disease and, if the disorder subsequently recurs, the patient may be more likely to
accept definitive therapy. While a patient is being treated with antithyroid agents,
serum FT4, TSH, and possibly T3 or FT3 should be measured periodically. The risk
of adverse effects from the antithyroid agents, such as agranulocytosis, liver func-
tion abnormalities, and skin rash, is low given the small dose of medication used.
Mudde et al. (260) and Faber (266) have shown a benefit of antithyroid agent ther-
apy on bone density values in patients with subclinical hyperthyroidism. Buscemi
et al. (267) showed that restoration of euthyroidism with antithyroid agents had a
favorable effect on cardiac and bone paratmeters. However, more detailed, prospec-
tive studies are required regarding all aspects of subclinical hyperthyroidism to
allow a more evidence-based approach to these patients.
Hyperthyroidism 73

THYROID STORM
The term thyroid storm refers to severe and exaggerated symptoms and signs of
hyperthyroidism, usually in association with tachycardia, fever, diarrhea, vom-
iting, dehydration, disorientation, or mental confusion (207,268). Patients usu-
ally experience severe restlessness and anxiety and may be unable to reason.
There is a continuum between “routine” hyperthyroidism and thyroid storm,
and different observers may vary in their definition of thyroid storm. Although
there have been attempts to establish a uniform set of criteria for the diagnosis
of thyroid storm (207), these have not been generally accepted. Thyroid func-
tion tests, for example, FT4 and FT3, overlap between routine hyperthyroidism
and thyroid storm, and mean values are similar in most studies (269). Sher-
man and Ladenson (270) have noted lower socioeconomic status in patients
with thyroid storm compared to those with controlled hyperthyroidism, indi-
cating that lack of access to medical care may be an important predisposing
factor.
Thyroid storm is typically precipitated by a specific event, such as surgery
(especially patients having thyroid surgery without adequate preparation), severe
systemic illness (e.g., pneumonia, pharyngitis), or parturition. It is important to
prevent thyroid storm whenever possible by trying to predict circumstances in
which it may occur. It is preferable, in general, to treat patients as if they had
thyroid storm when it is suspected, rather than to delay therapy in the hope that
thyroid storm will not develop or become fully manifest.

Treatment
Patients should be treated with antithyroid agents to restore euthyroidism prior
to anticipated stressful events, such as surgery. As noted earlier, hyperthyroid
patients should be prepared with antithyroid medications for several weeks prior
to thyroidectomy. It is generally believed that when thyroid hormone stores are
decreased the risk of exacerbating thyroid storm is decreased, since there may be
less preformed T3 and T4 that may be released into the circulation at surgery.
However, Hermann et al. (271) studied thyroid hormone venous effluent from
the thyroid gland in patients with hyperthyroidism undergoing thyroidectomy
without antithyroid agent pretreatment. There were no significant differences in
T3 and T4 levels in the venous effluent compared to the peripheral levels. It is
unclear if, however, if this study applies to all hyperthyroid patients undergoing a
thyroidectomy and it is prudent to perform careful monitoring at the time of surgery
with an experienced surgical and anesthetic team. The precise pathophysiology
underlying a possible increase of thyroidal release of T4 and T3 around the
time of thyroidectomy is not known but likely relates to surgery and anesthesia
itself.
Treatment for a patient with severe thyrotoxicosis or thyroid storm is more
aggressive than that for a patient with less severe thyroid dysfunction (207). The
doses of medications are higher in patients considered to have thyroid storm.
74 Burman and Cooper

Propylthiouracil, 100 to 200 mg q4 h, or methimazole, 10 to 20 mg q4 h, is


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

SOLITARY TOXIC NODULES


Introduction
A solitary autonomous toxic thyroid nodule produces sufficient thyroid hormone to
suppress TSH and cause overt or subclinical hyperthyroidism (278–282). Often,
a thyroid nodule may be autonomous and not yet be sufficiently functional to
suppress serum TSH. The capacity to secrete thyroid hormones varies with the
size of the thyroid nodule, and those that are ⬎3 cm in size are much more likely
to produce hyperthyroidism (283). The percentage of autonomous nodules that
secrete sufficient thyroid hormones to produce overt hyperthyroidism is relatively
low, in the range of 20%.
Hyperthyroidism 75

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

Pathogenesis
Autonomous function of the nodule is attributed to either a loss in suppression of
normal cell function due to a genetic defect in the TSH receptor or a downstream
pathway (e.g., G protein), causing excess stimulation of the thyroid cell and unreg-
ulated thyroid hormone production. The TSH receptor consists of seven transmem-
brane domains with three extracellular and three intracellular loops (291). The
TSH receptor is coupled to a G protein, which subsequently initiates cyclic AMP
production. Cyclic AMP is essential for production of thyroid cell products such
as thyroglobulin, thyroid peroxidase, and hormone production and secretion, as
well as cell growth and proliferation. The majority of solitary autonomous thyroid
nodule tissue contains mutations in the TSH receptor protein or, less often, in the
stimulatory G protein (292–295). Several different mutations in the TSH receptor
gene and the resultant mutated protein are associated with cyclic AMP–dependent
transcription independent of the presence of TSH. Mutated receptors retain a sig-
nificant 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 muta-
tions have been found in approximately 5% to 30% of toxic thyroid nodules
(293).
76 Burman and Cooper

Clinical Considerations
Approximately 1% of patients referred for thyroid disease and approximately
5% of hyperthyroid patients have an autonomous thyroid nodule (283). Patients
with autonomous functioning thyroid nodules present most frequently with a neck
mass but may also have subclinical hyperthyroidism (278,283). Overt symptoms
of hyperthyroidism are uncommon. The frequency of toxic adenomas increases
with age, and only about half of patients with autonomous nodules over the age of
60 manifest clinical signs or symptoms of hyperthyroidism. Autonomous nodules
are much more common in women. A solitary autonomous thyroid nodule is not
an autoimmune disease and is not associated with ophthalmopathy or dermopathy.
Patients with an autonomous nodule larger than 3 cm have approximately a 20%
chance of progressing to overt hyperthyroidism over several years, with smaller
lesions having a much lower progression rate (296). Toxic nodules may undergo
cystic or necrotic degeneration with return to euthyroidism (278). As many as 20%
to 30% patients with solitary autonomous nodules may have a restoration of normal
function secondary to hemorrhage (282,297). Iodine deficiency increases the risk
of iodine-induced hyperthyroidism in patients with autonomous thyroid nodules
(see Chapter 3, “Hyperthyroidism”). Even a small addition of iodine, perhaps
100 ␮g/day, to a low-iodine diet can initiate hyperthyroidism (298). Although
iodine deficiency is not a problem in the United States, hyperthyroidism has been
reported in patients with autonomous thyroid nodules within one to two months
after exposure to radiocontrast dyes as well as after exposure to iodine-containing
drugs such as amiodarone (299).

Diagnosis
Autonomous thyroid nodules are usually diagnosed by integration of the history
and physical examination with laboratory and nuclear medicine testing. The serum
TSH level is usually suppressed and is often unmeasurable. Free/total T4 and T3
are usually normal or slightly elevated but may vary depending upon nodule size
and iodine exposure. Preferential T3 secretion, that is, T3 toxicosis, appears more
common in patients with autonomous nodules than in Graves’ disease (262,296).
The identification of an autonomous nodule on technetium-99 m or (123 I) scinti-
graphic 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 dom-
inant nodule appear to be the sole area that traps radioactive iodine. When an
autonomous thyroid nodule is suspected, it may be appropriate to use radioiodine
rather than technetium as the diagnostic agent. Occasionally, a nodule may appear
to be “hot” with technetium, when it is actually a “cold” nodule with radioiodine.
This discordance is thought to relate to the ability of iodine to be trapped and
organified by thyroid tissue, whereas technetium can only be trapped (300).
Hyperthyroidism 77

Autonomous nodules lack an intact feedback mechanism to control iodine


uptake and hormone production. Therefore, several tests have been used in the
past to help diagnose the presence of autonomy. The T3 suppression test consists
of scintigraphic scanning of the thyroid before and after 10 days of exogenous
oral T3 administration at 50 to 100 ␮g/day. In addition, TSH, FT4, and FT3 are
drawn at baseline and on completion of the T3 dosing. A normal patient will have
suppression of endogenous TSH production; the second thyroid scan will show
no thyroid uptake and the FT4 level will have decreased. In contrast, a patient
with an autonomous thyroid nodule will show unchanged uptake over the nodule,
and the FT4 level will not have changed. T3 suppression testing in hyperthyroid
patients, especially elderly subjects, is fraught with potential danger by potentially
exacerbating already existing thyrotoxicosis. This test is rarely performed and its
use should be discouraged with the advent of third-generation TSH assays.

Treatment
Therapeutic decisions regarding autonomous nodules depend upon a variety of fac-
tors, including patient age, the severity of hyperthyroidism, and associated medical
conditions such as coronary artery disease and/or a history of cardiac arrhythmias.
Patients with overt hyperthyroidism in the presence of an undetectable TSH and
elevated FT4 and T3 should be treated. Older patients with undetectable TSH and
normal FT4 and T3 should be strongly considered for treatment because of possi-
ble deleterious effects on bone metabolism and the heart (see section “Subclinical
Hyperthyroidism” of this chapter). More controversial is whether young patients
with subclinical hyperthyroidism or people with nodules ⬎3 cm in diameter
should be treated prophylactically. Some patients desire treatment for cosmetic
reasons.
The most important therapeutic option is radioactive iodine ablation of the
toxic adenoma. Radioactive iodine concentrates in the autonomous nodule and may
accumulate in extranodular tissue, albeit to a much lesser extent. Although results
are variable, based upon size of the nodule, nodule uptake, dose administered,
and tissue radiation sensitivity, a typical toxic nodule will shrink approximately
40% within one year following an ablative dose. Radioactive iodine ablation of
an autonomous thyroid nodule may decrease the ability of that nodule to secrete
excess thyroid hormones; but the nodule itself, although functionally inactive,
may remain and must be monitored clinically over time (278,283). The beneficial
effects of radioiodine may not be maximal until 4 to 12 months after therapy.
Thyroid function may normalize or decrease to below the normal range in this
time period, but the nodule may still be palpable in perhaps half the patients.
Occasionally, a second or even a third dose of radioiodine is required to render
a patient euthyroid. It is recommended to wait at least six months after the ini-
tial dose before considering retreatment with radioiodine. Persistent or recurrent
hyperthyroidism can be expected in approximately 10% of patients, with studies
revealing a range of 0% to 41.3% (279,301,302).
78 Burman and Cooper

Following radioiodine therapy, hypothyroidism occurs at an average of


approximately 10% within the first year, with an annual rate thereafter of approx-
imately 3% (297,303,304). This occurrence rate may relate to the fact that the
contralateral normal tissue is exposed to significant amounts of radiation (279).
Underlying autoimmune thyroid disease may also predispose to the development
of hypothyroidism. Larger doses of 131 I appear to be a causative factor in stud-
ies finding a substantial rate of hypothyroidism. The dose per gram of thyroid
tissue, percent radioactive iodine uptake, pre- and/or posttreatment with antithy-
roid medications, and recent iodine exposure all may affect the outcome. In a
retrospective analysis of 45 patients with toxic adenomas receiving an average of
10.3 ± 3.5 mCi of 131 I, euthyroidism was achieved in 91% and 93% at 6 and 12
months, respectively (302), and no patients became hypothyroid. Three patients
had recurrent hyperthyroidism between 4.5 to 10 years and became hypothyroid
after a second therapy. However, two other studies found that 35% and 36% of
patients became hypothyroid following the first dose of 131 I, with an average
follow-up of 3.8 years and 8.5 years, respectively (303,305). Of note, these two
studies used a mean 131 I dose of 29.1 mCi and 23 ± 10 mCi. Higher doses are
associated with more prompt achievement of euthyroidism or hypothyroidism.
131
I is tolerated well by the majority of patients, although radiation thyroiditis
with or without exacerbation of the underlying thyrotoxicosis can occur. Repeat
scintigraphic scanning following radioactive iodine therapy may reveal relatively
normal thyroid distribution of tracer, the nodule may be cold, warm, or hot in
relation to the other tissue, or the autonomous nodule may remain evident with
continued suppression of extranodular tissue. In the latter case, the serum TSH
level will remain suppressed.
Surgery can also be performed to remove the affected lobe and isthmus,
leaving the remaining lobe intact (278,281,306). In experienced hands, surgery
has a low anesthetic risk and a low surgical complication rate of vocal cord
paralysis and hypoparathyroidism, especially if only a lobectomy rather than
a thyroidectomy is performed (306). Removal of the nodule alone or only a
portion of the affected lobe including the nodule is not recommended. Recurrence
following surgery is unusual. Multifocal autonomous nodules not appreciated on
the initial evaluation, and therefore not surgically removed, might be responsible
for some failures. Euthyroidism can be achieved relatively quickly with surgical
intervention, although hypothyroidism may occur. The hypothyroidism may be
secondary to inadequate residual thyroid tissue or possibly underlying autoimmune
thyroid disease. Although controversial, some experts recommend that patients
who have had a lobectomy and isthmusectomy be placed on lifelong thyroxine
therapy. The use of thyroxine therapy has not been proven to be effective in
decreasing growth of thyroid nodules on the contralateral side. However, following
a thyroid lobectomy, the risk of developing hypothyroidism is relatively high,
being 14% in one study (307). Hedman et al. (307) followed up 95 patients an
average of 15 years after thyroid lobectomy had been performed. Nine percent
of patients had an elevated TSH with normal serum thyroxine and an additional
Hyperthyroidism 79

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

TOXIC MULTINODULAR GOITER


Introduction
A toxic multinodular goiter is a thyroid gland that contains at least two autonomous
functioning thyroid nodules that secrete excessive amounts of thyroid hormone,
suppressing serum TSH and often causing typical symptoms and signs of hyper-
metabolism (311). These nodules may be more or less distinct on clinical examina-
tion 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 multinodu-
lar goiters are similar to those found in those with solitary autonomous nodules
80 Burman and Cooper

A B

Figure 7 (A and B) An elderly patient with a toxic multinodular goiter. It is frequently


difficult to discern by clinical examination the extent of substernal extension of the thyroid
gland (330).

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

A B C

Figure 8 Thyroid radioisotope scans may be helpful in assessing certain patients with
hyperthyroidism. Panel A demonstrates symmetric isotope distribution (pertechnetate tech-
netium 99 m) typical of a patient with Graves’ disease. The right lobe appears larger than
the left because of rotation. Panel B shows an autonomous functioning thyroid nodule.
There is intense activity in the left-lobe nodule with absent activity in the right lobe because
of suppression of TSH by thyroid hormone secretion of the nodule. Panel C shows a toxic
multinodular goiter. Radioactive isotope activity is heterogenous, with areas of intense
activity interspersed with areas of reduced activity (330).
Hyperthyroidism 81

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 multinodu-
lar 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 par-
ticular nodules grow and become autonomous. There are two theories concerning
the etiology of multinodular goiters. In the first, it is hypothesized that hyperplastic
nodules result from chronic activation by external factors such as TSH, iodide,
IGF-1, or thyroid growth–stimulating immunoglobulins (314,315). These factors
then cause the growth of polyclonal nodules. This theory does not have widespread
support, since trophic hormonal stimulation is not generally thought to result in
autonomous growth. The more widely held view is that several individual clones
develop, perhaps related to a genetic mutation, and that these cells gradually grow,
become autonomous, and finally result in excess hormonal secretion (316–319).
A rare entity, McCune-Albright syndrome, may be associated with the presence of
a toxic multinodular goiter due to a mutation in the gene encoding the Gs protein
alpha subunit which couples transmembrane-domain receptors to adenyl cyclase.
This results in constitutive activation of adenyl cyclases and overproduction of
cAMP. This syndrome is also associated with precocious puberty, fibrous dyspla-
sia of bone, abnormal gonadal function, and café-au-lait spots on the skin (320).
These patients may have a higher risk of thyroid cancer (320).

Diagnosis
Patients present with typical clinical and biochemical hyperthyroidism and small,
medium-sized, or large multinodular goiters. There is nothing particularly unusual
about their presentation, signs, or symptoms compared to patients with other
causes of hyperthyroidism, except the nodules and goiter may be sufficiently large
to cause local compressive symptoms. The radionuclide scan shows heterogenous
uptake with areas of hyper- and hypointensity (Fig. 8). There is a spectrum of
disease, ranging from minimal thyroid enlargement with small thyroid nodules
only detected on scan or sonogram to markedly enlarged thyroid glands and
large nodules. Color flow Doppler sonography may also be useful especially in
helping to differentiate nodular variants of Graves’ disease from toxic multinodular
goiters that are nonautoimmune mediated (321). Some multinodular goiters have
a significant substernal component.

Treatment
Radioiodine and surgery are the two major treatment modalities in patients with
toxic multinodular goiters, (311,322–324). Because multinodular goiters probably
are not responding to serum anti-TSH receptor immunoglobulins, it is not consid-
ered possible to induce a long-term remission with the chronic use of antithyroid
82 Burman and Cooper

agents. It may be appropriate to render a patient euthyroid with the use of antithy-
roid agents prior to radioiodine therapy, especially patients older than 60 years
or those with underlying heart disease. Selected patients can be maintained on
these agents for an indefinite period of time, for example, elderly patients with
accompanying serious medical disorders. However, this approach is applicable to
a minority of patients with toxic multinodular goiters.
Radioiodine therapy is most often used to restore euthyroidism or induce
hypothyroidism (322,323). 131 I therapy is generally thought to be less reliable
in controlling the hyperthyroidism, compared with Graves’ disease, and higher
doses are usually required (approximately 20–30 mCi 131 I). The explanation for
the difference in responses between Graves’ disease and toxic multinodular goiter
is unknown, but probably relates to the fact that there are different degrees of
autonomy and radiosensitivity among cells comprising the multinodular goiter.
The dose of 131 I varies, but it is reasonable to attempt to deliver approximately
160 to 200 ␮C 131 I/g thyroid tissue. In one recent study, following 131 I treatment
for a toxic multinodular goiter, 62% of patients were euthyroid, 19% hypothyroid
and 19% remained hyperthyroid. The mean size reduction overall was 32%
(325). It is often difficult to estimate the size of multinodular goiters, especially
because they may have a substernal component. A thyroid sonogram is helpful if
the gland is cervical in location, and CT scanning (without intravenous contrast)
is useful for estimating the size of a large multinodular goiter with substernal
extension.
It is difficult to predict the response to a given dose of 131 I; in one study,
the cure rate was relatively similar to that seen in Graves’ disease (325,326), but
others have not found similar degrees of success (327). Release of preformed and
stored thyroid hormones can occur after a dose of 131 I, so that these patients, who
are typically older, should be carefully monitored carefully. Not unexpectedly,
smaller thyroid glands seem to respond more consistently than larger glands,
although there is wide variation. Elderly patients or those with associated medical
disorders or heart disease should be treated with antithyroid agents prior to
administering 131 I, as this is thought but not proven to reduce the chance of
radioiodine-induced worsening of the hyperthyroidism. However, thionamide
exposure may cause a higher failure rate of radioiodine therapy (180), so higher
doses of radioiodine should be employed.
A near total thyroidectomy represents an alternative therapeutic option
(327,328). This procedure must be performed by an experienced thyroid sur-
geon, but even in this circumstance there is a risk of hypocalcemia and recurrent
laryngeal nerve paralysis as well as, in unusual circumstances, acute release of
stored thyroid hormone, with an exacerbation of hyperthyroidism. It is important
to establish a euthyroid state prior to surgery. The procedure of choice is a near
total thyroidectomy to remove as much thyroid tissue as the surgeon is comfortable
with, and to preserve the parathyroid glands and the recurrent laryngeal nerves.
Some clinicians prefer that patients be given thyroxine therapy postoperatively,
even if they have sufficient thyroid tissue remaining to prevent hypothyroidism.
Hyperthyroidism 83

This approach is controversial since, except for patients who have received exter-
nal radiation therapy in the past, thyroid hormone treatment to euthyroid patients
has not been proven to decrease the likelihood of recurrent nodule formation (329).
It does obviate the possibility of severe hypothyroidism developing, but periodic
monitoring is required whether or not thyroxine therapy is used.
Although therapy should be individualized and discussed with patients and
their families as appropriate, most patients with hyperthyroidism due to a multin-
odular goiter should be treated with 131 I therapy. Antithyroid agent therapy may
be useful for patients with smaller glands with less severe hyperthyroidism; long-
term antithyroid agent therapy should be reserved for selected patients. Surgery
addresses the problem expeditiously and can be used quite effectively; it should
be considered for patients with very large thyroid glands (above 150–200 g) since
the likelihood of such patients responding to 131 I therapy is lower. Compressive
symptoms such as hoarseness, superior vena caval syndrome, dysphagia, and/or
dyspnea are additional indications for surgery. However, in patients who are not
surgical candidates, radioiodine should be used.

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3
Thyroiditis and Other More
Unusual Forms of
Hyperthyroidism

Shon E. Meek and Robert C. Smallridge


College of Medicine, Mayo Clinic, Jacksonville,
Florida, U.S.A.

THYROIDITIS AND HYPERTHYROIDISM


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

101
102 Meek and Smallridge

the lack of occurrence in the tropical and subtropical areas is due to a lower
actual frequency or ascertainment bias. However, despite the possible geographic
variation, subacute thyroiditis is recognized more frequently during the summer
months (4,5). Subacute thyroiditis has been reported in all age groups. It is most
common in the third to sixth decades of life, and it is rare in children. Female
patients outnumber male patients in a ratio of up to 6:1 (6–8).

Pathophysiology
The cause of subacute thyroiditis is not known; however, it tends to occur following
an upper respiratory tract infection. Mumps, measles, influenza, common colds,
adenovirus, Epstein-Barr virus, coxsackievirus, and cat-scratch disease have all
been associated with subacute thyroiditis (9–15). Subacute thyroiditis is associated
with HLA-B35, approximately 72% of the time (14,16). Subacute thyroiditis has
been reported in twins and family members (17,18). Infiltrative diseases, such
as amyloid, have also been reported to cause a subacute thyroiditis–like picture
(19), and anaplastic thyroid cancer can rarely begin with painful, rapid thyroid
enlargement known as “malignant pseudothyroiditis” (20,21). Thyroiditis induced
by amiodarone can also occasionally present with a similar clinical picture.
The thyroid gland in subacute thyroiditis is enlarged and firm; it may adhere
to adjacent tissues. Thyroid tissue obtained by fine-needle aspiration (FNA) biopsy
shows an inflammatory infiltrate of neutrophils, lymphocytes, histiocytes, and
multinucleated giant cells (22–24).

Diagnosis
Patients with subacute thyroiditis usually present with an acute onset of malaise,
feverishness, and pain in the region of the thyroid gland. The pain may radiate
from the thyroid to the jaw and to the ears, or down to the anterior chest wall.
Coughing, swallowing, turning the head, or wearing tight clothing around the
neck can aggravate the pain. Approximately one-third to one-half of patients
may present with unilateral thyroid pain. Approximately one-third of patients
can have migratory pain throughout the thyroid, so-called “creeping thyroiditis”.
Approximately one-third of cases may present with diffuse pain in the thyroid
(1,15,25). Some biopsy-proven cases of subacute thyroiditis have been reported
to be painless (23,26,27).
Many patients may have systemic symptoms of malaise, myalgia, fever, and
anorexia. As noted above, approximately 50% of patients may have a history of
an antecedent upper respiratory infection. Symptoms of thyrotoxicosis are also
present in 50% to 60% of patients, and these may include heat intolerance, pal-
pitations, tremor, and nervousness. Cases of subacute thyroiditis causing thyroid
storm have been reported (28).
Physical examination shows an uncomfortable patient with a tender,
enlarged, and firm thyroid gland. The process is often asymmetric, and lym-
phadenopathy is usually not present. Symptoms of thyrotoxicosis may last 4 to
Thyroiditis and Other Forms of Hyperthyroidism 103

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

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

Figure 2 Natural history of subacute thyroiditis.

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

Silent Thyroiditis
Introduction
Silent or “painless” thyroiditis is a painless inflammation of the thyroid that pro-
duces a transient hyperthyroid state (35). The terms silent thyroiditis and painless
thyroiditis are used most commonly to describe this condition. However, silent
thyroiditis has also been called transient painless thyroiditis, painless thyroiditis
with transient hyperthyroidism, painless subacute thyroiditis, atypical thyroidi-
tis, occult subacute thyroiditis, lymphocytic thyroiditis, spontaneously resolving
lymphocytic thyroiditis, and transient thyrotoxicosis with lymphocytic thyroidi-
tis. Silent thyroiditis often occurs in the postpartum period, and is then called
postpartum thyroiditis.
Thyroiditis and Other Forms of Hyperthyroidism 105

Epidemiology
The incidence of painless thyroiditis was reported with increasing frequency in
the late 1970s and early 1980 s in the Great Lakes region of the United States
and Canada. Silent thyroiditis has also been reported in South America, India,
and Japan. However, it has been reported to be less frequent on the east and west
coasts of the United States and in Europe and Argentina (36). Patients are usually
between 30 and 60 years of age, but silent thyroiditis can occur in all age groups.
There is a female-to-male predominance of approximately 1.5 to 1. There is an
11% chance that patients may have recurrent episodes of silent thyroiditis (37).

Pathophysiology
In most cases, silent thyroiditis is an autoimmune disease and likely a variant
of Hashimoto’s thyroiditis. Histologically, silent thyroiditis is characterized by a
lymphocytic infiltration of the thyroid, and it is sometimes associated with lym-
phoid follicles (38,39). It is associated with other autoimmune diseases, such
as autoimmune adrenal insufficiency, lupus erythematosus, idiopathic thrombo-
cytopenic purpura, and rheumatoid arthritis (40–43). Silent thyroiditis has been
associated with HLA DR3, which suggests a genetic component to the disease
(44). Thyroid autoantibodies are present in the serum in up to 50% of patients,
which suggests an autoimmune process (35). No association with a viral infection
has been found. However, the lack of antibodies in some patients and lack of
clear female predominance suggests that silent thyroiditis maybe a heterogeneous
disorder.

Diagnosis
Patients with silent thyroiditis present with symptoms and signs of thyrotoxicosis.
The most common symptoms include palpitations, weight loss, nervousness, heat
intolerance, and fatigue. The thyrotoxic phase may last from 1 to 12 months,
but it usually lasts about 3 months. Approximately one-half of patients have a
goiter, in which the thyroid is 1.5 to 3 times the normal size, diffusely enlarged,
symmetric, firm, and nontender (35). The course of the disease typically follows
three different phases. The first phase is characterized by hyperthyroidism, and
many, but not all patients will go on to develop hypothyroidism as a second stage
of silent thyroiditis. Most patients then become euthyroid in the third stage, but
permanent hypothyroidism may develop months to years later.
During the first phase of silent thyroiditis, the serum T4 and T3 levels
are increased and serum TSH is decreased. The T4/T3 ratio is higher in silent
thyroiditis than in Graves’ disease, reflecting glandular hormonal stores. The
radioactive iodine uptake is very low. Thyroglobulin levels are increased, which
may be useful in distinguishing silent thyroiditis from factitious thyrotoxicosis.
Serum thyroglobulin concentrations may remain slightly increased even one to two
years after recovery of normal thyroid function (45). Thyroid autoantibody levels
are increased approximately 30% to 50% of the time. However, approximately
106 Meek and Smallridge

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

Postpartum Thyroiditis
Introduction
Postpartum thyroiditis is a syndrome of thyroid dysfunction that occurs within
the first year following parturition. It is usually characterized by transient painless
Thyroiditis and Other Forms of Hyperthyroidism 107

thyrotoxicosis with a low radioactive iodine uptake, often followed by a hypothy-


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

Hypothyroid Hyperthyroid-
40% Graves’
11%

Hyperthyroid-Thyroiditis
24%
Hyper/Hypothyroid
25%

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


dysfunction.

Many patients will have some enlargement of the thyroid. Postpartum thyroiditis is
almost universally painless, although one case of painful disease has been reported
(74). In postpartum thyroiditis, there is an absence of exophthalmos and, almost
always, an increase in antithyroid antibody titers. Patients may present at a time
when thyroid hormones levels are high, normal, or low. Since the hyperthyroid
phase is a destructive type of thyroiditis, there is a low 24-hour radioactive iodine
uptake.
Figure 3 shows the frequency of hyperthyroidism, hypothyroidism, or both
in postpartum thyroid dysfunction. The classical triphasic pattern of postpartum
thyroiditis is mild hyperthyroidism followed by transient hypothyroidism with
subsequent thyroid recovery. This pattern of postpartum thyroiditis occurs in 25%
of patients. The thyrotoxic phase usually presents one to six months postpartum.
Frequently, a period of hypothyroidism develops over the next three to four months,
followed by a return to normal thyroid function. Some patients with postpartum
thyroiditis only develop transient hyperthyroidism without subsequent hypothy-
roidism. This can either take the form of thyroiditis-induced hyperthyroidism in
approximately 24% of patients or hyperthyroidism caused by Graves’ disease in
approximately 11% of patients. Some patients (40%) with postpartum thyroiditis
present only with hypothyroidism that is followed by recovery of thyroid function
(75). Figure 4 shows the possible stages of thyroid function in the natural history
of postpartum thyroiditis.
All patients with postpartum thyroiditis should be monitored for the future
development of thyroid failure. Approximately 20% to 64% of patients with tran-
sient thyroid disease postpartum become hypothyroid with long-term follow-up
(62,65,66,76,77). Factors associated with the development of permanent hypothy-
roidism include higher titer of thyroid autoantibodies, greater severity of the
hypothyroid phase of postpartum thyroiditis, and a previous history of sponta-
neous abortion (74,76). Microsomal and thyroid peroxidase antibodies have been
reported to have a sensitivity range of 0.45 to 0.89 and a specificity range of 0.9
to 0.98 (75).
Thyroiditis and Other Forms of Hyperthyroidism 109

Figure 4 Natural history of postpartum thyroiditis.

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

Acute Infectious Thyroiditis


Introduction
Infectious thyroiditis is an inflammatory process caused by invasion of the thyroid
by bacteria, mycobacteria, fungi, protozoa, or flatworms. Infectious thyroiditis
may rarely cause thyrotoxicosis.
110 Meek and Smallridge

Epidemiology
Infectious thyroiditis is a rare disorder. The thyroid is felt to be relatively resistant
to infection because of its vascularity, its large concentration of iodine, the presence
of hydrogen peroxide, and its encapsulation. Infectious thyroiditis may be more
prevalent in the pediatric age group (79).

Pathophysiology
Many different bacteria can infect the thyroid including Streptococcus, Staphylo-
coccus, Pneumococcus, Salmonella, Bacteroides, Pasteurella, (80) and Treponema
pallidum (81). Mycobacterium tuberculosis (82) and several fungi, including Coc-
cidioides immitis, Aspergillus, and Candida albicans (83), have been associated
with thyroiditis. Pneumocystis carinii may also cause infectious thyroiditis (84).
Patients who are immunocompromised or have acquired immunodeficiency syn-
drome are at particular risk for infectious thyroiditis.
Most often, this infection is caused by a direct extension of an internal
fistulous tract between the pyriform sinus and the thyroid (85,86). This tract
is more common in children and may represent the course of migration of the
ultimobranchial body from its embryonic origin in the fifth pharyngeal pouch. This
extension tends to develop more commonly in the left thyroid lobe than in the right.
However, infection in the thyroid may occur in a normal thyroid, multinodular
goiter, or in a degenerating thyroid nodule as well. Immunocompromised patients
may have a higher risk of infectious thyroiditis (87). Infectious thyroiditis has
also been reported to occur after FNA by staphylococcus aureus in a patient with
atopic dermatitis (88).

Diagnosis
Patients with infectious thyroiditis usually present with pain and may have a
swollen, hot, and tender thyroid (94%) (81). As a result, affected individuals may
avoid extension of their neck due to pain, swallowing may be painful, and dyspha-
gia may be present (91%) (81). They may also present with signs of infection in
adjacent tissues, cervical lymphadenopathy, and systemic signs of fever and chills
(92%) (81).
Laboratory data include an increased white blood cell count and increased
sedimentation rate. The patient may have increased thyroid hormone levels and
present with symptoms of thyrotoxicosis, due to hormonal release from the thy-
roid (80,89). In one review, 12 of 56 cases had laboratory data suggesting hyper-
thyroidism (81). However, most patients are biochemically euthyroid, and the
radioactive iodine uptake will usually be normal. Thyroid ultrasound or computed
tomography (CT) scan of the neck may show a local abscess that can be aspirated
and cultured to make the diagnosis (90). A barium swallow can be obtained to
evaluate for possible predisposing factors such as a fistulous tract between the
pyriform sinus and the thyroid.
Thyroiditis and Other Forms of Hyperthyroidism 111

Treatment
Treatment depends on the identification of the organism causing the infection.
Aspiration of the thyroid should be obtained with appropriate Gram stain and
culture of the material. Systemic antibiotics, which are tailored to the specific
infectious agent, are administered (79). An abscess will require surgical explo-
ration and drainage, and fistulae also require surgery to prevent recurrent infection
(91).

Radiation Thyroiditis
Introduction
Radioactive 131 I and external beam radiation are used to treat thyroid disease.
Radiation thyroiditis with a thyrotoxic phase has been reported following radiation
treatment with both forms of radiation therapy.
Epidemiology
Radiation thyroiditis from 131 I occurs in approximately 20% of patients receiving
≥50,000 rads (50 Gy) to ablate residual normal thyroid tissue (92). It is more
common with larger thyroid remnants. Transient increases in thyroid hormone
are commonly seen in hyperthyroid patients treated with radioactive iodine. How-
ever, clinically significant exacerbation of hyperthyroidism was not observed (93).
Radiation thyroiditis causing transient thyrotoxicosis has also been reported with
external beam radiation. In a prospective study of external beam radiation directed
to the neck for metastatic cancer treatment, eight of 22 patients developed a sub-
normal TSH after receiving 40 Gy of external beam radiation over two weeks.
Levels of T4 and T3 tended to rise after 40 Gy of radiation, but the levels were
not statistically different from baseline (94). Several case reports of external beam
radiation–induced overt thyrotoxicosis have been reported (95,96).
Pathophysiology
Radiation presumably causes a destructive thyroiditis with release of preformed
thyroid hormone into the bloodstream. The thyrotoxicosis is transient. The radi-
ation dose that has been reported to cause external beam radiation–induced thy-
rotoxicosis varies between 37 and 50 Gy (95,97). It is likely that the greater
the external beam radiation dose, the more frequently thyrotoxic thyroiditis and
subsequent hypothyroidism occur.
Diagnosis
In radioactive iodine–induced thyroiditis, manifestations usually occur about four
days after radioactive iodine is administered. Symptoms, if present, consist of neck
and ear pain, dysphagia, thyroid tenderness, and/or transient symptoms of thyro-
toxicosis. External beam radiation–induced thyrotoxic thyroiditis usually occurs
within a few weeks of radiation exposure. It is characterized by increased serum
112 Meek and Smallridge

levels of thyroid hormones and suppressed serum levels of TSH. Serum thyroid
autoantibodies are typically negative. The 24-hour radioactive iodine uptake is
low.
Treatment
Since the thyrotoxicosis from radiation thyroiditis is transient, observation may be
all that is needed. Treatment with beta-adrenergic blocking agents can be used to
control tachycardia and tremor. Patients with 131 I-induced thyrotoxic thyroiditis
may have significant neck pain requiring treatment with corticosteroids, especially
in thyroid cancer patients treated with large doses to ablate remnant thyroid tissue.
After patients are treated with external beam radiation therapy, they should be
monitored long-term for the development of hypothyroidism.
Trauma-Induced Thyroiditis
Several reports of trauma-induced thyroiditis have been described, and this condi-
tion may be associated with thyrotoxicosis. Thyroid biopsy, parathyroid surgery,
surgical trauma, and trauma induced by a seat belt have all been reported to
cause thyrotoxicosis (98–100). The thyroid may be tender due to the trauma. The
thyrotoxicosis is transient and associated with a low uptake of radioactive iodine.

DRUG-INDUCED HYPERTHYROIDISM
Iodine-Induced Hyperthyroidism
Introduction
Iodine-induced hyperthyroidism was first described in 1821 (101). However,
iodine-induced hyperthyroidism is not a single entity, but rather an end result
that can occur from a variety of underlying thyroid problems. The common pre-
cipitant of the thyrotoxicosis is exposure to high doses of iodine.
Epidemiology
The incidence of iodine-induced hyperthyroidism has varied according to the
underlying thyroid abnormality, the geographic region, and the particular time in
history. The highest incidence of iodine-induced hyperthyroidism occurs in areas
of iodine deficiency and in individuals with multinodular goiters, when iodine
supplementation is introduced into their diet.
In four different iodine-deficient European regions, the incidence of iodine-
induced hyperthyroidism was determined before and after iodinization of salt. In
a region of Holland, the average yearly incidence of iodine-induced hyperthy-
roidism increased from 0.001% to 0.02% after introduction of dietary iodine. In
Yugoslavia, the incidence of newly diagnosed hyperthyroidism increased from
0.0025% to 0.01% in Serbia and from 0.02% to 0.07% in Belgrade. In Tyrol,
the number of toxic adenomas doubled to an average incidence of iodide-induced
hyperthyroidism of 0.03%. In general, the incidence of hyperthyroidism rose
Thyroiditis and Other Forms of Hyperthyroidism 113

140

120

100

80
<=39Yr
>=40Yr
60

40

20

0
60
62
64
66
68
70
72
74
76
78
80
82

84
86
88
90
92
19

Figure 5 Incidence of hyperthyroidism in Tasmania. Ordinate is number of cases, abscissa


is year. Separate lines for patients younger and older than 40 years. (Supplied by G. Vidor.)
Source: From Ref. 101.

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

Table 1 Iodine-Containing Drugs and Their Brand Names


Radiologic contrast agents
Ipodate (Oragrafin)
Iopanoic acid (Telepaque)
Iothalamate (Angio-Conray)
Metrizamide (Amipaque)
Topical agents
Povidone iodine (Betadine)
Iodoform gauze (Nu gauze)
Iodochlorhydroxyquin cream (Vioform)
Diiodohydroxyquin cream (Vytone)
Solutions
Saturated potassium iodide
Lugol’s
lodinated glycerol (Organidin, Tuss Organidin, lophen)a
Calcium iodide (Calcidrine syrup)
Echothiophate iodide ophthalmic (Phospholine)
Hydriodic acid syrup
Drugs
Amiodarone (Cordarone)
Vitamins containing iodine
Kelp
Iodochlorohydroxyquinolone (Entero-Vioform)
Food coloring containing iodine
a Iodine was removed from Organidin and Tuss Organidin in 1995.

even large doses of iodine (1 g/day) do not usually cause hyperthyroidism. Many
different iodine sources have been reported to cause iodine-induced hyperthy-
roidism. Compounds such as potassium iodide and iodoquinolones, which release
iodine rapidly, seem to cause hyperthyroidism less frequently than do other com-
pounds, such as amiodarone, which can release high levels of iodine for long
periods of time (104).
A large number of different iodine-containing substances and drugs have
been reported to cause hyperthyroidism. These iodinated substances include sea-
weed (105), iodinated glycerol (106,107), and topical povidone iodine (108,109).
Many cases of hyperthyroidism induced by iodinated contrast agents have also
been described (110). In general, it is prudent to avoid administering large doses
of iodine to patients with known nontoxic multinodular goiters, since doing so can
induce hyperthyroidism (111). Table 1 lists various drugs that contain iodine.

Diagnosis
Iodine-induced hyperthyroidism occurs in older patients more commonly than in
children, and it can lead to serious morbidity in the elderly. Men can be affected as
often as women can be affected. Exophthalmos is usually absent. The thyroid may
Thyroiditis and Other Forms of Hyperthyroidism 115

be nodular, diffusely enlarged, or normal. Serum TSH levels are suppressed and
serum thyroid hormone levels are increased. Thyroid autoantibodies are usually
absent. The 24-hour radioactive iodine uptake is usually low at the time of diag-
nosis of thyrotoxicosis in iodine-sufficient regions. However, radioactive iodine
uptake may be normal or high, particularly in iodine-deficient regions, which may
represent the onset of Graves’ disease or toxic, multinodular goiter after iodine
exposure or supplementation. Thyroid scans are often poorly visualized due to low
iodine uptake in iodine-sufficient regions, although they may show patchy areas
of iodine uptake in iodine-deficient regions. Urinary iodine levels are increased,
confirming the exposure to excess iodine.
Therapy
Iodine-induced hyperthyroidism may resolve spontaneously over time, usually
within a few weeks to a few months. Observation or beta-blocker therapy may be
all that is necessary in mild cases. Antithyroid drugs have been used, but they are
not uniformly effective (102,104). Corticosteroids can be effective in promptly
lowering thyroid hormone levels (102,104). Radioactive iodine has been used, but
high doses may be needed since the 24-hour uptake is usually low. Thyroidectomy
has occasionally been required to treat iodine-induced hyperthyroidism.

Amiodarone-Induced Hyperthyroidism
Introduction
Amiodarone is an iodine-rich benzofuran derivative that is used to treat supraven-
tricular and ventricular arrhythmias. Approximately 37% of amiodarone, by
weight, is organic iodine. Treatment with typical doses of amiodarone leads to a
major expansion of the total-body iodine pool (112). Amiodarone, therefore, can
have dramatic effects on thyroid function and its use has been associated with
hypothyroidism as well as hyperthyroidism.
Epidemiology
The prevalence of amiodarone-induced hyperthyroidism and hypothyroidism
varies geographically and seems to correlate with dietary intake of iodine. The
prevalence of AIT has been reported to be 1% to 23% (113). In West Tuscany, Italy,
where iodine intake is low, the prevalence of amiodarone-induced hyperthyroidism
was reported to be 9.6%, while hypothyroidism was reported in 5% of exposed
patients. On the other hand, in Worcester, Massachusetts, where iodine intake
is sufficient, amiodarone-induced hyperthyroidism was reported in only 2% of
patients, while hypothyroidism occurred in 22% (114). In Los Angeles, Califor-
nia, hyperthyroidism associated with amiodarone was found in 3% of patients,
while hypothyroidism was found in 8% (115) of patients. In a retrospective
review, amiodarone-induced hyperthyroidism was found in 4.2% of patients seen
at the Cleveland Clinic (116). However, in an area of moderately sufficient iodine
intake, the incidence of amiodarone-induced hyperthyroidism was 12.1% and the
116 Meek and Smallridge

Table 2 Amiodarone-Induced Thyrotoxicosis


Feature Type 1 Type 2

Thyroid abnormality Graves’ disease, multinodular Destructive thyroiditis


goiter, autonomous nodule
Pathogenesis Thyroid hormone production Thyroid hormone release
Thyroid examination Diffuse or nodular goiter Normal or small goiter
Radioactive iodine Low, normal, or increased Very low
uptake
Thyroid antibodies Increased or negative Negative
Interleukin-6 Normal to high (⬍200 fmol/L) Normal or high (⬎250 fmol/L)
Thyroid ultrasound Increased Decreased
Doppler flow
Therapy options Stop amiodarone Corticosteroids
ATD, KClO4 , thyroidectomy Stopping amiodarone may not
be necessary

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

incidence of amiodarone-induced hypothyroidism was 6.9% (117). A United


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

levels in patients with type 2 AIT have been markedly increased in some studies,
due to the release of IL-6 produced by destroyed thyrocytes (119). However, the
utility of IL-6 levels in the differential diagnosis of AIT has not been confirmed
by other authors (126).
Continuous-flow Doppler ultrasound has also been used to help distinguish
type 1 from type 2 AIT. Patients with type 1 AIT show normal to increased
parenchymal blood flow in the thyroid, while patients with type 2 AIT show
decreased blood flow consistent with thyroid inflammation (127,128). Although
reliable data are not available from the United States, most authorities agree that
type 2 AIT is far more common than type 1 AIT.

Diagnosis
The presentation of AIT may be subtle, with relatively few clinical signs (129).
However, patients typically present with tachycardia, tremor, weight loss, nervous-
ness, or irritability. One review found weight loss as the most common presenting
symptom, with goiter and tremor being the most common presenting signs (127).
Some patients may present with recurrence of the arrhythmia that was once con-
trolled with the use of amiodarone (115,130). However, tachycardia in AIT may
not always be present, due to the beta-blocking properties of amiodarone.
Amiodarone treatment itself leads to increases in serum T4 and free T4 levels
and decreases in serum T3 levels by inhibiting type 1 iodothyronine deiodinase.
Soon after therapy commences, serum TSH levels increase due to inhibition of T4
to T3 deiodination in the pituitary. Subsequently, within two to six months, serum
TSH levels return to normal. When thyrotoxicosis develops, there is a further
increase in T4 levels and an increase in T3 levels in most patients (120). Serum T3
levels may only be in the upper range of normal, but they are higher than before
the onset of hyperthyroidism. TSH levels are decreased (116).

Treatment
The treatment of AIT is often difficult and protracted because of the long 100-day
half-life of amiodarone and the high intrathyroidal and tissue concentrations of
iodine. If amiodarone is discontinued, it may take up to eight months for thy-
rotoxicosis to subside (104). Nevertheless, stopping the drug in type 1 AIT is
recommended. The appropriate medical treatment of AIT depends on making the
distinction between type 1 and type 2 forms of thyrotoxicosis. Type 1 amiodarone-
induced disease has traditionally been treated with large doses of antithyroid drugs
and potassium perchlorate. However, potassium perchlorate is no longer available
in the United States. Type 2 disease, in contrast, is treated with corticosteroids.
Sometimes, when the diagnosis is uncertain or when one treatment fails, the thera-
pies are used in combination. The high concentration of circulating iodine from the
amiodarone suppresses the uptake of radioactive iodine, which means it generally
cannot be used as a treatment option. In patients with type 1 disease, amiodarone
therapy should be discontinued if at all possible, although in many cases this
118 Meek and Smallridge

may not be feasible. In contrast, type 2 disease resolves even when amiodarone is
continued.
Patients with type 1 AIT usually respond to an antithyroid drug to decrease
thyroid hormone synthesis. Large doses, for example 40 to 80 mg/day of methi-
mazole or 400 to 800 mg/day of propylthiouracil, are often required because the
high, intrathyroidal iodine content renders the hyperthyroidism less responsive to
thionamide drugs. In areas where potassium perchlorate is available, doses of 200
to 1000 mg/day have been used to decrease intrathyroidal iodine content (123). In
general, it may take one to three months before thyroid function has normalized.
Since the side-effects of antithyroid drugs are dose-related, and since perchlorate
therapy can cause aplastic anemia in higher doses than recommended here, it
seems prudent to monitor white blood cell counts in patients receiving both drugs
together.
When it is very mild, patients with type 2 AIT may not require therapy at
all, since it usually resolves spontaneously. All but the mildest cases are treated
with prednisone 40 to 60 mg/day for one to two months with subsequent taper-
ing of the prednisone over three months. In classic type 2 amiodarone-induced
thyrotoxicosis, elevated levels of free T4 and T3 normalize within 7 to 10 days.
Care must be taken not to taper the corticosteroids too quickly, since there can be
a rapid recrudescence of hyperthyroidism (123). In a recent study, patients with
serum free T4 concentrations ⬍50 pg/mL and lower thyroid volumes achieved
more rapid control of hyperthyroidism when treated with prednisone compared to
patients with higher serum free T4 levels and larger thyroid glands (131–133). If
patients do not respond to corticosteroids alone or if the pathogenesis is unclear, a
combination of corticosteroids and antithyroid drugs would be reasonable. In one
small study, lithium in combination with antithyroid drugs was reported to help
control thyrotoxicosis faster than treatment with antithyroid drugs alone (132). The
use of the oral cholecystographic agents, sodium ipodate or sodium iopanoate, in
combination with antithyroid drugs have also been reported to be effective in type
2 AIT (133), but these drugs are not available in the United States.
Some patients have continuing hyperthyroidism despite combination therapy
with prednisone and antithyroid drugs. If drug therapy is unsuccessful after several
months, total thyroidectomy should be considered, although these patients are
often poor operative candidates because of their underlying cardiovascular disease.
Of course, the surgical risks and benefits must be weighed against the risks of
continuing hyperthyroidism (134–136).
Patients with type 2 AIT have a risk of developing transient or permanent
hypothyroidism after resolution of the thyrotoxicosis, similar to other forms of
thyroiditis, and periodic surveillance of thyroid status is recommended (137).
Although no guidelines exist regarding screening for amiodarone-induced thyroid
dysfunction, some authors recommend a baseline thyroid examination, TSH, free
T4 and T3, anti-TPO antibodies, along with monitoring of TSH and free T4 every
three months (138).
Thyroiditis and Other Forms of Hyperthyroidism 119

Cytokine-Induced Hyperthyroidism

Introduction
Interferon-alpha has been used to treat chronic viral hepatitis and certain neoplasms
with promising results. However, the immune-mediated effects of interferon have
been shown to increase the frequency of autoimmune thyroid diseases and other
immune-mediated disorders. Interferon-alpha has been most often shown to cause
hypothyroidism, but hyperthyroidism can also be induced by interferon-alpha
therapy.

Epidemiology
Interferon-alpha has been shown to induce thyroid dysfunction in approximately
6% of patients. The majority (approximately 4%) develop hypothyroidism, but
2% develop hyperthyroidism (139). Twenty percent of patients with multiple scle-
rosis treated with interferon-beta developed hypothyroidism and 4.9% developed
hyperthyroidism, which was transient (140). Females seem to be more suscepti-
ble to interferon-induced hyperthyroidism than males, likely because of the higher
background prevalence of thyroid autoantibodies in females. Hyperthyroidism has
been reported to develop as early as six weeks after the onset of interferon ther-
apy (141), to as late as six months after interferon therapy was completed (142).
Some reports indicate hyperthyroidism is more often transient, most likely due to
thyroiditis (139,143), while other reports indicate hyperthyroidism is more likely
permanent due to Graves’ disease (144–146). Interleukin-2 (IL-2) therapy has also
been reported to cause hypothyroidism and transient hyperthyroidism (147).

Pathophysiology
Thyroid dysfunction in association with interferon is more common among
patients who have circulating thyroid antibodies prior to treatment. In a meta-
analysis of the literature, thyroid dysfunction occurred in 46% of patients with
baseline thyroid antibody positivity, but only in 5% of thyroid antibody–negative
patients (139). Approximately 9% of thyroid antibody–negative patients develop
thyroid autoantibodies during interferon therapy, and 42% of these patients develop
thyroid dysfunction (139) suggesting that the thyroid dysfunction is mediated
through an immune mechanism.
However, some patients with thyroid dysfunction have no evidence of thy-
roid antibodies, raising the possibility of a direct toxic effect of interferon on the
thyroid (148). Patients with either hepatitis C or malignancy have been found
to have a higher frequency of thyroid abnormalities in the absence of interferon
therapy, which could also partly explain the higher rate of thyroid dysfunction
when interferon is used to treat these conditions (149).
120 Meek and Smallridge

Diagnosis
Hyperthyroidism induced by interferon therapy presents with the usual signs
and symptoms. The thyroid may be normal in size or mildly enlarged, serum
thyroid hormone levels are increased, with a suppressed serum TSH concentration.
In addition to thyroid peroxidase and thyroglobulin antibodies, some patients
develop circulating anti-TSH receptor antibodies (TSAb) and have normal to
increased radioactive iodine uptakes. These patients may have Graves’ disease
precipitated by cytokine therapy. However, most hyperthyroid patients develop
transient hyperthyroidism associated with low radioactive iodine uptakes, which
may be followed by hypothyroidism.

Treatment
Interferon therapy–induced hyperthyroidism, when associated with a normal or
increased radioactive iodine uptake, may have to be treated with the usual forms
of therapy, such as antithyroid drugs or radioactive iodine. Discontinuation of the
interferon therapy will not reliably lead to resolution of the hyperthyroidism.
Although patients with interferon-induced destructive thyroiditis with low
radioactive iodine uptake have been treated with corticosteroids (150), a recent
trial showed corticosteroids were not more effective than simple withdrawal of
interferon therapy in restoring euthyroidism (151). However, transient thyrotox-
icosis may give rise to hypothyroidism, which may require thyroid hormone
replacement. Finally, withdrawal of interferon therapy may be associated with
resolution of the thyroid dysfunction, and symptomatic therapy may be all that
is needed (152). Some authors have suggested screening patients with TSH, free
T4, thyroid antibodies, and perhaps thyroid ultrasound before interferon therapy
is started, in addition to monitoring thyroid levels periodically during treatment
(148,150).

Lithium-Associated Thyrotoxicosis
Lithium, commonly used to treat manic depressive disorders, is a recognized
cause of hypothyroidism. However, some reports have suggested that lithium may
also be associated with thyrotoxicosis. One study reported 14 cases of thyro-
toxicosis associated with lithium use (153). The majority of these patients had
diffuse toxic goiters. A few had toxic multinodular goiters and a few had pain-
less thyroiditis associated with a low uptake of radioactive iodine on scan. These
authors suggested that the incidence of lithium-associated thyrotoxicosis was three
times higher than predicted based on regional thyrotoxicosis rates. Others have
reviewed the cases of lithium-associated thyrotoxicosis, and they have also con-
cluded that the association was not coincidental (154,155). The majority of cases
of lithium-associated thyrotoxicosis and increased radioactive iodine uptakes have
been successfully treated with antithyroid drugs, even during continued lithium
therapy.
Thyroiditis and Other Forms of Hyperthyroidism 121

Hyperthyroidism Due to Exogenous Thyroid Hormone


Introduction
Thyrotoxicosis factitia or factitious thyrotoxicosis describes a condition due to
the excess use of exogenous thyroid hormone, leading to symptoms and signs of
thyrotoxicosis. The term is used most commonly when the use of thyroid hormone
is surreptitious, but may also be applied in cases where the exposure to thyroid
hormone is inadvertent.

Epidemiology
Thyroid hormone has been used for a variety of nonthyroid conditions in the
past, ranging from obesity to depression to infertility. Thyrotoxicosis occurs when
the thyroid hormone dose is escalated to supraphysiologic doses. The secretive
use of thyroid hormone by psychiatrically disturbed patients is another common
cause of thyrotoxicosis factitia. Thyrotoxicosis factitia has been noted in young
or older women, with a middle-aged predominance (156). Occasionally, patients
such as children will present with thyrotoxicosis due to accidental ingestion of
thyroid hormone (157). Thyrotoxicosis has been reported in a patient taking herbal
supplements that contained thyroid hormone (158).

Pathophysiology
Thyrotoxicosis factitia–induced thyrotoxicosis is due to the excessive use of a
variety of thyroid preparations. These preparations can include L-Thyroxine, tri-
iodothyronine, or desiccated thyroid tablets. Thyrotoxicosis induced by excessive
thyroid hormone has also been caused by “hamburger thyrotoxicosis.” Two epi-
demics of thyrotoxicosis in the United States were caused by bovine thyroid gland,
which was included in hamburger made by a meat processor (159,160).

Diagnosis
Patients with thyrotoxicosis factitia present with the usual symptoms and signs
of thyrotoxicosis. However, the thyroid gland is normal to small in size and the
patient lacks the eye signs of Graves’ ophthalmopathy. The thyroid is not tender.
Serum T4 and T3 levels are increased if the patient is consuming thyroxine or
desiccated thyroid. T3 levels are increased, while T4 levels are low if the patient is
consuming triiodothyronine. The radioactive iodine uptake is low and scans show
no evidence of functioning thyroid tissue elsewhere in the body. Low thyroglob-
ulin measurements are useful in distinguishing thyrotoxicosis factitia from other
forms of hyperthyroidism with low uptake of radioactive iodine (161). However,
occasionally the test may not be reliable because of circulating antithyroglobulin
antibodies. The finding of increased levels of thyroxine in the stool has also been
used to confirm the diagnosis of thyrotoxicosis factitia (162).
122 Meek and Smallridge

Treatment
The treatment of thyrotoxicosis factitia is discontinuation of the exogenous thyroid
hormone. This can sometimes be difficult in the psychiatrically disturbed patient
who is taking thyroid hormone secretly; psychiatric consultation may be helpful.
Beta-blocking agents may be needed temporarily while thyroid hormone levels
are decreasing.

THYROTROPHIN-INDUCED HYPERTHYROIDISM
TSH-Secreting Pituitary Adenomas
Introduction
Since the advent of the TSH radioimmunoassay, TSH-producing pituitary tumors
have been recognized as a cause of hyperthyroidism. Earlier reports described
large pituitary tumors, but microadenomas are being recognized more frequently
in recent case series.
Epidemiology
TSH-producing pituitary tumors (TSHomas) are rare, occurring in about one
per one million people (163). However, the number of cases being reported has
increased, along with the introduction of second- and third-generation TSH assays.
TSH-producing pituitary tumors may account for 0.5% to 3% of pituitary tumors
(164–166). TSH-producing pituitary tumors may occur at any age, with males and
females affected about equally (163,167).
Pathophysiology
TSHomas are macroadenomas approximately 90% of the time in older series, but
up to 25% are microadenomas in more recent series (168). Approximately 30%
of TSH-producing pituitary tumors are mixed tumors secreting other pituitary
hormones. Growth hormone and prolactin are the most common hormones that
are cosecreted, but tumors that cosecrete LH and FSH have also been described
(163,167). The alpha subunit of the pituitary glycoprotein hormones may also be
produced in TSH-producing pituitary adenomas. Two cases of an ectopic TSH-
secreting pituitary tumor have also been reported (169,170). Tumor-derived TSH
may have varying degrees of glycosylation along with varying molecular weight,
which may give rise to variable biologic activity of the TSH (171). In contrast to
some growth hormone-secreting tumors, no activating mutation in the gene coding
for G proteins has been found in TSH-producing pituitary tumors (163).
Diagnosis
Patients with TSH-producing pituitary adenomas present with the usual signs
and symptoms of thyrotoxicosis, but these may be mild. Most patients have a
goiter that is diffusely enlarged. Exophthalmos has been reported rarely. In one
Thyroiditis and Other Forms of Hyperthyroidism 123

Table 3 Characteristics of TSH-Producing Pituitary Tumors (TSHoma) Versus Thyroid


Hormone Resistance

Feature TSHoma (%) Thyroid resistance (%)

TRH stimulation of TSH 8 96


T3 suppression of TSH 12 100
Elevated sex hormone–binding globulin 94 2
Elevated alpha subunit/TSH ratio 81 2
Family history 0 82
MRI pituitary adenoma 98 2

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

case, it was due to orbital invasion by tumor, while Graves’ disease has been
present in several patients with coexisting TSHomas. Other manifestations of
Graves’ disease, such as dermopathy and acropachy are not found. If the tumor is
large, headache (23%) and visual field disturbance (40%) may be present (163).
Features of cosecreted hormones may be present, such as acromegaly (15%)
or the galactorrhea/amenorrhea (10%) syndrome (163). Hypopituitarism, most
commonly hypogonadism, may also be present.
Laboratory evaluation shows increased levels of thyroid hormones in the
presence of an inappropriately normal or increased serum level of TSH. A pituitary
adenoma should be distinguished from pituitary thyroid hormone resistance; both
conditions give rise to increased thyroid hormone levels with inappropriately nor-
mal or increased serum TSH levels. Table 3 compares the characteristics of TSH-
producing pituitary adenomas and thyroid hormone resistance. Thyroid autoan-
tibodies are usually not present, and the radioactive iodine uptake is increased.
Circulating levels of alpha subunit are increased in macroadenomas, but are usu-
ally normal in microadenomas (172). The alpha subunit/TSH molar ratio, which is
the molar concentration of serum alpha subunit divided by the molar concentration
of serum TSH, is usually ⬎1 [molar ratio = (alpha subunit ng/mL/TSH mU/L) ×
10]. However, the alpha subunit/TSH molar ratio is not reliable in postmenopausal
women and in men with primary hypogonadism since increased serum levels of
alpha subunit, due to increased serum levels of gonadotrophins, are present in
these conditions (163,167,173–175). An increased level of sex hormone–binding
globulin and bone carboxyterminal cross-linked telopeptide of type 1 collagen
have been proposed to help differentiate patients with TSH-producing adenomas
from those with thyroid hormone resistance (172,176).
Dynamic testing has also been used to differentiate TSH-producing ade-
nomas from thyroid hormone resistance. In adenoma patients, TRH stimulation
testing usually fails to stimulate TSH secretion, and the administration of T3
also fails to suppress TSH- or TRH-stimulated TSH. More recently, treatment
with long-acting somatostatin analogues for at least two months has been used
to distinguish between cases of TSH-producing pituitary tumors versus thyroid
124 Meek and Smallridge

hormone resistance syndrome, when the diagnosis was uncertain. Long-acting


somatostatin analogues caused a greater than 30% reduction in free T4 and free
T3 levels in seven out of eight patients with TSH-producing adenomas, compared
to four patients with thyroid hormone resistance of the pituitary, in which thyroid
hormone levels did not change (177).
Imaging of the sella turcica with CT scan or magnetic resonance imaging
(MRI) will usually reveal a pituitary tumor. For patients previously treated erro-
neously with thyroid ablation due to the mistaken diagnosis of Graves’ disease, the
pituitary tumor may enlarge and become invasive. In general, there is no correla-
tion between the serum TSH level and tumor size. In several case reports, routine
contrast–enhanced MRI has been normal. In one such case, inferior petrosal sinus
sampling disclosed a gradient consistent with a TSH-producing pituitary adenoma
(178). In another case, dynamic MRI imaging identified the tumor (179).

Treatment
Transsphenoidal surgical resection of the pituitary tumor is the treatment of choice
for TSH producing pituitary tumors. Approximately 35% to 50% of patients
can be cured with surgery alone, and earlier diagnosis improves the prognosis
(163,167,168). As is true for all pituitary tumors, the most important prognostic
factors for cure are smaller size of the pituitary tumor and the absence of cav-
ernous sinus invasion. Criteria for cure following surgery include biochemical
euthyroidism with a normalized TRH test and absence of residual tumor on MRI
(164,180). Unfortunately, TRH is not available in the United States. Antithyroid
drugs and beta-blockers or octreotide should be used to restore the euthyroid state
before surgery.
Radiation therapy is used for incompletely resected pituitary tumor.
Octreotide, 50 to 100 ␮g subcutaneously two to three times daily, has been suc-
cessfully used to treat patients with TSH-producing pituitary tumors (181,182).
The long-acting somatostatin analogue lanreotide has also been used successfully
to treat patients with TSH-producing tumors (183). Octreotide produces thera-
peutic success in up to 95% of patients, and in about one-half of cases there is
tumor regression (172). In addition, octreotide alters the glycosylation pattern, and
presumably the bioactivity, of serum TSH (184). Tachyphylaxis may develop in
approximately one-fourth of patients, necessitating an increased octreotide dose
(181). Approximately 10% of patients may escape from octreotide’s inhibitory
effects on TSH suppression. Octreotide has also been used to restore euthyroidism
in pregnant women with this disorder without apparent effects on fetal develop-
ment and thyroid function (185). Dopamine agonists have also been reported to
decrease TSH and thyroxine levels in a limited number of cases, but do not cause
tumor shrinkage (186). Iopanoic acid has been used to improve hyperthyroidism
acutely in the preoperative state in two cases (187), but is not available in the
United States. Ablation of the thyroid with radioactive iodine or surgery should
be avoided. However, patients who have refused surgery for their TSH producing
Thyroiditis and Other Forms of Hyperthyroidism 125

pituitary tumors have been successfully treated with either radioactive iodine or
thyroidectomy (172,188).

Thyroid Hormone Resistance


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

also been identified in patients from unrelated families with generalized thyroid
hormone resistance. In addition, within a family, the same receptor mutation may
result in generalized thyroid resistance in one family member, but in another,
thyrotoxicosis suggestive of pituitary thyroid hormone resistance.
Diagnosis
Patients with thyroid hormone resistance may have clinical symptoms and signs
that vary from hypothyroidism to hyperthyroidism. There is considerable overlap
of these findings between generalized resistance patients versus those thought to
have pituitary thyroid hormone resistance.
Patients with thyroid hormone resistance have a higher frequency of attention
deficit disorder, delayed speech development, lower IQ, shorter stature and lower
weight, delayed bone age, and hearing loss. There may also be a higher frequency
of ear, nose, and throat infections (197,200,201).
A goiter is found commonly (65–90%) in patients with thyroid hormone
resistance (197,198). Tachycardia and an increased frequency of arrhythmia have
been found in some thyroid hormone resistance patients. Increased levels of thy-
roid hormones, including T4 and T3, are found with inappropriately normal or
increased levels of TSH. The 24-hour radioactive iodine uptake is often increased.
Failure of serum TSH levels to increase in response to TRH, and failure of
serum TSH levels to decrease in response to supraphysiologic doses of thyroid
hormone suggest a TSH-producing pituitary adenoma. An increased molar ratio of
alpha subunit to TSH and a pituitary adenoma on MRI of the brain are diagnostic
of a TSH-producing pituitary adenoma (202).
Treatment
Most patients with generalized thyroid hormone resistance do not require treat-
ment. Patients who have been mistakenly treated with thyroidectomy or radioac-
tive iodine ablation of the thyroid typically require higher than normal doses of
thyroxine replacement to suppress TSH back to normal. One case of pituitary
enlargement was demonstrated in a patient previously treated with radioactive
iodine ablation. Supraphysiologic doses of thyroid hormone caused regression of
the pituitary gland back to normal size (203).
Patients with pituitary resistance to thyroid hormone who have mildly symp-
tomatic hyperthyroidism may be treated with beta-blocker therapy. Antithyroid
drugs are not ideal because they result in further increases in thyroid size, but rarely
may be needed in patients with severe hypermetabolism (195). Radioactive iodine
is not recommended as it may cause dramatic increases in TSH (197). Moderate
doses of T3 (25–50 ␮g daily) over a period of several months can decrease TSH
secretion, thyroid hormone levels, and clinical thyrotoxicosis (204), but they are
not often successful. D-thyroxine has also been reported to be beneficial (205,206).
Triiodothyroacetic acid (Triac) appears to be able to suppress TSH with minimal
peripheral thyromimetic actions (207–209). Bromocriptine and octreotide have
been used in some cases to suppress TSH production (193,195,208,210,211). In
Thyroiditis and Other Forms of Hyperthyroidism 127

general, it is appropriate to treat patients with pituitary thyroid hormone resistance


with conservative measures, if possible, including beta-blockers. If patients do not
respond to these measures, antithyroid drugs may be necessary.

HYPERTHYROIDISM OF EXTRATHYROID ORIGIN


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

iodine. However, the thyroid has been reported to be enlarged in several reports
(214,221,222). Some patients may present with a pelvic mass, and ascites may
be present even in the absence of malignant struma ovarii (214). The TSH is sup-
pressed and thyroid hormone levels are increased. The diagnosis is established by
finding radioactive iodine uptake over the pelvis or an ovarian teratoma containing
thyroid tissue (223). However, radioactive iodine uptake has been reported in a
hemorrhagic ovarian cyst that did not contain thyroid tissue (224).

Treatment
Treatment of struma ovarii, with or without thyrotoxicosis, consists of surgery to
remove the tumor. If thyrotoxicosis is present, beta-blockers and/or antithyroid
drugs should be used before surgery. Radioactive iodine should not be used to
ablate the thyroid tissue, since the thyroid tissue is neoplastic and potentially
malignant. It also often contains nonthyroid tissue (225), and the effect of radiation
on the other tissues is unknown.
Malignant struma ovarii is treated with hysterectomy, bilateral salpingo-
oophorectomy, and thyroidectomy. Metastatic struma ovarii has been treated with
radioactive iodine after thyroidectomy. Thyroid hormone treatment with TSH
suppression is also recommended for metastatic struma ovarii.

Trophoblastic Tumors
Introduction
Molar pregnancy and trophoblastic tumors can cause hyperthyroidism. Human
chorionic gonadotrophin (hCG), secreted in large amounts by these tumors, has
TSH receptor–binding activity. This hCG cross-reactivity can lead to thyrotoxico-
sis (226).

Epidemiology
The prevalence of thyrotoxicosis in patients with trophoblastic tumors is unknown.
One study evaluated 20 patients from a referral center over one year, and the
researchers found that five of the patients had thyrotoxicosis (227). Another study
found that 30 of 52 patients with gestational trophoblastic tumors had thyrotox-
icosis (228). It has been estimated that 20% of women with hydatidiform moles
have hyperthyroidism (229).
Hydatiform mole occurs in about one out of 1500 pregnancies in the United
States and is about 10 times more common in Asian and Latin American countries
(230). Choriocarcinoma occurs in one of 50,000 pregnancies (226). Thyrotoxicosis
is reported more frequently in women with hydatiform mole than in those with
choriocarcinoma. In addition, a few men with testicular tumors that produce hCG
have been reported with hyperthyroidism (231–233).
Thyroiditis and Other Forms of Hyperthyroidism 129

Pathophysiology
hCG is composed of an alpha subunit and a beta subunit. The alpha subunit is
identical to the alpha subunit of LH, FSH, and TSH. The beta subunit of hCG
is larger than the beta subunit of TSH but is similar in structure. Beta-hCG has
an additional 33–amino acid peptide at the carboxyl terminal. The thyrotropin
effect of hCG is weak. However, when hCG is secreted in large amounts, it can
stimulate the TSH receptor in thyroid tissue enough to cause thyrotoxicosis. It is
probable that some molecular variants of hCG secreted by trophoblastic tumors
have greater thyrotrophic activity than hCG secreted by normal placental tissue
(229,234). Removal of the tumor, and therefore the hCG, is associated with rapid
resolution of the hyperthyroidism.

Diagnosis
Women with trophoblastic tumors may or may not have clinical evidence of
hyperthyroidism. The nausea, vomiting, and toxemia that occur in molar pregnancy
may obscure hyperthyroidism. The thyroid gland is either normal in size or slightly
enlarged.
Chorionic gonadotrophin, secreted in large amounts by trophoblastic tissue,
serves as a marker for the tumor. The hCG levels exceed 100 U/mL in patients
with hyperthyroidism and often exceed 300 U/mL (235–238). TSH is suppressed
and levels of free T4 and free T3 may be minimally or markedly increased.
Hyperthyroid patients with trophoblastic tumors usually have higher T4/T3 ratios
than patients with hyperthyroidism due to Graves’ disease (157). The uptake of
radioactive iodine is increased (239).

Treatment
Surgical removal of the hydatidiform mole or choriocarcinoma in a patient with
hyperthyroidism rapidly cures the thyrotoxicosis. However, patients with chori-
ocarcinoma who have hyperthyroidism usually have a larger tumor mass that
may be metastatic. Chemotherapy is the principle therapy used to achieve remis-
sion of metastatic choriocarcinoma with associated hyperthyroidism. Effective
chemotherapy provides long-term survival ranges from 86% to 100% (240). The
prognosis for men with testicular choriocarcinoma and hyperthyroidism is usually
poor.
Medical therapy for hyperthyroidism due to trophoblastic disease may
include potassium iodide, beta-blockers, and antithyroid drugs. Preoperative
iodine can help lower thyroid hormone levels rapidly in patients who require
urgent surgery. Beta-adrenergic blockers are given to control tachycardia and
tremor. Antithyroid drugs are given to help control hyperthyroidism periop-
eratively or in patients with metastatic disease. Surgical thyroidectomy is not
recommended.
130 Meek and Smallridge

Metastatic Thyroid Cancer and Hyperthyroidism


Introduction
Differentiated thyroid cancer usually does not produce thyroid hormone efficiently.
However, thyroid cancers do produce thyroglobulin, which can become iodinated
and form thyroid hormone. Rarely thyroid hormone production from thyroid can-
cer can become excessive, giving rise to thyrotoxicosis.

Epidemiology
Thyrotoxicosis due to thyroid cancer is quite rare. However, the age and sex
distribution of patients with hyperthyroidism caused by thyroid cancer is similar
to that of patients with thyroid cancer without thyrotoxicosis (241,242). Eighty-
five percent of patients with hyperfunctioning thyroid cancer are older than 40
years. The female-to-male ratio is about 3:1 (242).

Pathophysiology
Malignant thyroid tissue is functionally less efficient than normal thyroid tissue
(243). The estimated efficacy of the iodine-concentrating ability of functioning
metastases is approximately 10% of normal thyroid tissue (244,245). The inef-
ficient thyroid hormone production is due in part to lower iodine trapping by
tumor tissue and in part to abnormal thyroglobulin synthesis. Further, there is
evidence that expression of the TSH receptor in malignant thyroid tissue may be
absent or low (246). Therefore, many of the cases of thyrotoxicosis caused by
thyroid cancer are due to large, bulky metastatic tumors, often weighing 2 to 3 kg
(242).
Follicular thyroid cancer is the most common thyroid malignancy reported
to cause hyperthyroidism (241,242,247), but papillary thyroid cancer may also
cause hyperthyroidism. Patients with functioning metastases more commonly
come from areas of low iodine intake (241). Thyroglobulin levels have been
reported to be higher in patients with functioning metastases, but this finding did
not reach statistical significance (241). Finally, the time to metastasis and the
10-year survival rate appear to be equal for metastatic follicular carcinoma with
or without thyrotoxicosis (241,242,247). The discovery of metastases precedes
or occurs simultaneously with the onset of hyperthyroidism (247). Anaplastic
thyroid cancer and thyroid lymphoma have been reported to cause thyrotoxicosis
with a low uptake of radioactive iodine, so-called “malignant pseudothyroiditis”
(20,21,248,249).

Diagnosis
In most instances, the diagnosis of thyroid malignancy has been made and thy-
roidectomy 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
Thyroiditis and Other Forms of Hyperthyroidism 131

the thyrotoxicosis is due to overzealous treatment with thyroid hormone. There-


fore, thyroid hormone treatment should be stopped to see if the signs and symptoms
of thyrotoxicosis resolve, and if the levels of T4 and T3 in the serum decrease. If the
signs, symptoms, and levels of thyroid hormone do not decrease, hyperthyroidism
may be due to functional thyroid metastases. In many cases, the thyrotoxicosis
may be due to T3 toxicosis, with suppressed TSH, and normal or even low serum
T4 levels (242,250,251). Hyperfunctioning metastatic cancer may be confirmed
by whole-body radioactive iodine scanning. However, uptake of radioactive iodine
in metastatic tissue may be low in the presence of the normal thyroid gland. The
distribution of hyperfunctioning metastatic thyroid cancer is typically the same as
in nonhyperfunctioning thyroid cancer, that is, in bone, lung, and mediastinum.

Treatment
Treatment of metastatic functioning thyroid cancer usually consists of radioac-
tive 131 I therapy. The usual dose of radioactive iodine ranges from 100 to
200 mCi. Treatment with radioactive iodine may exacerbate the thyrotoxico-
sis (252). Therefore, radioactive iodine should be administered with caution,
and patients are often treated prophylactically with beta-adrenergic blocking
agents. Some authors recommend treating the patient with antithyroid drugs
to control the hyperthyroid state prior to administering radioactive iodine to
prevent exacerbation of the hyperthyroid state (242). If normal thyroid tissue
is present, it must be removed prior to administering a therapeutic dose of
radioactive iodine to functioning thyroid metastases. If a small number of large,
accessible, and isolated metastases are producing the thyrotoxicosis, surgical
resection may be the best treatment option, following therapy with antithyroid
drugs.

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1979; 242(3):269–270.
4
Hypothyroidism

Michael T. McDermott and E. Chester Ridgway


University of Colorado Denver, School of Medicine, Aurora, Colorado, U.S.A.

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

145
146 McDermott and Ridgway

diagnosis of hypothyroidism but will focus primarily on practical issues in the


management of patients with thyroid hormone deficiency.

EPIDEMIOLOGY
Primary hypothyroidism is the most common functional disorder of the thyroid
gland. Overt hypothyroidism, or thyroid failure, is defined biochemically as an
elevated serum thyroid-stimulating hormone (TSH) and a serum free T4 concen-
tration that is below the population reference range. Subclinical hypothyroidism,
or mild thyroid failure, is defined as an elevated serum TSH with a serum free T4
concentration that is still within the population reference range. Hypothyroidism,
both overt and subclinical hypothyroidism, is distinctly more common in women
than in men and increases in frequency with age. Published statistics regarding
prevalence and incidence are variable because existing studies have differed sig-
nificantly in regard to population age range, geographic location, and criteria used
to define the presence and degree of thyroid failure. The annual incidence has
been estimated to be 4 to 5 per 1000 population per year in women and 0.6 to
0.9 per 1000 per year in men (8,9). The prevalence of overt hypothyroidism has
been reported to be approximately 1% to 3% in large population-based screening
studies (9–11).
Subclinical hypothyroidism is much more prevalent having been found in 4%
to 10% of multiple populations (9–19). The Colorado Thyroid Disease Prevalence
Study of 25,862 state residents reported an elevated serum TSH concentration in
9.5% of all subjects and in 8.9% of those who were not already taking thyroid
hormone; nearly 75% of these individuals had serum TSH values between 5 and
10 mU/L and ⬎95% had normal serum total T4 levels (18). The National Health
and Nutrition Examination Survey III (NHANES III) screened 17,353 adults
and children throughout the United States and found elevated serum TSH levels
(⬎4.5 mU/L) in 1.4% to 8.1% of subjects in all age brackets younger than 60 years
of age (19). This study and others have reported significantly higher prevalence
rates in the elderly population, varying from 7% to ⬎17% in subjects older than
60 years of age (10,13–19). A recent reanalysis of the NHANES data suggested,
however, that the 97th percentile for TSH in persons older than 80 years without
antithyroid antibodies extends to 7.5 mU/L, suggesting that the true prevalence of
SCH in the elderly may be considerably lower (20).
Progression from subclinical to overt hypothyroidism has been reported to
occur in 5% to 18% of patients per year (8,12,16,17,21,22). Individuals most
likely to undergo progression are those with higher initial serum TSH levels,
positive antithyroid antibodies, and a prior history of radioiodine or external beam
radiation therapy (13,23,24). On the other hand, individuals with minimal TSH
elevations may remain stable for years without developing overt hypothyroidism
(23–26), and up to 37% may have their TSH values return to within the population
reference range (24,25). Patients with milder TSH elevations are more likely to
Hypothyroidism 147

achieve normal serum TSH levels over a three- to five-year follow-up period
(24–26).

ETIOLOGY
Thyroid hormone deficiency may result from disease of the thyroid gland itself
(primary hypothyroidism), disorders of TSH secretion due to pituitary disease
(secondary hypothyroidism), or abnormalities of thyrotropin-releasing hormone
(TRH) production from the hypothalamus (tertiary hypothyroidism). The latter two
situations are more generally referred to as “central hypothyroidism” (27,28). Pri-
mary hypothyroidism accounts for over 99.5% of all diagnosed cases of hypothy-
roidism whereas central hypothyroidism is responsible for less than 0.5% (28),
although some sources suggest this may be as high as 5% (29). Conditions that
cause primary and central hypothyroidism are listed in Table 1 (30–39). Medica-
tions that have been reported to cause primary hypothyroidism (40) include amio-
darone (41,42), lithium (43–46), interferon-alpha (47–49), interleukin-2 (50), and
the tyrosine kinase inhibitors, sunitinib (51–54) and sorafenib (55). Bexarotene
causes central hypothyroidism by interfering with TSH secretion (56,57).

CLINICAL MANIFESTATIONS
Overt Hypothyroidism
General Features
Thyroid hormone deficiency results in a broad spectrum of symptoms, signs,
and laboratory abnormalities (58–62) that progress gradually over time. Affected
patients often experience fatigue, weakness, weight gain (usually ⬍10 lb), cold
intolerance, dry skin, facial puffiness, hair loss, constipation, arthralgias, myalgias,
decreased libido, menstrual irregularity and menorrhagia, difficulty concentrating,
and depression. Common physical findings include bradycardia, hypertension,
cool skin with a yellowish discoloration, periorbital edema, coarse hair, thinning
of the lateral eyebrow regions, muscle weakness, carpal tunnel syndrome, and
delayed relaxation phase of the deep tendon reflexes. The most frequently reported
features from studies in the 1930s (60) and in the 1990s (61) are shown in Table 2.
Depending upon the underlying etiology, the thyroid gland may be visibly or pal-
pably enlarged, normal, or nonpalpable. Patients whose hypothyroidism occurs
acutely (withdrawal of thyroid hormone therapy prior to a radioiodine scan or
treatment for thyroid cancer) tend to have more severe symptoms but less promi-
nent physical findings than do patients whose hypothyroidism developed over a
more prolonged period of time. Also, elderly patients tend to have fewer symptoms
of hypothyroidism than younger patients (63).
Hypothyroid patients may also exhibit a number of general laboratory abnor-
malities such as anemia (macrocytic, normocytic, or microcytic), hyponatremia,
hypercholesterolemia, elevated liver-associated enzymes, and increased creatine
148 McDermott and Ridgway

Table 1 Etiology of Hypothyroidism


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

kinase (CK). Prolongation of the bleeding time, suggesting platelet dysfunction,


is another frequent finding. Elevation of the serum prolactin level is commonly
present and may occasionally present a diagnostic dilemma (discussed further
later). Pleural and pericardial effusions may be seen on chest X-rays while elec-
trocardiograms are frequently characterized by bradycardia, diffuse low voltage,
and nonspecific ST segment- and T-wave abnormalities.
Symptoms of central hypothyroidism are similar to, but tend to be milder
than, those seen in patients with primary hypothyroidism. Since this condition most
commonly results from neoplastic or inflammatory processes involving the pitu-
itary gland and/or the hypothalamus, central hypothyroidism is often accompanied
by pituitary mass effects such as headaches, visual field defects, ophthalmoplegia,
Hypothyroidism 149

Table 2 Clinical Symptoms in Patients with Overt Hypothyroidism


Symptom % of Cases Symptom % of Cases

A. Early Studies—1930s (57)


Weakness 99 Constipation 61
Dry skin 97 Weight gain 59
Coarse skin 97 Hair loss 57
Lethargy 91 Lip pallor 57
Slow speech 91 Dyspnea 55
Eyelid puffiness 90 Peripheral edema 55
Cold intolerance 89 Hoarseness 52
Decreased sweating 89 Anorexia 45
Cold skin 83 Nervousness 35
Thick tongue 82 Menorrhagia 32
Facial edema 79 Palpitations 31
Coarse hair 76 Deafness 30
Pale skin 67 Precordial pain 25
Memory impairment 66
B. Recent Study—1990s (58)
Dry skin 76 Paresthesias 52
Cold intolerance 64 Cold skin 50
Coarse skin 60 Constipation 48
Periorbital puffiness 60 Slow movements 36
Diminished sweating 54 Hoarseness 34
Weight gain 54 Impaired learning 22

Source: Adapted from Refs. 57, 58.

deficiencies of other anterior pituitary hormones and, less commonly, diabetes


insipidus. These features often overshadow the manifestations of hypothyroidism
(27,28).

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

impair the ability of acutely ill hypothyroid patients to be weaned from assisted
ventilation devices (84).
Cardiovascular Abnormalities
Pericardial effusions may occur in up to 50% of patients with overt thyroid failure
(74,85,86); the effusions are usually small and have little clinical significance (87),
although pericardial tamponade can rarely occur (88). Myocardial dysfunction,
both systolic and diastolic, is another well-recognized feature of overt hypothy-
roidism (89–97); reversible asymmetric septal hypertrophy has been reported as
well (98). Thyroid hormone deficiency is known to increase systemic vascu-
lar resistance (90,99), which may further impair left ventricular performance.
Although hypothyroidism alone rarely causes congestive heart failure (29,100),
a severe dilated cardiomyopathy has been reported in a profoundly hypothyroid
young man with complete reversal upon institution of thyroid hormone replace-
ment therapy (101).
Hypothyroidism also predisposes to the development of coronary artery dis-
ease; the most commonly implicated mechanisms are the associated lipid disorders
and hypertension (18,102,103). Transient myocardial ischemia, due to regional
myocardial perfusion abnormalities, has been demonstrated in some patients with
severe thyroid failure (104). Hypothyroidism has also been shown to be associ-
ated with increased central arterial stiffness (105) and increased carotid intima-
medial thickness (106), both of which improve significantly after the institution of
levothyroxine replacement therapy (105,106). Serum CK levels are often increased
in hypothyroidism (107–110); although the CK is generally of the MM (skeletal
muscle) fraction, there may also be a component of the MB (myocardial) fraction
in some patients (111). Elevated CK levels may occasionally lead to a mistaken
diagnosis of acute myocardial infarction in hypothyroid patients experiencing
atypical chest pain (112).
Endocrine Abnormalities
Hypothyroidism can cause hyperprolactinemia (113,114). Patients with long-
standing hypothyroidism may sometimes develop marked prolactin elevations
associated with pituitary enlargement (pseudotumors) due to thyrotrope hyperpla-
sia (115–117). Reported patients have presented with high serum prolactin levels
and significant pituitary enlargement on imaging studies, suggesting the presence
of pituitary prolactinomas. Upon discovery of elevated serum TSH levels and
institution of thyroid hormone replacement therapy, the elevated prolactin levels
and pituitary enlargement have completely resolved. Hypothyroidism may, on
occasion, be associated with adrenal insufficiency. This most commonly occurs
in patients with type 2 autoimmune polyendocrine syndrome (APS 2; Schmidt’s
syndrome), humen leucocyte antigen (HLA)-DR3/DR4 related condition in
which circulating organ-specific autoantibodies cause thyroid failure; adrenal
failure; and, less often, type 1 diabetes mellitus (118). The two disorders may
also coexist in patients with tumors or infiltrative disorders of the pituitary gland
Hypothyroidism 151

or hypothalamus, resulting in central hypothyroidism and central adrenal insuf-


ficiency (119); such patients often have evidence of pituitary mass effects, other
anterior pituitary hormone deficiencies and, less frequently, diabetes insipidus
(27,28). Since thyroid hormone replacement may acutely lower serum cortisol
levels by increasing the cortisol metabolic clearance rate (120–122), initiating
thyroid hormone replacement without recognizing and treating coexisting adrenal
disease may precipitate an acute adrenal crisis (119). Adrenal function should
be assessed in any hypothyroid patient with a positive family history of adrenal
insufficiency or Schmidt’s syndrome, hyperkalemia, visual field defects, a known
pituitary mass, other anterior pituitary hormone disorders, or diabetes insipidus.
Children with hypothyroidism often have short stature, exhibiting an abrupt
departure from the normal growth curve corresponding to the onset of thyroid
failure; deficiencies of growth hormone secretion and action have been described
in these patients (123–126). Both delayed puberty (127,128) and precocious pseu-
dopuberty (129,130) have been described in hypothyroid children; the mechanism
for the latter is uncertain but may result from a type of hormonal cross-talk involv-
ing the effects of increased TRH and/or TSH on the gonadal axis (130). In adult
women, hypothyroidism may cause infertility, anovulation, irregular or heavy
menses, amenorrhea, and galactorrhea (128), while in men it may cause infertility,
defective spermatogenesis, and erectile dysfunction (131–133).

Psychiatric Disorders
Depression and other psychiatric disturbances in patients with hypothyroidism
were initially reported in the late 19th century (134–137). The term “myxedema
madness,” first used in 1949, referred to the relatively frequent discovery of
hypothyroidism in patients who were residents of mental hospitals (138). Neu-
ropsychiatric alterations that have since been described in association with
hypothyroidism span a wide spectrum of conditions, including irritability, poor
concentration, impaired memory, cognitive dysfunction, depression, paranoia, hal-
lucinations, and schizophrenia (139–141).

Neurological Disorders
Cretinism with mental retardation is a well-known consequence of endemic iodine
deficiency and of untreated congenital hypothyroidism, emphasizing the critical
role thyroid hormone plays in brain development (142). It has been well demon-
strated that euthyroid children whose mothers had untreated or inadequately treated
hypothyroidism during pregnancy have an increased likelihood of neuropsycho-
logical or cognitive impairment (143–149). Hypothyroid adults may, as discussed
earlier, exhibit a variety of psychiatric disorders (139–141). Peripheral metabolic
polyneuropathies and multiple entrapment neuropathies, including but not limited
to carpal tunnel syndrome, are also well described (150–153). Rarely, hypothy-
roidism has been reported to cause a central focal neurological disorder such as
cerebellar ataxia (154).
152 McDermott and Ridgway

Musculoskeletal Disorders
Arthralgias, myalgias and variable degrees of proximal myopathy are well-
recognized features of thyroid hormone deficiency (107,109,155–158). Mod-
erate to marked elevations of serum muscle enzymes are also well described
(107–112) and acute exertional rhabdomyolysis has even been reported (159).
Less commonly, a peculiar myopathy characterized by muscle hypertrophy, stiff-
ness, weakness, and slowness of movement have been described in association
with hypothyroidism; this has been referred to as Hoffman’s syndrome in adults
(160,161) and as the Kocher-Debre-Semelaigne syndrome in children (162).
Infections
Hypothyroid patients have an increased propensity to develop infections, par-
ticularly those of the upper and lower respiratory tract, urinary tract, and skin.
Symptoms and signs related to these infections may occasionally be the initial
manifestations of hypothyroidism. This increased susceptibility to infections is
not well understood but likely involves hypothyroid-related alterations of respira-
tory and bladder function, reduced cutaneous blood flow, and decreased activity
of circulating and tissue phagocytic cells (163–165).

Subclinical Hypothyroidism
Subclinical hypothyroidism (SCH) (Table 3) is often asymptomatic, but up to
30% of affected patients may experience nonspecific physical and psychiatric
symptoms (18,166–177). In the Colorado Thyroid Disease Prevalence Study (18),
patients with only mild TSH elevations had slightly but statistically significantly
more symptoms on a validated thyroid health questionnaire than did euthyroid
controls (Table 4). Symptomatic improvement following institution of thyroid
hormone replacement has been reported in most published studies (166–170,175),
depending largely on the baseline TSH of the affected subjects, with more symp-
tomatic benefit being demonstrated in subjects with TSH levels ⬎ 10 to 12 mU/L
(175–179).
Subtle disorders of myocardial function have been well described in patients
with SCH (166,167,169,177,180–192), but their clinical significance is uncer-
tain (177). Reported abnormalities include impaired myocardial contractility
(166,167,169,180–185,187,191) and diastolic dysfunction (185–187,190), at rest
(167,180,181,184–187) or with exercise (169,182–187). Abnormal myocardial

Table 3 Subclinical Hypothyroidism/


Mild Thyroid Failure—Definition

Few or no clinical signs


Normal free T4 and free T3
Elevated basal TSH
Hypothyroidism 153

Table 4 Clinical Symptoms in Patients with Subclinical Hypothyroidism


Percent having symptoms

Subclinical hypothyroidism Euthyroid controls


Symptom (n = 1799) (n = 22,842) p

Dry skin 28 25 ⬍.001


Poor memory 24 20 ⬍.001
Slow thinking 22 18 ⬍.001
Muscle weakness 22 18 ⬍.001
Fatigue 18 16 ⬍.01
Muscle cramps 17 15 ⬍.001
Cold intolerance 15 12 ⬍.001
Puffy eyes 12 10 ⬍.05
Constipation 8 7 ⬍.05
Hoarseness 7 5 ⬍.05

Source: Adapted from Ref. 17.

texture has been demonstrated in SCH subjects by videodensitometric analysis


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

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

hypertension, elevated triglycerides, and low HDL cholesterol) (209–215). One


large cross-sectional study in Australia, however, did not find an association
between SCH and hypertension (216). A positive association between serum TSH
levels and body mass index and obesity, even within the population reference
range for TSH, has also been reported (217,218). Levothyroxine replacement in
SCH patients with TSH levels ⬎10 to 12 mU/L results in statistically significant
reductions in LDL cholesterol (170,175,197–200,202) and non-HDL cholesterol
(203); several studies in patients with milder TSH elevations (5–12 mU/L) have
not been conclusive on this issue (177–179,219), but two carefully designed,
randomized, controlled studies have reported a similar beneficial reduction
in serum total cholesterol and LDL cholesterol (175,200). Two quantitative
literature reviews (197,198) of the prospective studies examining this issue have
concluded that levothyroxine treatment of patients with SCH lowers both serum
total cholesterol and LDL cholesterol by approximately 10 mg/dL.
Surrogate markers of cardiovascular disease have been reported to be
abnormal in patients with SCH. These include increased pulse wave velocity
(220), impaired endothelial function (175,221,222), increased levels of C-reactive
Hypothyroidism 155

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

protein (210), increased carotid artery intima-media thickness (CIMT) (200)


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

Figure 3 Meta-analysis of coronary heart disease (CHD) risk in subclinical hypothy-


roidism (SH). Odds ratio (OR; diamonds) and 95% confidence intervals (CI; horizontal
lines) for CHD in subjects with SH are shown. Abbreviations: CC, case-control study; CS,
cross-sectional study; PC, prospective cohort study. Source: From Ref. 228.

and myocardial infarctions and that, after controlling for other known cardiovas-
cular risk factors, SCH was found to be an independent and equally important
risk factor for myocardial infarction (224); however, no increase in myocardial
infarctions was observed in SCH over a 4.6-year follow-up period. A Japanese
study similarly reported that SCH was associated with ischemic heart disease and
with all-cause mortality in men only (226) (Fig. 4). The Busselton Health Study
also concluded that SCH was a significant and independent risk factor for coronary
heart disease (227). In contrast, other large population-based studies, including
the Health, Aging, and Body Composition Study (193), the New Mexico Elder
Health Study (230), and the Cardiovascular Health Study (231), did not show an
association between SCH and cardiovascular disorders or mortality (231). Another
study of subjects over age 85 actually reported enhanced four-year survival in a
cohort of very elderly subjects with untreated SCH (232). At this time, there is
little data concerning the effects of treating SCH on cardiovascular outcomes. One
small uncontrolled, retrospective analysis (233) showed progression of coronary
atherosclerosis in subjects with elevated serum TSH levels on levothyroxine ther-
apy compared to those with normal TSH levels (p ⬍ 0.02). An observational study
Hypothyroidism 157

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

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

Cross-sectional studies have demonstrated evidence of specific neurobehav-


ioral and neuromuscular symptoms in mild thyroid failure patients (18,174,235–
244). Depression (235–239), memory loss (18,174,235,240,241), cognitive
impairment (174,241,242), and a variety of neuromuscular complaints (243,244)
have all been reported to occur more frequently in patients with this condition.
Other studies, however, have found no evidence of depression (245), cognitive
loss (245), or neuropsychological dysfunction (246) in SCH patients. Objective
evidence of neurological dysfunction, including decreased peripheral nerve con-
duction amplitude (247), an abnormal stapedial reflex (248), abnormal cerebral
nerve latency (249), and alterations of cerebral blood flow (250) have been demon-
strated in these patients. Skeletal muscle abnormalities, including elevated serum
creatine phosphokinase levels (110), increased circulating lactate levels during
exercise (243) and repetitive discharges on surface electromyography (244) have
also been reported. Memory has been shown to improve significantly in one ran-
domized controlled trial (RCT) (240) and in two uncontrolled studies in which
mild thyroid failure patients were given levothyroxine therapy (235,241). Other
reported benefits from uncontrolled interventional studies include reduction in
neuromuscular complaints (235,244) and normalization of abnormal electromyo-
grams (244).

Myxedema Coma
Myxedema coma is a life-threatening condition that represents the extreme end of
the spectrum of thyroid hormone deficiency (251–254). It usually occurs in elderly
patients, with inadequately treated or untreated hypothyroidism, who then have a
superimposed precipitating event. Conditions reported to precipitate myxedema
coma include prolonged cold exposure, infection, trauma, surgery, myocardial
infarction, congestive heart failure, pulmonary embolism, stroke, respiratory fail-
ure, gastrointestinal bleeding, and the use of medications, particularly central
nervous system depressants. Affected patients generally present with hypother-
mia, 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 effu-
sions are frequent findings. An ileus is common and acute urinary retention may
also occur. Treatment, discussed later, must be instituted promptly because of the
very high mortality rate in this condition when appropriate therapy is delayed or
neglected (255,256).

DIAGNOSIS
Hormone Assays
The key to the accurate diagnosis of hypothyroidism is measurement and appropri-
ate interpretation of serum thyrotropin (TSH) and thyroid hormone levels. Thyroid
Hypothyroidism 159

Figure 5 Primary hypothyroidism development. In the earliest stage, mild hypothy-


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

gland failure is a gradual but generally progressive process. Although it exists on


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

Table 5 TSH and Thyroid Hormone Levels in Primary Hypothyroidism, Central


Hypothyroidism, Euthyroid Sick Syndrome and Thyroid Hormone Resistance Syndromes

TSH T4 Free T4 T3 Free T3 T3 RU

Primary hypothyroidism
Mild ↑ N N N N N
Moderate ↑↑ ↓ ↓ N N N
Severe ↑↑↑ ↓↓ ↓↓ ↓ ↓ ↓
Central hypothyroidism
Mild N N N N N N
Moderate ↓, N ↓ ↓ N N N
Severe ↓, N ↓↓ ↓↓ ↓ ↓ ↓
Euthyroid sick syndrome
Mild–Moderate N N N ↓ ↓ N
Moderate–Severe N, ↓ ↓ N ↓↓ ↓↓ ↑
Recovery N, ↑ N N, ↓ N N N
Thyroid hormone resistance
N, ↑ ↑ ↑ ↑ ↑ N, ↑

When thyroid gland failure is secondary to inadequate pituitary TSH secre-


tion (central hypothyroidism), the serum TSH level fails to rise, making the diag-
nosis of mild central hypothyroidism very difficult to make. Progressively more
severe degrees of central hypothyroidism are characterized by declining serum
T4 and T3 profiles similar to those seen with primary hypothyroidism (Fig. 6,
Table 5) with the exception that the serum TSH level remains normal or low
(27,28,260). In some cases, however, mildly elevated serum TSH concentrations
have been observed; such patients apparently produce a TSH molecule with nor-
mal immunological but reduced biological activity due to altered glycosylation
(261,262).
Hypothyroidism that occurs after antithyroid drug therapy or radioiodine
treatment of thyrotoxicosis is often characterized by a mixed hormone profile.
Serum T4 and T3 levels commonly decrease rapidly after therapy and become
frankly low by six to eight weeks. In approximately 90% of patients, the TSH
levels remain low or undetectable for several weeks, giving a picture similar to
that seen in central hypothyroidism (263). This transient phenomenon is likely
due to delayed recovery of chronically suppressed pituitary thyrotropes caused
by the antecedent thyrotoxicosis. Eventually, the thyrotrope cells do recover and
serum TSH levels increase as the majority of patients progress to develop typical
primary hypothyroidism (263). Approximately 15% of patients, however, may
later recover sufficient thyroid function to return to a euthyroid state (264).
TSH elevations are almost always indicative of some degree of primary
thyroid failure. However, variable elevations of the serum TSH level can sometimes
be seen in other conditions such as the recovery phase of the nonthyroidal illness
Hypothyroidism 161

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

syndrome (euthyroid sick syndrome) (265,266), untreated or inadequately treated


adrenal insufficiency (267), and rare genetic mutations in the TSH receptor (268).

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

Screening for Hypothyroidism


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

TREATMENT
Thyroid Hormone Preparations
Thyroid hormone replacement therapy was introduced in 1891 when George Mur-
ray reported on studies treating myxedema with injections of an extract of sheep
thyroid glands (282). Subsequently, Hector MacKenzie demonstrated similar ben-
eficial effects from an oral preparation of whole sheep thyroid and later from a des-
iccated extract of ovine thyroid (283). Following these reports, desiccated extracts
Hypothyroidism 163

Table 6 Conditions Associated with an Increased Risk of


Hypothyroidism

A. High-risk patients and conditions (prevalence ⬎10%)


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

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

(Lloyd, distributed by Forest), Unithroid (Jerome Stevens)] and generic


R

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

R R
and LT3 (Liotrix , Thyrolar ) and several brands of desiccated thyroid are also
164 McDermott and Ridgway

manufactured; their use is generally not recommended because these products


contain a higher T3/T4 ratio (1:4) (288,289) than is present in human thyroid
secretions (approximately 1:10–20). Due to the high T3 content and the rapid,
essentially complete absorption of T3 from the intestinal tract, serum T3 levels
rise significantly, often into the supraphysiological range, two to six hours after
ingestion of these medications (290).
Most thyroid specialists today consider LT4 to be the treatment of choice for
hypothyroidism (285,291). This is based on the principal that T4 is converted to T3
in peripheral tissues at a regulated rate that is appropriate for the overall metabolic
needs of the body. Physiological replacement of LT4 relieves symptoms and
normalizes serum TSH in the vast majority of hypothyroid patients. Furthermore,
LT4 therapy given to thyroidectomized individuals in doses sufficient to normalize
serum TSH levels has been demonstrated to produce serum T3 levels that are
similar to those in the euthyroid, prethyroidectomy state (292). LT4 is available
in multiple dose sizes, allowing precise titration of the dosage in each individual
patient according to their symptoms and serum TSH levels. Furthermore, its
relatively slow intestinal absorption and long serum half-life provide stable serum
concentrations with minimal diurnal variation. Side effects and toxicity occur
only with overtreatment, a condition that can be avoided by choosing a treatment
schedule that is appropriate for each patient and by regular monitoring of the
serum TSH.
Brand-name LT4 preparations are recommended by many thyroidologists.
Several early studies suggested that different LT4 brands were not equal in potency
(293–296), while a subsequent study called this into question, reporting that four
generic and brand-name preparations were all bioequivalent (297); this sparked a
burst of controversy over study design, interpretation of results and conflicts of
interest (298–300). In 2005, the FDA determined by its own methodology that
many of the brands and generic preparations of levothyroxine were bioequiva-
lent. However, subsequent investigations suggested that the FDA bioequivalence
methodology was imperfect, indicating that patients who were switched between
levothyroxine preparations may need to be retested with serum TSH measure-
ments five to six weeks later to assure adequate control. This would be especially
important for patients whose thyroid hormone levels require precise control, most
notably thyroid cancer patients and hypothyroid women during pregnancy. In
2009, the FDA will take a step toward enhancing the quality of all levothyroxine
products by requiring that they retain from 95% to 105% of their stated potency
throughout their entire shelf life; the previous standard was 90% to 110%. At
present, considering their overall low cost, and our desire to provide our hypothy-
roid patients with the most reliable supply of thyroid hormone, we continue to
recommend the use of brand-name LT4 preparations for thyroid hormone replace-
ment in order to assure that there is consistency every time patients refill their
prescription. If a patient does switch brands or is placed on a generic preparation
of thyroxine, reassessment of the serum TSH is recommended six weeks later,
since the preparations may not yield the same target serum TSH.
Hypothyroidism 165

The absorption of oral LT4 is approximately 80% whereas that of LT3 is


85% to 100% (301–303). Absorption of LT4 occurs at multiple sites throughout
the length of the small intestine but nearly two-thirds occurs in the proximal
small bowel (301,302). It is recommended that LT4 be taken fasting, on an empty
stomach, in the morning since the presence of food decreases LT4 absorption
by about 10% (304). Alternatively, taking LT4 in the evening or at bedtime may
provide better medication absorption than morning dosing (305), although this
study did not control for the fact that study subjects ate after the morning dose
but not after the bedtime dose. Administered LT4 accumulates slowly and has a
serum half-life of about seven days. It requires approximately five to six weeks for
serum levels of T4 to reach a new steady state on a given dose of LT4; therefore,
sampling for serum TSH and/or T4 levels should be performed no sooner than
five to six weeks after therapy is initiated or a dosage change has been made.
Both euthyroid and hypothyroid individuals exhibit a small but significant diurnal
variation in TSH secretion, having slightly higher serum TSH levels between the
hours of 11:00 p.m. and 4:00 a.m. (306). In addition, hypothyroid patients have
small decreases in serum TSH levels (307,308) and increases in serum total and
free T4 concentrations (307) several hours after exogenous LT4 administration.
When possible, TSH measurements should be obtained prior to LT4 ingestion.

Patient-Oriented Approach to Treatment


Thyroid hormone replacement therapy must be individualized for each patient.
The average full replacement dose of LT4 is 1.6 to 1.7 ␮g/kg/day (303,309,310).
Since dose requirements relate more strongly to lean body mass than to total body
mass (311), it may be preferable to estimate a starting dose based on ideal body
weight rather than actual weight in obese individuals. Alternatively, the initial
LT4 dose can be estimated based on the magnitude of the TSH elevation (312).
However, the starting dose, titration schedule, final dose, and ultimate goals of
therapy depend upon multiple factors such as the patient’s age, symptoms and
general state of health as well as the severity, duration, and underlying cause of
hypothyroidism.

Overt Primary Hypothyroidism


The young, otherwise healthy, patient with overt primary hypothyroidism can usu-
ally be started directly on a full LT4 replacement dose of 1.6 to 1.7 ␮g/kg/day
(310,313). After six weeks, the serum TSH level should be measured and the
results used to guide dosage titration until the serum TSH is normal (314)
(Table 7). Since TSH levels in the general population are not normally distributed
over the reported normal range, but are skewed with the majority of individuals
having values at the low end of the range, most practitioners attempt to maintain
serum TSH levels between 0.5 and 2.0 mU/L. Once the TSH concentration is in the
desired range, it should be rechecked in three months and then on an annual basis.
166 McDermott and Ridgway

Table 7 Fine Tuning LT4 Dosages

If serum TSH is Then

⬎ 5.0 mU/L Increase daily LT4 dose by 12.5–25 ␮g/day


0.5–5.0 mU/L Continue dose; recheck annually
⬍0.5 mU/L Decrease daily LT4 dose by 12.5–25 ␮g/day

When a hypothyroid patient is older than 60 years, it is prudent to adopt a


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

Table 8 Mild Thyroid Failure—Benefits and Costs of Early


Detection and Therapy

Benefits
1. Treat symptoms related to mild thyroid hormone deficiency
2. Control associated hypercholesterolemia
3. Prevent progression to overt hypothyroidism
Costs
1. Serum TSH assays
2. Levothyroxine therapy
3. Follow-up visits
4. Risk of iatrogenic hyperthyroidism

factors (209–215), and an increased risk of cardiovascular disease (169,224–229),


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

serum TSH into the desired range of 0.5 to 2.0 mU/L is reached (300,303). In the
oldest old (patients over age 80 years), the data suggest that mild thyroid failure
is associated with decreased mortality (232). Therefore, it has been recommended
that treatment be initiated when the serum TSH is higher (e.g., ⬎10 mU/L), and
that the target serum TSH be higher than it would be for younger patients, for
example, 4 to 6 mU/L. (319).
Mild thyroid failure in patients with known or suspected coronary artery
disease should be treated carefully using the more gradual approach described
earlier for heart patients with overt hypothyroidism. The goal TSH range of 0.5 to
2.0 mU/L is reasonable if the required LT4 dose does not worsen cardiac symptoms.
Otherwise, a more conservative TSH goal of 2.0 to 5.0 mU/L or slightly higher
would be recommended.

Postradioiodine Hypothyroidism
Since an elevated serum TSH level often occurs relatively late in the development
of postradioiodine hypothyroidism (263), LT4 replacement should be initiated
when the patient becomes symptomatic or the serum T4 or free T4 level first
becomes subnormal, even if the TSH is still suppressed. Such early replacement
may reduce the risk of developing subsequent Graves’ orbitopathy (320). Since
most of these patients are young and their hypothyroidism is of short duration,
initiating low dose LT4 with gradual titration upward is rarely necessary. Nonethe-
less, some individuals may have residual autonomous thyroid function and become
symptomatically thyrotoxic on full LT4 replacement doses. Therefore an initial
LT4 replacement dose of 1.2 to 1.3 ␮g/kg/day in these patients may be appropri-
ate, with careful monitoring of their clinical status, free T4 and TSH levels. About
three months after radioiodine treatment, TSH secretory capacity usually recovers,
after which serum TSH levels can be used to monitor therapy as in other patients
with primary hypothyroidism. The goal serum TSH range for these patients should
be 0.5 to 2.0 mU/L.

Central Hypothyroidism
This disorder is significantly more difficult to manage because of the inability to
use serum TSH measurements as an indicator of when to treat and as a guide to the
appropriate LT4 replacement dose (27,28,260). These decisions therefore require
a greater degree of clinical judgment. Treatment should generally be started when
patients develop symptoms consistent with thyroid hormone deficiency and the
serum free T4 level is in the low normal or frankly low range. As with primary
hypothyroidism, LT4 dosing schedules need to be determined with consideration
given to the patient’s age, severity of hypothyroidism, and the presence of under-
lying illnesses. Since TSH levels are usually uninformative and often misleading
in this condition, serum free T4 measurements should be used to monitor the
adequacy of LT4 replacement (260). The goal of treatment should be amelioration
of pertinent symptoms and maintenance of serum free T4 levels in the mid-normal
Hypothyroidism 169

to high-normal range (260,321). Because of the possibility of coexisting central


adrenal insufficiency, adrenal function should be assessed prior to LT4 treatment.
If adrenal function is found to be inadequate, glucocorticoid replacement should
be initiated at the same time LT4 replacement is started.

Thyroid Cancer
Patients with hypothyroidism resulting from thyroidectomy for thyroid cancer
may require as much as 20% more LT4 for replacement and suppression than
do patients whose hypothyroidism has resulted from autoimmune thyroid disease
or radioiodine treatment of Graves’ disease (322). The serum TSH concentration
remains the most accurate guide to the proper LT4 dosage (286,287,323). When
TSH suppression is the goal, serum TSH levels should be maintained below
or at the lower limits of the normal range, whereas for simple replacement the
goal TSH range should be 0.5 to 2.0 mU/L. There is considerable controversy
over the appropriate degree of TSH suppression in patients with thyroid cancer.
Some believe that LT4 doses sufficient to reduce serum TSH levels to between
0.1and 0.5 mU/L are satisfactory for all patients with thyroid cancer (322). Others
believe that full suppression of TSH levels to below the detection limits of third
generation TSH assays (⬍0.01 mU/L) is ideal (323–325). Evidence-based practice
guidelines from the American Thyroid Association recommend that in patients
with low-risk disease who have been shown to be free of disease following surgery
and radioiodine ablation therapy, the serum TSH be kept between 0.3 and 2 mU/L.
For patients with high-risk invasive or metastatic disease, it is recommended that
the TSH level be maintained at ⬍0.1 mU/L indefinitely. For patients with high-risk
disease who have no evidence of active disease, the TSH target is 0.1 to 0.5 mU/L
(326).

Transient Hypothyroidism
Hypothyroidism may occasionally be transient, as in the early recovery phase of
postpartum thyroiditis, silent thyroiditis, and subacute thyroiditis. Thyroid hor-
mone 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 thy-
roiditis (327–329). Thyroid hormone replacement is advisable for patients who
are symptomatic and for those whose serum TSH levels are ⬎20 mU/L. We rec-
ommend initiating treatment with an LT4 dose of 50 to 75 ␮g/day and a goal
TSH of 1.5 to 3.0 mU/L, thus permitting sufficient TSH secretion to stimulate
recovery of thyroid function as the inflammatory process subsides. After three to
six months of therapy, LT4 should be tapered in 25 ␮g decrements until eventual
discontinuation, provided serum TSH concentrations remain within the normal
range.
170 McDermott and Ridgway

Drug-Induced Hypothyroidism
Amiodarone is an anti-arrhythmic agent that is highly lipophilic, having a long
half-life of approximately 100 days and a propensity to accumulate in multiple
tissues, including the thyroid gland. Each molecule of amiodarone contains two
iodine atoms and the compound is 37% organic iodine by weight; a 200 mg
tablet delivers about 9 mg of iodine into the circulation. This medication inhibits
peripheral T4 to T3 conversion and thereby alters circulating thyroid hormone
concentrations (high T4, low T3, and transiently high TSH). It may also precipi-
tate overt symptomatic hypothyroidism or hyperthyroidism (40,41), particularly in
patients with underlying goiters or antithyroid antibodies living in iodine-replete
areas of the world, such as the United States. Hypothyroidism occurs in approx-
imately 20% of patients on chronic amiodarone therapy. The major mechanism
of this effect is probably high iodine delivery to the thyroid gland. High concen-
trations of intrathyroidal iodine acutely inhibit new thyroid hormone synthesis, a
phenomenon known as the Wolff-Chaikoff effect (330,331); while patients with
normal thyroid glands usually escape from this effect, patients with underlying
thyroid disease often do not and hypothyroidism ensues. Other potential mecha-
nisms for amiodarone-induced hypothyroidism include direct cytotoxic effects of
the drug on thyroid cells and possible initiation or augmentation of thyroid autoim-
munity. The condition resolves in approximately 50% of patients who discontinue
amiodarone administration but persists transiently or permanently in the remain-
der. We recommend treatment in most cases, particularly if they are symptomatic.
Because these patients have underlying heart disease, LT4 should be started in low
doses of 25 to 50 ␮g/day and increased carefully in 12.5 to 25 ␮g increments every
six to eight weeks in order to bring the TSH into the normal range. If arrhythmias
appear to be exacerbated with LT4 therapy, mildly elevated serum TSH levels may
be a more appropriate goal. Amiodarone treated patients have been reported to
require higher than expected LT4 replacement doses, possibly due to impaired T4
to T3 conversion within the pituitary gland (42).
Patients treated chronically with lithium also have a high likelihood of devel-
oping thyroid dysfunction. Approximately 50% of patients develop goiters, 20%
develop subclinical hypothyroidism, and up to 20% develop overt hypothyroidism
(40). Lithium administration is known to increase the intrathyroidal iodine con-
centration (43); lithium-induced hypothyroidism might therefore be due to the
Wolff-Chaikoff effect. Alternatively, since the majority of affected patients have
circulating antithyroid antibodies, lithium may also somehow enhance underlying
thyroid autoimmunity (44–46). If lithium withdrawal is not practical, we recom-
mend LT4 treatment for all patients who have goiters or elevated serum TSH
levels. The goal TSH should be 0.5 to 2.0 mU/L.
Interferon-alpha administration has been reported to cause thyroid dysfunc-
tion in up to 6% of patients; hypothyroidism and silent thyroiditis are the most
commonly found conditions and are believed to result from induction or aug-
mentation of preexisting thyroid autoimmunity (40,47–49). Interleukin-2 has also
Hypothyroidism 171

been implicated as a possible cause of silent (painless) thyroiditis (40,50). The


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

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

Pitfalls in the Management of Hypothyroidism


Patients Whose Symptoms Do Not Resolve on LT4 Replacement
Presenting symptoms persist in some patients despite seemingly adequate LT4
replacement with normalization of serum TSH concentrations (336–339); this is
particularly true of patients with mild thyroid failure who have nonspecific symp-
toms such as fatigue, weight gain, and depression. The most likely explanation is
that these patients’ symptoms are unrelated to their thyroid hormone deficiency.
Coexisting disorders such as poor physical conditioning, ineffective sleep habits,
stress, endogenous depression, anemia, electrolyte and mineral abnormalities,
diabetes mellitus, and other systemic disorders should be evaluated and managed
appropriately.
Theoretically, using an LT4/LT3 combination that approximates the normal
thyroidal secretion ratio might be beneficial, particularly in patients whose initial
symptoms persist. In 1999, Bunevicius et al. reported that replacing 50 ␮g of
the total LT4 dose with 12.5 ␮g of LT3 for a five-week period resulted in sig-
nificantly improved neuropsychiatric function, memory, mood, and overall sense
of well-being compared to full replacement doses of LT4 alone (340,341). The
main criticism of this study was that supraphysiological amounts of T3 were used,
since 12.5 ␮g of T3 is more than twice what a normal thyroid gland secretes
daily (6 ␮g). Multiple subsequent studies of combination LT4/LT3 therapy fol-
lowed this initial report (342–350). Although a few reported a mild subjective
benefit (340,346,347,349), there has been no statistically significant evidence that
patients benefit from combined LT4/LT3 therapy compared to monotherapy with
levothyroxine alone. A review (351) and a meta-analysis (352) of all the trials
concluded there was no benefit from combination T4/T3 therapy. Moreover, it
has been clearly demonstrated that LT4 therapy alone given to thyroidectomized
individuals in doses that normalize the serum TSH levels produce serum T3 lev-
els that are indistinguishable from those in the euthyroid, prethyroidectomy state
(292). Nonetheless, the possibility remains that some patients with suboptimal
clinical responses to LT4 treatment might benefit from the addition of a small
dose of LT3 (5 ␮g/day) and a trial of combination therapy may be reasonable in
select patients. The future use of combination LT4/LT3 therapy will likely involve
the development of slow release T3 preparations and careful comparative studies,
using physiological amounts of LT4 and LT3, testing their efficacy, safety, and
optimal dosing regimens.

Changing Thyroid Hormone Requirements


LT4 dose requirements may change under various circumstances (Tables 9 and 10).
Pregnant women without endogenous thyroid function often require a 30% to 50%
LT4 dose increase during the first 20 weeks of pregnancy (280,353–356). This is
particularly important to recognize since inadequately treated maternal hypothy-
roidism may impair intellectual development of the fetus in utero (143–149).
Hypothyroidism 173

Table 9 Conditions Associated with Altered LT4


Dose Requirements

A. Reasons for increased LT4 dose requirements


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

Table 10 Drugs That May Increase


Exogenous LT4 Dose Requirements

A. Drugs that decrease LT4 absorption


1. Ferrous sulfate
2. Calcium carbonate
3. Aluminum hydroxide
4. Sucralfate
5. Cholestyramine/colestipol
6. Fiber supplements
7. Soy supplements
8. Sevelamer
9. Raloxifene
10. Proton pump inhibitors
B. Drugs that increase LT4 metabolism
1. Phenytoin
2. Phenobarbital
3. Carbamazepine
4. Rifampin
C. Drugs that inhibit T4 to T3 conversion
1. Amiodarone
2. Glucocorticoids
3. Propranolol
4. Propylthiouracil
5. Ipodate
174 McDermott and Ridgway

Food and medications can interfere with the absorption of thyroid hormone in
the intestine; the most prominent effects have been reported with iron, calcium,
antacids, bile acid resins, fiber supplements, soy protein, raloxifene, and sevelamer
(357–365). Taking these products at a time of day that is separated by at least four
to eight hours from the LT4 dose will often bring about resolution of this problem.
Since gastric acid is important for LT4 absorption, patients with achlorhydria due
to chronic proton pump inhibitor use (366), Helicobacter pylori-related gastritis
(366), atrophic gastritis (366), or autoimmune gastritis (367) may have increased
LT4 requirements due to malabsorption of their medication (366,367). Intestinal
malabsorption due to Celiac disease (gluten sensitive enteropathy) (368) or to
lactose intolerance (369) should also be considered as a cause of escalating LT4
requirements and should be pursued when other causes are not evident. Moreover,
both autoimmune gastritis and Celiac disease occur more commonly in patients
with autoimmune thyroid disease (118,367,368). Nephrotic syndrome with mas-
sive urinary protein losses can also be a cause of increasing thyroid hormone
requirements (370). Other medications, particularly the anti-seizure and anti-
tuberculous agents, can significantly enhance hepatic T4 metabolism, resulting
in lower circulating serum T4 concentrations and the need for higher LT4 doses in
hypothyroid patients (371). Oral estrogen therapy has been shown to increase LT4
dose requirements by increasing circulating concentrations of thyroxine-binding
globulin and thereby reducing serum free thyroid hormone levels (372). Sertraline
may also increase thyroid hormone requirements but the mechanism of this effect
remains uncertain (373).
An apparent increase in LT4 requirements can also result from patient non-
adherence (374,375). One clue to this is the finding of an elevated serum TSH level
associated with a high-normal or elevated free T4. This profile suggests that the
patient missed multiple LT4 doses, resulting in elevation of the serum TSH, and
then took extra doses several days preceding blood sampling, acutely raising the
serum T4 concentration. The importance of adherence should be specifically dis-
cussed with all patients. An alternative solution to nonadherence is weekly, rather
than daily, ingestion of the calculated seven-day requirement (1.6–1.7 ␮g/kg ×
7) under the supervision of a health-care provider (376). Finally, patients who
have increasing LT4 needs may simply be having progression of their underlying
thyroid disease with worsening of endogenous thyroid function. When alteration
of the precipitating circumstances is not an option, the LT4 dose should be grad-
ually increased at six-week intervals as necessary to maintain the serum TSH
concentration in the desired range.
Conditions in which LT4 requirements are decreased are also listed in
Table 9. This is most commonly seen in elderly patients, in whom LT4 doses
are on average 25% lower than those in young patients (377,378). Prescribed or
surreptitious androgen use may also results in decreasing LT4 dose requirements
due to reductions in thyroxine-binding globulin with a consequent increase in free
thyroid hormone concentrations (379). Metformin has been reported to suppress
serum TSH levels by a postulated central mechanism (380); while this is not
Hypothyroidism 175

related to an increase in circulating thyroid hormone levels, dropping TSH levels


in response to metformin could lead one to erroneously believe that the LT4 dose
is too high. One must additionally consider the possibility that patients whose
LT4 dose needs are apparently dropping are intermittently or regularly taking
extra doses of their medications because they feel better on higher doses. While
difficult to confirm, this possibility can be investigated by reviewing pharmacy
refill records. Finally, increased endogenous thyroid hormone production due to
reactivation of Graves’ disease or to development of autonomously functioning
thyroid nodules must also be considered in patients whose LT4 dose requirements
decline. If the precipitating problem cannot be identified and corrected, the LT4
dose should be gradually decreased at six-week intervals in order to maintain
normal serum TSH levels.
Patients on stable doses of LT4 may have some inconsistency in their serum
TSH levels, varying within and slightly outside the normal range (303). We some-
times see patients with highly variable or “erratic” serum TSH levels (low, normal,
and high) while on the same doses of LT4. In these circumstances, poor or vari-
able adherence to the prescribed regimen must again be suspected. These patients
could also be taking their LT4 dose with iron, calcium, antacids, bile acid resins,
fiber supplements, or food without knowing the effects this may have on thyroid
medication absorption. Switching preparations between different brands can also
cause significant variations in serum TSH levels. Alternatively, minor differences
in serum TSH levels might simply result from having blood sampled at different
times of the day in relation to when the medication is taken. When serum TSH
levels vary significantly despite a seemingly constant LT4 dose, we recommend
that providers carefully review the patient’s medication administration habits and
instruct them to take their medications at the same time each day, to separate
their LT4 dose time by at least four to eight hours from food and drugs that may
interfere with LT4 absorption, and to consistently have their blood drawn for TSH
monitoring before their daily LT4 dose.

Patients Who Miss Their LT4 Dose


Patients sometimes inadvertently miss one or more daily doses of LT4. Some may
become quite concerned about potential adverse effects of this omission. While
missing doses should be discouraged, patients can be assured that LT4 has a long
half-life in the serum (seven days) and that there is virtually no harm resulting from
the occasional missed dose. However, the long serum half-life and slow absorption
of LT4 also allows providers the option of advising patients that taking an extra
“catch-up” pill the next day is permissible, particularly for those who appear to be
sensitive to even minor drops in their thyroid hormone levels.

Patients Who Are Treated With Desiccated Thyroid


Desiccated thyroid or “natural” thyroid preparations contain a higher LT3/LT4
ratio (1:4) than that produced by normal endogenous human thyroid secretion
176 McDermott and Ridgway

Table 11 Conversion from a Desiccated Thyroid Preparation to


Levothyroxine Therapy

Desiccated thyroid Levothyroxine


Equivalent
Dose T4 Content T3 Content Initial Dose

1.0 grain 38 ␮g 9 ␮g 100 ␮g


1.5 grains 57 ␮g 13.5 ␮g 150 ␮g
2.0 grains 76 ␮g 18 ␮g 200 ␮g
2.5 grains 95 ␮g 22.5 ␮g 250 ␮g
3.0 grains 114 ␮g 27 ␮g 300 ␮g
3.5 grains 133 ␮g 31.5 ␮g 350 ␮g
4.0 grains 152 ␮g 36 ␮g 400 ␮g

(approximately 1:10–20) (288,289). The excess LT3 content of these products


and the rapid absorption of T3 from the gastrointestinal tract often produce sup-
raphysiological serum T3 levels two to six hours following their ingestion (290).
Moreover, LT4 alone given in doses sufficient to normalize serum TSH levels has
been shown to normalize T3 levels also (292). For these reasons, most experts dis-
courage the use of desiccated thyroid and recommend that patients who are taking
these preparations be switched to brand-name LT4 products. Calculations that
take into account both T4 and T3 contents and rates of T4 to T3 conversion have
estimated that one grain (60 mg) of desiccated thyroid is approximately equal to
100 ␮g of LT4 (29,288,289). Accordingly, the recommended LT4 doses to be used
in patients being switch from desiccated thyroid products are shown in Table 11.
Once these changes are made, LT4 doses should be titrated by 12.5 to 25 ␮g every
six weeks until the serum TSH concentration is in the desired range. A significant
proportion of patients who have been converted from desiccated thyroid to LT4
complain of feeling worse, even when their TSH levels are normal and serum T4
levels high normal; this likely results from the lower serum T3 concentrations that
are present on LT4 therapy. Most patients, however, report that their symptoms
resolve over time. For those with persistent symptoms, deleting 25 to 50 ␮g of
LT4 and substituting 5 to 10 ␮g of LT3 might provide symptomatic relief. Caution
must still be exercised with such a regimen in order to avoid supraphysiological
T3 levels following medication ingestion, particularly in elderly subjects. As
discussed earlier, firm recommendations regarding LT4/LT3 combinations must
await the future development and careful testing of slow release T3 preparations.

Patients Who Are Sensitive to Thyroid Hormone Tablets


Patients occasionally complain of being “allergic” to thyroid hormone prepara-
tions. Provided the dose is correct, it is unlikely that a patient would have a true
allergic reaction to a hormone that is normally present in their body. However, a
patient may have sensitivity to a component of the pill such as coloring dye or
Hypothyroidism 177

a filler substance. When this is suspected, the 50 ␮g size of LT4, which in most
preparations is white with no added dye, can be given in quantities that add up
to the total intended dose. If reactions to the medication persist, changing to a
different preparation may be helpful.

Patients Who Are Temporarily Unable to Take LT4 Orally


Hypothyroid patients on LT4 replacement may be unable to take oral medications
for several days following a variety of general surgical procedures or during a
significant medical illness. If the anticipated duration of abstinence from LT4 is
no more than three days, no LT4 replacement during this brief interval is necessary.
However, if the period of abstinence is anticipated to be longer than three days,
the patient should be treated with intravenous LT4 in a daily dose that is 80% of
their usual oral dose; this amount is based on the determination that approximately
80% of an oral dose is absorbed into the circulation (301–303).

Surgery in Patients With Hypothyroidism


Surgery of various types may sometimes be needed in hypothyroid patients who
have been recently diagnosed but are not yet on adequate LT4 replacement. Most
studies indicate that hypothyroid patients tolerate surgery well and heal appro-
priately (381–383). However, in patients with more severe degrees of untreated
hypothyroidism, there is greater potential for some complications such as periop-
erative heart failure, ileus, absence of fever when infected, and neuropsychiatric
symptoms (384). It is advisable therefore to postpone elective surgical procedures
until patients are on LT4 replacement and have TSH levels that are in or near the
normal range (TSH ⬍10 mU/L). Patients requiring emergency surgery, including
coronary artery revascularization procedures (382,383,385), can proceed directly
to surgery without LT4 replacement until the postoperative period, at which time
dose schedules should be initiated, as discussed earlier, according to the patient’s
age, severity of hypothyroidism, and underlying general health.

Treatment of Nonthyroid Conditions With Thyroid Hormone


Obesity
Hypothyroidism is commonly associated with mild weight gain while thyrotoxi-
cosis usually causes weight loss. These observations prompted the use of high dose
thyroid hormone therapy to induce weight loss in the past (386,387), although this
practice was later abandoned because of the catabolic and potentially dangerous
consequences of iatrogenic thyrotoxicosis. Nonetheless, studies of obese subjects
placed on very low-calorie diets have shown that serum T3 concentrations and
resting metabolic rates decline in parallel, suggesting that these changes may con-
tribute to the plateau of body weight that is often seen after initial weight loss
occurs (388–391). High-dose T3 given during a very low-calorie diet has been
shown to prevent the drop in resting metabolic rate and to promote further weight
loss; however, this occurs at the expense of increased nitrogen loss suggesting
178 McDermott and Ridgway

protein catabolism (392–394). In contrast, lower-dose T3 therapy (40 ␮g/day)


has been shown in two small studies to promote weight loss in subjects on very
low-calorie diets without negatively affecting nitrogen balance (395,396).
At this time, there can be no justification for the use of thyroid hormone
preparations to assist with weight loss, except in hypothyroid patients in whom
only replacement LT4 doses are indicated. Nevertheless, the encouraging results
mentioned earlier will hopefully stimulate further study into the potential use of
new thyroid hormone analogs as an adjunct in the management of obesity.

Depression
Depression has been clearly identified as a symptom that may result from both
overt (139–141) and subclinical (235–239) hypothyroidism and that improves or
resolves with LT4 replacement therapy (141,338). Moreover, depression in appar-
ently euthyroid individuals has been shown to be associated with abnormalities of
the hypothalamic-pituitary-thyroid axis including abnormal TSH responses to the
administration of intravenous TRH (141). It is not surprising then that thyroid hor-
mone therapy has been used in the treatment of depression, even in patients with
normal thyroid function (397,398). LT4 has been used more commonly in bipolar
affective disorders, while LT3 has been given more often in depression (398).
While there is no substantial evidence that thyroid hormone alone has significant
antidepressant activity in euthyroid individuals, existing data do suggest that thy-
roid hormone supplementation may enhance the effect of standard antidepressant
medications in patients with refractory depression (397–400).

Premenstrual Syndrome
Disorders of the thyroid axis have been postulated to play a role in at least a subset
of patients with premenstrual syndrome (401). Controlled studies, however, have
failed to reveal any significant abnormalities of thyroid function or beneficial
responses to thyroid hormone therapy in patients with this disorder (402–404).
Therefore, there does not appear to be a current role for thyroid hormone therapy
in the management of premenstrual syndrome.
Consequences of Excess Thyroid Hormone Replacement
While our emphasis has been on the use of adequate doses of LT4 to alleviate the
symptoms of hypothyroidism, a caution regarding overtreatment must be raised
as well. If some is good, more is not necessarily better. Excess LT4 administration
most commonly occurs when serum TSH is not monitored regularly or when
patients request or self-administer higher LT4 doses to improve their energy level
or to help with weight loss. LT4 excess must be avoided, however, because of the
potentially deleterious effects on the cardiovascular system and the skeleton.
Low TSH levels in elderly subjects have clearly been demonstrated to be
associated with an increased risk of developing atrial fibrillation (231,405,406).
More subtle abnormalities of cardiac function, including increased heart rate,
atrial premature beats, increased left ventricular mass, increased left ventricular
Hypothyroidism 179

contractility, diastolic dysfunction, and impaired cardiac reserve have been demon-
strated in some studies during periods of even mild thyroid hormone excess (407–
410). Thyrotoxicosis has also been shown to stimulate osteoclastic bone resorption,
resulting in loss of bone mass. Although not a universal finding, several studies
have demonstrated that even mild thyroid hormone excess, as occurs in patients
taking excessive thyroid hormone doses, is associated with an increased risk of
bone loss and fractures, particularly in postmenopausal women (411–416). Thus,
there is ample evidence that even mild degrees of thyroid hormone excess should
be avoided in hypothyroid patents on chronic thyroid hormone replacement ther-
apy. Unfortunately, it has been shown that up to 20% of patients taking thyroid
hormone are over replaced (18).

SUMMARY
Hypothyroidism is a common disorder having multiple etiologies. Primary
hypothyroidism occurs far more frequently than does central hypothyroidism.
Thyroid hormone deficiency affects many tissues and organ systems, resulting
in a wide spectrum of clinical manifestations that include multiple symptoms,
signs, and laboratory abnormalities. Subclinical hypothyroidism is the mildest
form of this condition that may have physiologically relevant consequences and
beneficial responses to thyroid hormone replacement therapy. Myxedema coma,
the most severe form of hypothyroidism, is an extremely serious disorder with a
potentially high mortality rate without the prompt initiation of thyroid hormone
administration and appropriate treatment of precipitating causes.
Sensitive and accurate measurements of serum TSH levels have greatly
simplified the diagnosis of primary hypothyroidism. The diagnosis of central
hypothyroidism requires measurement of TSH along with free T4 or total T4 and
an assessment of other anterior pituitary functions. Measurement of antithyroid
antibodies helps to confirm the diagnosis of lymphocytic thyroiditis and aids in the
prediction of which patients with mild thyroid failure will progress on to develop
overt hypothyroidism.
The cornerstone of treatment of hypothyroidism is thyroid hormone replace-
ment. Treatment schedules and goals should be tailored to the individual patient
according to their age, severity of hypothyroidism, and underlying health status.
Serum TSH levels should be used to monitor LT4 therapy in patients with primary
hypothyroidism while free T4 levels are best when managing central hypothy-
roidism. 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.

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5
Thyroid Nodules and Multinodular
Goiter

Hossein Gharib
College of Medicine, Mayo Clinic, Rochester, Minnesota,
U.S.A.

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

203
204 Gharib

Table 1 Classification of Diffuse Goiter


Sporadic (nonendemic)
Iodine deficiency (endemic)
Autoimmune
Neoplasms
Genetic
Goitrogens

This chapter on nodular thyroid disease includes a discussion on the classi-


fication and prevalence of thyroid nodules; the pathogenesis of thyroid nodules;
laboratory tests; a review on the uses and limitations of FNA biopsy, thyroid
scanning, and US; management of clinically solitary nodules and multinodular
glands; and the problem of thyroid incidentalomas. It also includes recommen-
dations from recent practice management guidelines published by the American
Association of Clinical Endocrinologists in collaboration with the Associazione
Medici Endocrinologi (1), by the American Thyroid Association (2), and by the
European Thyroid Association (3) in the past 2 years.

CLASSIFICATION AND PREVALENCE


Thyroid gland enlargement (goiter) is one of the most common endocrine prob-
lems 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 thy-
roid 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 goi-
ter.” Worldwide, endemic goiter probably represents the most common endocrine
disorder. In the United States and Great Britain, nonendemic, or sporadic, goiter
affects more than 5% of the adult population (4–6). With declining iodine intake,
goiter incidence may increase. Additionally, nonendemic goiter may be caused by
excessive iodine intake (e.g., from amiodarone or kelp).
Solitary palpable thyroid nodules are found in 4% to 7% of the adult pop-
ulation in North America, 6.4% in women and 1.5% in men from 30 to 59 years
old (4,5,7,8). The prevalence of nodules increases throughout life, in women, and
in persons exposed to ionizing radiation in infancy or childhood. The data pro-
vided by the Framingham, Massachusetts, population study suggest an incidence
of 0.1% per year, or approximately 300,000 new nodules in the United States in
2007, and a 10% lifetime expectancy of nodule development (4,5,8).
However, these figures on palpable nodules substantially underestimate the
problem. For example, in an autopsy series, Mortensen and colleagues (9) reported
that in patients whose glands appeared clinically normal, one or more thyroid
Thyroid Nodules and Multinodular Goiter 205

nodules were detected in approximately 50%. Furthermore, 35% of patients had


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

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

presumably gained a growth advantage through somatic mutation of genes critical


for growth regulation.
The most widely held theory about nodule formation and growth is that
chronic TSH stimulation initially causes development of a diffuse enlargement,
which in turn leads to thyroid nodule development, and ends with the formation
of multiple nodules, typically an MNG. However, it is important to emphasize
that the exact role of TSH as a thyroid growth factor remains controversial (18).
In recent years, non-TSH growth factors have been identified that stimulate thy-
roid cell growth: growth-stimulating immunoglobulin(s), epidermal growth factor,
insulin-like growth factors, interleukin-1, interferon-␥ , and transforming growth
factor-␤ (19). It is also noteworthy that the growth-promoting effects of TSH in
vitro depend largely on the presence of insulin-like growth factors. Additionally,
somatic mutations known to occur in thyroid follicular cells include ras onco-
genes, G proteins, and the TSH receptor gene, which result in hyperfunctioning
adenomas (15).
In summary, the exact cause(s) or molecular mechanism(s) that stimulate
growth of a single cell within a thyroid follicle is not known. It is likely that both
intra- and extrathyroidal factors are important in the development and growth of
nodules. These factors include follicular cell mutations, stimulation by TSH and
other growth factors, and development of follicular necrosis, hemorrhage, and
fibrous tissue.

HISTORY AND EXAMINATION


Thyroid nodules are usually asymptomatic and are often discovered by a patient
or a physician after careful palpation of the neck (Fig. 1). MNGs are also often
asymptomatic, but they may be associated with hoarseness, neck pressure or pain,
cough, dyspnea, or dysphagia. Features that increase the likelihood of thyroid
malignancy include a family history of thyroid cancer, age younger than 20 or
older than 60 years, and a history of head or neck irradiation (7,20,21). Nodules
are more common in women but are more likely to be malignant in men (1,7).
On physical examination, common and different causes of thyroid nodules
should be kept in mind (Table 2). The characteristics of thyroid nodules, includ-
ing location, consistency, dimensions, and number, need to be carefully recorded.
Physical findings suggestive of malignancy include a hard, nontender nodule, fixa-
tion to adjacent tissue, and the presence of regional lymphadenopathy. However, it
should be emphasized that history and physical examination are often insufficient
for diagnosing thyroid cancer in most patients.

LABORATORY AND RADIOLOGIC DIAGNOSIS


Serum TSH should be measured in all patients by using a sensitive, third-generation
assay. If TSH levels are less than 0.5 mIU/L, levels of free T4 and triiodothyronine
(T3 ) in the serum should be measured. If serum TSH is greater than 5.0 mIU/L,
Thyroid Nodules and Multinodular Goiter 207

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

measurement of free T4 and thyroid peroxidase antibodies are necessary (1).


Routine measurement of serum thyroglobulin is not recommended (1,2).
Currently, the issue of routine serum calcitonin (CT) measurement in patients
with thyroid nodules is controversial (1–4). The prevalence of sporadic medullary
thyroid carcinoma (MTC) in patients with thyroid nodules ranges from 0.3% to
1.3% (22–27). In these reports, some patients received the correct diagnosis of
MTC on the basis of serum CT measurement and not by FNA biopsy. Thus, CT
measurement may detect unsuspected MTC, and hence, the recommendation by

Table 2 Common Causes of Thyroid Nodules


Benign
Colloid
Cyst
Thyroiditis
Hürthle cell lesion
Follicular cell lesion
Malignant
Primary—papillary, follicular, medullary, anaplastic cancer, lymphoma
Secondary—breast, lung, kidney (3 most common sources)
208 Gharib

Table 3 Indications for Ultrasonography


Palpable nodule(s)
Nodule detected incidentally by imaginga
Difficult thyroid palpation
Unexplained cervical adenopathy
History of neck irradiation
Family history of papillary or medullary thyroid carcinoma, or multiple endocrine
neoplasia type 2
Follow-up of thyroid cancer
a Imaging methods include positron emission tomography, computed tomography, and
magnetic resonance imaging.

some experts is that CT assays should be performed routinely in all patients with
thyroid nodules (3,28).
According to some European groups (3), if basal CT levels exceed 10 pg/mL,
pentagastrin stimulation should be performed, and if peak CT levels exceed 100
pg/mL, thyroidectomy should follow. For values between 10 and 100 pg/mL,
medical follow-up is suggested (28,29). However, in the United States, rou-
tine CT measurement was not endorsed either in a recent expert opinion (29)
or in practice guidelines (1), which stated that routine testing of serum CT in
all patients with unselected thyroid nodules does not seem to be cost-effective
and is not recommended. It is also important to note that pentagastrin is cur-
rently not available in the United States, and this issue limits the use of CT
measurement.

Ultrasonography
Indications
Three recently published guidelines recommend thyroid US for all patients with
one or more suspected nodules (1–3). US is recommended to confirm the presence
of a nodule. One study showed that 18% of palpable abnormalities were not thyroid
nodules when examined by US (30). This method can also be used to identify any
suspicious sonographic features in the nodule and to document the presence of
other potentially more clinically significant nodules. Additional indications for
US are detailed in Table 3.
Technique
High-resolution US uses frequencies between 5 and 10 MHz, which allow mea-
surement of the volume of the gland and the number, size, and characteristics
of the nodules within it (1,31). Sound waves are produced and received by the
transducer. Images are obtained in the longitudinal and transverse planes. Cur-
rently, transducers can identify cystic or solid lesions as small as 1 to 2 mm in
the gland. High-resolution US equipment has become less expensive and more
Thyroid Nodules and Multinodular Goiter 209

A B

C D

Figure 2 Evaluation of thyroid with high-resolution ultrasonography. (A) Transverse view


of right thyroid nodule containing both cystic and solid components; nodule was benign
on biopsy. (B) Longitudinal view of solid thyroid nodule with a “halo” at nodule periph-
ery. 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 con-
firmed with thyroidectomy. Abbreviations: C, carotid artery; T, trachea.

user friendly; many endocrinologists use it in the office for careful evaluation of a
broad spectrum of thyroid abnormalities.

Results
High-resolution US patterns of the thyroid include consistency, echogenicity, pat-
terns of calcification, and color Doppler flow (1,32–34). On the basis of consis-
tency, thyroid nodules are divided into three categories: solid, cystic, and mixed
solid and cystic. Simple or pure cystic lesions are extremely rare, and most cystic
lesions are considered mixed (or “complex”) lesions [Fig. 2(A)]. Benign nodules
are hyperechoic and may have a sonolucent rim (“halo”) surrounding the nodule
[Fig. 2(B)]. A malignant thyroid nodule is typically an irregular, solid, hypoechoic
210 Gharib

Table 4 Value of US Features Predicting Thyroid Malignancy


Positive Negative
Sensitivity Specificity predictive predictive Relative
US feature (%) (%) value (%) value (%) risk

Microcalcifications 26.1–59.1 85.8–95.0 24.3–70.7 41.8–94.2 4.97


Hypoechogenicity 26.5–87.1 43.4–94.3 11.4–68.4 73.5–93.8 1.92
Irregular margins 17.4–77.5 38.9–85.0 9.3–60.0 38.9–97.8 16.83
or no halo
Solid 69.0–75.0 52.5–55.9 15.6–27.0 88.0–92.1 4.2a
Intranodule 54.3–74.2 78.6–80.8 24.0–41.9 85.7–97.4 14.29
vascularityb
More tall than 32.7 92.5 66.7 74.8 10.5a
wide
a Unpublished data from a series of 400 patients undergoing surgery for thyroid nodular disease.

Regina Apostolorum Hospital, Albano, Rome. Courtesy of Papini E. and Guglielmi R.


b Patterns of nodule color Doppler flow and malignancy were described previously (1,4).

Abbreviation: US, ultrasonography.


Source: From Ref. 33.

mass, although follicular cancers can be hyperechoic. Calcification occurs in 13%


of nodules. Types of calcifications are important—peripheral eggshell calcifica-
tions are seen in benign, degenerating adenomas, whereas increased blood flow on
Doppler imaging and microcalcifications (seen as punctate deposits and indicative
of psammoma bodies) suggest papillary carcinoma [Fig. 2(C)]. MTC is suspected
when a solid nodule has scattered calcification [Fig. 2(D)].
No single ultrasonographic feature unequivocally differentiates benign from
malignant nodules. Although US results are highly operator dependent, in expe-
rienced hands, US is useful for predicting the risk of malignancy (Table 4). For
example, microcalcifications have 86% to 95% specificity for cancer, whereas
hypoechogenicity has a lower value of 43% to 94%. Overall, identification of at
least two clinically suspicious sonographic criteria is 85% to 95% accurate for
diagnosing malignancy (1,4).

Scintigraphy
Indications
With increasing use of FNA biopsy in the diagnosis of thyroid nodules, the role of
thyroid scintigraphy has declined progressively. Indications for radioisotope scan-
ning are summarized in Table 5. If a patient has a palpable nodule and suppressed
serum TSH levels, the next appropriate test is a thyroid scan to determine whether
the nodule is functional (1,2,4). Thyroid scanning is also useful for determining
goiter size because extent of the goiter may influence clinical management. Fur-
thermore, radioisotope scans can evaluate nodule function in MNGs, determine the
Thyroid Nodules and Multinodular Goiter 211

Table 5 Indications for Radioisotope Scan


Diagnose hot nodule
Determine goiter size
Assess nodule function in multinodular goiter
Evaluate substernal goiter
Identify ectopic thyroid tissue (sublingual thyroid, struma ovarii)

extent and size of substernal goiter, identify ectopic thyroid tissue, and determine
function in a nodule of a patient with Graves’ disease.

Technique
A gamma scintillation camera with a pinhole collimator is generally used for
thyroid scanning; it has replaced the rectilinear scanner. The most commonly used
radioisotope is radioiodine (123 I); technetium (99m Tc) is being used less frequently
(4,35,36). Both isotopes are transported into thyroid follicular cells, but only
iodine is organified, that is, incorporated into hormone production. Theoretically,
a rare nodule may exhibit discordance between 123 I and 99m Tc scan findings.
Because 99m Tc is trapped but not organified, a nodule may appear functional (hot)
on pertechnetate imaging and nonfunctional (cold) on 123 I imaging. In practice,
this has not been an important problem. For studies with 99m Tc, 1 to 10 mCi is
administered intravenously and imaging is performed 20 minutes later.

Results
The radionuclide scan may show several different patterns of function (Fig. 3).
The normal thyroid has a butterfly shape, the two “wings” of which are con-
nected by an isthmus that crosses the trachea anteriorly, below the level of the
cricoid cartilage. In a healthy subject, the radioisotope signal appears homoge-
neously distributed [Fig. 3(A)]. Characteristically, salivary glands are visualized
with 99m Tc, whereas they are not visualized with 123 I because images are obtained
6 to 24 hours later (the isotope has cleared from the salivary glands by then).
In hyperthyroidism with increased uptake (Graves’ disease), an enlarged gland
has intense, diffuse, and homogeneous uptake [Fig. 3(B)]. A hypofunctioning
(cold) nodule means no or subnormal isotope concentration in the nodular tis-
sue [Fig. 3(C)]. The likelihood of carcinoma in cold thyroid nodules varies from
approximately 5% to 15% (1,35,36). Because approximately 85% of nodules are
cold, surgical treatment based on radionuclide scan results is not cost-effective.
Another scan pattern is that of a hyperfunctioning (hot) nodule, with the absence
or near absence of isotope in the rest of the thyroid gland due to suppression
of endogenous serum TSH [Fig. 3(D)]. Some small, hot nodules make insuffi-
cient amounts of thyroid hormone to cause TSH suppression, so the remaining
normal thyroid tissue is still visible. In MNG, the pattern has an inhomoge-
neous, irregular, or patchy appearance, with functioning and nonfunctioning areas
212 Gharib

A B

C D

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

within an often enlarged gland. Patchy uptake may also be seen in Hashimoto
thyroiditis.

Other Imaging Techniques


Magnetic resonance imaging or computed tomography is used occasionally to
evaluate the size and extent of an MNG (Fig. 4). These imaging techniques
can be particularly helpful when evaluating substernal goiters and defining the
Thyroid Nodules and Multinodular Goiter 213

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

relationship of the goiter to surrounding structures, especially to exclude tracheal


compression. Neither technique separates benign from malignant thyroid growths,
and because of their relatively high cost, they are used less frequently than US and
scintigraphy (1,37).

FNA Biopsy
FNA biopsy—now clearly considered the most accurate test for the diagnosis
of thyroid nodules—has emerged as a safe, accurate, and cost-effective test (1–
4,7,37–52).

Indications
Biopsies may be performed with direct palpation for clinically solitary thyroid
nodules or with US guidance. Ultrasonographically guided FNA (US-FNA) biopsy
should be performed on patients with small or impalpable cystic nodules. Patients
with diffuse goiters, for example, Hashimoto thyroiditis, subacute (granulomatous)
thyroiditis, or amyloid goiter, can undergo diagnostic FNA biopsy. Primary or
metastatic malignancy of the thyroid and adenopathy due to thyroid malignancy
can be diagnosed reliably by FNA biopsy (39).
214 Gharib

Technique
Biopsies can be performed on the examining table in the office or on a hospital bed;
the patient is supine and the neck is hyperextended by placing a pillow under the
shoulders. This position allows maximal exposure (37,38,45). The area for biopsy
is identified clearly and the skin cleansed with alcohol or betadine. Although some
physicians use 1% lidocaine for local anesthesia (47) or apply ice cubes contained
in a plastic bag (45), some argue that biopsies can be performed without any such
preparation (43). A 27- or 25-gauge needle attached to a 10-mL disposable plastic
syringe is used; the syringe can be attached to a mechanical syringe holder. After
the free hand of the operator locates the nodule, the needle is inserted rapidly into
the nodule and mild suction is applied immediately. Too much suction may dilute
the specimen with blood; this should be avoided. The needle is moved back and
forth several times; after a few seconds, the suction is released and the needle
withdrawn. The needle is then dislodged from the syringe, air is drawn into the
syringe, the needle is replaced in the syringe, and the aspirated material is forced
onto glass slides. (Alternatively, 1 cc of air can be drawn into the syringe before
aspiration.) A drop of aspirate is placed on each of several slides, and smears are
prepared with an additional glass slide, in a manner similar to that of preparing
blood smears. For wet-fixed smears, glass slides are placed immediately in 95%
ethyl alcohol. Air-dried slides are left unfixed. Usually, 8 to 12 slides from 2 to 4
aspirations are prepared per nodule; some physicians advocate at least 6 separate
aspirations per nodule. Many clinicians also wash the syringe with cytology fluid,
centrifuge the suspension, and microscopically examine the cell pellet. For larger
nodules, aspirates are obtained from the center and circumferentially from the
periphery. Slides are then taken to the laboratory; wet-fixed slides are stained with
a modified Papanicolaou stain and air-dried smears are stained with Diff-Quik or
other stains (1,39,46).
After the procedure is complete, local pressure is applied to the biopsy sites.
The patient is observed for a few minutes and is then allowed to leave.

Results
Results of FNA usually are categorized into four diagnostic groups: benign (neg-
ative), clinically suspicious (indeterminate), malignant (positive), and unsatisfac-
tory (nondiagnostic) (1,4,40,51,53). The most common benign cytodiagnosis is
that of adenomatoid (or “colloid”) or benign thyroid nodule. The colloid nodule
shows abundant colloid, normal follicular cells, and some foam cells. Other benign
diagnoses include cystic lesions (usually adenomatoid nodules with cystic degen-
eration), lymphocytic thyroiditis, and subacute (granulomatous) thyroiditis. The
indeterminate category consists of specimens with features that are suggestive of
but not diagnostic for malignancy. This group includes cellular specimens (e.g.,
follicular neoplasms, Hürthle cell neoplasms, and other specimens with varying
degrees of cellular atypia) that require histologic evaluation for a conclusive diag-
nosis (38,44,45,54,55). Characteristically, these nodules produce hypercellular
Thyroid Nodules and Multinodular Goiter 215

aspirates with microfollicular patterns, or Hürthle cell changes with scant or no


colloid. The malignant (positive) group includes primary or metastatic carcino-
mas and thyroid lymphoma. Papillary carcinomas account for more than 80% of
malignant lesions and are usually diagnosed confidently with FNA (28,43,44).
Common cytologic findings of the thyroid are shown in Figure 5.
Hypocellular smears, which account for 5% to 15% of specimens, are con-
sidered nondiagnostic or unsatisfactory (49,53,56–58). The criteria for judging
specimen adequacy are neither well defined nor standardized. The variability
between laboratories and clinics regarding the definition of an “adequate” speci-
men is considerable. Most cytologists believe that a satisfactory smear must contain
at least six clusters of well-preserved cells, and each group must be composed of
at least 10 cells from separate aspirates (44). Unsatisfactory smears usually result
from poor biopsy technique and, less often, from cystic lesions yielding fluid and
foam cells, vascular lesions yielding too much blood, excessive air-drying, or poor
smear preparation.
Published FNA series from many centers in various countries confirm its use-
fulness and accuracy (38,41,49,50,52). For example, a 1995 review (42) described
combined results from more than 16,500 specimens from two institutions—the
diagnostic results were as follows: benign, 69%; malignant, 4%; and suspicious
or nondiagnostic, 27%. Analysis of published data (Table 6) shows that FNA has
a sensitivity of 65% to 98% (mean, 83%), a specificity of 72% to 100% (mean,
92%), and a diagnostic accuracy of 85% to 100% (mean, 95%). The predictive
value of a positive or suspicious cytologic result is 75% (range, 50–96%). The
false-negative rate may be as low as 1% and as high as 11% (mean, 5%), and
false-positive rates range from 0% to 7% (mean, 5%) (38,49).
Limitations of FNA biopsy include unsatisfactory or nondiagnostic results,
suspicious or indeterminate cytologic findings, and false-negative diagnoses
(37,46–52,57–60). Although nondiagnostic results can be as high as 20%, a repeat
biopsy yields satisfactory results in half of the cases. US-FNA further reduces

Table 6 Summary Characteristics for Thyroid FNA Biopsies: Results of a Literature


Survey

Feature Mean Range Definition

Sensitivity (%) 83 65–98 Likelihood that a patient with disease has


positive test results
Specificity (%) 92 72–100 Likelihood that a patient without disease
has negative test result
Positive predictive 75 50–96 Fraction of patients with positive test
value (%) results and disease
False-negative rate (%) 5 1–11 FNA negative; histology positive for cancer
False-positive rate (%) 5 0–7 FNA positive; histology negative for cancer

Abbreviation: FNA, fine-needle aspiration.


Source: From Ref. 1.
216 Gharib

A B

C D

E F

Figure 5 Thyroid cytology. (A) Nondiagnostic smear. Degenerative foam cells with-
out follicular cells (PAP; ×60). (B) Colloid nodule. Cohesive group of thyroid cells in
a patient with multinodular goiter (PAP; ×50). (C) Hashimoto thyroiditis. Lymphocytes
and Hürthle cells showing abundant granular cytoplasm (PAP; ×250). (D). Follicular neo-
plasm. Hypercellular aspirate with microfollicular pattern lacking colloid is indeterminate
(PAP; ×205). Nodule was a benign follicular adenoma at surgery (E) Papillary carcinoma.
Cellular specimen showing tumor cells with irregular, enlarged nuclei. Note lack of colloid
(PAP; ×100). (F) Medullary carcinoma. Loosely cohesive neoplastic cells with elongated
nuclei. (MGG stain; ×400). Abbreviations: MGG, May–Grunwald–Giemsa stain; PAP,
Papanicolaou stain.
Thyroid Nodules and Multinodular Goiter 217

nondiagnostic rates, but there may be a residual 5% to 10% frequency of non-


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

Table 7 Indications for Ultrasonographically Guided Fine-Needle Aspiration Biopsy


Impalpable or small (⬍1.5 cm) nodule with clinically suspicious ultrasonographic
features
Multiple nodules
Unexplained adenopathy or adenopathy in patients with history of cancer
Any size nodule in a patient with a history of neck radiation, medullary thyroid
carcinoma, or multiple endocrine neoplasia type 2
Initial biopsy was nondiagnostic
Any size nodule with ultrasonographic features suggestive of malignancy

Source: From Ref. 1.

Neither nodule number nor nodule size is predictive of malignancy (1,4,32).


When multiple nodules are present, selection for FNA should be made on the
basis of US features rather than size (1,4). When a patient has multiple, identi-
cally appearing spongiform nodules with little to no intervening normal thyroid
parenchyma, typical of a MNG, only the largest nodules require FNA. Some sug-
gest selecting only nodules larger than 1.0 or 1.5 cm in diameter for FNA (33),
citing the usual nonaggressive behavior of small (⬍1.5 cm) thyroid microcarcino-
mas. This issue is currently a matter of debate and controversy (34).

Conclusions
Recent treatment guidelines recommend routine serum TSH measurement, US
examination, and FNA biopsy in all patients with nodular thyroid disease (1–3).
US examination increasingly is used and has value in predicting malignancy.
However, the crux of nodule evaluation is thyroid cytology, and management
decisions should be made on the basis of FNA biopsy results. In experienced
centers, the probability of false-negative FNA rates (missed malignancy) is less
than 2%. The limitations of FNA include indeterminate (suspicious) cytology,
nondiagnostic smears, and false-negative FNA findings.

MANAGEMENT OF THYROID NODULES AFTER FNA


Solitary Nodules
A cytologically benign nodule can be monitored with or without additional aspi-
ration and with or without T4 therapy (Table 8). FNA-benign nodules account for
80% of satisfactory aspirates, require no further evaluation, and can be managed
expectantly. Considering 1% to 3% rate of false-negative diagnoses in this group,
some have suggested follow-up aspiration of benign nodules (67), whereas others
do not believe that additional biopsy is necessary (68). Generally, another aspira-
tion is required if nodules increase in size (1,2,4). Table 9 lists other indications
for performing additional biopsies.
Thyroid Nodules and Multinodular Goiter 219

Table 8 Management Options for Patients with FNA-Benign Nodules


Follow-up evaluation with palpation only
Follow-up evaluation with palpation and ultrasonography
Repeat FNA biopsy in 1 yr
T4 therapy

Abbreviation: FNA, fine-needle aspiration.

For patients with malignant FNA biopsy findings, surgical treatment is


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

Table 9 Reasons to Repeat FNA Biopsy


Enlarging, cytologically benign nodule
Recurrent cyst
Large nodule (⬎4 cm)a
Initial FNA biopsy was nondiagnostic
aTo minimize risk of missed malignancy in a large nodule.
Abbreviation: FNA, fine-needle aspiration.
220 Gharib

A B

C D

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

Immunohistochemical markers have been studied in an effort to separate


benign from malignant nodules when FNA results show cellular smears that
are suspicious for follicular or Hürthle cell neoplasm (73–77). HBME-1 (78),
galectin-3 (79), and peroxidase and telomerase (76) have been repeatedly helpful
for identifying benign follicular cell lesions. However, none of these markers have
sufficiently high sensitivity and specificity for routine clinical use, and current
guidelines from the American Association of Clinical Endocrinologists and Asso-
ciazione Medici Endocrinologi, American Thyroid Association, and European
Thyroid Association, as well as expert opinions, do not endorse their clinical use
(1–4,34).
Approximately 15% of nodules are nondiagnostic on initial biopsy
(4,38,44,56,80,81). A nondiagnostic result should prompt a second aspiration,
which may be satisfactory for half of the cases; however, US-FNA may be neces-
sary for diagnosis of some cases. The routine removal of all nondiagnostic nodules
is not recommended; however, it seems reasonable to surgically remove recurrent
Thyroid Nodules and Multinodular Goiter 221

cysts larger than 4 cm in diameter, repeatedly nondiagnostic solid nodules, or other


lesions meeting clinical criteria that increase the risk of malignancy (1,2).

Thyroid Hormone Therapy


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

T4 suppressive therapy
change in nodule size

Cheung et al. (83)


Gharib et al. (82)

Papini et al. (93) pooled RR of 1.83


(95% CI, 0.90–3.73)
Reverter et al. (84)
Zelmanovitz et al. (94)

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

Recent guidelines from the American Association of Clinical Endocrinol-


ogists and Associazione Medici Endocrinologi (1) and the American Thyroid
Association (2) suggest that patients with cytologically benign nodules prefer-
entially should be monitored by palpation, with US whenever indicated, and
without routine T4 suppression. Adverse effects of suppressive therapy include
osteoporosis and cardiac arrhythmias, which can be clinically significant risks in
postmenopausal women or elderly patients.
Percutaneous Ethanol Injection
In Europe, percutaneous ethanol injection (PEI) has been used successfully in the
treatment of solid and cystic thyroid nodules with normal function and of hyper-
functioning nodules (102–113). Currently, it is recommended only for treatment
of cystic nodules and shows a size reduction of 50% or more in almost 90% of
cases treated (1,106).
The usual treatment protocol is a single bolus of ethanol administered with
a 20- to 22-gauge needle using ultrasonographic guidance. The procedure is per-
formed 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,
Thyroid Nodules and Multinodular Goiter 223

ethanol is injected slowly after cyst fluid is removed; the volume of ethanol injected
is decided on the basis of the aspirated fluid volume. Generally, PEI is given once
or twice weekly, and treatment is usually completed in 4 to 8 procedures. Com-
plications include transient dysphonia, local pain, hematoma, and mild fever. In
experienced hands, adverse effects are transient and minimal, and treatment is
generally well accepted by most patients (1,103,106).
The recurrence rate of cysts after PEI is low; one injection frequently
is curative, and nodule shrinkage persists long after treatment ends (106,109).
Although PEI is not used for benign cysts in the United States, Italian physicians
have reported large, successful treatment groups and remain enthusiastic about
the technique (1,106–108). PEI treatment seems to be appropriate for recurrent,
symptomatic, benign thyroid cysts.

Percutaneous Laser Thermal Ablation


Percutaneous laser thermal ablation is another medical procedure used to treat
thyroid nodules. This minimally invasive procedure directs laser beams to nodules,
reducing their size and the local symptoms (114–118). The technique requires use
of US, local anesthesia, and special training. One adverse effect is local pain that is
often transient; other problems have not been reported. Percutaneous laser thermal
ablation is currently available in some European centers but is not used widely or
routinely in clinical practice; also, it has never been used in the United States.

Conclusions
Cytologically benign nodules should be monitored without T4 therapy. Nodule
shrinkage for its own sake is an outcome that may not be of clinical value to either
the patient or physician. The potential risks of long-term T4 therapy outweigh the
potential benefits in most patients, particularly postmenopausal women (4,7,97).
One study (119) suggested benefit from T4 therapy in previously irradiated patients
who had undergone subtotal thyroidectomy for benign nodules. Treatment of this
group of patients with T4 seems reasonable.

Multinodular Goiter
Evaluation of patients with MNG includes determination of thyroid function, esti-
mation of goiter size, exclusion of malignancy, and assessment of local symptoms
(120). Evaluation should begin with a US examination and serum TSH determi-
nation; if TSH is suppressed, serum levels of thyroid hormone (free T4 and T3 )
are determined and a radioiodine uptake (RAIU) test is performed. Toxic MNG is
treated with radioiodine or surgery; subclinical hyperthyroidism may be observed
for a period of time and then reassessed. A normal serum concentration of TSH
indicates a nontoxic MNG. Cytologic evaluation by US-FNA biopsy helps deter-
mine the management strategy (Fig. 8). In patients with benign goiters, periodic
evaluation—including thyroid palpation, determination of serum levels of TSH,
224 Gharib

Figure 8 Management of patient with a multinodular goiter (MNG). Evaluation begins


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

and cross-sectional imaging studies—is helpful in management. Cytologically


suspicious or malignant MNGs should be treated surgically.
Surgical excision is preferred in patients with nontoxic MNG and local
compression symptoms or cosmetic concerns. Bilateral subtotal thyroidectomy
is standard therapy for patients with MNG. The most frequent complications
of thyroidectomy include injury of the recurrent laryngeal nerve, hypoparathy-
roidism, hypothyroidism, and postoperative bleeding. However, with experienced
surgeons, complication rates are quite low. Postoperatively, T4 replacement is
frequently administered to prevent recurrence of goiter, but recent studies have
suggested that this therapy is probably ineffective; hence routine T4 therapy is no
longer advised (7,97). In patients with primary lobectomy, T4 therapy is advised
only if hypothyroidism develops.
Radioiodine (131 I) has been used successfully to treat toxic and nontoxic
MNGs (120–126). Radioiodine therapy results in amelioration of hyperthyroidism,
Thyroid Nodules and Multinodular Goiter 225

reduction of goiter size, and decreased local pressure or pain. Huysmans and col-
leagues (122,123) described patients with nontoxic goiters who were treated with
radioiodine and reported symptomatic improvement in 71%, decrease in tracheal
deviation in 20%, and increased tracheal lumen in 36%. Therapeutic doses of
radioiodine have ranged from 25 to 150 mCi, but the dosage depends on RAIU
and the mass of thyroid tissue. Adverse effects include posttherapy hyperthy-
roidism, hypothyroidism, and thyroiditis. Also, the possibility of malignant change
in residual thyroid tissue is always a concern (7,125–127).
Currently, radioiodine generally is considered an alternative and effective
treatment to surgical thyroidectomy; it is a good choice for treatment of small
(volume, ⬍100 mL) and nontoxic MNG, for patients previously treated with
thyroidectomy, or for elderly patients with high risk of surgical intervention (124).
In areas of high iodine intake, RAIU may be low or low-normal, thus reducing
the efficacy of radioiodine treatment and requiring increased doses of radioiodine
(120). Recent reports suggest that recombinant human TSH (rhTSH) may increase
RAIU and benefit patients who are candidates for this nonsurgical treatment
(128,129). The administration of small doses (0.10–0.30 mg) of rhTSH results
in 4-fold increased uptake, 24 to 72 hours after injection (127–131). Thus, the
131
I becomes more effective for goiter volume reduction, but rhTSH may increase
risk of respiratory problems (attributable to acute goiter enlargement), transient
posttherapy hyperthyroidism, and permanent hypothyroidism (132). Smaller doses
of rhTSH (0.01 mg) may be as effective and may have fewer serious adverse
effects.
In conclusion, serum TSH level, FNA biopsy, and imaging with radioiso-
tope scanning, US, computed tomography, or magnetic resonance help delineate
function, morphology, and extent of an MNG. Indications for treatment include
tracheal compression, cosmesis, and concern about malignancy on the basis of
growth or cytologic findings (or both). Thyroxine therapy reduces nodule or goiter
size in a minority of patients, and its routine use is no longer endorsed (1,2,7,8,97).
However, T4 should never be used in patients who already have low-normal or
suppressed serum TSH levels for fear of toxicity in an already autonomous gland.
Surgery is standard therapy for nontoxic MNGs, and radioiodine, in large doses,
is an attractive alternative therapy in elderly patients and those considered to have
high risk for surgery.

INCIDENTALOMA
Nonpalpable thyroid nodules discovered incidentally on imaging examination are
described as “incidentalomas.” They are usually less than 1.5 cm in diameter, are
a common clinical problem, and constitute a management dilemma for clinicians
(12,42,133). Most of them are discovered when high-resolution US is used for
parathyroid evaluation, carotid disease, or other nonthyroid diseases of the neck.
Incidentalomas are discovered in 30% to 50% of the normal population without
226 Gharib

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

Figure 9 Diagnostic approach to patient with incidentaloma. The algorithm separates


patients into high-risk and low-risk groups on the basis of clinical assessment. Nodule size
and appearance on high-resolution ultrasonography (US) also influence management. For
low-risk patients with benign-appearing incidentalomas less than 1.5 cm in diameter, obser-
vation and follow-up palpation are sufficient. Abbreviation: FNA, fine-needle aspiration.
Source: From Ref. 133.
Thyroid Nodules and Multinodular Goiter 227

incidentalomas do not have sonographic features of malignancy and are smaller


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

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

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6
Differentiated Thyroid Carcinoma

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

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

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

237
238 Sipos and Mazzaferri

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

EPIDEMIOLOGY
Cancers of the thyroid are rare, comprising approximately 2% of all diagnosed
cancers but accounting for ⬎93% of all cancers of the endocrine system (1).
Approximately 30,180 new cases and 1500 thyroid cancer deaths occur each year
in the United States: (1) ranking it 9th among malignancies for women and 19th
for men (2). Thyroid cancer is nearly three times more common in women than
men (1). It may occur at any age, but is more common in middle-aged women and
in men over the age of 60 years (Fig. 1). Thyroid cancer death rates are ⬍10%,
but vary significantly among the various types of thyroid cancer (Table 1) (3).
Data from the National Cancer Institute’s Surveillance, Epidemiology, and
End Results (SEER) program, demonstrate that the incidence of thyroid cancer
has more than doubled over the past three decades, increasing from a rate of
3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002, a twofold increase that is
statistically significant (p ⬍ 0.001 for trend) (4). New papillary thyroid cancers
Differentiated Thyroid Carcinoma 239

Table 1 Incidence and 10-Year Relative Survival Rates of the


Major Histological Types of Thyroid Carcinoma Among 53,856
Cases Diagnosed Between 1985 and 1995 (3)a

Thyroid carcinoma type Frequency (%) Survival (%)

Papillary 80 93
Follicular 11 85
Hürthle 3 76
Medullary 4 75
Anaplastic 2 14

a Relative survival is death attributed to thyroid carcinoma after correcting


for death from other causes.
Source: Adapted from Ref. 3.

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

Classification
Thyroid carcinomas are classified into four major types, which, in decreasing
order of frequency, are papillary (PTC), follicular (FTC), medullary (MTC), and
240 Sipos and Mazzaferri

(A)

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

anaplastic thyroid carcinomas (ATC) (Table 1). Although categorized as a separate


entity in some classifications, Oncocytic [Hürthle cell (HTC)] carcinomas are con-
sidered by the World Health Organization classification of tumors (8) as follicular
carcinomas composed exclusively or predominantly (⬎75%) of oncocytic cells,
the ultrastructure of which are filled with mitochondria producing a cytologic
Differentiated Thyroid Carcinoma 241

(B)

(C)

Figure 2 (Continued)
242 Sipos and Mazzaferri

appearance that is unique. PTC, FTC, and HTC—often termed differentiated thy-
roid carcinomas or DTC— arise from follicular cells, synthesize thyroglobulin
(Tg), and tend to be sporadic tumors, although occasionally PTC is familial.
MTC, which originates from thyroidal C cells that secrete calcitonin, may be spo-
radic or familial. ATC usually arises from well-differentiated thyroid carcinomas,
particularly PTC (9).

PAPILLARY AND FOLLICULAR THYROID CARCINOMAS


Papillary Thyroid Carcinoma
This tumor accounts for approximately 80% of all thyroid carcinomas in the United
States (3,5). It is three times more frequent in women than in men. Incidence is
highest in women in midlife, but it occurs at all ages. Often considered a separate
disease, occult microscopic PTC (≤1 cm) is found in 10% or more of autopsy
and surgical thyroid specimens obtained from men and women throughout adult
life (5).
A small group of nonmedullary thyroid cancers appear to be inherited, most
of which are PTC. Approximately 5% of PTCs are familial tumors inherited as
an autosomal dominant trait without other associated pathology. Familial PTC
is characterized by an earlier age of onset and more aggressive phenotype (10)
than sporadic PTC. One study of 258 cases (11) found that although patient
gender, age, and tumor histology were similar to that of sporadic PTC, familial
tumors were more likely to have intrathyroidal dissemination (41% vs. 29%) and
higher recurrence rates (16% vs. 10%) than sporadic tumors without displaying
significant differences in size, local invasion, or macroscopic metastasis.

Follicular Thyroid Carcinoma


This tumor occurs sporadically and accounts for approximately 10% of all thyroid
cancers in the United States, although it is more common in countries with low
dietary iodine (12). It usually occurs at a slightly older age than PTC (13,14), but
in some studies almost half of the patients are older than 40 years at diagnosis (15).
This tumor is rare in children, occurs infrequently after head and neck irradiation,
and is not commonly found incidentally.

RADIATION-INDUCED THYROID CARCINOMA


Epidemiology
Exposure to ionizing radiation during childhood is the best understood cause of
papillary, and less commonly, follicular thyroid carcinoma. Nevertheless, such a
history usually is now elicited in only approximately 5% of patients (16). Some
radiation exposure events have been associated with an increased risk of thyroid
cancer, while others have not. Possible explanations of this difference may include
Differentiated Thyroid Carcinoma 243

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

PAPILLARY THYROID CARCINOMA


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

Table 2 Prognosis of Main Histological Variantsa of Papillary and Follicular Thyroid


Carcinoma

Better Worse Possibly worse

Papillary thyroid carcinoma


Encapsulated Tall cell
Cystic Columnar cell Solid
Microcarcinoma Diffuse sclerosis Oncocytic (Hürthle cell)
Macrocarcinoma Diffuse follicular Associated with Graves’
disease
Insular cell
PTC with dedifferentiation
Follicular thyroid carcinoma
Oncocytic (Hürthle cell)
Insular cell
a Other histological variants—such as PTC with lipomatous stroma or fascitis-like stroma or myxoid

and cribriform variant PTC—have been reported too rarely to be certain about prognosis.
Source: Adapted from Ref. 23.

Multiple tumor foci are found in up to 80% of PTC cases when the thyroid
gland is examined in detail but are found in only 20% to 45% of specimens
examined routinely (26). This is important because multifocal PTMCs are
associated with an increased rate of lymph node and distant metastases. One study
(27) found lymph node metastases in 20% of unifocal and 35% of multifocal PTC
tumors and that multifocality increased lymph node recurrences almost sixfold.
Another study of PTMC found that 89% of distant metastases from these small
tumors were associated with multifocal tumors (28). Thought to be intrathyroidal
metastases in the past (26), newer studies using X-chromosome (29) BRAF
(the gene encoding B-type Rat Kinase) (30,31) or PTC/RET (RET is rearranged
during transfection proto-oncogene) analyses (32) find that many of tumors
within the same thyroid have different oncogene patterns that support the concept
that multicentric tumors arise de novo as independent tumors. Still, one study (33)
found that multifocal PTC tumors often have similar X-chromosome inactivation
patterns suggesting intrathyroidal metastases are a cause of multicentric tumor.
Thus, both intrathyroid metastasis and de novo tumors may play an important
role in the intrathyroidal spread of PTC, findings that have important therapeutic,
diagnostic, and prognostic implications.
Focal areas of infiltration with lymphocytes or plasma cells or classic
Hashimoto’s disease are usually present in or around the tumor and are intense
in up to 20% of cases (34). The presence of neoplastic cell phagocytosis by
macrophages and lymphocytic reaction has been associated with a more favorable
prognosis and reduced likelihood of distant metastases (35). It has been hypothe-
sized that this lymphocytic infiltration represents an immune reaction which helps
Differentiated Thyroid Carcinoma 245

to control tumor growth and proliferation (36). Lymphocytic infiltration has been
associated with a more favorable clinical outcome (34).

Lymph Node Metastases


PTC metastasizes to lymph nodes in the lateral and central neck and mediastinum.
Lymph node metastases are found in almost half the cases at the time of diagnosis
(37), while even more—up to 85% in some studies (38,39)—have microscopic
nodal metastases found on more careful histological study (39). The number
and size of lymph node metastases increase as the primary tumor size enlarges
beyond 5 mm (14). When the isthmus or both lobes are involved with tumor,
nodal metastases are often bilateral or extend into the mediastinum, with the most
common site being the lower paratracheal area (level VI) (40,41). Level VI is the
most common site of lymph node recurrence (42). Lymph node metastases have
variably been found to be of no prognostic importance in some studies (43) and
of significant prognostic importance in others (37), but a study from the SEER
database of 19,919 patients found with multivariate analysis that lymph node
metastases predicted a poor outcome. In some cases tumor penetrates the lymph
node capsule and invades the soft tissues, which is a particularly poor prognostic
sign (44).

Distant Metastases
Less than 5% of patients have distant metastases at the time of diagnosis and
another 5% develop them over the next two or three decades (12). The lung is the
most common site of distant metastases and is the most common disease-specific
cause of death from PTC. In a review (12) of 1231 patients with distant metastases,
49% were in the lung alone and another 15% were in lung and bone, 25% were
in bone alone, and 12% were in the central nervous system (CNS) or in multiple
organs (12). Lung metastases may be large and discrete [Fig. 3(A)] or may have a
“snow-flake” appearance from diffuse small metastases [Fig. 3(B)].
The lungs may concentrate sufficient 131 I to be detected on whole-body
scan. Some lung metastases are not seen on radiographs but are visible only on
131
I whole-body scans, sometimes only after administration of therapeutic amounts
of 131 I [Fig. 3(C) and 3(D)] (45,46). In other cases, the lungs do not concentrate
131
I for a variety of reasons.

Papillary Microcarcinoma
PTMC is a tumor ≤1.0 cm in diameter that is usually impalpable. Histologically
malignant, PTMC is generally found by coincidence during surgery for benign
thyroid disease and generally displays a benign clinical behavior. Still, not all
PTMCs are innocuous. Depending upon the study, up to 43% are multifocal, as
many as 69% have lymph node metastases, and up to 2.8% have distant metastases
(24). Recurrence rates vary. One study found a recurrence rate of 25.8% (47), but
246 Sipos and Mazzaferri

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

on average the rate is about 5% (24). Mortality from PTMC is rare, but rates as
high as 2% are found in some studies (48). Multifocal tumors tend to be more
aggressive than unifocal PTMCs (24,27,28,31). Lung metastases from PTMC are
rare but tend to occur more often in tumors with bulky cervical metastases (28,37).
Otherwise, the recurrence and cancer-specific mortality rates of PTMC are near
zero (24).
Differentiated Thyroid Carcinoma 247

Papillary Cancer within a Thyroglossal Duct


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

goiter, about one-third of whom have hyperthyroidism. These aggressive tumors


are more likely to be multicentric, have extrathyroidal extension, nodal and distant
metastases, and vascular invasion compared to common PTC and FVPTC (71).
Mortality rates are very high with this tumor (70).

Tall Cell Variant


Ten percent of PTCs have papillae with cells twice as tall as they are wide that
constitute at least 30% of the tumor (70). Compared with typical PTC, tall cell
variants tend to be diagnosed about two decades later (in patients in their mid-
50s), are larger, and are more often associated with invasion into local soft tissues
and with distant metastases (70,72,73). This tumor can be identified by FNA
cytology. It often expresses the p53 oncogene, BRAF mutation, RET/PTC gene
rearrangement, or NTRK1 mutation (74,75). Tall cell variant often loses or lacks
131
I uptake and the mortality is two- to threefold higher than those of typical PTC
(70,73).

Columnar Cell Variant


This rare variant, which is possibly related to tall cell carcinoma, is found mainly
in males and is composed of rectangular cells with clear cytoplasm (37). Dis-
tant metastases develop in 90% and are usually unresponsive to 131 I therapy or
chemotherapy, resulting in death in most patients (37,38). When it is encapsulated,
it has a much better prognosis (28).

Diffuse Sclerosing Variant


Approximately 5% of spontaneously occurring PTC and 10% of those found
among the Chernobyl children are of this type (70,76). The tumor is usually
bilateral and presents as a goiter with extensive squamous metaplasia, sclerosis,
psammoma bodies, and abundant lymphatic invasion involving the whole thyroid
gland. Almost all develop lymph node metastases and approximately 25% have
lung metastases (70). FNA cytology reveals squamous metaplasia, inflammatory
cells, and psammoma bodies, but this tumor may be difficult to differentiate from
thyroiditis (77). Although local and pulmonary metastases are more frequent than
usual, there is disagreement about whether its long-term prognosis is worse than
that of typical PTC (78–80).

Solid or Trabecular Variant


This tumor has a predominantly (⬎75%) solid architectural pattern but maintains
the typical nuclear features of PTC. It has a propensity for extrathyroidal spread
and lung metastases that impart a poor prognosis (70), but some find it to be
more common in children, in whom its prognosis is the same as that of typical
PTC (81).
Differentiated Thyroid Carcinoma 249

Oxyphilic (Hürthle Cell) Variant


Approximately 2% of PTCs have cellular features resembling those of Hürthle cell
(oxyphilic) FTCs (82). Some cases have multiple oxyphilic thyroid tumors and a
familial occurrence (83). This tumor cannot be identified as PTC by FNA cytology
but is recognized by its papillary architecture on the final histological sections.
Compared with typical PTC, oxyphilic PTC has fewer neck nodal metastases
at diagnosis but has higher recurrence and mortality rates and in this respect
resembles oxyphilic FTC (70).

Insular Carcinoma
Approximately 5% of all thyroid carcinomas show solid clusters of cells with small
follicles that resemble pancreatic islet cells but contain Tg. Often categorized as a
FTC variant, some tumors show papillary differentiation. LiVolsi believes that this
tumor should be considered a separate entity derived from follicular epithelium
(84). The tumors are unusually large and invasive and tend to grow through the
tumor capsule and into tumor blood vessels. Compared with PTC, insular carci-
noma presents at an older age (54 vs. 36 years) with larger tumors (4.7 vs. 2.5 cm),
fewer neck metastases (36% vs. 50%) but more distant metastases (26% vs. 2%),
and has a worse 30-year cancer-specific mortality rate (25% vs. 8%) (73). Insular
carcinoma also displays aggressive behavior in children but is usually responsive
to thyroidectomy and 131 I therapy (85).

FOLLICULAR THYROID CARCINOMA


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

FTC has compact cells with small, dark-staining, round nuclei that are more
uniform in shape, size, and location than the nuclei of PTCs and are difficult to
identify as carcinoma by FNA [Fig. 2(B)] (12,86).
Hürthle Cell Carcinoma
Oxyphilic cells, termed Hürthle or Askanazy cells, contain increased amounts
of acidophilic cytoplasm that contains numerous mitochondria on electron
microscopy. Greater than 75% of cells must be Hürthle cells to constitute HTC.
Some consider this to be a distinct clinicopathological entity while others consider
it to be a variant of FTC (87). HTCs demonstrate lymph node metastases more
frequently than typical FTC and metastases rarely respond to 131 I therapy. Regard-
less of its classification, HTC has a less favorable prognosis than nonoxyphilic
FTC, even though the former may not initially appear less differentiated or more
invasive (12).
Lymph Node Metastases
Compared to PTC, FTC metastasizes about half as often to regional lymph nodes,
occurring in approximately 20% of cases and is usually caused by the more
aggressive tumors that often have distant metastases (14).
Distant Metastases
FTC tends to metastasize to lung, bone, CNS, and other soft tissues with greater
frequency than does PTC, and the metastases often avidly concentrate 131 I. Distant
metastases at the time of diagnosis are about twice as common with FTC compared
to PTC (5). Unlike small PTCs that rarely metastasize to distant sites, small FTCs
can metastasize widely, and tumors ⬎3 cm are associated with a much higher
mortality rate (14,88)

DIAGNOSIS OF PAPILLARY AND FOLLICULAR


THYROID CARCINOMAS
Clinical Presentation
In the past, PTC was often diagnosed at a late stage, when the tumor was large
and invasive. Now, however, most are identified earlier by ultrasound-guided FNA
of small, asymptomatic thyroid nodules—frequently discovered incidentally by
imaging of the neck for other medical conditions (89). A few come to attention
as the result of pain, hoarseness, dysphagia, hemoptysis, or other signs of tis-
sue infiltration or rapid tumor growth. Such findings are associated with a high
probability of carcinoma in a nodule (90) and greater than usual mortality rates
(37). Sometimes palpably enlarged cervical lymph nodes are the only clue to the
diagnosis. A history of exposure to head or neck radiation is important, but only
about one-third of such nodules are malignant (17,91). A nodule in the setting
of a family history of PTC should be regarded with higher than usual suspicion.
Differentiated Thyroid Carcinoma 251

Nevertheless, the evaluation of familial or radiation-induced tumors is similar to


that of sporadic nodules. Most FTCs present as an asymptomatic neck mass with-
out palpable cervical lymphadenopathy. Less often, a distant metastasis is the first
manifestation, appearing as lung nodules, osteolytic bone lesion, or pathological
fracture or as a CNS tumor with neurological sequelae. Rarely, distant metastases
are seen in the absence of a palpable thyroid lesion (24). Bulky metastatic lesions
may be functional and cause thyrotoxicosis.
DTC usually becomes manifest by a palpably firm thyroid nodule that moves
upward when the patient swallows. PTC, however, may be cystic and soft or may
diffusely infiltrate one lobe or the entire thyroid gland; or its first manifestation
may be a palpable cervical lymph node metastasis. A midline mass above the
thyroid isthmus may be a metastatic (Delphian) lymph node or carcinoma within
a thyroglossal duct—the latter is suggested by upward movement with tongue
protrusion. Distant metastases are found less often at the time of diagnosis of
PTC than FTC, but when they are present, the primary tumor is usually large and
invasive. Only 10% of thyroid nodules have clear clinical evidence of malignancy
such as vocal cord paralysis or signs of invasion or metastases at the time of
diagnosis. Most appear benign and are associated with few or no symptoms. Thus
neither the history nor physical examination offers enough evidence of a nodule’s
benign nature that further testing can be deferred.

Fine-needle Aspiration
A serum thyrotropin (TSH) level should be measured in every patient found
to have a thyroid nodule. If the TSH level is below the lower reference range
(Fig. 4), then radionuclide imaging should be performed to determine if the nodule
is hyperfunctional (hot). Such a nodule is highly unlikely to be malignant and does
not routinely require FNA (92,93). Otherwise, FNA should be done to evaluate
a thyroid nodule in a clinically euthyroid patient (Fig. 4), whether the patient has
a single nodule or a multinodular goiter (92,93). Other tests—especially imaging
studies—are otherwise too nonspecific to be used early in the evaluation, except
perhaps in a patient with multinodular goiter and a suppressed TSH. All thyroid
nodules ⬎1 to 1.5 cm should undergo FNA (92), especially those with suspicious
ultrasound features. Fine-needle aspiration is best performed under ultrasound
guidance with on-site evaluation of cytology adequacy. This will decrease the
likelihood of obtaining a cytology specimen that is insufficient for diagnosis,
a common cause of missed cancer diagnoses, compared with performing the
procedure by palpation guidance alone. The ultrasonography-cytology assessment
approach is particularly important if the nodule is cystic (94). Thyroxine therapy
should not be used as a diagnostic test to identify thyroid carcinoma. Some
malignant nodules appear by palpation to shrink as the perinodular thyroid
parenchyma reduces in size in response to levothyroxine (86); in other cases,
ultrasound documented of reduction in size of malignant nodules has been
demonstrated (95).
252 Sipos and Mazzaferri

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

FNA yields cytology that can be categorized as malignant, benign, indeter-


minate (suspicious), or inadequate for diagnosis (Fig. 4). FNA is highly effective in
obtaining sufficient cytology to identify the distinctive features of PTC, including
most of its variants as well as most other malignant lesions (86).
Benign Hürthle cell tumors and follicular adenomas may be difficult to dif-
ferentiate from their malignant counterparts by FNA and frozen tissue sections.
Large-needle aspiration biopsies and cutting-needle biopsies usually yield results
similar to those of FNA but cause more complications and have lower diagnostic
specificity, especially for PTC, than FNA (96). FNA cytology specimens showing
normal or atypical follicular or Hürthle cells are often simply designated as follic-
ular or Hürthle cell neoplasms because their benign or malignant character cannot
Differentiated Thyroid Carcinoma 253

be determined with certainty until the final histological sections are available.
Even then there may be difficulty separating malignant and benign tumors (86).
Cytological material sufficient for diagnosis can be obtained in most palpa-
ble nodules, but the accuracy of FNA is enhanced by ultrasonographically guided
FNA, especially for small solid, cystic, and hypoechoic nodules (94,97). Patients
with nodules that yield malignant cytology should undergo total or near-total
thyroidectomy (Fig. 4) (86). Before performing surgery on nodules with inde-
terminate cytology (highly cellular specimens with normal or atypical follicular
cells without colloid), an 123 I thyroid scan should be done even in patients without
suppressed TSH levels to identify those occasional hyperfunctioning nodules
that are not active enough to cause TSH suppression, and which are usually
benign (93).

Evaluating Patients with a History of Head-and-Neck Irradiation


Children and young adults with a history of exposure to ionizing radiation such as
X-ray or external beam radiation therapy, and patients irradiated during childhood
for tumors or Hodgkin’s disease often develop hypothyroidism (98,99) and thyroid
neoplasia (98–100). As a result, measurement of serum TSH is recommended,
along with an FNA for those with a palpable thyroid nodule. However, controversy
exists regarding the diagnostic approach to an asymptomatic previously irradiated
person with a palpably normal thyroid gland. Schneider et al. (101) found that
87% of 54 patients who had been exposed to head-and-neck irradiation (X-ray
treatment for acne as a child or young adult) had one or more discrete ultrasound-
detected thyroid nodules. Of this group, 25% had nodules ≥1 cm, and about half of
the nodules 1.5 cm or larger were impalpable. This study confirmed that irradiated
individuals continue to develop thyroid nodules more than 20 years’ follow-up
from the time of irradiation (101), prompting the authors to advise indefinite
routine ultrasonography every 3 to 5 years in such patients. Still, others argue
that routine ultrasonography is too sensitive; it identifies benign thyroid nodules
in about half of the healthy middle-aged population and in most people exposed
to thyroid irradiation (101–103). Still, most authorities agree that the majority of
thyroid nodules ⬍1 cm discovered by serendipity and without ultrasonographically
suspicious characteristics are benign and can be followed by ultrasonography for
one to two years without FNA, providing the nodule volume grows no more than
50% (104) and the patient understands the small risk imposed by this approach.

FACTORS INFLUENCING PROGNOSIS AND AFFECTING OUTCOME


The prognosis of DTC is determined by an interaction of three clinical variables—
tumor stage, patient age, and therapy—and ranges from excellent to dismal. Over-
all mortality rates for DTC are low (⬍10% over three decades), but recurrence rates
are high. Distant metastases or local recurrences are often detected years after ini-
tial therapy (Fig. 5) (37) unless modern follow-up paradigms are employed (105).
254 Sipos and Mazzaferri

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

Patient Variables Influencing Prognosis


Age over 40 years at the time of initial therapy is the most important adverse patient
prognostic factor, which becomes progressively worse thereafter, increasing at a
particularly steep rate after the age of 60 years (Fig. 6) (12,37).
The best responses to therapy are in younger patients whose tumors con-
centrate 131 I (45,46,106). Although survival rates are most favorable in children,
their tumors are typically more advanced at the time of diagnosis, with more
local and distant metastases than found in adults (45,46). Up to 80% of children
develop cervical lymph node metastases and 15% to 20% develop pulmonary
metastases (106,107), rates that are almost twofold than those in adults. Also,
tumor recurrence rates over several decades are approximately 40% in children
compared with 20% in adults (37). Yet the prognosis for survival in children is
excellent, with or without a history of irradiation, except for those younger than
10 years, who have higher mortality rates (106,108). Very young children may
have unusual tumors that lack typical papillary architecture and behave more
aggressively (109).
Gender is an independent prognostic factor for survival (37). Thyroid cancer
recurrence and mortality rates are higher in men than in women (72,110). Ten-year
cancer-specific mortality rates for PTC among men and women older than 40 years
Differentiated Thyroid Carcinoma 255

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

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

Tumor Variables Influencing Prognosis


Tumor histology is a major determinant of outcome, being best with PTC, inter-
mediate with FTC, and worst with HTC. Distant metastases at the time of initial
diagnosis are found in 2.2%, 5.3%, and 35% of patients with PTC, FTC and
HTC, respectively (37). Tumor recurrence at distant sites occurs most often with
256 Sipos and Mazzaferri

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

Lymph Node Metastases


Cervical PTC lymph node metastases (12) reflect aggressive tumor behavior and
correlate with primary tumor size and multicentricity (72). The rate of lymph node
metastases depends upon the tumor features, the extent of surgery and the age of
the patient. A review (12) of 13 studies comprising 7845 PTC cases reported
before ultrasonography was widely employed, found a 36% rate of lymph node
metastases at the time of initial surgery. When neck ultrasonography is performed
preoperatively, a slightly larger number of patients are found to have lymph node
metastases (126–128). With immunohistochemical staining to identify micro-
scopic tumor, 53% have lymph node metastases (39) and with routine bilateral
cervical lymph node dissection, 60% of adults have them (40). The rates at the
Differentiated Thyroid Carcinoma 257

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

Thyroid Capsular Invasion and Extrathyroidal Extension


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

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

Irradiation-Induced Papillary Thyroid Carcinoma


The increase in thyroid carcinoma in post-Chernobyl children has been largely
confined to a specific subtype of papillary carcinoma (solid/follicular) that displays
more aggressive behavior with advanced primary tumor size and more multifocal-
ity and lymph node metastases than usual (140,141). From 44% to 70% express
RET/PTC3 mutations, depending upon how the specimens are studied (140–143).
Also, RET/PTC rearrangements are found in approximately 53% of benign tumors
in the Chernobyl children (144).
Cancer mortality rates are typically similar in other forms of radiation-
induced PTC compared with spontaneously occurring tumors, although tumors
associated with radiation are often large, multicentric and regionally metastatic
with high recurrence rates (91,145).

Other Tumor Factors


The histological variants of PTC and FTC affect prognosis (70). Also, coexistent
Hashimoto’s thyroiditis (usually with papillary thyroid carcinoma) is associated
with a low tumor stage and may be an independent predictor of a favorable prog-
nosis (34,146). Anaplastic tumor transformation that occurs in well-differentiated
thyroid carcinoma dramatically alters its course and results in aggressive local
tumor invasion and widespread, rapidly fatal metastases that do not concentrate
131
I (72).

Oncogenes
Protein tyrosine kinases (TKs) are enzymes that catalyze the transfer of phos-
phate from adenosine triphosphate (ATP) to tyrosine residues in polypeptides. The
human genome contains 90 TKs and 43 TK-like genes (147). The importance of
TKs became apparent when imatinib mesylate, an inhibitor of the BCR-ABL TK,
was shown to have a dramatic effect in the treatment of chronic myeloid leukemia.
It is now widely recognized that TKs play an important role in thyroid cancer and
are now the source of important targets for thyroid cancer chemotherapy.
The BRAF V600E mutation is the most common oncogene in sporadic PTC
in adults (148). The incidence of this mutation in PTC varies with the geographical
location of the study. In the Ukraine and Belarus it can be seen in 22.9% of tumors,
while the incidence is as high as 62% in France and Brazil. Pooled data analysis
of all patients studied reveals an overall incidence of 39.6% (149). The clinical
significance of this mutation has not yet been elucidated. One multicenter study
found an association between the presence of this mutation and lymph node
metastases, extrathyroidal invasion, and advanced tumor stage at initial surgery
(150). The BRAF mutation was also found to be an independent predictor of
tumor recurrence regardless of tumor stage, and was associated with absence of
131
I tumor avidity and treatment failure in patients with recurrent disease (150). A
recent study in Italy, however, found no correlation among the presence of BRAF
and tumor multicentricity, lymph node metastases, stage at diagnosis, or outcome
Differentiated Thyroid Carcinoma 259

(151). This discordance in findings between these two studies may be attributable
to geographic differences in the patient populations studied.

Treatment Variables Influencing Prognosis


Treatment of DTC has a major impact on long-term outcome, as discussed later
in sections dealing with surgical and medical therapy. Delay in therapy is an
important problem. We found that the median time from the first manifestation of
thyroid cancer—nearly always a neck mass—to initial therapy was 4 months in
patients who survived and 18 months in those who died of thyroid cancer (p ⬍
0.001) (37). The 30-year cancer mortality rate was nearly doubled when therapy
was delayed longer than a year (13% vs. 6%, p ⬍ 0.0001) (37).

TUMOR STAGING SYSTEMS AND PROGNOSTIC SCORING SYSTEMS


A number of tumor staging systems have been used to predict outcome with DTC.
Still, outcome cannot be accurately forecasted in individual patients. Two studies
(152,153) that critically compared the predictive accuracy of available prognos-
tic staging systems found that none accounted for more than a small portion of
the uncertainty in predicting outcome and that there was no statistically signif-
icant superiority of any system over that of the TNM (tumor, node metastasis)
classification of the American Joint Commission on Cancer (AJCC) and the Inter-
national Union Against Cancer (UICC) (Table 3) (154). The authors advised that,
because the TNM classification is universally available and widely accepted for
other disease sites, it should be used for all reports of the treatment and outcome
of patients with thyroid carcinoma, an opinion also expressed by the American
Thyroid Association (ATA) (93) and European Thyroid Associations (ETA) (155).
The greatest utility of staging systems is in epidemiological studies and
as tools to stratify patients for prospective therapy trials (72). Staging systems
may be less useful in determining treatment for individual patients unless a

Table 3 TNMa Classification of the AJCC and UICC Sixth


Edition Papillary or Follicular

Stage ⬍45 yr ≥45 yr Medullary

I M0 T1 T1
II M1 T2–3 T2–4
III T4 or N1 N1
IV M1 M1
a T is primary tumor: T1 , <2 cm; T2 , 2 cm to 4 cm; T3 , >4 cm; T4 ,
extension beyond thyroid capsule. N is regional lymph nodes: N1 , regional
lymph node metastases (cervical and upper mediastinal nodes). M is distant
metastases: M0 , no distant metastases; M1 , distant metastases present. All
undifferentiated (anaplastic) carcinomas are stage IV.
260 Sipos and Mazzaferri

reproducible group of patients can be identified with a very low risk of recur-
rence and cancer-specific mortality. Because the TNM classification of the AJCC
and UICC is universally available and widely accepted for other disease sites, it is
often recommended for thyroid carcinoma (152). Still, most patients are classified
as stage I with this classification (Table 3), which de facto categorizes most patients
as being at low risk (123). One study (123) found that patients with TNM stage-I
tumors had a 15% recurrence rate after an 11-year median follow-up, which would
argue against less aggressive therapy for this group. The numerous staging and
prognostic scoring systems that have been proposed underscore the fact that none
fully provides information to guide therapy.

TREATMENT OF PAPILLARY AND FOLLICULAR


THYROID CARCINOMAS
Surgery
Subtotal Lobectomy
Resection of less than a thyroid lobe, sometimes done as a nodulectomy, is inad-
equate therapy for thyroid carcinoma and is not the current standard of practice
(72,156). Even microscopic thyroid carcinoma requires more surgery than subtotal
lobectomy (157).
Ipsilateral Lobectomy and Isthmusectomy
A few surgeons prefer lobectomy, often referred to as subtotal thyroidectomy,
and regional lymph node dissection as the initial therapy for nearly all patients
with DTC (158). When the diagnosis of thyroid carcinoma is known preopera-
tively, however, most advise total or near-total thyroidectomy for all patients (159)
because it improves disease-free survival, even in children and adults with low-risk
tumors (160). Patients treated with lobectomy alone have a 5% to 10% recurrence
rate in the opposite thyroid lobe (5), an overall long-term recurrence rate ⬎30%
(12), and the highest frequency (11%) of subsequent pulmonary metastases (161),
compared with recurrence rates of only 1% after total thyroidectomy and 131 I ther-
apy (12). Higher recurrence rates are also observed with cervical node metastases.
Multicentric tumors—often found on study of the final histological sections—also
justify more complete initial thyroid resection (37). Lobectomy may be adequate
surgery for PTMC discovered serendipitously on the final pathology studies of
surgery done for benign disease provided that the patient has not been exposed to
radiation, has no other risk factors, and has a truly low-risk carcinoma—a tumor
⬍1.0 cm that is unifocal and confined to the thyroid without vascular invasion
(28,37,157,162). Complications with lobectomy are few, and survival in this latter
group is virtually assured (28,37,157,162). Nonetheless, the thyroid remnant tissue
hampers long-term follow-up with serum Tg determinations and whole-body 131 I
scans; therefore the decision to forgo complete thyroidectomy must be discussed
with the patient.
Differentiated Thyroid Carcinoma 261

Total or Near-total Thyroidectomy


Total or near-total thyroidectomy (ipsilateral total lobectomy, isthmusectomy, and
nearly total contralateral lobectomy) is the preferred surgical approach for the
majority of patients with a diagnosis of thyroid cancer. If any of the following
criteria are present, the patient should undergo total or near-total thyroidectomy:
tumors that are ≥l.0 cm in diameter, multicentric (any size), metastatic, penetrating
the thyroid capsule, histological variants with aggressive behavior, if the patient has
a first-degree relative with differentiated thyroid cancer, or patients with a history
of radiation therapy to the head and neck (163–165). Total thyroidectomy should
also be considered if there are contralateral nodules present, or if the patient is older
than 45 years. Complete or nearly complete thyroid resection removes multifocal
and bilateral carcinoma and provides the opportunity to ablate residual thyroid bed
uptake with small doses of 131 I, which substantially facilitates long-term follow-
up. Total thyroidectomy reduces the rates of recurrence and may also improve
long-term survival (166). If metastatic lymph nodes have been identified either
pre- or postoperatively, modified neck dissection (levels II to VI) that preserves
the sternocleidomastoid muscle is performed to remove involved cervical lymph
nodes. Radical neck dissection is done only for tumors that extensively invade the
strap muscles.

Completion Thyroidectomy
When subtotal thyroidectomy has been performed, it is best to consider completion
thyroidectomy for lesions that are anticipated to have the potential for recurrence
and because large thyroid remnants are difficult to ablate with 131 I (167,168). This
surgery has a low complication rate and is appropriate to perform routinely for
aggressive thyroid cancer variants, metastatic disease, PTC ⬎ 1 cm, FTC ⬎1 cm
with more than minimal capsular invasion, or multifocal carcinomas of any size,
because about half the patients have residual carcinoma in the contralateral thyroid
lobe (Table 4) (169). When there has been a local or distant tumor recurrence
following subtotal thyroidectomy, carcinoma is found in ⬎60% of the excised
contralateral lobes (170).

Table 4 Residual Carcinoma in Contralateral Thyroid Lobe Found with Completion


Thyroidectomy

Number of Patients (Percent with Residual Disease in Contralateral Lobe)

Total
Total number of patients residual
from seven studiesa Papillary Follicular Hürthle cell cancer

545 327 (58%) 206 (38%) 12 (57%) 244 (45%)


a Sources: Adapted from Refs. 43, 73, 76–78, 272, 273.
262 Sipos and Mazzaferri

Surgical Complications
The main complications of thyroidectomy are hypoparathyroidism and recurrent
laryngeal nerve damage, which are most common after total thyroidectomy. The
rates of hypoparathyroidism immediately after surgery are as high as 5% in adults
(128) and even higher in children (171,172) undergoing total thyroidectomy. How-
ever, the rates of persistent hypocalcemia are much lower. For example, one study
reported a 5.4% rate of hypocalcemia after total thyroidectomy that persisted in
only 0.5% of the patients one year after surgery (173). In a review of seven pub-
lished surgical series, the average rates of permanent recurrent laryngeal nerve
injury and hypoparathyroidism, respectively, were 3% and 2.6% after total thy-
roidectomy and 1.9% and 0.2% after subtotal thyroidectomy (174). When experi-
enced surgeons perform the surgery and the posterior thyroid capsule is left intact
on the contralateral side, hypoparathyroidism occurs at a lower rate. A study of
5860 patients treated in the state of Maryland found that surgeons who performed
more than 100 thyroidectomies a year had the lowest overall complication rates
(4.3%), which were fourfold lower than those of surgeons who performed ⬍10
cases annually (175).
Thyroidectomy during Pregnancy
Thyroid carcinoma may occasionally progress rapidly during pregnancy, per-
haps due to high maternal ␤-hCG levels, which have a TSH-like effect (133).
Nonetheless, most DTCs are slow growing and have an excellent prognosis during
pregnancy; therefore, surgery can usually be delayed until after delivery (176).

Radioiodine (131 I) Therapy


Sodium-Iodide Symporter
DTCs concentrate iodide much less avidly than normal thyroid tissue, perhaps
due to abnormalities in the sodium-iodide symporter. Increased sodium-iodide
symporter activity in PTC was reported in one study (177), but most find
reduced sodium-iodide symporter activity and heterogeneous immunohistochem-
ical sodium-iodide symporter staining in DTC (178,179).
Rationale for Thyroid Remnant Ablation
Because it is nearly impossible to remove all thyroid tissue with routine surgery,
131
I uptake is almost always seen postoperatively in the thyroid bed (including nor-
mal tissue of thyroglossal duct remnants). These foci must be ablated before 131 I
will optimally detect and be concentrated in metastatic deposits (180). Although
there continues to be debate concerning 131 I ablation of thyroid bed uptake after
near-total thyroidectomy, there are four compelling reasons to do this. First, a
thyroid remnant with high radioiodine uptake can obscure cervical or lung metas-
tases when their contribution to the total radioiodine uptake is low (180). Second,
high levels of circulating TSH, necessary to enhance tumor 131 I uptake, cannot
Differentiated Thyroid Carcinoma 263

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

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

thyroidectomy, functioning metastases, continued thyroid hormone ingestion, or,


rarely, hypopituitarism, but is more often related to advanced age more than
60 years (190). On the other hand, elevating the TSH level ⬎30 mIU/L does not
improve the therapeutic response to 131 I (191), and the optimal magnitude of TSH
elevation is unknown and differs among patients.
The other way to increase serum TSH levels is by intramuscular adminis-
tration of recombinant human TSH (rhTSH), which was approved by the FDA in
2007 for remnant ablation, while the patient continues thyroid hormone therapy
and thus avoiding symptomatic hypothyroidism (192). The drug is administered
intramuscularly at a dosage of 0.9 mg for two consecutive days and 131 I is adminis-
tered 24 hours after the last injection (Fig. 7) (193). Mean peak TSH concentrations
are reached between 3 and 24 hours after injection (median of 10 hours) and the
mean half-life is 25 ± 10 hours (192,194). Serum TSH levels are almost always
⬎50 mU/L (192,195,196). However, measurement of serum TSH is not gener-
ally advised after rhTSH injection because by the time the patient undergoes 131 I
treatment, the serum TSH levels are below the usual limits recommended for
treatment. Still, when given to euthyroid patients taking levothyroxine, rhTSH
injection is as effective as thyroid hormone withdrawal in preparing patients for
remnant ablation and produces an equally favorable therapeutic response (193).
Moreover, the use of rhTSH reduces total body radiation from 131 I by 33% com-
pared with withdrawal-induced hypothyroidism, which delays the renal excretion
of 131 I thus increasing whole-body irradiation (193). Also, remnant ablation with
Differentiated Thyroid Carcinoma 265

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

50 mCi of 131 I after rhTSH preparation is as effective as 100 mCi 131 I (197),
lowering whole-body irradiation to an even greater extent. Studies show that
short-term hypothyroidism after thyroid hormone withdrawal is associated with a
significant decline in quality of life that is abrogated by the use of rhTSH (198).

Diagnostic Whole-Body 131 I Scan and the Stunning Effect


Prior to remnant ablation, some physicians perform a diagnostic (“pretreatment”)
whole-body scan in order to establish the size and radioiodine avidity of the
thyroid remnant, and to search for the presence of cervical nodal disease. If a
diagnostic scan is ordered, it is usually obtained 24 to 72 hours after giving 2 to
4 mCi of 131 I (Fig. 7). Larger amounts of 131 I should not be given because focal
abnormalities not seen with 2 mCi are less likely to be ablated successfully (199),
and 131 I doses as small as 3 mCi diminish the subsequent uptake of therapeutic
131
I, which is termed the “stunning effect” (200,201). To avoid stunning, doses of
1 to 3 mCi of 131 I have been recommended; however, these doses are slightly less
sensitive than larger scanning doses of 131 I in identifying thyroid remnants, and
they require longer imaging times (202). Administration of the therapeutic dose
as soon as possible after the diagnostic dose of 131 I helps to minimize stunning
(202,203). Although 123 I in doses of ≥1.5 mCi has been reported to yield excellent
images without stunning, its use to date has been somewhat limited by issues of
266 Sipos and Mazzaferri

cost and availability. Furthermore, the logistics of doing pretreatment scanning


using rhTSH are complex, so that pretreatment scanning is usually not done in
this setting.
Amount of 131 I for Thyroid Remnant Ablation
Usually remnant ablation can be achieved with 30 to 50 mCi of 131 I, which is
as effective as larger doses in ablating the thyroid remnant and preventing tumor
recurrence (37,197,204). This has been a popular way to avoid hospitalization but
is no longer necessary in most states because of changes in federal regulations
permitting outpatient use of much larger 131 I doses in most states (205). Even
so, considering the differences in cost and radiation exposure and the fact that
doses to the thyroid remnant more than 30,000 rad do not substantially improve
the rate of successful ablation, it may be reasonable to use a relatively low dose
for remnant ablation (206). Successful thyroid remnant ablation with doses of
approximately 30 and 51 mCi of 131 I were reported as 63% and 78%, respectively,
in one study from New Delhi (206). However, this optimal dose of approximately
51 mCi was reported to deliver approximately 30,000 rad to the thyroid remnant.
In comparison, in one American study, 30,000 rad was achieved with a mean
I31
I dose of approximately 87 mCi and completely ablated the remnant in 86%
of cases (167). Another prospective study comparing 30 and 50 mCi doses of
131
I found no significant difference in ablation rates (207). Increasing the dose
to deliver more than 30,000 rad does not increase the success rate (167,206).
A recent meta-analysis of all the prospective trials showed no difference among
various doses of radioiodine (208). A subsequent prospective randomized study
of rhTSH to prepare patients for remnant ablation with 50 or 100 mCi also found
that the two were equally successful in achieving remnant ablation (197). The rate
of successful ablation is significantly lower when patients have less than a total or
near-total thyroidectomy or have a thyroid remnant calculated to be ⬎2g (167).
Posttreatment Scans and False-Positive Scans
Following therapy with 131 I, a posttreatment scan is performed with 5 to 10 days
later in order to visualize areas in the neck (and elsewhere) that contain iodine-
avid tissue. In most patients, an area in the midline corresponding to the thyroid
remnant is all that is seen. However, cervical nodal disease may be visualized in
papillary thyroid cancer, and more rarely diffuse lung uptake is seen, especially in
children and adolescents. Many things can infrequently cause false-positive 131 I
scans, including body secretions, transudates, inflammation, nonspecific mediasti-
nal uptake (e.g., blood pool), and neoplasms of nonthyroidal origin, which may
uncommonly concentrate 131 I (209). False-positive scans can also be seen with
physiological secretion of 131 I from the nasopharynx, salivary and sweat glands,
stomach, and genitourinary tract and from skin and hair contamination with spu-
tum or tears (210). Diffuse hepatic uptake of 131 I is rarely due to occult liver
metastases but more commonly due to hepatic clearance of Tg labeled with 131 I
by functioning thyroid remnants or extrahepatic thyroid cancer metastases. The
Differentiated Thyroid Carcinoma 267

more 131 I uptake by residual thyroid tissue, the more 131 I appears in the liver. In
one large study (211), 12% of all diagnostic scans showed uptake in the liver.
The frequency of hepatic uptake in posttherapy scans was related to the dose of
131
I, being 39% with 30 mCi, 61.5% with 75 to 100 mCi, and 71.3% with 150 to
200 mCi. On the other hand, hepatic uptake of 131 I without 131 I uptake elsewhere
suggests hidden metastases (211).

Treatment of Residual or Recurrent Carcinoma with 131 I


Thyroid carcinoma (especially macroscopic disease) should be treated surgically
whenever possible. Only 50% to 75% of DTCs and their metastases and about
one-third of Hürthle cell carcinomas concentrate 131 I (212–214). Moreover, the
larger the tumor mass, the less likely that 131 I therapy will successfully ablate
the tumor. One study found that two-thirds of 283 patients with lung or bone
metastases had tumors that concentrated 131 I, which is crucial to survival (215).
Another study found that 10-year survival rates were 83% or 0%, respectively,
depending on whether pulmonary metastases did or did not concentrate 131 I (139).
Lung metastases that concentrate 131 I most avidly are the smallest lesions found
in young patients (139).
There are three approaches to radioiodine therapy: empiric fixed doses,
upper-bound limits set by blood dosimetry, and quantitative dosimetry (205).
Dosimetric methods are often reserved for distant metastases or unusual cases,
as when renal failure is present or therapy with rhTSH stimulation is deemed
necessary.

Empirical Fixed Doses


With empirical doses, a fixed amount of 131 I is given based on tumor stage.
Generally, approximately 30 to 125 mCi are given to ablate thyroid remnants, 150
to 200 mCi for residual carcinoma in cervical nodes or neck tissues, and 200 mCi
for distant metastases. Tumor 131 I uptake in amounts adequate for imaging with
4-mCi diagnostic doses is usually sufficient for 131 I therapy, using empirical doses
from 30 to 200 mCi (216). However, two retrospective studies (217,218) found
that administering ⬍140 mCi of 131 I may rarely expose older patients to blood
doses of ⬎200 cGy, the upper allowable exposure limit. Administering 200 to
250 mCi of 131 I frequently exceeded the blood exposure limit in patients 70 years
of age or older. Consequently, dosimetry-guided 131 I therapy may be preferable
to fixed-dose 131 I treatment in older patients with thyroid cancer and in patients
with 131 I-avid diffuse bilateral pulmonary metastases, even when renal function is
normal (217,218).

Upper-Bound Limits Set by Blood Dosimetry


This approach establishes an upper limit on the amount of 131 I in a single dose that
can be given safely, which is generally considered to be 200 rad to the whole blood
(205). In patients with diffuse pulmonary metastases, the dose is also limited, so
that ⬍80 mCi of 131 I remains in the lungs after 48 hours to avoid pulmonary fibrosis.
268 Sipos and Mazzaferri

Without diffuse pulmonary metastases, most authors suggest that the whole-body
retention be ⬍120 mCi at 48 hours; however, this limit is usually greater than that
of the blood dosimetry and thus not a limiting factor. Based on these calculations,
therapy doses of 450 to 600 ± mCi are sometimes used. However, two studies
have shown that larger amounts of 131 I may be given to patients pretreated with
rhTSH injections compared with levothyroxine withdrawal with a lower risk of
bone marrow suppression (219,220).

Quantitative Tumor Dosimetry


This approach calculates the amount of 131 I that is required to deliver 30,000 rad
to ablate the thyroid remnant or 8000 to 12,000 rad to treat nodal or discrete soft
tissue metastases. For pulmonary metastases, an amount of 131 I is administered
that will deliver 200 rad to whole blood with no ⬎80 mCi of whole blood retention
at 48 hours (205). The mass of residual tissue and the effective half time of 131 I
in that tissue are the two most important factors in determining success (205). In
one study, an 80% response was found in tumor deposits that received at least
8000 rad (167). Lesions that receive ⬍3000 to 4000 rad from 150 to 200 mCi 131 I
should be considered for alternative therapy.

Repeat 131 I Treatments


Treatment with 131 I should be continued every 6 to 12 months, as long as metastatic
deposits are present and continue to concentrate 131 I and a favorable response
to previous therapy has been demonstrated, such as a decreasing Tg level or
decreasing tumor mass. Repeat 131 I doses should not be given until the bone
marrow has fully recovered from the previous dose. Few adverse effects occur
with this approach to 131 I therapy (219). Before large cumulative 131 I activities
(⬎500–600 mCi) are given over an extended period to treat neck metastases
or well-localized disease, especially in the CNS or spine, serious consideration
should be given to excising the tumor surgically.

Lithium
This drug inhibits iodine release from the thyroid without impairing iodine uptake,
thus enhancing 131 I retention in normal thyroid and tumor cells (221). One study
(222) showed that the mean increase in the biological or retention half-life was 50%
in tumors and 90% in thyroid remnants. The effect was greater in lesions with poor
131
I retention (222). Nevertheless, there are no outcome data showing improved
survival or efficacy of treatment in patients receiving lithium as an adjunct to
radioiodine therapy. In patients withdrawn from thyroid hormone, serum lithium
levels should be measured frequently if not daily and maintained between 0.8 and
1.2 nmol/L.

Immediate Complications of 131 I


There are few immediate serious risks of 131 I therapy except when metastases are
in critical locations that will not tolerate posttherapeutic swelling. For example,
Differentiated Thyroid Carcinoma 269

brain or spinal cord metastases can undergo potentially catastrophic edema and
hemorrhage 12 hours to 2 weeks after 131 I treatment (223). In patients with disease
in “critical areas” such as the CNS, pretreatment with high doses of glucocorticoids
has been recommended (224). Another example is severe radiation thyroiditis,
which can occur within a week of administering a large dose of 131 I to a patient
who has undergone only lobectomy, causing pain, swelling, and rarely airway
compromise that may require prednisone therapy (225). Thyroid storm may rarely
occur approximately 2 to 10 days after administering a therapeutic amount of 131 I,
especially when there is a large burden of functioning tumor (205). Acute bone pain
is sometimes experienced after 131 I treatment. Radiation sickness characterized
by headache, nausea, and occasional vomiting is experienced by about two-thirds
of patients approximately 4 to 12 hours after the oral administration of 200 mCi
or more of 131 I, which resolves in approximately 24 hours; this almost never
occurs with smaller amounts of 131 I (205). Patients with extensive neck tumor
may rarely develop transient vocal cord paralysis, and facial nerve paralysis has
been reported after very high doses of 131 I (205). Radiation cystitis does not occur
if the patient is well hydrated. Mild radiation sialadenitis, leukopenia, and a slight
drop in the number of platelets often occur approximately six weeks after therapy,
but ordinarily these effects are mild and transient unless very large doses of 131 I
are administered (226).

Parotid Dysfunction
Transient parotid swelling reminiscent of Stensen’s duct obstruction may occur
for nearly a year after 131 I therapy. Having the patient suck on hard lemon candy
starting 24 hours after therapy increases salivary flow, which may decrease but
does not prevent the adverse effect of 131 I radiation on the salivary gland. In
one study approximately 60% of patients reported side effects lasting longer than
three months, which included sialoadenitis (33%) and transient loss of taste or
smell (27%) (227). More than a year after the last 131 I treatment, 43% suffered
from reduced salivary gland function and ⬎4% had complete xerostomia, and
approximately 23% of the patients reported chronic or recurrent conjunctivitis,
complications that were related to the cumulative dose of 131 I (227).

Radiation Pneumonitis
Pulmonary fibrosis is a potential complication of 131 I therapy for diffuse pul-
monary metastases when the lung retention of 131 I is ⬎80 mCi 48 hours after treat-
ment. Some reports suggest that diffuse pulmonary metastases can be treated with
150 mCi of 131 I without risking pulmonary fibrosis (228) and smaller amounts of
131
I doses in the range of approximately 100 mCi are often given when there is dif-
fuse and intense uptake of the scanning dose in the lungs. However, a randomized
controlled study to investigate outcome of distant metastases treated with these
relatively low doses versus dosimetrically determined much higher doses (often
200–800 mCi) has not been conducted, so optimal therapy is not known.
270 Sipos and Mazzaferri

Leukemia, Second Tumors, and Other Bone Marrow Effects of 131 I


There is a small risk of developing acute myelogenous leukemia after 131 I therapy,
which in several studies has been estimated to range from 3 to 22 excess cases
per 1000 patients treated with 131 I, depending upon the cumulative amount of 131 I
administered (205,229). The late health effects associated with 131 I therapy for
thyroid cancer have been difficult to fully assess since the number of patients who
develop leukemia after being treated with 131 I is limited. For example, a Swedish
study found only two cases of leukemia among 834 thyroid carcinoma patients
treated with 131 I, which was not a statistically significant increase rate over that
found in the general population (230).
However, much larger studies have found a significantly greater risk of
second primary malignancies (SPM) in patients treated with 131 I. A European study
of 6841 patients with thyroid cancer (mean age 44 years) that was diagnosed from
1934 to 1995 found that 17% had been treated with external beam radiotherapy
and 62% had received 131 I therapy. An SPM was found in 576 (8%) of the thyroid
cancer patients, representing a 27% increase over that found in the population (95%
CI: 15–40). There was a significantly increased risk of cancer of the digestive tract,
bone and soft tissue, skin melanoma, kidney, CNS, and endocrine glands other
than thyroid, and leukemia. The risk of solid tumors and leukemias increased
as the cumulative amounts of administered 131 I increased, resulting in an excess
absolute risk of 14.4 solid cancers and of 0.8 leukemias per GBq (27 mCi) of 131 I
per 100,000 person-years of follow-up. A group of Utah investigators determined
the risk of a nonthyroidal SPM in 30,278 American patients with thyroid cancer
diagnosed between 1973 and 2002 in centers participating in the National Cancer
Institute’s Surveillance, Epidemiology, and End Results (SEER) program (231).
Median follow-up was 103 months (range, 2–359). A total of 2158 patients (7%)
developed nonthyroidal SPMs, which was significantly more than expected in the
general population [observed/expected (O/E) = 1.09; 95% CI: 1.05–1.14; p ⬍
0.05]. The absolute excess risk per 10,000 person-years was 6.39. Compared with
the general population, the risk of SPM was significantly greater than expected
(O/E = 1.20; 95% CI, 1.07–1.33; AER = 11.8) as was the increased risk observed
in nonirradiated patients (O/E = 1.05; 95% CI, 1.00–1.10; AER = 3.53). Still,
the risk of SPM was greater for irradiated patients than the nonirradiated cohort
(relative risk = 1.16; 95% CI, 1.05–1.27; p ⬍ 0.05). The greatest risk of second
primary cancers occurred within five years of the diagnosis of thyroid cancer and
was also elevated for younger patients.
When 131 I treatments are given at 12-month intervals and total cumulative
doses are limited to 500 mCi in children and 600 mCi in adults, long-term effects
on the bone marrow are minimal and few cases of leukemia occur (229,232,233).
Limiting the cumulative dose is usually not a problem unless large single doses of
131
I are given, because tumor tissue that concentrates 131 I is likely to be ablated by
a few 131 I treatments, leaving either no residual tumor or metastases that do not
concentrate 131 I. For example, all patients cured of pulmonary metastases by 131 I
Differentiated Thyroid Carcinoma 271

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

become permanent when large doses of 131 I are delivered year after year (238).
Since this might pose a significant risk of infertility, it seems prudent to advise
young men to bank their sperm before repeated high dose 131 I therapy.

Thyroid Hormone Therapy


Levothyroxine (T4) Suppression of TSH
DTCs contain TSH receptors that stimulate the cell growth and iodine uptake of
well-differentiated follicular cancer cells (111). Thyroid hormone therapy signifi-
cantly reduces recurrence rates and cancer-specific mortality rates (Fig. 8) (121).
A meta-analysis of thyroid hormone suppression therapy in thyroid cancer patients
showed an association with reduced risk of major adverse clinical events, defined
as disease progression and/or recurrence and death (239). The National Thyroid
Cancer Treatment Cooperative Study (NCTCS) that has prospectively performed
follow-up of 2936 patients with DTC found that thyroid hormone therapy signifi-
cantly reduced recurrence rates and cancer-specific mortality rates in patients with
stage II to IV disease (Fig. 8) (240). However, the study was unable to show any
impact, positive or negative, of any form of surgical or medical therapy in stage I
patients, which may be due to the relatively short duration of follow-up (median
three years, range 0–14) in this group of patients.
The levothyroxine dosage needed to attain serum TSH levels in the euthy-
roid range is greater among patients with thyroid cancer (2.11 ␮g/kg/day) than
among those with primary hypothyroidism caused by nonmalignant disease
(1.62 ␮g/kg/day) (241). One study found that patients who had undergone total
thyroid ablation for thyroid carcinoma required 2.7 ± 0.4 (SD) ␮g/kg/d of levothy-
roxine to achieve an undetectable basal serum TSH level that does not increase
after TRH administration (242). A French study found that a constantly sup-
pressed TSH (⬍0.05 ␮U/mL) was associated with a longer relapse-free survival
than when serum TSH levels were always 1 ␮U/mL or greater, and that the degree
of TSH suppression was an independent predictor of recurrence (243). A more
recent study showed a beneficial effect of thyroid hormone therapy, but only in
those patients whose serum TSH level was consistently ⬎2 mU/L (244). Hence,
these data do not support the concept that a great degree of TSH suppression
(into the undetectable, thyrotoxic range) is required in patients with stage I or II
disease but may be beneficial in patients with more advanced disease stage. The
most appropriate dose of thyroid hormone for patients with DTC who are free
of disease is that which reduces the serum concentration to just below the lower
limit of the normal range for the assay being used (93). The ATA management
guidelines for patients with thyroid cancer recommend that the TSH in patients
with persistent disease should be maintained ⬍0.1 mU/L indefinitely as long as
there are no contraindications. For patients at high risk of recurrence, the TSH
should be maintained at 0.1 to 0.5 mIU/L for 5 to 10 years. Patients with low-risk
tumors who are free of disease are advised to maintain the TSH within the low
normal range (0.3–2 mU/L).
Differentiated Thyroid Carcinoma 273

Complications of Levothyroxine Therapy


Potential problems associated with subclinical thyrotoxicosis are an increased
risk of atrial fibrillation (245) in older patients (older than 60 or 65 years), a
higher 24-hour heart rate, more atrial premature contractions per day, ventricular
hypertrophy, diastolic dysfunction, and impaired cardiac reserve (246). Patients
with thyroid carcinoma treated with suppressive doses of levothyroxine have a high
rate of bone turnover that decreases acutely after withdrawing treatment (247),
which is of most concern in postmenopausal women not receiving estrogen-like
or bisphosphonate therapy (248). Studies of fracture risk in women treated with
thyroid hormone suggest that there may be an increased risk when suppressive
doses are used (249). However, TSH suppression has no significant effects on
bone mass in men, according to one study (250).

Other Therapy
External Beam Radiation Therapy
This therapy is generally considered third-line therapy for localized DTC after
surgical resection and 131 I therapy. Typical candidate sites of disease for external
beam radiation therapy include the neck, upper mediastinum, or bone lesions
that are symptomatic or in critical locations to prevent fracture. External beam
radiation therapy is frequently reserved for inoperable, non-iodine-avid disease;
however, in some iodine-avid situations, it is considered for adjuvant therapy
following 131 I therapy such as in patients with T4 N1 disease and over the age
of 45 years, aerodigestive invasion, nonresectable local bulk disease, or selected
osseous metastases (132).
Gamma KnifeTM
Brain metastases from thyroid carcinoma are an extremely poor prognostic sign.
Surgical resection of brain metastases may be associated with a limited prolonga-
tion of survival and rarely with apparent cure (251). While controlled studies are
lacking, inoperable CNS metastases should probably be treated with gamma knife
rather than external beam radiation therapy if possible (251).
Chemotherapy
Patients with papillary thyroid cancer who no longer respond to the usual modes
of therapy—surgery, radioiodine, and external beam radiotherapy—and still show
signs of progressive disease may be candidates for investigational drugs. Histori-
cally, traditional chemotherapy (doxorubicin) has proven to be of limited benefit in
thyroid cancer and at best provides palliation. However, recent discoveries of the
molecular pathogenesis of papillary thyroid cancer have led to the use of promis-
ing molecular-targeted therapies. Numerous clinical trials are currently underway
to investigate the effects of various targeted therapies. These new agents can
be divided into several categories: oncogene inhibitors, angiogenesis inhibitors,
274 Sipos and Mazzaferri

redifferentiation agents, and gene therapy (252). Two recently published stud-
ies suggest some modest benefit from multi-kinase inhibitors such as sorafenib
(253) and motesanib (254). The RET/PTC oncogene is targeted by the tyrosine
kinase (TK) inhibitors; various steps in the molecular pathway may be inhibited
by this family of agents. Potential targets include monoclonal antibodies directed
against the tyrosine kinase ligand or its receptor, inhibition of ATP binding to
the TK receptor, inhibition of receptor phosphorylation or activation, or blocking
downstream signals (252). Several compounds are also being studied to determine
their ability to induce redifferentiation of tumors, particularly the ability to restore
function of the sodium-iodine symporter and thereby increase uptake of radioac-
tive iodine by the tumor cells. It may be necessary to use combination therapy
with these agents to achieve maximal tumor response in light of the complex and
overlapping relationships between the various mitogen activated protein kinase
pathways (252).
The patient should have evidence of disease progression before initiating
such therapies as many of these agents offer disease stabilization and a treatment
effect cannot be demonstrated unless the tumor is actively growing. In this fast
moving area, the best way to get current information on clinical trials for thyroid
cancer is to use the National Institutes of Health website or that of the ATA
(http://www.thyroid.org) or the National Cancer Institute (http://www.cancer.gov/
clinicaltrials).

Follow-up
It is convenient to stratify follow-up into three stages (Fig. 9): Phase 1 is four to
six weeks after surgery when the completeness of tumor resection is evaluated,
Phase 2 occurs approximately 6 to 12 months after remnant ablation to assess
the status of the initial surgical and medical therapy together, and Phase 3 is the

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


Differentiated Thyroid Carcinoma 275

long-term follow-up that occurs after patients are deemed free of disease. At each
stage of follow-up different studies may be necessary, depending upon the patient’s
response to therapy.

Changing Follow-up Paradigms


The follow-up of patients with PTC has changed considerably over the past decade.
In the past, follow-up depended heavily upon the use of diagnostic whole-body
131
I scanning (DxWBS) and the assessment of serum Tg levels performed during
levothyroxine suppression of TSH (Tg-on). This approach, which was less accurate
than current follow-up strategies, resulted in long delays in identifying patients
with persistent metastases (37), which has the potential to reduce survival rates
(37,255). Risk stratification is now established immediately after completion of the
initial therapy, when follow-up strategy is adapted to fit the patient’s clinical status.

Identifying Patients Who Are Free of Disease


Identifying patients who are free of disease following initial therapy is a key
follow-up issue because this identifies 80% of those who have undergone adequate
therapy, which usually consists of total thyroidectomy and 131 I remnant ablation.
The ATA (93) and ETA (155) guidelines define disease-free status as follows: (1)
no clinical evidence of residual tumor; (2) No imaging evidence of tumor, which
generally means that the posttreatment whole-body 131 I scan (RxWBS) shows 131 I
uptake only in the thyroid bed and that neck ultrasonography is negative; and (3)
an undetectable Tg (⬍1 ng/mL) during both TSH suppression and stimulation, in
the absence of interfering serum antibodies.

Risk Stratification Based upon the Patient’s Clinical Status After


Initial Therapy
The AJCC TNM patient risk stratification and most tumor staging classifications
depend heavily upon patient age and tumor stage at the time of diagnosis. While this
provides a uniform means of comparing patient outcome in studies, it fails to take
into account other important tumor features that predict outcome. For example, the
TNM system does not account for tumor variables (e.g., tall cell papillary thyroid
cancer), tumor molecular features such as BRAF mutation, or patient variables
such as familial non-medullary thyroid cancer, all of which have an impact on
outcome. The ATA (93) and ETA (155) thyroid cancer guidelines stratify risk
on the basis of patient age and tumor stage at the time of diagnosis, and patient
response to initial therapy, which is usually defined by TSH-stimulated serum Tg
levels and neck ultrasonography. This is considerably more accurate than DxWBS
and Tg-on that was used in the past to define patient status after initial therapy.
Patients with low-risk tumors undergo a follow-up strategy that is substantially
different from that for high-risk patients (Fig. 10). This is done by stratifying risk
after initial surgery with or without postoperative radioiodine ablation into three
groups as follows:
276 Sipos and Mazzaferri

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

Low-risk patients are those whose tumors have no local or distant metastases;
all macroscopic tumors have been resected; no invasion of locoregional
tissues or structures by the tumor; no aggressive histology of the tumor
(e.g., tall cell, insular, or columnar cell tumors); no vascular invasion; and
if radioiodine ablation has been given, there is no evidence of 131 I uptake
outside the thyroid bed on posttreatment whole-body scanning (93).
Intermediate-risk patients have tumors which show microscopic invasion into
perithyroidal soft tissues, have tumors with aggressive histology, or tumors
which have vascular invasion (93).
High-risk patients have macroscopic tumor invasion, incomplete tumor resection,
distant metastases, or 131 I uptake outside the thyroid bed on posttreatment
whole-body scanning (93).

rhTSH in Follow-up
During follow-up, serum TSH concentration must be periodically increased to
levels sufficiently elevated to stimulate thyroid tissue sodium-iodide symporters
so that serum Tg measurement and radioiodine scanning can be performed. For
follow-up rhTSH is given as an intramuscular dose of 0.9 mg for two consecutive
days followed by 4 mCi of 131 I orally on the third day and a whole-body scan and Tg
Differentiated Thyroid Carcinoma 277

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

after initial therapy has become a widely accepted means of anticipating the result
of therapy.

Tg and Whole-Body 131 I Scans


Serum Tg determinations and whole-body 131 I imaging can almost always detect
residual thyroid tissue, whether benign or malignant, in patients who have under-
gone thyroidectomy. The serum Tg concentration correlates with the mass of
normal or malignant thyroid tissue, the amount of thyroid physical damage or
inflammation, and the level of TSH receptor stimulation. Tg measurement is more
sensitive when thyroid hormone has been stopped or rhTSH is given to elevate
the serum TSH and, under these conditions, has a lower false-negative rate than
whole-body 131 I scanning (256). The highest NPV (99.5%) and sensitivity (96%)
was achieved with rhTSH-stimulated serum Tg and neck ultrasonography com-
pared with a 93% sensitivity and 99% NPV for DxWBS and rhTSH-stimulated
Tg measurements (261).

Serum Anti-Tg Antibodies


Serum antithyroglobulin antibodies must be measured in the serum sample
obtained for Tg assay because they are present in up to 25% patients with thyroid
carcinoma and almost always invalidate serum Tg measurement (181,262). These
antibodies must be quantitated because they can serve as a surrogate marker for
Tg, rising when there is an exacerbation of tumor and falling when the tumor
burden declines (263).

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

Whole-Body Positron Emission Tomography


Scanning with F-18-fluorodeoxyglucose (FDG) provides two important pieces of
information. First, it may identify DTC metastasis that cannot be identified by
scintigraphy with 131 I or 99m Tc. Second, Fluorine-18-FDG uptake is an indicator
of poor functional differentiation and poor prognosis in thyroid cancer (264). A
retrospective study of 400 patients with thyroid cancer studied at one institution
(265) found an inverse relationship between patient survival and the glycolytic
rate of the most active lesion. Likewise, the number of FDG-avid lesions was
inversely correlated with survival (265). The likelihood of observing an FDG-
avid lesion increases with the serum Tg level, especially when the serum Tg
is ⬎10 ng/mL (266). False-positive 18 F-FDG uptake may occur with benign
lung disease, inflammatory conditions, and other malignancies (267). Positron
Differentiated Thyroid Carcinoma 279

Emission Tomography (PET) scanning may be of most value in the setting of high
serum Tg levels and negative neck ultrasonography and other imaging studies.

Treatment of Patients with High Serum Tg Levels and Negative


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

Tg Cutoffs for Treatment with 131 I


A serum Tg above the lower detection limit (usually 0.2–1.0 ng/mL in newer
assays) during levothyroxine therapy in a patient who has undergone total or near-
total thyroidectomy and 131 I ablation is a sign of persistent normal tissue (thyroid
remnant) or DTC. This is an indication for repeat 131 I scanning in high-risk patients
or neck ultrasonography alone in low-risk patients when there is no other evidence
of disease (Fig. 9). If serum Tg rises ⬎10 ng/mL after levothyroxine is discontinued
or rises ⬎5 ng/mL after rhTSH is administered, normal or malignant thyroid tissue
is usually present, even if a 2 to 4 mCi (74–148 MBq) 131 I diagnostic scan is
negative (⬍1% 131 I uptake) (159,192). A serum Tg that is rising over time and
increases to ⬎10 ng/mL after rhTSH stimulation or THW may be an indication
of persistent tumor. If tumor is not identified by ultrasound and other imaging
modalities, it is reasonable to give one therapeutic dose of 131 I, usually 100 mCi,
and to perform a posttreatment scan. Depending upon the age of the patient, as
many as 20% of children and young adults with greatly elevated serum Tg levels
and negative diagnostic 131 I scans have lung metastases. When the RxWBS is
negative, an 18 FDG-PET/CT scan may detect occult tumor that is amenable to
surgical excision. Even if it does not identify tumor, this is a good prognostic sign
(265) that can reassure the patient.

Rationale for 131 I Therapy


Although some skepticism has been voiced about empirically treating patients with
100 mCi of 131 I without imaging evidence of disease, there is increasing evidence
that this approach is beneficial to some patients. A multivariate analysis has shown
the independent prognostic significance of the size of pulmonary metastases at the
time of therapy (268). Another multivariate analysis of prognostic factors in 134
patients with pulmonary metastases showed that an early diagnosis (a normal chest
roentgenogram with pulmonary metastases found only on 131 I scintigraphy) and
treatment of the metastases with 131 I were the most important elements giving
rise to a significant improvement in survival rate and a prolonged disease-free
time interval (269). Two studies (270,271) found clearly beneficial effects of 131 I
therapy for such patients: 80% achieved a negative whole-body 131 I posttherapy
scan, 60% had a serum Tg ⬍5 ng/mL off thyroid hormone and six of eight patients
280 Sipos and Mazzaferri

had normalization of the CT scan, and two patients had negative lung biopsies.
Improvement sometimes occurs with one or two 131 I treatments, but complete
resolution of pulmonary metastases after 131 I therapy is often difficult to achieve
(137). When a partial reduction of metastatic disease is achieved, patients usually
have a good quality of life with no further disease progression and a low mortality
rate (137). It seems intuitively wrong to withhold therapy in this group of patients
who are usually young and have a small tumor burden. Withholding therapy seems
especially harsh given the fact that 131 I treatment directly targets the metastatic
deposits and is effective in reducing tumor burden. Early diagnosis and treatment of
cancer is a desirable and effective therapeutic goal, especially when the treatment
has relatively few serious side effects. On the other hand treating patients on the
basis of a rising Tg when distant metastases are not found on a previous RxWBS
on the basis of an elevated serum Tg level is not advisable. Some patients are
found in retrospect to have regional lymph node metastases or a thyroid remnant
not seen on the diagnostic 131 I scan to account for the high serum Tg level. In
other cases, the Tg begins to gradually fall spontaneously without treatment or
following an apparently unsuccessful treatment. Giving repeated 131 I treatments
without clear evidence of efficacy is strongly discouraged.

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