Clinical management of thyroid disease

386 Pages·2009·10.086 MB·English

by  F. Wondisford, S. Radovick

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CLINICAL MANAGEMENT OF THYROID DISEASE   ISBN: 978-1-4160-4745-2
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Library of Congress Cataloging-in-Publication Data
Clinical management of thyroid disease/[edited by] Fredric E. Wondisford; associate editor,  
Sally Radovick—1st ed.
p. ; cm
ISBN 978-1-4160-4752-2
1. Thyroid gland—Diseases—Textbooks. I. Wondisford, Fredric E. II. Radovick, Sally.  
[DNLM: 1. Thyroid Diseases—therapy. 2. Thyroid diseases— physiopathology. WK 200 c641 2009] 
RC655.C63 2009 
616.4’4—dc22  2009001594
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Publishing Services Manager: Frank Polizzano
Senior Project Manager: Robin E. Hayward
Design Direction: Louis Forgione
Printed in China.
Last digit is the print number: 9  8  7  6  5  4  3  2  1
Contributors
Suzanne Myers Adler, MD Alexandra M. Dumitrescu, MD, PhD
Chronic Thyroiditis Postdoctoral Scholar, Department of Medicine, University of 
Chicago, Chicago, Illinois
Kenneth B. Ain Cell Transport Defects
Follicular Carcinoma
Thomas P. Foley, Jr., MD
Douglas W. Ball Professor Emeritus, Department of Pediatrics, Division of 
Associate Professor of Medicine and Oncology, Johns  Endocrinology, University of Pittsburgh School of Medicine; 
Hopkins University School of Medicine, Baltimore,  Director Emeritus, Division of Pediatric Endocrinology, 
Maryland Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Medullary Thyroid Cancer Hypothyroidism
Paolo Beck-Peccoz, MD Stephanie Gaillard
Professor of Endocrinology, Department of Medical  Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone
Sciences, Endocrinology and Metabolism Unit, Fondazione  Receptor
Ospedale Maggiore IRCCS, Milan, Italy
Thyroid-Stimulating Hormone–Induced Hyperfunction Annette Grueters
Pediatric Endocrinology, University Children’s Hospitale 
Antonio C. Bianco, MD Charite, Berlin, Germany
Harvard Medical School; Thyroid Section, Division   Screening for Congenital Disease
of Endocrinology, Diabetes, and Hypertension, Brigham  
and Women’s Hospital, Boston, Massachusetts Koshi Hashimoto, MD
Thyroid Hormone Metabolism Assistant Professor, Department of Medicine and Molecular 
Science, Gunma University Graduate School of Medicine, 
Gregory Brent Maebashi, Gunma, Japan
Endocrinology and Diabetes Division, VA Greater Los  Thyroiditis
Angeles Healthcare System, Los Angeles, California
Pregnancy Bryan R. Haugen
General Clinical Research Center, University of Colorado, 
Kenneth D. Burman Denver, Colorado
Chief, Endocrine Section, Washington Hospital Center,  Solitary Thyroid Nodule
Washington DC
Chronic Thyroiditis Jerome M. Hershman
UCLA/VA Greater Los Angeles Healthcare System,  
Naifa L. Busaidy Los Angeles, California
University of Texas M. D. Anderson Cancer Center, Division  Hyperthyroidism and Trophoblastic Disease
of Internal Medicine, Department of Endocrine Neoplasia 
and Hormonal Disorders, Houston, Texas Jason M. Hollander, MD
Papillary Thyroid Carcinoma Department of Medicine, Division of Endocrinology, 
Diabetes, and Bone Diseases, Mount Sinai School of 
Patrizio Caturegli, MD Medicine, New York, New York
Anatomy of the Hypothalamic-Pituitary-Thyroid Axis Graves’ Disease
Ronald N. Cohen Anthony N. Hollenberg, MD
Drugs Associate Professor, Harvard Medical School; Chief, Thyroid 
Unit, Beth Israel Deaconess Medical Center, Boston, 
Terry F. Davies, MD
Massachusetts
Mount Sinai Medical Center, New York, New York
Role of Thyroid-Releasing Hormone in the Regulation of the Thyroid
Graves’ Disease
Axis
Mario De Felice, MD
Brian W. Kim, MD
Professor of Pathology, Department of Molecular Biology and 
Thyroid section, Division of Endocrinology, Diabetes, and 
Pathology, University of Naples, Federico II, Naples, Italy; 
Hypertension, Department of Medicine, Brigham and 
Scientific Coordinator, Biogem scarl, Ariano Irpino, Italy
Women’s Hospital, Boston, Massachusetts
Thyroid Development
Thyroid Hormone Metabolism
Roberto Di Lauro, MD
Richard T. Kloos
Professor of Human Genetics, Department of Cellular and 
Papillary Thyroid Carcinoma
Molecular Biology and Pathology, University of Naples, 
Federico II, Naples, Italy
Thyroid Development

Contributors
Ronald J. Koenig, MD, PhD Tetsuro Satoh, MD
University of Michigan Medical Center, Ann Arbor, Michigan Assistant Professor, Department of Medicine and Molecular 
Nonthyroidal Illness Syndrome Science, Gunma University Graduate School of Medicine, 
Maebashi, Gunma, Japan
Peter Kopp, MD Thyroiditis
Associate Professor and Associate Division Chief for 
Education, Division of Endocrinology, Metabolism, and  Pamela R. Schroeder, MD
Molecular Medicine, Northwestern University, Chicago,  Johns Hopkins University, Department of Endocrinology 
Illinois and Metabolism, Baltimore, Maryland
Thyroid Hormone Synthesis Toxic Nodular Goiter: Toxic Adenoma and Toxic Multinodular
Goiter
Paul W. Ladenson
Johns Hopkins University, Department of Endocrinology  Aniket Sidhaye
and Metabolism, Baltimore, Maryland Johns Hopkins University, Department of Endocrinology 
Toxic Nodular Goiter: Toxic Adenoma and Toxic Multinodular and Metabolism, Baltimore, Maryland
Goiter Central Hypothyroidism
Melissa Landek Juan Carlos Solis, MD
Anatomy of the Hypothalamic-Pituitary-Thyroid Axis Division of Endocrinology, Metabolism, and Molecular 
Medicine, Northwestern University, Chicago, Illinois
Juliane Léger, MD Thyroid Hormone Synthesis
Professor of Pediatrics, Paris 7 University; Professor of 
Pediatrics, Pediatric Endocrinology Unit and Reference  Emily J. Tan
Center for Endocrine Growth Disease, Hospital Robert  UCLA/VA Greater Los Angeles Healthcare System, Los 
Debre, Paris, France Angeles, California
Hyperthyroidism Hyperthyroidism and Trophoblastic Disease
Meranda Nakhla, MD Neil Tran
Assistant Professor and Pediatric Endocrinologist, Division  Division of Endocrinology and Diabetes, UCLA/VA Greater 
of Endocrinology and Metabolism, Children’s Hospital of  Los Angeles Healthcare System, Los Angeles, California
Eastern Ontario, Ottawa, Ontario, Canada Pregnancy
Hypothyroidism
Guy Van Vliet, MD
Joanna M. Peloquin Professor of Pediatrics, University of Montreal Medical 
Nontoxic Diffuse and Nodular Goiter School; Chief, Endocrinology Service, CHU Sainte-Justine, 
Montreal, Quebec, Canada
Luca Persani, MD Genetics and Epigenetics of Congenital Hypothyroidism
Fondazione Ospedale Maggiore IRCCS, Milan, Italy
Thyroid-Stimulating Hormone–Induced Hyperfunction Roy E. Weiss, MD
The University of Chicago, Chicago, Illinois
Samuel Refetoff Syndromes of Resistance to Thyroid Hormone
The University of Chicago, Chicago, Illinois
Syndromes of Resistance to Thyroid Hormone; Cell Transport Defects Fredric E. Wondisford, MD
Professor and Chief, Metabolism Division, Departments of 
Joanne F. Rovet, PhD Pediatrics, Medicine, and Physiology; Director, Diabetes 
Professor of Pediatrics and Psychology, University of Toronto  Research and Training Center, Johns Hopkins University 
Medical School; Senior Scientist, Neuroscience and Mental  School of Medicine,
Health Program, The Hospital for Sick Children, Toronto,  Baltimore, Maryland
Ontario, Canada Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone
Hypothyroidism Receptor; Nontoxic Diffuse and Nodular Goiter
Amin Sabet, MD Masanobu Yamada
Johns Hopkins University, Baltimore, Maryland Department of Medicine and Molecular Science, Gunma 
Thyroid Hormone Action University Graduate School of Medicine, Maebashi, Gunma, 
Japan
Sherif Said
Thyroiditis
Solitary Thyroid Nodule
Paul M. Yen
Thyroid Hormone Action


section a
anatomy
anatomy of the
hypothalamic-pituitary-thyroid
Chapter
1
axis
Melissa Landek and Patrizio Caturegli������
Key points
n The thyroid is regulated mainly by pituitary TSH and hypothalamic TRH.
n The thyroid is the largest endocrine gland and is made of a collection of follicles that synthesize
and store thyroid hormones.
The thyroid has the longest phylogenetic history of all
hypothalamus and pituitary
endocrine glands, being present not only in all verte-­
brates but also in protochordates (e.g., the lancelet)
hypothalamic thyrotropin-releasing
and ascidians (e.g., the sea squirt). In humans and
hormone neurons
most vertebrates, the thyroid gland is situated in the
neck, but its gross morphologic arrangement varies The neurons that produce TRH and are involved
among species. For example, in teleost fish such as in the regulation of the thyroid gland via the ante-­
the tuna, thyroid follicles aggregate along blood ves-­ rior hypophysis (hypophysiotropic TRH neurons)
sels and occasionally can be found far away from the are located in the paraventricular nucleus of the
neck, even in the kidney. hypothalamus. This is an intricate structure adjacent
The main goal of the thyroid is to produce to the third ventricle composed of two major parts,
and store thyroid hormones, which are involved in a lateral part containing magnocellular neurons and
numerous fundamental processes ranging from body a medial part with parvocellular neurons. Each part
growth, differentiation, and metamorphosis to ther-­ has numerous subdivisions; the hypophysiotropic
mogenesis. Thyroid hormone synthesis is regulated by TRH neurons are in the medial and periventricular
a complex interplay involving the thyroid-­stimulating parvocellular subdivisions.1 These neurons project
hormone (TSH, thyrotropin), secreted by the ante-­ their processes to the median eminence, where they
rior hypophysis, and the thyrotropin-­releasing hor-­ release TRH, a tripeptide hormone synthesized from
mone (TRH), secreted by the hypothalamus, as well a large precursor of 242 amino acids that contains
as other factors. This chapter will discuss the key six copies of TRH. TRH then diffuses to the anterior
anatomic features of the hypothalamic-­pituitary thy-­ pituitary through the portal circulation, and binds to
roid axis. a specific G protein– coupled receptor present on the
plasma membrane of the thyrotrophs.2 The binding
*Supported by grant DK55670 from the National Institutes initiates a cascade of intracellular events that leads to
of Health. the prompt secretion and glycosylation of TSH.

Part I normal thyroid axis
The synthesis of TRH by hypophysiotropic stimulated cells are known as thyroidectomy cells;
neurons is inhibited by fasting and restored to nor-­ they have an eccentric nucleus and abundant cyto-­
mal by feeding or the administration of leptin.3 The plasm containing dilated rough endoplasmic reticu-­
action of leptin occurs mainly through the arcuate lum, a prominent Golgi apparatus, large lysosomes,
nucleus of the hypothalamus,4 but also through oth-­ and few secretory granules.6,7 This hyperplasia and
er regions of the brain, such as the brainstem, fourth hypertrophy secondary to hypothyroidism can cause
ventricle, and dorsal vagal complex, which all inner-­ a radiologically detectable enlargement of the pitu-­
vate the paraventricular nucleus by monosynaptic or itary gland and mimic a pituitary tumor. The dis-­
multisynaptic projections. tinction between the two entities is critical for the
TRH-­producing neurons are also located in patient because the pituitary enlargement caused
the anterior subdivision of the parvocellular neu-­ by thyrotroph hyperplasia and hypertrophy does
rons. Although similarly regulated by fasting, they not require surgery and is reversible on thyroid hor-­
are anatomically and functionally distinct from the mone replacement.
hypophysiotropic neurons described. Their role is TSH is a 28-­kD glycoprotein hormone com-­
poorly known. They remind us that TRH, in addi-­ posed of two subunits, alpha and beta. The alpha
tion to its control of the hypothalamic-­pituitary subunit is shared among follicle-­stimulating hor-­
thyroid axis, exerts other effects on the central ner-­ mone, luteinizing hormone, and human chorionic
vous system centered on food intake and thermo-­ gonadotropin; the beta subunit, instead, is specific
regulation. for TSH. TSH binds to a specific G protein–coupled
receptor, located on the basolateral membrane of
pituitary thyrotrophs
thyroid follicular cells, and is the master regulator of
The cells of the anterior pituitary that produce TSH thyroid gland function.
(thyrotrophs) are the least abundant cell type, com-­
thyroid Gland
prising less than 5% of the total adenohypophyseal
cell population. They are located in isolation or in The thyroid gland develops from a diverticulum of
small clusters in the anteromedial portion of the the pharynx, similarly to the adenohypophysis, para-­
pituitary gland. Thyrotrophs are basophilic (a shade thyroid glands, and thymus. It originates at the base
of blue color) when stained by conventional dyes of the tongue (as evidenced by the foramen cecum)
such as hematoxylin and eosin, and contain periodic and migrates downward along the midline to its final
acid–Schiff (PAS) material, but can only be identi-­ location by the trachea. The course of this migration
fied with certainty by immunohistochemistry using is indicated by the thyroglossal duct, remnants of
an antibody specific for the beta subunit of TSH. which become apparent in adult life when they give
Thyrotrophs are medium to large elongated angu-­ rise to mucus-­filled cysts.
lar cells, with a central nucleus, abundant cytoplasm, The thyroid is composed of two pear-­shaped
and cytoplasmic processes. The secretory granules of lobes, bordering the right and left sides of the tra-­
thyrotrophs are small, 100 to 200 nm, round, elec-­ chea and held together by an isthmus, giving over-­
tron-­dense, and often positioned near the plasma all the appearance of a Greek shield. It is the largest
membrane. endocrine gland, weighing about 2 g at birth and 15 g
Thyrotrophs are constant throughout in adults. In about 50% of the population, a third
life and similar in both genders. Their cytologic lobe, called the pyramidal lobe, emerges upward
appearance, however, is affected by the secretion from the isthmus, most commonly from its left part.8
of TSH. In cases of hyperthyroidism, secretion of Its presence is not reliably diagnosed by scintigraphic
TSH is suppressed, the thyrotrophs become small, or ultrasound imaging; the anterior cervical region
and their immunoreactivity for TSH-­β is greatly should be investigated carefully during surgery so
diminished or almost absent.5 When patients with as not to leave residual thyroid tissue when total thy-­
hyperthyroidism are treated, thyrotrophs return roidectomy is indicated.8
to their original size and TSH-­β immunoreactivity The thyroid gland has a rich blood flow of
returns to normal.5 In patients with long-­standing approximately 5 mL/g/min, supplied by the supe-­
hypothyroidism, the thyrotrophs undergo hypertro-­ rior, inferior, and lowest accessory thyroid arteries.
phy and hyperplasia.6 The thyrotroph area within There is significant variation in the anatomy of these
the anterior pituitary enlarges and the thyrotrophs arteries, both among races and within individuals of
extend to other regions of the anterior pituitary. the same race.9 This is a critical consideration dur-­
These changes are caused by the loss of the negative ing imaging of the parathyroid glands and en bloc
feedback of thyroid hormones. These chronically transplantation of larynx and thyroid. In Graves’

Anatomy of the Hypothalamic-Pituitary-Thyroid Axis
disease or other hyperthyroid states, the blood flow is functional activity of the gland. They become thin
markedly increased, so that a thrilling vibration can and flat in hypothyroid states, and much taller and
be felt when palpating the gland. Venous drainage columnar in hyperthyroidism. Thyroid follicular
occurs via the superior, lateral, and inferior veins and cells (thyrocytes) have a clear polarity—their apex
lymphatic drainage is into the cervical lymph nodes, is oriented toward the colloid-­filled lumen of the fol-­
which are frequently involved in metastatic papillary licle, whereas their base is toward the interfollicular
thyroid cancer. space.12 The apex is densely populated by micro-­
The thyroid makes contact with two important villi that project into the central colloid, and the
structures, which can be damaged by an inexperien-­ base is separated from the interfollicular space by
ced surgeon during thyroidectomy. The parathyroid a basement membrane approximately 400 Å thick.
glands, usually four in humans, are often located Thyrocyte activity is stimulated by TSH and also by
behind the thyroid lobes, but their location is extremely factors that mimic TSH action, such as the antibod-­
variable, so that extreme care must be taken during ies against the TSH receptor found in patients with
surgery to preserve their integrity. Graves’ disease.
The inferior laryngeal nerve, better known as In the interfollicular space, fenestrated capil-­
the recurrent nerve, is a branch of the vagus nerve laries and collagen fibers are found, and occasionally
that supplies motor function and sensation to the lar-­ one or two circulating lymphocytes. Dietary iodine
ynx. It follows a tortuous route because it descends enters the thyrocytes at this basolateral surface
down into the thorax and then ascends back up in the through the action of the sodium iodide symporter.13
neck, running between the trachea and esophagus It then moves through the thyrocyte, reaching the
behind the thyroid gland. The left recurrent nerve apex, where it is incorporated by thyroperoxidase
loops under and around the arch of the aorta before onto specific tyrosines of the large thyroglobulin
ascending, whereas the right one loops around the molecule. Thyroglobulin is the most abundant pro-­
right subclavian artery. These nerves can be damaged tein of the thyroid gland, representing about 20% of
during thyroidectomy and cause dysphonia and less the total thyroid weight. Thyroglobulin is found in
efficient coughing. the colloid and inside the thyrocytes (Fig. 1-­1). When
The superior laryngeal nerve can also be thyroid hormones are needed, portions of colloid
injured during thyroidectomy, although its lesion are engulfed at the apex by pseudopodia, enclosed
usually goes unrecognized because it is clinically sub-­ in vacuoles within the thyrocytes and hydrolyzed to
tle. The lesion was publicized by the operatic soprano release thyroxine and also triiodothyronine into the
Amelita Galli-­Curci, who underwent thyroidectomy bloodstream.
in 1935 for a large (170-­g) nontoxic multinodular This follicular structure, with a central depot
goiter and was apparently incapable of reaching the area, renders the thyroid unique among endocrine
high notes afterward, although a report has discred-­ glands because it is the only gland in which hor-­
ited the story.10 mones are stored in an extracellular location. It has
The thyroid gland is attached loosely to probably evolved in response to the uncertain and
neighboring structures, especially in the posterior scarce availability of iodine in the environment.
and inferior sides, so that a thyroid enlargement Iodine is the key component of thyroid hormones,
(goiter) will most commonly extend backward and which have a simple chemical structure (two modi-­
downward, or even below the sternum. The thyroid fied tyrosines) and yet are fundamental in numerous
is encapsulated by a fine connective tissue, which processes, from brain development to body growth
invaginates into the gland to form smaller lobules. and thermoregulation.
Each lobule is composed of about 30 follicles, which In addition to the thyrocytes, the thyroid
represent the functional unit of the gland. There are gland also contains parafollicular cells, or C cells.
approximately 3 million follicles in an adult thyroid. These are neuroendocrine cells that originate from
Each follicle can be compared to a watermelon, with the ultimobranchial body, which develops from the
the red, largest inner part corresponding to the col-­ fourth pharyngeal pouch and then migrates into the
loid and the green thin capsule representing the thy-­ thyroid gland to give rise to the C cells. They consti-­
roid epithelium. The follicles are relatively uniform tute only about 0.1% of the thyroid mass, and are dif-­
in size and shape but have different orientations, ficult to identify with standard hematoxylin and eosin
so that the plane of section gives the impression on staining. They are located in the interfollicular stro-­
histologic slides that large follicles are interspersed ma, sometimes bordering and inserting in between
with small ones.11 The follicles are lined by a single follicular cells, either as individual or small groups
layer of epithelial cells, whose height varies with the of cells.14 C cells are larger than thyrocytes and have