Medical Management of Thyroid

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Medical Management
of Thyroid Disease
Third Edition

Edited by
David S. Cooper and Jennifer A. Sipos
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742

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Library of Congress Cataloging‑ in‑ Publication Data

Names: Cooper, David S. (Physician), editor. | Sipos, Jennifer, editor.

Title: Medical management of thyroid disease / [edited by] David S.Cooper and
Jennifer Sipos.
Description: Third edition. | Boca Raton : Taylor & Francis, 2019. | Includes
bibliographical references and index.
Identifiers: LCCN 2018030183| ISBN 9781138577237 (hardback : alk. paper) |
ISBN 9781351267489 (ebook)
Subjects: | MESH: Thyroid Diseases--therapy | Thyroid Diseases--diagnosis
Classification: LCC RC655 | NLM WK 267 | DDC 616.4/4--dc23
LC record available at https://lccn.loc.gov/2018030183

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Contents

Preface vii
Editors ix
Contributors xi

1 The laboratory and imaging approaches to thyroid disorders 1

Jacqueline Jonklaas and David S. Cooper
2 The diagnostic evaluation and management of hyperthyroidism due to Graves’ disease,
toxic nodules, and toxic multinodular goiter 37
David S. Cooper
3 Thyroiditis 81
Robert C. Smallridge and Victor Bernet
4 Rare forms of hyperthyroidism 97
Nicole O. Vietor and Henry B. Burch
5 Drug-induced thyroid dysfunction 107
Victor Bernet and Robert C. Smallridge
6 Hypothyroidism 129
Michael T. McDermott
7 Thyroid nodules and multinodular goiter 159
Poorani N. Goundan and Stephanie L. Lee
8 Differentiated thyroid carcinoma 181
Carolyn Maxwell and Jennifer A. Sipos
9 Medullary thyroid carcinoma in medical management of thyroid disease 225
Mimi I. Hu, Elizabeth G. Grubbs, and Julie Ann Sosa
10 Anaplastic thyroid carcinoma and thyroid lymphoma 243
Ashish V. Chintakuntlawar and Keith C. Bible
11 Surgical approach to thyroid disorders 261
Vaninder K. Dhillon and Ralph P. Tufano
12 Thyroid disease and pregnancy 275
Alisha N. Wade and Susan J. Mandel

Index 297

v
Preface
It has been more than 10 years since the second
edition of Medical Management of Thyroid Disease
was published. When I was asked by the publisher
to edit this third edition of the text, I invited Dr.
Jennifer Sipos from The Ohio State University to
be my coeditor. Together, we have continued the
tradition of this book, which was initially devel-
oped to be a practical guide on the management
of both common and uncommon thyroid prob-
lems. We have tried, as much as possible, to limit
the discussion to the clinical manifestations, diag-
nostic procedures, and treatment of the gamut of
thyroid disorders in adults. As before, to the great-
est degree possible, all of the recommendations
in the text are “ evidence-based” or recapitulate
evidence-based clinical practice guidelines. We
­ Dr. Sipos and I want to thank the contributors to
have invited a number of new authors to provide a
fresh approach to some of the topics.
Since the last edition of this text was published
in 2008, there have been remarkable strides in our
ability to care for thyroid patients. In the realm
of benign thyroid disease, we now recognize that
drug-induced thyroid dysfunction includes a large
array of new drugs that inhibit tyrosine kinases,
have effects on the immune system as “ checkpoint
inhibitors,” or have other more ill-defined effects.
An entire chapter is devoted to this topic, in rec-
ognition of its importance. In the treatment of
hypothyroidism, clinicians are now feeling more
justified in using T4/T3 combination therapy in
some patients, reflecting a better understand-
ing that T4 monotherapy may not recapitulate
the serum hormonal profile of the thyroid gland
itself. There has been a revolution in the manage-
ment of thyroid nodules, including a new classifi-
cation for cytopathology (the Bethesda system), as
well as the development of molecular testing for
improved diagnosis of indeterminate thyroid nod-
ules. There has also been a sea change in the way
low-risk thyroid cancer is managed, based on the
2015 American Thyroid Association clinical prac-
tice guidelines. Instead of a “ one-size-fits-all”
approach, we now have a more personalized set of
management strategies, based on the recognition
that more aggressive treatment (i.e., total thyroid-
ectomy, radioiodine ablation, and full suppression
of serum TSH) is not necessary for the vast major-
ity of thyroid cancer patients. Furthermore, there
are now a number of randomized clinical trials
which have helped to define the best management
for advanced thyroid cancers.
this text for their time and expertise. We also want
to express our gratitude to two of our mentors, Dr.
E. Chester Ridgway and Dr. Ernest Mazzaferri.
Both were giants in the field of thyroidology, both
contributed to the first and second editions of this
text, and both have sadly passed away in the last
several years. We wish to recognize them for their
guidance, and for being inspiring role models and
colleagues. Finally, we hope that practitioners
will benefit from reading this textbook, but we
understand that the ultimate beneficiaries of the
knowledge gained will be the millions of patients
suffering from thyroid disease around the world.
David S. Cooper, MD
The Johns Hopkins University School of Medicine
Jennifer A. Sipos, MD
The Ohio State University Wexner Medical Center
vii
Editors

David S. Cooper, MD, MACP, received his medical degree from Tufts University School of Medicine
and completed his endocrinology fellowship training at the Massachusetts General Hospital/Harvard
Medical School. He is Professor of Medicine and Radiology at The Johns Hopkins University School
of Medicine and Director of The Johns Hopkins Thyroid Clinic. He serves as editor-in-chief for
­endocrinology at Up-to-Date . He is a former contributing editor at JAMA and former deputy editor of
the Journal of Clinical Endocrinology and Metabolism . He is the past chair of the Subspecialty Board
for Endocrinology, Diabetes, and Metabolism of the American Board of Internal Medicine. Dr. Cooper
is the past president of the American Thyroid Association and the recipient of the American Thyroid
Association’ s Distinguished Service Award and its Paul Starr Award. He is also the recipient of the
Distinction in Clinical Endocrinology Award from the American College of Endocrinology and the
Endocrine Society’ s 2016 Outstanding Scholarly Physician Award.

Jennifer A. Sipos, MD, is a Professor of Medicine and Director of the Benign Thyroid Disorders Program
at The Ohio State University. She obtained her medical degree and received her internal medicine res-
idency training at Wake Forest University. She completed her endocrinology and metabolism fellow-
ship at the University of North Carolina in Chapel Hill. Dr. Sipos has developed an interest in the use
of ultrasonography for the diagnosis and management of thyroid cancer and has taught and served as
a course director for numerous ultrasound courses nationally and internationally, including meetings
for the Endocrine Society, American Thyroid Association, European Thyroid Association, American
Association for Clinical Endocrinologists, Asia and Oceania Thyroid Association, Indian Endocrine
Society, and International Congress for Endocrinology. Additionally, she is actively involved in several
clinical research projects with a particular interest in factors implicated in the development of salivary
damage after radioiodine therapy. She also participates in clinical trials for the evaluation of multikinase
inhibitor therapies in refractory thyroid cancer and the diagnostic use of molecular markers in thyroid
nodules.

ix
Contributors

Victor Bernet Stephanie L. Lee

Mayo Clinic Boston Medical Center
Jacksonville, Florida Boston, Massachusetts
Keith C. Bible Susan J. Mandel
Mayo Clinic University of Pennsylvania
Rochester, Minnesota Philadelphia, Pennsylvania
Henry B. Burch   Carolyn Maxwell
National Institutes of Health Stony Brook University Hospital
Bethesda, Maryland Stony Brook, New York
Ashish V. Chintakuntlawar Michael T. McDermott
Mayo Clinic University of Colorado Denver School of
Rochester, Minnesota Medicine
David S. Cooper Denver, Colorado
The Johns Hopkins University School of Medicine Jennifer A. Sipos
Baltimore, Maryland The Ohio State University
Vaninder K. Dhillon Columbus, Ohio
The Johns Hopkins University Robert C. Smallridge
Baltimore, Maryland Mayo Clinic
Poorani N. Goundan Jacksonville, Florida
Boston Medical Center Julie Ann Sosa
Boston, Massachusetts University of California at San Francisco
Elizabeth G. Grubbs San Francisco, California
The University of Texas MD Anderson Cancer Ralph P. Tufano
Center The Johns Hopkins University
Houston, Texas Baltimore, Maryland
Mimi I. Hu Nicole O. Vietor  
The University of Texas MD Anderson Cancer Walter Reed National Military Medical Center
Center Bethesda, Maryland
Houston, Texas Alisha N. Wade
Jacqueline Jonklaas University of the Witwatersrand
Georgetown University School of Medicine Johannesburg, South Africa
Washington, DC

xi
 1
The laboratory and imaging
approaches to thyroid disorders

JACQUELINE JONKLAAS AND DAVID S. COOPER

Introduction 1 Screening and case findings 16

Physiology of the hypothalamic-pituitary- Imaging approach to thyroid disease 17
thyroid axis 2 Ultrasonography and nuclear medicine studies 17
Laboratory evaluation of thyroid function 3 Ultrasonography 17
Assays of thyroid hormones 3 Technique 17
Total serum iodothyronine concentrations 3 Indications 17
Determination of free T4 and T3 Normal thyroid appearance 17
concentrations 4 Diffuse thyroid disease 17
Causes of increased T4 and/or T3 Thyroid nodules 21
concentrations 6 Risk stratification systems for thyroid nodules 21
Causes of decreased T4 and/or T3 Lymph nodes 23
concentrations 9 Nuclear medicine studies 23
Assays of thyroid-stimulating hormones 10 Technique 23
Causes of hypothyrotropinemia 12 Indications 24
Causes of hyperthyrotropinemia 12 Normal thyroid appearance 25
Specialized studies of thyroid function 13 Diffuse thyroid disease 26
Thyroglobulin 13 Thyroid nodules 27
Thyroid autoantibodies 14 Ectopic thyroid tissue 27
Tissue responses to thyroid hormone action 15 Thyroid cancer 27
Laboratory evaluation for thyroid disease 15 References 28

INTRODUCTION levels in serum, and sensitive immunoassays have

The central role of the thyroid gland in control-
ling metabolism was recognized in the 19th cen-
tury, but evaluation of the function of the thyroid
remains an evolving science. Initial approaches
to the assessment of thyroid function centered
on measuring end-organ responses as biological
markers of thyroid hormone actions. Development
of in vitro competitive binding assay methods
allowed the direct quantification of hormone
demonstrated the subtleties of pituitary and hypo-
thalamic control of the thyroid. Abnormalities
of hormone binding by serum proteins necessi-
tated sensitive estimation of free hormone levels.
With the detection of serum markers of autoim-
mune and malignant diseases of the thyroid gland,
earlier diagnosis and improved monitoring of
these conditions have been achieved, often with
greater sensitivity than may be clinically relevant.
Limitations to the measurement methods utilized

1
2 Medical management of thyroid disease
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 dis-
eases, and appropriately monitor the treatment of
patients with disorders of the thyroid.
PHYSIOLOGY OF THE
HYPOTHALAMIC-PITUITARY-
THYROID AXIS
Excellent reviews and books provide detailed
explorations of the physiology of the hypotha-
lamic-pituitary-thyroid axis, and the reader is
invited to delve into those worthwhile sources (1).
For the purposes of this chapter, a brief review
of the biosynthesis and transport of thyroid hor-
mones and the regulation of thyroid function by
the hypothalamic-pituitary complex will suffice
(Figure 1.1).
The synthesis of thyroxine (T4 ) and triiodo-
thyronine (T3 ) begins with the active transport of
iodide into the cell via a sodium-iodine symporter
Figure 1.1 The hypothalamic pituitary thyroid axis. (From Refetoff S, Dumitrescu A. Best Pract Res Clin
Endocrinol Metab. 2007;21:277– 305. Used with permission.)
located in the basal membrane. Following oxida-
tion by thyroid peroxidase, the iodide moiety is
covalently attached to tyrosyl residues of thyro-
globulin, and the resulting iodotyrosines are cou-
pled 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 the release of
T4 and T3 into the circulation. This process results
in the total daily output of 80 to 100 µ g of T4 . In
contrast, only 20% of the circulating T3 is pro-
duced by the thyroid, the remaining 80% is derived
from the enzymatic outer-ring or 5¢ -monodeio-
dination 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), transthyre-
tin (thyroxine-binding prealbumin [TBPA]), and

albumin. Although TBG is present in lower con-
centrations 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 nor-
mal and abnormal thyroid hormone‑binding pro-
teins are responsible for much of the methodologic
limitations in assays that attempt to measure con-
centrations of free T4 and T3 . This large pool of
protein-bound hormone provides a stable reser-
voir that maintains the supply of free, unbound
hormone available for transport into the cells.
Once within target cells, T4 is further deiodinated
to T3 , which in the nucleus binds to the thyroid
hormone receptor, modulating the transcription of
thyroid hormone-responsive genes and producing
most of the clinical effects recognized as the meta-
bolic effects of thyroid hormones.
The primary regulatory influence on thyroid
gland function is the circulating level of thyro-
tropin (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 β -sub-
unit; the α -subunit is structurally similar to
that of follicle-stimulating hormone, luteinizing
hormone, and human chorionic gonadotropin.
Negative feedback by T4 and T3 influences TSH
synthesis and release, as evidenced by a complex
inverse relationship between the concentrations
of TSH and free iodothyronine (2, 3). It is likely
that each individual has a genetically determined
set-point for this TSH/free T4 relationship, based
on twin studies (4, 5). TSH levels peak just before
nocturnal sleep, and the nadir occurs in the late
afternoon; this nocturnal surge is lost early in
the course of nonthyroidal illness. TSH levels
in various populations conform best to a log-
Gaussian rather than Gaussian distribution (6).
The hypothalamic tripeptide thyrotropin-releas-
ing 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 opi-
oids, TRH may be responsible for modulating the
setpoint for the negative feedback loop that con-
trols thyroid hormone levels. Hypothalamic pro-
duction of TRH itself is regulated by circulating
thyroid hormones, as well as by multiple central
nervous system factors.
L aboratory evaluation of thyroid function 3
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 (7). Thus, measurement of
total iodothyronine concentration can pro-
vide a reasonable surrogate for estimating the
amount of free iodothyronine present. Either
serum or plasma can be used to assay hormone
concentrations, although serum is generally
preferred. The most commonly employed tech-
nique for the determination of total T4 (TT4 )
and T3 (TT3 ) concentrations is competitive
immunoassay, using either polyclonal or mono-
clonal “ capture” antibodies directed against
the specific iodothyronine. To ensure measure-
ment of bound as well as free hormones, inhibi-
tors of iodothyronine binding are added— e.g.,
8-­a nilino-1-naphthalene sulfonic or salicylic
acids for TBG and barbital for TBPA. These
agents successfully dissociate the hormone from
binding proteins without interfering with hor-
mone binding to immunoglobulin.
Radioimmunoassay (RIA) depends upon mea-
surement 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 cap-
ture antibody and the radiolabeled iodothyronine
to be measured, the antibody-antigen complexes
are separated from the serum. Separation tech-
niques vary, including ammonium sulfate or sec-
ond 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 par-
ticles. The concentration of either TT4 or TT3 is
then determined by comparison of the amount of
antibody-bound radiolabel with a simultaneously
derived standard curve. A fundamental assump-
tion, therefore, is that there is no difference in the
4 Medical management of thyroid disease
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.
Nonisotopic methods avoid reliance upon
radioactive reagents and are now the most com-
monly used assays. The heterogeneous enzyme-
linked immunosorbent assay (ELISA) incorporates
enzymes, fluorescent, or chemiluminescent mole-
cules that create a quantitative signal when inter-
acting with a specific enzyme bound to the tracer
hormone— e.g., alkaline phosphatase, horseradish
peroxidase, or glucose-6-phosphate dehydroge-
nase. As in RIA, numerous physical and chemical
approaches exist for separating signal bound to
the anti-iodothyronine antibody from unbound
signal. In contrast, homogeneous enzyme immu-
noassays do not require a separation step. Instead,
the binding of the antibody to a tracer hormone
directly affects the activity of the signal-generating
enzyme bound to the tracer. Other technologies,
such as liquid chromatograph-tandem mass spec-
troscopy (LC-MS/MS) have also been applied to
provide greater specificity and less analytical inter-
ference (8).
Due to common alterations in serum TBG lev-
els, TT4 and TT3 are generally not used as stand-
alone tests in clinical practice, but are combined
with direct measurements of TBG or TBG-binding
capacity, which can then be used to calculate a Free
Thyroxine Index (see below).
Reference ranges vary to some degree, but
commonly cited ranges are 4.5– 12.6 mcg/dL
(58– 160 nmol/L) for TT4 and 80– 180 ng/dL
(1.2– 2.7 nmol/L) for TT3 (9). As developed by
their manufacturers, these assay techniques have
similar performance characteristics, although
each may be affected by different sources of inter-
ference. TT4 assays tend to be more reliable than
TT3 assays. For example, in a recent study, in
which 11 TT4 and 12 TT3 assays were compared,
with LC-MS/MS values as the reference serum
concentrations, only 4/10 TT4 assays and 4/11 TT3
assays failed to agree to within 10% of the refer-
ence concentrations, with greater deviation seen
with the TT3 assay (10). Contributing factors to
measurement error include qualitative differ-
ences between the protein constituents of sample
diluents used for calibration and those found in
patient sera, leading to differential dissociation of
hormone from binding proteins.
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 sig-
nificantly 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: distinguish-
ing between the 3– 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 sepa-
rating 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 all potential clinical situations. As a
result, in a study comparing the results of 15 FT4
and 13 FT3 immunoassays to values obtained by
the reference method equilibrium dialysis-LC-MS/
MS, all the FT4 immunoassays and 9 of the FT3
immunoassays produced results that were outside
the 10% agreement with the reference method (11).
Direct methods for measuring FT4 and FT3
include equilibrium dialysis, ultrafiltration, and
gel filtration to separate the free hormone from its
binding proteins. In the case of equilibrium dialy-
sis, 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, capa-
ble of detecting nanogram (or picomole) quantities
of hormones, is then used to measure the hormone
content of the protein-free dialysate, comparing to
a standard curve generated with gravimetrically
determined amounts of hormone (12). Faster turn-
around can be achieved by using ultrafiltration
rather than equilibrium dialysis, but greater vari-
ability can result from minimal amounts of serum
proteins that leak through the filtration device as
well as a hormone that is adsorbed to either the
membrane or container surface. Such direct mea-
surements are generally expensive, time consum-
ing, and not widely used commercially. Expected
adult values for these direct methods are about 0.8
to 2.3 ng/dL for free T4 and 210 to 440 pg/dL for
free T3 . As mentioned above, the LC-MS/MS assay

used above as the reference method for assessing
FT4 and FT3 assays employed separation by equi-
librium dialysis (11). Separation by ultrafiltration
has also been combined with LC-MS/MS (13). The
LC-MS/MS technique to measure free T4 levels
provides high specificity; hence its use as a refer-
ence assay (11). LC-MS/MS can also offer simulta-
neous measurement of other thyroid analytes (13).
Immunoassay methods for estimation of free
hormone concentration are now widely used. 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 mix-
ture 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 propor-
tional 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 dis-
placement is rarely achieved. Therefore, these
methods depend on the assumption that there is
no difference in hormone-binding affinity for pro-
teins 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
occurs in renal failure or other nonthyroidal ill-
nesses, or major alterations in hormone-binding
protein concentrations (14). Because the analogues
used generally bind to albumin, although not with
the same kinetics as T4 or T3 , this method may not
correct for abnormalities in albumin binding.
In “ two-step” assays, serum is exposed to a solid
phase containing an 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
(12). After removal of the serum and its proteins,
a tracer quantity of radiolabeled T4 is incu-
bated with the solid phase, equilibrating with the
remaining unoccupied antibody molecules. The
amount of radiolabeled T4 complexed to the solid
phase is thus inversely proportional to the free
T4 concentration of the serum. Because the label
is unable to interact with serum-binding proteins
or endogenous inhibitors of hormone binding to
protein (due to the physical separation step), the
L aboratory evaluation of thyroid function 5
“ two-step” method has a good correlation with the
free T4 determined by direct equilibrium dialysis.
Nonradioactive assays have also been developed,
and automated two-step procedures are in com-
mon use.
For free T3 measurements, methods that rely
upon physical separation of bound from free hor-
mones, such as dialysis or ultrafiltration, are not
generally commercially available. The same tech-
nology for “ one-step” assays of free T4 is used to
measure free T3 . Interference from serum proteins
and difficulty avoiding stripping T3 from its bind-
ing proteins is a greater problem than in free T4
assays (15). New methods that utilize tandem mass
spectrometry following equilibrium dialysis or
ultrafiltration may allow faster and more reliable
assays (16).
The thyroid hormone‑binding ratio (THBR),
another calculated value proportional to the
fraction of hormone that is free in circulation,
derives from measurement of the availability of
protein-binding sites in the patient’ s serum. In
the traditional uptake method, a tracer quantity of
radiolabeled iodothyronine is added to the serum
and allowed to partition between unoccupied
specific protein-binding sites and a nonsaturable
adsorbent— e.g., talc, charcoal, resin, or anti-iodo-
thyronine antibodies. T3 is generally preferred as
the labeled ligand, as it has a lower affinity for TBG
and therefore does not displace T4 from 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 reli-
able formula expresses the ratio as the amount of
tracer attached to adsorbent to the amount initially
added. The THBR is then calculated as the percent
uptake in the patient’ s serum and normalized to
that of a control or reference serum; the expected
normal range is centered around unity. The THBR
is increased when there are few endogenous bind-
ing sites, which can occur with an increased
amount of T4 available to bind (thyrotoxicosis),
the presence of competing ligands (certain drugs
and nonthyroidal illness), or a decreased amount
of binding protein (TBG deficiency). Conversely,
hypothyroidism and TBG excess will produce an
increased number of available binding sites, pro-
ducing a decreased THBR. As a general rule, true
6 Medical management of thyroid disease

thyroid function abnormalities produce concor- Table 1.1 Causes of increased T4 and/or T3
dant increases or decreases in the total serum T4 concentrations
and THBR, whereas discordant changes in the two
Thyrotoxicosis
tests typically result from protein-binding abnor-
Euthyroid hyperthyroxinemia
malities. Alternate methods use nonisotopic labels,
such as enzyme-linked tracers and light emitters. Increased binding to plasma proteins
These all rely on the similar principle of estimating Thyroxine-binding globulin excess
the partitioning of the labeled hormone between Congenital
serum-binding proteins and a solid phase. A free Hyperestrogenemia: Exogenous, endogenous
hormone index is estimated by multiplying the Acute and chronic active hepatitis
total serum hormone concentration by the THBR. Acute intermittent porphyria
In most conditions of endogenous thyroid func- HIV-1 infection
tion abnormalities or protein-binding alterations, Familial dysalbuminemic hyperthyroxinemia
the index corrects for effects of protein binding on Transthyretin excess
total T4 levels, and correlates well with free T4 lev- Congenital
els measured by reference methods. Paraneoplastic
Potential pitfalls in the interpretation of THBR
Antithyroxine immunoglobulins
tests occur when there is a ligand that can interfere
with binding to both the solid phase and serum Impaired T 4   to T 3   conversion
proteins, for example, nonthyroidal illness. Falsely Iodinated contrast agents
elevated free thyroxine index values can also be Amiodarone
present when the protein‑binding abnormality Glucocorticoids
is specific for T4 and masked by the use of T3 in Propranolol
the THBR— for example, familial dysalbumin- Congenital
emic hyperthyroxinemia, in which an abnormal Generalized resistance to thyroid hormones
albumin binds only thyroxine with high affinity.
Nonthyroidal illness
Similarly derived from the total T3 , the “ free T3
Acute psychosis
index” can be useful in evaluating cases of abnor-
Acute medical/surgical illness
mal serum binding.
Hyperemesis gravidarum
CAUSES OF INCREASED T4 AND/OR T3 Lead intoxication
CONCENTRATIONS Drugs
The majority of patients with hyperthyroidism, Clofibrate
regardless of the etiology, have increased total 5-fluorouracil
serum concentrations of both T4 and T3 , as well Perphenazine
as high levels of the free hormones (Table 1.1). Methadone
In a minority of cases, there may be an isolated Heroin
elevation of either iodothyronine. T3 -toxicosis is l-thyroxine therapy
especially prominent in patients with mild and
recurrent Graves’ disease or hyperfunctioning
adenomas and those patients overtreated with hyperthyroidism, and iatrogenic thyrotoxico-
triiodothyronine-containing thyroid hormone sis due to exogenous levothyroxine administra-
preparations. The relative magnitude of T3 eleva- tion. Mild hyperthyroxinemia can even be seen in
tion is often greater than T4 in forms of hyperthy- patients being treated with exogenous levothyoxine
roidism caused by increased glandular synthesis of for hypothyroidism but whose TSH levels are nor-
hormone; in Graves’ disease, the proportion of cir- mal on therapy (18, 19) (Tables 1.2 and 1.3).
culating T3 that derives from thyroidal production Increased total T4 concentrations without thy-
nearly doubles (17). The opposite— that is, a lower rotoxicosis, termed euthyroid hyperthyroxinemia,
T3 :T4 ratio— is true in thyrotoxicosis due to an result from both acquired and congenital eti-
inflammatory thyroiditis, in which there is a release ologies. One commonly encountered situation is
of the previously formed hormone, iodide-induced acquired TBG excess due to hyperestrogenemia.
 L aboratory evaluation of thyroid function 7

Table 1.2 Causes of decreased T4 and/or T3 Table 1.3 How various serum constituents are
concentrations altered in hyperthyroidism and hypothyroidism

Hypothyroidism Increased Decreased

Euthyroid hypothyroxinemia
Hyperthyroidism
Decreased binding to serum proteins
Alkaline phosphatase Cholesterol (total, LDL)
Thyroxine-binding globulin deficiency
Angiotensin-converting Apolipoprotein b,
Chronic liver disease
enzyme apo (a)
Congenital
Calcium Corticosteroid-
Cushing’ s syndrome
Factor VIII binding globulin
Drugs
Ferritin
l-Asparaginase
Osteocalcin
Androgens
Sex hormone-binding
Nicotinic acid
globulin
Growth hormone excess
Urine nitrogen excretion
Nephrosis
Urine pyridinoline cross
Protein-losing enteropathy
links
Thyroxine-binding globulin and transthyretin
variants with reduced affinity Hypothyroidism
Inhibition of T4 binding by drugs Carcinoembryonic Aldosterone
Carbamazepine antigen Angiotensin-
Diphenylhydantoin Cholesterol (LDL and converting enzyme
Fenclofenac HDL fractions) Factor VIII
Furosemide Creatine phosphokinase Osmolarity
Heparin Creatinine Sex hormone-binding
Meclofenamic acid Lactic dehydrogenase globulin
Myoglobin Corticosteroid-
Mefenamic acid
Norepinephrine binding globulin
Salicylates
Sertraline Prolactin
Nonthyroidal illnesses

in the total serum concentration of T4 . Other

Elevated hepatic exposure to estrogen leads to
increased sialylation of carbohydrate side chains of
TBG, thereby decreasing the clearance of the gly-
coprotein 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—for example, pregnancy—and even
administration of selective estrogen receptor mod-
ulators, such as tamoxifen and raloxifene (20, 21).
Exogenous estrogen administered transdermally,
by avoiding first pass metabolism in the liver, does
not cause elevated TBG levels and hyperthyroxin-
emia (22). Acquired TBG excess may also be respon-
sible for the slight increase in T4 levels reported in
male cigarette smokers (23). X-linked inherited
TBG excess occurs with a frequency of 1 in 25,000
newborns, and can cause up to 2.5-fold elevations
abnormal serum-binding proteins can contribute
to euthyroid hyperthyroxinemia. In the autoso-
mal dominant condition familial dysalbuminemic
hyperthyroxinemia (FDH), one or more abnormal
species of albumin contain a high-affinity binding
site for thyroxine. Because the defect is specific for
T4 and does not affect T3 binding, these patients
have an elevated total T4 ; a normal THBR using
T3, but a decreased THBR using T4 as the ligand;
a normal total T3; and either a normal or increased
free T4, depending on the type of direct assay used.
Equilibrium dialysis typically yields normal lev-
els of free T4 in this syndrome. The diagnosis is
established by paper or gel electrophoresis of serum
enriched with radiolabeled T4, which permits iden-
tification of the abnormal binding proteins.
Elevations of free T4 concentrations can occur
as a result of interference in binding to serum
8 Medical management of thyroid disease

proteins. In vivo, hormones can be displaced from
protein by medications such as furosemide, causing
a true, albeit rapidly reversible, minimal hyperthy-
roxinemia after rapid intravenous administration
of the diuretic. Activation of lipases by both low-
and high-molecular-weight heparins leads to
increased levels of free fatty acids that displace
thyroid hormones ex vivo, causing an artefactual
elevation of measured free hormone (24).
In autoimmune thyroid diseases and mono-
clonal gammopathies, endogenous 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 (25). In a clas-
sic RIA for total hormone concentration, the auto-
antibody will compete with the capture antibody
for the 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 the 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 auto-
antibodies. 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 hetero-
philic, it appears to bind to the nonhuman capture
antibody, preventing interaction with the radio-
labeled ligand and leading to a falsely increased
hormone concentration (26). Preincubation of the
serum specimen with a nonspecific animal immu-
noglobulin, ethanol, or polyethylene glycol reduces
this antibody-mediated interference.
Assay interference by biotin supplements is a
recently recognized cause of artefact in a number
of thyroid-related assays that employ biotinylated
components, potentially falsely decreasing results
in sandwich immunoassays or falsely increasing
results in competitive immunoassays (27). Thus,
depending on the assay system, biotin ingestion
can cause falsely elevated or falsely low serum FT4 ,
FT3 , and TSH, and even falsely increased levels of
thyroid-stimulating antibodies mimicking Graves’
disease (28) (Table 1.4).
Decreased function of the 5¢-monodeiodinase
causes impaired conversion of T4 to T3, decreas-
ing T4 clearance and increasing T4 levels. Iodinated
radiocontrast dyes—for example, sodium ipo-
date—are potent inhibitors of T4 to T3 conversion
and have been used therapeutically in severely hyper-
thyroid 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

Table 1.4. Biotin-related assay interference

Relationship
between signal
and analyte Type of potential Example of
Type of assay concentration Impact on signal error analyte
Competitive Signal intensity of Biotin interferes Overestimation of FT4
washed solid with binding of concentration of FT3
phase is antigen antibody analyte TRAb
inversely complexes to
proportional to solid phase
analyte
concentration
Non- Signal intensity of Biotin interferes with Underestimation of TSH
competitive, washed solid binding of concentration of hCG
Sandwich phase is sandwich to solid analyte Thyroglobulin
proportional to phase
analyte
concentration

hyperthyroidism can also occur, great care must be
taken in interpreting hyperthyroxinemia in patients
receiving iodinated medications (29). An inher-
ited defect in 5¢-monodeiodinase function, due to
a mutation in a selenocysteine insertion sequence
binding protein, has recently been described, and
is probably responsible for hyperthyroxinemia
observed in these patients (30).
Patients with resistance to thyroid hormones
have an inherited partial defect in tissue respon-
siveness to thyroid hormones. Serum concentra-
tions of total and free thyroid hormones are both
increased as compensation for partial resistance.
Most kindreds that have been evaluated have been
found to have a dominant negative mutation in a
single allele of the thyroid hormone receptor beta
gene. Although affected individuals are generally
described as being clinically euthyroid, consider-
able variation exists in the measurable degrees of
hormone resistance among specific target organs
for thyroid hormone (31).
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, con-
sistent with coexistent hyperthyroidism, in most of
these patients normal thyroid hormone levels are
restored with recovery (32). Transient increases in
total and free T4 and T3 can be seen in 8 to 33%
of patients admitted for acute psychiatric disorders
(33, 34). TSH concentrations have been reported as
increased in up to 10% of acutely psychotic patients
(35), but they are frequently suppressed in severely
depressed outpatients as well as those suffering
from post-traumatic stress disorders (36, 37).
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 hypothy-
roidism, reflecting impairment of hormone syn-
thesis and release by the gland (Table 1.2). Due to
TSH stimulation of residual gland function and
elevation in the fractional conversion of T4 to T3
by 5¢ -monodeiodinase in both thyroid and periph-
eral tissues, 30% of patients with primary hypo-
thyroidism maintain normal T3 levels despite
decreases in T4 . Thyroxine synthesis is also sup-
pressed in patients receiving T3 exogenously or
with autonomous T3 overproduction.
L aboratory evaluation of thyroid function 9
Euthyroid hypothyroxinemia can be due to a
variety of mechanisms. Analogous to the abnor-
malities 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 deg-
radation of unstable variants, occurs in 1 in 4,000
births. X-linked complete TBG deficiency is less
common, found in 1 in 15,000 male births; female
heterozygotes have TBG levels that are partially
reduced. Numerous variants of TBG with reduced
affinity for thyroid hormones have been described,
with varying frequencies in different populations
(38). Acquired impairment of hormone binding
develops secondary to decreases in binding protein
levels, due to either reduced production (as occurs
in hyperthyroidism) or increased clearance (as
from nephrotic syndrome). In most patients with
quantitative or qualitative defects in TBG, direct
and indirect estimates of free T4 levels are normal.
In the extreme case of complete deficiency, 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 underesti-
mated by two-step and direct measurements.
Hypothyroxinemia and hypotriiodothyronin-
emia are common findings in patients with non-
thyroidal illness, with more severe reductions in
total hormone levels associated with more severe
or critical illness (39, 40). Milder degrees of ill-
ness are typically accompanied by reductions in
T4 to T3 conversion, resulting in a low T3 state
but the preservation of T4 levels. In addition to
deficiency of albumin and transthyretin, another
proposed mechanism includes the inhibition of
hormone binding to TBG, perhaps due to certain
free fatty acids released from damaged tissues
or cytokines, such as tumor necrosis factor (41).
Numerous medications interfere with thyroid
hormone binding to serum proteins, including
diphenylhydantoin, furosemide, heparin, sertra-
line, and certain non-steroidal anti-inflammatory
agents (42, 43). Inhibition of 5¢ -monodeiodinase
activity in nonthyroidal tissues accelerates clear-
ance of T4 through nondeiodinative mechanisms,
particularly in nonthyroidal illness and starva-
tion, 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 (44).
Medications such as glucocorticoids, amiodarone,
10 Medical management of thyroid disease
oral radiocontrast agents, gold, and high-dose pro-
pranolol and propylthiouracil (PTU) also inhibit
T4 deiodination to T3 ; however, clinical signs of
hypothyroidism are unlikely to develop, except
with unmonitored PTU use. Hypothyroxinemia
has been described in patients treated with novel
anti-cancer agents that inhibit vascular endothelial
growth factor receptors, with evidence of multiple
potential mechanisms that include primary thy-
roid dysfunction, but also effects on either thy-
roid hormone absorption or metabolic clearance
(45, 46). Pituitary TSH production is suppressed
by endogenous and/or exogenous glucocorticoids,
dopamine, somatostatin, and endorphins and may
also be mediated by reduced hypothalamic TRH
secretion (47). Alteration of TSH sialylation and
bioactivity may occur in critical illness as well
(48). However, in general, the serum TSH is the
most reliable measure of thyroid function in this
patient population. With increasing severity of
nonthyroidal illness, all of the proposed mecha-
nisms 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 inflamma-
tion) 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 thyrox-
ine index. Most analogue and some two-step pro-
cedures for measuring free T4 are also adversely
affected by binding inhibition in nonthyroidal ill-
ness (7, 14). These laboratory abnormalities reverse
with recovery from the nonthyroidal illness or
discontinuation of the interfering medication.
Although most of the effects of nonthyroidal ill-
ness may represent energy-conserving adaptive
mechanisms, the traditional view of these patients
as being euthyroid is not universally held (49).
However, no benefit from thyroid hormone supple-
mentation has yet been demonstrated.
Low serum FT4 levels are often encountered
in the second and third trimester of pregnancy, a
finding which is thought to be a methodological
artefact related to expanded plasma volume, high
serum TBG serum levels, and other unknown fac-
tors (50). Since a low FT4 and a normal serum TSH
suggest central hypothyroidism, it is important to
be aware of this pitfall. Many experts recommend
using the total T4 with or without serum TBG
assessment, as a more reliable assessment of thy-
roid hormone levels in the second and third trimes-
ters, taking into account the normal elevation of T4
because of higher serum TBG concentrations (50).
Assays of thyroid-stimulating
hormones
Early TSH assays utilized a single polyclonal anti-
body in a radioimmunoassay and were capable of
detecting elevated levels of TSH in patients who
have primary hypothyroidism. With a sensitivity
of about 1 mU/L, these tests were unable to distin-
guish the low-normal TSH levels in serum of 25%
of euthyroid individuals from subnormal concen-
trations. With the introduction of immunometric
(IMA) methods that use two or more antibodies
directed at different antigenic determinants on
the TSH molecule, assay sensitivities have been
improved by 10- to 200-fold. The first antibody,
usually a mouse monoclonal construct, is linked
to a solid phase, permitting the target molecule
to be separated from the serum with high affin-
ity; the second antibody, which may be polyclonal,
is labeled, providing a signal proportional to the
amount of ligand bound. With these more sensi-
tive assays, hyperthyroid patients can be identi-
fied 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 utilizing a chemi-
luminescent acridinium ester to generate the anti-
body-linked signal. High intraassay and interassay
precision with chemiluminometric methods may
permit routine detection of TSH levels as low as
0.01 mU/L or lower.
The ability of TSH assays to accurately measure
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 “ analyti-
cal sensitivity,” which is based on intraassay mea-
surements of the blank calibrator, and does not
reflect a clinically meaningful result (9). 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 genera-
tion” when the functional sensitivity is 0.1 mU/L,

and “ third generation” when the functional sensi-
tivity is 0.01 mU/L (51).
Multiple sources contribute to the total variation
observed in TSH assay results (52). Endogenous,
biologic variation exists due to the heterogeneity
of TSH isoforms, based on posttranslational modi-
fications that can alter the immunoreactivity as
well as the bioactivity of the molecule; this poten-
tially may be overcome with the use of variants
of recombinant TSH that mimic these individual
modifications (53, 54). Circadian and seasonal
effects contribute to within-person variation as
well. But, within-person variation during serial
measurements is relatively minimal compared
with between-person variation, raising concern
that population reference standards may be inad-
equate to distinguish a healthy from diseased state
(52, 55, 56).
Debate now exists about the optimal refer-
ence range for TSH assays. Typically, the lower
and upper limits of a population reference range
of the analyte’ s concentrations are the 2.5th and
97.5th percentiles (the 95% confidence interval),
measured in a rigorously defined normal cohort
without any evidence of relevant disease. Applying
this criterion to TSH levels, as determined in the
U.S. National Health and Nutrition Examination
Survey (NHANES III), the population reference
range would be 0.45– 4.12 mU/L (57). Similar
ranges have been reported in other populations,
differing to some degree due to variations in iodine
intake, race, age, gender, and even the time of day
that blood is sampled (58). As most functional
thyroid disorders are due to autoimmune thyroid
disease, the relationship between levels of thyroid
autoantibodies and TSH has also been evaluated,
demonstrating a U-shaped curve with the lowest
prevalence of autoantibodies at TSH levels between
0.1 and 1.5 mU/L in women and 0.1 and 2.0 mU/L
in men (59). Additionally, the likelihood of even-
tual development of overt primary hypothyroid-
ism has been reported to be markedly higher in the
setting of a TSH level of at least 2.0 mU/L and ele-
vated levels of antithyroid peroxidase antibodies
(60). 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 (61, 62). Other
studies have suggested that age-specific reference
ranges would be appropriate, with the 97.5th per-
centile being well above 4.5 mU/L with succes-
sively increasing deciles of age (63). However, in
L aboratory evaluation of thyroid function 11
the absence of definitive evidence that defining
hypothyroidism as a TSH greater than 2.5 mU/L
leads to unequivocal clinical benefit from treat-
ment with thyroid hormone, and given the over-
all concern that the population reference range
may not be optimal for defining a disease state
when inter-individual variation is relatively large,
changes in the TSH reference range have not been
made, and is generally in the 0.4– 4.5 mU/L range
in most laboratories (64).
During pregnancy, the placenta is responsible
for the production of high levels of hCG, a glyco-
protein hormone sharing a common alpha sub-
unit with TSH. While there is no cross-reactivity
of hCG in TSH immunometric assays, hCG in
high serum concentrations can stimulate the thy-
roid to produce thyroid hormone, thereby lower-
ing serum TSH concentrations. Most laboratories
have now established trimester specific TSH serum
concentrations that, in general, are decreased by
0.1– 0.2 mU/L and 1 mU/L at the low- and high-
end, respectively, of the usual TSH reference
range of 0.4– 4 mU/L in nonpregnant women (65).
Indeed, levels less than 0.1 mU/L in the first tri-
mester can be seen in about 10% of normal women
(66). Since serum hCG levels peak at the end of the
first trimester, the effect on serum TSH wanes, so
that the TSH reference range becomes closer to the
normal nonpregnant range by the third trimester.
Interference with TSH immunoassays is
uncommon. Patients with endogenous hetero-
philic antibodies directed against mouse immu-
noglobulin can have falsely elevated TSH levels, as
the heterophilic antibody can substitute for TSH
and bridge between the two antibodies in the assay
(67). 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 non-linear relation-
ship; alternatively, the sample can be tested using
another manufacturer’ s assay (9, 67). MacroTSH,
in which TSH is complexed to immunoglobulins
to form a high molecular weight species with no
biological activity, is another cause of artefactu-
ally elevated serum TSH, analogous to the case of
macroprolactin (68). In this case, serial dilution of
the sample is linear for TSH, and the presence of
macroTSH in the serum needs to be detected by
measuring TSH in the supernatant after polyethyl-
ene glycol precipitation (68).
12 Medical management of thyroid disease
CAUSES OF HYPOTHYROTROPINEMIA
In severe hyperthyroidism, serum 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. Subnormal but detectable TSH levels
can be seen in patients who have mild or asymp-
tomatic hyperthyroidism of any etiology, or they
may be due to TSH suppression from nonthyroidal
illness. More sensitive TSH immunoassays provide
adequate separation between hospitalized hyper-
thyroid patients with medical illness, in whom
basal TSH levels generally remain undetectably
low, and euthyroid patients with nonthyroidal ill-
ness, 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. Hypothyroidism due to pituitary or hypo-
thalamic disease can also present with inappro-
priately normal or even slightly elevated levels of
immunologically intact but biologically inactive
TSH secondary to alternative glycosylation of the
protein (69, 70). Among the drugs that can affect
TSH production, the rexinoid bexarotene appears
to suppress TSH gene transcription directly and
causes a dose-dependent central hypothyroid-
ism (71, 72). The hypoglycemic drug metformin
has been reported to lower TSH levels by an as yet
unknown mechanism (73).
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
(51). 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 impair-
ment can have elevated TSH concentrations. These
patients with so-called subclinical hypothyroid-
ism have T4 and T3 levels within the normal range
associated with increased serum TSH concentra-
tions. Although the clinical management of such
patients remains controversial, those individuals
with a predisposition to developing clinical hypo-
thyroidism— for example, those with autoimmune
thyroiditis or a history of thyroid irradiation or sur-
gery, should be treated or followed longitudinally
for development of overt hypothyroidism (74).
Medications that have been associated with hyper-
thyrotropinemia include cytokines that can cause
autoimmune thyroiditis (such as interferon-α ),
and antineoplastic agents such as tyrosine kinase
inhibitors, and immune checkpoint inhibitors (45).
In neonates, various maternal causes of fetal dis-
tress, including preeclampsia and gestational dia-
betes mellitus, are associated with elevated TSH
levels in cord blood, but whether this reflects tran-
sient primary hypothyroidism or a central stimu-
lation of TSH production is unknown (75).
The differential diagnosis of hyperthyrotropin-
emia also includes conditions associated with inap-
propriate 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 usu-
ally present with a goiter and clinical evidence of
thyrotoxicosis, with or without clinical evidence
of a sellar mass lesion. In half of the cases, there is
co-secretion of other anterior pituitary hormones
(e.g., growth hormone or prolactin) and the α-sub-
unit of TSH is commonly overproduced. A molar
ratio of α-subunit to intact TSH that is greater than
unity is strongly suggestive of a pituitary adenoma
(76). Resistance to thyroid hormone (RTH) is a rare
inherited disorder characterized by reduced respon-
siveness of target tissues to thyroid hormone due
to mutations in the thyroid hormone receptor gene
(77). The diagnosis of RTH should be considered
when thyroid function tests reveal elevated T4 and
T3 levels and a non-suppressed TSH. Due to very
similar thyroid function test abnormalities, RTH
must be distinguished from a TSH-producing ade-
noma. RTH patients exhibit normal α-subunit and a
normal molar ratio of α-subunit to intact TSH of ≤1.
The resistance of the thyroid to TSH, present-
ing with nongoitrous congenital hypothyroidism
and elevated TSH levels, has been described both
in isolated form as well as in pseudohypoparathy-
roidism type Ia (78). In this latter congenital con-
dition, deficiency of the stimulatory subunit of the
guanine nucleotide‑binding proteins that mediate
activation of adenylate cyclase can cause resistance
to multiple hormones, including TSH and parathy-
roid hormone.

In infants, exposure to cold temperatures
i­mmediately following birth or during hypother-
mic 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 (79). 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 circulat-
ing free T4 and T3 . However, seasonal changes in
serum TSH (i.e., during colder vs warmer tempera-
tures) have been recently observed (80).
Specialized studies of thyroid
function
THYROGLOBULIN
In most forms of thyroid disease, thyroglobulin
(Tg) is released from thyroid follicular cells pro-
portional to the synthesis and release of T4 and T3 ,
increasing size of the gland, and the degree of cyto-
toxic inflammation. The reference range in subjects
with intact thyroid glands and normal TSH levels is
about 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
(81). In determining the cause of hyperthyroidism,
an undetectable serum Tg suggests factitious or
iatrogenic thyrotoxicosis. Undetectable levels are
also seen in hypothyroid patients with congenital
or acquired absence of the thyroid gland. Presently,
the primary indication for measurement of serum
Tg concentrations is as a tumor marker for the
longitudinal follow-up of patients with differenti-
ated thyroid carcinoma, which necessitates greater
functional sensitivity at lower concentrations than
the euthyroid reference range (82). Although intro-
duced more than 15 years ago, these assays are now
being increasingly used to detect Tg in fine needle
aspirations of neck masses or cystic lesions as an
adjunct to cytologic interpretation to diagnose
recurrent or metastatic cancer (83).
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 limita-
tion is the potential for interference by anti-Tg
autoantibodies, which can be found in up to 25% of
L aboratory evaluation of thyroid function 13
patients with differentiated thyroid carcinoma. In
the immunometric assays, the serum Tg concentra-
tion 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. Detecting the presence and
degree of autoantibody interference in an immu-
noassay may also be difficult (84). Conversely, in
radioimmunoassays, anti-Tg autoantibodies can
cause falsely high values because they bind radio-
labeled 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 sug-
gest the presence of antibody interference, but can-
not be used to quantify the problem. A measure of
serum Tg should therefore always be preceded by a
test for anti-Tg antibodies, and it is recommended
that laboratories withhold reporting low results of
Tg immunometric assays when autoantibodies are
identified (9). 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 (85).
Despite a trend toward assay standardization,
the variability of results using differing Tg assays
remains at at least 25% due to variations in the anti-
thyroglobulin antibodies used and the molecular
heterogeneity of Tg. Occasionally, immunometric
assays may fail to detect very high serum Tg concen-
trations due to the so-called hook effect, in which
the high concentrations of Tg bind to one antibody,
preventing the formation of the two-antibody
sandwich upon which the assay depends. If this
effect is suspected, the sample should be reanalyzed
after dilution. Another cause of a false-negative Tg
in patients with differentiated thyroid cancer can
be tumor production of variants of Tg that fail to
be recognized by the antibodies used in an assay
(86). Recently, thyroglobulin LC-MS/MS assays
have been introduced that purport to circumvent
the problem of anti-Tg antibody interference (87).
However, recent data suggest that these assays are
still capable of generating falsely low serum Tg lev-
els in patients with known residual disease (88).
Measurement of serum Tg has become a cor-
nerstone of differentiated thyroid cancer follow-up
(89). There is a very high negative predictive value
of an undetectable TSH-stimulated serum Tg level to
identify those patients with differentiated thyroid
14 Medical management of thyroid disease
cancer who have no evidence of disease. Recent
data suggest that similar high negative predictive
values of an non-TSH-stimulated serum Tg < 0.1
are seen using a second-generation Tg immuno-
chemiluminometric assay (ICMA) with a func-
tional sensitivity of 0.05 ng/mL (90).
Alternatively, the positive predictive value is
limited in the presence of remnant normal thyroid
cells left after thyroidectomy, and thus one indica-
tion for postsurgical adjuvant radioiodine therapy
is to eliminate such normal sources of Tg (89).
However, in most patients who have not under-
gone remnant ablation after total thyroidectomy,
serum Tg levels are generally  < 1– 2 ng/ml, and a
rising serum Tg is still useful in the detection of
recurrent disease (91). The thyroglobulin doubling
time, analogous to the calcitonin doubling time
in medullary thyroid cancer, is a useful prognos-
tic parameter to monitor in patients with known
residual disease (92). False positive Tg results can
also be caused by heterophilic antibodies, a prob-
lem in many immunometric assays that has only
been partially resolved by the addition of blocking
antibodies, but rare false-negative results have also
been reported (93, 94).
THYROID AUTOANTIBODIES
Antibodies directed against the cell surface (TSH
receptor), intracellular components (microsomal
membranes, thyroglobulin), and extracellular
antigens (T4 , T3 ) are often found in sera of patients
with autoimmune thyroid diseases. Although
autoantibodies tend to target fewer antigenic epi-
topes than heterologous antibodies, these autoan-
tibodies can still be quite a heterogeneous mixture
of proteins, leading to problems with both specific-
ity and sensitivity in assays.
In Hashimoto’ s disease, cytotoxic antibodies
may bind to a thyroid microsomal antigen that is
expressed on the apical cell surface, and these anti-
bodies subsequently fix complement. These anti-
thyroid 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 antithyroglobu-
lin antibodies. Among commercially available
assays, immunometric procedures, including RIA,
immunoradiometric assay, and enzyme-linked
and fluorescent methods are superior to routine
hemagglutination techniques. Improvements in
sensitivity and specificity have been obtained using
monoclonal antibodies directed against thyroid
peroxidase (TPO), and purified or recombinant
TPO in the assay systems (95, 96). International
standardization now exists against a specific ref-
erence preparation, MRC 66/387, permitting
reporting of results in “ international units,” but
concordance among multiple assays remains sub-
optimal (97). Reference ranges vary widely among
different assays, with manufacturers often citing
levels greater than 10 kIU/L as being clinically rel-
evant predictors of autoimmune thyroid disease.
However, long-term follow-up studies that identi-
fied anti-microsomal antibodies as being predic-
tive 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 (60, 98).
Antithyroglobulin antibodies are less specific
for autoimmune thyroiditis but have achieved
greater significance for their potential to interfere
with thyroglobulin assays in patients with thyroid
cancer. Contemporary immunoassays are con-
siderably more sensitive and specific than older,
agglutination methods, and can detect antithyro-
globulin antibodies in up to 10% of the clinically
disease-free population and 3.4% of those who
lack anti-TPO antibodies (57). Nevertheless, ref-
erence 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 the interchangeability of
assays (99). As with anti-TPO antibody measure-
ments, differences exist in the definitions used for
reference ranges. Assays that report detectable lev-
els of antithyroglobulin antibodies below 10 kIU/L
as abnormal may have low specificity both for
actual pathology and for antibodies that can inter-
fere with thyroglobulin assays (99).
No correlation exists between the severity of
hypothyroidism and titers of antithyroid antibod-
ies, 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, anti-
thyroid antibody titers often decrease but are not
clinically useful measures of disease activity.

Multiple procedures have been developed to
measure the TSH-receptor stimulatory immuno-
globulins that are pathogenetic for Graves’ dis-
ease, detecting either stimulation of biochemical
functions in thyroid cells (thyroid-stimulating
immunoglobulins) or blockade of receptor bind-
ing by TSH (TSH-binding inhibitors). The origi-
nal long-acting thyroid stimulator (LATS) assay
of Adams and Purves had been largely replaced by
quantitation of cyclic AMP production, typically
by Chinese hamster ovary cells transfected with
human TSH receptors or chimeric human/rat TSH
receptors (100). TSH-binding inhibitors can be
detected by quantitation of radiolabeled TSH bind-
ing to recombinant human TSH receptors in the
presence of serum, followed by polyethylene gly-
col precipitation to separate bound from unbound
radiolabel (101). Alternatively, recombinant TSH
receptors can be affinity-immobilized on an anti-
body-coated tube, which is then incubated with
TSH with an attached radioactive or chemilumi-
nescent label (102). In general, the most sensitive of
these assays can detect thyroid-stimulating immu-
noglobulins in up to 95% of hyperthyroid Graves’
sera, and TSH-binding inhibitors in 60 to 85%. In
general, there is an excellent correlation between
the bioassay methods and the TSH receptor– based
assays (103). However, thyroid-stimulating immu-
noglobulins levels may be more useful for identify-
ing Graves’ disease as the cause of exophthalmos
(104). Blocking antibodies that bind to but do not
stimulate the TSH receptor have also been identi-
fied in hypothyroid and euthyroid patients with
autoimmune thyroiditis or Graves’ disease.
The measurement of thyroid autoantibodies is
of value in selected clinical situations. The pres-
ence of thyroid-stimulating immunoglobulins in
patients in whom the etiology of hyperthyroid-
ism is uncertain can lead to a diagnosis of Graves’
disease. Current third generation TRAb assays
have a 95% sensitivity and specificity for diagnos-
ing Graves’ disease (105). Assessment of anti-TSH
receptor antibody levels before treatment can be
predictors of the likelihood of remission after a
course of antithyroid drug therapy or the develop-
ment of Graves’ ophthalmopathy (106). Persistence
of high levels of thyroid-stimulating immunoglob-
ulins in Graves’ disease following therapy is asso-
ciated with increased rates of recurrence (107, 108).
When detected during the third trimester of preg-
nancy in a woman with Graves’ disease, significant
L aboratory evaluation for thyroid disease 15
increases in either TSH-binding inhibitors or thy-
roid-stimulating immunoglobulins titers correlate
with the development of intrauterine and neonatal
hyperthyroidism due to transplacental passage of
immunoglobulins (109).
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 pri-
mary means of evaluating thyroid hormone func-
tion. 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 hor-
mones. 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 (110).
Numerous serum constituents have altered
levels in hyperthyroidism and hypothyroidism,
mostly reflecting changes in synthesis and/or clear-
ance of these substances (Table 1.3). There is con-
siderable 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 dur-
ing therapy of underlying thyroid disorders and in
the evaluation of patients with discordant thyroid
function tests. Combinations of biophysical and
serum parameters of thyroid hormone action are
particularly useful in the evaluation of patients
with possible thyroid hormone resistance states.
To characterize the presence and extent of resis-
tance, parameters of pituitary and peripheral tis-
sue response are measured before and during the
administration of increasing doses of T3 (50, 100,
and 200 μ g per day). Among the various tests per-
formed, changes in sex hormone‑binding globulin,
basal metabolic rate, and body weight provide the
strongest distinction between normal responsive-
ness and generalized resistance to thyroid hor-
mones (111).
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
16 Medical management of thyroid disease
unsuspected disease in an asymptomatic general
population, case finding to detect thyroid disease
in patients whose symptoms and signs are suf-
ficiently subtle that the examining clinician may
not suspect thyroid dysfunction as the etiology,
diagnosis to prove the presence of clinically sus-
pected disease, and optimization of management
of proven thyroid disease.
Screening and case findings
Population screening is generally warranted if the
prevalence of such disease is not small, the health
consequences of undiagnosed disease are sub-
stantial, and the treatment is effective. With these
criteria in mind, there is considerable controversy
about the appropriateness of screening asymptom-
atic adults for thyroid dysfunction (112–114). The
Whickham study demonstrated an annual inci-
dence of thyroid hormone excess and deficiency of
0.5% in women and 0.06% in men in the United
Kingdom (60). 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 sig-
nificant enough consequences to justify the costs
of screening. Using a decision analysis model, add-
ing a serum TSH determination to the quintennial
cholesterol screening recommended starting at age
35 was found to be reasonably cost-effective (115).
Deferring periodic TSH screening until older ages
and decreasing cost for TSH assays are key factors
in improving cost-effectiveness even further. As a
result, three endocrine professional organizations
(the American Thyroid Association, American
Association of Clinical Endocrinologists, and The
Endocrine Society) all support routine screening
of asymptomatic adults (116). Conversely, other
organizations with a broader focus than these
endocrine groups do not recommend screen-
ing for thyroid dysfunction, including the U.S.
Preventive Services Task Force, American College
of Physicians, Royal College of Physicians, and
Institute of Medicine (113, 117, 118).
There is uniform agreement, however, that
screening for neonatal hypothyroidism is necessary
(119). Neonatal hypothyroidism occurs with a fre-
quency of 1 in 4,000 live births and is associated
with significant neurological and developmental
morbidity, much of which can be prevented by
early treatment with thyroid hormone replace-
ment. Mandatory neonatal screening is based
either upon the measurement of total (not free) T4
or TSH in whole blood collected on filter paper. In
strategies that measure T4 first, determination of
the TSH concentration is performed if the T4 level
is below the 10th percentile, and serum assays are
then used to confirm a diagnosis of hypothyroid-
ism. The advantage of a T4 -first strategy is the
ability to detect central hypothyroidism and mini-
mized impact of the neonatal TSH surge (120). An
alternative strategy employs primary TSH screen-
ing, followed by confirmatory T4 testing; this
approach is more commonly used in Europe and
in areas of iodine deficiency (121).
Case findings are best reserved for patients
whose clinical assessment may be sufficiently com-
plex as to obscure suspicion for thyroid dysfunc-
tion. Often, these patients are elderly, and their
symptoms may be primarily constitutional, neuro-
psychiatric, 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 ini-
tial test for case finding, a sensitive TSH assay has
excellent sensitivity and specificity for both hyper-
thyroidism and hypothyroidism. In contrast, hos-
pitalized patients with acute illnesses have a high
frequency of transient thyroid function abnor-
malities and are unlikely to have primary thyroid
disease diagnosed on the basis of routine tests. In
the absence of strong clinical evidence of thyroid
dysfunction, patients hospitalized with acute ill-
nesses should probably not undergo thyroid test-
ing for case finding (39).
Postpartum women have a high frequency of
transient thyroid dysfunction, especially those
with pre-existing euthyroid autoimmune thy-
roiditis. Within the first 3 months after delivery,
at least 5% of women develop postpartum thyroid-
itis, a painless inflammatory condition that can
cause thyrotoxicosis and/or hypothyroidism. More
than one-half of these patients require therapeu-
tic intervention. Furthermore, 25% of women with
postpartum thyroiditis eventually develop chronic
hypothyroidism requiring lifelong therapy. Case

finding with serum TSH measurements 3 and 6
months after delivery is recommended for women
with type 1 diabetes mellitus, personal history of
postpartum thyroiditis, or those known to have
elevated levels of anti-TPO antibodies (122).
IMAGING APPROACH TO THYROID
DISEASE
Ultrasonography and nuclear
medicine studies
Two imaging modalities have proven to be of con-
siderable utility for the evaluation of thyroid dis-
ease. These modalities are ultrasonography, which
has become the gold standard for the initial evalu-
ation of diffuse and nodular thyroid disease, and
radioiodine scanning and uptake, which are of
crucial importance for the diagnosis and manage-
ment of hyperthyroidism and thyroid cancer.
Ultrasonography
TECHNIQUE
Ultrasound (US) examination of the thyroid gland
is performed using high-frequency sound waves
(10– 15 MHz) generated by a linear transducer. The
reflections of the sound waves are used to generate
an image which can then be displayed. The magni-
tude of the echo from each point in the field of view
is mapped to the gray level or brightness of the cor-
responding pixel in the image (B-mode, grayscale
image). In order to perform a US assessment, the
patient is placed in a supine position with the neck
extended. Axial (or horizontal or transverse) scans
of the whole thyroid gland are obtained at the
upper, middle, and lower poles, with a comparison
of the size and echogenicity of each lobe and docu-
mentation of their width and anterior-posterior
diameters (123). Longitudinal (or sagittal) scans
provide the length of the lobes. Focal lesions are
then documented and described using standard-
ized reporting criteria (123, 124). The following
characteristics of nodules are reported: size, loca-
tion, shape, composition, description of any calci-
fications, echogenicity, and vascular pattern. The
vascularity of the lobes and the associated nodules
is also depicted using color Doppler imaging, in
which blood flow information is color-coded and
superimposed on the B-mode grayscale image.
Imaging approach to thyroid disease 17
INDICATIONS
In addition to documenting the presence of thy-
roid nodules, US can also provide information
about their risk of malignancy. The nodule char-
acteristics described above are used to assign a
risk of malignancy. For those nodules with a sig-
nificant risk of malignancy, US can also be used to
guide fine needle aspiration biopsy. Nodules that
are determined not to be malignant can be moni-
tored by US for changes in their size and other
characteristics. Other roles for US examination
are to document cervical lymphadenopathy, eval-
uate other thyroid lesions, and evaluate changes
in the thyroid parenchyma. US is also invaluable
for monitoring the post-thyroidectomy neck for
tumor recurrence or suspicious lymph nodes in
a patient being followed after initial treatment of
thyroid cancer.
NORMAL THYROID APPEARANCE
The normal thyroid gland consists of right and left
lobes and a connecting isthmus. A normal thy-
roid gland weighs approximately 30 gm, but the
size, shape, and volume of the gland vary with
age and sex. Measurement of the width, depth,
and length of each thyroid lobe can be used to
calculate thyroid volume. Normal volumes are
10– 15 ml and 12– 18 ml for females and males,
respectively. The echogenicity of a normal thy-
roid gland is greater than the echogenicity of the
surrounding muscles. The normal gland appears
homogeneous with a “ ground glass” appearance
(123) (see Figure 1.2).
DIFFUSE THYROID DISEASE
US can be used to document a diffusely enlarged
thyroid gland and can document extension into
the superior mediastinum. It can also document
the parenchymal changes associated with various
diffuse thyroid diseases based on the echogenicity
compared with the normal thyroid gland (123).
A gland affected by Hashimoto’ s thyroiditis can
appear heterogeneous with multiple hypoechoic
micronodular areas (see Figure 1.3a), as com-
pared with the more homogeneous appearance
of normal thyroid parenchyma (Figures 1.2d and
1.2e). As the disease progresses, the parenchymal
fibrosis is manifest as linear bands of echogenicity.
Vascularity, as indicated by color Doppler imaging,
is usually normal or increased early in the disease
course (see Figure 1.3b) and reduced in the later
18 Medical management of thyroid disease

isthmus

carotid
le thyroid lobe

trachea
carotid trachea

(a) (b)

right thyroid lobe

carotid
left thyroid lobe
trachea

(c) (d)

right thyroid lobe

(e)

Figure 1.2 Ultrasound of a normal thyroid gland showing (a) the isthmus in transverse view, (b) the
left thyroid in transverse view, (c) the right thyroid lobe in transverse view, (d) the left thyroid lobe in
sagittal view, (e) the right thyroid lobe in sagittal view.

atrophic stage. In the case of Graves’ disease, the
gland is enlarged and lobulated with reduced echo-
genicity secondary to increased blood flow and
decreased colloid (see Figure 1.4a), as compared
with normal thyroid gland parenchyma (Figures
1.2d and 1.2e). In comparison to Hashimoto’ s
thyroiditis, the gland is less heterogeneous, and
when color Doppler imaging is employed, has
increased vascularity and increased blood flow (see
Figure 1.4b). Subacute granulomatous thyroiditis
is characterized by ill-defined patchy hypoechoic
areas in the thyroid gland. The thyroid gland in
both silent and postpartum thyroiditis appears
either diffusely hypoechoic or has multiple areas of
low echogenicity throughout both lobes. Riedel’ s
thyroiditis appears as an enlarged hypoechoic
gland that has a coarse echotexture with linear
echogenic streaks corresponding with fibrotic
 Imaging approach to thyroid disease 19

Figure 1.3 Ultrasound imaging of a thyroid gland affected by Hashimoto’s thyroiditis with (a) gray
scale imaging showing hypoechoic micronodular areas and (b) color Doppler showing increased
vascularity.
20 Medical management of thyroid disease

Figure 1.4 Ultrasound imaging of a thyroid gland affected by Graves’ disease with (a) grayscale imag-
ing showing reduced echogenicity and less heterogeneity than Hashimoto’s thyroiditis and (b) color
Doppler showing increased vascularity and blood flow.

bands. Color Doppler imaging has been used to
distinguish the causes of amiodarone-induced
thyrotoxicosis, as type 1 disease is characterized by
increased blood flow and type 2 disease is associ-
ated with normal or decreased flow.
THYROID NODULES
US has become a key tool for determining whether
a thyroid nodule, which has been found by palpa-
tion or incidentally by imaging, requires biopsy
to exclude malignancy (124). Benign thyroid nod-
ules are generally isoechoic or hyperechoic. Pure
cysts are anechoic and are always benign and do
not require biopsy. Spongiform nodules contain-
ing scattered microcystic structures also have a
very low (< 3%) risk of malignancy. The most com-
mon thyroid malignancy, papillary thyroid cancer,
is generally hypoechoic, with other features such
as irregular margins, microcalcifications, a “ taller
than wide” configuration in the transverse view,
and internal vascularity. Follicular thyroid can-
cers are often hypoechoic with a rounded shape.
Anaplastic thyroid cancer is typically hypoechoic,
with irregular margins and areas of necrosis.
Medullary thyroid cancer is also hypoechoic in
appearance and may have echogenic foci due to
amyloid deposition. US can also provide infor-
mation about the number and characteristics of
additional nodules, in addition to the index nod-
ule. The presence of multiple nodules within the
thyroid gland is associated with a very slightly
reduced overall risk of thyroid cancer for the indi-
vidual patient (125).
RISK STRATIFICATION SYSTEMS FOR
THYROID NODULES
Systems used to stratify the risk of malignancy
within a thyroid nodule have been based on a
description of the individual ultrasound features,
or various scoring systems that accommodate the
US patterns or number of suspicious ultrasound
features (126). A 2005 guideline recommended
biopsy with different size cut-off criteria based on
individual US features (127). A recent meta-anal-
ysis examining the predictive value of individual
US features using combined data from 31 studies
suggested that the highest diagnostic odds ratio
for malignancy of 11.14 (CI 6.6– 18.9) was provided
by the taller than wide characteristic (128). Other
individual predictive features were infiltrative
margins, internal calcifications, hypoechogenicity,
Imaging approach to thyroid disease 21
and a solid nodule. However, each of these indi-
vidual features had relatively modest likelihood
ratios, and when the prevalence of thyroid cancer
was taken into account, they resulted in a relatively
modest post-test probability of thyroid cancer
being present. Other meta-analyses have produced
similar conclusions (129). Thus, the use of a single
US feature does not take into account the altera-
tion in risk that can occur with a combination of
features, nor does it incorporate individual patient
risk factors.
Combinations or patterns of US features have
higher predictive value for thyroid cancer (126)
compared with individual features. The American
Thyroid Association (ATA) has developed criteria
for assessment of the risk of malignancy within a
nodule using the pattern of sonographic features
(89) (see Figure 1.5). Using this system, a solid
hypoechoic nodule that also has either irregular
margins, microcalcifications, a taller-than-wide
shape, an extrusive soft-tissue component, or extra
thyroidal extension is considered to be high suspi-
cion and to have at least a 70– 90% risk of malig-
nancy. Figure 1.6 shows a nodule with high-risk
ATA sonographic features that was found to be
papillary thyroid cancer when subject to biopsy.
Solid hypoechoic nodules without these additional
features are considered to be intermediate risk with
a 10– 20% risk of malignancy. Isoechoic or hyper-
echoic nodules without these features have a low
risk (5– 10%) of malignancy. A hyperechoic nod-
ule with low-risk features is shown in Figure 1.7.
Spongiform nodules have very low (< 3%) risk of
malignancy, whereas purely cystic lesions are con-
sidered benign with < 1% risk of malignancy. Based
on these differing assessments of the risk of thyroid
cancer, different size criteria are suggested by the
ATA for making a decision to pursue fine needle
aspiration biopsy. For example, nodules with high
and intermediate risk sonographic patterns are
recommended for biopsy if they are greater than
1 cm in size, whereas low risk nodules are recom-
mended for biopsy if they are greater than 1.5 cm
in dimension.
Several other systems for assessing the risk of
a thyroid nodule harboring malignancy have been
developed. Some of these are quantitative and are
based on calculating the number of suspicious US
features and generating a risk score. The Thyroid
Imaging Reporting and Data Systems (TIRADS),
originally formulated in 2009 (130), has since been
22 Medical management of thyroid disease

Figure 1.5 Risk stratification of thyroid nodules as proposed by the American Thyroid Association
(ATA) 2016 Guidelines.

Figure 1.6 Nodule with ATA high suspicion sonographic pattern. (Right upper pole nodule is solid and
hypoechoic with irregular margins and multiple microcalcifications. Color flow is present. Nodule is
taller than it is wide. No extrathyroidal extension.)
Another random document with
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that and the second shoe were gone. Yussuf was much pleased and
rewarded Abou with a new coat later, but for the present he was not
done. Judging by long experience that the peasant had either bought
the sheep and was taking it home or that he was carrying it to market
to sell, he said to Abou: ‘Let us wait. It may be that he will return with
another.’”
“Ah, shrewd,” muttered Ajeeb, nodding his head gravely.
“Accordingly,” went on Gazzar-al-Din, “they waited and soon the
peasant returned carrying another sheep. Yussuf asked Abou if he
could take this one also, and Abou told him that when he saw the
sheep alone to take it.”
“Dunce!” declared Chudi, the baker. “Will he put another sheep
down after just losing one? This is a thin tale!” But Gazzar was not to
be disconcerted.
“Now Yussuf was a great thief,” he went on, “but this wit of Abou’s
puzzled him. Of all the thieves he had trained few could solve the
various problems which he put before them, and in Abou he saw the
makings of a great thief. As the peasant approached, Abou motioned
to Yussuf to conceal himself in a crevice in the nearby rocks, while
he hid in the woods. When the peasant drew near Abou placed his
hands to his lips and imitated a sheep bleating, whereupon the
peasant, thinking it must be his lost sheep, put down behind a stone
the one he was carrying, for its feet were tied, and went into the
woods to seek the lost one. Yussuf, watching from his cave, then ran
forth and made off with the sheep. When the peasant approached,
Abou climbed a tree and smiled down on him as he sought his
sheep, for he had been taught that to steal was clever and wise, and
the one from whom he could steal was a fool.”
“And so he is,” thought Waidi, who had stolen much in his time.
“When the peasant had gone his way lamenting, Abou came down
and joined Yussuf. They returned to the city and the home of Yussuf,
where the latter, much pleased, decided to adopt Abou as his son.”
Gazzar now paused upon seeing the interest of his hearers and held
out his tambour. “Anna, O friends, anna! Is not the teller of tales, the
sweetener of weariness, worthy of his hire? I have less than a score
of anna, and ten will buy no more than a bowl of curds or a cup of
kishr, and the road I have traveled has been long. So much as the
right to sleep in a stall with the camels is held at ten anna, and I am
no longer young.” He moved the tambour about appealingly.
“Dog!” growled Soudi. “Must thy tambour be filled before we hear
more?”
“Bismillah! This is no story-teller but a robber,” declared Parfi.
“Peace, friends,” said Gazzar, who was afraid to irritate his hearers
in this strange city. “The best of the tale comes but now—the
marvelous beauty of the Princess Yanee and the story of the caliph’s
treasury and the master thief. But, for the love of Allah, yield me but
ten more anna and I pause no more. It is late. A cup of kishr, a
camel’s stall—” He waved the tambour. Some three of his hearers
who had not yet contributed anything dropped each an anna into his
tambour.
“Now,” continued Gazzar somewhat gloomily, seeing how small
were his earnings for all his art, “aside from stealing and plundering
caravans upon the great desert, and the murdering of men for their
treasure, the great Yussuf conducted a rug bazaar as a blind for
more thievery and murder. This bazaar was in the principal street of
the merchants, and at times he was to be seen there, his legs
crossed upon his pillows. But let a merchant of wealth appear, a
stranger, and although he might wish only to ask prices Yussuf would
offer some rug or cloth so low that even a beggar would wish to take
it. When the stranger, astonished at its price, would draw his purse a
hand-clap from Yussuf would bring forth slaves from behind
hangings who would fall upon and bind him, take his purse and
clothes and throw his body into the river.”
“An excellent robber indeed!” approved Soudi.
“Yussuf, once he had adopted Abou as his son, admitted him to
his own home, where were many chambers and a garden, a court
with a pool, and many servants and cushions and low divans in
arcades and chambers; then he dressed him in silks and took him to
his false rug market, where he introduced him with a great flourish as
one who would continue his affairs after he, Yussuf, was no more.
He called his slaves and said: ‘Behold thy master after myself. When
I am not here, or by chance am no more—praise be to Allah, the
good, the great!—see that thou obey him, for I have found him very
wise.’ Soon Yussuf disguised himself as a dervish and departed
upon a new venture. As for Abou, being left in charge of the rug
market, he busied himself with examining its treasures and their
values and thinking on how the cruel trade of robbery, and, if
necessary, murder, which had been taught him, and how best it was
to be conducted.
“For although Abou was good and kind of heart, still being taken
so young and sharply trained in theft and all things evil, and having
been taught from day to day that not only were murder and robbery
commendable but that softness or error in their pursuit was wrong
and to be severely punished, he believed all this and yet innocently
enough at times sorrowed for those whom he injured. Yet also he
knew that he durst not show his sorrow in the presence of Yussuf, for
the latter, though kind to him, was savage to all who showed the
least mercy or failed to do his bidding, even going so far as to slay
them when they sought to cross or betray him.”
“Ay-ee, a savage one was that,” muttered Al Hadjaz, the cook.
“And I doubt not there are such in Yemen to this day,” added
Ajeeb, the cleaner of stalls. “Was not Osman Hassan, the spice-
seller, robbed and slain?”
“Soon after Yussuf had left on the secret adventure, there
happened to Abou a great thing. For it should be known that at this
time there ruled in Baghdad the great and wise Yianko I., Caliph of
the Faithful in the valleys of the Euphrates and the Tigris and master
of provinces and principalities, and the possessor of an enormous
treasury of gold, which was in a great building of stone. Also he
possessed a palace of such beauty that travelers came from many
parts and far countries to see. It was built of many-colored stones
and rare woods, and possessed walks and corridors and gardens
and flowers and pools and balconies and latticed chambers into
which the sun never burst, but where were always cool airs and
sweet. Here were myrtle and jasmine and the palm and the cedar,
and birds of many colors, and the tall ibis and the bright flamingo. It
was here, with his many wives and concubines and slaves and
courtiers, and many wise men come from far parts of the world to
advise with him and bring him wisdom, that he ruled and was
beloved and admired.
“Now by his favorite wife, Atrisha, there had been born to him
some thirteen years before the beautiful and tender and delicate and
loving and much-beloved Yanee, the sweetest and fairest of all his
daughters, whom from the very first he designed should be the wife
of some great prince, the mother of beautiful and wise children, and
the heir, through her husband, whoever he should be, to all the
greatness and power which the same must possess to be worthy of
her. And also, because he had decided that whoever should be wise
and great and deserving enough to be worthy of Yanee should also
be worthy of him and all that he possessed—the great Caliphate of
Baghdad. To this end, therefore, he called to Baghdad instructors of
the greatest wisdom and learning of all kinds, the art of the lute and
the tambour and the dance. And from among his wives and
concubines he had chosen those who knew most of the art of dress
and deportment and the care of the face and the body; so that now,
having come to the age of the ripest perfection, thirteen, she was the
most beautiful of all the maidens that had appeared in Arabia or any
of the countries beyond it. Her hair was as spun gold, her teeth as
pearls of the greatest price, lustrous and delicate; her skin as the
bright moon when it rises in the east, and her hands and feet as
petals in full bloom. Her lips were as the pomegranate when it is
newly cut, and her eyes as those deep pools into which the moon
looks when it is night.”
“Yea, I have heard of such, in fairy-tales,” sighed Chudi, the baker,
whose wife was as parchment that has cracked with age.
“And I, behind the walls of palaces and in far cities, but never
here,” added Zad-el-Din, for neither his wife nor his daughters was
any too fair to look upon. “They come not to Hodeidah.”
 “Ay-ee, were any so beautiful,” sighed Al Tadjaz, “there would be
no man worthy. But there are none.”
“Peace!” cried Ahmed. “Let us have the tale.”
“Yea, before he thinks him to plead for more anna,” muttered
Hadjaz, the sweeper, softly.
But Gazzar, not to be robbed of this evidence of interest, was
already astir. Even as they talked he held out the tambour, crying:
“Anna, anna, anna!” But so great was the opposition that he dared
not persist.
“Dog!” cried Waidi. “Wilt thou never be satisfied? There is another
for thee, but come no more.”
“Thou miser!” said Haifa, still greatly interested, “tell thy tale and
be done!”
“The thief has rupees and to spare, I warrant,” added Scudi,
contributing yet another anna.
And Zad-el-Din and Ahmed, because they were lustful of the great
beauty of Yanee, each added an anna to his takings.
“Berate me not, O friends,” pleaded Gazzar tactfully, hiding his
anna in his cloak, “for I am as poor as thou seest—a son of the road,
a beggar, a wanderer, with nowhere to lay my head. Other than my
tales I have nothing.” But seeing scant sympathy in the faces of his
hearers, he resumed.
“Now at the time that Abou was in charge of the dark bazaar it
chanced that the caliph, who annually arranged for the departure of
his daughter for the mountains which are beyond Azol in Bactria,
where he maintained a summer palace of great beauty, sent forth a
vast company mounted upon elephants and camels out of Ullar and
Cerf and horses of the rarest blood from Taif. This company was
caparisoned and swathed in silks and thin wool and the braided and
spun cloth of Esher and Bar with their knitted threads of gold. And it
made a glorious spectacle indeed, and all paused to behold. But it
also chanced that as this cavalcade passed through the streets of
Baghdad, Abou, hearing a great tumult and the cries of the multitude
and the drivers and the tramp of the horses’ feet and the pad of the
camels’, came to the door of his bazaar, his robes of silk about him,
a turban of rare cloth knitted with silver threads upon his head. He
had now grown to be a youth of eighteen summers. His hair was as
black as the wing of the duck, his eyes large and dark and sad from
many thoughts as is the pool into which the moon falls. His face and
hands were tinted as with henna when it is spread very thin, and his
manners were graceful and languorous. As he paused within his
doorway he looked wonderingly at the great company as it moved
and disappeared about the curves of the long street. And it could not
but occur to him, trained as he was, how rich would be the prize
could one but seize upon such a company and take all the wealth
that was here and the men and women as slaves.
“Yet, even as he gazed and so thought, so strange are the ways of
Allah, there passed a camel, its houdah heavy with rich silks, and
ornaments of the rarest within, but without disguised as humble, so
that none might guess. And within was the beautiful Princess Yanee,
hidden darkly behind folds of fluttering silk, her face and forehead
covered to her starry eyes, as is prescribed, and even these veiled.
Yet so strange are the ways of life and of Allah that, being young and
full of the wonder which is youth and the curiosity and awe which
that which is unknown or strange begets in us all, she was at this
very moment engaged in peeping out from behind her veils, the
while the bright panorama of the world was passing. And as she
looked, behold, there was Abou, gazing wonderingly upon her fine
accoutrements. So lithe was his form and so deep his eyes and so
fair his face that, transfixed as by a beam, her heart melted and
without thought she threw back her veil and parted the curtains of
the houdah the better to see, and the better that he might see. And
Abou, seeing the curtains put to one side and the vision of eyes that
were as pools and the cheeks as the leaf of the rose shine upon him,
was transfixed and could no longer move or think.
“So gazing, he stood until her camel and those of many others had
passed and turned beyond a curve of the street. Then bethinking
himself that he might never more see her, he awoke and ran after,
throwing one citizen and another to the right and the left. When at
last he came up to the camel of his fair one, guarded by eunuchs
and slaves, he drew one aside and said softly: ‘Friend, be not
wrathful and I will give thee a hundred dinars in gold do thou, within
such time as thou canst, report to me at the bazaar of Yussuf, the
rug-merchant, who it is that rides within this houdah. Ask thou only
for Abou. No more will I ask.’ The slave, noting his fine robes and the
green-and-silver turban, thought him to be no less than a noble, and
replied: ‘Young master, be not overcurious. Remember the
vengeance of the caliph.... ‘Yet dinars have I to give.’... ‘I will yet
come to thee.’
“Abou was enraptured by even so little as this, and yet dejected
also by the swift approach and departure of joy. ‘For what am I now?’
he asked himself. ‘But a moment since, I was whole and one who
could find delight in all things that were given me to do; but now I am
as one who is lost and knows not his way.’”
“Ay-ee,” sighed Azad Bakht, the barber, “I have had that same
feeling more than once. It is something that one may not overcome.”
“Al Tzoud, in the desert—” began Parfi, but he was interrupted by
cries of “Peace—Peace!”
“Thereafter, for all of a moon,” went on Gazzar, “Abou was as one
in a dream, wandering here and there drearily, bethinking him how
he was ever to know more of the face that had appeared to him
through the curtains of the houdah. And whether the driver of the
camel would ever return. As day after day passed and there was no
word, he grew thin and began to despair and to grow weary of life. At
last there came to his shop an aged man, long of beard and dusty of
garb, who inquired for Abou. And being shown him said: ‘I would
speak with thee alone.’ And when Abou drew him aside he said:
‘Dost thou recall the procession of the caliph’s daughter to Ish-Pari in
the mountains beyond Azol?’ And Abou answered, ‘Ay, by Allah!’
‘And dost thou recall one of whom thou madest inquiry?’ ‘Aye,’
replied Abou, vastly stirred. ‘I asked who it was that was being borne
aloft in state.’ ‘And what was the price for that knowledge?’ ‘A
hundred dinars.’ ‘Keep thy dinars—or, better yet, give them to me
that I may give them to the poor, for I bring thee news. She who was
in the houdah was none other than the Princess Yanee, daughter of
the caliph and heir to all his realm. But keep thou thy counsel and all
thought of this visit and let no one know of thy inquiry. There are
many who watch, and death may yet be thy portion and mine. Yet,
since thou art as thou art, young and without knowledge of life, here
is a spray of the myrtles of Ish-Pari—but thou art to think no further
on anything thou hast seen or heard. And thou dost not—death!’ He
made the sign of three fingers to the forehead and the neck and
gave Abou the spray, receiving in return the gold.”
“Marhallah!” cried Soudi. “How pleasant it is to think of so much
gold!”
“Yea,” added Haifa, “there is that about great wealth and beauty
and comfort that is soothing to the heart of every man.”
“Yet for ten more anna,” began Gazzar, “the price of a bed in the
stall of a camel, how much more glorious could I make it—the
sweetness of the love that might be, the wonder of the skill of Abou
—anna, anna—but five more, that I may take up this thread with
great heart.”
“Jackal!” screamed Ajeeb fiercely. “Thou barkst for but one thing—
anna. But now thou saidst if thou hadst but ten more, and by now
thou hast a hundred. On with thy tale!”
“Reremouse!” said Chudi. “Thou art worse than thy Yussuf
himself!” And none gave an anna more.
“Knowing that the myrtle was from the princess,” went on Gazzar
wearily, “and that henceforth he might seek but durst not even so
much as breathe of what he thought or knew, he sighed and returned
to his place in the bazaar.
“But now, Yussuf, returning not long after from a far journey, came
to Abou with a bold thought. For it related to no other thing than the
great treasury of the caliph, which stood in the heart of the city
before the public market, and was sealed and guarded and built of
stone and carried the wealth of an hundred provinces. Besides, it
was now the time of the taking of tithes throughout the caliphate, as
Yussuf knew, and the great treasury was filled to the roof, or so it
was said, with golden dinars. It was a four-square building of heavy
stone, with lesser squares superimposed one above the other after
the fashion of pyramids. On each level was a parapet, and upon
each side of every parapet as well as on the ground below there
walked two guards, each first away from the centre of their side to
the end and then back, meeting at the centre to reverse and return.
And on each side and on each level were two other guards. No two
of these, of any level or side, were permitted to arrive at the centre or
the ends of their parapet at the same time, as those of the parapets
above or below, lest any portion of the treasury be left unguarded.
There was but one entrance, which was upon the ground and facing
the market. And through this no one save the caliph or the caliph’s
treasurer or his delegated aides might enter. The guards ascended
and descended via a guarded stair. “Anna, O friends,” pleaded
Gazzar once more, “for now comes the wonder of the robbing of the
great treasury—the wit and subtlety of Abou—and craft and yet
confusion of the treasurer and the Caliph—anna!—A few miserable
anna!”
“Jackal!” shouted Azad Bakht, getting up. “Thou robbest worse
than any robber! Hast thou a treasury of thine own that thou hopest
to fill?”
“Give him no more anna,” called Feruz stoutly. “There is not an
anna’s worth in all his maunderings.”
“Be not unkind, O friends,” pleaded Gazzar soothingly. “As thou
seest, I have but twenty annas—not the price of a meal, let alone of
a bed. But ten—but—five—and I proceed.”
“Come, then, here they are,” cried Al Hadjaz, casting down four;
and Zad-el-Din and Haifa and Chudi each likewise added one, and
Gazzar swiftly gathered them up and continued:
“Yussuf, who had long contemplated this wondrous storehouse,
had also long racked his wits as to how it might be entered and a
portion of the gold taken. Also he had counseled with many of his
pupils, but in vain. No one had solved the riddle for him. Yet one day
as he and Abou passed the treasury on their way to the mosque for
the look of honor, Yussuf said to Abou: ‘Bethink thee, my son; here is
a marvelous building, carefully constructed and guarded. How
wouldst thou come to the store of gold within?’ Abou, whose
thoughts were not upon the building but upon Yanee, betrayed no
look of surprise at the request, so accustomed was he to having
difficult and fearsome matters put before him, but gazed upon it so
calmly that Yussuf exclaimed: ‘How now? Hast thou a plan?’ ‘Never
have I given it a thought, O Yussuf,’ replied Abou; ‘but if it is thy wish,
let us go and look more closely.’
“Accordingly, through the crowds of merchants and strangers and
donkeys and the veiled daughters of the harem and the idlers
generally, they approached and surveyed it. At once Abou observed
the movement of the guards, saw that as the guards of one tier were
walking away from each other those of the tiers above or below were
walking toward each other. And although the one entrance to the
treasury was well guarded still there was a vulnerable spot, which
was the crowning cupola, also four-square and flat, where none
walked or looked. ‘It is difficult,’ he said after a time, ‘but it can be
done. Let me think.’
“Accordingly, after due meditation and without consulting Yussuf,
he disguised himself as a dispenser of fodder for camels, secured a
rope of silk, four bags and an iron hook. Returning to his home he
caused the hook to be covered with soft cloth so that its fall would
make no sound, then fastened it to one end of the silken cord and
said to Yussuf: ‘Come now and let us try this.’ Yussuf, curious as to
what Abou could mean, went with him and together they tried their
weight upon it to see if it would hold. Then Abou, learning by
observation the hour at night wherein the guards were changed, and
choosing a night without moon or stars, disguised himself and
Yussuf as watchmen of the city and went to the treasury. Though it
was as well guarded as ever they stationed themselves in an alley
nearby. And Abou, seeing a muleteer approaching and wishing to
test his disguise, ordered him away and he went. Then Abou,
watching the guards who were upon the ground meet and turn, and
seeing those upon the first tier still in the distance but pacing toward
the centre, gave a word to Yussuf and they ran forward, threw the
hook over the rim of the first tier and then drew themselves up
quickly, hanging there above the lower guards until those of the first
tier met and turned. Then they climbed over the wall and repeated
this trick upon the guards of the second tier, the third and fourth, until
at last they were upon the roof of the cupola where they lay flat.
Then Abou, who was prepared, unscrewed one of the plates of the
dome, hooked the cord over the side and whispered: ‘Now, master,
which?’ Yussuf, ever cautious in his life, replied: ‘Go thou and report.’
“Slipping down the rope, Abou at last came upon a great store of
gold and loose jewels piled in heaps, from which he filled the bags
he had brought. These he fastened to the rope and ascended.
Yussuf, astounded by the sight of so much wealth, was for making
many trips, but Abou, detecting a rift where shone a star, urged that
they cease for the night. Accordingly, after having fastened these at
their waists and the plate to the roof as it had been, they descended
as they had come.”
“A rare trick,” commented Zad-el-Din.
“A treasury after mine own heart,” supplied Al Hadjaz.
“Thus for three nights,” continued Gazzar, fearing to cry for more
anna, “they succeeded in robbing the treasury, taking from it many
thousands of dinars and jewels. On the fourth night, however, a
guard saw them hurrying away and gave the alarm. At that, Abou
and Yussuf turned here and there in strange ways, Yussuf betaking
himself to his home, while Abou fled to his master’s shop. Once
there he threw off the disguise of a guard and reappeared as an
aged vendor of rugs and was asked by the pursuing guards if he had
seen anybody enter his shop. Abou motioned them to the rear of the
shop, where they were bound and removed by Yussuf’s robber
slaves. Others of the guards, however, had betaken themselves to
their captain and reported, who immediately informed the treasurer.
Torches were brought and a search made, and then he repaired to
the caliph. The latter, much astonished that no trace of the entrance
or departure of the thieves could be found, sent for a master thief
recently taken in crime and sentenced to be gibbeted, and said to
him:
“‘Wouldst thou have thy life?’
 “‘Aye, if thy grace will yield it.’
“‘Look you,’ said the caliph. ‘Our treasury has but now been
robbed and there is no trace. Solve me this mystery within the moon,
and thy life, though not thy freedom, is thine.’
“‘O Protector of the Faithful,’ said the thief, ‘do thou but let me see
within the treasury.’
“And so, chained and in care of the treasurer himself and the
caliph, he was taken to the treasury. Looking about him he at length
saw a faint ray penetrating through the plate that had been loosed in
the dome.
“‘O Guardian of the Faithful,’ said the thief wisely and hopefully,
‘do thou place a cauldron of hot pitch under this dome and then see
if the thief is not taken.’
“Thereupon the caliph did as advised, the while the treasury was
resealed and fresh guards set to watch and daily the pitch was
renewed, only Abou and Yussuf came not. Yet in due time, the
avarice of Yussuf growing, they chose another night in the dark of
the second moon and repaired once more to the treasury, where, so
lax already had become the watch, they mounted to the dome. Abou,
upon removing the plate, at once detected the odor of pitch and
advised Yussuf not to descend, but he would none of this. The
thought of the gold and jewels into which on previous nights he had
dipped urged him, and he descended. However, when he neared the
gold he reached for it, but instead of gold he seized the scalding
pitch, which when it burned, caused him to loose his hold and fall.
He cried to Abou: ‘I burn in hot pitch. Help me!’ Abou descended and
took the hand but felt it waver and grow slack. Knowing that death
was at hand and that should Yussuf’s body be found not only himself
but Yussuf’s wife and slaves would all suffer, he drew his scimitar,
which was ever at his belt, and struck off the head. Fastening this to
his belt, he reascended the rope, replaced the plate and carefully
made his way from the treasury. He then went to the house of Yussuf
and gave the head to Yussuf’s wife, cautioning her to secrecy.
 “But the caliph, coming now every day with his treasurer to look at
the treasury, was amazed to find it sealed and yet the headless body
within. Knowing not how to solve the mystery of this body, he
ordered the thief before him, who advised him to hang the body in
the market-place and set guards to watch any who might come to
mourn or spy. Accordingly, the headless body was gibbeted and set
up in the market-place where Abou, passing afar, recognized it.
Fearing that Mirza, the wife of Yussuf, who was of the tribe of the
Veddi, upon whom it is obligatory that they mourn in the presence of
the dead, should come to mourn here, he hastened to caution her.
‘Go thou not thither,’ he said; ‘or, if thou must, fill two bowls with milk
and go as a seller of it. If thou must weep drop one of the bowls as if
by accident and make as if thou wept over that.’ Mirza accordingly
filled two bowls and passing near the gibbet in the public square
dropped one and thereupon began weeping as her faith demanded.
The guards, noting her, thought nothing—‘for here is one,’ said they,
‘so poor that she cries because of her misfortune.’ But the caliph,
calling for the guards at the end of the day to report to himself and
the master thief, inquired as to what they had seen. ‘We saw none,’
said the chief of the guard, ‘save an old woman so poor that she
wept for the breaking of a bowl!’ ‘Dolts!’ cried the master thief. ‘Pigs!
Did I not say take any who came to mourn? She is the widow of the
thief. Try again. Scatter gold pieces under the gibbet and take any
that touch them.’
“The guards scattered gold, as was commanded, and took their
positions. Abou, pleased that the widow had been able to mourn and
yet not be taken, came now to see what more might be done by the
caliph. Seeing the gold he said: ‘It is with that he wishes to tempt.’ At
once his pride in his skill was aroused and he determined to take
some of the gold and yet not be taken. To this end he disguised
himself as a ragged young beggar and one weak of wit, and with the
aid of an urchin younger than himself and as wretched he began to
play about the square, running here and there as if in some game.
But before doing this he had fastened to the sole of his shoes a thick
gum so that the gold might stick. The guards, deceived by the
seeming youth and foolishness of Abou and his friend, said: ‘These
are but a child and a fool. They take no gold.’ But by night, coming to
count the gold, there were many pieces missing and they were sore
afraid. When they reported to the caliph that night he had them
flogged and new guards placed in their stead. Yet again he
consulted with the master thief, who advised him to load a camel
with enticing riches and have it led through the streets of the city by
seeming strangers who were the worse for wine. ‘This thief who
eludes thee will be tempted by these riches and seek to rob them.’
“Soon after it was Abou, who, prowling about the market-place,
noticed this camel laden with great wealth and led by seeming
strangers. But because it was led to no particular market he thought
that it must be of the caliph. He decided to take this also, for there
was in his blood that which sought contest, and by now he wished
the caliph, because of Yanee, to fix his thought upon him. He filled a
skin with the best of wine, into which he placed a drug of the dead
Yussuf’s devising, and dressing himself as a shabby vendor, set
forth. When he came to the street in which was the camel and saw
how the drivers idled and gaped, he began to cry, ‘Wine for a para! A
drink of wine for a para!’ The drivers drank and found it good,
following Abou as he walked, drinking and chaffering with him and
laughing at his dumbness, until they were within a door of the house
of Mirza, the wife of the dead Yussuf, where was a gate giving into a
secret court. Pausing before this until the wine should take effect, he
suddenly began to gaze upward and then to point. The drivers
looked but saw nothing. And the drug taking effect they fell down;
whereupon Abou quickly led the camel into the court and closed the
gate. When he returned and found the drivers still asleep he shaved
off half the hair of their heads and their beards, then disappeared
and changed his dress and joined those who were now laughing at
the strangers in their plight, for they had awakened and were running
here and there in search of a camel and its load and unaware of their
grotesque appearance. Mirza, in order to remove all traces, had the
camel killed and the goods distributed. A careful woman and
housewifely, she had caused all the fat to be boiled from the meat
and preserved in jars, it having a medicinal value. The caliph, having
learned how it had gone with his camel, now meditated anew on how
this great thief, who mocked him and who was of great wit, might be
taken. Calling the master thief and others in council he recited the
entire tale and asked how this prince of thieves might be caught. ‘Try
but one more ruse, O master,’ said the master thief, who was now
greatly shaken and feared for his life. ‘Do thou send an old woman
from house to house asking for camel’s grease. Let her plead that it
is for one who is ill. It may be that, fearing detection, the camel has
been slain and the fat preserved. If any is found, mark the door of
that house with grease and take all within.’
“Accordingly an old woman was sent forth chaffering of pain. In
due time she came to the house of Mirza, who gave her of the
grease, and when she left she made a cross upon the door. When
she returned to the caliph he called his officers and guards and all
proceeded toward the marked door. In the meantime Abou, having
returned and seen the mark, inquired of Mirza as to what it meant.
When told of the old woman’s visit he called for a bowl of the camel’s
grease and marked the doors in all the nearest streets. The caliph,
coming into the street and seeing the marks, was both enraged and
filled with awe and admiration for of such wisdom he had never
known. ‘I give thee thy life,’ he said to the master thief, ‘for now I see
that thou art as nothing to this one. He is shrewd beyond the wisdom
of caliphs and thieves. Let us return,’ and he retraced his steps to
the palace, curious as to the nature and soul of this one who could
so easily outwit him.
“Time went on and the caliph one day said to his vizier: ‘I have
been thinking of the one who robbed the treasury and my camel and
the gold from under the gibbet. Such an one is wise above his day
and generation and worthy of a better task. What think you? Shall I
offer him a full pardon so that he may appear and be taken—or think
you he will appear?’ ‘Do but try it, O Commander of the Faithful,’ said
the vizier. A proclamation was prepared and given to the criers, who
announced that it was commanded by the caliph that, should the
great thief appear on the market-place at a given hour and yield
himself up, a pardon full and free would be granted him and gifts of
rare value heaped upon him. Yet it was not thus that the caliph
intended to do.
“Now, Abou, hearing of this and being despondent over his life and
the loss of Yanee and the death of Yussuf and wishing to advantage
himself in some way other than by thievery, bethought him how he
might accept this offer of the caliph and declare himself and yet,
supposing it were a trap to seize him, escape. Accordingly he
awaited the time prescribed, and when the public square was filled
with guards instructed to seize him if he appeared he donned the
costume of a guard and appeared among the soldiers dressed as all
the others. The caliph was present to witness the taking, and when
the criers surrounding him begged the thief to appear and be
pardoned, Abou called out from the thick of the throng: ‘Here I am, O
Caliph! Amnesty!’ Whereupon the caliph, thinking that now surely he
would be taken, cried: ‘Seize him! Seize him!’ But Abou, mingling
with the others, also cried: ‘Seize him! Seize him!’ and looked here
and there as did the others. The guards, thinking him a guard,
allowed him to escape, and the caliph, once more enraged and
chagrined, retired. Once within his chambers he called to him his
chief advisers and had prepared the following proclamation:

“‘BE IT KNOWN TO ALL

“‘Since within the boundaries of our realm there exists
one so wise that despite our commands and best efforts
he is still able to work his will against ours and to elude
our every effort to detect him, be it known that from having
been amazed and disturbed we are now pleased and
gratified that one so skilful of wit and resourceful should
exist in our realm. To make plain that our appreciation is
now sincere and our anger allayed it is hereby covenant
with him and with all our people, to whom he may appeal if
we fail in our word, that if he will now present himself in
person and recount to one whom we shall appoint his
various adventures, it will be our pleasure to signally
distinguish him above others. Upon corroboration by us of
that which he tells, he shall be given riches, our royal
friendship and a councillor’s place in our council. I have
said it.
“‘Yianko I.’
 “This was signed by the caliph and cried in the public places. Abou
heard all but because of the previous treachery of the caliph he was
now unwilling to believe that this was true. At the same time he was
pleased to know that he was now held in great consideration, either
for good or ill, by the caliph and his advisers, and bethought him that
if it were for ill perhaps by continuing to outwit the caliph he might
still succeed in winning his favor and so to a further knowledge of
Yanee. To this end he prepared a reply which he posted in the public
square, reading:

“‘PROCLAMATION BY THE ONE WHOM

THE CALIPH SEEKS
“‘Know, O Commander of the Faithful, that the one
whom the caliph seeks is here among his people free from
harm. He respects the will of the caliph and his good
intentions, but is restrained by fear. He therefore requests
that instead of being commanded to reveal himself the
caliph devise a way and appoint a time where in darkness
and without danger to himself he may behold the face of
the one to whom he is to reveal himself. It must be that
none are present to seize him.
“‘The One Whom the Caliph Seeks.’

“Notice of this reply being brought to the caliph he forthwith took

counsel with his advisers and decided that since it was plain the thief
might not otherwise be taken, recourse must be had to a device that
might be depended upon to lure him. Behind a certain window in the
palace wall known as ‘The Whispering Window,’ and constantly used
by all who were in distress or had suffered a wrong which owing to
the craft of others there was no hope of righting, sat at stated times
and always at night, the caliph’s own daughter Yanee, whose tender
heart and unseeking soul were counted upon to see to it that the
saddest of stories came to the ears of the caliph. It was by this
means that the caliph now hoped to capture the thief. To insure that
the thief should come it was publicly announced that should any one
that came be able to tell how the treasury had been entered and the
gold pieces taken from under the gibbet or the camel stolen and
killed, he was to be handed a bag of many dinars and a pardon in
writing; later, should he present himself, he would be made a
councillor of state.
“Struck by this new proclamation and the possibility of once more
beholding the princess, Abou decided to match his skill against that
of the caliph. He disguised himself as a vendor of tobacco and
approached the window, peered through the lattice which screened it
and said: ‘O daughter of the great caliph, behold one who is in
distress. I am he whom the caliph seeks, either to honor or slay, I
know not which. Also I am he who, on one of thy journeys to the
mountain of Azol and thy palace at Ish-Pari thou beheldest while
passing the door of my father’s rug-market, for thou didst lift the
curtains of thy houdah and also thy veil and didst deign to smile at
me. And I have here,’ and he touched his heart, ‘a faded spray of the
myrtles of Ish-Pari, or so it has been told me, over which I weep.’
“Yanee, shocked that she should be confronted with the great thief
whom her father sought and that he should claim to be the beautiful
youth she so well remembered, and yet fearing this to be some new
device of the vizier or of the women of the harem, who might have
heard of her strange love and who ever prayed evil against all who
were younger or more beautiful than they, she was at a loss how to
proceed. Feeling the need of wisdom and charity, she said: ‘How
sayst thou? Thou are the great thief whom my father seeks and yet
the son of a rug-merchant on whom I smiled? Had I ever smiled on a
thief, which Allah forbid, would I not remember it and thee?
Therefore, if it be as thou sayst, permit it that I should have a light
brought that I may behold thee. And if thou art the rug-merchant’s
son or the great thief, or both, and wishest thy pardon and the bag of
dinars which here awaits thee, thou must relate to me how it was the
treasury was entered, how the gold was taken from under the gibbet
and my father’s camel from its drivers.’ ‘Readily enough, O Princess,’
replied Abou, ‘only if I am thus to reveal myself to thee must I not
know first that thou art the maiden whom I saw? For she was kind as
she was fair and would do no man an ill. Therefore if thou wilt lower
thy veil, as thou didst on the day of thy departure, so that I may see,
I will lift my hood so that thou mayst know that I lie not.’
“The princess, troubled to think that the one whom she had so
much admired might indeed be the great thief whose life her father
sought, and yet wavering between duty to her father and loyalty to
her ideal, replied: ‘So will I, but upon one condition: should it be that
thou art he upon whom thou sayst I looked with favor and yet he who
also has committed these great crimes in my father’s kingdom, know
that thou mayst take thy pardon and thy gold and depart; but only
upon the condition that never more wilt thou trouble either me or my
father. For I cannot bear to think that I have looked with favor upon
one who, however fair, is yet a thief.’
“At this Abou shrank inwardly and a great sorrow fell upon him; for
now, as at the death of Yussuf, he saw again the horror of his way.
Yet feeling the justice of that which was said, he answered: ‘Yea, O
Princess, so will I, for I have long since resolved to be done with evil,
which was not of my own making, and will trouble thee no more.
Should this one glance show me that beloved face over which I have
dreamed, I will pass hence, never more to return, for I will not dwell
in a realm where another may dwell with thee in love. I am, alas, the
great thief and will tell thee how I came by the gold under the gibbet
and in thy father’s treasury; but I will not take his gold. Only will I
accept his pardon sure and true. For though born a thief I am no
longer one.’ The princess, struck by the nobility of these words as
well as by his manner, said sadly, fearing the light would reveal the
end of her dreams: ‘Be it so. But if thou art indeed he thou wilt tell
me how thou camest to be a thief, for I cannot believe that one of
whom I thought so well can do so ill.’
“Abou, sadly punished for his deeds, promised, and when the
torch was brought the princess lifted her veil. Then it was that Abou
again saw the face upon which his soul had dwelt and which had
caused him so much unrest. He was now so moved that he could not
speak. He drew from his face its disguise and confronted her. And
Yanee, seeing for the second time the face of the youth upon whom
her memory had dwelt these many days, her heart misgave her and
she dared not speak. Instead she lowered her veil and sat in silence,
the while Abou recounted the history of his troubled life and early
youth, how he could recall nothing of it save that he had been beaten
and trained in evil ways until he knew naught else; also of how he
came to rob the treasury, and how the deeds since of which the
caliph complained had been in part due to his wish to protect the
widow of Yussuf and to defeat the skill of the caliph. The princess,
admiring his skill and beauty in spite of his deeds, was at a loss how
to do. For despite his promise and his proclamation, the caliph had
exacted of her that in case Abou appeared she was to aid in his
capture, and this she could not do. At last she said: ‘Go, and come
no more, for I dare not look upon thee, and the caliph wishes thee
only ill. Yet let me tell my father that thou wilt trouble him no more,’ to
which Abou replied: ‘Know, O Princess, thus will I do.’ Then opening
the lattice, Yanee handed him the false pardon and the gold, which
Abou would not take. Instead he seized and kissed her hand
tenderly and then departed.
“Yanee returned to her father and recounted to him the story of the
robbery of the treasury and all that followed, but added that she had
not been able to obtain his hand in order to have him seized
because he refused to reach for the gold. The caliph, once more
chagrined by Abou’s cleverness in obtaining his written pardon
without being taken, now meditated anew on how he might be
trapped. His daughter having described Abou as both young and
handsome, the caliph thought that perhaps the bait of his daughter
might win him to capture and now prepared the following and last
pronunciamento, to wit:

“‘TO THE PEOPLE OF BAGHDAD

“‘Having been defeated in all our contests with the one
who signs himself The One Whom the Caliph Seeks, and
yet having extended to him a full pardon signed by our
own hand and to which has been affixed the caliphate
seal, we now deign to declare that if this wisest of