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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

Acquisitions Editor: Pamela Hetherington
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


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


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
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
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,
Sherif Said Thyroiditis
Solitary Thyroid Nodule
Paul M. Yen
Thyroid Hormone Action


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

The course of this migration fied with certainty by immunohistochemistry using is indicated by the thyroglossal duct.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. In about 50% of the population. called the pyramidal lobe. with a central nucleus. and dorsal vagal complex. which become apparent in adult life when they give Thyrotrophs are medium to large elongated angu-­ rise to mucus-filled cysts. It is the largest membrane. The thyroid is composed of two pear-shaped and cytoplasmic processes. the anterior cervical region and their immunoreactivity for TSH-β is greatly should be investigated carefully during surgery so diminished or almost absent. which all inner-­ a radiologically detectable enlargement of the pitu-­ vate the paraventricular nucleus by monosynaptic or itary gland and mimic a pituitary tumor. and thymus. most commonly from its left part. and often positioned near the plasma all the appearance of a Greek shield. fourth hypertrophy secondary to hypothyroidism can cause ventricle. and human chorionic vous system centered on food intake and thermo-­ gonadotropin. 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.8 to their original size and TSH-β immunoreactivity The thyroid gland has a rich blood flow of returns to normal. nucleus of the hypothalamus. 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. such as the brainstem. 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. remnants of an antibody specific for the beta subunit of TSH. com-­ prising less than 5% of the total adenohypophyseal THYROID GLAND cell population. is specific regulation.Part I  Normal Thyroid Axis The synthesis of TRH by hypophysiotropic stimulated cells are known as thyroidectomy cells. alpha and beta. phy and hyperplasia. (thyrotrophs) are the least abundant cell type. para-­ pituitary gland. They remind us that TRH. In Graves’  .3 The plasm containing dilated rough endoplasmic reticu-­ action of leptin occurs mainly through the arcuate lum.6. but can only be identi-­ location by the trachea. and lowest accessory thyroid arteries. endocrine gland.4 but also through oth-­ and few secretory granules. secretion of Its presence is not reliably diagnosed by scintigraphic TSH is suppressed. Although similarly regulated by fasting.5 When patients with as not to leave residual thyroid tissue when total thy-­ hyperthyroidism are treated. the thyrotrophs become small. TSH binds to a specific G protein–coupled receptor. the same race. supplied by the supe-­ hypothyroidism.5 In patients with long-standing approximately 5 mL/g/min. lar cells. instead. the beta subunit. located on the basolateral membrane of Pituitary Thyrotrophs thyroid ­follicular cells. giving over-­ tron-dense. 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. elec-­ chea and held together by an isthmus. In cases of hyperthyroidism. similarly to the adenohypophysis. and is the master regulator of The cells of the anterior pituitary that produce TSH thyroid gland function. emerges upward appearance. large lysosomes.8 of TSH. These ­ chronically transplantation of larynx and thyroid.6 The thyrotroph area within There is significant variation in the anatomy of these the anterior pituitary enlarges and the thyrotrophs arteries. Their cytologic lobe. and contain periodic and migrates downward along the midline to its final acid–Schiff (PAS) material. both among races and within individuals of extend to other regions of the anterior pituitary. thyrotrophs return roidectomy is indicated. The secretory granules of lobes. is affected by the secretion from the isthmus. The dis-­ multisynaptic projections. inferior.7 This hyperplasia and er regions of the brain. for TSH. or ultrasound imaging. Their role is TSH is a 28-kD glycoprotein hormone com-­ poorly known. however. 100 to 200 nm. Thyrotrophs are basophilic (a shade thyroid glands. the thyrotrophs undergo hypertro-­ rior. they not require surgery and is reversible on thyroid hor-­ are anatomically and functionally distinct from the mone replacement. a third life and similar in both genders. round. hypophysiotropic neurons described. weighing about 2 g at birth and 15 g Thyrotrophs are constant throughout in adults. bordering the right and left sides of the tra-­ thyrotrophs are small. abundant cytoplasm. a prominent Golgi apparatus. in addi-­ posed of two subunits. 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. luteinizing hormone.

in 1935 for a large (170-g) nontoxic multinodular This follicular structure.14 C cells are larger than thyrocytes and have  . so that a thyroid enlargement Iodine is the key component of thyroid hormones. The parathyroid a basement membrane approximately 400 Å thick. where it is incorporated by thyroperoxidase loops under and around the arch of the aorta before onto specific tyrosines of the large thyroglobulin ascending.12 The apex is densely populated by micro-­ The thyroid makes contact with two important villi that project into the central colloid. from brain development to body growth invaginates into the gland to form smaller lobules. ficult to identify with standard hematoxylin and eosin so that the plane of section gives the impression on staining. They consti-­ roid epithelium. which In addition to the thyrocytes. space.11 The follicles are lined by a single follicular cells. Thyroglobulin is the most abundant pro-­ right subclavian artery. These are neuroendocrine cells that originate from Each follicle can be compared to a watermelon. and much taller and be felt when palpating the gland. with a central depot goiter and was apparently incapable of reaching the area. The thyroid fied tyrosines) and yet are fundamental in numerous is encapsulated by a fine connective tissue. and occasionally that supplies motor function and sensation to the lar-­ one or two circulating lymphocytes. better known as In the interfollicular space. whereas their base is toward the interfollicular thyroid cancer. approximately 3 million follicles in an adult thyroid. or C cells. When The superior laryngeal nerve can also be thyroid hormones are needed. Dietary iodine ynx. portions of colloid injured during thyroidectomy. The lesion was publicized by the operatic soprano release thyroxine and also triiodothyronine into the Amelita Galli-Curci. lateral. They become thin markedly increased. is oriented toward the colloid-filled lumen of the fol-­ which are frequently involved in metastatic papillary licle. or even below the sternum. 1-1). the colloid and inside the thyrocytes (Fig. The follicles are relatively uniform tute only about 0. which develops from the the red. Thyroid follicular occurs via the superior.13 neck. which can be damaged by an inexperien­ base is separated from the interfollicular space by ced surgeon during thyroidectomy. although a report has discred-­ glands because it is the only gland in which hor-­ ited the story. Thyroglobulin is found in efficient coughing. either as individual or small groups layer of ­epithelial cells. Graves’ disease. and inferior sides. fenestrated capil-­ the recurrent nerve. The inferior laryngeal nerve. although its lesion are engulfed at the apex by pseudopodia. representing about 20% of during thyroidectomy and cause dysphonia and less the total thyroid weight. (goiter) will most commonly extend backward and which have a simple chemical structure (two modi-­ downward. and thermoregulation. and the structures. and are dif-­ in size and shape but have different orientations.1% of the thyroid mass. is a branch of the vagus nerve laries and collagen fibers are found. and inferior veins and cells (thyrocytes) have a clear polarity—their apex lymphatic drainage is into the cervical lymph nodes. renders the thyroid unique among endocrine high notes afterward. so that extreme care must be taken during ies against the TSH receptor found in patients with surgery to preserve their integrity. are often located Thyrocyte activity is stimulated by TSH and also by be­hind the thyroid lobes. which processes. whereas the right one loops around the molecule. such as the antibod-­ variable. reaching the behind the thyroid gland. but their location is extremely factors that mimic TSH action. usually four in humans. Venous drainage columnar in hyperthyroidism. glands. They are located in the interfollicular stro-­ histologic slides that large follicles are interspersed ma. The left recurrent nerve apex. sometimes bordering and inserting in between with small ones. who underwent thyroidectomy bloodstream. 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. Each lobule is composed of about 30 follicles. There are gland also contains parafollicular cells. enclosed usually goes unrecognized because it is clinically sub-­ in vacuoles within the thyrocytes and hydrolyzed to tle. the thyroid represent the functional unit of the gland. running between the trachea and esophagus It then moves through the thyrocyte. These nerves can be damaged tein of the thyroid gland. 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. 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. with the ultimobranchial body. Anatomy of the Hypothalamic-Pituitary-Thyroid Axis ­ isease or other hyperthyroid states. so that a thrilling vibration can and flat in hypothyroid states. the blood flow is d functional activity of the gland. whose height varies with the of cells.10 mones are stored in an extracellular location.

C cells Rom J Morphol Embryol 45:53-61.   7. Ergeb Anat Entwicklungsgesch section was incubated with an antibody directed against 39:1-71. gene-related peptide. Dohan O.. Della Casa C. et al: Cytology of pituitary thyrotroph hyperplasia in protracted primary hypothyroidism. Laws ER Jr. Braun EM. Ahima RS. ally requires immunostaining for calcitonin. Scheithauer BW. adult mouse thyroid. 13. Windisch G. Kovacs KT. somatostatin. Wolfe HC. However. Segerson TP. 1967. Mayo Clin Proc 67:22-26.   9. Kovacs K.   4. Sugiyama S: Histological studies of the human thy-­ roid gland observed from the viewpoint of its post-­ Figure 1–1  Section of a normal. 2007. Endocrinology 138:2569-2576. thyroglobulin (dark red staining) and then counterstained 12. Leptin prevents fasting-induced suppression of prothyro-­ tropinreleasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricu-­ lar nucleus.15 More recently. Evaluation of the role of mammalian mone that lowers the serum calcium level by inhibit-­ thyroid parafollicular cells. Emerson CH. Ahima RS. Turcu M. Toni R.  . such as calcitonin 16. et al. Nitsch L. Receptors for thy-­ rotropin-releasing hormone on rat lactotropes and thyrotropes.Part I  Normal Thyroid Axis   3. 399. 14. they secrete many other factors. Surg Radiol Anat 29:21-27. with a clear nucleus (blue color) and a cytoplasm containing 1985. 1987. Mosca S. 1995. but their identification usu-­ rent concepts on normal histology and hyperplasia.   2. Eur J Cell Biol 38:57-66. 1997. Leptin. 1998. The thyroid follicular cells are cuboidal. Fernández-Santos JM. Hinkle PM. Scheithauer BW.   6. Légrádi G. et al. Borda A. Tramontano D. 1999. Flier JS. The natal development.   8. Young WF Jr. 10.   5. usually referred to as autocrine or paracrine of C-cells? Histol Histopathol 20:713-718. Utrilla JC. Acta Histochem 97:389- ing osteoclast-mediated bone resorption. Surg Neu-­ rol 29:218-226. Thyroid 8:887-894. et al: Thyroid hor-­ mone regulates TRH biosynthesis in the paraven-­ tricular nucleus of the rat hypothalamus. Randall RV: The pituitary gland in hyperthyroidism. De Miguel M. The C-cells: Cur-­ a granular cytoplasm. et al: The pyrami-­ dal lobe: Clinical anatomy and its importance in thyroid surgery. Alkhani AM. with hematoxylin (blue staining). Kauer J. Ambesi-Impiombato FS. 2000. 2003. Recabaren JA: Injury to the superior la-­ ryngeal branch of the vagus during thyroidectomy: lesson or myth? Ann Surg 233:588-593. thyroglobulin (red color). et al: Anthropologi-­ cal variations in the anatomy of the human thyroid arteries. Ashworth R.16 References   1. Mol Cell Endocrinol 213:59-70. 2005. implicating a possible role of C cells in thyroid homeostasis. 1992. factors. 1988. the 32–amino acid hor-­ 15. Berger N. TRH has also been found to be expressed in C cells. are the source of calcitonin. Note the intense red color et al: Morphological and functional polarity of an filling the follicles. Pituitary 1:291-295.. Science 238:78-80. 2003. epithelial thyroid cell line. Cusimano M. 1999. et al: Com-­ bined thyrotroph and lactotroph cell hyperplasia simulating prolactin-secreting pituitary adenoma in long-standing primary hypothyroidism. Carrasco N: Advances in Na+/I– symporter (NIS) research in the thyroid and beyond. Thyroid 13:183-192. Wolf G. Pioro EP. Crookes PF. Annu Rev Physiol 62: 413-437. 2001. 11. and other pep-­ Thyrotropin-releasing hormone receptor expres-­ sion in thyroid follicular cells: A new paracrine role tides. Yu R. et al. Sawicki B.

transient embryonic structures whose anterior portion is called the foregut. ing embryonic life. eventually give rise to different organ primordia. Data including that of the thyroid. different districts are defined that fully elucidated. In humans. also known as calcitonin. Follicular and C cells derive from different embry- onic structures. which budded off from the fourth pharyngeal pouch. Parafollic. n Studies in animal models have identified a number of transcription factors expressed in thyroid cells indispensable in controlling thyroid ­development. known as follicles have been discovered mainly through the study and express a number of specific proteins required of murine models. thyroid development subsequently undergo differential development and initiates around the third week of gestation and ter. Chapter Thyroid Development 2 Mario De Felice and Roberto Di Lauro* Key Points n Thyroid follicular cells derive from a few endodermal cells of the primitive pharynx. through the effects of signaling molecules and Both the organogenesis of the thyroid gland specific transcription factors. d At week 10 thyroid hormone synthesis begins. the same pathways in all mammals. the completed by E17. mostly in mice. because it is likely that thyroid development follows related polypeptide alpha. This chapter will focus on the genes and tered in the interfollicular space. the ventral wall of the primitive pharynx. in which thyroid develop- the thyroid is composed of two distinct endocrine ment starts around embryonic day (E) 8 to 8. be extended to other species.5 to 18 at the end of gestation. which in particular spheroid structures.5 and is cell types—the thyroid follicular cells (TFCs). the presumptive thyroid- forming district. TFCs are organized mechanisms controlling thyroid development. a small group of MORPHOLOGIC ASPECTS endodermal cells of the primitive pharynx.1-3 on thyroid organogenesis in humans are scarce. Dur. As devel- parafollicular cells occur through processes not yet opment proceeds. Grant line thickening of the endodermal epithelium in GGPO5161. The thyroid anlage. is evident by E8 to 8. scat. ter. the endo- of origin of the TFCs. including humans. derm germline is transformed in a primitive gut tube.5 as a mid- *This work was supported in part by Telethon. the thyroid anlage and the UBBs The tube initially appears as a homogeneous epithe- migrate from their original sites and fuse to form the lial tube surrounded by mesoderm. runs along the anteroposterior axis of the embryo. and the parafollicular or C cells. ular C cells express the peptide hormone calcitonin. chial bodies (UBBs). ­models. the morphogenesis and differentiation of connected by an isthmus and located anterior to the the thyroid have been extensively studied in animal trachea at the base of the neck. minates around the tenth week of gestation. is the site In mammals. Shortly thereaf- definitive thyroid gland. n In humans thyroid precursor cells are evident by the third week of gestation. The thyroid gland consists of two elongated lobes How­ever. most abundant. Thyroid anlage. This information can plausibly to produce and export thyroid hormones. C cells derive from ultimobran. Molecular Genetics of Thyroid Dysgenesis. In adult mammals.4 At this  . by the end of gastrulation. Mutations in these genes are associated with ­thyroid dysgenesis in humans. the gut tube begins to and the functional differentiation of follicular and be patterned along its anteroposterior axis. At week 7 the ­ eveloping thyroid reaches its final position in front of the trachea and becomes a bilobed organ.

surrounded by a capillary network. thus contributing to the beginning of thyroid expansion of the thyroid bud. One day later. the it has been proposed that these cells can be derived hypothalamic-pituitary-thyroid axis starts functioning from the endodermal epithelium of the fourth pha- at midgestation. in addition. revealing fish and birds. This double nizing into cords of cells. By E9.and calcitonin- the thyroid anlage. the adult thyroid gland in mammals is expand by E15 to 16 and the thyroid gland assumes assembled from two different embryologic struc- its definitive shape. After a few days.5.6 roid cells can be considered reasonably proved in A thickening of the floor of the pharynx. Furthermore. the thyroglossal Thyroglossal duct starts 32-34 11-11.5 to break duct disappears and the thyroid primordium loses Median primordium 34-38 12. the hypo. TFCs begin to form the first follicular and humans. TFCs start orga. Other cells from the pha- First follicles containing 70-80 16-16. in turn. the region of the first branchial arch that gives rise to the median portion of the tongue.5-10 dally migrating but still ­ connected to the pharynx from floor of pharynx and by a transient. the developing DIFFERENTIATION OF THYROID FOLLICULAR thyroid reaches its definitive pretracheal position and CELLS joins with the UBBs which.9 In humans. in mice. a migrating primordium. In late fetal life (E17 to 18). the thy. the bud evaginates Embryonic Day (E) from the floor of the pharynx and. begins to migrate the thyroglossal duct. By week 4. gestation. the thyroid bud continues its downward migration and begins to expand laterally. Studies of chick quail chimeras9 have demonstrated nected to the pharynx by the thyroglossal duct.5-13 any contact with the floor of the pharynx. cau. the bud appears as an outpouching of the Table 2–1  C  hronology of Thyroid endoderm apposed to the aortic sac and localized Organogenesis in Humans and Mice caudal to the tuberculum impar. Origin and Specification geal pouch. the thyroid anlage and UBBs. con. in addition. some  .10 its final position in front of the trachea at week 7.8. in which thyroxine. the developing thyroid. ryngeal pouch. The two rudimentary paratracheal lobes As noted.5 invades the surrounding mesenchyma. TFCs are endoder- increases in size and its parenchyma is organized into mal cells derived from the thyroid anlage and C cells small follicles. At E11. In humans.7 According to this picture.5 the thyroid primordium. Thyroid primordium buds 26-28 9. originate from neural crest cells that have colonized and enclosing thyroglobulin in their lumen. connection with the pharynx and becomes a bilobed lineage studies in zebrafish have shown that all TCFs organ. The ectodermal origin accomplished only by weeks 10 to 12. thyroid morphogenesis follows The different lineage of the endocrine thy- essentially the same patterns as in mice (Table 2-1).5 roid bud appears as an elongated structure. On the contrary.5 ryngeal endoderm could have been recruited into colloid become visible. the developing thyroid loses any crest and which have colonized UBBs. the of C cells in mice has been recently questioned11 and thyroid continues to grow until birth. intense cell proliferation is detectable in the thyroid primordium. although it is clear that thalamic-pituitary axis is fully active only after birth. tures. UBBs. TFCs derive mostly from the thyroid anlage. which merges with the UBBs and reaches derive from endodermal cells of the thyroid anlage. at the same time. At early ­appears as bilobed stages of morphogenesis. At E13 to 14. narrow. is evident by the third week of producing cells are found in separate gland organs. forming small ­rudimentary origin reflects the composite cell population of the follicles.Part I  Normal Thyroid Axis stage. endodermal-lined channel.5. the thyroid gland. is visi. that avian C-cell precursors originate from the neural ble. the growth of the thyroid ­structure primordium does not seem to be affected by the Median primordium 44-46 14 proliferation of cells of the primitive thyroid anlage fuses with ­ultimobranchial bodies because of the low proliferation rate of the cells in Thyroid migration ­complete 46-50 14.5 hormone synthesis By E12 to 12. maintaining a Event Humans Mice close association with the aortic sac. Thyroid anlage appears 20-22 8. At this stage. These assumptions have not yet been proved in mice By this time. have completed their ventrocaudal migration from the fourth pharyn. in whom thyroid primordium and UBBs ­structures although the follicular organization is merge in the definitive gland.

whereas in the absence of Foxe1. However.12-14. are recruited to establish the Foxe126—distinguishes these cells from the other cells thyroid anlage. which are involved in the regionalization of individual roles in the organogenesis of the gland. DiGeorge syndrome precursors because the presence of this factor in the is characterized by congenital heart defects and thyroid bud is absolutely required to allow the cells to an increased risk of congenital hypothyroidism.24 Titf1/Nkx2-1.29 These findings are short-range inductive signals from the mesenchyma consistent with data obtained in studies of the devel- or adjacent cardiac mesoderm. the thyroid anlage is correctly development. Pax8. In bud specification because in the absence of either of addition. other morphogenetic mesoderm of the transcription factor han is required events occurring in the neck region and in the mouth for thyroid development. This process. endoderm-derived organs. members of the Gata.23 example.29 However.5 This spatial correlation is con.29 The presence of Titf1/Nkx2-1.34 Although much evidence such as Nodal.20 In this species it has been roid. cardiac malformations represent the key molecules required for migration. or Sox has suggested that these transcription factors play family. this process mostly involves active migration demonstrated that the expression in the cardiac of the precursors. oping human thyroid.30.17 Hhex. two among Titf1/Nkx2-1. As an ­dysgenesis.25 Pax8 25 and from their neighbors. the endoder- expected if only C cells were missing. A specific cells is initiated when a group of endodermal cells. and Pax8 has been dem- transcription factors downstream of Nodal signal. Hhex. Interestingly. formed but the subsequent thyroid morphogenesis is Although in zebrafish the morphology of the severely impaired. the coexpression of four tran- acquiring specific signatures that distinguish them scription factors—Hhex. In zebrafish. called thyroid specifi. The specific genes required to induce thyroid tissues. or from the endothe.37 Foxe1 central role of heart development in thyroid specifi. Hhex. Thyroid Development evidenced has suggested that the epithelial cells of most frequent birth defects associated with thyroid UBBs can also contribute to the follicular cells.15 mal cells present in the thyroid anlage can be already The differentiation of thyroid follicular considered as the precursors of the TFCs.7. in mutant murine models in which UBBs fail to fuse with the thyroid bud (persistent UBB).32 and Pax833 is required for the survival of the fish and mammals probably use the same molecular TFC precursors. of these transcription factors is also expressed in other tion. in humans. Bon and Gata5. the mechanisms to accomplish the differentiation of the thyroid primordium disappears or remains in an ecto- TCFs. could be required for the formation of complex network of reciprocal regulatory interactions the thyroid anlage. molecular signature.4 Budding and translocation from the anlage forms in the primitive pharynx adjacent to gut tube is a developmental process shared by many the heart mesoderm.7 In the absence of Titf1/Nkx2-1.5 in mice and E32 in humans. differentiated thyroid follicular cells and their precur- ful for the study of this process. is a consequence of the foregut regionaliza.31 thyroid gland differs from that in mice or humans.19 In mice. the thyroid geal position. but such a combination is a unique hallmark of fate are unknown and murine models are not use. onstrated in the developing thyroid. valuable for the study of the early steps of thyroid Hhex. thyroid cells are never detected. Shortly after specification. the simultaneous presence of Titf1/Nkx2-1.16 It is possible to hypothesize that H proteins pic sublingual position. It is worth noting that each cation. plays a crucial role in the active migration of TFC cation. such as the liver and lung18.27 Their expression is downregulated only after of genes involved in foregut patterning generally transformation of TFCs. Cell migration  . Each controls ing. In humans. and patients affected by thyroid dysgenesis have indi- clude assessment of thyroid specification. Fgf. TFC precursors lial lining of the adjacent aortic sac. The inactivation sors. Early Events in Thyroid Cell Differentiation the size of the thyroid appears smaller than would be From E8.28 Studies of animal models causes the death of the embryos at stages that pre.29 Foxe1 probably controls the expression of In addition.7.35 of endodermal organs.22 move. Signals from the are identified by the presence of both TITF1/NKX2-1 cardiac mesoderm are relevant to the development and PAX8 at E32.36 In the case of the thy- served also in zebrafish.21 This finding suggests a could also contribute to thyroid translocation. and Pax8 is required for the expression of Undifferentiated endodermal cells could Foxe1. foregut defects can be secondary to an mordium begins to migrate to reach the sublaryn- impaired heart development. a the foregut. of the primitive pharynx. cated that these factors are essential for the develop- evidence obtained from other models could be ment of the thyroid. suggesting that Foxe1 is located downstream in be specified toward their thyroid fate as a result of the thyroid regulatory network. or Foxe1. the thyroid pri- in addition. these. both seem to be specifically required for thyroid the maintenance of expression of the other factors. and FOXE1 appears 1day later.

development. present at E16. lary network.5 In humans. probably tion of the developing thyroid is not a prerequisite because of the high proliferation of TCFs. Conversely. the last of Tg and Tshr. is achieved a phenomenon called ­ epithelial-mesenchymal tran. become functional follicular program is completed in 3 days in mice (thyroxine is cells.6 respectively. undergo hallmarked by the synthesis of thyroxine.43 Duox appears at E15. in which dium has reached the sublaryngeal position. such as gastrulation. at least in mice. These processes begin after the thyroid primor. the gland expands Tshr.5 but its expression is not by an isthmus. mainly because of the availability of genetically mainly the vessels located close to the thyroid tissue. thyroid lobula. Furthermore. modified mice. whose expression is restricted to the and is never in close contact with vessels. the finding that ectopic thyroids are functional in In the last stages of thyroid organogenesis. the correct patterning The growth of the thyroid continues after of the vessels is disturbed and the developing thyroid birth. expression of a number of genes.42 crest migration.Part I  Normal Thyroid Axis is a phenomenon observed in many relevant events truncus arteriosus syndrome. and heart formation. In addition. a the thyroid continues to grow until birth. key regulator of embryogenesis. and pen- in the case of migration of TFC precursors. The expres- sion of TPO and NIS. thyroxine has been detected at about week 10. the In the early 1990s. appear. This discovery made it possible sues surrounding the developing thyroid and are never to begin the study of the molecular genetics of thyroid detectable in the thyroid itself. TFC precursors. fied. During this time. tified for the first time.34 same time. the cells. through a differentiative program characterized by the sition (EMT). complet. two transcription factors. 10 in humans. two lobes connected of Tg.38 They lose their epithelial pheno. dependent on TSH-Tshr signals. mice and in humans indicates that the correct loca. E17 to 18 in mice. It is worth developing thyroid and a few other tissues. characterized by congen- ­during embryogenesis. the two key enzymes involved in Late Events in Thyroid Cell Differentiation the process of Tg iodination. Howev. which also display impaired lobulation of thyroid.44 The differentiative ing their differentiation. However. This phase expression of TPO and Nis is their dependence on the will be completed at birth in mice and at about week pathway activated by the binding of TSH to its receptor. small follicles that are accumulating thy- The molecular mechanisms leading to the for. follicular organiza- tion) are now beginning to be understood.39 week 7 in mice25 and humans.5 and in 3 weeks in humans).40 It is most likely that the impaired thy. oxidase (Duox). Hence. as a consequence MOLECULAR GENETICS of the absence of caudal pharyngeal arch arteries. TSH-Tshr signaling appears as a single midline tissue mass located laterally controls the growth of the adult thyroid. The fully functional differentiation of TFCs. a number of genes tion is a non–cell autonomous process controlled by involved in thyroid morphogenesis have been identi- inductive signals originating from adjacent structures. A possible mechanism for the delayed phase of thyroid development is initiated. Here we will describe 10 .43 As expected. Tshr is not necessary for the onset and acquires its definitive shape. TFC pre. These genes are not activated simul- cursors maintain an ­epithelial ­phenotype throughout taneously but follow a precise temporal pattern that the entire translocation process and never acquire a begins with the expression of Tg and Thsr at E14 and mesenchymal identity. were iden- noting that both Shh and Tbx are expressed in the tis. characterized by thyroid peroxidase (TPO). In both humans and mice. neural ital anomalies of the heart and great vessels. during the process of migration. drin (PDS) genes.41 In these mutant embryos. At the for the final differentiation of TCF ­precursors. and acquire mesenchymal features. signals triggered by TSH do not seem roid morphogenesis is secondary to Shh-dependent to be relevant for the expansion of the fetal thyroid. sodium-iodide symporter an increased expression of N-­cadherin.46 defective patterning of vessels. This hypothesis seems The mechanisms controlling the growth of fetal TCFs to be confirmed by analyzing the phenotype of Tbx are still unknown. lin (Tg). and surrounded by a capil- mation of the two lateral lobes of the gland (lobula. the study of patients This hypothesis is consistent with the finding that affected by thyroid dysgenesis is also offering addition- impaired thyroid morphogenesis has been reported al insights into the molecular mechanisms involved in in human diseases such as DiGeorge syndrome22 and normal thyroid development. Titf1/ thyroid primordium is enclosed by the mesenchyme Nkx2-1 and Pax8. roglobulin in the lumen. null embryos. thyroid reduced nicotinamide adenine dinucle- should be stressed that EMT has never been reported otide phosphate (NADPH). follows the expression From E14 in mice and week 7 in humans. such as thyroglobu- type. as shown by a downregulation of E-cadherin. the gland expands.6 er. In these cases. it (NIS). In mouse tion is evident after 10 to 11 weeks of gestation6 and embryos deprived of the Sonic hedgehog gene (Shh). thyroid-stimulating hormone receptor (Tshr). In the last few years. to the trachea.

diencephalon Thyroid. myelencephalon and ­spinal cord. Thyroid Development Table 2–2  C  hromosomal Localization and Expression Patterns of Genes Encoding Thyroid-Specific ­Transcription Factors Gene Chromosome Expression Pattern in Embryos Humans Mice Humans Mice Humans Mice TITF1/NKX2-1 Titf1/Nkx2-1 14q13 12 Thyroid.25 as a hypoplastic bud composed of a few cells. forebrain. endo. The gene encodes a 270–amino acid transcription 2. At later stages. hair Thyroid. Titf1/Nkx2-1 is ex­­ and express Titf1/Nkx2-1. ­mesonephric ­nephrogenic cord. follicles. fourth pharyngeal pouch. factors. However. thymus. TFC precursors are present In the mouse embryo. The expression pattern of Titf1/Nkx2-1 in humans Titf1/Nkx2-1 does not appear different from that described in Titf1/Nkx2-1 was formerly called TTF-1. diencephalon. roid and lung. as demonstrat. is The Hhex gene is located on chromosome 19 in located on chromosome 14q13. thyroid. and spinal cord.5 kb.35 11 . Pax8. C cells PAX8 Pax8 2q12-14  2 Thyroid. myelencephalon Thyroid. whereas the human orthologue. for thyroid mice (Table 2-2). and of the developing diencephalon. encode proteins 401 and 371 amino factor containing a homeodomain. Titf1/Nkx2-1 maintains diseases have been described so far in humans. such as the hypo- then TFC precursors are found to disappear.24 lated serine residues have been replaced by alanine Hhex has a crucial role in the morphogenesis of residues show impaired differentiation of both thy- the liver. esophagus ­choanae. and Foxe1 until E9.51 In these mutant embryos. It is a homeodomain from which the ultimobranchial body develops. In mice. thus confirming the relevant role of ed from the analysis of the Hhex null mouse embryos. ­nephrogenic cord. heart. Titf1/ Nkx2-1 is encoded by a gene located on chromosome Hhex 12. fourth pharyngeal pouch. pressed in the thyroid primordium and in the epithe- However. and thyroid. we cannot state definitively and also in other cells—C cells52 and epithelial cells that the absence of these factors is the direct cause of of the ultimobranchial body33—which merge with the thyroid phenotype displayed by Hhex −/− embryos. the phosphorylation could be a regulatory thelium of the developing vasculature and heart. including the thyroid anlage. tubules mesonephric tubules. respectively. At early stages of acids long. lungs. except that TITF1/NKX2-1 is not transcription factor-1. ­esophagus only those genes that are particularly relevant to the c­ ontaining transcription factor that belongs to the development and differentiation of the thyroid.32 post-translation ­modifications of Titf1/Nkx2-1. or T/EBP. from which Hhex guarantees the survival of TFC precursors and the neurohypophysis develops.32 in humans. and mechanism to modulate its binding and transactivat- primordia of several organs derived from the foregut ing properties. and brain.29 Hence. lungs. lungs. 1 day later. Hhex is detected in the primitive is the shorter isoform that is phosphorylated in several and then in the definitive endoderm.48 have been identified of which the major transcripts. Mutated mice in which phosphory- endoderm. thyroid-­specific expressed in humans in the fourth pharyngeal pouches enhancer-binding protein. the developing thyroid appears lial cells of the developing trachea. In the adult thyroid.3 and 2. Nkx-2 family of transcription factors. TITF1/NKX2-1. Pax8. ­palate. Titf1/Nkx2-1 is detectable in TCF precursors scription factors.25 In the developing maintains the expression of other thyroid-specific tran. serine residues. otic vesicle. which do Titf1/Nkx2-1 is expressed in the brain in some areas not express Titf1/Nkx2-1. or Foxe1 mRNA. As described for other transcription it is expressed in the developing blood islands. foregut. ­ ureteric bud FOXE1 Foxe1 9q22  4 Thyroid.50 The most abundant protein mouse development. its expression in follicular and parafollicular cells. thalamic areas and the infundibulum. hair follicles. otic ­vesicle.49 Multiple transcripts mice47 and on chromosome 10q23. the thyroid anlage to assemble the definitive thyroid No Hhex mutations associated with thyroid gland.

There is no clear correla- Nkx2-1 on brain development are rather complex.29 At E11. suggesting that Titf1/Nkx2-1 lon.31 Heterozygous point mutations or chromosomal dele- Calcitonin-producing cells and epithelial cells of the tions in the TITF1/NKX2-1 locus have been reported ultimobranchial body follow the same fate of TFCs. the TITF1/NKX2-1 and Congenital Hypothyroidism thyroid bud disappears. the Titf1/Nkx2-1+/− mice (Table 2-3) show which starts by E12. protein remains the most likely mechanism that chea development—the number of cartilage rings of causes the disease. in subjects with thyroid affections associated with ultimobranchial bodies form but degenerate by E12. Finally. probably through apoptosis.5. without pinemia.30 Until E9. a highly variable thyroid phenotype. and brain. in the mutants. In the case of the chorea. its role can be elucidated only ­ during In addition. which nor- lungs. Because mice die at birth in the absence of primordium appears as a striatum-like structure. the absence The reduction of levels of functional TITF1/NKX2-1 of Titf1/Nkx2-1 causes two peculiar alterations in tra. but a shared tube is visible. TITF1/NKX2-1+/− subjects display the trachea is reduced and this structure is not separat. an autosomal dominant movement disor- lung.30 hypoplastic and TFC precursors show reduced or lack of expression of Pax8. Titf1/Nkx2-1 null embryos have nei- embryonic life. tion between the phenotype severity and the type of 12 . in its neurologic defect. as a result. phenotype. of the pallidal structures is impaired and the pallidal nation.53 respiratory distress and neurologic problems. and Hhex. causing the regression of Rathke’s pouch. This variability ed from the esophagus. is impaired and.55 Titf1/Nkx2-1. thyroid anlage is not affected by the absence of Titf1/ the lack of endocrine signals from the pituitary could Nkx2-1. at E10. In accordance with this finding.60 The mechanisms explaining the dominant normal pulmonary parenchyma. these patients. NKX2-1 as the candidate gene in benign hereditary ible in Titf1/Nkx2-1 null newborns. neither the follicular nor parafollicular cells numerous data point to the identification of TITF1/ develop. the branching process of bronchi. Titf1/Nkx2-1 in the infundibulum of the diencepha- mally express the factor.54 could be caused by other modifier genes that con- The consequences of the absence of Titf1/ tribute to the phenotype. in addition to the lung defects. Although loss of func- as lung lobar bronchi are visible in Titf1/Nkx2-1 null tion of a single allele in humans produces an overt embryos. The development gene has been disrupted by homologous recombi. the thyroid bud appears affect the morphogenesis of adrenal glands. Titf1/Nkx2-1 is not required for the specifica. the mild neurologic defects and a slight hyperthyrotro- lungs develop as dilated saclike structures.63 Homozygous TITF1/NKX2-1 mutations have the initial specification because the lung bud as well not been reported in humans. ranging from Slight Not reported Athyreosis a ­normal-sized gland to ­hyperthyrotropinemia ­athyreosis Pax8 Variable. Titf1/Nkx2-1 does not seem to be required for der. in which the corresponding the ventral region of the forebrain. absence.30 In Titf1/Nkx2-1 null effect of TITF1/NKX2-1 have not yet been delineated. the development of the mally gives rise to the anterior hypophysis. Titf1/Nkx2-1−/− embryos show an ther pituitary nor adrenal glands. the development of neurohypophysis is blocked. Foxe1. ranging from Normal Not reported Athyreosis a ­normal-sized gland to a severe hypoplasia Foxe1 Normal Normal Athyreosis or Athyreosis or ectopic hypoplasia of thyroid thyroid The functions of Titf1/Nkx2-1 in vivo have Titf1/Nkx2-1 null embryos show evident alterations in been studied in mice.Part I  Normal Thyroid Axis Table 2–3  C  onsequence of Loss-of-Function Mutations in Genes Encoding Thyroid Specific ­Transcription Factors Heterozygous Thyroid Phenotype Homozygous Thyroid Phenotype Defective Gene Humans Mice Humans Mice Titf1/Nkx2-1 Variable. This could be why no thyroid rudiment is vis.56-62 In Thus. In the absence of impaired morphogenesis of all the structures that nor. However. choreoathetosis is the most frequent tion of cell types that will form the thyroid but. embryos. is essential for the correct development of the thyroid.

is located on chromosome 9q22.33 It has patients. PAX8.5.64 The gene is split of the developing thyroid change. It has been demonstrated sors. it is expressed sion. In the nervous system. This indicates that in in mouse embryos (see Table 2-2). the expression of Foxe1 and Hhex is scripts that differ in their carboxy-terminal regions. developing spinal cord. ranging from a normal- presence of Pax8 expression is not affected. the thyroid phenotype is variable. loss of function of a single allele is sufficient in the developing thyroid. alternative splicing produces tran. in these subjects. Pax8 is expressed in been reported in sporadic and familial cases of con- the myelencephalon. proper position and begins to migrate but. allele-specific regulation has been also suggested.26 The human orthologue. Because the pheno- The study of the phenotype of Pax8 null type shows discrepancy. kidneys. The boring severe alterations in TSH/Tshr signaling. Furthermore. which is necessary for the onset of its expres- nervous system. whereas the human orthologue. All vesicle. is encoded by a gene located on chromo- Consistent with a severe hypothyroid phenotype.68 esis of the kidneys.68 On the contrary. and to produce the disease (see Table 2-3).69 been proposed that kidney organogenesis is normal However. additional gene defects in Pax8 null mice because of the presence of Pax2. In the developing kidney. upper role in the genetic network that maintains the ment. is much smaller. heterozygous mutations in PAX8 have ureter. it is worth noting that the TSH control on pathogenic role of the reduced dosage of the gene Pax8 expression seems to be effective only in adult product (haploinsufficiency) has been proposed.29 This indicates that fied in mice and five in humans. the thyroid anlage is correctly formed in its In mice. mosome 2. pups show growth retardation and die after weaning. In addition.70 Foxe1 is a phos- The administration of thyroxine to these mice leads phorylated 42-kD protein71 that is a member of the 13 . finally. by E12. in epithelial structures PAX8 and Congenital Hypothyroidism generated on induction by the nephric duct and In humans. kidneys.35 is evident in humans only. and by Pax8. at E11. otic vesicle. Foxe1 the gland appears as a rudimentary structure com. factor-2. A However. Foxe1.66 In the thyroid anlage. affected individuals are heterozygous for the muta- but is no longer detected by E12. factors. An exhaustive analysis of thyroid development in Pax8 null embryos offers Pax8 some insights into the functional role of this factor. thyroid devel- opment is impaired in the absence of Pax8.66 The pattern of tions and the familial cases show an autosomal domi- PAX8 expression in human embryos is similar to that nant transmission of the disease. strongly downregulated and. Pax8 is encoded by a gene located on chro. precursors are still not detected. the some 4 in mice. a variable phenotype has also to their survival. target of Pax8. Foxe1 is tightly regulated Pax8 is expressed in the thyroid. is both the morphologic and molecular phenotypes located on chromosome 2q12-q14. ism has caused their death. FOXE1. could not be excluded. TFC At least six different Pax8 variants have been identi. formerly called TTF-2. but TFCs. At birth. Pax8 has a specific and spatially regulated during early mouse develop. Pax8-deficient mice show Pax8 and Pax2 share many biochemical features and renal malformations only if they harbor a concomi- could have redundant functions during morphogen. Pax8 belongs to the Pax family of transcription factors. The thyroid bud into 12 exons65. otic genital hypothyroidism with thyroid dysgenesis. effects of affects only the thyroid. Thyroid Development mutations. confirming that severe hypothyroid- been reported in the same familial cluster.29 Pax8 is expressed in the nephrogenic cord and meso- nephric tubules and. At E9.67 respectively. because in the developing thyroid of mice har. The reason for the domi- induced signals can regulate Pax8 expression in TFCs. even in familial cases in which mice suggests that the absence of Pax8 apparently related individuals carry the same mutation. This indicates that Foxe1 can be a transcriptional only in TFCs precursors. This feature central nervous system at E32. although we do not know the target genes that that the expression of different isoforms is temporally execute this program. not show any phenotype.5. In TFC precursors. by E13.43 sized gland to a severe hypoplasia. PAX8 is detected humans. in addition. thyroid transcription posed only of C cells. renal hemiagenesis has been reported. because Pax8+/− mice do In vitro studies have indicated that TSH. nant effect caused by PAX8 mutations is unknown. Pax8 isoforms display different expression of other thyroid-enriched transcription transactivating activities when tested in cell lines. tant heterozygous null mutation for Pax2 gene. The longest isoform in the developing thyroid. whereas TFCs are undetectable. Pax8 is involved in the is composed of 457 and 450 amino acids in mice66 control of survival and/or expansion of TFC precur- and humans. and at the midbrain-hindbrain boundary. These mutant mice are born other modifier genes could be hypothesized. In two without any apparent brain or kidney defects.

the homozygous loss-of-function muta. made and hair follicles. in humans. up of 10 exons. The role of TSH/Tshr signaling during The generation of mice with Foxe1 disrupted embryonic life has been studied in genetically modi- by homologous recombination has been a tool for fied mice. a normal or hypoplastic gland.35 outer follicular of TFCs. in the ­endodermal layer of the primitive pharynx and pha. actually. is translated in a protein 765 amino roid and foregut. the impaired response to TSH could be responsible for patient presented with eutopic thyroid tissue. displaying extrathyroidal defects (cleft palate. several years ago.80 The gene. Foxe1 Tshr (thyroid-stimulating hormone receptor) is is expressed in tissues that have developed from the a member of the glycoprotein hormone receptor pharynx and pharyngeal arches. the role of syndrome75).5.43 It is worth noting that although the Tshr located in a sublingual position. relevant for the growth of the gland. The most frequent allele. contains different effects of the various mutations. both TPO and NIS are undetectable in TFCs. cleft palate. the normal thyroid primordium embryos deprived of TSH/Tshr signaling do not is close to the aortic arch. However the requirements for the development characterized by athyreosis. showing lutely required for the differentiation process of the either the presence of a severely hypoplastic thyroid. and spiky hair (Bamfort-Lazarus between mice and humans.25. TFC precursors by E14 to 14. The phenotype is consistent with the TSH/Tshr signaling for the growth of the thyroid is expression domain of FOXE1 and partially overlaps also relevant during fetal life. palate. This finding suggests that Foxe1 is of the fetal thyroid also begins. in which the Tshr gene has been disrupted studying the role of this factor in vivo. family. is also present in ectoderm derivatives such as whiskers located on chromosome 14q31. Howev- more evident.81 At later stages of bertal testis.71 In humans.76 responsible for a syndrome characterized by elevated ­Recently.Part I  Normal Thyroid Axis winged helix–forkhead family of transcription fac.72 ­possibility is the role of modifier genes in making the Foxe1 is widely expressed in mouse embryos. At E11to 11. FOXE1 expression (see Table 2-2) is acids long.83 E16 mouse floor. tongue. this signaling is not involved not only in the translocation of TFC precur. which absence of Foxe1. but it still remains on the pharyngeal mutation in the Tshr gene (Tshr  hyt/hyt). this form of a group of cells attached to the pharyngeal finding demonstrates that the TSH pathway is abso- floor. in the show defects in the morphology of the gland. bilat.26 At E15. or the absence of the pathway becomes active by E15.34 trast with the role of TSH/Tshr signals in differenti- ated TFC. the nonmigrating phenotype is displays a normal size and follicular structure. At the same stage. This is in con- sors but also in the survival of TFCs. spontaneous mutant mice carrying a loss-of-function fied at E8. a different mutation in TSHR and Congenital Hypothyroidism FOXE1 was recorded in two siblings with athyreo. before TSHR was cloned and iden- eral choanal atresia. variable thyroid phenotype displayed by patients TSHR mutations have been identified in a number 14 .82 and in mouse embryos. After this report. and esophagus.46 that displayed by Foxe1 null mice (see Table 2-3). the thyroid.5.5. the thyroid anlage is correctly speci. choanae. in addition to the thy. carrying FOXE1 mutations could be the result of tors. phenotype manifest. with the developing thyroid in the er. in the latter. Tshr ryngeal arches and in Rathke’s pouch. in which the TSH-induced cAMP pathway FOXE1 and Congenital Hypothyroidism is the main regulator of thyroid growth.84 Notably. expressed on the basolateral membrane also found in the embryonic thymus. TSHR. Tshr is detected in hair sheath.82 whereas at birth the gland appears nor- affected by syndromic congenital hypothyroidism mal.34 In mutant by homologous recombination (Tshr  −/−). Another 14 alanine residues and is 371 amino acids long. tified. Stanbury and colleagues85 suggested that an tal hypothyroidism but not athyreosis. In the mouse embryo. expressed in adult life.43. The phenotype is variable at E15. thyroid. and seminiferous tubules of the prepu. Foxe1 is 12 in mice79 and the human orthologue. Tshr expression increases and remains spatial regulation.73 The expression of Foxe1 is subjected to development.5.78 The Tshr gene is located on chromosome epiglottis. bilateral of a normal-sized thyroid gland seem to be different choanal atresia. and spiky hair) and congeni. Foxe1 is tightly regulated in the thy. It is detected early in the thyroid anlage. Loss-of-function mutations in the TSHR gene are sis and a less severe extrathyroidal phenotype. when the expansion thyroid bud itself. FOXE1 forkhead domain was described77 in a child and variable levels of thyroid hormones. and Tshr hyt/hyt mice display a severe hypoplastic adult tion FOXE1 gene was first reported74 in two siblings thyroid.29. Both Tshr −/− In humans. The congenital hypothyroidism in the absence of goiter. a third loss-of-function mutation within the levels of TSH in serum. roid bud by Pax8 and in the pharyngeal cells by Shh.

2002. migration. This finding indicates that TD is caused by inheritable genetic defects. ­differentiation mutations in some of these genes are associ- Hoxa5 Defects in functional differentiation ated with thyroid dysgenesis (TD) in mice and humans. Kikuchi Y: Endoderm development in obscure—candidate genes may be those still vertebrates: Fate mapping. Pax8. However. their absence does not affect the specification process.89 which is a consequence of disturbances 13 monozygotic twins. Polak M. Hhex Athyreosis ing a ­ variable phenotype. and Foxe1 are detected in the developing thy- roid by E8.   5. ing program of the thyroid gland. et al: Molecular Defects in several genes have been demon. in most patients. Hhex. Dev Dyn thyroid follicular cells.88 ­development will be valuable to elucidate the molec- 3. Grapin-Botton A. even though Table 2–4  Mouse Models of Thyroid Dysgenesis most of them present with borderline elevations of Thyroid Phenotype in Mouse Embryos TSH. ranging from hyperthy- rotropinemia associated with a normal gland to Titf1 severe hypothyroidism with a hypoplastic gland. In addi. ment: From patterning to organogenesis. Horm Res 62:14- strated to impair the development of the thyroid in 21. Trends 4.5. Pax8. Bard J (eds): The Anatomic Basis of Mouse 5. Titf1/Nkx2-1. 2005. Thyroid Development of families. and Foxe1 are tran. Dev Biol 249:191- downstream genes that execute the differentiat- 203. Shh 1. that must interact with 235:444-455. and Hhex   2. 1999. It is worth noting that many genes relevant Tshr Hypoplasia and defects in functional for thyroid development have been identified. of congenital hypothyroidism are caused by thyroid tion. albeit in only a small fraction of human patients. 2. the efforts of many research Pax3 groups have led to the elucidation of many of the steps involved in thyroid development. the disease is transmitted as an autosomal recessive trait display. The identification delian events must be considered as responsible of new genes and mechanisms involved in thyroid for most cases of the disease. the genetic defects animal models (Table 2-4). Academic Press. Nilsson M: The devel- mination of the final shape of the thyroid gland oping mouse thyroid: Embryonic vessel contacts requires autonomous events. Dev Growth Differ 47:343-355. and lobulation. Despite the fact that Titf1/Nkx2-1. the discordance for TD. ular pathology of thyroid dysgenesis. Fagman H. Shivdasani RA: Molecular regulation of vertebrate early endoderm development. 15 . Sura-Trueba S.87 suggests that nonmen. Kaufman MH. Melton M: Endoderm develop- expression in the thyroid bud. 2004.86 Pax8 Fgfr2 The residual functional activity of the mutant TSHR Fgf10 could be responsible for the differing severity of the Foxe1 Athyreosis or ectopia ­phenotype. Andersson L. even if crucial Tbx1 Hypoplasia and impaired lobulation issues of this process are still unknown. Most of these   4. Hoxa3 Hypoplasia CONCLUSIONS Eya 1 Edn-1 Over the past 15 years. pp 165-166. during thyroid organogenesis. for the onset of Titf1/Nkx2-1. In humans. restricted to the and parenchymal growth pattern during specifica- tion. budding. Hhex. Recent evidence has suggested that the deter. San Diego. an appropriate cellular environment. The mechanisms regulating the shape and posi. induction and regional unidentified encoding factors responsible specification. Chauty A.   6. MH. mechanisms of thyroid dysgenesis. occurring in 12 of dysgenesis. scription factors that control the expression of   3. Individuals carrying heterozygous loss-­ of-function mutations are euthyroid. Development. Pax8. Genet 16:124-130. Subjects homozygous or compound hetero- Gene Symbol Homozygous for Null Mutations zygous for the mutation are affected. 2000. In Kaufman target genes have not yet been identified. 2006. Fukuda KY. Calif. The prime mover of the References initial specification of the thyroid anlage is   1. tion of the gland are still a matter of debate. 85% of cases underlying TD are yet to be discovered. Bard J: The thyroid.

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The large glycoprotein Compared to the mechanism controlling iodide thyroglobulin (TG) serves as a matrix for the synthe- sis of thyroxine (T4) and triiodothyronine (T3) in the follicular lumen. at least in part. an enzyme that requires a specific where it is transported into the follicular lumen. Section B tHYRoID hORMONE Chapter Thyroid Hormone Synthesis 3 Peter Kopp and Juan Carlos Solis-S* Key Points n Normal thyroid hormone synthesis requires a normally developed thyroid gland. 3-1). The oxidation of iodide by (NIS. mediated by pendrin a series of regulated biochemical steps. Fig. defective hormonogenesis requires biallelic mutations in the involved gene products ­(autosomal recessive inheritance).and diiodotyrosines. and Iodide efflux is. then oxidized by thyroperoxidase (TPO) and incorporated into selected tyrosyl residues of thyroglobulin (TG). (PDS/SLC26A4). n Usually. hormone synthesis defects are more commonly found in inbred families and populations. maturation factor. Iodide then reaches the apical membrane. clinical defects in thyroid hormonogenesis typically result in goiter development if the condition is not recognized early because of thyroid gland stimulation by thyrotropin. monoallelic mutations in the dual oxidase DUOX2 are associated with transient hypothyroidism.1-3 At the baso. results in the formation of monoiodotyrosines (MITs) 19 . a normal iodide intake. after pino­cytosis of TG into thyrocytes. The severity of the defects varies and results in a ­clinical ­spectrum from severe congenital hypothyroidism to a euthyroid metabolic state with an enlarged ­thyroid.K+. H2O2 generation is catalyzed by the dual ATPase. developed thyroid gland. iodide lateral membrane. partly by pendrin. TPO iodinates selected tyrosyl *This work has been supported by 1R01DK63024-01 from residues on TG (organification or iodination). n Defects in all major steps in thyroid hormone synthesis have been identified. DUOXA2. T3 are released into the ­bloodstream. the efflux of iodide is less well understood. oxidase DUOX2. Within the follicular lumen. Therefore. (H2O2). The synthesis of thyroid hormones requires a normally uptake. This NIH/NIDDK and by David Wiener. it is hydrolyzed in lysosomes and T4. iodide is actively transported into is then oxidized by the membrane-bound enzyme thyroid follicular cells by the sodium-iodide symporter thyroperoxidase (TPO). The function of NIS is dependent on TPO requires the presence of hydrogen peroxide the electrochemical gradient generated by the Na+. it is transported at the apical membrane into the follicular lumen. n After iodide uptake in thyrocytes by the sodium-iodide symporter (NIS). this results in formation of mono. n Iodotyrosines are subsequently coupled by TPO to form thyroxine (T4) and triiodothyronine (T3). and an adequate nutritional iodide intake. a series of highly r­ egulated biochemical steps. First.

Iodide is oxidized by the enzyme thyroperoxidase (TPO). and T4 and T3 are secreted into the bloodstream through unidentified channels.Part I  Normal Thyroid Axis 4 5 + P NAD 2 O 2 + H DP NA XA2 TPO DUO 3 OX 2 I. The oxidation of iodide requires the generation of hydrogen peroxide (H2O2) by the dual oxidase DUOX2. Thyroglobulin (TG) is secreted into the follicular lumen. This step is dependent on the generation of an electrochemical gradient generated by the Na+. A. where it serves as the matrix for the synthesis of thyroxine (T4) and triiodothyronine (T3). DIT). 6. Iodinated TG is then internalized by micro. 3. 20 . Iodide is transported into the follicular lumen. an enzyme that requires a specific maturation factor. DUOXA2. Key steps in thyroid hormone synthesis. B. 6 DU H2O2 TG OI. 8. -ATP ase 1 8 A K+ CH2 DIT CH2 DIT CH2 T4 TG TG TG Organification Coupling O HO HO CH2 CH2 TPO TPO HO H2O2 CH2 MIT CH2 DIT H2O2 HO HO TG CH2 T3 OI- TG HO HO O HO B Figure 3–1  Thyroid hormone synthesis. TPO iodinates selected tyrosyl residues on TG (organification or iodination). DIT ase NI Na + alogen 2N S Deh a+ Na/K I. which results in the formation of mono.and macropinocytosis and digested in lysosomes. 7. at least in part by pendrin (PDS/SLC26A4). 5. The iodotyrosines are then coupled (coupling reaction) by TPO to form T4 or T3. 1.and diiodo- tyrosines (MIT. 2. MIT and DIT are deiodinated in the cytosol by the iodotyrosine dehalogenase DEHAL1. Detailed schematic representation of the organification and the coupling reactions. 4. Iodide is transported into the cell by the sodium-iodide symporter (NIS). and the released iodide is recycled for hormone synthesis. PO H2O2 T MIT TG O DIT H2O2 TP TG T4 T3 I- PDS TG T4 T4 T3 T3 I- I- 2 T 7 MI T DI MIT I.K+-ATPase.

In the standard perchlorate test. and the amino terminus is located extracellularly and the car- released iodide is recycled for hormone synthesis.16. in particular perchlorate and thiocyanate.9 The SLC5 the cell. a loss of 10% or more indicates an organification defect.K+-ATPase. MITs and DITs are deiodinated in the cytosol presumably 13 transmembrane domains.12 Electrophysiologic studies in ies and the phenotype encompasses a spectrum from oocytes have demonstrated that NIS is electrogenic severe congenital hypothyroidism to a euthyroid met. ratio of sodium to iodide of 2:1. The severity of the defects var.8 Human NIS. released into the follicular lumen by pendrin The rat NIS cDNA was isolated in 1996 using an and one or several other anion channel(s). defects of DUOX and DUOXA2. Iodinated TG is primarily internalized into the encoded by a single-copy gene with 15 exons that is follicular cell by micro.13 NIS is blocked by sev- eral anions.7. T4 (approximately family members rely on an electrochemical sodium 80%) and T3 (approximately 20%) are then released gradient as the driving force for solute transport. which permits determination of the extent of iodide organification. Sodium-Iodide Symporter Function. offi- p ­coupled (coupling reaction) by TPO to form T4 or cially designated as solute carrier 5A (SLC5A). 21 . the transport of perchlorate is by NIS. 1 g of KClO4 NH2 or NaClO4 is administered. 3-2).11 The by the iodotyrosine dehalogenase DEHAL1. Within located on chromosome 19p13 (Fig. Inhibition they typically result in the development of a goiter by Competitors. into the bloodstream through unidentified chan. indicating that NIS translocates differ- iodide ion into the cell. After the lowed by cloning of the human NIS cDNA using inhibition of NIS by perchlorate.7 This results in a iodide ent substrates with different stoichiometries.and macropinocytosis.7 This was promptly fol.2-p12 idly released into the bloodstream at the basolateral membrane and cannot be transported back into thy- rocytes. is T3.10. Human NIS is a 643–amino acid glycoprotein with nels.6. any intrathyroidal iodide that has not been incorporated into TG is rap- 19p13. In the secondary protein defect (total iodide organification defect [TIOD]). organified on tyrosyl residues of TG by TPO. ximately 36 μM. recent evidence has indicated requires a sodium gradient. In individuals with normal iodide organification. there is no decrease in intrathyroidal counts because the iodide has been incorporated into TG. Next. Genetic defects in all steps involved in thyroid hormonogenesis have been described. IODIDE UPTAKE BY THE SODIUM-IODIDE by competitive inhibition. because of the influx of sodium with a stoichiometric abolic state with a compensatory goiter. the green symbols depict glycosylation sites. such as Pendred’s syndrome.14. and then expression cloning strategy. NIS/SLC5A gene and current model of the secondary struc. which is generated by that it is actively transported by NIS. iodotyrosines are ­ rimers complementary to rNIS. Thyroid Hormone Synthesis and diiodotyrosines (DITs).4-6 Active iodide transport is mediated the transport of iodide. the thyroidal counts are measured at frequent intervals after the 1 13 administration of radioiodine to determine the uptake into the thyroid gland. If untreated. it is digested in lysosomes. which transports two sodium ions and one electroneutral. In contrast. common causes include thyroiditis and con- COOH genital defects with abnormal efflux of iodide into Figure 3–2  Chromosomal location and structure of the the follicular lumen. Sodium-Iodide Symporter Gene and Protein iodide is transported very rapidly into thyroid cells Structure by NIS.15 Although there was SYMPORTER some controversy in the past as to whether perchlorate The uptake of iodide at the basolateral membrane is a substrate for NIS. or dysfunction of ture of the sodium-iodide symporter (NIS) protein.18-20 In the case of a complete organification and the coding region in blue. such as in patients with complete inactivation of TPO. and the amount of intra- thyroidal radioiodine is monitored ­longitudinally. The 5′ and 3′ untranslated regions of the gene are shown in red TPO.4 rate test.15 Under normal conditions. boxy terminus is located in the cytosol. One hour later. ­structure.17 In contrast to Na+. concentration in the thyrocyte that is up to 40-fold Perchlorate is used for the so-called perchlo- higher compared with plasma. and Perchlorate Test caused by the chronic stimulation of the thyroid gland The Michaelis-Menten constant (Km) of NIS is appro­ by thyrotropin (TSH).

45 The SLC26A fam- 250 mg/mL.6 efflux can be mediated by two apical iodide chan- Iodide accumulation and organification are nels with different affinities (Km of approximately also directly regulated by iodide itself. iodide efflux posttranscriptional activation of NIS. 22 . This inhibition is transient and drome.32. as well as of the TSHR. which vary from 0. Exposure to Iodide efflux at the apical membrane is less well TSH results in increased NIS gene expression and characterized. 21 exons.Part I  Normal Thyroid Axis there is no meaningful organification and the tracer Suppression of NIS expression by TG decrea­ is completely released from the gland. PDS mRNA is upregulated by TG.27 TSH apical membrane while leaving efflux in the basal also regulates the subcellular distribution of NIS. TG is a suppressor of its SLC26A3 (downregulated in adenoma and congenital own mRNA expression.31 High doses of iodide molecular level. initially called human uptake. NIS is electrophysiologic studies performed with inverted redistributed from the plasma membrane to intracel.43 In primary porcine thyrocytes grown in a of NIS in FRTL-5 cells is approximately 5 days.42. Based on basolateral membrane. uptake in vivo.37-40 In addition.44 However.21-23 TSH upreg.51 downregulation of NIS expression.1 to 2343 base pairs (bp) (Fig. spe. encompasses is thought to represent the lower range of intrafol.24-26 In the presence of TSH.38 This ute carrier 26A4).56-58 The PDS/SLC26A4. Pendred’s syndrome is an autosomal recessive disor- cellular TG downregulate NIS transcription. a homologue of NIS. the fraction of the tracer that has amount of follicular TG and uptake of radioiodine in not been incorporated is released from the gland. In the situa. TG in the follicular lumen correlates with low iodide such as in Pendred’s syndrome or partially inactivat.36. vivo. In cell culture. now officially designated as SLC26A4 (sol- experiments using rat thyroid FRTL-5 cells. possibly an increase in NIS protein turnover. suggesting sion. of these channels has not been established at the tion of NIS mRNA expression. together with the inhibition of the organification process.26. high concentrations of extra.50 However. plasma membrane vesicles.31 At the molecular level. TG decreases the mRNA expression of ily contains several anion transporters and the motor thyroid-restricted transcription factors such as PAX8 protein prestin (SLC26A5). In the absence of TSH. TTF-2. one of the channels.39 a common ancestral gene. which is expressed in and thyroid-restricted transcription factors TTF-1 outer hair cells.52-55 The mg/mL are effective in altering gene expression in PDS gene. was cloned in 1997. increases rapidly in the poorly polarized FRTL-5 rat ulates NIS mRNA and protein expression in vivo and thyroid cells. functional studies in referred to as escape from the acute Wolff-Chaikoff oocytes and polarized MDCK cells did not show any effect.37 der defined by the triad of sensorineural deafness. DRA/CLD/ and TTF-2. and a decrease in NIS activity Pendrin (PDS/SLC26A4) Gene and Pendred’s contribute to this autoregulation.10. the intracellular concentrations decrease apical iodide transporter (hAIT). appears to Regulation of Sodium-Iodide Symporter be of importance in the regulation of follicular func- and Iodide Uptake tion under conditions of constant TSH levels. 3-3). thus facilitating the vectorial cifically the targeting to and retention of NIS in the transport of iodide into the follicular lumen. the so-called clinical phenotype in patients with Pendred’s syn- Wolff-Chaikoff effect.33-35 Syndrome Interestingly. ses iodide uptake in vitro. and PAX8 expres. an iodide-induced evidence for iodide translocation by SLC5A8.45-49 It had been proposed that Because the inhibition results in a decrease in iodide SLC5A8. final TG concentrations of 1 to 10 goiter. which is the consequence of differential gene regulation within thyroid follicular cells. and contains an open reading frame of licular TG concentrations. is also involved in and the inhibitory effect disappears. direction unchanged. in its bicameral system.40 Iodide uptake is stimulated by TSH through the cyclic adenosine monophosphate–protein kinase A Iodide Efflux (cAMP-PKA) pathway and by iodide. The demonstration of iodide trans- block thyroid hormone synthesis acutely through port by the anion channel pendrin.41 as well as in polarized porcine thyro- in vitro. In contrast. identity doses of nutritional iodide result in the negative regula. suggests that pendrin could correspond to dependent on the intracellular iodide concentration. the half-life cytes. TSH stimulates iodide efflux at the absence. and prestin/SCLC26A5 genes are and TPO genes. and have a very similar genomic structure. This may in part be the consequence located in close proximity on chromosome 7q21-31 of the repression of TTF-1. chloride diarrhea). After exposure to TSH.37.28-30 Moderate 70 and 33 μM. and the accumulation of tion of a partial iodide organification defect (PIOD). a ­ phenomenon apical iodide efflux. it is assumed that iodide lular compartments. NIS. respectively). and impaired iodide organification. it decreases to approximately 3 days.37 The inverse relationship between the ing TPO mutations.

Pesce in blue.64. TTF-1. pendrin was first shown to tating mice.39. but protein expression. Thyroid Hormone Synthesis 7q22-31. to TSH. and TTF-2. suggested that the STAS domain of SLC26 members. breast.73 In thyroid follicular cells. and testis.64 23 .64. In differentiated thyroid carcinomas. Using Xenopus oocytes. TPO. the impaired organification of iodide in prostate.78 COOH Remarkably.60 It has been able or decreased.64 the endolym. The 5′ and 3′ untranslated regions of the gene are shown in red and the coding region drin-mediated increase in iodide efflux (L. which con- trasts with the downregulation of thyroid-restricted genes such as TSHR.81-83 and the expression of ductance regulator) in some epithelial cells.65.79 This results in a pen- structure of the PDS protein.and carboxy-terminus. the green and P.67-69 and syncytiotrophoblast cells of the placenta. and the apical pendrin is located at the apical membrane. 2008). PDS/SLC26A4 mRNA sites. personal communication.76 Exposure of FRTL-5 cells to TG results in a signifi- cant upregulation of SLC26A4 mRNA. patients with Pendred’s syndrome. Functional Characterization of Pendrin trium. PDS/ thought to have 12 transmembrane domains with an SLC26A4 mRNA and total pendrin protein expres- intracellular amino. cantly decreased. 3-3). cer. which symbols depict putative glycosylation sites.39 Consistent with this low or absent PDS/SLC26A4 mRNA and protein expression are expression of the PDS/SLC26A4 gene in thyroid can- found in thyroid follicular cells. Exposure of rat NH2 thyroid PCCL3 cells transfected with SLC26A4 pro- STAS domain moter constructs to TG results in a significant upreg- ulation of transcriptional activity. and this induction is thyroid-specific. which may be of ­importance for the interaction with other proteins. In the secondary protein structure. hypermethylation of the PDS/SLC26A4 promoter phatic system of the inner ear. appears to be consisting of 780 amino acids (see Fig.70 endome.1 I­ mmunostaining for pendrin is more abundant in thyroid tissue from patients with Graves’ disease. can interact with the regulatory mRNA and pendrin protein expression are signifi- domain of CFTR (cystic fibrosis transmembrane con.39.72 Very low levels of PDS/SLC26A4 mRNA mediate the uptake of chloride and iodide in a sodium- expression of unknown physiologic relevance have ­independent manner.84 cell of the renal cortical collecting duct. determined by immu- Pendrin is a highly hydrophobic membrane protein nohistochemistry and immunoblotting.37-40. The intracellular may explain the rapid increase in iodide observed in carboxyterminus contains a STAS (sulfate transporter and FRTL-5 and porcine thyroid cell efflux in response antisigma factor antagonist) domain.41-43 PDS/SLC26A4 mRNA levels are similar in hyperfunctioning adenomas compared with normal Protein Structure of Pendrin tissue. TG. NIS.59 Pendrin contains a so-called STAS (sulfate expression is similar compared with normal thyroid transporter and antisigma factor antagonist) domain tissue.71 and mammary glands of pregnant and lac.45.74. sug- gesting a possible correlation of protein abundance with increased iodide organification. Kopp.74 Whether SLC26A4 mRNA levels are regulated 1 21 by TSH in FRTL-5 cells is controversial.80 In contrast.59. transport.39. PDS/SLC26A4 mRNA is also scarce in thyroid Expression Pattern and Regulation of PDS cancer cell lines. and pendrin immunostaining is highly vari- in its intracellular carboxyterminus.75 TTF-1 appears to be involved in the positive regulation of the rat and human SLC26A4 gene promoter.49 and sion are not increased in follicular adenomas.59 In it has three putative extracellular N-glycosylation hypofunctioning adenomas.77 Iodide does not have a major effect on SLC26A4 gene expression in vitro.61-63 pendrin protein does not correlate with NIS expres- sion.46 The demonstration of iodide also been reported in tissues such as lung. exposure of rat PCCL3 cells to Figure 3–3  Chromosomal location and structure of the TSH leads to a rapid increase in pendrin protein PDS/SLC26A4 gene and current model of the secondary abundance in the membrane. PAX8.64 localization of pendrin in thyroid follicular cells39.45 It is higher in most follicular cells.66 type B intercalated was found in most thyroid cancers. PDS including pendrin.75.

and inner ear are not readily corroborates a physiologic role of pendrin in bicar. kidney.49 do not express this channel.47.106 The open reading frame mouse. argued that the distinct functional roles for pendrin cal membrane to the cytosol.Part I  Normal Thyroid Axis have suggested a possible role in iodide transport anion and fluid transport and maintenance of the into the follicle. pendrin localizes to the a role of pendrin as an apical iodide transporter. acceptable. and pendrin is relocalized from the api. 3-4). However. TG is encoded by a large 270-kb gene that consists of nal cochlear sulcus region by in situ hybridization. pendrin may interact with other proteins. TG reen- ters the cell to be digested in lysosomes.91 Remarkably. pendrin was found to act as an brane independently of pendrin through another exchanger of chloride for bicarbonate.99-101 It is located on chromosome This expression pattern involves several regions for 8q24. and in non. non-B intercalated cells. This. confirming that pendrin is a chloride-base an overt thyroid phenotype.92. SLC26A4 mRNA is readily found in the kidney. however. is upregulated after treatment with aldosterone ana- logues and with chloride restriction. and PAX 8.67.44 ment reverse transcriptase–polymerase chain reac. and T4 and Pendrin in the Inner Ear T3 are secreted into the bloodstream (see Fig. and in the exter. but their molecular identity remains uncertain. iodide.3. whereas type A intercalated cells iodide intake have no or only a mild thyroidal phe- are hydrogen-secreting cells.88. In the developing mouse.93 it is currently unknown exchanger.89 In contrast. which has endolymphatic fluid resorption. is regulated by the transcription factors TTF1.66.67 In cells cultured in a bicameral system are ­consistent with the cortical collecting duct. which is normally pendrin-mediated apical iodide efflux was obtained generated by the basolateral potassium channel in a model system with polarized Madin-Darby canine KCNJ10 located in intermediate cells. In mice.96 function in terms of iodide transport.86 notype97 indicates that iodide crosses the apical mem- Functionally.48 ­ Further evidence for lack the ­ endocochlear potential. hyd­roxide. Slc26a4 mRNA is predomi- nantly detectable in the endolymphatic duct and sac. and increased membrane insertion. whereas tubules patients homozygous for completely inactivating NIS from alkali-­loaded Pds −/− mice fail to secrete bicar. patients with Pendred’s syndrome and the Pds null TTF2. pendrin which could lead to variable anion selectivity. On demand for thyroid hormone.49.68 Type B intercalated cells tions in the SLC26A4 gene and a sufficiently high secrete hydroxide. the Consistent with the partial organification defect endolymphatic calcium concentration is elevated in observed in patients with Pendred’s syndrome.93 More cells have subsequently demonstrated that pendrin recent studies have revealed that Slc26a4 −/− mice can mediate iodide efflux. an aldosterone analogue. the fact that individuals with biallelic muta- A.85 Controversies Concerning the Role Pendrin in the Kidney of Pendrin in Apical Iodide Efflux In addition to its expression in the thyroid and inner Studies performed with thyroid cell membrane vesi- ear. because they kidney (MDCK) cells expressing NIS and pendrin.45 cles have suggested that iodide crosses the apical mem- in particular in the renal cortex. of T4 and T3 and the storage of thyroid hormone and sterone pivalate (DOCP). the Slc26a4 −/− mouse through inactivation of two rally occurring mutations of pendrin lead to a loss of apical calcium channels. brane through two anion channels or transporters.98 It has also been ing duct cells.56 Functional studies in transfected endo­­cochlear potential in the inner ear. that many bonate secretion.2-8q24. The tion (RT-PCR) assays have led to the detection of results of functional studies performed in ­ polarized ­positive signals in the cortical collecting duct. natu.105. bicarbonate loading SLC26A family members transport several anions. TRPV5 and TRPV6. and the typi. Structure of the Thyroglobulin Gene in areas of the utricule and saccule. strongly suggest that pendrin is involved in consists of 8307 bp and encodes a protein of 2768 24 . results in upregulation of pendrin protein expression Moreover. remarkable structural similarity with the TPO pro- cal enlargement of the endolymphatic system in moter. It should be noted. mutations. this observation further in the thyroid.68 Acid loading of mice results in reduction whether the phenotype could become apparent under of pendrin protein expression in the cortical collect.90. Very high formate. and iodide channel or unspecific channels.65 48 exons (Fig.102-104 The TG promoter.95 In addition.94.55 apical brush border membrane in type B.87 Renal tubules isolated from alkali-loaded iodide intake can even mitigate the phenotype in wild-type mice secrete bicarbonate. 3-1). conditions of scarce iodide intake. and nephron seg.6 Although Pds knockout mice do not have bonate. THYROGLOBULIN Slc26a4 knockout mice do not develop weight gain Thyroglobulin serves as the matrix for the synthesis and hypertension after treatment with deoxycortico.

the outer ring of the iodothyronine amino acid at an terase. The type 1 repetitive region contains 11 type 1 cancer. Among the 20 potential glycosyl- 1 48 ation sites of the TG monomer. result- The monomer of TG is composed of a 19–amino acid ing in the release of thyroid hormones. and 2747 (see Fig. stream.121 From the Golgi apparatus. The 5′ and 3′ untranslated regions of the gene are shown in red and the coding region in blue. are located at tyrosines 130. From the Golgi apparatus.128 In contrast. in vitro.2-24. In the sec. a tyrosyl resi- into three regions that contain repetitive elements and the due donates its iodinated phenyl group to become carboxyterminus shares high homology with acetylcholines.117 and TTF-1 interact directly through protein-protein 25 . TSH and insulin-like growth motifs formed by a cysteine-rich consensus sequence factor I (or insulin) need to be present ­concomitantly CWCV(D). which defines it as a specific and sensitive major regions based on internal homology (see Fig. 16 are known to be Acetylcholinesterase glycosylated. The carboxy.105 The PAX8 and TTF1 sites are overlap- linesterase.111 In the follicular lumen.112 About 10% of the molecular weight is accounted for by carbohydrates.118 Other secondary modifications of TG domain include sulfation and phosphorylation.123 genes contain multiple synonymous and nonsynony. to induce expression of the TG gene.110. is initiated by the interac- folding and dimerization. In cell culture.108 After trans.109 Moreover. can also be transported from the apical to basolat- lation of the mRNA. genic acceptor sites are localized at positions 5. where the TG polypeptide is submitted to referred to as transcytosis.122 Donor sites amino acids. where TG is digested. Thyroid Hormone Synthesis 8q24.1 This organification reaction results in Figure 3–4  Chromosomal location and structure of the TG the generation of MITs and DITs (see Fig.124.110. where they are glycosylated. glycosylated TG Donor 847 Donor 1448 migrates to the apical membrane in small secretory Donor 130 Acceptor 2554 vesicles and is secreted into the follicular lumen. the four main hormono- (numbering after cleavage of the signal peptide). 1291. is secreted into follicular lumen in a tightly regulated process. a receptor located on the glycosylated TG migrates to the apical membrane and apical membrane of the thyroid follicular cells. also ulum (ER).108 Alternative splicing generates vari. where it is released into the blood- conducts the TG molecule into the endoplasmic retic.111 Acceptor 1291 where selected tyrosyl residues of the TG polypeptide Acceptor 2747 Acceptor 5 are iodinated. and TTF2.2 The gene and current model of the secondary structure of the coupling reaction then leads to the formation of T4 TG protein. among others. teins. or T3 from one DIT and one ondary protein structure. 847. and 1448. The most ous transcripts and subsequently a heterogeneous important T4-forming sites are the acceptor tyrosine population of TG polypeptides. ping and. the TG protein has been divided MIT.113-115 Type 1 repeats may bind and inhibit cys. tumor marker for papillary and follicular thyroid 3-4).116 These structural characteristics sug. 3-4).129 The human TG gene the processing and degradation of TG. promoter has similarities with the TPO promoter terminal part of the TG monomer (residues 2192 to and contains. leaving dehydroalanine at the donor number 5 and the major donor site is at tyrosyl number 130 position. To generate T4 and T3 for release into the mous single-nucleotide polymorphisms (SNPs).112 The TG gene is expressed exclusively in thyroid fol- The TG protein has been divided into four licular cells. bloodstream.127 This transepithelial transport. 2568. the 19–amino acid signal peptide eral membrane. the TG 5 and the donor tyrosine 130 (see Fig. 3-1). TG is present as Expression and Regulation of Thyroglobulin a 19S dimeric glycoprotein of 660 kD.126.120 It has Type 1 repeats Type 3 repeats Type 2 repeats been suggested that tyrosine sulfation may play a role NH2 COOH in the hormonogenic process. tion of TG with megalin.2 During the coupling reaction. 3-4).3 Intact TG signal peptide followed by 2749 residues. The major acceptor site is at tyrosyl acceptor site. In human TG. a module found in a large family of pro. the binding of the two transcrip- gest that the TG gene emerged from the fusion of tion factors to DNA is mutually exclusive. from two DIT residues. The main acceptor and donor tyrosyls are shown in yellow and light blue.125 The TG-containing vesicles Thyroglobulin Protein Structure fuse with lysosomes.112. binding sites for PAX8 2716) shares remarkable homology with acetylcho.107. TG is internalized predominantly by micropinocytosis. 2554.130 PAX8 two ancestral genes.3 Properly folded TG dimers migrate to the Golgi apparatus.119. a feature that could play a role in by the two growth factors. expression of the TPO gene can occur independently teine proteases.

two everted finger (EF) DUOX1 and DUOX2 mRNA expression is almost motifs in the first intracellular loop. are now officially designated as dual oxidases. 3-1). its organification. have also been reported in the intestinal tract (duo- branes. Human DUOX1 has an open reading frame of 1551 Intriguingly.144 Subsequently. 3-5). EF Hand and sequence information derived from this protein FAD led to cloning of a partial cDNA of DUOX2 (see lat- er) by RT-PCR. colon) of the adult rat. In the secondary protein structure.141 intact follicles. which are dase.150 Sec- ondary structure analysis has predicted seven puta.145 These two oxidases.145 Only very weak signals for DUOX2 The intracellular location of the calcium-binding EF mRNA have been reported in the stomach and tra- domains is consistent with the activation of the H2O2 chea. cific maturation factors DUOXA2 and DUOXA1.135-138 It then NH2 became apparent that this enzyme system contains a membrane-bound flavoprotein using flavine adenine dinucleotide (FAD) as a cofactor.148 The two DUOX genes are closely linked and located Only the 190-kD form is resistant to ­ endoglycosidase on chromosome 15q15 (Fig.141-143 A functional NADPH oxidase. two cDNAs encoding thyroidal NADPH oxidases have been cloned using a NADPH strategy assuming a homology between the NADPH oxidase systems in thyroid follicular cells and neu. and cytosolic FAD and NADPH binding thyroid cells using serial analysis of gene expression sites. Expression and Regulation of DUOX tive transmembrane domains. initially Figure 3–5  Chromosomal location and structure of the DUOX2 and DUOX1 genes and the genes encoding the spe- referred to as THOX1 and THOX2 for thyroid oxi. and one FAD binding site (see Fig. the amino termini of both DUOX amino acids.134 and thyroid slices.151 denum.153 An Western blots have detected two proteins with a expressed sequence tag (EST) for DUOX2 has also molecular weight of approximately 180 to 190 kD caused been reported in a pancreas library. and DUOX2 has 1548 residues.146 DUOX2 tain two putative Ca2+-binding everted finger motifs in the first has also been detected as an abundant transcript in intracellular loop. proteins have a homology of approximately 43% with The DUOX genes encode two highly related TPO. was finally solubilized from porcine plasma membranes.144. protein size is reduced to approximately 160 kD. COOH trophil granulocytes.138. exclusively detected in thyroid tissue using Northern ing sites.149.134 and involves the oxidation of reduced nicotinamide adenine dinucleotide phos. and this domain of DUOX1 and its Caenorhabditis proteins with a similarity of 83%. the kb and the DUOX2 gene encompasses about 22 kb. the DUOX1 gene spans about 36 processed form.148 They both hydrogen digestion. After complete deglycosylation. DUOXA1 tion of iodide. four NADPH bind. DUOX Gene and Protein Structure by glycosylation of five putative glycosylation sites. MOX1).147 26 .132.152 Using RT-PCR assay.144.Part I  Normal Thyroid Axis interaction and synergistically activate the TG gene 15q15. suggesting that it is the completely consist of 33 exons. DUOX2 transcripts generation system by cytosolic Ca2+ in thyroid mem. 1 33 phate (NADPH) by an NADPH oxidase.140 and that it Peroxidase-like domain requires micromolar concentrations of calcium for its activity.3-21. small intestine. generating H2O2 in a Ca2+-dependent manner.145. The DUOX proteins con- oxidase domain and peroxidase activity.134. The extracellular amino terminus contains a peroxidase- (SAGE).146 several other oxidases (NOX2. and the coupling reaction (see Fig. essential for trafficking of the enzymes.147 like domain whose function awaits further characterization.145. the H2O2 generating system is localized at the apical membrane133.144 blot analysis. 3-5).132 As shown through cytochem- ical studies.1 promoter.131 HYDROGEN PEROXIDE GENERATING SYSTEM DUOXA2 DUOX2 DUOX1 Hydrogen peroxide (H2O2) is essential for the oxida.139. The 5′ and 3′ untrans- DUOX1 and DUOX2.136. This nomenclature is based lated regions of the gene are shown in red and the coding on the fact that these oxidases contain an NADPH region in blue. They are related to elegans homologue displays peroxidase activity. the green symbols depict glycosylation sites.

157 the fraction of DUOX proteins reaching be acutely stimulated through the phosphatidylino- the membrane is modest. proper membrane targeting and enzymatic activity. synthesis under conditions of low iodine intake and mic reticulum to the Golgi apparatus.2 A more recent model has proposed immunostaining is higher in thyroid tissue from that O2 is directly converted into H2O2 by a complex patients with hypothyroidism. Ca2+-dependent NADPH oxidase system containing a cant differences between normal tissue and multi.152.148 These findings ­ suggested with iodide downregulates NIS and TPO mRNA levels. DUOXA2 is coexpressed with DUOX2 and of the mechanisms that results in efficient hormone permits transition of the protein from the endoplas. is therefore dependent on the presence of DUOXA2 to achieve normal function. Thyroid Hormone Synthesis The expression of DUOX1 and DUOX2 Functional Analyses of DUOX2 mRNA levels is rapidly stimulated through the cAMP and Generation of Hydrogen Peroxide pathway in human.159 The expression of DUOX1.167 whereas low concentrations mining that analyzed tissue-specific transcripts. in downregulating hormone production when iodide and translocation to the plasma membrane. 27 . Studies performed in canine and porcine In nonthyroidal cells transfected with DUOX1 and cells have documented a stimulatory role of TSH and DUOX2 cDNAs.143. functions. referred to as DUOXA2.155 Exposure to iodide antagonizes the cAMP. and coexpression of DUOX2 and This phenomenon may contribute to the mechanisms DUOXA2 permits to reconstitute an H2O2-generating underlying the Wolff-Chaikoff effect. before it can serve as an iodinating agent. 3-5).158 DUOXA2 was identified by data 2-iodohexadecanal. maturation.154. ­oxidation of iodide requires the presence of H2O2 whose physiologic role remains to be determined.1. pathway. porcine. H2O2 generation remain controversial. This has recently been Thyroperoxidase corroborated by the finding of biallelic inactivating Iodide must be oxidized to a higher oxidation state mutations in DUOXA2 in a patient with congeni. maturation factors.145 and the successful reconstitution of ease. DUOX2 and DUOXA2 will now permit clarification Membrane insertion of DUOX2 is dependent of this question.142. In rats treated enzyme in heterologous cells. the expressed proteins reside pre. DUOX2 intake is high or excessive. unclear whether H2O2 is formed directly or through a sue. Immunopositivity for NIS and DUOX expres. stimulators of the cAMP pathway on H2O2 genera- dominantly in intracellular compartments and are tion.144. It is stimulate H2O2 generation in thyroid tissue slices.143. an H2O2-generating system through coexpression of sion shows an inverse relationship. on a specific maturation factor.148 It has been proposed sitol pathway.151. As noted.154 Treatment of porcine thyroid follicles other oxidases. DUOXA2. is and is catalyzed by TPO.145. High concentrations of iodide inhibit H2O2 produc- tor. canine. The biochemical mechanisms resulting in but this is not the case in cultured thyroid cells. for proper processing tion. Regulation of Hydrogen Peroxide Activity roid follicular cells and colocalize with TPO. membrane insertion of the DUOX pro- induced glycosylation of DUOX2 to its mature form.168 arranged head to head with the DUOX2 gene (see This inverse regulation of H2O2 generation is one Fig. es H2O2 production in pig and FRTL-4 cells.144.156 Protein expression determined by mediate step.164.154 possibly through the intermediary product of the protein. DUOX2 mRNA levels are reduced. Recent findings have revealed that the H2O2 generation is regulated by iodide.160-163 The secondary structure of the nodular goiters.166. bound glycoprotein with a prosthetic heme group.152 As The generation of H2O2 is Ca2+-dependent and can for TPO. scripts. the mRNA expression of the two DUOX genes process that includes the formation of O2− as an inter- is variable.2. flavoprotein.153 Treatment of thyroid cells with system through transfection of DUOX cDNAs. failed.162 whereas chronic exposure to TSH decreas- only present as a 180-kD form. there are no signifi. This tal hypothyroidism. teins is dependent on the presence of their specific and may explain the decrease in H2O2 generation.165 TSH also modulates the that this could serve as a regulatory mechanism of production of H2O2 through the protein kinase A the cell to limit the generation of oxidative agents.134. alone iodide inhibits H2O2 generation and NADPH activity or in combination with components required for in vitro.158 with methimazole.169 TPO is a membrane- dependent on its own paralog. a need for additional components for achieving but does not affect the abundance of DUOX2 tran.145.139. DUOX2 protein requires a specific maturation fac. and only few positive cells in thyroid DUOX proteins is consistent with these predicted tissue are obtained from patients with Graves’ dis. It is currently In benign and malignant human thyroid tis. DUOXA1. and rat thyroid Initial attempts to reconstitute an H2O2-generating cells in vitro. DUOX proteins are located at the apical membrane of thy.

which results TSH.179-181 In FRTL-5 cells. regulated by a thyroid- contains a region with high homology to the complement specific enhancer located 5. scriptional start site.129. The 5′ and 3′ untranslated regions of the gene PAX8 also interacts with the nuclear coactivator p300 are shown in red and the coding region in blue. TSH and pharmacologic stim. It is distinct from the heme b (protopor- abundance. 3-6).128. bound to glutamine 399 and aspartate 238 of the ulators of the cAMP pathway increase TPO mRNA apoprotein. acting in a coun- located in the follicular lumen (Fig.184 It does not 1 16 involve stimulation of a CRE (cAMP response ele- ment) or TTF-1. TPO and PAX8. the increase phyrin IX) found in many other hemoproteins and is in TPO mRNA levels seems to be the consequence composed of a bis-hydroxylated heme b.172 The full-length human TPO is not explained by the translation of TPO2. Figure 3–6  Chromosomal location and structure of the TPO cooperates with TTF2 in TPO promoter regulation.130 PAX8 and TTF1 interact synergistically. which lacks enzymatic activity.171 spans about 150 kb. downregulates the expression of TTF1. TPO.189 One region of the enhancer has overlapping binding sites for TTF1 and PAX8 that seem to be mutually exclusive. and TSH receptor expression. whereas transcriptional directly coordinated to the iron atom or positioned stimulation of the TPO gene has been implicated in in its immediate proximity are critical for modulating canine thyroid cells.176-178 In The prosthetic heme group is covalently cultured thyroid cells. follicular TG.187 gene and current model of the secondary structure of the TPO protein.182 enzyme reactivity and specificity.188 Expression of site of the enzyme faces the follicular lumen.174 The most by two intramolecular disulfide bonds in the case of abundant alternative transcript is lacking 171 nucleo.186 The CCAAT-binding transcription fac­tor COOH CTF/NF-1. The catalytic to enhance TPO gene transcription. human TPO. a mechanism that leads to a decrease in is also required for the coupling of iodotyrosines to NIS.185 Peroxidase domain The human TPO gene promoter contains NH2 three binding sites for TTF1 and a binding site for Hinge PAX8 and TTF2 in the region between −170 to +1 bp CCP-like domain relative to the transcriptional start site. 3-6).173. in vitro.36.2. ­Phorbol esters. a phenomenon that exons (see Fig.192-194 The human TPO gene is located on chromosome In immunoblot analyses. amino terminus of TPO is located extracellularly and Several shorter transcripts of unknown biologic the extracellular region forms a loop that is created relevance have also been identified. which is inducible by cAMP and insulin. TTF2.175 (see Fig.Part I  Normal Thyroid Axis 2p25 TSH and forskolin rapidly upregulate TPO promoter activity.37 generate T4 and T3 (see Fig. the binding EGF-like domain of the two transcription factors to DNA is mutually exclu­sive. TG. In addition terregulatory fashion to the stimulatory effect of to catalyzing the oxidation of iodide. 3-1).183 This direct effect does not require protein synthesis and correlates with an increase in TTF2 binding activity. Amino acids of enhanced mRNA stability.105 The PAX8 and TTF1 sites overlap and.196-198 The single membrane-spanning tides secondary to deletion of exon 10 encoding codons domain is in close proximity to its carboxy terminus 533-590 (TPO2). interferon-gamma. in the iodination of selected tyrosyl residues.190.105.191 As noted.5 kb upstream of the tran- control protein (CCP) and the epidermal growth factor (EGF).105. The protein the human TPO gene is. Human TPO has five potential glyco- sylation sites and about 10% of its weight stems from Expression and Regulation the addition of carbohydrates. but the location of of Thyroperoxidase the N-linked glycosylation sites have only been deter- The activity of TPO is enhanced by TSH in vivo mined for porcine TPO. and ­interleukin- 1α (IL-1α) and IL-1β downregulate TSH-induced Thyroperoxidase Gene and Protein TPO mRNA expression in human thyroid cell Structure ­cultures. TPO appears as 2pter-p12. and consists of 17 a doublet of 110 and 105 kDa.170.199 through increased TPO protein expression. 3-6). possibly through interactions between enhancer and promoter.200-202 28 .195 The cDNA encodes a protein of 933 amino acids (TPO1). in part.

236. subsequent of albumin. the reaction product is referred to TPO and MPO. 3-1). or iodinium (I+).196. a tyrosyl resi- tion with TSH increases the abundance of TPO at the due donates its iodinated phenyl group to become apical membrane and results in enhanced enzymatic the outer ring of the iodothyronine amino acid at an activity.124. but display modest catalytic mediated endocytosis. The most important T4-forming site is located at tyrosine 5 and tyrosine 130 is the Functional Characterization dominant donor site.226-234 tidase I results first in the release of the dipeptide 29 . 1291. T3. binant protein has been successfully expressed using For a detailed review. result- with MPO210 and the polypeptide region interacting ing in the reduction of H2O2 to H2O and oxidation with the heme group is 74% homologous between of the enzyme. which tivity is also found in the cytoplasm. 130. In The chemical nature of the oxidizing iodide vitro. many of the recombinant through micropinocytosis.201 but the three.224 Remarkably.212. The release acterized with different biochemical assays such as of thyroid hormone requires uptake of iodinat- guaiacol oxidation. digestion of TG with lysosomal extracts results is not known with certainty. Donor sites include tyrosines TPO requires the presence of thyroid-specific factors.123 of Thyroperoxidase Catalytically active TPO was first successfully puri. 2568. possibly because of their cleavage of TG by endopeptidases.240 The transiently transfected Chinese hamster ovary (CHO) main hormonogenic acceptor sites in human TG cells and stably transfected rat PCCl3 thyroid cells. and MIT. Cellular Uptake and Proteolysis fied by solubilizing thyroid membrane fractions of Thyroglobulin and by immunoaffinity chromatography. it undergoes ability to glycosylate the protein. digestion in lysosomes. The structure of MPO has initially as compound I (E-O or TPO-O).225 Eukaryotic cells may be more suitable as globulin is dependent on several endopeptidases.8 Å. The reaction of TPO and other per- amino acids of TPO display a 42% sequence identity oxidases with H2O2 is a two-electron reaction. only a sub- dimensional structure of TPO has not been modeled.217 These observations indicate that TPO is acceptor site. carrying T4.237 In the coupling reaction. and transport of the thyro- After the molecular cloning of TPO cDNAs. and 1448. 3-4). tions. and coupling of DIT within TG to T4.241. B. II. at a reduction of compound I generates compound resolution of 1. theo. Thyroid Hormone Synthesis All mammalian peroxidases belong to a Oxidation of Thyroperoxidase single gene family.223 Iodinated TG. position.239 In the formation of T4.243.244 After soluble recombinant TPO.197. iodide oxidation.202 TPO displays a high degree of to Compound I and Compound II se­quence similarity with myeloperoxidase (MPO)203-206 In native peroxidase.2 More recent studies have in the preferential release of hormone-rich frac- suggested that iodide is oxidized in a two-­electron reac. which is initiated by TPO preparations have been particularly useful for nonselective fluid phase uptake and by receptor- immunologic studies. and a second one-electron reduction brings the retical three-dimensional structures have been derived enzyme back to its native state. and H. the sorting and trafficking stems from a DIT residue and in the formation of T3 of TPO are cell type–dependent and.215 Acute stimula. recom. leaving dehydroalanine at the donor brought to the plasma membrane through the secre.112. In the iodination reaction. Interestingly. stored as colloid in the follicular lumen. fected heterologous cell systems.122.122.218-221 In con.2 set of the 132 tyrosyl residues of the TG dimer are Immunohistochemical studies localize TPO at iodinated. see Dunn3 and Dunn and several mammalian and nonmammalian expression Dunn.245 and digestion with the endopeptidase tion that may result in the formation of hypoiodite cathepsin B and the exopeptidase lysosomal dipep- (OI−). the heme is in the ferric (iron and other mammalian peroxidases.2.235 A one-electron been solved at 3 Å resolution211 and.237. is The catalytic activity of these preparations was char. an expression system for obtaining a functional and including the cathepsins D.214 but abundant immunoposi. more recently. Uptake of TG occurs predominantly systems.207-209 The first 735 III) form (Fe3+).238. DIT. DIT. have been localized at positions 5. it stems from MIT. 847.242 Digestion of thyro- activity.213 Based on this structure. further degradation by several exopeptidases. species and must be defined by their location in the trast.112. TPO is often largely Hormonogenic sites are conserved in various retained in intracellular compartments. results in the formation of T4 or T3. resulting in the formation of MIT and the apical membrane.112. These findings suggest that membrane insertion of and 2747 (see Fig. TPO reaches the plasma membrane efficiently in three-dimensional structure of TG. iodination ed TG into the thyroid follicular cell.222. hypoiodous acid (HOI).216. in stable trans. 2554. for other mammalian peroxidases. the outer ring tory pathway. L. nines T4 and T3 into the bloodstream (see Fig.3.

but they are one of the steps required for thyroid hormone syn- only released in minute amounts into the circula. and a decreased saliva-to- tent with the previously obtained biochemical data serum radioiodide ratio. Under conditions of scarce iodide and subsequent release of T4. but not T4. 3-7). 1 FMN domain 5 and a positive perchlorate test that indicates a NH2 COOH PIOD.246 After degradation of intake. The iodotyrosines MIT and DIT are much more thyroid dysgenesis.249. dyshormonogenesis (approximately 10% to tion.53-55 and goiter of the gene are shown in red and the coding region in blue. 3-1) and are briefly summarized here. or inborn errors of metabolism in abundant within the TG molecule. several cases of hypothyroidism resulting that DEHAL1 corresponds to the iodotyrosine deio. Certain mutations affect NIS function DEHAL1 mutations spill MIT and DIT into the by substituting key functional residues. Formal thyroxine. and into the bloodstream at the basolateral membrane.147 The A small subset of patients with dyshormonogen- predicted protein.97 Individuals with Pendred’s ­syndrome 30 . contains a nitroreductase domain and patients have a low or absent uptake of radioiodide a flavin mononucleotide domain. which is also expressed at the usually scarce. Patients with the NIS gene.250 The chronic stimulation with TSH.254-256 Defects in thyroid hormone synthesis already been identified in 1952 .5. a finding consis. an element that is transporter MCT8. severe hypothyroidism. the channel(s) mediating the transport of thyroid follicular cells have developed an intricate thyroid hormone across the basolateral membrane system to reduce the loss of the hormonally inactive have not been identified. most individuals with Pendred’s syndrome DEHAL1 gene and current model of the secondary structure are clinically and biochemically euthyroid under of the DEHAL1 protein. T4 and T3 are secreted of thyroid hormone. in scintigraphic studies.257 These (DEHAL1).252 However.52.264 The thyroid phenotype varies and Nitroreductase domain depends on the nutritional iodide uptake. which ultimately leads to the urinary hormonogenic site 5 and glutamine at position 6.55. If these Importantly. referred to as dehalogenase 1 esis have an iodide trapping defect (ITD).251 Using the Gene Mutations SAGE technique. These findings illustrate that As of yet. candidate. loss of iodide. is a potential of DEHAL1 is still pending. level. this is associated with insufficient synthesis TG in the lysosomal pathway. The thyroid hormone iodotyrosines to recycle iodide. tion is high.18.56.261 and oth- ers lead to misfolding and retention in intracellular compartments. goiter development.258-260 These individuals are homozygous or tal hypothyroidism and mutations in the DEHAL1 compound heterozygous for inactivating mutations in gene could be identified (see later).Part I  Normal Thyroid Axis T4 glutamine. The protein contains a flavin mononucleotide (FMN) development may be absent if the iodide consump- binding domain and a nitroreductase-like domain.262 6q25.263. thesis. patients with defects in thyroid hormone identification of the gene encoding this enzyme synthesis usually develop a goiter because of the has only been obtained very recently. A thyroidal iodotyrosine dehalogenase had 15%).1 Mutations in the SLC26A4/PDS Gene and Pendred’s syndrome Pendred’s syndrome is an autosomal recessive dis- order defined by sensorineural deafness. from ITD have been characterized at the molecular dinase was pending until patients with congeni. it was also shown that the released conditions are not recognized and treated with levo- iodide is reused for hormone synthesis. functional or genetic proof NIS gene. corresponding to the amino terminal bloodstream.247 DEFECTS IN THYROID HORMONE SYNTHESIS Dehalogenation of Monoiodotyrosine Congenital hypothyroidism can be caused by develop- and Diiodotyrosine mental defects of the thyroid (approximately 85%). dehalogenase was known to be a flavin mononu- cleotide (FMN)–dependent enzyme.253 A more detailed characterization basolateral membrane of thyrocytes. After the cloning of the (Fig. ­ goiter. Despite Figure 3–7  Chromosomal location and structure of the the PIOD. several thyroid-restricted genes were isolated and one of them was postulated to be Mutations in the NIS Gene the long-sought iodotyrosine dehalogenase.248 Fig. The 5′ and 3′ untranslated regions conditions of normal iodide intake. and was shown to have been identified in all steps discussed earlier (see deiodinate MIT and DIT efficiently.

DUOXA2 is necessary for the exit of folded indicating an activation of the iodine concentration wild-type DUOX2 from the endoplasmic reticulum. Recently.278-280 The maturation of tein and thus results in an inability to escort DUOX2 TG is controlled by several molecular chaperones. This leads to a significant loss of iodide Mutations in the TPO Gene and. under conditions of scarce iodine intake. but have distinct functional roles. whereas misfolded goiter to severe congenital hypothyroidism. severe Biallelic mutations in the TPO gene are a relatively hypothyroidism and goiter develop.edu/ synthesis of H2O2 and thyroid hormone synthesis.109. but is not facilitated by DUOXA2. characterization of the mutations revealed absent or tal hypothyroidism.49.272 tive folding of DUOX2 in the endoplasmic reticulum appears to be the rate-limiting step in the maturation Mutations in the TG Gene of the enzyme.20 The mutation leads to a complete loss of indicated that most of the mutations are retained in function caused by a truncation of the DUOXA2 pro- the endoplasmic reticulum.277 Molecular analyses have roidism. for expression of a functional enzyme. As noted. Mutations in the DUOXA2 Gene tinuous growth. all were homozygous for inactivating mutations in the DEHAL1 gene. deficiency in DUOX2.275 In many cases.45 Mutations vation of a single allele causes transient congenital in the SLC26A4/PDS gene display impressive allelic hypothyroidism and a PIOD. All mutations disrupt the nitroreduc- Defects in the DUOX2 Gene tase domain of the enzyme (see Fig. no mutations have been found in the DUOX1 Some SLC26A4/PDS mutations result in gene. mutations in the and TPO gene defects are the most common cause DEHAL1 gene were identified in four individuals250. In patients who are not treated with levothyroxine. Further proof for the related parents and are homozygous for inactivating essential role of DUOXA2 has recently been provid- mutations in the TG gene. Others are inserted into the membrane. this finding explains why it was not possible to TG levels are usually very low.19 Biallelic mutations result in severely impaired enzymatic activity to deiodinate 31 . Thyroid Hormone Synthesis are homozygous or compound heterozygous for a severe phenotype and a TIOD. mechanism caused by chronic TSH stimulation. of TIOD.158 In retro- ed.45.287 Remarkably.159 Oxida- deafness.276 More rarely. the affected individuals have heterologous cell systems. or in the low-normal reconstitute active DUOX enzymes in the past using range. the TSH levels at neonatal screening may be normal. affected ed by the identification of a patient homozygous for patients are compound heterozygous for inactivating a DUOXA2 gene mutation and congenital hypothy- mutations in the TG gene. ­ Coexpression of display impaired or abolished ability to mediate DUOX2 mutations with its specific maturation factor.htm. inacti- mutations in the SLC26A4/PDS gene.271 Pendred’s syndrome is probably DUOXA2.285. and DUOX1 is unable to compensate for the retention of the protein in intracellular compart. indicates that the mutations are retained the most common form of syndromic deafness and by the quality control system within the endoplasmic accounts for about 10% of all cases with hereditary reticulum or reduced surface expression.265-270 (More information can provided evidence that it is essential for the normal be found at http://www. Biallelic mutations in the TG gene result in a wide Folded DUOX2 is dependent on DUOXA2 for exit phenotypic spectrum that ranges from euthyroid from the endoplasmic reticulum. the perchlorate test is usually normal. The radioiodine uptake is elevated. Of laboratories/pendredandbor/slcMutations.) note. This suggests that the enzymes ments. goiters are often remarkably large and display con. 3-7) and one of Monoallelic and biallelic mutations in the DUOX2 them also affects the FMN-binding domain.healthcare. infancy or childhood.47. iodide efflux. Misfolded TG that accumulates in the ER is translo- cated back into the cytoplasm and undergoes degra. from the endoplasmic reticulum. sis associated with congenital hypothyroidism. Mutations in the DEHAL1 Gene dation by the proteasome system.274 DUOX2 mutations are directed toward degradation. The documentation of a heterogeneity and more than 150 mutations have TIOD in patients with biallelic DUOX2 mutations has been documented.286 MIT (ERAD). a process referred Patients with a defective thyroid dehalogenase system to as endoplasmic reticulum–associated degradation were identified more than 5 decades ago. and DIT leak into the circulation and are excreted in the urine.uiowa. and the maturation factor is necessary and sufficient Because the organification process itself is not affect. In contrast.281-284 and the phenotype only becomes apparent later in Patients with TPO mutations have a PIOD or TIOD. Serum spect.273. Functional gene result in transient or permanent congeni.263. frequent cause of defective thyroid hormone synthe.

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Endocrinology 128:3073-3080. co N: Molecular characterization of V59E NIS. 1979. et al: acterization of a flavoprotein from bovine thyroid Thyroglobulin structure and function: Recent ad. Arch Biochem Biophys 334:284. Endocr Rev 25:722-746. 240. 1984. Rabilloud R. Duprez L. 2004. 1998. De la Vieja A. J Biol Chem 265:17373-17380. Kopp P: Genetic regulation of thy- 330:24-32. 1996. Ginter CS. tion of two thyroidal proteases releases T4 from 263. 1952. J Clin 246. Horm Res 60:96-102. tal deafness with goitre: The nature of the thyroid docrinol Metab 19:50-56. 1996. Levy O. Digestion of thyroglobulin with purified thyroid 262. 1981. Gillam MP. Lissitzky S: Sur la Analyses of catalytic intermediates of hog thyroid déshalgénation enzymatique des iodotyrosines peroxidase during its iodinating reaction. Major sites transport defect. Carras- ogy 132:2645-2653. et al: Predominant 242. Taurog A. Clin Genet 63:445-455. Lancet 1:607-609. Dunn JT. 1989.

 Hishinuma A. Rivolta CM. Stanbury JB: The iodotyrosine 276. et al: A 3¢ splice Netherlands: TPO gene mutations in total iodide site mutation in the thyroglobulin gene respon. J Clin Invest 88:1901-1905. Fugazzola L. 1999. et al: demiology of deafness. Borgfors N. ­Ceballos C. Terpstra 275. 2002. 287. J Med Genet 40:242-248. fetal goitrous hypothyroidism. Hirschberg K. nol Metab 80:3356-3360. 1204. Targovnik HM. Vulsma T. deiodinase defect. 1998. Karamanoglu Arseven O. Vono J. Eur J Hum Genet 24:24. Varela V. Medeiros-Neto G. 1998. et al: Non-en. de Vijlder JJ: Identifica- hearing loss associated with enlarged vestibular tion of five novel inactivating mutations in the thy- aqueduct: A unique spectrum of mutations in Jap. CRC Press. nol Metab 85:3708-3712. endoplasmic reticulum (ER) storage diseases: Dis- 267. lin gene. Endocr Rev 14:165. and magnetic resonance imaging studies of the 279. 2001. tions in Pendred’s syndrome and nonsyndromic 282. quence of the human thyroid peroxidase gene 270. Malet D. demic goitre and deafness. Identification of a mutation in the coding se- 2003. Stanbury JB. homozygosity mapping. Coucke P. Nilsson LR. Gamstorp I. Cerutti N. Arvan P: Endocrinopathies in the family of Hum Mol Genet 7:1099-1104. Stanbury type analysis reveals founder effects of thyroglobu. JB (eds): Inherited Disorders of the Thyroid lin gene mutations C1058R and C1977S in Japan. et al: Haplo. Maruvada P. Caron P. Bikker H. 284. J Clin Endocri- 268. J Clin Invest 90:1200- bution and frequencies of PDS (SLC26A4) muta. Acta Paed 53:117-131. Tsukamoto K. 1994. Rotman-Pikielny P. Weiss RE. 278. McGirr EM. Fla. and south Asians: Global implications for the epi. roid peroxidase gene by denaturing gradient gel anese. Liu X-Z. 286. 1995. et al: Two decades 1964. Lancet Naturally occurring mutations in the thyroglobu. et al: Mo. Fukata S. Boca Raton. defective thyroglobulin synthesis. 183. Hum Mol (1143delC and 6725G>A [R2223H]) resulting in Genet 7:1105-1112. Vono-Toniolo J. et al: Compound analysis of the PDS gene in Pendred’s syndrome heterozygous mutations in the thyroglobulin gene (sensorineural hearing loss and goitre). orders of protein trafficking and the role of ER mo- lecular analysis of the Pendred’s syndrome gene lecular chaperones. 283. et al: studies in non-endemic goitrous cretinism. 1953. Metab 88:3546-3553. Van Hauwe P.and di-iodotyrosine tive thyroglobulin synthesis and secretion causing in the blood of a patient with congenital goiter. electrophoresis. 84:1061-1071. System. et al: Clinical and molecular analysis of 280. et al: Distri. Abramowicz MJ. Medeiros-Neto G. 281. Endocr Rev 19:173-202. J Clin Endocrinol Metab 15:1216-1227. Targovnik HM. Kim PS. quent missense mutations in Pendred’s syndrome. et al: Congeni- three Mexican families with Pendred’s syndrome. et al: A 138- inner ear are essential for the diagnosis of true nucleotide deletion in the thyroglobulin ribonu- Pendred’s syndrome. Thyroid Hormone Synthesis 265. Harada D. Nishiyama S. J Clin Endocrinol 266. 1:1117-1120. 2000. Vulsma T. Kim PS. et al: Two fre. Identification of an endoplasmic reticulum 269. 2005. J Clin Invest 98:2838-2844. goiter and hypothyroidism. of screening for congenital hypothyroidism in the 273. Thyroid 15:1021-1033. Ieiri T. Baas F. Meijer JW. J: The occurrence of mono. Moya CM. 2006. 2003. Medeiros-Neto G. Mannavola D. J Clin Endocrinol Metab 272. Hum Mol Genet 11:2625-2633. Herbrick JA. 1991. Suzuki H. Targovnik HM. Reardon W. 2003. Jackson CE. Billerbeck AE. Cochaux P. et al: Origins and storage disease with induction of molecular chap- frequencies of SLC26A4 (PDS) mutations in east erones. 41 . 1955. pp J Clin Endocrinol Metab 91:3100-3104. Park H-J. J Clin Endocri- sible for congenital goiter with hypothyroidism. 1992. Targovnik HM. Everett LA. causing congenital goiter. J Clin Endocrinol Metab cleic acid messenger in a congenital goiter with 85:2469-2475. 1998. et al: Molecular 277. Yoo SE. Bikker H. 139-159 . Shaukat S. Gonzalez Trevino O. 271. Vassart G: Defec. Bakker B. In Medeiros-Neto G. 1993. lin. 2000. 1995. 285. organification defects (an update). Targovnik HM. Coyle B. Kassenaar AA. tal hypothyroid goiter with deficient thyroglobu- Europ J Endocrinol 144:1-9. et al: Two differ- et al: Retention of pendrin in the endoplasmic ent mutations in the thyroid peroxidase gene of a ­reticulum is a major mechanism for Pendred’s large inbred Amish kindred: Power and limits of syndrome. 1996. Pannain S. Hutchison JH: Radioactive-iodine 274. Human Mutation 6:9-16.

similar tabolism. Tata and coworkers proposed that thy-­ tions correlating thyroid function with the syndromes roid hormones might be involved in ­transcriptional of myxedema and hyperthyroidism established that regulation of target genes. diverse actions have long been the subject of study. Early clinical observa-­ In the 1960s. Thyroid hormones have a critical role in differentia-­ bound to nuclear thyroid hormone receptors (TRs). with all of the others representing a to steroid hormone receptors. n In addition to direct transcriptional effects mediated by nuclear thyroid hormone receptors (TRs) on thyroid hormone response elements (TREs). In the introduction yielded different-sized receptors. of v-erbA. we During the past 40 years.7. studies The extreme variety of effects is generally inter-­ of the induction of the rat growth hormone (GH) preted as indicating a single primary action of gene by T3 suggested that TRs recognized enhancer the thyroid hormone. the estrogen receptor suggested that there is a family Sided to support this view is such evidence as a of nuclear hormone receptors. In contradistinction to this is the the-­ prising homology with a known viral oncogene prod-­ sis advanced by some biologists that the thyroid uct. thyroid hormone availability and activity are ultimately ­ overned by intracellular hormone transport. we have learned have learned much regarding the molecular mecha-­ that most thyroid hormone effects are mediated by nisms of thyroid hormone action. thyroid hormones exert direct effects on extranuclear proteins.15. more than 20 years ago. and metabolism. and other conditions. In his Principles and Practice of Medicine. suggesting that transcriptional regulation by T3 Physiology studies from the 1930s and 1940s demon-­ might involve nuclear thyroid hormone receptors strated major effects of thyroid hormone on oxygen (TRs). and availability of nuclear receptors as g well as associated cofactors. ­hypercholesterolemia.4 Subsequently.13 Subsequent cloning of dent of any effect on energy transformations.8 Meanwhile.3. or TR response elements (TREs). although demonstrated that they are the cellular homologues the thyroid gland stimulates both processes.9-12 The glucocorticoid secondary dependence upon integrity of energy receptor was cloned in 1985 and found to have sur-­ pathways.4 They showed that thyroid hormones have profound effects on almost all l-­triiodothyronine (T3) treatment stimulated RNA tissues. growth. metabolism.5. Barker2 stated the following: bility of multiple TR isoforms. n Thyroid hormone analogues are being developed and studied as potential therapies for obesity. raising the possi-­ to his 1951 review. Chapter Thyroid Hormone Action 4 Amin Sabet and Paul M. heart failure.6 Photoaffinity labeling of nuclear extracts consumption and metabolic rate. We now know that direct transcriptional effects of thyroid hormone there are multiple TR isoforms that bind to TREs 43 . Yen Key Points n At the cellular level in target tissues. probably on energy me-­ sequences.16 Since then. lack of increase in metabolic rate during some researchers cloned two different TR isoforms and stages of amphibian metamorphosis. which in conjunction with v-erbB can cause has a specific developmental function indepen-­ erythroblastosis in chicks.14 The following year. Osler synthesis in the liver of hypothyroid rats and that referred to the effects of thyroid hormone replace-­ these effects preceded protein synthesis and mito-­ ment therapy as “astounding—unparalleled by any-­ chondrial oxidation. tion. research stud-­ thing in the whole range of curative measures. v-erbA.”1 The ies demonstrated high-affinity nuclear binding sites mechanisms by which thyroid hormones exert their for radiolabeled T3 in different T3-sensitive tissues.3.

brain.18 Type I deio-­ thyroid hormone are regulated at many levels. found in peripheral tissues such as liver and factors controlling thyroidal synthesis and release. and tain type II deiodinase can potentially modulate their availability of nuclear receptors. Here. thyronine-specific transporters monocarboxylate trans-­ called nongenomic effects of thyroid hormones are porter 8 (MCT8) and the organic anion transporting mediated by rapid effects on extranuclear proteins. reverse l-triiodothyronine. polypeptide 1C1 (OATP1C1). D3 Nucleus Protein THYROID HORMONE RECEPTORS ? In 1986. covered elsewhere (see Chapter 3). integrators. Although it was previously thought that thy-­ In contrast to this classic nuclear mode of thy-­ roid hormones enter the cell by simple diffusion. by intracellular conversion to T3. Type II deiodin-­ as well as plasma transport of thyroid hormones. pituitary. TRs are tightly associated with chromatin. rT3. thyroxine. and sequences. as well as associated response to a given circulating concentration of T4 cofactors (Fig. in T3 T3 T3 keeping with their proposed role as DNA binding CoA. It Although both thyroxine (T4) and T3 are syn-­ has been shown that TRs interact with other nuclear thesized by the thyroid gland. T4 is the principal secret-­ proteins.15. are ase is found primarily in the pituitary gland. Together with type I deiodinase.2.Part I  Normal Thyroid Axis with variable orientation. This chapter will discuss what is known psychomotor retardation and resistance to thyroid hor-­ about the molecular mechanisms of thyroid hormone mone. T3. including corepressors and coactivators. more roid hormone action. The dinase. whether thy-­ D3 roid hormone (TH) is present or absent. the viral oncogene product v-erbA. Int proteins that regulate gene expression. These so. GTFs.16 By amino acid sequence comparison. which is an inactive T2 thyroid hormone metabolite. encoded by a gene on chromosome Xq13. and thyroid. the pathogenesis of which is believed to involve action.21 More-­ over. which occur cell via a number of transporters. Tissues that con-­ governed by intracellular transport. CoA. general transcription libraries. to distinguish those actions that are not mediated kidney. Mutations in MCT8 have by direct transcriptional effects of thyroid hormone been implicated in a familial X-linked syndrome of bound to TRs. kidney.22-24 Nuclear D1 D2 RXR TR mRNA GTFs TRs are approximately 50% saturated with thyroid TRE hormone in the liver and kidney and 75% saturated T4 T4 with thyroid hormone in the brain and pituitary.20. At the cellular and brown fat. Int. almost exclusively in brain capillaries and may be nec-­ given that some of these extranuclear actions of thy-­ essary for T4 transport across the blood-brain barrier. binding to TRs with 10-fold greater affinity THYROID HORMONE METABOLISM than T4. Intracellularly. spacing. brain.17 tion by thyroid hormones. with a focus on direct transcriptional regula-­ a defect in the neuronal entry of T3. where it contributes to peripheral and level in target tissues. is gene transcription. including liver.19 Unlike related steroid hormone receptors. metabolism. Type III deiodin-­ ase is found mainly in the placenta. It was soon noted 44 . plasma free levels of T3 and T4 are basal transcriptional machinery. type III deiodinase converts T4 to reverse T3 (rT3). and skin. researchers independently reported the rT3 cloning of cDNAs encoding two different TRs from embryonal chicken and human placental cDNA Figure 4–1  Cellular transport and metabolism of thyroid hormones. However. roid hormones have downstream effects on target MCT8. to ed hormone. Production of circulating T3 occurs mainly AND TRANSPORT via 5′ deiodination of the outer ring of T4 by a class of The ultimate availability and activity of intracellular selenoproteins known as deiodinases. 4-1). including the iodo-­ at the plasma membrane or in the cytosol. T3 is the more potent hor-­ mone. because T4 is tightly bound to form complexes that interact with and regulate the carrier proteins. was shown that TRs are the cellular homologues of l-triodothyronine. converts circulating T4 to T3. nongenomic will be used expressed in a wide variety of tissues. ? TRs are found primarily in the nucleus. T4. several mechanisms of thyroid recent work has established that T3 and T4 enter the hormone action have been identified. it factors. coactivators. ­similar. OATP1C1 is expressed The term nongenomic may be somewhat misleading. thyroid hormone availability is intracellular conversion of T4 to T3.

are structurally distinct ligands. TR�-1 + + + DNA-binding domain.27. DBD 492 c-erbA�-2 + – – that TRs have amino acid sequence homology with Figure 4–3  Comparison of amino acid homologies and functional properties of thyroid hormone receptor (TR) steroid hormone receptors. This was surprising at isoforms. crystallographic studies of the liganded rat TRα and TRα-1 and TRβ-1 are expressed in almost all human TRβ have shown that thyroid hormone nests tissues. whereas TRβ-1 expression is made up of 12 amphipathic helices. ligand-binding domain.33. of c-erbAα-2 is highest in the testis and brain. 6. 4-2). whereas helices 3. Mammalian TR isoforms range from TR isoforms are highly conserved across 400 to slightly more than 500 amino acids in length mammalian species. suggesting that TRs may exhibit isoform- and c-erbAα-2. where it can help promote adipogenesis. Both contain DBDs and for nuclear translocation of the receptor. the hinge region contains two isoforms are identical. 5. and is unable to the thyroid-stimulating hormone β (TSHβ) and GH transactivate thyroid hormone responsive genes. is generated from the opposite strand of TR structural domains resemble those of the TRα gene. encode the major internal start sites or alternate splicing are expressed in TR isoforms. Each embryonic stem cells and fetal bone cells. are noted in the case of specific TR isoform deletion The Thra gene encodes two proteins.35 Another gene product. it has since LBD. and kidney.43 Expression tions with coactivators and corepressors. vary-­ specifically regulate the TRH and myelin basic pro-­ ing greatly thereafter. Recently. TRβ-2 expression is largely restricted to 4. liver. located on human short forms of TRα and TRβ generated by the use of chromosomes 17 and 3. TRα-1 in animals. TRα-1 expression is highest in skel-­ inside a hydrophobic pocket within the LBD.44. hypothalamus. binds TREs weakly. They have a central DNA the NR superfamily. where some of these receptor isoforms binds T3 with similar affin-­ of them may exert dominant negative activity. Helices 3.26 X-ray LBDs with high homology to those of TRα-1. which its phosphorylation state. and 6 interact with corepressors. which of TRE nucleotide sequences. In contrast to other and 12 interact with coactivators. cDNA microarray studies per-­ certain target genes. 5. been demonstrated that TRs belong to a superfamily of nuclear hormone receptors. the dominant vitamin D. TRβ-1. affecting TR interac-­ is also expressed in the developing retina.38 These between these two domains. c-erbAα-2 may act as a dominant formed in TR isoform knockout mice have suggested inhibitor of thyroid hormone action by competing that TRα and TRβ provide compensatory regulation 45 . However. whereas TRβ-2 may differentially regulate cannot bind T3. and retinoic acid negative activity of c-erbAα-2 may be regulated by receptors. Thyroid Hormone Action DBD LBD DNA-binding Transactivation T3-binding DBD LBD 461 Dimerization regions TR�-1 + + + Nuclear localization sequence Co-repressor interaction sites DBD LBD 514 Co-activator interaction sites TR�-2 + + + Figure 4–2  Organization of major thyroid hormone DBD LBD 410 ­receptor domains and functional subregions.39-42 In the chick and mouse.34 Furthermore.28 etal muscle and brown fat. and a carboxy-terminal encode transcripts for two major TRβ isoforms. respectively. Rev-erbA. is expressed in muscle and adi-­ binding domain (DBD) containing two zinc fingers. LBD. because T3 and cholesterol-derived steroids indicated just above its diagram. DBD. On genes. Several The Thra and Thrb genes. and TRβ-2 (Fig. highest in brain. DNA-binding domain. developing T3 induces major confrontational changes within the brain.45 transcription. In the rat and human. 4-3).29-32 Binding of the anterior pituitary gland. distinct phenotypes and feature highly conserved DBDs and LBDs. peroxisomal proliferator. particularly in helix 12. and inner ear. The amino acid length of each TR isoform is the time. these proteins genes. In contrast to TRα-1.46-49 However.36 which intercalate with the major and minor grooves The Thrb gene contains two promoters. ligand-binding domain. through their alternate use. 4-3). TRα-1. rev-erbA.25. c-erbAα-2 tein genes. in addition to orphan receptors. ­ lack known ligands.37. for binding to TREs. blocking ity and mediates thyroid ­ hormone–regulated gene wild-type TR transcriptional activity. TR isoforms. it has been suggested that TRβ-1 may are identical from amino acid residues 1 to 370.39 In rats. DBD. also an orphan member of other family members. TRβ-2 LBD. In addition. including the ­steroid. pocytes. Located in and TRβ-2. with the exception of their a stretch of multiple lysine residues that are required amino termini (see Fig. generated by alternative splicing of specific transcriptional effects on particular target TRα mRNA. TRβ-1 ligand-binding domain (LBD) (Fig.

It is now Whereas the DBDs interact with the major grooves known that NCoR possesses a third nuclear receptor of the half-sites on the same face of DNA.57 Pro-­ to interact only with the TR and not other nuclear tein-protein contacts between the TR and RXR DBDs receptors. which corepressor (NCoR) and silencing mediator for RAR are arranged as direct repeats. and TR (SMRT). which preferentially inter-­ (Fig. TRs can bind to half-sites.64-66 NCoR and six. within the interaction domains resemble pairs. Figure 4–4  Half-site orientation and optimal spacing within thyroid hormone response elements (TREs). respectively SMRT are 270-kD proteins. However. whereas vitamin D receptor/RXR and RXR/ the LXXLL sequences that enable coactivators to RXR activate direct repeats spaced by three and five interact with nuclear hormone receptors. which are generally located in the Transcriptional Repression by Thyroid upstream promoter regions of target genes. the car-­ interacting domain. it is not known whether TR contribute to heterodimerization and determine homo.69.38 but the role of TR monomers Inverted palindrome T GA CC T N NNN N N AGG T C A and homodimers in regulating transcription is not well understood. with which ligand enhances homodimer Palindrome AGG T C A T G A CC T binding to hormone response elements (HREs). THYROID HORMONE RESPONSE ELEMENTS TRs bind to TREs. They serve as key that have been described. RXR binds to the upstream interact with similar amino acid residues on helices 3.68 This third interacting domain appears DNA minor groove between the two half-sites. respectively (the proposed 3-4-5 rule). roles in mediating basal repression. 4-4).59 Helices 10 and 11 of vator interaction sites.51 TRE half-site sequence. basal transcription of positively regulated target genes which are positively regulated by T3. homodimers. This characteristic of TRs contain two or more hexamer half-site sequences of contrasts with steroid hormone receptors. which are AGGT(C/A)A arranged in tandem. direct repeats occur most components of transcription complexes that repress frequently. gesting that the TR homodimer may mediate gene repression in the absence of thyroid hormone. These corepressors contain three transfer-­ erodimeric partners for TRs.25 Unligan-­ sion in specific cells.25 basal transcription of target genes in the absence of RXR proteins are the most important het-­ ligand. although ­Hormone Receptors in certain cases they may be found in 3′ flanking regions In the absence of T3. inverted palindromes. combined with ligand-induced 46 . LXXI/HIXXXI/L sequences. may be the principal determinant TR heterodimers with corepressors in vitro.58.50 Thus. and 6 of the TR ligand-binding domain.27 A TRs can form monomers. characterized by an altered heli-­ boxy-terminal of the TR DBD forms an α-helical cal structure that preferentially recognizes the TR structure that interacts with the spacer region in the homodimer. In contrast to steroid hormone receptors. Significant degen-­ transcriptionally inactive in the absence of ligand.or heterodimers are the preferred interaction half-site spacing specificity.52. and Direct repeat AGG T C A NNN N A GG T C A heterodimers on TREs in electrophoretic mobility shift assays (EMSAs). presence of ligand. followed by inverted palindromes. Two major TR-interacting proteins. TREs generally in cotransfection studies.26 eracy exists in the primary nucleotide sequences of half.67 These base pairs. able repression domains in addition to two carboxy- spacing.Part I  Normal Thyroid Axis G G the TR LBD appear to contain residues necessary for Consensus TRE half-site AGG T C A heterodimerization.60-63 sug-­ of target gene activity. or zero nucleotides between half-sites.25 It is therefore likely that TR/ RXR heterodimers have a major role in T3-mediated gene activation. Unliganded TRs can bind as homodi-­ of target genes in the liver.70 Currently. Arrows show TRs bind predominantly as heterodimers in the direction of half-sites on the sense strand. the most critical partner with corepressors.53 sequences allow both corepressors and coactivators to In direct repeat TREs. orientation. where X represents any TR/RXR activates direct repeats spaced by four base amino acid. half-site and TR binds to the downstream half-site.54-56 5. In target genes. have been shown to play important and palindromes containing optimal spacings of four. rather than expression of spe-­ ded TR homodimers bind better than unliganded cific TR isoforms. and sequence context determine terminal α-helical interaction domains. nuclear receptor sites. total TR expres-­ mers or as heterodimers to TREs in vitro. Consensus specificity and affinity for the TR/RXR heterodimer. TRs bind to TREs and repress downstream from the coding region. Among the approximately 30 natural TREs act with unliganded TR and RAR.51 In addition. Differences in the length interaction sites for heterodimerization are thought and specific sequences of the corepressor and coacti-­ to be located in their LBDs.

It is therefore likely that his-­ TR-responsive reporter gene.25. See text for details.71 In addition to enzymes that deacetylate his-­ Corepressors can form a larger complex tones.72 to interact with unacetylated N-terminus histone H4 Addition of T3 relieves this repression and also causes tails and mediate gene repression in an integrated chromatin remodeling. unliganded TR may promote RXR masks a corepressor binding site in RXR. Thyroid Hormone Action conformational changes in the conserved AF-2 region containing Sin 3 and histone deacetylase. suggest-­ of helix 12.76 tone deacetylation. the unliganded receptor is predicted DRIP/TRAP complex TRAP 220/ Transactivation PCAF DRIP205 Histone acetylation GTFs CBP/p300 +T3 NF SRC/p160 complex CoA TFIIE. TR-mediated gene repression in vitro has been with other repressors. help determine whether a corepressor ing that DNA methylation may play a role in basal or coactivator binds to TR. which silencing in some cases through direct interaction becomes available for corepressor binding after het-­ with the basal transcription factor TFIIB.74.F.67 as well as transducin beta-like chromatin by disrupting DNA-histone interactions. general transcription factors. This complex induces histone The imitation switch (ISWI) family of ATPases is a deacetylation near the TREs of target genes. CoR. ADA2. PCAF. TATA binding protein (TBP)-associated factors. histone deacetylases. coactivator. In addition. corepressor. N-CoR.67 In addition.etc I/S TAFs Relative target gene expression RNA polymerase II SW T3 RXR TR TFIIB TBP TRE TATA Basal transcription De-repression Repression GTFs Histone HDACs Sin 3 –T3 deacetylation CoR TFIIE. TAFs. helix 12 of ­repression.76 These remodeling of well-characterized yeast transcriptional repressors enzymes use ATP hydrolysis to alter the structure of RPD1 and RPD3. which are mammalian homologues chromatin remodeling enzymes. and acetylation on the addition The fact that TR alters the level of gene tran-­ of ligand. p300-CBP-associated factor. in which hormone concen-­ proteins can associate with a corepressor complex trations are low.75 erodimerization with TR. such as Sin 3 and histone recently demonstrated to require ATP-dependent deacetylase 3. methyl CpG -binding In the hypothyroid state. and TFIIB) domains. HDACs.26.77 protein 1 (Fig. CoA.etc H TAFs F2 RNA polymerase II SN TR TR TFIIB TBP TRE TATA Figure 4–5  Model for basal repression in the absence of l-triiodothyronine (T3) and transcriptional activation in the presence of T3 in a positively regulated gene.F. Studies of TRβA promoter in a conserved ISWI catalytic core and C-terminus SANT Xenopus oocyte system have demonstrated that simul-­ (SW13. gene transcription.78 The taneous chromatin assembly and TR/RXR binding mammalian ISWI ATPase SNF2H has been shown are necessary for basal repression of transcription. modulate the chromatin structure and scription in the absence and presence of ligand has nucleosome positioning that are critical for target important implications for thyroid hormone action. CBP. cAMP response element binding (CREB)-binding protein. 47 . GTFs. result-­ heterogeneous group of chromatin remodeling ing in a chromatin structural state that shuts down enzymes distinguished by the presence of a highly basal transcription. 4-5).73 Finally.

and nuclear factor-kappa B direct targeting of SWI-SNF to chromatin. none of the DRIP-TRAP subunits Although many cofactors have been shown to inter-­ are members of the SRC family or their associated act with liganded nuclear hormone receptors and proteins. Of note.83.84 SRCs also interact with and Snf have been shown to associate with nuclear the cAMP response element binding (CREB)-binding hormone receptors and activate transcription in protein (CBP). and the other major coactivator and tion sites. Additionally. that hypothyroidism. SMRT co-repressor complexes and may enhance 2 and SRC-3. which contains a LXXLL motif similar to that found which normally accompanies the hypothyroid state. Additionally.88 This suggests that TR (SRC) complex and the vitamin D receptor inter-­ recruitment of the DRIP-TRAP complex may help acting protein–TR-associated protein (DRIP-TRAP) recruit or stabilize RNA Pol II holoenzyme. AP-1. Howev-­ to be at least two major complexes involved in ligand. 5.90 Interestingly.25. the coactivator for cAMP-stimulated vitro.81 As coactiva-­ eling with altered DNA topology.94-97 nonrepressed protein 5 (GCN5). The structure (HAT activity). SRC-1. PCAF itself is has been shown that glucocorticoid and progesterone part of a preformed complex containing TATA bind-­ receptors can recruit different SRC coactivators on the ing protein (TBP)–associated factors (TAFs). DNA-PK. complex (see Fig. apparently functioning to anchor the rest of Transcriptional Activation by Thyroid the proteins in the complex to the nuclear hormone ­Hormone Receptors receptor. which targeting of SWI-SNF followed by chromatin remod-­ interacts with the viral coactivator E1A. In addition.91 The precise interplay among have multiple nuclear hormone receptor interac-­ TRBP. er. for the most The DRIP-TRAP complex contains approxi-­ part. Oñate and coworkers have identified the first activator that has been shown to interact with TR member of the SRC family. CBP.81 there appear not appear to possess intrinsic HAT activity.81.85 Chromatin immunoprecipitation assays of CBP-p300 also interacts with PCAF (p300. and 12).92 Activation by TR is associated with promoter transcription. the mammalian homologue recruitment of receptor and coactivator complexes to of a yeast transcriptional activator.Part I  Normal Thyroid Axis to repress expression rather than to simply exist as of nuclear receptors to the basal transcriptional an inactive receptor. milder than the clinical features of congenital mately 15 subunits.80 This milder phenotype observed directly or indirectly interact with liganded vitamin D in the setting of TR deletion may be explained by the receptors (VDRs) and TRs. which mone receptors—the steroid receptor coactivator associates with RNA Pol II. which MMTV promoter. 6. This model is supported by data machinery and as enzymes that can alter chromatin from the targeted deletion of TRα and TRβ genes. the DRIP-TRAP complex does enhance transcriptional activation.93 molecules for multiple cell signaling pathways. is a critical subunit within the coactivator complex. it primarily toward H3 and H4 histones. a process (NF-κB). sequence motif. is found as part of a stable complex recruited may be two key determinants of transcrip-­ with RNA polymerase II (RNA pol II). Subsequent work has shown subunits Ku70 and Ku86 can interact with the NCoR- at least two other members of the SRC family. Whereas the ISWI family of chromatin remod-­ This sequence is important for coactivator binding to eling enzymes has been implicated in transcriptional coactivator interaction sequences within the TR LBD repression by TR. the temporal recruitment can interact with SRC-1 and SRC-3. SRC.89 TRBP can also interact with tein directly interacts with TRs and other nuclear hor-­ CBP-p300 and DRIP130 as well as a DNA-dependent mone receptors. phenotypes of these knockout mice are. which also pattern of coactivators and the particular coactivators has HAT activity.88 DRIP205-TRAP220. Using the yeast two-hybrid TR-binding protein (TRBP) is another co­­ system. CBP and p300 may function as integrator facilitated by histone acetylation from CBP-p300. absence of the receptor-mediated gene repression. varying from 70 to 230 kD.86 Thus. p300 appears to tors for CREB. proteins bound to HREs have suggested that the CBP–associated factor). 4-5). PCAF tional activation on a given target gene. several DRIP-TRAP components are mammalian dependent transcriptional activation of nuclear hor-­ homologues of the yeast mediator complex. as well as the related protein p300.82 This 160-kD pro-­ via an LXXLL motif. general control response elements may occur in a cyclical fashion.87. which also can enhance transcription ­histone deacetylase (HDAC) activity through phos-­ by liganded nuclear hormone receptors. serving both as ­adaptors there has been evidence that histone methylation 48 .85 PCAF has intrin-­ leading to increased histone acetylation of the promot-­ sic histone acetyltransferase (HAT) activity directed ers of positively regulated target genes. and CBP possess dual roles.87. where X represents any amino acid. each of which contains a signature LXXLL corepressor complexes is not currently known. DNA-PK transcriptional activity. in SRCs.98 Thus. mammalian homologues of Swi (helices 3. p53.79. enhancing their ligand-dependent protein kinase (DNA-PK).81 The SRCs phorylation of HDAC3.

116. sion of β-MHC remains incompletely understood. therapeutic targeting of of the TSH and TRH genes. T3-mediated repression of the prolactin absence of miR-208 may enhance TR repression on a promoter has been proposed to occur by the preven-­ negative TRE in the β-MHC gene. and repression in one third of human genes are predicted targets for the presence.109 whereas coactiva-­ miRNAs may provide yet another means by which to tors may. Negative regu-­ stress and hypothyroidism. p53. exhibit defective negative The direct transcriptional regulation of target genes regulation of TSH. TR can inhibit the activity of AP-1. Corepressors increase basal transcription processes.112 Final-­ associated with transcriptional activation. Thyroid Hormone Action and demethylation may play an important role in promoter (Yen. T3-dependent repression of negatively regulated genes. the mechanism whereby T3 mediates the repres-­ bind weakly to the putative TREs of these promoters.108 models.101.104. As an example of an off.114 Hun-­ tively regulated genes are characterized by transcrip-­ dreds of miRNAs have been identified. in the regulation of β-MHC expression in response to pituitary-thyroid (HPT) axis (HPT).98a. there may be a future clinical during T3 negative regulation have not been well char-­ role for siRNA delivery in modulating TR-mediated acterized.­ factors. HDACs can be recruited by TRs during ligand- because demethylation of H3K9 and H3K4 has been dependent negative regulation in some cases. and more than tional activation in the absence.105 However.117 so it is not known whether regulation occurs through Deletion of miR-208 in mice prevented the upregu-­ direct TR binding to negative thyroid response ele-­ lation of β-MHC normally seen with propylthiouracil ments (nTREs. recent studies using adenovi-­ inappropriately elevated TSH levels. including NF-1. Pit-1. Negative regulation of TRH ­miRNA antagonism. which have mutant TR that cannot HORMONES interact with co activators. is DNA mechanism.114.118 tion of AP-1 binding. suggesting that siRNA duplexes have demonstrated the ­ feasibility direct DNA binding by TR is necessary for negative of gene silencing using these methods in animal regulation of the HPT axis by thyroid hormone. and represents the “classic” concept of thyroid 49 .98a MicroRNA Effects on TR Function MicroRNAs (miRNAs) are small.107 However.99-103 The T3-responsive elements of these regulated by thyroid hormone. and it has been sug-­ a heterodimeric transcription factor composed of gested that an increase in THRAP1 resulting from the Jun and Fos. despite high ral delivery and direct administration of synthesized circulating thyroid hormone levels. ly. a compo-­ cofactors (off-DNA model). Oct-1. Whereas T3 signaling negatively regulated genes have been localized to occurs via a positive TRE to stimulate α-MHC transcrip-­ their proximal promoter regions.111 We recently have shown that by nuclear TRs was discussed earlier in this chap-­ T3 can induce histone acetylation on the TSHα subunit ter. TRB knock-in mice expressing selected genes in various biologic processes in vitro.25. nega-­ translation or promote mRNA degradation. as well as his-­ negative regulation of some target genes. a P-box mutation within the DNA-binding domain Although introduction of siRNAs in vivo has been that severely impaired its ability to bind DNA had technically challenging. in some cases. TRs tion. negatively regulated by miR-208. on-DNA model of TR action) or via (PTU)-induced hypothyroidism. endog-­ Negative Regulation by Thyroid Hormone enous RNAs that are believed to suppress gene tran-­ Receptors scription by pairing with specific mRNAs to inhibit In contrast to positively regulated target genes.115 A cardiac-­specific miRNA and the TSHβ and TSHα subunit genes has been (miR-208) encoded by an intron of the alpha myosin studied extensively because these are critical control heavy chain (a-MHC) gene has recently been implicated points for feedback control of the hypothalamic. On the other gene activation by TRs and ­ other nuclear receptors hand.106 TRs have also been shown Small interfering RNA molecules (siRNAs). noncoding.98b Thus. there may be TR isoform-specific functions in the histone demethylation of specific sites. of THs. be paradoxically involved in exert specific control over thyroid hormone action. Both SRC-1 knockout mice and helix 12 mutant NONGENOMIC EFFECTS OF THYROID knock-in mice.105. Sp-1. and have been used with great success in the study of CTCF. to interact with several other classes of transcription which exploit the endogenous processing of miRNAs. Thyroid hormone protein-protein interactions between TRs and other receptor–associated protein 1 (THRAP1). unpublished results). α-MHC and β-MHC are antithetically of the TR. Furthermore.115 Although off-target effects are of great The precise changes in histone acetylation and concern in the therapeutic application of RNA inter-­ resultant alterations in chromatin structure that occur ference in humans.110. nent of the TR-associated protein (TRAP) complex.113 tone acetylation of specific sites—notably H3K9—may be involved in positive regulation of transcription.116 In the mammalian car-­ lation of the HPT axis is mediated by the β isoform diac myocyte.

particularly TR located outside the and activates the PI3K-Akt/PKB-mTOR-p70S6K path­ nucleus. p28 is Figure 4–6  Examples of thyroid hormone receptor imported into the mitochondrial inner membrane. p43 and p28. arterial blood pressure. corepressor. Two truncated isoforms related to TR� TRα-1.124 It is pos-­ ­phosphoinositide 3-kinase (PI3K) and rac activity. and use of observed that in cultured human skin fibroblasts. structure-function mediate some of the neurologic features of RTH. occurrence in mation. CoR.119 Evidence for these so-called non-­ tion by T3. secretion. thyroid hormones may TR� have direct effects on mitochondria. nontranscriptional thyroid hor­ lular locations.121 At the activity of endothelial nitric oxide synthase (eNOS). Some of these effects TRβ1 binds to the p85α regulatory subunit of PI3K may involve TR. seconds to minutes). The interaction with 50 . differences in dent extranuclear actions of thyroid ­hormones. signal transduction cascades. sible that eNOS mediates thyroid hormone effects on which in turn stimulates voltage-activated potassium systemic vascular resistance. and induces early stimulation of organelle Integrin transcription after the addition of T3. and perhaps cell-specific effects. Figure 4-6 depicts ­translational modifications of TRβ and p85 in the an overview of select TR-dependent and TR-indepen-­ cytoplasm versus plasma membrane.122 Increasing KCNH2 these effects contribute to an increase in cardiac out-­ activity results in reduced excitability and hormone put. GTFs. TRβ was found to interact with the regula-­ PI3K activation by T3 also leads to a direct increase tory subunit p85α of PI3K and inhibit PI3K activity. rapid onset of cell processes such as cellular proliferation. mone actions can take place anywhere in the cell. receptor-enzyme complex formation at these subcel-­ TR-mediated.Part I  Normal Thyroid Axis hormone action (see Fig. which in turn stimulates the translation of binding proteins. and blood volume. interacts with mitochondrial DNA response actin PKC� elements.127. Gray arrows denote movement. TRα1 has also been shown to interact with Although primarily located in the nucleus. which is a prominent feature of hyperthyroidism. platelet-type phos-­ P110 Akt/PKB phofructokinase (PFKP). where it interacts with adenine nuclear translocase general transcription factors. thyroid hormones exert direct effects on extra-­ to thyroid hormone (RTH) blocked KCNH2 stimula-­ nuclear proteins.123 It is not clear why the mechanism of of these extranuclear actions of thyroid hormone liganded TR activation of PI3K signaling differs in may have genomic effects through the initiation of this setting from that described in rat pituitary cells. membrane-signaling pathways.128 p28 also �V�3 binds T3 but lacks a DNA-binding domain because it is initiated at an internal methionine within T4 T3 the hinge region of TRα. In response to T3. mediated by nuclear TRs on deletion in the TRβ gene of a patient with resistance TREs. (TR)-dependent and TR-independent extranuclear actions of thyroid hormones. and glucose uptake. See text for and uncoupling proteins. 4-1). up to p85 in a T3-dependent manner and modulate the 10% of TRs are located in the cytoplasm. It has recently been the presence of transcriptional blockade. TRα-1. and the monocarboxylate P85� transporter 4 (MCT4). in the transcription of hypoxia-inducible factor 1 (HIF-1) and indirect increases in the transcription of KCNH2 glucose transporter 1 (GLUT1). a T337 addition to these effects. This finding illustrates a potential non-­ genomic actions of thyroid hormones include the lack transcriptional mechanism whereby a mutant TR may of dependence on nuclear TRs. We now know that in T3 decreased this interaction. such as the integrin αVβ3. thyroid hormones stimulate another downstream target of Akt/PKB.120 Some ZAKI-4. CoR Nucleus p43 binds T3 with similar affinity to that reported for Soluble F actin PLC. channels encoded by the ether-a-go-go gene KCNH2 renal sodium reabsorption. inflam-­ action (typically. Others may use additional thyroid hormone– way. a rapid thermogenic response. have been described in mito-­ MAPK MAPK TR� chondria.126 TR� P110 In addition to actions at the plasma mem-­ T3 T3 P85� T3 Akt/PKB mTOR brane and within the cytosol. Interestingly. relationships of thyroid hormone analogues that are Activation of the PI3K cascade is critical for different than their affinities for TRs.125 All in a rat pituitary cell line. plasma membrane. which are estab-­ D2 GTFs mRNA lished target organelles for regulation of the cellu-­ T4 T4 TR� p53 TR� lar energy state. which in turn may generate details. Neither of these is detected in the nucleus. with downstream effec-­ Potential reasons include differences in post- tors affecting gene transcription.

These a thyroid hormone–related compound with low data provide strong evidence that thyroid hormone affinity for nuclear TRs and modest effects on meta-­ binding to a membrane receptor. but not T3. siRNA knockdown detectable effects on the cardiovascular system.140 Thyroid hormone analogues designed integrin αVβ3 as a plasma membrane binding site for cholesterol reduction have exploited several mech-­ for thyroid hormone. KB2115 (3-[[3. Recent studies cardiac tissues. bolic activity.144 A single injection of binds to an endoplasmic reticulum–associated pro-­ T1AM or T0AM induced transient hypothermia and tein.142 In a pilot clinical study of chick chorioallantoic membrane (CAM) model. effects of thyroid hormone excess. Thyroid Hormone Action p28 may thus represent a direct mechanism whereby been used to avoid the tachycardic and ­arrhythmogenic T3 can stimulate oxidative phosphorylation. particularly those that are posi-­ Because the TRα isoform predominates in tively regulated by thyroid hormone. prolyl hydroxylase. Further clinical trials of DITPA in congestive heart T4. promotes actin polymeriza-­ failure are ongoing. leading to MAPK and TRβ specificity.139 ity of target genes. patients with moderate to severe (New York Heart Davis and Davis119 have shown that both T4 and T3 Association Class II or III) congestive heart failure. includ-­ that both T4 and T3 activates mitogen-activated pro-­ ing hepatic first-pass uptake. integrin αVβ3. tein kinase (MAPK) signaling. Moreover. p53.5-Diiodothyropropionic acid (DITPA) is activation by thyroid hormone in CV-1 cells. and whereby nuclear TRs regulate transcriptional activ-­ heart failure. Davis and Davis have identified heart rate. thyroid hormone analogues may prove useful in providing TSH suppressive therapy for thyroid THYROID HORMONE ANALOGUES cancer patients.121. and the heart. TRβ isoform–specific compounds have have broadened our appreciation for the scope of 51 . 3-Iodothyronamine (T1AM) and thyron-­ Regulation of actin polymerization may contribute to amine (T0AM) are naturally occurring byproducts of thyroid hormone effects on neuronal arborization. decreased isovolumetric relaxation time. the TRβ-specific agonist KB-141 promoted been reported to occur in the absence of thyroid hor-­ weight loss and increased Vo2 without increasing the mone binding to TRs. hypercholesterolemia. In a recent phase II randomized translocation into the nucleus. thyroid hormone that do not bind TRs but are ago-­ axonal transport.129 compound designed for liver-specific uptake and TRβ Two independent laboratories have found that specificity. tions. In several animal A number of thyroid hormone actions have models.130 Purified panoic acid).136-138 The functional stroke in mice. a reduction in serum choles-­ action may be of therapeutic value in selected cases terol. tion in astrocytes132. Activa-­ DITPA treatment was associated with an improved tion of MAPK by T4 also causes rapid phosphoryla-­ cardiac index.143 decrease in its transcriptional activity. decreased systemic vascular resistance tion of p53 via a complex containing TRβ.133 and may influence the down-­ Other thyroid hormone analogues that act regulation of type II deiodinase activity. serine phosphoryla-­ controlled trial.134.119 They previously had shown anisms to achieve selective action in the liver. excess thyroid of thyrotoxicosis. a process via TR-independent extranuclear pathways have been that depends on an intact actin cytoskeleton.135 described.131 This phosphorylation of p53 results in a reduced serum cholesterol and triglyceride levels. and improved cardiac output. such as those associated with the hormone is associated with undesirable effect on use of amiodarone. was shown to induce a 40% reduction radiolabeled T4 and T3 specifically and reversibly in serum cholesterol over a 2-week period without bind to integrin αVβ3. the development of analogues Whereas beneficial effects of thyroid hormones that antagonize TR-mediated thyroid hormone include weight loss. skeletal muscle. and cell-cell contacts during central nists of trace amine–associated receptor (TAAR1). and index. as well as to the monomeric reduced infarct size when given after experimental subunit of pyruvate kinase. one such thyroid hormone mimetic tion of TRβ. promote angiogenesis via activation of MAPK.145 significance of these interactions has not been well In addition to the aforementioned applica-­ characterized. DITPA has been shown to bind αVβ3 leads to activation of the MAPK cascade. and corepressor release from TRβ. Using a and activate MAPK. Thyroid hormone also G protein–coupled receptor. and MAPK. tissue-selective uptake. a nervous system development.141 of either the αV or β3 integrin subunit blocks MAPK 3. bone.5-dibromo-4-[4-hydroxy-3- addition of thyroid hormone also results in prompt (1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopro-­ translocation of TRβ to the nucleus. Novel thyroid hormone analogues that attempt to minimize these CONCLUSIONS untoward effects are being developed as potential We have learned a great deal about the mechanisms therapies for obesity. Also.

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T3 modulates gene expression in almost every considerable similarity (approximately 50% sequence vertebrate tissue through ligand-dependent tran. n Primary changes in D2 or D3 expression and activity provide a mechanism for local control of thyroid hormone signaling. D2. and several clusters. n Novel roles for the deiodinases have emerged in development and metabolic control. realms of ­developmental biology and metabolism. 5-2). The proteins and have regions of high homology in the deiodination of T4 to T3 occurs in the phenolic outer area surrounding the active center. the relationship between the Heightened interest in the field has been generated βαβ and ββα motifs is locally interrupted by interfer- following the discovery that D2 can be an important ing elements. and changes in typical of alpha helices or beta strands. thesis. Chapter Thyroid Hormone Metabolism 5 Antonio C. The three deiodinases. It is interesting that within static role but revealed surprising new connections. defined and combinations7 has not only confirmed this homeo. Kim Key Points n The three deiodinases are selenoenzymes containing the rare amino acid selenocysteine. insights into their structures syl (inner or 5¢) ring. con.to 33-kD scription factors.8 mone molecule (half-life [t½] is approximately 7 days in humans) that must be activated by deiodination DEIODINASES: THIOREDOXIN to the short-lived biologically active form T3 (t½ is FOLD–CONTAINING PROTEINS approximately 1 day) to initiate thyroid hormone The three deiodinase proteins (D1. Bianco and Brian W. T4 activation can be prevented and T3 can eukaryotic-specific pathway for selenoprotein syn- be irreversibly inactivated by deiodination of the tyro. are present in all vertebrates. a reaction catalyzed by the type have been obtained through silicoprotein modeling 3 deiodinase (D3) and by D1.9-11 Structural or 5¢ ring of the T4 molecule and is catalyzed by type 1 analyses of these proteins have been hindered by and type 2 iodothyronine deiodinase. All are integral membrane 29. 5-1). identity).3 globular domains.6 the presence of the thioredoxin (TRX) fold.12 A striking common feature is targeted disruption of D2 (Dio2−/−)4. the canonical TRX fold. in the ingestion of iodine. transmembrane segment.1 (Fig. it The coordinated changes in the expression has become clear that the three deiodinases share and activity of these enzymes ensures thyroid hormone a common general structure composed of a single homeostasis and the constancy of T3 production.5 or D3 (D3−/−). based on ­linkage to hedgehog and bile acid signaling pathways. and D3) show action. a feature also observed in other pro- receptor 1 (GPBAR1)–mediated signaling cascade. Nevertheless. teins of the TRX fold family. extending into the derives from the fact that T3 is a long-lived prohor. D1 and D2 their integral membrane nature and the inefficient (Fig. and D3. enzymes that activate thyrox. Based on hydrophobic cluster analysis. the thyroid hormone receptors. which is present in the stituting a major mechanism for adaptation to changes N termini of D1. Their relevance ­broader role than once thought.13 57 . These sequences correspond to distinct component in the hedgehog signaling pathway and secondary structure elements added to the canonical metabolically important G protein–coupled bile acid TRX fold core. The discov­ery of these new roles for the deiodinases ine (T4) and inactivate both T4 and triiodothyronine indicates that tissue-specific deiodination plays a much (T3). by βαβ and ββα motifs. The study of animals with ing to core secondary structures of the deiodinase targeted disruption2 or deficiency of D1 (C3H mouse). correspond- environmental temperature. D2. n The deiodinases are coordinately regulated to promote thyroid hormone homeostasis. starvation.

15-17 The presence of D1 in the plasma studies also indicated that the D3 catalytic globular 58 . the much longer half-life of D3 (12 hours) than D1 whereas D2 is an endoplasmic reticulum (ER) resi. tor (TR) occupancy in such tissues.9 However. Sec is encoded generates T3 in the perinuclear cytosol. suggesting Distinct Subcellular Localizations that D3 is recycled between plasma membrane and of ­Deiodinases early endosomes. or is constant internalization of D3 that is blocked by SECIS element. the nocysteine (Sec).14 Exposing cells to a weak base such as primaquine increases the pool of internalized D3. rin but not with two ER-resident proteins. Such recycling could account for D1 and D3 are located in the plasma membrane.K+-ATPase alpha.15 There This structure is termed the Sec Insertion Sequence. which is present in the deiodinases sucrose or methyl-β-cyclodextrin–containing medium. (8 hours) or D2 (~40 minutes). T4 Reverse. The critical element of locally generated T3 to the overall thyroid recep- in the active center pocket is the rare amino acid sele. and the poor contribution one of the interfering elements. T3 NH2 NH2 D2 D1 D1 HO HO O O D3 H O H O OH OH T3 T2 NH2 NH2 Figure 5–1  Basic deiodinase reactions. which may by UGA. mRNAs as a STOP codon. which catalyzes the deiodination action of D2 at the cytoplasmic face of the ER16.19 reactions of all three deiodinases. Although these dent protein. The reactions catalyzed by the deiodinases remove iodine moieties (blue spheres) from the phenolic (outer) or tyrosil (inner) ring of the iodothyronines. These pathways can activate thyroxine (T4) by ­transforming it into triiodothyronine (T3) via D1 or D2 or prevent it from being activated by conversion to the metabolically inactive form. The three-dimensional general model of the ­ embrane explains previous findings of rapid equil- m deiodinases predicts that the active center is a pocket ibration of plasma T3 with T3 generated via D1. as defined by the β1-α1-β2 motifs of the TRX fold and seen in liver and kidney. a specific RNA D3 colocalizes with Na+. stem loop immediately downstream of the UGA codon with the early endosomal markers EEA-1 and clath- allows for the Sec incorporation in the STOP codon. In contrast. reverse T3 (via D1 or D3). which is recognized in the vast majority of facilitate access to its nuclear receptors.Part I  Normal Thyroid Axis HO HO O O D3 D1 H O H O OH OH Thyroxine. T2 is an inactive product common to both pathways that is rapidly metabolized by further deiodination. and all other selenoproteins.18.

Replacement with serine. and Dentice M.20 More stud. loss of D2 activity was also inhibited by MG132 in acterizes D2’s homeostatic behavior is its short half-life these cells. et al: The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate.1 A number of transcriptional and post-trans. 2003. N terminus. is critical for enzyme kinetics. The orange dotted loop indicates the D2- ­specific segment that mediates interaction with the E3-ubiquitin ligase. and in experimental situations by reverse T3 or roid hormone via plasma membrane transporters is even high concentrations of T3. et al: The iodothyronine ­selenodeiodinases are thioredoxin-fold family proteins containing a glycoside hydrolase-clan GH-A-like structure. reduced by physiologic concentrations of its substrate. in which the half- to-mRNA ratios are variable.21 D2 activity.12 C-ter.31 Substrate-induced sion. indicating that both pathways affecting (approximately 40 minutes). J Biol Chem 278:36887-36896. The active center contains the rare amino acid selenocysteine (Sec). tration based on how much T4 is available. Thyroid Hormone Metabolism Active center A 3D model of D2 Figure 5–2  Structure of the deiodinases. and a ­thioredoxin fold–containing globular domain. turns both D2 and D3 into low-affinity and PTU-sensitive enzymes. Curcio-Morelli C. Position 135. 59 . a short hinge region. A three-dimensional (3D) model of the D2 globular domain is shown on the right.22. suggesting that tion of D2 by its substrate constitutes a rapid. which is naturally found in D1. D2 and D3 have high affinity for their substrates and are not sensitive to inhibition by propylthiouracil (PTU).24 which can be further loss of D2 activity are mediated by the proteasomes. (Adapted from Callebaut I.23 The decisive biochemical ­property that char. which in D2 and D3 is occupied by proline. a modification that tar- lational mechanisms have evolved to ensure limited gets proteins for destruction in the proteasomes. Letters and numbers shown indicate different β sheets and α-helices. Nat Cell Biol 7:698-705. Bandyopadhyay A. potent the D3 active center is inside the cell. limiting enzymes whose half-lives can be modified ticity. Inset.) domain is located in the extracellular compartment. a proteasome inhibitor. WSB-1. generalized regulatory feedback loop that efficiently ies in this area are necessary to establish the determi. controls T3 production and intracellular T3 concen- nants of D3 topology. D2 is considered the critical homeostatic T3 -generating Important metabolic pathways often contain key rate- deiodinase because of its substantial physiologic plas. other studies have indicated that cellular entry of thy. which is critical for nucleophilic attack during the deiodination reaction.24-28 This downregula- critical for D3-catalyzed deiodination.30 expression and tight control of D2 levels. Although the deiodinases have not yet been crystallized. The mechanism that underlies the feedback Inactivation of D2 by Ubiquitination Pathway regulation of D2 by its substrate is ubiquitination. by selective ubiquitination. indicating that there is life of endogenous D2 was noted to be stabilized by significant post-translational regulation of D2 expres. 2005. protein modeling indicates that they share a common general structure composed of a single amino terminal anchoring segment.29. The residues that putatively interact with the T4 molecule (green) are also shown. which is The first evidence that D2 is regulated in this man- inherent to its homeostatic function. T4. ner was obtained in GH4C1 cells. N-ter. Gereben B. MG132. Mornon JP. C terminus.

Nat Cell Biol 7:698-705. glucose uptake. a ubiquitin ligase known to ­ ubiquitinate uitinating machinery have been identified as being other ER resident proteins37. including brain. unknown whether TEB4. a ferentiation. The WD40 pro- peller of WSB-1 recognizes an 18–amino acid loop in D2 that confers metabolic instability. and skel- of WSB-1 recognizes an 18–amino acid loop in D2 etal muscle. it is ­presently important for D2 (Fig. and energy expenditure. the ubiquitinating machinery has been identified as Ubiquitinated D2 is not automatically de- being WSB-1. BC-Cul5-Rbx1 (ECSWSB-1). et al: The Hedgehog-inducible ubiquitin ligase subunit WSB-1 ­modulates thyroid hormone ­activation and PTHrP secretion in the developing growth plate.) This implies that the loss of D2 activity is. suggesting that another E3 ligase could D2 were shown to parallel D2 activity. Thus.32 a recent report in which yeast-expressed D2 is ­targeted A number of elements in the cellular ubiq. stasis to include brain development. (Adapted from Dentice M. 2005. In the developing tibial growth plate. by Doa10.38 mediates D2 degradation in vertebrates. ECSWSB-1. 5-3). caused by proteolysis.39 The find- hedgehog signaling in embryonic structures as shown ing that VDU1 and VDU2 are coexpressed with D2 in in chicken development. ceptibility to exposure to T4 or prevent proteasomal firmed after the levels of immunoprecipitable labeled degradation. Bandyopadhyay A.33. However. and with D2 being critical for feedback feres with WSB-1–mediated ubiquitination so that D2 regulation of T4 on thyroid-stimulating hormone activity is not increased during WSB-1 knockdown.Part I  Normal Thyroid Axis Figure 5–3  Ubiquitinating complex for D2. modeled as Elongin B-Cul5-Rbx1. a SOCS box–containing WD- 40 protein g­raded. however. the ubiq. Serum T3 is relatively constant in healthy subjects. whereas the SOCS mechanism may extend well beyond thermal homeo- box domain mediates its interaction with an ubiqui. The deiodinases play an impor- can affect local control of the hedgehog-PTHrP nega. both under mediate the ubiquitination of D2.19 (TSH) secretion.34 In particular. cardiac perfor- tinating ­ catalytic core complex. its likely human ortho- uitin ligase responsible for the recognition of D2 by logue. The hedgehog-inducible WSB-1 is an E3-ubiquitin ligase for D2. with deiodinase-mediated peripheral T4 The removal of the six amino terminal resi. finding that is not surprising considering that T3 is a nism whereby “locally generated” thyroid hormone pleiotropic molecule. a premise that was con.39-41 indicates that the importance of this that confers metabolic instability.36 The WD-40 propeller many human tissues. thereby regulating chondrocyte dif. ECSWSB-1 mediates a novel mecha. whereas the SOCS-box domain mediates its interaction with ubiquitinating catalytic core complex. heart. but instead can be reactivated via the actions of previously unknown function that is induced by of the deubiquitinases VDU1 and VDU2. Gereben B. in humans. to T3 conversion being the major source of plasma T3 dues of the 18–amino acid D2 instability loop inter.35. 60 .36 homeostasis. tant role in the maintenance of thyroid hormone tive feedback loop and thus skeletogenesis. modeled as Elongin mance. this truncation does not eliminate the sus- tially. This is supported by ba­sal conditions and after exposure to substrate. hedgehog-stimulated D2 ubiquitination Role of Deiodinases in Thyroid Hormone via ECSWSB- 1 induces parathyroid hormone–related ­Homeostasis ­peptide (PTHrP). at least par.

11. This has been demonstrated in mild favored the D2 pathway under euthyroid conditions. whereas tissue T3 concentrations centrations lead to homeostatic reciprocal changes were reduced by only 50%. TtT-97 and TαT1. especially within those ubiquitinating capacity. D2 plays a key role in the feedback regu- ing T3 clearance.66 Studies using two tribution are specifically concentrated in the hypo. it has been found hypothyroidism. even ity. Thus. net T3 production in these cells are sustained.22 the physiologic range. As expected. of both circulating T3 and T4 are required to sup- sage will be lower in hypothyroidism. D2. D2 activity and subregions of the brain expressing high D2 activ. edly decreased.51-57 Brown adipose tissue (BAT) trophs and confirm its sensitivity to negative regula- shows similar adaptation mechanisms. Not surprisingly.67 D2 in of a decrease in central nervous system (CNS) D3 the brain itself may also be important for TSH regula- activity. Both total fetal press TRH mRNA in the paraventricular nucleus 61 . D2 expression in these cells. 5-4). For example. Because tion by T4-induced proteasomal degradation of this of the negative regulation of Dio2 gene transcrip. decreasing D3 activity. expression of the Dio2 gene tion by thyroid hormone. is the pathway whereby most plasma T3 is ity is decreased by 80% to 90% in the cerebral cortex. as in thyrotoxic patients. however. in hippocampus.42-46 More from T4 by D2.1 As serum T3 concentra. and cerebellum.23 D2 mRNA increases in in TαT1 cells is higher than their T4-induced D2 iodine-deficient animals. in a PTU-insensitive manner. to moderate hypothyroidism by tracer studies in but also suggest that D1 becomes predominant as rodents62 and confirmed directly by Campos-­Barros serum T3 levels increase. the D3 mes. propylthiouracil (PTU) treat.55. This illustrates the effec- in the activity of D2 and D3. although only modest (two- globulin (15:1 in humans). tions increase. tiveness of these compensatory mechanisms. accelerating D2 ubiquitination and deg. it was found that D3 activ- than D1. It can also The clearance of T3 from the brain is account for the increase in TSH at the early stages of reduced during hypothyroidism.10.58-60 As with extent by intrathyroidal conversion of T4 to T3. whereas the D2 gene is modestly lation of T4 on TSH secretion (Fig. Recently. Fluctuations in serum T4 and T3 con.50 The increase in D2 seen in that D2 and TSH are coexpressed in rat pituitary this setting has been particularly well documented thyrotrophs and that hypothyroidism increases for the brain. changes of a much patients with primary hypothyroidism receiving fixed higher magnitude than those that occur in the brain doses of exogenous T4. A number pus and cerebral cortex. approximately 50% ver. the increases in D2 at free T4 concentrations that are several-fold above activity are much greater than those in D2 mRNA.48 This suggests that but not D2.61 However. produced in euthyroid individuals. thalamic tanycytes and the ­arcuate ­nucleus/median have demonstrated high expression of D2 in thyro- eminence region. in general. the D3 gene is upregulated. would production in cultured cells by the D1 or D2 pathway be expected to mitigate the effects of severe iodine across a range of substrate concentrations have also deficiency. As a result. sus 25% in the euthyroid state. This was downregulated. given evidence showing that the ­normalization T3 dependence of the Dio3 gene—that is. The first recognized following the observation that T4 overall fractional conversion of T4 to T3 is increased rapidly reduces TSH release in the hypothyroid rat in the hypothyroid patient.63-66 Given that D1. This decrease can be explained by the tion. both T4 and T3 for normalization of TSH. Thyroid Hormone Metabolism The thyroid gland secretes T4 and T3 in a and adult rat brain respond to iodine deficiency by proportion determined by the T4/T3 ratio in thyro. murine-derived thyrotroph cells. enzyme. is inhibited by PTU. Despite this. possibly as a result iodine deficiency.55 ment even at very high doses (1000 mg/day) only The increased fractional production of T3 leads to a decrease of 25% in serum T3. account for the requirement for physiologic levels of radation per se. when only T4 is decreased. This is explained by the hypothyroxinemia of iodine The presence of D2 in thyrotrophs can deficiency. by focusing on of lines of evidence have suggested that D2. tissue T4 was mark- centrations. subsequent work D2-catalyzed T4 to T3 conversion is an important was directed toward understanding the significance mechanism to preserve T3 production in primary of D2 in the pituitary.60. modified to an unknown fold) reductions have been observed. with high focal expression in the hippocam- nine in healthy iodine-sufficient subjects. concentrations in various regions of the CNS in thus promoting the maintenance of serum T3 con. in which D2 activity and mRNA dis.47 and colleagues. increas. combined with the prolonged resi- recent in vitro modeling estimates comparing T3 dence time of T3 (a result of low D3 activity).56 who measured thyroid hormone The actions of the deiodinases are ­integrated.49. decreasing T3 production. iodine-deficient rats. rather specific brain subregions. the distribution of D3 in the CNS is heteroge- the prohormone T4 is the major secreted iodothyro. neous.

For example.68.72 binding proteins that regulate the transcription of The importance of primary changes in deio- T3-dependent genes. high-affinity nuclear T3 cold exposure. In the brown fat.74 which in turn leads to the induc- provide a uniform signal to all tissues of the body. Furthermore. resulting in relative ­local ­hypothyroidism. Shh. where D2 is expressed. ­ Tissues present in this portion of the hypothalamus but expressing D2 have an additional intracellular rather it is concentrated in the arcuate nucleus and source of T3.Part I  Normal Thyroid Axis Development T3 T2 Shh D3 cytoplasm T3 Gli(?) TGR5 T3 BA WSB-1 WSB-1 cAMP Dio2 D2 D2 VDU-1 VDU-1 �AR cold NE T4 T4 D3 T4 rT3 Figure 5–4  Pathways regulating D2 expression and thyroid hormone signaling. which is determined by the affinity of in rodents.54. in brown adipose tis- sue the levels of D2 activity and TR occupancy are Tissue-Specific Control of Thyroid Hormone dynamic and change according to the metabolic Signaling requirements of the tissue (discussed later). ing from a TR occupancy of approximately 70% at ated through the binding of T3 to nuclear thyroid room temperature to approximately 100% during hormone receptors (TRs). with heat being generated as a nucleus.51- 53. Other signaling pathways can decrease D2 activity. both on T3 from the plasma and T4 from the ­plasma cytes. Both these pathways activate cyclic AMP (cAMP) ­production and stimulate Dio2 transcription (nucleus is a blue circle). cAMP also promotes VDU-1 ­expression. stimulation of D2 expression increases local triiodothyronine (T3) production. it into the pituitary portal plexus. or by bile acid (BA) stimulation of TGR5. the saturation of the TRs is normally approximately rotrophs via T3 released from the tanycyte processes 50% whereas in the CNS. Surprisingly. presumably via the Gli cascade. such as during cold stimulation.71 The magnitude of the importance of D2 for raising the possibility that a signal from T4 in the nuclear T3 levels is considerable: in liver and kidney. is close to 95%. the contribution from serum T3 1).73 Cold-induced thermogenesis in BAT has been alone results in an approximately 50% saturation of shown to depend on the cyclic adenosine monophos- thyroid hormone receptors in most tissues. This increase can be mediated by norepinephrine (NE) stimulation of β-adrenergic receptors (βAR). tion of T3-responsive thermogenic genes including 62 . This tissue is the major site of adaptive ther- the receptor for T3 and the T3 concentration in the mogenesis in rodents. the hedgehog cascade decreases D2 activity by promoting WSB-1 expression and thus D2 ubquitination. In D2-expressing cells such as brown ­adipocytes. phate (cAMP)–mediated acceleration of D2-catalyzed Although plasma thyroid hormones may T3 production. D2 activity is not their biologic impact is not homogeneous. sonic hedgehog.69 These specialized cells have their cell that has been converted to T3 by D2 (see Fig. resulting in increased ­saturation of T3 receptors.70. 5-4). the nuclear T3 concentration depends median eminence. specifically in glial cells and tany. ­amplifying the D2 induction via deubiquitination. The extent of thyroid hormone dinase activity in determining local T3-dependent signaling in a given cell ultimately depends on TR effects has been clearly illustrated in studies of BAT occupancy. bodies in the inferior portion of the third ventricle. central system fluid could be transduced to the thy. thyroid hormone action is initi. increas- At the cellular level. These values are such that at normal serum result of the actions of uncoupling protein 1 (UCP- T3 concentrations. of the hypothalamus.

The importance of this but not with serum T3. However.85 More importantly.49 local intracellular thyroid status without necessarily Various studies have supported a previously altering serum T3 concentrations. and Spot14—observed in amounts of BAT.90 whereas the double–liver X receptor (LXR) knock. this effect the BMR with free T4 and inversely with serum TSH. With the real. the increase in that bile acids can confer resistance to diet-induced BMR observed in subjects fed a high-carbohydrate obesity in mice via upregulation of D2 expression in diet is typically associated with an increase in the brown adipose tissue. such that UCP-1 knockout mice are paradoxically lean77 and energy expenditure is several-fold higher in hyper- have ectopic expression of D2 in their white fat.5. this presumption unrecognized role of D2 in influencing the thyroid has been deservedly challenged. given that it mice fed a high-fat diet supplemented with bile is the only cAMP-dependent deiodinase. these data could mechanism in rodents fed a normal diet remains indicate that D2-produced T3 might be a significant to be determined and D2-independent bile acid physiologic determinant of energy expenditure in ­activated pathways may play a role. expenditure. except in those in whom brown ing that that D2 can have tissue-specific metabolic adipose tissue mass is increased.and hyperthyroidism. thyroid as compared with hypothyroid patients. noteworthy that D2 is overexpressed in two other Thyroid hormone is one of the few truly rodent models of resistance to diet-induced obesity: potent stimulators of the metabolic rate. Thyroid Hormone Metabolism UCP-1. binding of bile serum T3/T4 ratio. survival in the cold is gene expression profiling in the case of the double- only possible because the mice begin shivering. In normal nection with D2 can be easily imagined. little is known about how D2-generated T3. ectopic expression of D2 in these animals results Although many T3-responsive candidate genes have in tissue-specific thyrotoxicosis.34.80-82 note that in spite of the large D2-mediated increase It could thus be assumed that the D2 pathway is in BAT nuclear T3 seen in cold-exposed animals. a response that is in humans peaks at the time of birth. demonstrat. with pheochromocytoma. do not have substantial dehydrogenase (G6PD). such as patients effects. However. in particular D2.86 a condition that is also observed acids to the plasma membrane G protein–­coupled in adult subjects chronically treated with terbutaline. receptor TGR5 triggers an increase in cAMP forma. oxygen consumption increases and the mice more. this would certainly support behavior not normally seen in small mammals.88 Further- acids. In D2 knockout mice.11. cose (FDG) positron emission tomography (PET) or roid hormone documented in human subjects dur. out mice express D2 ectopically in the liver. the relative constancy of serum of D2 activity in human skeletal myocytes. However. given the finding homeostasis. mones in brown adipose tissue (BAT) is to mediate a Human newborns grow less dependent on three. one would anticipate focal deposits in the mediastinum and in extramedi- a major physiologic role of this hormone in energy astinal areas. when brown blunted in hypothyroid rats. computed tomography (CT) imaging have identified ing hypo. It is nonetheless humans.84. glucose 6-phosphate unlike small mammals. Earlier stud- Evidence for a role for D2 in the control ies consistently found that diet-induced changes of metabolic pathways beyond cold-induced ther­ in serum thyroid hormones could be explained by mogenesis was recently provided by the discovery changes in D2 activity.75 the concept that the D2 pathway increases energy An additional role played by D2 and ­ thyroid hor. as is suggested by been identified. is lost in D2 knockout mice. a LXR knockout mice. the amount of brown adipose tissue in adults may be greater than Novel Role for D2 in Metabolic Control once thought. studies of patients receiving T4 replacement did not gain weight or become as insulin-resistant as at various dosages have shown a direct correlation of mice only fed the high fat diet.83 However. status and metabolic rate in humans. most important for thermogenesis in infants and less serum T3 concentrations do not change. and adult humans.to fourfold increase in the activity of lipogenic BAT thermogenesis with maturity. For example.89 Together.42-44 It is important to adipocytes comprise almost 1% of body weight.87 A con- tion and subsequently D2 expression. accelerates energy expenditure.78 If the or T3 from plasma.79 The mass of brown adipose tissue this tissue during cold exposure. important in adults. proteins—malic enzyme (ME). thermogenesis and insulin-induced glucose disposal ization that deiodinases. a β-adrenergic receptor (β-AR) stimulator. a larger T3 concentration seemed to preclude a major role metabolic role for D2 in humans may be anticipated. their exact contribution remains to 63 . because studies using fluorodeoxyglu- Given the generalized metabolic sensitivity to thy. of T3 in the basal metabolic rate (BMR) variations because skeletal muscle is the predominant site of observed after a meal or during sleep. could alter in adult humans.76 In this tissue.

of the protean nature of the underlying diseases but prising that its administration has a greater effect on also because of interspecies variations in the response thyrotoxic than on euthyroid subjects. recommendation that large doses of PTU. Another general mechanism effects on deiodinases. be used in the acute treatment clusion is further supported by the observation that of the severely hyperthyroid individual. ation and/or increased clearance of T3. but because T4 production is increased. suggest- data. ­kidney in a dose-dependent fashion. not only because Given that PTU blocks D1 activity. have led to the does not stem from a lack of central T3 production.107. it is not sur. this also decrease and an increase in total reverse T3 may has been demonstrated in Graves’ thyroid tissue and also be seen. life-threatening trauma. Nevertheless. indicating a predominance of D1 in thyrotoxic ing that the severely reduced T3 seen in ill patients subjects and inhibition of D1 by PTU.92 T4.111-113 Animal studies have suggested gene95. if any.109.114 but the enzyme activ- determined.Part I  Normal Thyroid Axis be established.125 Amiodarone is a potent iodine-containing cardiac Recent data from critically ill patients have antiarrhythmic that shares some structural homol.91 Similar results by 10% to 25%. along with decreases of T3 mildly thyrotoxic human volunteers. whereby T3 may increase energy expenditure would The T4 to T3 conversion rate may fall from be to accelerate the turnover of enzymes that use ATP.97-99 Which. rone therapy. but there are also uncoupling proteins. and this effect plasma T4 (approximately 40%) and reverse T3 has been demonstrated in the skeletal muscle of (170%) concentrations. or major circulating concentration is about twofold higher surgery can trigger a stereotypic pattern of changes relative to that of T4 in hyperthyroid patients.100 in pituitary-thyroid function sometimes referred to This is ­reflected in the markedly greater elevation in as the low T3 syndrome or euthyroid sick syndrome.110 These effects stem mainly from the fact that but it is not clear whether this effect is mediated by the drug is 37% iodine by weight. D1 becomes ­predominant during thyrotoxicosis.122-124 in mononuclear leukocytes of patients with Graves’ Understanding the pathogenesis of the low disease.100 These is not suppressed unless illness is extreme. and it is possible that an as yet unidenti.101-103 T3 syndrome has proven difficult. human Dio1 promoter is T3-responsive. and fied mechanism could play a major role. ­metabolites. The concentrations of T4 and TSH may nificantly increased in hyperthyroid patients. D3 is nor- results may be abnormal during its administration as mally expressed in multiple fetal structures. This has been of the thyroid axis to illness. ity is inhibited in homogenates of liver.115-119 The same is observed in hepatocytes exposed to amiodarone. of these some primary effects of amiodarone on deiodinase genes is most responsible for the observed increase activities. or other but rather from decreased peripheral T4 deiodin- agents that block T4 to T3 conversion. in rats given amiodarone. substantiated a previously unsuspected role for D3 in ogy with thyroid hormones. one would with the decrease being inversely related to the sever- anticipate that D1 activity or mRNA would be sig. 26% to 43% (range) to 10% to 17% during amioda- Several T3-responsive genes have been ­ implicated. changes in shown in a study in which the effects of PTU versus peripheral T3 generation via the deiodinases and/or methimazole on serum T3 production were exam. such as iopa. clearance of T3 must certainly play a role.120 DEIODINASES IN ILLNESS The mechanism of inhibition of D1 in amiodarone- treated animals is likely to be competitive inhibi- Hyperthyroidism tion with substrate by the drug per se or one of its Whereas D2 is thought to be the major T3-produc. Serum TSH ined in euthyroid and thyrotoxic patients. but the a result of alterations in the metabolism of thyroid endometrium and the placenta are the only normal 64 . It has been Deiodinases in Nonthyroidal Illness established that the production rate of T3 and its Any critical illness.121 ing deiodinase in euthyroid individuals. net T3 production and plasma-free T3 concentra- mic endoplasmic reticulum Ca2+-ATPase (SERCA) tions normalize.104-106 serum T3 and T4 concentrations decrease during ill- ness in patients with hypothyroidism who are given Amiodarone l-­thyroxine every day during their illness. free T3 than in free T4 in such patients. Similar ­changes occur in free T3 and were reported in hepatocytes of thyrotoxic rats. For example.94 and the sarcoplas. such as the Na+/K+-ATPase93. Thyroid function test the pathogenesis of the low T3 syndrome.108 with rapid development of increased has been proposed as one mechanism.96 among others. D1 in energy expenditure driven by T3 remains to be mRNA levels are normal. This con- noic or ipodipic acid. Increased mitochondrial uncoupling hormones. heart. ity of illness. Because the These patients exhibit low serum T3 concentrations.

a significant frac- tional level. in metabolic control is proven istration leads to increases in serum TSH.132 leptin admin. and vascular anomalies. in peripheral deiodination may be necessary for the The deiodinases can be seen as playing an analo­ pathogenesis of the syndrome. Whereas dopamine and glucocorticoids play a only now being recognized. in a study that determined serum roidism with an elevation in serum TSH. 11β-hydroxysteroid dehydrogenase in ­glucocorticoid pensate for decreases in T3 production in peripheral metabolism. ases. the breadth of actions of these enzymes is terized. presenting with severe hypothy- unit. The first patient documented with this condition fetal thyroid hormone transfer in the uteroplacental was 3 months old. These observations may indicate tissue.131 The molecular determinants of central toxicosis have obvious implications for the clinician. Thyroid Hormone Metabolism tissues known to express high levels of D3 activity in large. rather than a in which hormones are activated or inactivated in a pathologic mechanism. hepatic hemangiomas can be fatal. Although extensive expression of both deiodinases at the pretransla. Accordingly. D3 expression has been found in human brain tumors. The seemingly coordinated changes in the expression of the three deiodinases seen in ill patients Conclusions could be taken as circumstantial evidence for the From a broad perspective. obesity. 2002.136 although it remains ­speculative whether this ­induction of D2 leads to local References thyrotoxicosis. liver D1 was downregulated infantile hemangiomas and D3 expression is notable and D3 was induced ectopically in liver and skeletal because it identifies a previously unrecognized cause muscle. the rate of thyroid hormone inactivation can the mature human. tion of these infants survive as a result of therapy and ­specific mechanisms for the reduction of thyroid the natural tendency of these tumors is to regress. the medial basal hypothalamus of rats ­following lipo- polysaccharide injection. Fiering SN.129 Whether ectopic D3 occurs or is important in complication of irreversible mental retardation later milder illness is not yet known.127. D2. these patients may require replacement more.    2. which usually occurs at a critical with enzyme activities. suggesting regulation of the age for neurologic development. and to be relevant for human subjects. mice.135. Given the remarkable capacity P-450 aromatase in sex steroid metabolism and to of the hypothalamic-pituitary-thyroid axis to com. in life. Gereben B.    1. 65 . and high reverse T3 and D3 in liver and skeletal muscle from deceased and thyroglobulin levels. an increase in D3 activity could contribute to with large quantities of thyroid hormone in addition the observed increase in reverse T3 seen in the syn. as demonstrated in the deiodinase-deficient regulatory mechanism for thyroid hormone action. then understand- T3 concentrations in fasting rats133 and humans.127 D1 and D3 mRNA levels corresponded of hypothyroidism. The relationship between intensive care patients. Schneider MJ. The main previously recognized exceed the maximal rate of thyroid hormone synthe- role for D3 had been in the regulation of maternal. Thai B: Targeted ­disruption certain malignant cell lines. et al: Bio- chemistry. sis. cellular and molecular biology and D3 in Hemangiomas physiological roles of the iodothyronine selenode- iodinases.137 If these tumors are sufficiently mice. and the meta- factor κB (NF-κB) cascade. Salvatore D. hypothyroidism in these patients are not well charac. Endocrine Rev 23:38-89. 2006. to therapy directed at their hemangiomas.126 However. and continuous infusion of TRH has been ­characterized homeostatic roles in the defense shown to increase serum T4 and T3 concentrations against hypothyroidism and the generation of thyro- strikingly. of the type 1 selenodeiodinase gene (dio1) results D3 expression occurs at high levels in rare infantile in marked changes in thyroid hormone economy in hemangiomas. which upregulates D2 in bolic syndrome. In any case. although ­changes controlled fashion in specific extraglandular tissues. The three deiodinases constitute a major tissues. Thyroid drome. they are probably not gous role to that of 5α-reductase and cytochrome sufficient to cause it.130 TSH secretion is decreased in critically mechanism at the prereceptor level. T4. along with decreased reverse T3 clearance via hormone treatment is also imperative to prevent the D1.135 ing these pathways may become of great importance Another pathway that could be involved is the nuclear for the treatment of diabetes. serum T4 and T3 concentrations. Endocrinology 147:580-589. deiodination of iodothy- hypothesis that the nonthyroidal illness syndrome is ronines can be seen as an example of a paradigm in fact a physiologic response to illness.128 Further. central hypothyroidism must also be part of the perhaps the most important peripheral regulatory syndrome. If the role of deiodin­ suppressive role with respect to TSH. hormone bioactivity during illness. Bianco AC. However. undetectable thyroid hormone levels and the expression of D1. Their well- ill subjects. particularly D2.

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2000. Zeold A. Aarbakke J: Amio. Ceppi JA. et al: Charac- ces during illness in six hypothyroid subjects ren. Horm Metab Res 18:114. Aanderud S. DeJong M. inhibition of thyroxine deiodination. 2004. Sundsfjord J. Endocrinology 138:2569-2576. Huang SA. 1984. Faber J. 134. lar nucleus.5. et al: The role of immunoassay: Evidence that free triiodothyronine falling leptin levels in the neuroendocrine and and free thyroxine are normal in many patients metabolic adaptation to short-term starvation in with the low triiodothyronine syndrome. J Clin Endocrinol Metab 83:309- relationships of amiodarone analogues on the 319. Ha HR.3¢-triiodothyronine in undi. J Biol Chem enzyme levels in rat liver. triiodothyronine (T3) in non-thyroidal somatic 133. Doleschal M. et al: Identification of a odarone inhibits T4 to T3 conversion and alpha. Med Clin 122. Laurberg P. roid hormone serum parameters and hormone nine in rat myocardium. 8:249-257. et al: Structure-effect secretagogues. tion. Thyroid healthy men. 126. Huang SA: Physiology and pathophysiology of 137. et al: Reduced 343:185-189. Kaplan MM. Eur J Clin 132. Heist K. Kakyo M. Am J Med plications for the nonthyroidal illness syndrome. 129. Zaninovich AA: Effects of amiodarone G: The sick euthyroid syndrome: Changes in thy- on 5¢-deiodination of thyroxine to tri-iodothyro. Boye N. novel gene family encoding human liver–­specific ­glycerophosphate dehydrogenase and malic organic anion transporter LST-1. 130. Pekary AE. Hershman JM. et al: darone inhibits the conversion of thyroxine to Neuroendocrinology of prolonged critical illness: ­triiodothyronine in isolated rat hepatocytes. De Groot LJ: Non-thyroidal illness syndrome is a 119. Larsen PR. 2000. Crantz FR. et al: Ami. Endocrinology 147:4419-4429. et al: Severe hy- type 3 deiodinase in humans. et al: Lipo- 124. 128. Thyroid 15:875-881. Endocrinology 145:1649-1655. and drugs on thyroid function tests. terization of the NF-kappa B responsiveness of the dered euthyroid with levothyroxine therapy. 2006. 1986. J Endocrinol 121:431. Tu HM. 1993. et al: Preva. iodinase in infantile hemangiomas.3¢. 118. 1991. Wadwekar D. J Clin Endocrinol Metab 88:3202-3211. Crit Care Clin 22:57-86. 125. 434. and in view of current evidence. 1997. Doleschall M. activation and increased inactivation of thyroid hormone in tissues of critically ill patients. 2003. J Cardiovasc Pharmacol treated with appropriate replacement therapies. Andreasen F: manifestation of hypothalamic-pituitary dysfunc- Rat heart thyroxine 5¢-deiodinase is sensitively de. prevents fasting-induced suppression of prothyro- noextraction. Effects of exogenous thyrotropin-releasing hor- docrinology 115:1605-1608. 72:9-16. Gereben B. Clin Endocrinol Diabetes 112:373-377. 135. Kabadi UM: Thyroid hormone indi. metabolism. 1989. 274:17159-17163. Peeters RP.Part I  Normal Thyroid Axis 116. as measured by ultrafiltration and immu. 2006. et al: Leptin illness. Fekete C. 136. Chopra IJ: Simultaneous measurement of free acid in neurons of the hypothalamic paraventricu- ­thyroxine and free 3. Clin Endocrinol 39:499-518. polysaccharide induces type 2 iodothyronine lence of abnormal thyroid function test results in deiodinase in the mediobasal hypothalamus: Im- patients with acute medical illnesses. should be pressed by amiodarone. Krenning EP. 1999. Docter R. Chan JL. luted serum by direct equilibrium dialysis/radio. mone and its combination with growth hormone 121. 2004. 1982. pothyroidism caused by type 3 iodothyronine de- 2005.5. Ahima RS. Siersbaek-Nielsen K: Serum free 3. Hennemann 118. 1998. Van den Berghe G. 1998. Grassi G. 129. DePaoli AM. Abe T. 1996. Wouters PJ. N Engl J Med 127. North Am 75:27-39. Kaptein E. Harney JW. 1989. En. Clin Chim Acta 256:115-123. Legradi G. Baxter RC. 2003. Tokui T. de Zeghe F. Gotzsche LS. Exp human dio2 gene. Haffner MP. Cavalieri RR: The effects of nonthyroid disease Pharmacol 55:807-814. Emerson CH. Reed AW. Stieger B. tropin-releasing hormone messenger ribonucleic 123. J Clin Invest 111:1409-1421. 14:836-841. 70 . 131.

1. Genetic produced from a larger prohormone (proTRH) by experiments in mice and human studies have dem. Although the synthesis and release of TRH in the Furthermore. n TRH and thyroid hormone levels may be influenced by nutritional status. regulation of TRH production in the hypothalamus thyroid hormone levels must be set at the appropri. The regulation of circulating thyroid hormone levels to be curtailed. This is accomplished by roid axis in health and disease. TRH. However. n n TRH is primarily regulated by thyroid hormone levels. such as severe illness or nutritional is critical for normal human physiologic function as deprivation. making can sense their deficiency and excess and respond to any judgment about their conserved role difficult.5. Section C Thyroid axis Role of Thyrotropin-Releasing Hormone in the Regulation Chapter of the Thyroid Axis 6 Anthony N.or underproduction. can sense states in which TH production may need see later) is essential for normal regulation of the 71 .4 Thus. helps explain changes in thyroid function seen during such states. roid-stimulating hormone (TSH) from the pituitary presumably by impairing the production of mature and for normal TH levels.8 this feedback in an attempt to reset the thyroid axis. a feedback system in which thyroid hormone targets its regulators to prevent over. ciency of these enzymes can disrupt the thyroid axis. the enzymes proconvertase 1.2 In addition to allow. TRH neurons in the hypothalamus can may play a role in physiology. Genetic defi- are required for the synthesis and secretion of thy. n TRH is regulated by critical illness. To accomplish this. is critical to understanding the regulation of the thy- ate level for each individual. Mature TRH is a tripeptide (pyroGlu-His-ProNH2) duce thyrotropin-releasing hormone (TRH). TRH neurons in the hypothalamus paraventricular nucleus of the hypothalamus (PVH.3. THYROTROPIN-RELEASING HORMONE: Among the most important regulators of TH levels STRUCTURE AND FUNCTION are a group of neurons in the hypothalamus that pro.5-7 The gene encoding TRH in multiple species ing for the normal production of TSH and thyroid also allows for the production of other peptides that hormone. and downregulate the thyroid axis to thyroid hormone (TH) remains one of the principal limit metabolism. an understanding of the regulators of human metabolism. these pep- be ­ dynamically regulated by TH levels so that they tides appear to vary from species to species. proconvertase 2 (PC1 onstrated that the production and action of TRH and PC2). Hollenberg Key Points n Thyrotropin-releasing hormone (TRH) synthesis and secretion from the hypothalamus is required for ­ ormal thyroid function. and carboxypeptidase E.

4. TRH mRNA HORMONE is regulated by T3 only in the PVH and not in other regions of the hypothalamus. Hypophysiotropic thyrotropin-releasing hormone (TRH) is transported to the median eminence. The ­neurons project to the median eminence and release TRH into TSH subunit synthesis and secretion in the pituitary the portal system. is to stimulate the production of TSH via its receptor on thyrotrophs. and lateral TR�2 hypothalamus. oxytocin. A model is shown in tropin-releasing hormone. Thyroid 18:131. once it is secreted into the portal system and reaches the pituitary. TRH is also synthesized in other regions of the hypothalamus. Remarkably. mRNA rises in the hypothyroid state and falls in the REGULATION OF THYROTROPIN-RELEASING setting of hyperthyroidism. interpret energy stores.10 However. T4. although mice lacking TRH TRH develop glucose intolerance. The PVH also contains hormone production. dorsomedial. brain. which in turn reaches the pituitary and (Fig. A Target Tissues tion of the thyroid axis.) and sense severe illness. 2008. whereas other species appear to express a second TRH receptor whose func. when TRH lev- els are high. The PVH is present on B D2 both sides of the third ventricle and is triangular in Figure 6–1  The hypothalamic-pituitary-thyroid axis.3 The TRH receptor is also expressed widely in the brain. given their key role in the secretion. 6-1A).9 Anatomy of Thyrotropin-Releasing Hormone Neurons MCT8 T3 SRC-1 TRH is synthesized in multiple regions of the hypo.9 The principal action of TRH. structure. which local T3 produced by type 2 deiodinase accesses TRH To play a key role in the regulation of the neurons in the PVH via the monocarboxylate 8 transporter thyroid axis. including the ventromedial. suggesting that pancre- atic TRH may play a role in glucose homeostasis. Although it ments performed 20 years ago demonstrated that T3 remains unclear which of these mechanisms is opera- specifically regulates TRH in the PVH so that TRH tive. the function of TRH T3 in these regions is not clear. and peripheral organs.3. TRH receptors are also present on prolactin-secreting cells in the pituitary T4.2 TRH signals through a single G protein– coupled receptor in humans. prolactin levels can also be high. Seminal experi. where it is neurons are present in the paraventricular nucleus of the released into the portal circulation and can regulate hypothalamus that surrounds the third ventricle. and ity to sense T3 or the acquisition of a key molecular in particular triiodothyronine (T3).13 Thus. supporting the notion that TRH may have other actions in addition to its central role in the regula. such as the pancreas and heart. mus (PVH) to regulate TRH synthesis. B. (Adapted from Hollenberg AN: The role of the thyrotropin-releasing hormone [TRH] be able to sense TH levels. Mature TRH that is synthesized in the PVH A. it is important to understand how T3 reaches the 72 .12. Its function in these 3V other areas is not clear. TSH tion is unknown. these hypophysiotropic neurons must (MCT8). and vasopressin. in hypothyroidism. ­neuron as a metabolic sensor. Triiodothyronine (T3) feeds back at the level of the paraventricular nucleus of the hypothala- distinct neuronal populations that synthesize cortico. It is likely that their discrete location in the PVH has developed to allow them to integrate all these inputs. thyroxine. the hypophy- Regulation by Thyroid Hormone siotropic TRH neurons have acquired the ability to Critical to the role of TRH in maintaining the thyroid mediate T3 regulation of TRH through a unique abil- axis is its ability to sense circulating levels of TH. TSH then acts on the thyroid to control thyroid regulation of pituitary TSH. switch in the neuron that allows T3 to act.Part I  Normal Thyroid Axis t­ hyroid axis. T4 thalamus in addition to the paraventricular nucleus.11 These TRH neurons are thus referred regulates thyroid-stimulating hormone (TSH) synthesis and to as hypophysiotropic. T3 (lactotrophs) and.

TRH present in tanycytes. 6-1B). D2 is actively. is suggested by by T3. and a host of coregulatory proteins. when T3 levels are high. a cell type that lines the third can be partially suppressed in MCT8 knockout ani- ventricle (see Fig. suggesting that T3 does regulation of TRH. negative regulation the TRH neurons in the PVH. which would explain the selective nature of the TR to modify the local chromatin environment regulation in the PVH. in the and peptide production are specific to hypophysio- hyperthyroid state. 2. This nTRE. These allow ic nuclei. setting of Graves’ disease or exogenous T3 adminis. Further- mutant gene present in the Allan-Herndon-Dudley more. although hormone response element (nTRE) in the proximal there appears to be no gross neurologic phenotype promoter of the TRH promoter that is conserved in the knockout (KO) mice. binds TRβ2 abnormalities are recapitulated. an understanding of the mechanisms under­ Thus. When given large doses of T4 or T3. PC2 mRNAs. do not sense T3. which likely occurs at the level of sible that other hypothalamic areas that express TRH transcription. much is known about how T3 acts to medi- T3 leads to cell-specific regulation. within the PVH is at two levels: A role for the type 3 deiodinase D3. T3 can directly gain access to TRH neurons to TRH neurons. TRH gene is supported by earlier studies that dem- cally on TRH neurons. although it is pos. Role of Thyrotropin-Releasing Hormone in the Regulation of the Thyroid Axis PVH and how it acts at the molecular level to mediate hepatic hyperthyroidism. which was first identified as a gene.22 Two groups have recently onstrated the presence of a unique negative thyroid disrupted the MCT8 gene in mice and. It is likely that than normal TH levels presumably because central this sensitive system plays a role in the unique abil- levels of T3 are inadequate. an X-linked disorder resulting in an early ing. It is now apparent that once T3 gains access tration. However.15 The role of D2 in the mals. the thyroid function test across species.24 These mice have and mediates downregulation of the TRH promoter 73 .20 MCT8 was identified as the downregulate TRH mRNA in response to T3. making it unlikely that access to gene.14. recent studies have surrounding the TRH or PC1 and PC2 genes and shown that T3 produced in the hypothalamus acts in allow for regulation by T3.22 MCT8 has been subse. TRH mRNA levels are directly regulated inactivates T3 in the hypothalamus.27 The role of TSH and low T4 levels. ate its regulation.24 Thus. The likely transporter is the monocarboxylate TRβ2 isoform for negative regulation of the TRH 8 transporter (MCT8).16 D2 plays a role in the ity of hypophysiotropic neurons to respond to T3. lying negative regulation by T3 are key to under- temic T4 is taken up by tanycytes and converted to T3 standing the regulation of TRH production in the by D2. not require MCT8 to gain access to hepatocytes. termed site 4. with elevated T3 levels in the setting of normal tion in the hypothalamus and pituitary.19 Whereas all TR isoforms have the ability to Once T3 reaches the PVH. Like positive regulation. a model can be proposed in which sys. it can be hypothesized that delivery and the fact that D2 knockout mice have TSH levels that transport of T3 to and within TRH neurons in the are inappropriately elevated in the setting of higher PVH are required for its regulation. but it although it still remains possible that the molecular is not clear that D2 activity is required at all sites mechanisms governing regulation of TRH mRNA in the brain for this purpose. DNA binding in the TRβ2 isoform regulation of the quently shown to be expressed in the brain. This is the result of prolonged neonatal regulated by T3 via the direct regulation of PC1 and hyperthyroidism. which normally 1. studies have demonstrated the requirement of the rons. It is tempting to specu. specifi. the fact that D3 knockout mice have central hypo. In the case of the TRH the arcuate nucleus. these animals have elevated TRH mRNA the PVH in the euthyroid or hypothyroid state is expression in the PVH. In Most T3 that acts on the TRH neurons in contrast. it is now clear mediate negative regulation. elegant mouse genetic that it must be actively transported into TRH neu.18 Thus. because mice expressing a mutant TRβ2 that is presentation of psychomotor retardation in affected unable to bind DNA cannot mediate negative regula- males. local production of T3 in the hypothalamus.25 sion of the thyroid axis.17 In addition. as in the tropic neurons. suggesting that other mechanisms for T3 access central regulation of the thyroid axis is supported by exist. consistent with the require- thought to be produced centrally from circulating ment for MCT8 to transport T3 into TRH neurons thyroxine (T4) by type 2 deiodinase (D2). requires thyroid hormone receptor (TR) isoforms late that T3 cannot be presented to other hypothalam. the regulation of TRH production in the PVH without having to be produced locally. Processing of proTRH by PC1 and PC2 is thyroidism.21. which causes ­permanent suppres.26 Mice that lack this isoform are unable to T3 transporter in 2003. TRβ2 likely mediates its action via DNA bind- syndrome.23. The locally produced T3 is then presented to PVH.

the administration of leptin may be paradoxically critical for negative regulation prevents the fasting-induced suppression of the thy- of TRH. An understanding of the path- neurons in the PVH or on thyrotrophs in the pitu. although per. can be rescued by physiologic leptin administra- However. On a Although the regulation of TRH production in the classic positive TRE.39 The in vivo role of NCoR and SMRT in roid axis by rescuing TRH expression in the PVH. contrast. weight regulation. istration of replacement doses of leptin.43 Similarly. with the long-held view that fasting.44 Both these groups of patients appear refrac. fasting in rodents also causes a fall in T4 lev- roid receptor coactivator 1 (SRC-1) have defective els. In the last complex that mediates transcriptional repression via 10 years. Its role in vivo remains to is separate and distinct from classic negative be determined. and indirectly via the arcuate nucleus.40 A similar model for the regulation of PC1 onstrated by studies showing that the daily pulsations and PC2 can likely be proposed because nTREs have of TSH secretion. arcuate nucleus that play a key role in body weight manent suppression of TRH synthesis in the PVH regulation and also project to the TRH neurons in cannot be excluded. Long-term fasting of TRH because TRH mRNA is upregulated in the in humans causes a decrease in TSH and T3 levels. As noted.53 Taken term suppression of the thyroid axis occurs in the together. mice that lack the coactivator ste. matically reduce leptin levels. this was shown many years ago to be secondary to negative regulation of the thyroid-stimulating hor. which suggests that the at high levels on two neuronal subpopulations in the defect is at the level of the pituitary. TRβ2 likely binds to the TRH promoter to mediate negative regulation. in rodents. This suggests lates the thyroid axis via its ability to target the TRH that there may be long-term actions of T3 on TRH neuron in the PVH.48 mone (TSH)–beta gene. tially TRH secretion.42 fast.34-37 Clearly.52. like TRH. which are diminished by a 24-hour been identified in the promoters of these genes. T4 and T3 levels can be restored by the admin- rapid response.28. without an increase in TSH on TRH production in the hypothalamus predicts a levels.57 Thus.51 Furthermore.18 It is likely that the molecular the pathways that leptin engages play a central role in mechanism underlying this long-term ­ suppression body weight regulation. a dramatic decrease in TRH expression in the PVH. a similar situation the PVH. controlled weight loss experi- understand negative regulation of these genes by T3 ments in human volunteers that cause a decrease in ­completely.54 The arcuate nucleus of the hypothala- present with central hypothyroidism requiring treat.41.55 In addition. the leptin recep- weeks following treatment. absence of T3 and downregulated in the presence of whereas T4 levels remain constant or may fall.38.56. treatment-induced low TH levels can still be Leptin exerts its effects in the hypothalamus associated with inappropriately low TSH levels for by engaging its cognate receptor. T3 and leptin signaling in TRH neurons. suggesting that coactivators Remarkably. leptin levels have also demonstrated a decrease in Although the classic negative feedback of T3 thyroid hormone levels. on target neurons in a number of separate nuclei mothers with poorly controlled Graves’ disease can (Fig. ism. given the intersection of itary. corepressors NCoR and SMRT in the absence of T3. The leptin receptor is expressed tory to TRH administration. Surprisingly.29 regulation. it has become clear that circulating leptin histone deacetylation.50 the regulation of TRH has not been tested in genetic The relevance of this axis in humans has been dem- models. releases the expression and production in hypophysiotropic TRH corepressor complex.45 Given that leptin levels are reliable indi- coactivator complex that mediates transcriptional cators of nutritional status. Regulation of Synthesis by Nutritional Status lators in the actions of TRβ2 remain unclear. which implies that regulation 74 .30-33 In the presence of T3.46. leptin receptors are found on is seen in D3 knockout mice. ways involved is important. which can dra- including acetylation and methylation. TR isoforms recruit the nuclear PVH is controlled most dramatically by TH levels. more work is necessary to tion. there are clearly cases in which long. Importantly. leptin has the very high levels of T3 during development leads to potential ability to target TRH production directly long-term suppression of TSH secretion and poten. this is entirely consistent activation via a variety of histone modifications. In patients with long-standing hyperthyroid.49. mus is one of the most important nuclei in body ment. it is also clear that other signaling pathways affect which in turn serve as a platform for a multiprotein these neurons and possibly TH regulation. but the role of coregu. in which exposure to TRH neurons in the PVH. these data demonstrate that leptin regu- setting of persistently high T3 levels. can regulate the thy- this paradigm cannot apply to negative regulation roid axis in rodents and humans. newborns of tor. 6-2).47 In T3. the produced in adipocytes can regulate TRH mRNA TR undergoes conformational changes.Part I  Normal Thyroid Axis in cell culture experiments. and recruits a multiprotein neurons.

Interestingly. a portion of hypophysiotropic rons.71 Both MC4-R and NPY-R iso- receptor and activate TRH production. α-melano. AgRP and NPY prevent activation of CREB and inhibit estingly. leptin inhibits agouti-related peptide the PVH coexpress the MC4-R and NPY-R isoforms.56. in turn.57 In cyte–stimulating hormone (α-MSH). but a more recent larger study be driven by leptin’s actions on the arcuate nucleus. As noted. levels of α-MSH fall but AgRP and NPY levels are increased.71. a key mediator of the genomic actions of major product of POMC/CART neurons. during a fast. leptin signaling. tion appear to have central hypothyroidism. in particular. The importance of leptin in the ­regulation of Indeed. with the predominant control of the on both groups of neurons. tides proopiomelanocortin (POMC) and cocaine and leptin-­mediated activation of the transcription fac- amphetamine-related transcript (CART) and are tor signal transducer and activator of transcription thus referred to as POMC/CART neurons. α-MSH. (AgRP) and neuropeptide Y (NPY) neurons. mediate activation of TRH expression. has shown that humans with leptin receptor muta.78 Taken together. leptin receptors in the arcuate ­other pathways must also affect TRH neurons. is derived from addition. action. both humans and mice with defective MC4-R tions have normal TH levels. Leptin crosses the blood-brain and NPY-5R are expressed in the PVH. In contrast. α-MSH activates CREB via the MC4-R and the thyroid axis is further supported by the fact that CREB.69 nucleus are present on two groups of target neu. hormone. TRH neurons also express the leptin receptor. Role of Thyrotropin-Releasing Hormone in the Regulation of the Thyroid Axis levels are low. AgRP is an antagonist or inverse agonist.73 TRH neurons in the PVH.72 Moreover. can be seen in TRH neurons.79 Given the importance of the thyroid axis.60 signaling have normal TH levels. in the presence of leptin.55 The second group synthesize agouti. TRH gene expression can was true in humans.74-77 Thus.69. Both α-MSH and AgRP signal principally through neurons in the PVH that express the melanocortin-4 receptor (MC4-R). In contrast. can bind to the TRH promoter to mouse models with defective leptin receptor func. 75 . allowing the TRH neuron to sense arcuate nucleus Alternatively. it Thus.68 – POMC/CART NEURONS The importance of this system is supported by the Figure 6–2  Thyrotropin-releasing hormone (TRH) ­neurons fact that mutations in the MC4-R cause severe obe- are regulated by leptin signaling.64-67 Many rodent models of diet-induced obesity manifest low levels of α-MSH and high levels of AgRP and NPY. forms engage the cyclic adenosine monophosphate (cAMP) signaling pathway and modulate the activity of the transcription factor cAMP response element– of the thyroid axis is an important arbiter of leptin binding protein (CREB) through phosphorylation. suggesting that As noted. Although leptin receptors are present leptin or α-MSH. there appear to be two AgRP and NPY are orexigenic and decrease energy groups of TRH neurons in the PVH that respond to expenditure.70 NPY signals through a variety of ­peripherally by adipocytes and regulates TRH production via NPY receptor (NPY-R) isoforms. Leptin is produced sity in humans. which also project to the PVH and function to inhibit TRH production.56 Whereas α-MSH is an agonist of – AgRP/NPY NEURONS the MC4-R. barrier and activates proopiomelanocortin (POMC) and cocaine and amphetamine-related transcript (CART) ­neurons. including those located in the PVH. which explains their contrasting physiologic roles.58 Inter. an initial report also suggested that the same TRH expression. the production of is likely that the direct and indirect pathways provide α-MSH is increased and NPY and AgRP expression a redundant system to ensure that TH levels remain is decreased. However. Both nucleus input. both POMC/CART and ARP/NPY neurons synapse which in turn project to the paraventricular nucleus of the on hypophysiotropic TRH neurons and are thus hypothalamus (PVH) and stimulate TRH production in poised to regulate TRH synthesis.61-63 The 3 (STAT3). when leptin normal. these results suggest that leptin can directly reach the related peptide (AgRP) and neuropeptide Y (NPY) PVH and regulate TRH without the need for arcuate and are referred to as AgRP/NPY neurons. The first group synthesizes the neuropep. regulatory elements in the TRH promoter the processing of POMC and is a potent anorexigenic can respond to and bind STAT3. NPY-1R direct and indirect pathways.59. In contrast. leptin activates POMC/ thyroid axis emanating from those that respond to CART neurons while inhibiting AgRP/NPY neurons. leptin can signal directly to the PVH via its output directly. Leptin These critical neuropeptides regulate body weight based on their ability to project to second- order neurons.

88 levels are low. a better hypophysiotropic neurons. IL-1β. thus linking action is not required. in models of cachexia induced by LPS. ness. with an increase in reverse T3 (rT3). supporting the concept determined. suggesting that even if D2 is increased Furthermore. the weight loss seen in mouse action of D1 in the liver. This antagonist. It Each of these could play a role in central suppression has recently been shown that T3 enhances the fir. such Elegant studies in humans have demonstrated that illness could be expected to induce the euthyroid sick intensive care unit (ICU) patients who have died sec.82. can be activated by nuclear factor-kappa B (NF-κB). without low T3 levels. a model for nonthyroidal ill- ing.86 ing of AgRP/NPY neurons.84 Similarly. TRH mRNA expres. as would be expected if leptin T3 levels. the and TSH levels.80 Alternatively. and IL-6.89 However. However. the formal role of this pathway in euthyroid sick syndrome needs Regulation of TRH in the Euthyroid Sick to be tested in D2 knockout mice. the human D2 promoter binds to and there would be little T4 available to produce T3. it has become clear that D2 then mediate suppression of TRH expression in the mRNA in tanycytes can also be upregulated by LPS PVH. suggesting again that in fasting-induced suppression of TRH expression. but is greatly influenced by TH levels. is not suppressed. there is often a decrease in T4 and TSH. TRH expression a role for this axis in this disorder. including interleukin 1(IL-1). In humans.90 Moreover. administration to rats. but it is becoming increasingly clear that low TSH secretion in euthyroid sick syndrome that those with central hypothyroidism do worse is secondary to suppression of TRH secretion from than those with just low T3 syndromes. This signaling was playing a role in suppression of TRH is likely secondary to the decreased production and production. axis was not studied in these same experiments. leading to suppression of TRH of changes in glucocorticoids. of the thyroid axis but definitive proof is lacking. raising the possibility remains uncertain because lipopolysaccharide (LPS) that local production of T3 could be altered by fast. TRH mRNA is still transcription factor complex that is activated by LPS actively suppressed during fasting. understanding of the pathways involved could lead to ate suppression of TRH in the PVH is seen in rodent further insights for treating the underlying process. tion. a number expression.19 Although increased local T3 could play a role administration to rodents. consistent with the central origin of this portion of the disorder. Furthermore. Further study of the role of other neuropeptides in patients who have succumbed acutely because of secreted by the arcuate nucleus is required to rule out cardiac factors. a and (2) in TRβ2 knockout mice. TRH levels still fall when systemic TH in the PVH seen in euthyroid sick syndrome. or severe cases.87. it is also clear that and can suppress TRH production.Part I  Normal Thyroid Axis Although most evidence supports the notion glucocorticoid levels increase in inflammatory states that the leptin axis regulates TRH. This suggests that increased T3 could be deliv. renal failure can be reversed by the use of an MC4-R which is often associated with a higher mortality.26. The exact cause of central hypothyroidism sion in this first group of patients was directly propor.81 D2 activity to cytokine activity. increased local T3 may of cytokines are predicted to play a role in severe ill- act via a separate neuronal population that then proj. can still suppress TRH expression in the absence ered to the PVH. tumor growth. implying that T3 administration and by other cytokines. models of euthyroid sick syndrome. it has been found that leptin levels are euthyroid sick syndrome is heralded by a decrease in high rather than low.83 After this initial phase.85 Certainly. Although static. it is tempting to speculate that the The euthyroid sick syndrome is viewed by most as an leptin axis somehow plays a role in the euthyroid sick adaptive process that allows for a slowing of metabo. However. syndrome. implying that the cachexia is induced by decrease in TSH is likely secondary to a decrease increases in α-MSH action. be predicted to lead to an increase in TRH produc- pressed expression of TRH in the PVH. CONCLUSIONS A number of different hypotheses have been The production of TRH in the PVH (hypophysiotropic proposed to explain the resistance of TRH neurons TRH neurons) is absolutely required for the normal to the initial decrease in T3 levels and then to the function of the thyroid axis. sible for the suppression of TRH mRNA expression mals are fasted.82.92 Although the thyroid in TRH production in TRH neurons in the PVH. which could potentially More recently. present in the euthyroid sick syndrome has not been tional to serum TSH levels. TRH production is not suppression of TRH mRNA production. inappropri. syndrome. increased α-MSH action would ondary to severe disease with low T3 levels have sup. ects to TRH neurons to suppress TRH expression. ness. as well as 76 . Syndrome (Nonthyroidal Illness) Finally.91. their role in vivo D2 is upregulated by fasting. In contrast. Thus. it increased local production of T3 could be respon- is unlikely for two reasons: (1) when hypothyroid ani. in patients with sepsis and low T3 lism during acute or chronic illness.

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9 kb long. but only a 112–amino THYROTROPIN acid protein is derived by purification of beta sub-­ TSH is a member of the endocrine glycoprotein units in human pituitary preparations. Negative feedback through the biologic specificity of the hormone controlling inhibition of TSH and TRH production is effected by receptor-specific binding and hormonal activity. Thyroid hormone synthesis involves the coordinated c­ horionic gonadotropin (CG). is 4. three exons and two introns.2 The gene regulatory cascades that ultimately results in thyroid for the human thyrotropin beta subunit is located on hormone synthesis and the modulation of thyroid chromosome 1. is the main regulator of thyroid hormone biosynthesis and secretion. receptor results in activation of the cyclic adenosine The gene is 9. Chapter Thyroid-Stimulating Hormone 7 and Thyroid-Stimulating Hormone Receptor Stéphanie Gaillard and Fredric E. TSH). pitu-­ synthesized in the anterior lobe of the pituitary and in itary. and it has been speculated that the difference may reflect 81 . 7-1A). Thyrotropin Structure primarily exerts its effects by binding to the thyro-­ The human alpha subunit common to the four glyco-­ tropin receptor (TSH-R) on the basal surface of the protein hormones consists of 92 amino acid residues follicular cells within the thyroid. while gain of function mutations have been implicated in hyperfunctioning thyroid adenomas. toxic ­multinodular goiters. and is comprised of hormone–responsive genes (see Fig. TSH-R blocking antibodies inhibit receptor function resulting in chronic autoimmune hypothyroidism and thyroid atrophy. Structurally.4 kb long and is comprised of four monophosphate (cAMP) and phosphatidylinositol exon regions separated by three introns. and congenital nonautoimmune hyperthyroidism. as in Graves’ disease. follicle-stimulating hormone (FSH). and thyroid. Thyrotropin (TSH) is the main the placenta during pregnancy. result in hyperproduction of thyroid hormone and thyrotoxicosis. n������ Alterations in the regulation of TSH synthesis and mutations in the TSH beta subunit result in ­pathologic conditions.1 The beta subunit carries thalamus (Fig. There is no ­hormone family. Wondisford Key Points n������ Thyrotropin (thyroid-stimulating hormone.3-5 The gene predicts a 118–amino acid coding region. Activation of the encoded by a single gene located on chromosome 6. thyroxine (T4) and triiodothyronine (T3) activity on both the pituitary and hypothalamus. n������ Thyrotropin resistance syndrome is primarily caused by loss-of-function mutations in TSH-R. the hor-­ stimulator of thyroid hormone production and mones are noncovalently linked heterodimers com-­ its secretion is under the control of thyrotropin-­ posed of a common alpha subunit and a beta subunit releasing hormone (TRH) secreted by the hypo-­ unique to each hormone. 7-1B). such as central hypothyroidism. through its interaction with the TSH receptor (TSH-R). which includes luteinizing hor-­ difference in the bioactivity of the two proteins and mone (LH). These hormones are regulation of signals from the hypothalamus. n������ Stimulating autoantibodies to the TSH-R.

beta subunit (blue) wraps around loop 2 of the alpha subunit A. ing hormone receptor structure-function relationships. In the B ribbon model. The Figure 7–1  Thyroid hormone synthesis and regulation. However.) Clinical Text. and Braverman LE. and homology ture on the C-terminal side (Fig.6.” securing the subunit in place.8. Ronin C. The Asn 78). (Adapted from Kondo T. J Clin Invest 97:1250-1256. indicating that other 82 . giving the ties among the other glycoprotein hormones. Williams & Wilkins. from Szkudlinski MW. Lippincott. Herodotou DT. such as transforming growth factor-β2 placing the seat belt region of TSH with the ­corresponding (TGF-β2) and platelet-derived growth factor. Weintraub in turn exhibit negative feedback to inhibit the hypotha-­ BD: ­Thyroid-stimulating hormone and thyroid-stimulat- lamic production of TRH and pituitary production of TSH. Utiger RD: logically inactive thyrotropin caused by a mutation in the Werner and Ingbar’s The Thyroid: A Fundamental and beta subunit gene. A. into a cystine knot motif. Nat Rev Neto G. Asn 52. A loop of the models have confirmed expected structural similari-­ beta subunit wraps over the alpha subunit.) flanked by two beta hairpin loops (L1 and L3) on proteolytic cleavage during purification.9 The appearance of a seat belt holding the alpha subunit alpha subunit contains 10 half-cystine residues. The c19-c105 cystine bond acts as (TRH). T3 & T4 subunit (αL2) and stabilizes the TSH heterodimer. The cystine knot of each subunit is activation of the FSH ­ receptor. α-subunit loop. the alpha subunit is represented by a gray line and the beta subunit is represented by a black line. thyroxine (T4) and triiodothyronine (T3). Asa SL: Pathogenetic Physiol Rev 82:473-502. β-subunit loop. 9th ed. The seat belt region thyroglobulin is where the beta subunit wraps around loop 2 of the alpha iodine. TSH stimulates the follicular agine N-linked oligosaccharides are shown (Asn 23. B.Part I  Normal Thyroid Axis Hypothalamus α-subunit Asn 78 αL1 αL3 α11-20 TRH + βL2 Pituitary − T3/T4 TSH + α88-92 TS HR Thyroid α88-105 Asn 52 α33-38 A α51-52 Gs AC CA αL2 Gq M α40-45 Asn 23 P PK PL DA A c19-c105 C G PK C βL1 β58-65 βL3 IP TP β-subunit 3 TG T3 O T4 A B Follicular cell Figure 7–2  Diagram of the structure of human thyrotropin Colloid (TSH) based on human chorionic gonadotropin crystallogra-­ containing phy and TSH structure-function studies.8 There is evidence that the seat belt region form five intramolecular disulfide linkages that fold can confer glycoprotein hormone specificity. which in place. with a long dimensional structure of human CG (hCG) has been loop (L2) of a double-stranded beta sheet–like struc-­ elucidated by x-ray crystallography. 2002. 2005. αL. stimulating the release of thyrotropin (TSH) from the “buckle. the N-terminal side of the cystine knot. B adapted from Medeiros- mechanisms in thyroid follicular-cell neoplasia. and full activation of.10-12 sequence of CG has resulted in binding of the chi-­ Although there is no significant sequence similarity meric protein to. forming a seat belt. similar experiments replacing the seat of each glycoprotein hormone also fold into a cys-­ belt region of TSH with that of FSH did not result in tine knot motif. B. 1996. Rajan S. Philadelphia. (A adapted thyroid hormones. the CG recep-­ between the subunits. Fremont V. 7-2). The sites of aspar-­ the anterior pituitary gland. et al: A circulating bio- Cancer 6:292-306. structurally the beta subunits tor. 2006.7 The three. βL. Ezzat S. cells to synthesize and secrete thyroid hormones. The hypothalamus secretes thyrotropin-releasing hormone (violet). this is also found in some The generation of chimeric hormone by re- growth factors.

The RNA transcript for cidate residues important for the proper synthesis the beta subunit does not have exon 2.32 The most common mutation alpha-alanine 36 to glutamic acid results in normal appears to be a frameshift mutation that substitutes a interactions with the hTSH beta subunit. Six of ly truncated TSH beta subunits lacking the cystine the mutations are located in the coding region for knot.22 TSH and bioactivity. in translational start site. of another disulfide bond (C31-C85) by substitution of arginine for cysteine at codon 85 (part of the cys-­ Naturally Occurring Thyrotropin Mutations tine knot structural motif) likely results in confor-­ Seven thyrotropin mutations have been identified mational changes. In beta subunit thought to lay across the alpha subunit similar experiments. This cysteine is critical region (alpha-phenylalanine 33 and alpha-arginine 35) for a disulfide linkage in the seat belt region of the are critical for hCG but not hTSH receptor binding.19 N-terminal protein Turkish20 Frameshift and stop at F57Sfs62X Missense mutation amino Not specified21 codon 62 acids 57-61.26. but some TSH was detectable.13 Mutagenesis studies of of the glycine is essential to maintain proper subunit the alpha 33-38 domain have shown that mutation of heterodimerization. decreased subunit stability. loops. results in exon skipping and translation of an out of frame 25aa transcript regions of the hormone are likely important in deter-­ ­ eterodimerization. along with its of functional ­thyrotropin hormone. all among all the glycoprotein ­ hormone beta subunits the mutations are inherited in an autosomal ­recessive and. bioactive heterodimer.16 The CAGY region is conserved no acids with no biologic activity.16 cystine knot region prevents heterodimer formation Missense C85R Disruption of disulfide bond Greek17 C31-C85 Nonsense E12X Truncated 11–amino acid Greek18 N-terminal protein Nonsense Q49X Truncated 48–amino acid Greek. impaired heterodimerization.29 Substitution IVS2 + 5 G → A G → A transition at +5 of Not specified31 donor splice site of intron 2. 7-2). and hormone activity. E12X. receptor binding. but this does not form a dimer which results in diminished beta subunit synthesis and with the hCG beta subunit.22 German. 15-31 ­ Interestingly. Brazilian. It is possible that a mutant pro-­ several families.14 Other mutations in this impaired heterodimerization. no mutations in the gene for the and F57Sfs62X mutations appear to result in severe-­ ­common alpha subunit have been identified.23-25 114 C105 in the seat belt region Belgian. This suggests that conservation h mining receptor specificity.15. or seat belt region.28 Argentinian28.9 Therefore the amino terminal portion levels were typically ­ diminished in patient with this of the alpha subunit is important for heterodimeriza-­ mutation.” the alpha subunit increased receptor binding affinity securing the subunit in place (see Fig. For example. The mutations elu-­ → A) results in exon skipping.8.27 Swiss. Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Table 7–1  Natural Human Thyrotropin Beta Subunit Mutations Type of Mutation Amino Acid Change Resultant Structural Change Population Missense G29R Arginine introduced into the Japanese15. was found to be essential for fashion and most are the result of ­ homozygous 83 .31 Interestingly. whereas the seventh affects sensus region at the donor splicing site (IVS 2 + 5 G the donor splice site of intron 2.17 The Q49X. and that result in central hypothyroidism (Table 7-1). conversion of the beta-glycine 29 to tein may be translated from the first ATG in exon 3. arginine in the CAGY region resulted in undetect-­ but this would result in a nonsense sequence of ami-­ able levels of TSH. leading to a valine for the cysteine 105 residue on the beta subunit.17 Egyptian. mutagenesis of residues 11-20 of with the C19-C105 cystine bond acting as the “buckle. Mutation of the con-­ the beta subunit of TSH. in studies on hCG. with truncation of amino acids 62-118 Frameshift and stop at codon C105Vfs114X Disrupts disulfide bond C19. Disruption tion.

followed by removal of the final glucose residue.) ­ utation. fucose. In the Golgi complex. Cleavage of signal peptides (wavy lines) and glycosylation of asparagine residues occur in the RER. Glycosylation of the truncation and the other encoded for the disrupted alpha and beta subunits occurs cotranslationally seat belt disulfide bond (C105Vfs114X). 84 . Two high-mannose carbohydrate units (Y) are added to the alpha subunit. TSH heterodimers enter a regulated pathway of secretory granules. Excess alpha subunits exist in the RER and also undergo glycosylation. Williams & Wilkins. In the endoplasmic reticulum. and sialic acid. whereas one is added to the beta subunit. like those of intracellular ­degradation and is essential for prop-­ the other glycoprotein hormones. Sulfate (SO4) and/or sialic acid (SA) ­residues are added in the distal Golgi. The alpha subunit of TSH (Fig. 8th ed. oligosaccharides are ­generated by the addition of N-acetylglucosamine. N-galactosamine. are covalently er folding. Oligosaccharides added en bloc generally contain three glucose residues (small circles). galactose. proximal Golgi. 7-3). 7-2). particularly O-glycosylation (solid circle). N-acetylglucosamine. distal Golgi. Philadelphia. secretory vesicles. 2000. and fucose (F in triangle). One example exists of congenital hypo-­ m contains two asparagine N-linked oligosaccharide thyroidism resulting from compound heterozygous sites (N52 and N78) but the beta subunit only con-­ mutation. and excess alpha subunits enter a more constitutive pathway of secretory vesicles. Combination of alpha and beta subunits begins in the RER while subunits still contain high-mannose oligosaccharides. Lippincott. galactose. The carbohydrate chains are formed from combinations of man-­ Carbohydrate Modification of Thyrotropin nose. and secretion linked to carbohydrate chains. (Adapted from Braverman LE. in which one allele encoded for the Q49X tains one (N23) (see Fig. N-acetylgalactosamine.Part I  Normal Thyroid Axis β β β β β α α α α α F β α β SA SA F F F SO4 β β β β Secretory α α α α granules α SO4 SA SO4 α α α α α SO4 SA SO4 α SA Vesicles SO4 α α α α RER PROXIMAL DISTAL GOLGI GOLGI Figure 7–3  Model of thyrotropin (TSH) biosynthesis depicting transit through the rough endoplasmic reticulum (RER). Circles and squares represent alpha and beta subunits of TSH.33 in the ­ endoplasmic reticulum. Utiger RD: Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text. respectively. and granules toward secretion at the membrane of the thyrotroph cell. The cotranslational Synthesis and Secretion of Thyrotropin attachment of oligosaccharides protects against The alpha and beta subunits of TSH. two of which are rapidly removed. heterodimer ­ formation.

In addi-­ Thyrotropin is not secreted as one distinct hormone. in addi-­ phosphate carrier is preassembled in the rough tion to type of carbohydrate structure. The resultant glycoprotein is fur-­ size the importance of post-translational modifica-­ ther processed by glucosidases and ­ mannosidases tions for proper heterodimer formation. In patients with primary hypothy-­ carbohydrate structures terminating in a sulfate or roidism. A ­ dolichol within the protein sequence of the ­subunit. Mature animals secreted a larger lized by the liver as compared with the kidney. and in be at odds with each other.52.45 Liver percentage of thyrotropin with complex oligosac-­ metabolism of TSH is slower than in the kidney. ­bioactivity. and (mannose)9 (N-acetylglucos-­ bohydrate chain of the beta subunit preferentially amine)2.47. and fucose. the hypothyroidism.38 As a result of the multi-­ not been completely elucidated. but its activity is markedly sialic acid content. Location glucose and nine mannose residues. thus charides (multiantennary and complex ­biantennary 85 .35. secreted TSH molecules carbohydrate structure are apparent in different ­contain complex biantennary and triantennary thyroid states. sialylated hormones in vivo displayed higher secreting pituitary adenomas have shown that het-­ bioactivity largely because of a lower rate of meta-­ erogeneous isoforms of thyrotropin are secreted and bolic clearance.54 Studies in patients with TSH- active. transport. sulfate and sialic acid may be incorporated but rather as a group of isohormones with differ-­ onto the terminal oligosaccharides. resistance to thyroid hormone results of in vitro and in vivo studies can appear to (RTH). Sulfated oligosaccharides are recognized were also identified during the ­ development and by N-­acetylgalactosamine (GalNAc) sulfate receptors maturation of the rodent hypothalamus-­pituitary- located in the liver. and secretion of thyrotropin. In addition to their presence in activity. ported through the endoplasmic reticulum to the Golgi apparatus and ­complex oligosaccharides are Alteration of Carbohydrate Structures in Thyroid generated by the addition of N-acetylglucosamine. resulting in physi-­ tion of proper oligosaccharide attachment during ologic microheterogeneity. there is an increase in the proportion of sialic acid cap. tion. At times. Although an enzymati-­ nonthyroidal illness such as chronic uremia and sick cally desialylated hormone was more biologically euthyroid illness.53 These findings likely reflect reduced. oligosaccharides ­containing three clearance and as a consequence. to leave a three-unit core. Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor t­ hyrotropin subunits are glycosylated with high-man-­ the sialylation-to-sulfation ratio determines ­metabolic nose precursors.34. The high-mannose precursors are trans-­ affects metabolic clearance of the hormone versus ferred en bloc onto the asparagine residues of alpha subunit glycosylation.47-49 One Biologic Activity and Metabolic Clearance of Thyrotropin mechanism of regulating sialylation is suggested by The role of oligosaccharides is not limited to the syn-­ the finding that the level of mRNA of sialyltransfer-­ thesis. as well as bioactivity and metabolic processing continues as the glycoprotein is trans-­ ­clearance.51 TRH stimulation also modu-­ hydrate composition.41-43 tightly regulated in response to small variations in More important than their effect on in vitro ­biologic physiologic states.37 Inhibi-­ ent oligosaccharide composition.50. TSH-secreting pituitary adenomas. oligosaccharides also regulate metabolic hypothyroid states.55- metabolic clearance can supersede effects on in vitro 57 Different patterns of carbohydrate structures activity.39. The ases in thyrotropes of the pituitary is increased in biologic activity of TSH is also dependent on carbo-­ hypothyroid mice. Glycosylation of the single­ car-­ (glucose)3. whereas sialylation was the regulation of thyroid hormone production is shown to attenuate the activity of the hormone. modulating circulating have also been identified in patients with central hormone levels and potency in vivo. galactose. Enzymatically deglycosylated lates microheterogeneity by varying sulfate and TSH binds to its receptor.46 These studies empha-­ is any amino acid). The functional effect of translation results in aggregation and intracellular changes in the carbohydrate structure of TSH has degradation of TSH.40 The oligosaccharides located on the ­another ­ element of the classic hypothalamic-pitu-­ alpha subunit were shown to be necessary for full in itary-thyroid negative feedback loop. metabolic clearance.43. whereas glycosylation nascent peptides presenting the sequence aspara-­ of N52 appears to be more important than that of gine-X-serine or asparagine-X-threonine (where X N78 in the alpha subunit. variable carbohydrate structures clearance of the hormone. ensuring that vitro activity of the hormone. Function and Dysfunction N-galactosamine. which decreases in the set-­ ting of levothyroxine replacement therapy. transport. but alterations in step maturation process. influences endoplasmic reticulum with the ­ oligosaccharide.34.36. shifting the proportion metabo-­ thyroid axis. sialylated TSH secreted.35 Post-translational and secretion.43-45 This emphasizes that effects on octreotide treatment alters glycosylation patterns.

The hypotha-­ CBP lamic hormone TRH is the predominant positive reg-­ TSH-β ulator of TSH subunit gene ­ expression. PKA. TRH. on the other hand. nTRE. Philadelphia. shown to activate intracellular signal transduction Lhx2 and Lhx3. the ratio of sialylated ­versus ­sulfated forms transduction pathways and enhances transcription increased during development. Gi. in a TRH-dependent manner microheterogeneity and the relative balance of oli-­ contributes to alpha subunit transcription.65 ­Further binding to TSH-R. One possibility is that TRH stimulation through increased CBP binding of the ­ oligosaccharide composition of TSH influences different DNA-binding transcription factors.65. Therefore. does not TSH surge as compared with the daytime circulating contain any Pit-1 DNA-binding sites. resulting in different downstream studies have shown that TRH-directed stimulation of effects (see later). AC. were two ­members of the LIM family of homeobox genes. normal development and maturation. however. ­thyrotropin-releasing hormone.67 Pit-1–mediated TSH beta subunit transcription is enhanced through interactions with the cAMP response element-binding (CREB) protein structures) than prenatal or perinatal animals. of other transcription factors. are implicated in the ­activity than biantennary variants. CREB-binding beta subunits is not identical. This possibility is suggested by the TSH subunits is mediated through a complex array experiments in which pituitary TSH preparations. phospholipase C. protein kinase A. TSH-α a member of the seven-­transmembrane G protein– CREB nTRE coupled receptor superfamily. inhibitory ing transcription.61-65 The transcriptional Figure 7–4  Overview of regulation of thyrotropin (TSH) response to TRH stimulation by the TSH alpha and ­subunit gene expression (see text for details). essential for the increase in transcription of the TSH (Adapted from Braverman LE. including GATA-2 and fractionated to isolate glycosylation variants. adenylyl ­ cyclase. thyroid hormone deficiency and central hypothyroidism. The TSH 1was noted in normal patients ­during the nocturnal alpha subunit promoter. suggesting that different protein. gosaccharide composition result in the generation of the transcription of TSH subunit genes is enhanced by different downstream signals. a protein that integrates a number of signal addition. In (CBP). TRH acts through its receptor. AVP. In ­ addition Pit-1 nTRE to the regulation of post-translational modifications described earlier. transcription. but instead con-­ TSH in the same subject. Gs.58 Higher sialylation by recruiting transcriptional coactivators. arginine vasopressin. changes in the dis-­ tains two cAMP response elements (CREs) that bind tribution of TSH isoforms occur as a result of diur-­ CREB. a syndrome associated with abnor-­ On the other hand. 9th ed. Gs AV Gi Regulation of Thyrotropin Subunit Gene Gq ­Expression PLC PKA PKC Physiologic stimuli regulate TSH subunit gene expres-­ sion through the coordinated control of ­positive and negative regulatory pathways (Fig. TR. cyclic adenosine monophosphate response pathways downstream of TRH are involved in activat-­ element-­binding protein. CBP.68-70 pathways selectively.) gene promoter. high-­mannose Pit-1 and Lhx3 are two of several transcrip-­ variants were more potent stimulators of cAMP tion factors that. TRH stimulation results in phosphorylation of nal variations. Utiger RD: Werner and beta subunit in response to TRH stimulation through ­Ingbar’s The Thyroid: A Fundamental and Clinical Text. TRH binding results T3 in the activation of both the inositol phospholipid- calcium-protein kinase C and cAMP-protein kinase A transduction pathways.59 Thus. 7-4). P-Lim (Lhx3). but stimulated ino-­ development of combined pituitary hormone defi-­ sitol phosphate (IP) production to a similar  degree. stimulatory gua-­ tion factor that is implicated in pituitary development nine nucleotide-binding protein. with no effect on the cAMP cascade. CREB. is hormone receptor. PLC. when mutated.66 Pit-1. DA. Lippincott. and enhanced gene and pathologic states. TRH-R. CREB. ciency (CPHD).60 Specifi­cally. PKC. when mutated. enhanced CBP binding. dopamine. results in combined pituitary protein kinase C. Williams & Wilkins. a pituitary-specific transcrip-­ ­guanine–nucleotide-­binding protein. only fucosylated  variants could mal hypothalamic-pituitary development that causes 86 . CBP binding to another transcription It is not yet clear.Part I  Normal Thyroid Axis s­ timulate IP production but unfucosy­lated forms did AVP DA TRH not. and. negative thyroid hormone response element. three Pit-1 DNA-binding sites in the TSH beta subunit 2005. whether or how factor.

The TR beta gene generates two isoforms priately normal levels of TSH and do not respond to through differential promoter usage. thyroid-stimulating hormone. particularly in the hypothalamus.89 ative regulator of TSH subunit gene expression TR-mediated inhibition of the hypothalamic- through regulation of TSH at the level of the pitu-­ ­pituitary-thyroid axis is dependent on the DNA- itary and indirectly by reducing TRH production. resulting in central hypothyroid-­ mRNA in the brain.71 A common mutation of Pit-1 (R271W) beta.78 Negative regulation of TSH hyperplastic thyroid gland caused by inappropriate ­subunit and TRH genes requires binding of the neg-­ secretion of TSH from the anterior pituitary. this study also showed that TRH is abso-­ lation. Thra and Thrb. occurs in the POU homeodomain of the Pit-1 pro-­ TR alpha 1 and alpha 2 (also designated c-erbAa-2). because it lutely required for TSH upregulation in the setting appears to be the only isoform responsible for the of hypothyroidism.84 Knock-­ that the TRH-mediated regulation of TSH glycosyl-­ out experiments in mice in which one or more of ation is an important contributor to TSH activity. DBD region LBD TRs consist of a DNA-binding domain that allows for *Alternative TRα1 Thra binding to specific DNA elements (TREs in the case splice site TRα2 * of TRs) and a ligand-binding domain that determines ligand-­binding specificity. TR alpha 1 mRNA is gene for TRH express slightly higher than normal more highly expressed in skeletal muscle and brown levels of TSH. The alternative ­splicing mutation leads to the production of a mutant Pit-1 of the C terminus of alpha 2 disrupts the ­ ligand- that binds DNA but does not transactivate properly. resulting in TRH stimulation. auditory system. The ative ­regulatory units in the subunit gene ­promoters thyroid hormone responsive regions of the TRH by the thyroid hormone receptor (TR). Two separate gene loci. DBD.82 Like other nuclear hormone receptors. the TR isoforms were deleted have shown that the More recent studies have suggested that although TR beta isoforms are the most potent regulators of TRH is not absolutely required for TSH synthesis.91 These mice displayed thesis and a more than 95% decrease in TSH beta elevated serum levels of thyroid hormones and a subunit mRNA. prolactin. 7-5). liver. binding domain and generates a non–T3-binding Patients develop hypothyroidism but have inappro-­ isoform. but the TSH expressed shows reduced fat. Once T3 binds to the dimerized TR. a region responsible for DNA binding. transcription. Histone deacetylation results in DNA-binding domain. each with a different amino in TRH-mediated transcription of TSH beta. emphasizing the importance of Pit-1 two beta receptors.73 Similarly. The TR isoforms are variably expressed Interestingly. some patients with TRH-R mutations almost exclusively expressed in the hypothalamus. nuclear corepressors are released and coactivators are recruited that enhance transcriptional ­activity. The TR alpha gene generates two isoforms. a mem-­ and TSH subunits have been localized to the proxi-­ ber of the nuclear hormone receptor superfamily mal promoter regions.81 TR alpha 1 and TR beta 1 transcription of TSH. TR beta 2 is ism. and kidney. deficiency of growth hormone.88 Although TRH and thyroid hormone signaling pathways in TR beta 2 also appears to be the most important hypothyroidism. Thra. the respectively.77-80 binding activity of the receptor.83.92. terminus.76 dominant mediator of the negative feedback regu-­ However. suggesting crosstalk between the negative regulation of the TRH gene. as shown in mice Thyroid hormone administration to mice results in with a knock-in mutation in the DNA binding a 75% decrease in TSH alpha subunit mRNA syn-­ domain of TR beta. a class of proteins that either have ***Mutation hot spots implicated histone deacetylase activity or recruit proteins that in resistance to thyroid hormone syndrome Figure 7–5  Schematic of thyroid hormone receptors. genes encoding for thyroid receptor α (TRα) and TRβ. and/or encode for the TRs.75 This suggests pituitary. Thrb In the absence of hormone. Thyroid hormone is the predominant neg-­ TR alpha 1 and TR beta 1 can also play a role.85-87 TR beta 2 is the TRH deficiency results in decreased bioactivity.74.77. have this activity. also have central hypothyroidism.72 This through alternative splicing.93 87 . TRH is not required for the in mammalian tissues. increased chromatin packing and decreased gene Thrb.81. whereas there is higher expression of TR beta 1 ­biologic activity. ligand-binding domain. designated as TR alpha and TR thyrotropin.90. Knockout mice that lack the are expressed in most tissues. isoform for negative feedback in the pituitary. Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Hinge (Fig. tein. TRs bind constitutively promoter use TRβ2 *** *** *** to corepressors. TRs can homodimerize or Alternative TRβ1 *** *** *** ­heterodimerize with the retinoid X receptor (RXR). and retina. LBD.

104-106 Administration of a single ­therapeutic and (3) impaired deiodinase activity as a result of dose of a dopamine antagonist.107 The physiologic role of nium incorporation and production of functional dopamine regulation of TSH has not yet been eluci-­ enzyme. vasopressin.111 However. monocarboxylate transporter 8 (MCT8). resulting in dominant negative by a Chinese hamster ovary (CHO) cell line stably inhibition.110.97 A similar effect was shown in a patient THYROTROPIN RECEPTOR with Cushing’s syndrome secondary to an adrenal The thyrotropin receptor (TSH-R) is a member of ­adenoma. secretion.101 to no evidence of thyrotoxicosis. Therefore. a beta1 agonist structurally similar to dopa-­ cells caused by mutation of a thyroid hormone trans-­ mine. it is composed of oligosaccharide chains terminating sialic Regulation of Thyroid-Stimulating Hormone acid in a pattern that is more similar to the sialylated Secretion by Other Circulating Hormones TSH that circulates in patients with primary hypothy-­ Thyrotropin secretion has been shown to be regu-­ roidism. mutation in SECISBP2. TSH and free T4 suppression was reversed the glycoprotein hormone receptor family.100 There was no effect on ­tissues to thyroid hormone. 7-5).95 Mutations in TR beta are responsible for dated. one within the hinge region and two within the ligand-binding domain (see Fig.102. Mutant The molecular cloning of the TSH subunits and an receptors retain the ability to dimerize and bind improved understanding of the importance of glyco-­ DNA-binding elements but have a reduced binding sylation in TSH activity have allowed for large-scale affinity for T3. the rhTSH is metabolically cleared lated by other hormones. The mutations cluster into three distinct hot Hormone spots. Although their importance as regulatory maximum stimulatory effect of rhTSH is similar to that hormones is likely less than that of TRH and thyroid of pituitary TSH in in vitro bio.98 larger superfamily of G protein–coupled ­ receptors 88 . and GalNAc-­sulfotransferase necessary to add the ­GalNAc and a terminal sulfate to TSH. androgens. including glucocorticoids. part of the after surgical removal of the tumor. more slowly and is slightly less potent compared with estrogens.and immunoassays. well as an increase in pituitary TR. rhTSH has become an alternative to conditions or during exogenous hormone or drug withdrawal of thyroid hormone for use in the detec-­ administration. Mutant TR beta inhibits the func-­ ­production of the hormone. the dopamine. the TR beta gene have been associated with this syn-­ Recombinant Human Thyroid-Stimulating drome. increased suppression hormone (both T3 and T4). such as radioablation in nodular goiter. somatostatin. were shown to enhance thy-­ as one cause of RTH syndrome. possibly as a result in the thyroid hormone signaling pathway: (1) of stimulation of dopamine receptors present on the impaired binding of T3 to TR beta secondary to muta-­ surface of anterior pituitary cells. they may play a role in some pathologic Because of this. however.112 hormone. with ­inappropriately nor-­ occurred in hypothyroid animals treated with T3. Studies in which subjects received tion of recurrence or metastases in well-differentiated exogenous dexamethasone or cortisol showed sup-­ thyroid carcinoma and is being evaluated for other pression of TSH secretion and lower circulating uses.113 free T3 levels as a result of glucocorticoid adminis-­ tration.94. (2) defective transport of the receptor into mine. As a result. estradiol and Mutations in the TR beta gene have been ­implicated dihydrotestosterone.96. have also been shown to decrease thyrotropin porter. This phenomenon explains the autoso-­ transfected with cDNAs for the alpha and beta sub-­ mal dominant pattern of inheritance seen in all but units. as mal or even slightly elevated levels of thyrotropin.108-110 Recombinant tion of TR alpha and nonmutant TR beta through human TSH (rhTSH) is produced for clinical use heterodimerization.95 The syndrome is basal TSH concentrations and no effect was seen in characterized by elevated levels of circulating thyroid euthyroid animals. metoclopramide. a rare syndrome in roid hormone suppression of TSH mRNA produc-­ which there is decreased responsiveness of target tion in hypothyroid rats. CHO cells do not express the pituitary-specific one family in which RTH was caused by TR beta gene N-­acetylgalactosamine transferase (GalNAc-transferase) defects. a protein involved in sele-­ enhanced TSH secretion.Part I  Normal Thyroid Axis Resistance to Thyroid Hormone Syndromes Two other steroid hormones. but these studies reflect the many factors that most cases of RTH syndrome and 122 mutations in affect circulating TSH levels. suggesting that Patients typically exhibit evidence of goiter. with mild the sex hormones may influence TR synthesis. and pituitary TSH from euthyroid patients. RTH has clinically The neurotransmitter dopamine rapidly been shown to be caused by three molecular defects decreases TSH subunit secretion.99.103 Dopamine tions within the TR beta hinge and ligand-binding agonists (l-dopa and bromocriptine) and dobuta-­ domain.

(Adapted from Szkudlinski MW.120 The thyrotropin receptor is primarily expressed on the basolateral surface of thyroid follicu-­ lar cells. regulate the expression of its cognate receptor. and in the ophthalmopathic ­manifestations of Graves’ dis-­ ease. Studies of the TSH-R promoter have determined that it is primarily activated by thyroid transcription factor 1 (TTF-1). 2002. neurons. how-­ ture-function relationships. a 397–­amino ilar nature of their signaling pathways. bone. extracellular domain. activation of the downstream signaling cascades. and has led to the hypothesis that the glycoprotein hormone receptors evolved through the incorpora-­ tion of an extracellular domain. and astrocytes.136 LRRs 89 . ­Physiol Rev 82:473-502. whereas the remainder of approximately half of the receptor and is composed the last exon encodes for the entire transmembrane of two cysteine clusters flanking a central portion and cytoplasmic domains. leukocytes. Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor LRR many genes for GPCRs that do not contain introns. Weintraub BD: Thyroid-stimulating manner.119 This is consistent with made of nine leucine-rich repeats (LRRs). insulin through an insulin-responsive element. dic-­ Extracellular Ectodomain (A or Alpha Subunit) tating the activity of the receptor.135 Exchang-­ acid ectodomain.132 Thus. reflecting the acid signal peptide that is cleaved prior to incorpora-­ specificity of each receptor while maintaining the sim-­ tion into the extracellular membrane. consisting of a 21–amino is significantly lower (35% to 45%).115-118 The gene hormone binding specificity but does not impair is more than 60 kb long and is divided into 10 exons.129. The amino terminal ecto­ domain confers ligand-binding specificity to the Structure of Thyrotropin Receptor receptor. which then down-­ ECD.131 Contrary to this. There is significant homology of the transmembrane The gene encoding human TSH-R has been domains among the glycoprotein receptors (approxi-­ localized to chromosome 14q31114 and encodes for mately 70%).128. conferring greater ligand specificity to a traditional GPCR. TMD. increase expression of TR alpha 1. but homology among the ectodomains a 764–amino acid protein. However. although there appears to be evidence for a role in bone ­remodeling. skin. TSH can positively and negatively hormone and thyroid-stimulating hormone receptor struc.131. leucine-rich repeats. The promoter for the (GPCRs). in cooperation with CREB. and a 346–amino acid transmem-­ ing the ectodomains of the receptors changes the brane domain and cytoplasmic arm. the major effect of TSH appears to be downreg-­ ulation of TSH-R expression. orbital ECD connective tissue.134. regulates TSH-R promoter activity in a T3-dependent Fremont V. a seven. and (2) TSH can receptor in complex with thyroid-stimulating ­hormone (TSH). TSH-R mRNA transcripts and/or protein have been identified in adipocytes.130 The ability of TTF-1 to activate TSH-R transcription is enhanced when it is phos-­ phorylated as a result of TSH activation of the pro-­ TMD tein kinase A (PKA) cascade. in the dermatologic manifestations of thyroid disorders.) ever. and the transmembrane and cytoplasmic portions of the receptor interact with G proteins. LRR.121-127 The role of TSH-R in ­nonthyroid tis-­ sue has not yet been clarified. The The ectodomain is encoded by the first nine exons large extracellular domain of the TSHR accounts for and part of the last exon. TSH has also been shown to regulate TSH-R ­ expression negatively through at least two mechanisms: (1) TSH results in decreased TTF-1 mRNA production and in Figure 7–6  Schematic representation of thyrotropin (TSH) turn decreased TSHR expression. transmembrane domain. but it transmembrane serpentine portion with many of the is not known which transcription factors are involved features typical of GPCRs. 7-6). a transcription factor responsible for thyroid-specific gene expression.133 cytoplasmic arm (Fig. and a short C-terminal in mediating this process. Ronin C. The glycoprotein hormone receptors TSH-R in rats also appears to be positively regulated by consist of a large extracellular ectodomain.

to form a beta sheet followed by an alpha helix. sulfation of a tyrosine residue (Y385) is essential for also resulted in reduced inositol phosphate signaling TSH binding and activation of the receptor. the cAMP cascade con-­ does not play a significant role in hormone recogni-­ trols proliferation and differentiation of thyroid cells. The activation of the phospholipase C pathway requires ectodomain alone is sufficient to interact with TSH higher concentrations of thyrotropin.Part I  Normal Thyroid Axis TSH α β A B C Figure 7–7  Model for thyroid-stimulating hormone receptor (TSH-R) activation. FEBS Lett 409:469-474. although cave surface of the ectodomain (see Fig. suggests that the LRRs together form a lation of adenylyl cyclase and phospholipase C cas-­ ­horseshoe-like structure and that TSH binds the con-­ cades by interacting with Gs and Gq/11.145 The two with a similar affinity as the whole receptor. the third extracellular loop (TSH-R L653V). 7-7). ­ another LRR-containing Ligand-bound TSH-R results in the stimu-­ ­protein. TSH-R Y601H was no longer constitu-­ of LRR5 and X7 of LRR7) confer hormone-­binding tively active. this may hydrophobic transmembrane domains and an intra-­ allow for the development of TSH analogues that cellular tail.148 Glycosylation and the addition of in increased constitutive activity. resulting carbohydrates. inhibiting the of a highly conserved consensus sequence that folds constitutive activity of the receptor.141 Similar to thyrotropin. A mutation of a distinct region of the B activity and specificity to the ectodomain.146 domain. Almost 40% of the that abrogate an inhibitory interaction between the mass of the extracellular domain is made of complex extracellular and transmembrane domains. Studies of studies to be responsible for hormone specificity. Importantly.141-143 of ribonuclease inhibitor. In this model. transport. In this model.138 The inner surface of the horseshoe.139 two mutations in the receptor.144. it is hypothesized that the TSH-R exists in two forms. three free has resulted in the inability of TSH to activate the acidic residues were shown to be important in the for-­ phospholipase C–inositol phosphate signaling cas-­ mation of an acidic groove in the center of the LRR cade. one in a family with Exchanging residues found on the inner surface of resistance to TSH (see later) have shown that the the receptor for those found on the inner surface two pathways are dissociable. Mod-­ TSH binding leads to stabilization of the full agonist eling of the TSH-R based on the crystal ­ structure conformation of the receptor (Fig. formed whereas the inositol phosphate pathway regulates by the beta sheets.) are found in a variety of proteins and are composed ectodomain acts as an inverse agonist. cellular domain is removed have revealed that the transmembrane domain exhibits constitutive activity Post-translational Modifications and does not require ligand binding for activation. Parma J.149 Although all 90 . These three residues (positions X3 and X5 In addition. post-translational modifica-­ Spontaneous activating mutations within the extra-­ tions are important in the synthesis. Mutation of a tyrosine of the LH receptor has resulted in a receptor with (TSH-R Y601H) in the fifth transmembrane domain increased sensitivity to LH. whereas the open form in the absence of ligand (B) results in ­constitutive activation of the receptor. and cellular domain of the receptor have been identified proper functioning of the TSH-R. 1997. has been shown by mutagenesis iodination and thyroid hormone synthesis. In addition. In particular.137. but adenylyl cyclase was only mildly reduced.140 and reduced thyroid hormone synthesis. specifically. et al: Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain. Experiments in which most of the extra-­ preferentially activate a desired pathway. Costagliola S.142 These data have complex carbohydrates can occur on six asparagine led to the hypothesis that in the unliganded state the residues of the extracellular domain. subunit. the inactive or closed form (A) or the active or open form (B). (Adapted from Duprez L. indicat-­ pathways are thought to regulate different down-­ ing that the transmembrane portion of the receptor stream pathways. 7-6). tion.147 These studies have indicated that the TSH-R may have sev-­ Transmembrane Serpentine Domain (B or Beta Subunit) eral active conformations that allow for ­ differential The B subunit of the receptor consists of seven affinity to couple to Gs or Gq. Binding of TSH to the receptor ­results in stabilization of the active conformation (C).

157-159 The physiologic significance of the to one monomer of a pair of TSH-Rs leads to amplifi-­ two forms has yet to be defined. two.167. but each appears to cation of the signaling pathway is not yet known.169 In the latter. There appear to be two intra-­ complexes on the surface of thyroid cells.163 After cleavage. one is unable to bind TSH and the other tors on the surface of thyroid cells: cleaved. they were able to restore been widely debated. More than 50 different naturally occur-­ with earlier studies which suggested that cleavage does ring mutations have been indentified in the TSH-R not depend on a specific amino acid motif but rather (Fig. When the two were proportions of cleaved and uncleaved receptors has present together in the cells. promoting the other glycoprotein receptors. enhances cleavage of the receptor. fide isomerase.168 The transmembrane domain from cells or media expressing TSH-R. The human TSH-R con-­ in the inactivated state and that TSH induces disso-­ tains 11 cysteine residues. Although the ectodo-­ that the resultant fragment is removed through main is not required. interact with TSH with similar affinity and is activated to the same degree. resulting in the removal of a that also occurs in other GPCRs.152 processes. receptor. are relatively rare. it may enhance complex forma-­ sequential cleavage.150 ally two to three times more B subunits than A subunits Compared with the LH and FSH receptors. it was found that there is ing that a disulfide bond at this position is a critical crosstalk between the monomers of the dimer. 8 of which are conserved in ciation of the receptors to monomers.157. It has been shown that there is proportion-­ extracellular membrane. a member of the disintegrin and Several mechanisms of abrogating the appropriate metalloprotease (ADAM) family of metalloproteases function of the TSH-R have been identified. consistent antibodies. This process requires receptor cleavage as well as expression of a fully functional receptor is depen-­ reduction of the disulfide bridges by a protein disul-­ dent on the glycosylation of at least four of the sites.169 There are conflicting results on the functional by disulfide bonds formed between the C-terminal significance of TSH-R oligomerization. termed been identified to the LH-CG receptor and only rarely ectodomain shedding. no TSH-R C peptide has ever been ­isolated tion. suggest-­ active states. C-terminal portion of the ectodomain. Recent stud-­ region of the ectodomain and N-terminal portion of ies have suggested that the TSH-R exists in oligomers the transmembrane domains. 7-8). These specifically expressed in the thyroid. consistent with several reports showing that TSH the molecular mechanisms regulating TSH-R action.161. other reports have suggested tion 41 has been identified as required for proper that TSH-Rs are present as dimers in the inactive and folding and multimerization of the receptor. a process unique to the TSH-R among the TSH-R has been shown to form multimeric glycoprotein receptors.154 Cysteine in posi-­ activation. particularly activating fixed distance from a protease attachment site. naturally occurring autoantibodies have not a large portion of receptors lose the A subunit. leaving behind the B subunit. a process molecular cleavage sites.165 This suggests the TSH-R contains an additional 50 residues in the that the A subunits may be lost into the bloodstream. including protein trafficking.172 These mutations activity of ADAM10 was increased in the presence of have provided a unique opportunity to understand TSH. in which the protein is cleaved at a naturally occurring mutations. impaired intracellular trafficking. on the surface of human thyroid cells.151. Cells post-translational step in protein synthesis. internaliza-­ However.162 The mutations.171. was shown to include loss-of-function and gain-of-function muta-­ cleave the ectodomain.164 The shed A subunit is considered Inhibition of glycosylation has resulted in improper to be the antigenic stimulus for the formation of the protein folding. ADAM10. and signaling. the segment termed the C peptide (analogous to the C pep-­ formation of complexes is thought to regulate several tide produced in the processing of proinsulin). In other glycoprotein hormone receptors. antithyrotropin receptor antibodies in Graves’ disease and reduced incorporation of the receptor into the (see later).161 The sequence recognized tions and thyroid-stimulating and thyroid-blocking by ADAM10 is not the active proteolytic site.153 The two subunits are bound tion. and it is likely is sufficient for oligomerization. with reports variously stating that the TSH signaling pathway.156.155 were transfected with two different loss-of-function There appear to be two populations of recep-­ mutants.166 In GPCRs. This region where they may become the stimulus for autoimmune is cleaved in the post-translational processing of the thyroid diseases.160 A protease involved in Thyroid Diseases Related to Inappropriate the proteolytic cleavage of the receptor was recently Function of the Thyrotropin Receptor identified. Similarly. a molecular ruler. to the FSH receptor. Whether TSH binding major form.­subunit can bind the hormone but cannot activate G protein receptors and uncleaved holoreceptors. in which they are thought to 91 . suggesting that they were the cleaved form of the receptor is either the minor or functionally acting as a dimer. Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor six appear to be glycosylated in wild-type receptors.170 However.156 The relative signaling in response to binding.

Loss- of-function mutations are widely distributed throughout the extracellular and intracellular domains. low to normal 92 . Thus. Persani L. 2006.Part I  Normal Thyroid Axis C41S NH2 R109Q Intron 5 Intron 6 G to A+1 P162A G to C+3 I167N Dell57-182 C310R S281N L252P Q324X C390W Loss of function T477I T486F/M deletion 406-412 A647V N650Y V473I 1568 D410N Activating L467P G498S A593V T655∆ deletion 613-621 A553T F666L M453T W546X V597L N670S/Y C600R C672Y R450H S505N/R L677V V509A Y601L R519C/G F525L R609X D619G Activating deletion 613-621 A623I/V/S L629F I630L COOH F631L/C T632I/A/P D633E/Y/H/A P639S Figure 7–8  Schematic of naturally occurring thyroid-stimulating hormone receptor (TSH-R) mutations. Blue triangles identify loss-of-function exonic point mutations. Calebiro D. Positions of activating and loss-of-function deletions are also indicated by arrows. red triangles identify gain-of-function mutations. which can range from partial to complete resis-­ binding. Best Pract Res Clin Endocrinol Metab 20:529-546. whereas gain- of-function mutations are concentrated in the intracellular domain with the exception of S281N. targeting seems to be a relatively unique feature. impairing inheritance pattern). impaired TSH binding. and ­subsequently the phenotype of the disorder. identified. including improper ­ synthesis.95 More than 30 different mutations have been tance.173.) cause premature ovarian failure. (Adapted from Beck-Peccoz P. and defective signaling through loss of appropriate crosstalk with Resistance to Thyrotropin downstream G proteins. The mutations result in a variety of recep-­ antigenic stimulation of the thyrotropin receptor tor defects. 7-8). the level of receptor impair-­ the ability of the receptor to signal in response to TSH ment. of the receptor. they reside both within the ­ extracellular ranging from mild to ­profound ­hypothyroidism. et al: Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis. and vertical bars ­illustrate intronic loss-of-function mutations. the ­common Fig.174 domain and the transmembrane domain and do not Patients with thyrotropin resistance gener-­ appear to concentrate in any particular location (see ally exhibit elevated TSH levels. The type of mutation dictates Thyrotropin resistance syndrome is primarily caused the mode of transmission (recessive versus dominant by loss-of-function mutations in the TSH-R.

Recently. whereas only one activating mutation was TSHR inappropriately. in patients with by Chorionic Gonadotropin partial resistance. condition is often recognized early in life because of the growth and ­developmental delays associated with Activation of the Thyroid-Stimulating Hormone Receptor congenital hypothyroidism. although the receptor. protein signaling pathways (Gs from Gq/11). partic-­ ularly in the second extracellular loop.183 A subunit was the antigenic stimulus for autoanti-­ The D727E polymorphism has been associated with body formation in Graves’ disease patients.187 Therefore.191 This supported the hypothesis that the free in the intracellular tail of the receptor (D727E). but neity among the antibody-binding sites and sites in whether the mutations result in malignant transfor-­ the C-terminal region have been identified.186. resulting in activation of the receptor roidism. the relationship between activating muta-­ domains are shed as a result of normal processing of tions and thyroid carcinoma is unproven. including thyroglobulin and thyroid per-­ important in maintaining the receptor in an inactive oxidase. Further increased cAMP activity in response to TSH stimu-­ support for this hypothesis stems from studies that lation and has been implicated in the pathogenesis have shown that the epitope for the thyroid-stimulat-­ of toxic multinodular goiter.185 located in the N-terminal region of the extracellular Whether polymorphisms contribute to thyroid dis-­ domain and compete with TSH for binding to the ease is still unclear. the mutant receptor is more goiters. However.184 However. result-­ In high hCG states.188 However. two in ism was more efficiently induced by the free subunit the extracellular domain (D36H and P52T) and one alone. Activating mutations have also extracellular domain. another ing antibodies is partially hidden in the holoreceptor study in 128 European patients failed to find an asso-­ but the epitope is exposed in the free A subunit. When mice were immu-­ Asn674 in the seventh transmembrane segment.175.181 The and inducing increased thyroid hormone secretion third intracellular loop lies adjacent to the sixth trans-­ and thyroid proliferation. autoantibodies directly bind Fig. the toxic adenomas. and or may be found incidentally. pro-­ Gain-of-Function Somatic Mutations longed expression of elevated hCG levels associated Constitutive activation of the TSH-R or the Gs sec-­ with molar pregnancy. Polymorphisms have a holoreceptor unable to be cleaved. at Although it is thought that TSH-R extracellular this time. and a normal to hypoplas-­ transformation to malignancy rarely occurs in thyro-­ tic thyroid gland. thought to be a normal physiologic process of pregnancy.192 ciation between differences in codon 727 polymor-­ Most epitopes for thyroid-stimulating hormones are phisms and toxic nonautoimmune thyroid disease. it may not be ­identified until later The structural homology between TSH and hCG. such as during a brief ­ period of ing in partial TSH resistance and isolated defects in the first trimester of pregnancy. a condition in which women for binding to TSH have been implicated in hyper-­ have recurrent thyrotoxic symptoms during pregnan-­ functioning thyroid adenomas.180 To date.193-195 mation has yet to be determined.190 Although Graves’ dis-­ membrane segment and the clustering of activating ease patients have antibodies against several thyroid mutations in these regions suggests that they are antigens. A TSH-R mutation in the extracellular Gain-of-function mutations of the TSH-R that consti-­ domain (K183R) has been associated with familial ges-­ tutively activate the receptor and abrogate the need tational hyperthyroidism. it is the antibodies against TSH-R that are conformation. but there is some heteroge-­ been identified in differentiated thyroid cancer. hyperthyroid-­ also been detected within the TSH-R gene. thyroid-stimulating antibodies are not 93 . activating adenylyl cyclase found in the extracellular loop (Ser281Asn). and hCG- ondary messenger leads to constitutive activation of secreting tumors results in thyrotoxicity. choriocarcinoma.189 In these patients. third intracel-­ Thyrotropin Receptor–Stimulating Antibodies lular loop. toxic multinodular cy. and congenital nonautoimmune hyperthy-­ sensitive to hCG. In profound TSH resistance. 7-8). nancy or tumor. allows for the binding of hCG shown that some ­mutations can dissociate the two G to the TSH-R when present in high concentrations. it has been between their receptors. There is a direct interaction between most critical in causing hyperproduction of thyroid Asp633 in the sixth transmembrane segment and hormone and thyrotoxicosis.147 miscuous activation of TSH-R. the mutations are primarily and hyperthyroidism despite normal hCG levels. concentrated in the transmembrane domain. The thyrotoxic adenylyl cyclase and has the potential to drive the symptoms resolve after surgical removal of the preg-­ formation of hyperfunctioning thyroid adenomas. this results in the pro-­ one arm of the TSH signaling axis.182 nized with either an adenovirus expressing the extra-­ Mutations of either of these residues results in inap-­ cellular domain alone or an adenovirus expressing propriate constitutive activity. and sixth transmembrane segment (see In Graves’ disease. Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor levels of thyroid hormone.

 Takata K. 1997. Annu Rev Biochem the beta-subunit. Gene 73:489-497.   12. 2002. all likely con-­   10.    7. Hiraoka Y. roidism. Watanabe S. Hayashizaki Y. there must be other    8. 1989. 2001.   17. Vuissoz JM. Szkudlinski MW. Therefore. 1981.197 superfamily.Part I  Normal Thyroid Axis universally present.or hypothyroidism. 1988. Commun 165:1035-1042. in some patients. et al: Hyper-­ Genet 43:462-470. 1996. et al: New BD: Thyroid-stimulating hormone and thyroid. Wong R. 1990. et al: Familial hypothyroidism caused by a non-­ gene. Sun PD. Fiddes JC. Hiraoka Y. 1988. to become an antigen-presenting cell. ing antibodies have also been identified in patients   14. Bonomi M. 94 . J Mol Biol 231:445-458. J Clin Endocrinol Metab 71:792-796. progression to Graves’ disease. et al: Crys-­ factors that contribute to antibody formation and the tal structure of human chorionic gonadotropin. Winkler FK. the epitope for the block-­ corresponding regions of choriogonadotropin or ing antibodies is primarily located on the C-terminal follitropin confers luteotropic but not follitropic activity to chimeric TSH. Differences in gene gene in one sporadic case C85R and of mutation structure and promoter function from murine Q49stop in two siblings with congenital hypothy-­ species. Site-directed mutagenesis of amino acids 33- of the antibodies determine whether the patient 44 of the common alpha-subunit reveals different experiences hyper. Mouse studies have ­Nature 369:455-461. et al: Thyroid- References stimulating hormone TSH deficiency caused by a    1. Am J Hum   19. et al: agents in some cases of Hashimoto’s thyroiditis Substitution of the seat-belt region of the thyroid- and idiopathic myxedema. Stanger BZ. Drakopoulou structure of the human thyrotropin beta subunit M. Pediatr Res 52:935-941. Littlejohn A. J Mol Appl Genet 1:3-18.199 at 1.198. EMBO J 8:2291-2296. Buyukgebiz A. Dracopoli NC. Weber G. et al: The role of hormone alpha-subunit. et al: The   18. shown that aberrant MHC class I and class II expres-­    9. Szkudlinski MW. Deladoey J. in whom relative concentrations D. 50:465-495. et al: with Graves’ disease. Sertedaki A. Weintraub   20. glycoprotein hormones. 1988. Grutter MG: Refined crystal struc-­ and resulting in chronic autoimmune hypothyroid-­ ture of human transforming growth factor beta 2 ism and. Ito CY. Biochem Biophys Res thyroidism due to mutations of the TSH beta gene. et al: Engi-­ neering human glycoprotein hormone superactive sion.201 production and growth promotion are potentially dissociable functions of human thyrotropin. Mol Endocrinol 10:769-779. J Clin Endocrinol Metab 86:4468-4471. Hirono M. 1989. short arm of human chromosome I. Schlunegger MP. thyroid atrophy. Endo. Papadimitriou A.200 TSH-R block-­ 15540. autosomal recessive mutation of the TSH-beta sub-­ stimulating hormone receptor structure-function unit gene causing central isolated hypothyroidism. Dacou-Voutetakis C. Thyrotropin Receptor–Blocking Antibodies   11. Moates JM. EMBO J 11:3921-3926. relationships. Te NG. Physiol Rev 82:473-502.196. linkage map of 27 loci from PND to FY on the 1990. plastic pituitary gland. high serum glycoprotein    6. Hayashizaki Y. 1995.   16. Davies DR: The cystine-knot growth-­factor tribute to the pathogenesis of Graves’ disease. Hiraoka Y. et al: Deoxyri-­    2. Pierce JG. Szkudlinski MW. These antibodies have been identified as the ­causative   13. Proverbio MC.   15. et al: Low TSH congenital hypothyroidism: Identifica-­ I­solation and characterization of the human thy-­ tion of a novel mutation of the TSH beta subunit rotropin beta subunit gene. J Biol Chem 272:15532- portion of the extracellular domain. Am J Hum Genet 46:988-993. along with changes in the thyrocyte allowing it analogues. sense mutation in the thyroid-stimulating hormone    5. Harris DC. and variable circulating the carboxyl-terminal 6 amino acid extension of thyrotropin TSH levels as hallmark of central hypo-­ human TSH beta subunit. Dias JA. Lapthorn AJ. Grossmann M. 2002. 1981.95 A resolution. Parsons TF: Glycoprotein hormones: single base substitution in the CAGYC region of Structure and function. Radovick S. Szkudlinski MW. D’Arcy A. inhibiting the receptor BB.5�-monophosphate fetal hypothyroidism. Voutetakis A. J Clin Endocrinol Metab 86:1600-1604. structural requirements for heterodimer expres-­ blocking TSHR antibodies that develop in patients sion among the glycoprotein hormones and sug-­ with Graves’ disease during pregnancy may cause gests that cyclic adenosine 3�. In contrast to the TSH. Hayashizaki Y. 1996.    4. Fremont V. Nat Biotechnol 14:1257-1263. Similarly. Wondisford FE. 1992. Tatsumi K. 2001. Feltquate DM. et al: A ­genetic beta subunit gene. stimulating hormone TSH beta subunit with the R–stimulating ­antibodies. Tatsumi K. 1993. Grossmann M. Goodman HM: The gene encoding bonucleic acid analyses of five families with familial the common alpha subunit of the four human inherited thyroid stimulating hormone deficiency. 1994. Annu Rev Biophys Biomol Struct 24:269-291. Ronin C. et al:    3. et al: Crystal TSH-R blocking antibodies bind to the receptor and structure of human platelet-derived growth factor prevent activation by TSH. J Biol Chem 263:12538-12542. Oefner C. Grossmann M.

 Sairam MR.   22. J Biol genital central hypothyroidism due to homozygous Chem 263:25-35. 1990. and intracellular degradation. 1995. Joshi L. of the alpha subunit in transduction of biological   29. Biochem Biophys Res Commun a homozygous mutation in the TSH-beta subunit 133:680-687. Baenziger JU: Asparagine-linked gous mutation in the thyrotropin beta subunit ­oligosaccharides on lutropin. Weintraub BD: The role   28. et al: Con-­ residues of alpha. gene. ovine. Wondisford FE. Doeker BM. 1985. Boime I: Elimination ­chimera with the human chorionic gonadotropin- of disulfide bonds affects assembly and secre-­ beta carboxy-terminus is biologically active. Thotakura NR. Schoenle E. Pohlenz J. Szkudlinski MW. 1999. Gesundheit N. Domene HM. Andler W: Con-­ Res Commun 165:788-794. 2003. and gene follows an autosomal recessive inheritance. Thomas CG Jr. 2004. Gruneiro-Papendieck L. Szkudlinski MW. et al: Con-­ human pituitary glycoprotein hormones. 2002. signal in glycoprotein hormones. 2000. I. ovine. 1988. Krone N. Riepe FG. ­deoxynojirimycin. Manjunath P. Pediatr Res 112:1331-1345. Vuissoz JM. Thyroid 12:1141-1146. et al: Novel TSH   34. ance and organ distribution of pituitary and ­recombinant 2004. et al:   35. follitropin. due to a homozygous mutation of the TSH beta   37. and thyrotropin. ­Endocrinology   33. et al: A circulating biologically inactive thyrotropin Differential effect of inhibitors of oligosaccharide caused by a mutation in the beta subunit gene. et al: Differential patients with congenital central hypothyroidism. thyrotropin. Tropea JE. Suganuma N. Matzuk MM. Emeis M. et al: Compound 136:3839-3848. Structural elucidation of the sulfated and si-­ 2006. genital central hypothyroidism due to a homozy-­   36. Genetic study of five unrelated families from Swit-­   41. Thotakura NR. Parma J. 2002. 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Devi LA: G-protein. 2001. et al: Germ-­ EMBO J 24:1954-1964. Endocr Rev 21: of codon 727 of the human thyrotropin receptor 551-583. membrane regions V and VI of the human luteiniz-­ 186. et al: 1996. ­Invest 99:3018-3024. et al: Cleavage of the 176. J Biol Chem 277:45059-45067. Arturi F. loop. J Biol Chem 276:22991-22999. 2004. 1995. Schlumberger M. 1996. 2000. N Engl J Med 332:155-160. 1995. Wawrowsky KA. J Mol Med 79:226. Corvilain B. Latif R. Loosfelt H. Van Sande J. 2000. Activating thyrotropin receptor mutations are 165. 2001. Urizar E. Loy T. Eur J Biochem 222:711-719. Montanelli L. Hsueh AJ: Trans-­ crinol Metab 85:2640-2643. Wonerow P. Abramowicz MJ. Vlase H.Part I  Normal Thyroid Axis 158. de Bernard S. line polymorphism of codon 727 of human thy-­ 170. transfected L cells and baculovirus-infected profound hypoplasia of the thyroid gland. Duprez L. 171. 2002. 180. tor ectodomain. Davies TF: Ligand-dependent in-­ roid-stimulating hormone receptor is associated hibition of oligomerization at the human thyrotro-­ with toxic multinodular goiter. modulating receptor function. Van Sande J. 1992. 2007. Jolivet A. acid motif. Grant CS. McLachlan SM. Loosfelt H. J Clin Endocrinol Metab 82:3885- coupled receptor dimerization: Implications in 3891. Gupta A. Gomes I. 166. 178. 2000. et al: Famil-­ cursors of the human thyroid-stimulating hormone ial congenital hypothyroidism due to inactivat-­ receptor in various eukaryotic cells (human thyro-­ ing mutation of the thyrotropin receptor causing cytes. Hayashi Y. J Clin Endo-­ 172. et al: Lack of gonadotropins and gonadotropin receptors: Elu-­ association of nonautoimmune hyperfunctioning cidating the physiology and pathophysiology of thyroid disorders and a germline polymorphism ­pituitary-gonadal function. 2000. Huhtaniemi IT: Mutations of 185. Sar S. Clin Endocrinol Oxf 162. Tonacchera M. Lefort A. Jordan BA. 2001. Endocrinology 141:3573-3577. 145:5580-5588. 2000. Nature 365:649-651. N Engl J Med in the shedding of human thyrotropin recep-­ 332:150-154. Bobovnikova Y. goiter. Rapo-­ 55:143-158. gene. Muhlberg T. et al: G protein roid nodules. 159. 1994. switch in the activation of the thyrotropin recep-­ coupled receptor dimerization: Modulation of re-­ tor. Chazenbalk GD. Graves PN. Jordan BA. et al: Somatic receptor in solubilized thyroid membranes. 1997. Pharmacol Ther 92:71-87. Herrmann K. Nagy ZU. Dumont JE. Oncogene 11:1907-1911. Kaczur V. Tanaka K. 1996. et al: A con-­ 242. 1995. Govaerts C. Misrahi M. 1999. Costagliola S: A physiological role for 175. Ando T. Graves P. Parma J. J Clin Endocrinol pin receptor. port B: Evidence that cleavage of the thyrotropin 177. homodimerization and negative cooperativity. Costagliola S. Gomes I. et al: Cell Congenital hyperthyroidism caused by a mutation surface protein disulfide-isomerase is involved in the thyrotropin-receptor gene. Tonacchera M. Gabriel EM. J Mol Recognit 20:392-404. Davies TF: Monomerization as a mutations in the thyrotropin receptor gene cause prerequisite for intramolecular cleavage and shed-­ non-autoimmune autosomal dominant hyperthy-­ ding of the thyrotropin receptor. Kopp P. Nat Genet 7:396-401. 160. 100 . Puskas LG. Couet J. Chiovato L. Endo-­ mutations in the thyrotropin receptor gene and crinology 137:3915-3920. 183. van Sande J. Bergert ER. Kudo M. ceptor and thyroid diseases. Parma J. spatial shift in cleavage site 1 independent of amino 1993. Holzapfel HP. 184. J Clin insect cells). Proc nodules of toxic or autonomous multinodular Natl Acad Sci U S A. 2004. 182. et al: 173. Russo D. Biochemistry 35:14800-14805. Pinchera A: Thyrotropin receptor 169. 161. Vassart G. et al: Brief report: 164. Chazenbalk GD. J Biol Chem 271:22470-22478. ceptor function. Vassart G: human thyrotropin receptor by ADAM10 is regulat-­ Somatic and germline mutations of the TSH re-­ ed by thyrotropin. Chen CR. J Clin Endo-­ tein hormone receptors: Link between receptor crinol Metab 85:2637-2639. Duprez L. Davies TF: 2000. et al: Activat-­ ing hormone receptor are required for constitutive ing mutations of the TSH receptor in differenti-­ activation by a mutation in the third intracellular ated thyroid carcinomas. not in the Gs alpha protein gene in 31 toxic thy-­ 167. Endocrinology roidism. 1997. et al: Germline 163. 2006. Rios CD. in a European Caucasian population. Parma J. Multimeric complex formation by the thyrotropin 181. Endocrinology 147:3107-3113. Gottschalk ME. 2001. Duprez L. Van Sande J: Somatic mutations receptor involves a “molecular ruler” mechanism: in the thyrotropin receptor gene cause hyperfunc-­ Deletion of amino acid residues 305-320 causes a tioning thyroid adenomas. J Clin Endocrinol Metab 85:2270-2274. 2005. Evidence that human thyroid cells express un-­ Refetoff S: Brief report: Resistance to thyrotropin cleaved. receptor? Endocrinology 145:1-3. Rev Endocr Metab Disord 1:123-129. Agretti P. Fuhrer D. 89:3765-3769. 179. Yen PM: Thyrotropin receptor mutations in thy-­ the posttranslational cleavage of the thyrotropin roid diseases. Latif R. et al: Glycopro-­ polymorphisms and thyroid diseases. Joba W. Kobilka BK. Pichon C. Metab 84:3328-3335. Themmen APN. served Asn in transmembrane helix 7 is an on/off 168. et al: Two-subunit present in nonadenomatous hyperfunctioning structure of the human thyrotropin receptor. Sunthornthepvarakui T. et al: Processing of the pre-­ 174. Osuga Y. Parma J. single-chain thyrotropin receptors on caused by mutations in the thyrotropin-receptor their surface. Ghine N.1994.

Harii N: Thyrotropin receptor autoan-­ ism with intramuscular injecton of adenovirus tibodies TSHRAbs: Epitopes. et al: studies of the thyrotropin receptor and Gs alpha Affinity purification and diagnostic use of TSH in human thyroid cancers: Low prevalence of mu-­ receptor autoantibodies from human serum. J Immunol significance. antibodies and with thyroid-stimulating blocking not the thyrotropin holoreceptor. Thyroid 17:911-922. Yamaguchi K. J Clin ­ Invest antibodies in idiopathic myxedema: These deter-­ 110:209-217. 1988. Kasagi K. Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor 187. Kung AW. Tahara K. thyrotropin-stimulated iodide uptake in FRTL-5 1826. 2000. Ban T. Morgenthaler NG. in a Graves’ animal model requires the N-terminal segment of the TSHR extracellular domain. Kohn LD. Bremont C. 2003. Rapoport B. thyrotropin receptor hypersensitive to human 198. Glinoer D: The regulation of thyroid function in preg-­ Rev Immunol 19:633-664. 1998. et al: 251-258. Iida Y. Mol tations predicts infrequent involvement in ma-­ Cell Endocrinol 212:73-79. origins and clinical ­expressing the thyrotropin receptor. et al: Structural 195. Shimojo N. Nagayama Y. Kohn LD: Identifica-­ 192. Ando T. Lau KS. N Engl J Med 339:1823. thyroid cells by crude immunoglobulin fractions 190. minants have no homologous sequence on go-­ 193. 2000. Endocr Rev 18:404-433. Tokuda Y. et al: Inhibition of chorionic gonadotropin. Willnich M. Akamizu T. ies on the extracellular domain of the human thy-­ 201. et al: Epitopes nadotropin receptors. et al: The for-­ that appear during pregnancy. Sanson ML. Arima T. Yamamoto K. Chen CR. 168:2789-2794. Sharifi N. mune thyroiditis. et al: A novel ology to pathology. et al: tion of separate determinants on the thyrotropin ­Thyroid-stimulating autoantibodies in Graves’ dis-­ receptor reactive with Graves’ thyroid-stimulating ease preferentially recognize the free A subunit. 2001. 1996. Shimojo N. Elisei R. for thyroid stimulating and blocking autoantibod-­ 1992. J Clin Endocrinol mation of thyrotropin receptor TSHR antibodies Metab 86:3647-3653. Int Rev Immunol 19:619-631. tsh receptor-blocking antibodies in Graves’ disease 194. 1997. Kikuoka S. Mol Endocrinol 6:168-180. lignant transformation. mouse model of Graves’ disease: Implications for 189. 1998. Singer DS. 200. et al: Graves’ 81:3898-3901. 2007. Napolitano G. 2002. Kosugi S. Chazenbalk GD. Ishikawa N. 101 . Endo-­ crinology 139:1891-1898. Autoimmunity 36:331-337. Kita-Furuyama M. Yamaguchi KI. 2002. et al: Familial a role of aberrant MHC class II expression in its gestational hyperthyroidism caused by a mutant pathogenesis. 1997. Pichurin P. Int 188. Kohn LD. Thyroid 7:867-877. Kohn LD: Epitope mapping of rotropin receptor. Rodien P. J Clin Endocrinol Metab 67: 191. Spambalg D. nancy: Pathways of endocrine adaptation from physi-­ 197. Minich WB. J Clin Endocrinol Metab 196. McLachlan SM: The thyrotropin re­ from patients with goitrous and atrophic autoim-­ ceptor in Graves’ disease. 2003. A novel murine model of Graves’ hyperthyroid-­ 199. disease: A host defense mechanism gone awry.

The replacement handling. which Modifications of CH ­screening programs have been are collected for a variety of newborn screening tests introduced to improve the detection of infants with including amino acid disorders. is rare. The average threshold shown to detect newborns with central hypothyroid- value for a significant TSH elevation is 15 to 25 mU/L ism. defects of thyroid hormone biosynthesis. gone significant changes. The most common forms are more than 30 years ago and now is routine in most thyroid dysgenesis (75% to 80%) and defects of thy- industrialized countries. early screening for CH increases screening strategies. the increase in serum to the results of outcome studies.. ing at 2 to 6 weeks of age has detected an additional most current programs screen for elevated serum 10% of infants with CH5 and addition of a T4 or T4 TSH concentrations as the most reliable marker plus thyroxine-binding globulin (TBG) has been of primary hypothyroidism. after birth. roid hormone biosynthesis (10% to 15%. Although screening program protocols vary.g. genesis (e.7 105 . Table 8-1). the threshold value established for a significant TSH grams. Most of these newborns have multiple pituitary and the common time for sampling is 48 to 72 hours hormones deficiencies and isolated TSH deficiency.6 birth. Causes include thyroid dys- quate dosage of thyroid hormone replacement ther. central hypothyroidism (only in programs measur- SCREENING STRATEGIES ing TSH and thyroxine [T4]).4 Repeated test- tosemia. and to those newborns with severe CH CH detected by newborn screening programs is 1 in whom TSH levels remain elevated despite an ade. for several days or weeks after delivery. birth. The rea- thyroidism are related to newborns with persistent. Early measurement of TSH increases the prev. cause. different approaches for the the frequency of false-positive results. those with central hypothyroidism.3 The ­ prevalence of the confirmed cases of centrations. ­ hypoplasia. data analysis. Thus. testing. were made available in the ­procedures grams. However. and immaturity of the hypotha- mildly elevated thyroid-stimulating hormone (TSH) lamic-­pituitary axis has been suggested as a possible levels and normal peripheral thyroid hormone con. and transient forms Newborn screening for CH has been introduced of hypothyroidism. Special aspects of TSH concentration in the affected infant is delayed the management of patients with congenital hypo. In rare cases. in 3500 to 4000 births.1 Screening for CH is usu. disorders of fatty acid delayed increase in serum TSH concentration and oxidation. Chapter Screening for Congenital Disease 8 Annette Grueters-Kieslich Since the introduction of newborn screening pro. sons are unclear. or communication therapy with thyroid hormones has been adjusted of the results. depending on the varying individual. Screening strategies have It has been shown that as many as 5% of changed and new technologies. including molecular CH infants are missed in newborn screening pro- genetic studies. congenital adrenal hyperplasia. In a recent consensus paper of the American alence of infants demonstrating elevation of TSH Academy of Pediatrics. the simultaneous measure- concentration caused by a physiologic neonatal TSH ment of T4 and TSH was considered as the “ideal surge. depending on confirmational diagnosis have been recommended. and galac. some mothers are discharged most commonly caused by mutations of the TSH- from the hospital as early as within 24 hours after beta gene. ally performed in dried blood spot samples.2 Most of these relate to errors in specimen of the conformational diagnosis. aplasia. the management of the newborn and infant elevation for infants discharged within 24 hours of with congenital hypothyroidism (CH) has under. roidea). ectopy. which varies considerably from individual to screening approach” and. hemithy- apy and compliance to treatment.

Part II  Pediatric Thyroid Disease Table 8–1  Thyroid Disorders Detected in Newborn Screening Programs Disorder Examples Thyroid dysgenesis (70%-80%) Agenesis. thyroid-stimulating hormone. TSH or TSH-T4-TBG measurement is performed. Thus. CONFIRMATIONAL DIAGNOSIS in newborns. hypoplasia. TSH. including hemithy- and defects of thyroid hormone biosynthesis with a roidea and ectopic or hypoplastic thyroid glands normally developed or enlarged thyroid gland.THOX2. To confirm or rule out CH.5 μg/dL). or loss-of-function mutations of the TSH edly elevated TSH levels during replacement therapy. thyroid hormone replacement therapy. 90% have TSH ing studies and the measurement of Tg may avoid the levels above 50 mU/L and 75% have T4 concentra. ­thyroglobulin. The goals of the be present in an ectopic position (Table 8-2). in whom no thyroid tissue is detectable A positive screening report for CH in a newborn in the normal position but T4 and thyroglobulin (Tg) demands the prompt evaluation of the newborn so as are measurable. Down syndrome. However. an ses. If accompanied by the determination for the defective organogenesis remain obscure in of the serum thyroglobulin concentration. ectopy. Thyroid Dysgenesis imaging studies are initially performed to ­distinguish The term thyroid dysgenesis describes infants with devel- between the different forms of thyroid dysgenesis opmental defects of the thyroid. ble on ultrasound despite high TSH concentration. because anes- ed according to age and method-related reference thesia of the newborn or infant is necessary. the female-to-male ectopy without scintigraphy. It is crucial that the results are interpret. recommended as a routine procedure. Hypothyroidism is confirmed when TSH levels to be performed immediately. as well as those with total thyroid agenesis. phy.g. interruption of replacement therapy. TPO. syndromes (e. the correct definition would be hypothyroidism is permanent. infants with a normally developed or enlarged gland cult to diagnose. a determination of This has also been elegantly shown with magnetic serum TSH and T4 or free T4 (FT4) concentration is resonance imaging (MRI). but MRI studies are not performed. CH. some functional thyroid tissue must not to delay the onset of treatment. hyperthyrotropinemia Iodine contamination. Williams-Beuren The same is true for patients who have shown repeat- syndrome. TSH receptor defect FT4. The disorder has been 106 . which should be tions below 84 nmol/L (6.8 data because TSH and T4 ­ levels in the first weeks If hypothyroidism is confirmed by the analy- of life are significantly different from those in later sis of serum TSH and T4. thyroid peroxidase. dehalogenase Central hypothyroidism (only detectable in programs Developmental defects of the hypothalamus or pituitary. receptor have to be considered as possible causes). ­combining TSH and T4-FT4) isolated TSH deficiency Transient hypothyroidism. if imag- T4 (FT4) levels are below the age-related reference ing studies are not readily available. With diagnostic procedures in a newborn with a screening new ultrasound techniques using Doppler sonogra- result suggesting CH are the confirmation of hypo. free thyroxine. thyroxine. This can be done because ratio approximates 2 to 3:1. thyroid oxidase 2.. such as hypothalamic dysfunction. maternal ­antibodies. hemithyroidea Defects of thyroid hormone biosynthesis (10%-15%) Defects in sodium-iodide symporter. antithyroid drugs. imag- range.6 To investigate the cause of congenital hypothyroidism. these investigations have life. the direct detection of small thyroid remnants thyroidism and the attempt to specify the cause of in a typical and ectopic position has been described. specific ­genetic interruption of replacement therapy is not necessary. it is even most affected infants. If there is no gland visi- ­hyperthyrotropinemia and other differential diagno. If only the TSH performed at the age of 2 to 3 years if there is doubt that level is elevated. Ultra. TPO. In infants with proven CH. an interruption of therapy can be restricted to Hypothalamic-pituitary hypothyroidism is more diffi. Most of these infants are missed in with constant normal or suppressed TSH levels during screening programs unless a simultaneous T4 (FT4). T4. Dysgenesis is more prevalent possible to distinguish between thyroid agenesis and in female than in male infants. It is not acceptable to are higher than the age-related ­reference range and delay the replacement therapy—for example. THOX2. Thyroid sound studies have been accepted as the first-line dysgenesis usually is sporadic and the mechanism(s) investigation.

functionally defective TPO. may never develop a ­deficiency of hydrogen peroxide generation. and urologic systems and TSH responsiveness and hyperthyrotropinemia or cleft palate and eye. These disorders are summarized in Table 8- 3. An increased prevalence (8% to Defects in Gs subunits have been reported in 10%) of other anomalies has been reported in infants families with dominantly inherited pseudohypopara- with congenital hypothyroidism. including homozygous and compound 107 . More than 20 different mutations have been mal serum T4 and increased TSH concentrations. thyroglobulin. recessive traits. Affected subjects may have reduced musculoskeletal. Ultrasound No gland No gland Eutopic gland and stimulation of the several intracellular events of Serum T4 Low/absent Low/absent Low thyroid hormone synthesis and release. The ­goiter. and the diagnosis is based on the presence of goiter. Molecular genetic studies (sequencing of the Newborns with defective TSH signaling are usually TPO gene) are necessary for a definitive diagno- detected by newborn screening with low or nor. Na+-I− symporter (NIS) gene in patients with congeni- inant mode of inheritance with a low penetrance. First-degree relatives of children hypothyroidism. described. and ectopic thyroid. loss-of-function and gain-of-function phenotypes Meas. Organification Defects the clinical manifestations of congenital hypothy­ Newborns with defective organification of iodide roidism caused by a biochemical defect are similar have been reported to present with increased to those in infants with thyroid dysgenesis. sup. with Elevated Thyroid-Stimulating The thyroid follicular cell response to TSH Hormone* involves a series of coordinated steps.to 2-hour peri- ­Hormone od. or a good long-term compliance. A defect at Serum Tg Low/absent Meas/normal Meas/normal/ high one of several sites could lead to an abnormality in thyroid responsiveness to TSH. measurable. Screening for Congenital Disease ­ hyroid radioiodine uptake is low or low-normal and T Table 8–2  D  iagnostic Approach for Newborns unresponsive to TSH. phosphorylation of receptor protein(s).14 with thyroid dysgenesis have an increased prevalence of thyroglossal duct cysts. including TSH binding to a receptor in the plasma membrane. A few ­cases of severe CH with absent iodine Hispanic infants.16 The defects include enlargement may be manifest at birth but patients a complete deficiency of thyroid peroxidase detected by newborn screening and treated early. Thyroid TSH in newborn screening. Approximately 2% to 3% of thyroid uptake and thyroid hypoplasia on ultrasound and dysgenesis cases are familial and can be attributed to apparent athyrosis on scintigraphy have been mutations in genes encoding for transcription factors reported.12 or the TSH receptor. abnormal. osteodystrophy. synthesis of cyclic adeno­ Test Findings sine monophosphate (cAMP).9 The most prevalent thyroidism and in patients with Albright’s hereditary are cardiac but include anomalies of the nervous. sis. with (TPO).15 These patients present with CH porting the hypothesis of a genetic predisposition.11 Most of the loss-of-­function defects lead to asymptomatic hyperthyrotropin- emia and most patients described have been com- reported to be less prevalent in black (1:32.13. Sodium-Iodide Symporter Defects thyroid hemiagenesis. tal hypothyroidism. acti- Screening vation of adenylyl cyclase. a pyramidal thyroid lobe. thyroxine. Tg. with a rapid and profound discharge Resistance to Thyroid-Stimulating of thyroidal radioiodine during a 1. with normal heterozygous in white infants and is more frequent (1:2. Except for the familial ­incidence and tendency of affected individuals to develop a goiter. Germline mutations of the thyrotropin Diagnosis Agenesis Ectopy Defect of biosynthesis receptor gene have been described in association with congenital or acquired thyroid disease. limited or absent radioiodine uptake. and an elevated Defects of Thyroid Hormone Biosynthesis serum TSH level. complete defect can be detected by a perchlorate discharge test. have been described. digestive. activation of protein kinase(s).000) than pound heterozygous.000) in parents.10 These Several reports have documented mutations in the abnormalities are compatible with an autosomal dom. T4. Heterozygous family members were These disorders usually are transmitted as autoso­mal not clinically affected. both *Found by newborn screening.

two genes encoding nicotinamide adenine dinucleotide phosphate (NADPH) oxidases Hypothalamic-Pituitary Hypothyroidism have been cloned.18 pituitary or central hypothyroidism can result from hypothalamic and/or pituitary dysgenesis or ­isolated Defects in Thyroglobulin Synthesis TSH deficiency. thyroglobulin. with a prevalence in the range of 1 in ize with TPO at the apical membrane of thyroid fol. (hypopituitarism) ­hormone deficiencies and LHX4 gene mutations TSH resistance AR No Normal gland. variable and includes goiter.000 to 30. is already present at birth. with goiters presenting at homozygous mutations in the TSHβ subunit gene on birth or shortly thereafter.Part II  Pediatric Thyroid Disease Table 8–3  Inborn Errors of Thyroid Hormone Metabolism* Disorder Inheritance Goiter Diagnostic Feature Molecular Genetics Familial TSH deficiency AR No Absent TSH ­response to TRH TSH-beta gene mutations Developmental defect AD. AR No GH and other pituitary Pit-1. diiodotyrosine. THOX2). The phenotype is tion from codon 105 of the βTSH-beta gene (C105V). or tions. 20. congenital hypothyroidism. DIT DEHAL1 gene mutations defect *Detectableby newborn screening. and LHX3. The patients originally while other pituitary functions are intact. Inactivating mutations in THOX2 were detected in newborn thyroid screening programs originally described in four patients and inactivating using initial T4 and/or T4/TBG ratio measurements mutations were seen in four other patients. MIT.6 Hypothalamic- ­(homozygous mutation) CH. Serum T4 and TSH concentrations are low roid and are excreted in urine.23 The most prev- the iodothyronine dehalogenase (DEHAL1) has been alent mutation identified in different populations is cloned.000 to 1 in 100. growth hormone. 108 .19 A goiter ­frequently ­hypothalamic-pituitary dysgenesis. GLi3 mutation in the Failure to deiodinate thyroid monoiodotyrosine (MIT) ­Pallister-Hall syndrome. Recently. LHX4. PROP1. disorder.24 It involves a 1 bp dele- ism from three ­ different ­ families. Various transcription factor gene Thyroglobulin synthesis defects occur in about 1 in defects have been described in association with 80.20 Mutations of the DEHAL1 gene have been derived from a common ancestor and results in severe identified in patients with congenital hypothyroid. Prop-1.000 newborns. and diiodotyrosine (DIT) as they are released from and POUIFI defects in hypopituitarism. monoiodotyrosine. TRH. with no Tg Tg gene mutations response to TSH Iodotyronine deiodinase AR Yes High serum MIT. autosomal recessive.000 newborns. ­hypoplasia or Mutations of the TSH ­apparent athyrosis ­receptor gene Iodide transport defect AR Yes Salivary. because Familial isolated TSH deficiency is a rare the nondeiodinated MIT and DIT leak out of the thy. AR. thyrotropin-releasing hormone. heterozygous ­missense mutations. and SIX3 defects have been identified in patients with holoprosencephaly. Hesx-1. HESX1 defects in associa- Iodotyrosine Deiodinase Defect tion with septo-optic dysplasia. autosomal dominant. These infants are only licular cells.17 The proteins colocal. GLi2. gastric tissues also Mutations of the fail to concentrate iodide Na+-I− symporter (NIS) Organification defects AR Yes Positive perchlorate ­discharge Thyroid peroxidase and test THOX2 gene mutations Thyroglobulin defects AR Yes Usually low Tg. DIT.21 Recently. associated or simultaneous TSH and T4 measurements to detect with ­ transient (heterozygous mutation) or severe infants with central hypothyroidism. the gene ­encoding chromosome 1 have been described. thyroid-stimulating hormone. TSH. referred to as thyroid oxidase 1 Newborns with central hypothyroidism are ­relatively and 2 (THOX1. A number of described were hypothyroid. mental retardation. frame shift muta. SHH. LHX3. ZIC2. and single-nucleotide normal mental development despite delayed thyroid substitutions. GH. AD.22 thyroglobulin leads to severe iodine wastage. Tg.16 hormone substitution. base pair duplications. uncommon.

birth.40 Other causes could include defects of the biologic activity of TSH or the TSH receptor. where it is detected in about 1 higher thyroid hormone concentrations in the first in 18. which is expressed not only in the inhibits technetium or radioiodine uptake. CH. treatment should be instituted.33 IQ scores and mental and motor deve­ is similar to therapy for other CH states. with vari. These using a relatively low replacement dose of T4 or in infants manifest low or normal T4 levels.29 iodine or possibly antithyroid drug ingestion should In some patients with remaining deficits and be considered in all cases of CH. range. in the term infant weighing 3 to 4. low-normal or occasionally low IQ mone deficiencies is necessary. Maternal TSH receptor blocking antibody-induced hypothyroidism should SPECIAL CONSIDERATIONS be suspected in any case in which the mother has a Since the introduction of newborn screening pro- history of autoimmune thyroid disease.43 Elevated TSH values frequently weeks of life and to guarantee adequate hormone normalize spontaneously within 6 months. ably elevated serum TSH concentrations. sistent TSH elevations remains unclear. Screening for Congenital Disease Therapy of hypothyroidism in these infants therapy.44 Hyperthyrotropin- to 15 µg/kg/day is ­recommended. Most were compound het- ration for treatment of infants with CH is T4. whereas thyroid but also in the central nervous system during drug or dietary goitrogens typically increase uptake development. therapy. Autoantibody. erozygotes with normal heterozygous parents. iodine usually factor NKX2-1. ­values and motor impairments have been ­reported in treated children with severe CH as assessed by a very Transient Congenital Hypothyroidism low serum T4 level and delayed bone maturation at Transient CH comprises 5% to 10% of infants detect. asymptomatic hyperthyrotropinemia has sient CH in these infants usually is of short duration become a relatively common disorder and may be (1 to 2 weeks) in the case of drugs or longer dura. explain the unfavorable outcome. transient or permanent.45 Physical growth and development of infants Serum TSH concentrations in some treated with CH usually are normalized by early and ­adequate infants with proven CH may remain relatively 109 .41. grams.29-32 Regarding the not as rare in Japan. an initial dose of presence of FT4 levels in the upper half of the normal 50 µg daily is therefore recommended. More recent studies with a double-blind areas of endemic iodine deficiency. The prevalence of transient tion (1 to 4 months) if related to maternal blocking hyperthyrotropinemia in Europe approximates 1 in antibody.29 For the average emia in the newborn is usually treated but. The mechanism in patients with per- age-related reference range during therapy.25 In early IQ loss.26 Maternal even in patients with severe CH. exposure.38 This deficit. a THYROID HORMONE REPLACEMENT THERAPY mild thyroid hormone bio­synthesis defect. an initial dose of levothyroxine (l-T4) of 10 for some of the familial cases. Because most of thyroid hormone in the Germline mutations of the TSH receptor gene have CNS is derived from local T4 to triiodothyronine (T3) been associated with a phenotype of asymptomatic ­conversion. it is desirable to maintain the serum an abnormal TSH molecule or TSH receptor defect T4 and FT4 levels in the upper half of the normal in these subjects.39 and produce a ­positive scan. Partially inac- malize the serum T4 concentration in the CH infant tivating mutations in the TSH receptor gene accounts rapidly. The thyroid scan neurologic problems.34 However.42 The dosage of T4 should normalize the serum Transient neonatal hyperthyrotropinemia is T4 level as quickly as possible. subtle The goal of newborn CH screening is the institution developmental defects such as a hemithyroid. or a of early. adequate thyroid hormone replacement disturbance of the TSH feedback control system. with 50% caused by perinatal iodine beyond 2 weeks. roid hormone replacement with an adequate dosage ciency associated with increased thyroid hormone can completely restore normal mental development.28 the preferred thyroid hormone prepa. To nor.35-37 This outcome has been found in programs ed in newborn thyroid screening programs. In addition. transient CH is randomized approach have demonstrated that thy- more frequent and is caused by a relative iodine defi. requirements in the neonatal period. Early therapy agents and transplacentally derived TSH receptor with 10 to 15 µg/kg/day of levothyroxine reduces blocking maternal autoantibodies. If biochemical hypothyroidism CH persists 8000 births. infants in whom treatment is delayed. he or she could be managed ­expectantly.27 The tran. The most although variable. ­hyperthyrotropinemia. lopment also are normalized in most infants with replacement of other pituitary or end-organ hor. mutations in the transcription result varies depending on the cause.000 newborns. amounts to several IQ points for common causes in North America are goitrogenic every week of delayed early treatment. excluding to all infants. the serum TSH level more rapidly and minimizes the ­mediated CH accounts for 1% to 2% of cases.5 kg.

els in these children is beneficial remains open. Dumont JE. 2002. Mastroiacovo P. tive randomized IQ outcome data for this particular 11. Horm Res 65 (Suppl 4). Fisher DA: Effectiveness of newborn screening pro- hypothyroidism. et al: Color Doppler Molecular genetics of hypothalamic-pituitary ultrasonography: Diagnosis of ectopic thyroid gland ­development. Pediatrics New York. 2002. thyroglobulin iodination site. 2002. Corvillain B. 1985. Thyroid 13:771.   3. 1987. Kusugi S. et al: Screen- 16. pp 63-79. 2005. ing for congenital hypothyroidism with speci- In Beudet AL. et al: Inacti- Screening for congenital hypothyroidism: The value vating mutations in the gene for thyroid oxidase 2 of retesting after four months in neonates with low (THOX2) and congenital hypothyroidism. 20. nine dehalogenase (DEHAL1) is a transmembrane   7. In Pescovitz OH.   5. 1995. the Somatic and germline mutations of the TSH recep- tor and thyroid diseases. N Engl or very low birth weight. Kempers MJE. Valle D (eds): The Metabolic men collection at two time periods. Utiger RD (eds): grams for congenital hypothyroidism: Prevalence The Thyroid. ial congenital hypothyroidism due to inactivating roid hormone replacement in affected newborns mutation of the thyrotropin receptor causing pro- has effectively prevented symptoms of CH. ism. ism: Status report. et al: Update of newborn crinology (ESPE) 45th Annual Meeting. one of the major achievements of pediatrics in the 1997. Noda H. Van Sande J. Sato H. Philadelphia. Spiegel AM: The molecular basis of disorders caused by defects in G proteins. Stazi MA. 2006. Horm Res 48: bers of the NADPH oxidase family. 7th ed. Tran PV. Section protein involved in recycling of iodide close to the on Endocrinology and Committee on Genetics. ­congenital hypothyroidism: Data from the Italian Registry for Congenital Hypothyroidism (1991- centration relative to T4 concentration in CH infants 1998). De Vijlder JJM: Genetic defects causing   2. Health Committee. Endocrinol Metab 87:575. Northwest Regional screening program. Moreno JC: European Society for Paediatric Endo- docrine Society. FASEB J 18:1574. Many MC. The   9. Hanna CE. Rhodes SJ:   8. 17. Derriene. 275:23227. Trends Endocrinol 2:129. 2006. Horm Res 47:89. Leger J. Rose SR. Public 2004. Abramowicz MJ. Delange F: Neonatal screening for congenital hypo­ two human thyroid cDNAs encoding new mem- thyroidism. LaFranchi SH. Krainz PL. Ingraham HA. Foley T. Philadelphia. Parma J. 88:5145. Moreno JC. Williams & Wilkins. J Clin Endocrinol Metab 87:557. screening for CH can be considered as 13. Dumont JE. Therefore. et al: A elevation of serum TSH is marked during the first ­population-based study on the frequency of ad- 2 years of therapy but can persist to some degree in a ditional congenital malformatons in infants with minority of patients. Bikker H. Talbot M. question of whether treatment to decrease TSH lev. 14. Vassart G: group of children with hyperthyrotropinemia. et al: Iodothyro- 2005. despite normalized levels of T4 or FT4. et al: Cloning of   4. 2001. 2005. American Academy of Pediatrics. J Med 347:95. Tylek-Lemanska D. 2003. et al: ited disorders of the thyroid hormone generating Neonatal detection of congenital hypothyroidism system. et al: Thyroid de- threshold for T4 suppression of TSH release in CH. In Braverman LE. Starzyk J: 18. by thyroid dysgenesis. Refetoff S: Thyroid disorders.Part II  Pediatric Thyroid Disease e­ levated. J Med Screening 12:166. Results and perspectives. 1997. Lippincott. As long as there are no prospec. Savage JJ. Duprez L. 76:734. Medeiros-Neto G: An outline of inher-   6. presumably is caused by a difference in the feedback 10. Olivieri A. 1997. Vulsma T.46 The elevated serum TSH con. 15. 110 . et al: Extending the clinical heterogeneity of iodide transport defect (ITD): A novel mutation R124H of the sodium/ References iodide symporter gene and review of genotype- phenotype correlations in ITD. Szinnai G. 2003. 2000. J Clin remains obscure. pp 2883-2887. Rotterdam. de Vijlder JJM. velopmental anomalies in first-degree relatives of This difference exists perinatally. 2004. Garel C. but the mechanism children with congenital hypothyroidism. J Clin Invest mental retardation. Fisher DA: Screening for congenital hypothyroid- Metab 91:1199. Brown RS. 12. 1991. pp 714-730. Wang D. J Clin Endocrinol Metab Williams & Wilkins. Verbeeten B Jr. screening and therapy for congenital hypothyroid- June-July 2006. Marinovic D. ­American Thyroid Association. Lippincott. DeDeken X. McGraw Hill. Clin Endocrinol 55:143. Lawson Wilkins Pediatric En- 21. Pediatrics 117:2290. Eugster EA (eds): in patients with congenital hypothyroidism caused ­Pediatric Endocrinology. Results of the and Molecular Bases of Inherited ­Disease. Pediatr Clin N Amer 34:881. 9th ed. J Biol Chem 51. J Clin Endocrinol   1. 19. Gnidehou S. et al: Famil- Newborn screening for CH and early thy. 2006. especially found hypoplasia of the thyroid gland. Ohnishi H. Sly WS. Caillou B. Vassart G. 22. J Clin Endocrinol Metab 90:3350. Knobel M. of central origin. 99:3018. last 3 decades. of missed cases. van Tijn DA. in 1 of 3500 to 4000 newborns. Kumorowicz-Kopiec M.

34. Laboureur I. et al: The ­Dynamics of the plasma concentrations of TSH FT4 ­hypothalamic-pituitary-thyroid negative feedback and T3 following thyroxine supplementation in con. 2004.5. N Engl J mental outcomes in congenital hypothyroidism: Med 303:738. Miyai K. Van Sande J. LaFranchi S: Congenital hypothyroidism. Harper A. behavioral development in children with congeni. J Clin Endocrinol Metab 72:523. mone replacement on mental. 2000. Oikawa T. diagnosis and management. velopmental gap with early high dose levothyroxine 26. Glorieux J. Bakker B. 1980. Lie SO: Intellectual develop- ment of children with congenital hypothyroidism in relation to recommended thyroxine treatment. Ruiz de Ona C. Rivas S. 1998. Vassart G: 29. Brumm J. Screening for Congenital Disease 23. 1996. Bellisario R. 1992. genital hypothyroidism treated early with high-dose 2002. control axis in children with treated congenital genital hypothyroidism. 1991. 33. Biebermann H. 44. Deal C. Calvo R. Yamada Y. Dumont JE. Biebermann H. Bongers-Schokking J J. Schuetz B. Matsuura N. levothyroxine. Thyroid 9:741. Fisher DA. Grueters A: ­inhibiting ­immunoglobulin G in transient neonatal Transient congenital hypothyroidism and hyperthy- ­hypothyroidism. Arch Dis Child 64:1177. Wondisford FE: 35. 32. Obregon MJ.3�‑­triiodothyronine in mutations and thyroid disease. Medeiros-Neto GA. Nohara Y. psychomotor and 2001. Richer F. ternal thyrotropin receptor blocking antibodies in 38. J Clin Endocrinol Metab 57:384. Parma J. tal central hypothyroidism due to a homozygous 36. Comparison of initial T4 dose and time to reach 45. et al: 46. 1994. ism. Pfeufer A. Arch Dis Child 70:464. neonatal transient hypothyroidism due to maternal 31. Bain P. et al: Neurodevelop. et al: Cognition thyrotropin beta 313 delta T mutation is caused by and behavior at school entry in children with con- a founder effect. gies. Trends Endocrinol the protection of the fetal brain. 1999. Nose O. 27. 2002. et al: Choreo- of marginally low iodine intake. 43. Kempers MJE. et al: Sequen. 1999. et al: Maternal treatment. and neonatal thyroid function at birth in an area 39. Kase BF. and pulmonary altera- Metab 75:800. Res 61:228. Glinoer D. J Pediatr 118:850. Clin Endocrinol 55:143. 41. 30. 111 . J Clin Invest 86:889. J Pediatr 144:747. 1991. Clin Endocrinol 57:529. Boileau P. et al: Transient infantile tal hypothyroidism. hypothyroidism. J Pediatr 147:768. J Clin Endocrinol Metab severe congenital hypothyroidism: Closing the de- 81:1147. Schoen EJ. Corvillain B. tor and thyroid diseases. J Clin Endocrinol Metab 81:222. DeVijlder JJM. the more important factor for IQ at 7 years? Horm 24. 1996. Botero D. hypothyroidism as studied in rats: Crucial role of ma. tial ­ serum measurements of thyrotropin binding 40. de Muinck Keizer-Schrama Somatic and germline mutations of the TSH recep- SM: Influence of timing and dose of thyroid hor. Fisher DA: Management of congenital hypothyroid- target T4 and TSH. Biebermann H. et al: ­Congenital crinol Metab 81:1563. 2002. ­hyperthyrotropinemia. Shimizu M. development at the ages of 6-14 years. Brown R. de Laserda L. outcome. Krude H. J Clin Endo- 28. Grant DB: Growth in early treated congenital hypo- thyroidism. 2004. 42. J Clin Invest 109:475. 1989. Duprez L. Thyroid 9:735. Downs A. tions due to human NKX2-1 haploinsufficiency. etiolo. Iseki M. Marti S. 1996. 9:133. Delange F. Dubuis JM. rotropinemia: Normal thyroid function and ­physical 1983. Schnabel D. Toublanc JE: Earlier Familial congenital hypothyroidism caused by ab. 1997. J Clin Endocrinol Metab 87:4811. J Pediatr 147:775. et al: TSH receptor ternal thyroxine but not of 3. hypothyroidism. Selva K. onset of treatment or increment in LT4 dose in normal and bioinactive TSH due to mutations in screened congenital hypothyroidism: Which was the β subunit gene. LaFranchi S. Trends Endocrinol 8:15. Van Sande J. et al: Outcome of over one million babies. J Clin Endocrinol Metab 85:2722. Miki J. 25. 2005. et al: Congeni. Simoneau-Roy J. Kohler B. J Clin Endocrinol athetosis. Heyerdahl S. Rovet JF: Congenital hypothyroidism: Long-term of transient congenital hypothyroidism due to ma. et al: Incidence 37. et al: Familial. 2005. TSH-binding inhibitor immunoglobulins. 1990.

Recently. Finally. or Pax8 the foramen cecum and the neck.5 In the latter situation. central vascular supply to the gland.4 Whether the HYPOTHYROIDISM thyroglobulin-producing tissue is ectopic or ortho- topic in these patients is unknown. the shape.3 ­hypothyroidism can also occur. either isolated or The second most common defect underly- associated with other pituitary hormone deficiencies. This results in an has been genetically ablated. appears to be essential to the lobulation process and even some transient forms of primary CH have may play a role in the development of an appropriate been shown to have a genetic basis. of the 113 . Hypothyroidism. plasma thyroglobulin. of these patients and true athyreosis when there is no opment of the gland during embryogenesis. the defect is ectopic are generally hypothyroid. cifically been demonstrated to be responsible for the nuclide scanning. is the most common congenital endocrine dis. It is noteworthy that in mice in whom anywhere along its normal path of descent between thyroid transcription factor 1 (Ttf-1. PPCH follicular cells is controversial. and may have a genetic basis as well. but this may most commonly lies at the level of the thyroid gland simply reflect a smaller number of cells. occasionally.6 location. In humans.1 As is true at other stages of life. It is important to realize that up to 50% of patients with no detectable uptake on radionuclide scan have PERMANENT PRIMARY CONGENITAL detectable plasma thyroglobulin levels. Apoptosis has spe- follicular cells. it is unclear why patients whose only thyroid tissue order. the most common follicular cell ever differentiated during organogen- developmental defect associated with PPCH is an esis or if thyroid cells differentiated initially and then arrest in the migration of the median thyroid anlage disappeared. The devel. which detectable radionuclide uptake and an undetectable are collectively called thyroid dysgenesis. it is opment of the thyroid is reviewed elsewhere in this unknown whether these are individuals in whom no text (see Chapter 2). We have used Nomenclature and Clinical Features the term apparent athyreosis to describe the condition PPCH most often results from defects in the devel. ectopic thyroid glands have an abnormal The third gross developmental defect. the median thyroid bud ectopic mass of otherwise well-differentiated thyroid always forms and disappears later. which is best evidenced by radio. 3000. bution of the lateral thyroid anlage to the pool of mary congenital hypothyroidism [PPCH]). ing PPCH is thyroid aplasia or agenesis (athyreosis). Chapter Genetics and Epigenetics 9 of Congenital Hypothyroidism Guy Van Vliet Key Points n Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. but this lateral anlage is therefore reviewed first in this chapter. lacking the lateral lobes typical of the normal absence of one of the lobes—and.2 In addition to their abnormal disappearance of the thyroid in Ttf-1 −/− mice. n Thyroid dysgenesis is predominantly non-Mendelian. n Functional defects leading to CH (thyroid dyshormonogenesis) are inherited in autosomal recessive fashion. Ttf-2). n CH most often results from defects in thyroid development (thyroid dysgenesis). which affects one neonate in about t­ hyroid. The contri- itself and is of a permanent nature (permanent pri. Because ectopic thyroid cells are functional.

no familial case of focal plasia. The loss of het- generally had detectable and even high. a systematic survey undefined mechanisms.11 Deladoey and associates have12 proposed PAX8 Mutations a unifying model that would be compatible with Relatively speaking. Thus. heterozygous mutations in PAX8 the evidence of a genetic contribution and with the are the ones that have been most frequently encoun- almost universal discordance of monozygotic twins. A.21 of monozygotic twins revealed a discordance rate of 92%. the thyroid-stimulating that the quality of imaging may not have been the same hormone (TSH) receptor (TSH-R) becomes expres­ in all cases from the same family. hyperinsulinism is a sporadic disease. apparent athyreosis). focal hyperinsulinism.Part II  Pediatric Thyroid Disease isthmus as well—is only rarely encountered in patients be combined with a somatic mutation or epigenetic with PPCH. The putative germline mutation is unlikely to be in dren by ultrasound have shown that this anatomic PAX-8. Milder TSH resistance can CH from thyroid dysgenesis was classically described also be observed as part of pseudohypoparathyroid- as a sporadic entity until. plasma thyroglobulin creatic lesion. Thyrotropin Resistance ed in the same pedigree. If PPCH is severe. has PPCH have thyroid glands that are of normal shape been shown to result from such a two-hit model. a figure 15-fold higher than by chance for TSH-R–­inactivating mutations20 or by other still alone. together with loss of the maternal on very careful ultrasonography. because systematic ­screening variant is encountered in about 1 in 500 individuals. the homozygous or compound heterozygous state ally dimorphic mechanisms. but not ­ectopy.2 will not take up radionuclides but may be visualized genes is found. their study at the molec- genesis represent a spectrum with potentially common ular level has yielded interesting insights about the mechanisms or discrete entities with specific causes is genetic control of ­ thyroid gland development and controversial. Assess.9 although one should realize During prenatal development. In favor of athyreosis and ectopy being function.18 Accord- the different gender ratios in ectopy and in athyreosis ingly. In the pancreatic lesions found in these patients. relative to erozygosity is a somatic event restricted to the pan- the amount of thyroid tissue. This phenotype is transmitted in an auto- Possible Molecular Mechanisms somal recessive fashion. inactivation of the TSH-R should not interfere (with female predominance more pronounced in the with migration and. or TTF-2.10 have apparent athyreosis. genital endocrine disorder that is much less common Finally. have been shown to be associated with PPCH will be clide scanning is the technique of choice for revealing reviewed (Table 9-1).17 and location but that are small (orthotopic hypopla. Stanley. TTF-1. which explains why focal congenital (see earlier. even patients bearing former) suggest that. 114 . the total num- In this two-hit model. 2007). However. Rather than specu- the phenotypic characterization of the specific defect lating further. Whether of cases of thyroid dysgenesis remain unknown. a nationwide sur. especially when they sed in the fetal thyroid well after it has completed were from different generations. it is in patients with orthotopic hypo. this can be caused by heterozygosity cases was 2%. remain euthyroid. the two-hit model is applicable to thyroid dysgen- ing progress in this area requires understanding that esis remains to be determined. hyperinsulinism has been observed (C. ism19 or with an autosomal dominant pattern of vey in France revealed that the percentage of familial ­inheritance. athyreosis and ectopy have been report. its initial differentiation and migration. if there is a common molecular ­mutations that severely impair TSH-R function in cause to the two phenotypes. Although they account for a ectopic thyroid tissue. sia). these small orthotopic glands a paternally inherited mutation in the SUR1 or KIR6. Most subjects with thyroid hemiagenesis ­difference in genes involved in thyroid development. personal communication. In ­ contrast Ironically. Systematic studies of schoolchil. the rare single-gene disorders that in thyroid development is essential and that radionu. that single-gene disorders have been identified. to thyroid dysgenesis. On the other hand. who account for less than 5% of cases of PPCH.9 At about the same time. These patients have 11p15 allele (loss of heterozygosity). small proportion of PPCH. but this may reflect the molecular mechanisms underlying the vast majority the extreme rarity of the latter condition. tered in patients with PPCH. in 2001. a germline mutation would ber of mutations identified to date is still only about 10.13-16 Another sporadic con- present with PPCH is unknown. as defined earlier. part of a spectrum is the observation that in the rare familial forms. it is modulated by sexu. a small percentage of patients with than thyroid dysgenesis.8 Whether all types of thyroid dys.7 of relatively large numbers of patients with CH from The mechanism underlying the hypothyroidism in thyroid dysgenesis for mutations in these genes has the small fraction of patients with hemiagenesis who yielded negative results. indeed.

28 Ini.1 Apparent athyreosis Respiratory distress TTF-2 or TITF-2 Recessive True athyreosis Cleft palate FKHL15 Kinky hair FOXE1 Bifid epiglottis PAX 8 Dominant Normal None Orthotopic hypoplasia Apparent athyreosis TSHR Recessive Normal None Orthotopic hypoplasia Apparent athyreosis GLIS3 Recessive Apparent athyreosis Neonatal diabetes Hepatic fibrosis Congenital glaucoma Polycystic kidneys They were observed in either sporadic or familial reported. which is polymorphic. kinky hair.35 but this remains controversial.32-34 erozygous chromosomal 14q13 deletion detected However. nant transmission of the full syndrome has now been several studies have found an increased incidence of 115 . from thyroid dysgenesis is typically isolated. the thyroid is normal to congenital hypothyroidism. originally described by Bam- TTF-1 Mutations forth and colleagues.16. and bifid epiglottis. The phenotype is components of the syndrome has now been shown very variable both between families and even within to be wide and includes lethal neonatal respiratory the same family.22 The case initially or hypoplastic but is always in the normal position reported as “hypoplasia and ectopy”23 in fact never and has a normal shape.26. as had all the others. most cases were sporadic. CH tially.16 The length of the polyala- that haploinsufficiency for TTF-1 itself is responsible nine tract in TTF-2.25 The concept have TTF-2 mutations. It has also recently been shown that distress caused by the effect of TTF-1 on surfactant PAX8 mutations can lead to early onset rather than production.27 Mutations inactivating TTF-1 have now also been found in a condition that had NKX2. but autosomal domi.5 Mutations been described as benign hereditary chorea. may play a for the association of respiratory distress. Postulated mechanisms scription factor. germline mutations in TTF-2 result include monoallelic expression of the mutant allele in a phenotype that is not restricted to the thyroid. most cases of CH with cleft palate do not by fluorescence in situ hybridization. Genetics and Epigenetics of Congenital Hypothyroidism Table 9–1  G  ene Disorders Shown to Be from Thyroid Dysgenesis Associated with Primary Congenital Hypothyroidism Gene Name(s) Transmission Thyroid Morphology Other Abnormalities TTF-1 or TITF-1 Dominant Normal Hypotonia T/EBP De novo Orthotopic hypoplasia Choreoathetosis NKX2. cleft palate. Aside from the rare syndromes described earlier. had a scintiscan and likely had orthotopic hypoplasia.24 A complex syndrome of athyreosis.30 Morphologically. However. spring of three marriages between first cousins. in the thyroid. caused by homozygous TTF-2 mutations in the off- drome in humans was based on an infant with a het.31 has now been shown to be The initial description of the TTF-1 deficiency syn.10.29 The spectrum of severity of all three cases with dominant transmission. and neurologic symptoms has since dysgenesis.36 been confirmed. The reason why heterozygous TTF-2 Mutations mutations in PAX8 lead to a phenotype in humans Consistent with the expression pattern of this tran- and not in mice is unknown. primary role in the genetic predisposition to CH from thyroid thyroid failure.

may be the link to PPCH. encoding GLI simi.Part II  Pediatric Thyroid Disease mild congenital heart malformations. and only one had recessive disease. congenital glaucoma. pseudodominant transmis- disruption in the development of the arterial supply. the perchlorate dis- caused by mutations in GLIS3. The organification is abnormal. PPCH These sequence variants were transmitted by one of from thyroid dyshormonogenesis is an autosomal the ­parents. and polycystic kidneys has been shown to be cal for the diagnostic scintiscan. The involvement of NKX2.41 the transmission of TPO deficiency is typically auto- Our group has been following a 5-year-old girl with somal recessive. mostly septation (NIS) to its recycling through dehalogenase defects. has also been described. can cause CH and will lead to goiter forma- duction defects caused by mutations in NKX2. hepatic (which is not organified) as the radiopharmaceuti- fibrosis. with orthotopic thyroid hypo.37 Dominant transmission of heart con. in which case a mutation ­thyroid phenotype corresponds to that of apparent in thyroperoxidase (TPO) is the most likely. from the lies.10. intermediate values may not be easy to interpret and perchlorate is not available in all centers.50 However. cause of goitrous PPCH.5%. in two fami- in thyroid hormone synthesis (Table 9-2). and Williams syndrome.48 Partial maternal syndrome. With very few exceptions.23. However. If there is a goiter clinically and/or by ultrasound. a recently identified transcription factor. but this appears to be A recessively inherited syndrome of CH associated rare. GLIS3 Mutations a mutation in NIS is likely. With Syndromes Associated with Permanent the increased availability of sequencing techniques. clinician is available. PPCH is usually mild and maps. as defined earlier. which is caused by a deletion of the isodisomy for chromosome 2p. (DEHAL). but its precise a specific molecular diagnosis is sought.5 had tion. Trying to establish a specific diag- a heart defect. Among chlorate discharge test is not available.38 More recently. a linkage ­Hypothyroidism Caused by Thyroid study of 23 families in Sweden with presumably auto- ­Dyshormonogenesis somal recessive CH and no goiter has revealed linkage Mutations inactivating any one of the steps involved to the TG locus in 44.43 but in trisomy 21 observed such a pedigree. suggesting promoter or intronic muta- morphology on technetium scanning.39 er. to which the TPO gene elastin gene on 7q11. In ­ Williams tions or monoallelic expression.45 TPO clearly shown that patients with trisomy 21 present mutations have been found to be the most common a mild form of PPCH.5 in CH in nosis does not affect genetic counseling and should humans therefore remains to be confirmed.40 In DiGeorge syndrome. but no uptake of radioisotope. PPCH has plasma thyroglobulin (TG) level is high. even if a per- nature has not always been well defined. some of whom had cardiac anomalies. never delay treatment. The first description of a mutation in TG in humans was in a hypothyroid patient with a large goiter con- Permanent Primary Congenital trasting with a low plasma TG. charge test can be used to determine whether iodide lar 3. Interestingly.47 Although been reported but without scintigraphic diagnosis. given that ­associated with orthotopic thyroid hypoplasia. In centers using iodine rather than technetium with neonatal diabetes. who did not have CH. apparently manifesting heterozygotes DiGeorge syndrome and PPCH with normal thyroid are common.49 Finally. accounting for up to 46% of plasia. Moreover. which results from patients. sion can be expected.9. TPO Mutations The studies of van Trotsenburg and associates have Ever since their first description in 1992. the goiter was not only absent at birth but did up­take of iodine through the sodium-iodine symporter not develop during childhood in spite of growth and 116 .42 In carriers of mutated TPO alleles are frequently found DiGeorge syndrome. the goiter may not be present at birth been described in 1998.44 the best studied and most common syndromes are trisomy 21 and DiGeorge and Williams syndrome. Howev- athyreosis. even in nonconsanguineous essential for stabilization and growth of the thyroid families. rare NKX2.5 and can develop over the lifespan. the mechanisms underlying the link between the chromosomal lesion and PPCH Thyroglobulin Mutations are unknown. the candidate gene is TBX1 and in the general population. even CH (the imaging modality used to establish cause was when the neck is hyperextended and an experienced not specified). a ­Primary Congenital Hypothyroidism search for mutations in the genes involved in thyroid A great many dysmorphic syndromes are thought to hormone synthesis can now be carried out whenever be associated with hypothyroidism.46 A goiter is almost invariably present and the a deletion of chromosome region 22q11. and Deladoey and coworkers44 have recently lobes. goiters sequence variants were found in 4 of 241 patients with are difficult to detect with certainty in neonates.

It is caused by mutations in PDS.60 On the other hand. Recently.56. 117 . usually normal NIS Depends on iodine intake No uptake PDS Develops late High uptake. Pendrin is origin for transient CH has been confirmed in nine also expressed in the cochlea. contrasting with other forms gene that encodes pendrin. hypothalamopituitary unit and is associated with tained in iodotyrosines.51 in infancy and still lead to mental deficiency. or the association of deaf mut. hypothyroidism and goiter develop in late childhood and adulthood. where its role is thought other patients. which bears the G2320R mutation in TG type.57 factor have recently been identified in humans. PDT. PDT. mental retardation from late treatment of CH. hypoglycemia.52 only 30 more patients have been described. the enzymatic caused by sporadic developmental defects of the activity responsible for the recycling of iodine con. chronic iodine deficiency. abnormal TG May be absent ++ High uptake. tion of H2O2 at the apical membrane of the thyroid genital deafness. goiter.62 It is generally Mutations affecting dehalogenation. the expression of to be through its chloride transport capacity. all recognized causes of transient CH were A high iodine intake may prevent or delay the expres. and whose expression strongly depends d notion that TG ­mutations do not necessarily lead to on iodine intake. Screening patients gene products is correlated with the age at which the with CH caused by a total iodide organification defect phenotype becomes apparent. mimicking iodine microphallus) that leads to the diagnosis. involving the transplacental transfer of sion of the full phenotype of hypothyroidism and anti–TSH-R antibodies. Genetics and Epigenetics of Congenital Hypothyroidism Table 9–2  Mutations Inactivating Steps Involved in Thyroid Hormone Synthesis Scintigraphy and Gene Name(s) Goiter Hypothyroidism PDT ­Findings TPO ++ ++ High uptake. CENTRAL CONGENITAL HYPOTHYROIDISM Central congenital hypothyroidism is approximately Dehalogenase Mutations 10 times less common than PPCH. have been postulated to deficiencies of other pituitary hormones. The ­ eficiency. mutations in DEHAL1 goiter formation also stems from observations in the have been described in four patients with this pheno- WIC-rdw rat. heterozygous subjects had involved in the transport of iodine across the apical transient CH. perchlorate discharge test. normal PDT. of unknown cause. is thought to account for 10% of con. the hypothyroidism may not be and does not develop a goiter.. CH with excessive loss of iodine.g. a transmembrane protein of dyshormonogenesis. the enzyme responsible for the genera- ism and goiter.53 Until 2002. not genetic. normal or abnormal DEHAL ++ May develop after birth High uptake. However. NIS Mutations Transient Primary Congenital Since the first description of a mutation in NIS in ­Hypothyroidism: Mutations in DUOX2 1997.61a More typically.63 However.55 The DUOX activity in vitro requires a maturation factor.58 Importantly. a follicular cells. This first demonstration of a genetic membrane of the thyroid follicular cells. presumably because present at the time of neonatal screening but develop the rdw mutation is toxic to the host ­thyrocytes. Moreno and colleagues59 have found one patient with PPCH who was homozygous PDS Mutations for mutations in the gene encoding dual oxidase 2 Pendred’s syndrome.61 thyroid phenotype is variable and affected patients are and mutations in the gene encoding this maturation only rarely identified by neonatal TSH screening.54 The residual enzyme activity of the mutated and/or acute iodine overload. PDT. PDT. It is the explain an autosomal recessive form of goitrous clinical expression of the latter (e. (DUOX2).

1999. 118 .72 13. Lanzerath K. Perry R. C105Vfs114X. Ward JM. Dev Dyn tions in the thyrotropin-releasing hormone receptor 235:444-455. Deal C. Vassart G. Eur J Pediatr 159:456-458. Freson M. which was the clue to the molecular diagnosis. 1997. Delange F. Polak M. et al: A search for the Deficiencies possible molecular mechanisms of thyroid dysgen- In patients with mutations of PIT-1. Andersson L. CH with various combinations of other anterior pitu. J Clin in association with severe growth hormone and pro. Central 4072-4077. patients with mutations in the pituitary transcription ­Endocr Dev 10:29-42. tion. ­Associated with Other Pituitary Hormone 10. (TRH-R) has been reported.67 Bio. all patients with mutations in factor 1 is not required for the initial specification the gene encoding the TSH beta subunit gene that of the thyroid and lung primordia.   3. Rodd C. lactin deficiency. He presented with a relatively esis in infants with congenital hypothyroidism. et al: ­Discordance of monozygotic twins for thyroid dys- present with the same combination of deficiencies genesis: Implications for screening and for molecu- but may develop partial deficiencies of gonadotropin lar ­ pathophysiology. Clin mild phenotype (slow growth. 9th ed. 1999. Endocrinol Metab 84:2502-2506. ­Biochem 37:818-822. Isolated Central Congenital Hypothyroidism 2004. Arch Dis Child 24:972-976.69. Biochimie 81: have been reported since 199065. In Braverman LE. Van Vliet G: Hypothyroidism in infants and chil.66 presented with a 321-327. 12. Fireman BH: The also been reported. Bettendorf M. 2006. Philadelphia. key role of newborn thyroid scintigraphy with iso­ topic iodide (123I) in defining and managing con- genital hypothyroidism. Kimura S. factors LHX3. 2000.68 After TRH. but whether this represents a founder   9. and HESX1. 2007. hypothyroidism (CH) with thyroid dysgenesis. central CH occurs esis: Sex ratios and associated malformations. Chiovato L. Bonaiti-Pellie C. Clapp W. Pediatrics 114:e683-e688. of thyroid hemiagenesis: Ultrasound screening chemically. Fagman H. tive in the diagnosis of congenital hypothyroidism ly. 2005. Nilsson M: The devel- Mutations in the Thyrotropin-Releasing Hormone Receptor oping mouse thyroid: Embryonic vessel contacts (TRHR) and parenchymal growth pattern during specifica- So far. 2001. ­enhancer-binding protein/thyroid transcription tion described earlier.   5. and lobulation. To TT. Although thyroxine was   4. whereas the high basal prolactin level increases than single scanning. Biochemi. Heinrichs C. Castanet M. et al: Screen- ing for Pax8 mutations in patients with congenital hypothyroidism in South-West Germany. et al: Mutations dren. Shabana W. Devos H.71 Patients with PROP1 mutations 11. Central Congenital Hypothyroidism J Clin Endocrinol Metab 86:2009-2014. Maroo S. Bourdoux P. TSH was not elevated. Maclennan AC.   6. Gagne N. 14. Fillion M. TSH increases slight. Van Vliet G: Possible non- itary hormone deficiencies can also be observed in mendelian mechanisms of thyroid dysgenesis. Djemli A. further. 2004. et al: Twenty years low at neonatal screening. migration. Belgoudi J. Utiger RD (eds): Werner in the gene encoding thyroid transcription factor-1 and Ingbar’s The Thyroid: A Fundamental and (TTF-1) are not a frequent cause of congenital Clinical Text. LHX4. et al: Apparent con- cally.70 ­Nineteen years of national screenbing for congeni- tal hypothyroidism: Familial cases with thyroid dys- genesis suggest the involvement of genetic factors. ­Thyroid 7:383-387. Lapi P. plasma TSH may be recognized in some in normal children. et al: Prevalence mental retardation if not promptly recognized.   1. severe phenotype and were consequently at risk for   7. pp 1029-1047. immunoassays and the TSH value may be slightly ele. Macchia PE.Part II  Pediatric Thyroid Disease rare cases of isolated central hypothyroidism have   2. 2006. Schoen EJ. only one case of compound heterozygous muta. retarded bone matura. Perry RJ. The most common mutation appears to be 2006. et al: Combined vated. but not as would be expected for the degree of ultrasound and isotope scanning is more informa- hypothyroxinemia. Deladoey J. ­ Lippincott. Parma J. ­Williams & Wilkins. Horm Res References 66:96-100. Minoo P: Thyroid-specific In contrast to the single patient with a TRH-R muta. et al: effect or a hot spot is controversial. Haag C. so the later: A reevaluation of the contribution of plasma thyroglobulin to the diagnosis of thyroid dysgen- patient was not recalled. 2002. tion.64 thyroglobulin levels and associated with inactivat- ing mutations in the thyrotropin receptor gene: Mutations in the Thyroid-Stimulating Hormone Beta Are athyreosis and ectopic thyroid distinct entities? ­Subunit Gene J Clin Endocrinol Metab 83:1771-1775.   8. Gagne N. J Clin Endocrinol Metab 87: and adrenocorticotropin over their lifespan. budding. 1998. neither TSH nor prolactin rose after exogenous genital athyreosis contrasting with normal plasma TRH. and bradycardia) at the age of 9 years.

 Devriendt K. J Med Genet 26:49-51. 1997. spiky hair. Eur J Endocrinol for Congenital Hypothyroidism (1991-1998). Kuribayashi T. Stazi MA. Eur J Endocrinol 145:385-389. 2001. 25. et al: PAX8 mutations 38. Schutz B. et al: Mutation of FOXE1 gene expression patterns during human de. 23. Ohtsuka T. van Dongen JW. et al: Germ. et al: Thyroid 27. Endocrinol Metab������������������������������������������������� 87:557-562. Horm Res 66:289-296. Ribeiro M. Bellanne-Chantelot C. dysgenesis. et al: PAX8. mations. Krude H. 2002. et al: A novel loss- 19. 2006. 2007. et al: A popu- cohort of 170 patients with congenital and early-onset lation-based study on the frequency of additional hypothyroidism: Identification of a novel PAX8 congenital malformations in infants with congeni- mutation in dominantly inherited early-onset non. nonautoimmune subclinical hypothyroidism. J Clin Invest 109:475-480. congenital tory failure and mild primary hypothyroidism in a term hypothyroidism. J Clin Endocrinol Metab 91:4183-4187. Breedveld GJ. 2002. opment and thyroid dysgenesis-associated malfor. 2001. Auge J. neonatal respiratory distress. as a distinct entity in five multigenerational ­kindreds: 36. Castanet M. 1998. morphology and subclinical hypothyroidism in athetosis. Lapi P. et al: Autosomal 39. Clin 156:521-529. Limanova Z. thyroid agenesis and thyroid hormone levels: The earliest diagnostic clue cleft palate. Mimouni-Bloch A. 2002. et al: Partial de. et al: Deletion of thyroid transcription factor-1 gene in Trisomy 21 causes persistent congenital hypothy- an infant with neonatal thyroid dysfunction and roidism presumably of thyroidal origin. ing for mutations in transcription factors in a Czech 37. J Clin Endocrinol Metab 90:4025-4034. Nat Genet 19:83-86. 2006. Senee V. Zundel D. Scavina M: Auto- ­Absence of mutations in the gene encoding ­thyroid somal dominant transmission of congenital hypo- transcription factor. 2005. TITF1. Hum et al: Autosomal dominant resistance to ­thyrotropin Genet 122:467-476. Maquet E. Ohyama Y. Bamforth JS. Grasberger H. Schrumpf P. ­hereditary chorea. Sura-Trueba S. Thyroid respiratory failure. et al: Congenital associated with congenital hypothyroidism caused heart disease caused by mutations in the transcrip- by thyroid dysgenesis. linism. and pulmonary altera. 2002. and 32. ed with congenital hypothyroidism but not athyreo- line mutations of TSH receptor gene as cause of sis. J Clin 35. et al: Con- Molecular mechanisms of neonatal hyperinsu­ genital hypothyroidism. 17. Parma J. Duchatelet S. in GLIS3 are responsible for a rare syndrome with poplasia due to loss-of-function mutation of PAX8. Cambiaso P. children and adolescents with Williams syndrome. Hishinuma A. Banco M. 1989. et al: Choreo. Basson CT. Scuccimarri R. tions due to human NKX2-1 haploinsufficiency. or isolated cleft palate. Trueba SS. caused by a mutation of NKX2-1. Rydlewski C. mutation in human TTF-2 (FKHL15) gene associat- 20. Krude H.338 16:671-680. Clifton-Bligh RJ. analysis of TTF-2 gene in children with congeni. et al: Genetic 190-193. Perna MG. 24. Ohzeki T: of-function mutation in TTF-2 is associated with ­Hyperthyrotropinemia in a neonate with normal ­congenital hypothyroidism. Smith A. cleft palate and choanal atresia. Pohlenz J. the gene encoding human TTF-2 associated with velopment: New insights into human thyroid devel. J Clin Endocrinol Metab 94:197-203. 2005. Development 133:3797-3804. Schott JJ. Thyroid abnormalities as 26. Matsuo M. 2004. Olivieri A. et al: Clinical characterization and exclusion of candidate ­Polymorphism of the polyalanine tract of thyroid loci. Yokoro S. Hughes IA. 2006. et al: Screen. 1998. Proverbio MC. 2008. de Zegher F. Kempers MJ. hypothyroidism. Thyroid 7:377-381. mice. 2006. De Filippis V. phic length of FOXE1 alanine stretch: Evidence for 21. 2004. 2002. Hum Mol Genet 11:2051-2059. et al: 29. N Engl J Med 1998 Apr 30. et al: Mutations dominant transmission of congenital thyroid hy. Costagliola S. Chelala C. transcription factor-2 gene in patients with thyroid 22. 1998. Arisoy AE. et al: Lethal respira- tal hypothyroidism and cleft palate. Carré A. 2007. 18. Endert E. Lapi P. Danesino C. Biol Neonate 58: 34. Nat Genet 38:682-687. 2002. roidism. Costagliola S. et al: Polymor- Endocrinol Metab 87:2549-2555. and ­ataxia ­thyroid dysgenesis. 1998. 1990. Alt B. J Clin Invest 109:469-473. Vanhole C. Nat Genet 19:399-401. Biebermann H. Tonacchera M. Mattei G. et al: Arteries define 28. 33. (18):1317-8. Biebermann H. Vantyghem MC. 119 . et al: 31. Smith A. 41. Wentworth JM. Alberti L. Mastroiacovo P. a feature of DiGeorge syndrome: A patient report ficiency of thyroid transcription factor 1 produces and review of the literature. Orazi C. for pseudohypoparathyroidism. Science 281:108-111. Gonzalez I. 30. Baris I. Vilain C. Doyle DA. Lazarus JH. J Pediatr Endocrinol predominantly neurological defects in humans and Metab 11:273-276. van Trotsenburg AS. J Pediatr 145: 16. 2006. Giurgea I. J Clin Endocrinol Metab 90:455-462. et al: A novel missense 69-72. genetic susceptibility to thyroid dysgenesis. 42.1 (TTF-1) in patients with thyroidism. 43. Rodd C. Thomas B. Genetics and Epigenetics of Congenital Hypothyroidism 15. Civitareale D. J Pediatr 150:62-65. Al Taji E. gene. Dumitrescu A. neonatal diabetes mellitus and congenital hypothy- J Clin Endocrinol Metab 86:234-238. Elsalini OA. Hum Mol Genet 11:971-979. Duprez L. 40. tal hypothyroidism: Data from the Italian Registry autoimmune hypothyroidism. 1998. thyroid agenesis. Benson DW. Castanet M. Macchia PE. Matthijs G. et al: the position of the thyroid gland during its develop- ­Mutations in TITF-1 are associated with benign mental relocalisation. tion factor NKX2-5. Digilio MC. Thyroid girl with a de novo heterozygous mutation in the TTF1 14:584-588. and cleft palate. Park SM. 2007.

Endocr Dev 10:99-117. Nat Genet bonucleic acid analyses of five families with familial 17:122. Eur J Endocrinol 152:193-198. in silico studies. of the human thyroid peroxidase gene causing con. Riepe FG. Grasberger H. gene. Eur J study of five unrelated families from Switzerland Pediatr 167:777-783. et al: Pseudodomi. C105Vfs114X thyrotropin-beta mutation: Genetic tion of two novel PDS/SLC26A4 mutations. Evolution of Endocrinol 156:511-519. 69. Glaser B. Biebermann H. ital secondary hypothyroidism due to a mutation roidism detected by neonatal screening: Identifica. et al: High DUOX2 mutations. Hiraoka Y. factor 2 (DUOXA2) gene as a novel cause of con- 2005. 2003. Clin Endocrinol Diabetes 114:227-234. 2003. Cochaux P. Thyroid 10:387-391. Heinrichs C. Domene HM. et al: Neona- causing total iodide organification defect. 53. 4811-4816. van Heijst AF. Vuissoz JM. thyrotropin beta 313 Delta T mutation is caused mally located gland: A regional cohort study. Soares JP. Targovnik HM. J Clin tal screening for congenital hypothyroidism based Endocrinol Metab 88:3264-3271. 1990. Bhayana S. J Clin Endocrinol gene. Ding M. Cinek O. J Pediatr for congenital goiter with hypothyroidism. Bikker H. 93:605-610. 2006. Czernichow P. 64. J isodisomy for chromosome 2p causing severe con. Scherberg NH. Deladoey J. Al TE. tal hypopituitarism associated with neonatal hypo- 50. et al: Con- portion of various types of thyroid disorders among genital central hypothyroidism due to homozygous newborns with congenital hypothyroidism and nor. 1992. 1991. et al: Initially elevat- 54. N Engl Identification of a mutation in the coding sequence J Med 347:95-102. Thyroid 13:553-559. J Clin Endocrinol Metab 63. thyrotropin. 120 . tivating mutations in the thyrotropin-releasing goitrous congenital primary hypothyroidism in the hormone receptor gene. 2008. et al: A 3� splice glycemia and microphallus: Four cases secondary site mutation in the thyroglobulin gene responsible to hypothalamic hormone deficiencies. Grasberger H. Varela V. Fujiwara H: Congenital hypothyroidism caused 65. an eukaryotic operon equivalent. Kosugi S. J Clin 87(Pt 2):1171-1181. Avbelj M. Ieiri T. J Clin Endocrinol Metab 93:627. J Clin Endocrinol Metab 87: Endocrinol (Oxf) 62:444-448. Leger J: Pro. lelic expression of mutant thyroid peroxidase allele 62. Beck JC. Clin by a Founder effect. 2006. 68. J Clin Invest 90:1200-1204. 1999. J Clin Endocrinol gene: Case report and review of the literature. Deladoey J. Moreno JC. 2006. et al: A missense muta. 2002. 2008. Brumm H. Tang J. 58. Szinnai G. 1975. 2006. screening of the thyroid peroxidase gene in a 61a. Visser TJ: New phenotypes in thy- genital goiter. Pfeufer A. Lovinger RD. Partsch CJ. et al: Con- drome is caused by mutations in a putative sulphate genital central isolated hypothyroidism caused by transporter gene (PDS). genital hypothyroidism. 1997. Exp Metab 84:3248-3253. Abramowicz MJ. Metab 91:1199-1204.Part II  Pediatric Thyroid Disease 44. et al: A novel mecha- 51. on thyroxine. Kempers MJ. Bakker B. Rodrigues C. et al: (THOX2) and congenital hypothyroidism. et al: Monoal. et al: Deoxyri- by a mutation in the Na+/I− symporter. et al: Pendred syn. et al: Congen- ­syndrome among patients with congenital hypothy. Hennekam RC. 2008. Kempers MJ. vating mutations in the gene for thyroid oxidase 2 45. Tatsumi K. Menon S. 2005. 2001. Dean HJ: A novel mutation in ed TSH and congenital central hypothyroidism due the sodium/iodide symporter gene in the largest to a homozygous mutation of the TSH beta subunit family with iodide transport defect. J Clin Endocrinol Metab 48. Gaudino R. Dacou-Voutetakis C. 52. 59. Pfarr N. Mannavola D. 1990. Collu R. 57. Derrien C. 67. Eur J maturation factor for dual oxidase. Tahirovic H. Invest 88:1901-1905. 1997. 56. and Argentina. genital hypothyroidism. Mol Endocrinol 14:1944-1953. Cerutti N. 60. a homozygous mutation in the TSH-beta subunit 1997. Bikker H. in the thyroid-stimulating hormone beta-subunit phenotype correlations in ITD. Banghova K. N Engl J Med 358:1811-188. 2007. inherited thyroid stimulating hormone deficiency. Parma J. Moreno JC. J Clin Endocrinol Metab WIC-rdw rat. Everett LA. 2002. et al: Mutation 18269-18272. et al: Pendred 70. Am J Hum Genet 46:988-993. Grumbach MM: Congeni- 86:1164-1168. 82:1561-1565. in the iodotyrosine deiodinase gene and hypothy- roidism caused by TPO mutations: Molecular and roidism. Castagne J. Vuissoz JM. Clin Endocrinol Metab 91:3370-3376. roid dyshormonogenesis: Hypothyroidism due to 46. Kosugi S. Lanting CI. et al: Inacti- 633. J Biol Chem 281: 47. Kaplan SL.Zamproni I. Fugazzola L. 2007. Hayashizaki Y. and thyroxine-binding 49. et al: Bial­ ­cohort of 55 Portuguese patients with congenital lelic inactivation of the dual oxidase maturation hypothyroidism. Moreno JC. Jorge P. 2000. et al: Familial (ITD): A novel mutation R124H of the sodium/­ hypothyroidism caused by a nonsense mutation iodide symporter (NIS) gene and review of genotype. van TH. et al: Maternal globulin measurement: Potentials and pitfalls. 2008. clinical heterogeneity of iodide transport defect 66. Krone N. Feltquate DM. Klootwijk W. Garel C. prevalence of thyroid peroxidase gene mutations 61. Refetoff S: Identification of the in patients with thyroid dyshormonogenesis. Debeljak M. et al: Extending the J Clin Endocrinol Metab 71:792-796. 55. Kim PS. Cortinovis F. Targovnik HM. 2000. et al: Mutations nant inheritance of goitrous congenital hypothy. Nat Genet 17:411-422. nism for isolated central hypothyroidism: Inac- tion G2320R in the thyroglobulin gene causes non.

Genetics and Epigenetics of Congenital Hypothyroidism

71. Ward L, Chavez M, Huot C, et al: Severe congenital 72. Kelberman D, Dattani MT: The role of transcription
hypopituitarism with low prolactin levels and age- factors implicated in anterior pituitary ­development
dependent anterior pituitary hypoplasia: A clue to in the aetiology of congenital hypopituitarism. Ann
a PIT-1 mutation. J Pediatr 132:1036-1038, 1998. Med 38:560-577, 2006.



Hypothyroidism 10
Joanne F. Rovet, Thomas P. Foley, Jr., and Meranda Nakhla

Key Points

n������ Distinct challenges in managing hypothyroidism in the pediatric population
n������ Thyroid hormones’ unique role in early brain development and subsequent brain function
n������ Congenital and acquired hypothyroidism—causes, clinical features, diagnosis, and treatment;
common pitfalls in diagnosis or misdiagnosis, including consequences of late diagnosis
n������ Persisting subtle deficits in adequately treated congenital hypothyroidism and associated risk factors
n Outcome following therapy for acquired hypothyroidism and potential adverse effects of therapy

Hypothyroidism is caused by a deficiency in the role in later brain functioning.1 Thyroid hormone
secretion of thyroid hormones produced in the thy- is involved in fundamental neurobiologic processes
roid gland. Because thyroid hormone is essential for such as neurogenesis,2 axon and dendrite forma-
normal growth and development, adequate metab- tion,3 neuronal migration,4-6 myelination,7 and syn-
olism, and proper brain development, the conse- aptogenesis,8 with the timing of need for thyroid
quences of hypothyroidism in childhood can be hormone varying among different brain structures.
devastating, particularly in children with neonatal In the brain, the need for thyroid hormone proceeds
hypothyroidism. A delay of treatment in this group in a subcortical to cortical direction and, within the
can result in permanent brain damage and mental cortex, in a posterior to anterior direction, with the
retardation. frontal lobes needing thyroid hormone last.9 Struc-
There are two major forms of hypothyroidism tures showing the greatest need for thyroid hormone
in the pediatric population: (1) congenital hypothy- include the following: the thalamus, which is impor-
roidism (CH), which represents a group of ­diseases tant for perception; the cerebellum, important for
developing at conception or during gestation and motor coordination; the caudate, important for
are present at birth; and (2) acquired hypothyroid- attention; the hippocampus, important for memory;
ism (AH), which usually appears after 6 months of and the cortex, important for multiple aspects of cog-
age and arises from autoimmune destruction of the nitive functioning. In addition, thyroid hormone is
thyroid. The management of hypothyroidism in an also involved in cochlear10 and retinal11 development
infant or young child poses challenges distinct from and, in the retina, rod versus cone distribution and
those of adult hypothyroidism because of the need the patterning of the cone subtypes underlying color
to diagnose and treat affected children as quickly as vision.12-14 In rodents, a lack of thyroid hormone dur-
possible. This is particularly vital for children younger ing gestation and/or early life contributes to damage
than 3 years. Additionally, among older children pre- in the various thyroid hormone–­dependent brain
senting with severe AH, it is important to introduce structures; although this can be reversed or mini-
replacement hormone slowly to prevent adverse reac- mized by the administration of exogenous hormone,
tions that may result from exposing the brain to high it must be provided within a critical developmental
levels of exogenous hormone after having adjusted window to have an effect.15,16
to its hypothyroid state over the long term. Thyroid hormone acts by regulating specific
Regarding the loss of thyroid hormone in brain genes,17,18 which underlie the basic processes
infants and children, results of extensive animal of brain development described. Thyroid-specific
studies have demonstrated that thyroid hormone is gene regulation is accomplished via a set of distinct
essential for early brain development and plays a key thyroid hormone receptors,2,19,20 which along with


Part II  Pediatric Thyroid Disease

specific coactivators and corepressors21,22 activate common in Hispanic than white infants and less com-
or deactivate particular brain genes.23 Receptor dis- mon in blacks than in whites. CH is also comorbid
tribution varies ontologically and regionally,24 with with Down syndrome (DS) and may occur in as many
some brain structures showing a greater need for as 1 in 128 DS cases.41
thyroid hormone than others.25 This finding is sig- The two major CH subcategories are (1) pri-
nificant for humans, in whom impairment from early mary hypothyroidism, resulting from a defect at the
thyroid hormone loss is more likely to result in spe- level of the thyroid gland and (2) central hypothyroid-
cific rather than global deficits; the exact nature will ism, reflecting a defect in hypothalamic or pituitary
depend on the precise timing of thyroid hormone regulation of thyroid hormone levels. At the thyroidal
insufficiency. level, CH can result from thyroid dysgenesis caused by
Thyroid hormone also plays an important role a missing, ectopic (lingual or sublingual), or hypoplas-
in neurotransmission.26-30 During early life, t­hyroid tic gland or from thyroid dyshormonogenesis caused
hormone controls production of neurotransmit- by a gene defect in one of the many stages of thyroid
ter systems29 whereas in later life, thyroid hormone hormone synthesis and transport42 (see Chapter 9).
regulates catecholamine production and responsive- In thyroid dysgenesis, girls are twice as frequently
ness.31,32 Studies with transgenic hypothyroid mice affected as boys and, in most forms, this occurs spo-
show impaired GABAminergic (­gamma-­aminobutyric radically.43 Several genes found to be associated
acid, GABA) circuit formation accompanied by with thyroid dysgenesis include TTF-1, TTF-2, and
reduced exploratory behavior and increased freez- PAX8; however, because defects in these genes have
ing in fear conditioning.33 Thyroid hormone also ­accounted only for about 10% of all cases with thyroid
modulates the production of tyrosine hydroxylase, dysgenesis to date, the picture is far from complete.
the rate-limiting enzyme in dopamine and norepi- In thyroid dyshormonogenesis, males and females are
nephrine production,34 and is thought to act as a equally affected and inheritance is autosomal reces-
cotransmitter,35 traveling along central noradren- sive, often with multiple family members affected.
ergic pathways.36 In addition, thyroid hormone (1) Additionally, 1 in 50,000 children may have
activates neurons via astrocytes,37 (2) affects synaptic thyroid hormone resistance caused by a mutation in
transmission between neurons through the release the gene encoding the thyroid hormone receptor β
of glutamate,8 (3) upregulates a sodium-dependent (TRβ) receptors. Inheritance is autosomal dominant
neurotransmitter transporter gene38 and other genes and the distribution of receptor mutations within
involved in neurotransmitter function,39 and (4) con- an individual and family is generally heterogeneous.
trols GABA release and reuptake,40 as well as GABA Thyroid hormone resistance is classically categorized
receptor function.38 Furthermore, thyroid hormone as the following: (1) central, with receptors within the
effects on neurotransmitter function are different in pituitary affected; (2) peripheral, with only receptors
the developing than in the adult brain38 where, for in the peripheral tissue affected; or (3) generalized,
example, thyroid hormone stimulates GABA func- with receptors in both the central nervous ­ system
tion in early life and inhibits it later. Because these (CNS) and peripheral tissue affected. Clinically,
actions have functional implications for humans, patients may be hypothyroid (2, 3), euthyroid (1, 2,
they underscore the need to maintain proper levels 3), or hyperthyroid (1), depending on the severity of
of thyroid hormone beyond the period of early brain the receptor mutation and tissue distribution of the
growth. Thus, a further purpose of this chapter will mutant genes.
be to examine outcomes in children with CH and AH In a small proportion of children, CH may
in relation to adequacy of therapy. be transient because of intrauterine transmission of
maternal antibodies, which block the developing fetal
EPIDEMIOLOGY, RISK FACTORS, thyroid from functioning, or because of pre- and peri-
AND PATHOGENESIS natal exposure to excess iodine from radiocontrast
The epidemiology and associated risk factors for con- and antiseptic solutions.44,45 Based on animal studies,
genital and acquired hypothyroidism vary, depend- it is also possible that some children can experience
ing on the cause. Table 10-1 compares some of the mild hypothyroidism from certain environmental
most common causes of the two conditions. chemicals,46 such as flame retardants or polybro-
minated diphenyl ethers (PBDEs), mercury, lead,
Congenital Hypothyroidism ­dioxins, and polychlorinated biphenyls (PCBs).47
In areas of iodine sufficiency, CH sporadically affects However, studies directly examining the impact of
between 1 in 3000 to 4000 newborns. This incidence these chemicals on children’s thyroid function have
is higher in areas of iodine insufficiency. CH is more not been conducted.



Table 10–1  Causes of Hypothyroidism

Congenital Hypothyroidism Acquired Hypothyroidism

Permanent Sporadic Hypothyroidism Late-onset, mild congenital hypothyroidism
Thyroid dysgenesis Ectopic thyroid dysgenesis
Athyrosis Familial thyroid dyshormonogenesis
Ectopia Peripheral resistance to thyroid hormone action
Hypoplasia, iatrogenic Acquired primary hypothyroidism
Maternal exposure to 131I-iodine—congenital defects in Chronic autoimmune thyroiditis
­embryogenesis; PAX8, TTF1, TTF2 Lymphocytic thyroiditis of childhood and adolescence with
Idiopathic hyperthyrotropinemia (subclinical ­hypothyroidism
of infancy) Hashimoto’s thyroiditis with thyromegaly
Isolated Chronic fibrous variant
Down syndrome Acquired autoimmune-mediated infantile hypothyroidism
Drug-induced hypothyroidism
Idiopathic primary hypothyroidism—PAX8, TTF1, TTF2
Antithyroid drugs (propylthiouracil, methimazole,
Permanent Familial Hypothyroidism
Lithium (therapeutic doses to treat bipolar diseases)
Dyshormonogenesis Endemic goiter
TSH-beta loss-of-function mutations Iodine deficiency with or without selenium deficiency
TSH receptor loss-of-function mutations Environmental goitrogens
Unresponsiveness with mild-to-severe hypothyroidism Therapeutic radioiodine
Iodide trapping defect (sodium iodide symporter Environmental exposure to thyroid disruptors (PCBs, PBDEs,
­mutations) lead, dioxins, perchlorate)
Iodide oxidation defects Surgical excision (cancer, hyperthyroidism)
Pendred’s syndrome Subacute thyroiditis: transient phase
Thyroperoxidase mtuations External irradiation of nonthyroid tumors
Iodotyrosine deiodinase defect Irradiation of thyroid by external irradiation, ingestion
Permanent hypothalamic-pituitary hypothyroidism and inhalation from environmental sources (e.g., nuclear
Multiple hypothalamic hormone deficiencies power plant accidents, atomic bomb detonations, terrorist
Idiopathic attacks with dirty bombs)
Associated with midline central nervous system anatomic
Isolated TRH deficiency
Isolated TSH deficiency
Transient hypothyroidism
Iodine deficiency
Congenital nephrosis, iatrogenic
Maternal or neonatal exposure to iodine
Maternal antithyroid drug therapy
Maternal TSH receptor-blocking antibodies
Maternal chronic autoimmune thyroiditis
Transient dyshormonogenesis
Oxidation defect

PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating

Acquired Hypothyroidism The most common cause of AH is Hashimo-
AH can affect as many as 1% to 2% of adolescents. to’s thyroiditis, an autoimmune disorder caused by
AH is more common in children older than 10 years, abnormalities of the humoral and cellular immune
very rare in infants, and more frequent in females systems. Although the specific genetically pro-
than males. grammed immune-mediated mechanisms ­producing


Part II  Pediatric Thyroid Disease

AH are poorly understood, the primary effect appears (see Chapter 8). Typically, diagnosis from newborn
to be an immune response against normal thyroid screening occurs before most physical signs and symp-
cells, which leads to inflammation, destruction, and toms are evident. In neonates, the most common
death of thyroid follicular cells, destroying as much signs and symptoms of CH after birth are ­prolonged
as 75% of the thyroid tissue. Hashimoto’s thyroiditis neonatal jaundice, hypothermia, large anterior
is also often associated with other autoimmune dis- and posterior fontanelles, an umbilical hernia, and
eases, such as type 1 diabetes mellitus, Addison’s a puffy face. An Australian study has reported that
­disease, and rheumatoid arthritis, and it is common 62% of infants diagnosed with CH have ­ jaundice,
in DS and Turner’s syndrome. 54% have an umbilical hernia, 41% have edema,
In addition, AH may be induced by certain and 21% have a protruding tongue, whereas only 6%
psychotropic medications, which can also alter thyroid show an enlarged thyroid on palpation.48 In addi-
function tests to yield false-positive data indicative of tion, approximately 15% of CH children also show
­hypothyroidism. For example, lithium carbonate in an increased incidence of major congenital malfor-
high doses used to treat bipolar diseases, iodinated mations,48 particularly cardiac (7%) and urogenital
drugs such as amiodarone, and cytokines (e.g., inter- (3%) abnormalities.
feron-gamma [IFN-γ], interleukin-6 [IL-6], granulo- Most neonates with CH are born full term,
cyte-monocyte colony stimulating-factor [GM-CSF]) with a substantial number born past 42 weeks gesta-
all interfere with thyroid hormone synthesis and/or tion and at birth weights more than 4 kg. With age,
secretion to cause primary hypothyroidism. This those infants not promptly treated show general-
effect usually occurs in biochemically and clinically ized myxedema, carotenemia of the skin, wiry and/
euthyroid patients with little thyroid reserve caused or excessive dark hair, macroglossia, and increased
by an existing thyroid disease, such as autoimmune floppiness and muscle weakness (Fig. 10-1) and may
thyroiditis. In similar patients, as well as those on a also ­develop strabismus and nystagmus. In addition,
fixed dose of thyroxine, antiepileptics (e.g., pheno- they display marked lethargy, little activity, decreased
barbital, phenytoin, carbamazepine) and the antitu- appetite, and severe constipation over time.
berculosis drug rifampicin can stimulate cytochrome Rarely, but not uncommonly, some children
P450 inducers to accelerate the hepatic degradation with CH are missed by the newborn screening pro-
of thyroxine, whereas other drugs such as propylthio- gram. Lack of detection can arise from problems in
uracil (PTU), beta blockers, dexamethasone, and submitting and shipping samples, errors in labeling,
other iodinated preparations inhibit 5′-deiodinase. laboratory error, and problems with data entry. In a
Phenytoin and substances such as heparin, free fatty few cases, children may fail to receive the newborn
acids, and salicylates compete with thyroxine (T4) for screening test for reasons such as transfer to ­another
T4-binding proteins to cause low T4 values and even hospital or home birth. In other cases, children may
interfere with many of the free T4 tests. Thus, when pass the screening test but show delayed presenta-
thyroid function test results do not make sense, the tion of CH, particularly if T4 screening is used; in
problem could be other medications that might be still others, the particular condition may not be
inducing hypothyroidism or interfere with the labo- identified by the particular screening method (e.g.,
ratory analysis. central hypothyroidism and the TSH test). Although
some states provide a second screen between 2 and
CLINICAL FEATURES 4 weeks of age, which is capable of catching these
The most common symptoms and signs of CH and delayed presentation cases, second screening is not
AH are listed in Table 10-2. The appearance of a spe- universal and costly and it is not known to what
cific symptom or sign depends on the age at which degree these children still suffer residual dam-
the hypothyroidism develops, duration of the disease, age during the period between the two screening
and disease severity. Often, findings may not be obvi- tests. Although many parents of children missed
ous to parents or physicians until the child’s growth by screening are usually very aware and concerned
velocity declines or hypothyroidism progresses to a their infant was not developing normally, their phy-
moderate or severe stage. sicians failed to make the proper diagnosis and did
not conduct diagnostic tests despite seeking advice
Congenital Hypothyroidism from geneticists, ophthalmologists, and gastroen-
Today, almost all infants with CH born in the United terologists (who also failed to make the diagnosis).
States and Canada are identified through ­ newborn Thus it is critical that all physicians be cognizant of
screening programs, which assess for abnormal the possibility for a missed screening test and thus
­thyroid-stimulating hormone (TSH) and/or T4 ­levels be prudent of the need to diagnose CH clinically,



Table 10–2  Common Symptoms and Signs of Hypothyroidism

Congenital Hypothyroidism Acquired Hypothyroidism

Findings During the First 2 Postnatal Weeks Findings Between 6 Months and 3 Years of Age
Prolonged neonatal jaundice Deceleration of linear growth
Edema of the eyelids, hands, and feet Coarse facial features
Gestation > 42 wk Dry skin with carotenemia
Birth weight > 4 kg Hoarse cry and large tongue
Poor feeding Umbilical hernia
Hypothermia Muscular pseudohypertrophy (enlargement of the arm
Protuberant abdomen and leg muscles)
Large anterior and posterior fontanelles
Findings During Childhood
Findings Beyond Age 1 Month Deceleration of linear growth with or without short
Darkened and mottled skin stature
Stressful, frequent, and labored breathing Delay in eruption of teeth and in shedding of primary
Failure to gain weight
Muscle weakness and pseudohypertrophy (enlargement
Poor sucking ability of the arm and leg muscles)
Decreased stool frequency Infrequent and hard stools
Decreased activity and lethargy Dry skin with carotenemia
Generalized swelling or myxedema
Findings During the First 3 Months
Precocious sexual development—breast development
Umbilical hernia without sexual hair in girls; enlarged testes without sexual
Infrequent and hard stools hair in boys
Dry skin with carotenemia
Macroglossia Findings During Adolescence
Generalized swelling or myxedema Delayed onset of puberty
Hoarse cry Generalized swelling of myxedema
Infrequent and hard stools
Cool, dry pale skin with carotenemia, sallow color,
Peripheral vasoconstriction and, rarely, ecchymoses
Dry, coarse brittle hair with diffuse or partial alopecia
Madarosis or loss of the lateral third of eyebrow hair
Thick, brittle, and slow-growing nails
Galactorrhea (girls)

Figure 10–1  Children with
A B con­genital hypothyroidism prior to
(A) and after (B) newborn screening.


Part II  Pediatric Thyroid Disease

particularly given the devastating consequences of ism. Table 10-3 summarizes the evaluation of thyroid
delaying a diagnosis. function in different types of hypothyroidism. At
3 years of age, children should be taken off therapy
Acquired Hypothyroidism for 1 month and thyroid function tests repeated to
In acquired hypothyroidism, the most common pre- ascertain whether the hypothyroidism was transient.51
senting feature is failure or deceleration of growth In patients with central hypothyroidism, other pitu-
with delayed skeletal maturation. Although changes itary and peripheral hormones should be measured,
in body shape and a coarsening of facial features do especially cortisol, before thyroxine therapy is started.
become evident over time, the appearance of a child
with AH is usually not as striking as a child with cre- Acquired Hypothyroidism
tinism (Fig. 10-2). Children with AH may be slow in The diagnostic procedures for AH should include thy-
shedding their primary or developing teeth and also roid function tests and measuring thyroid peroxidase
have constipation, myxedema, coldness, dry skin, and thyroglobulin antibodies to establish the diagnosis
and muscle weakness. They also present with delayed of autoimmune thyroiditis. FT4 is preferred over total
puberty or rarely isosexual precocious puberty. T4 because the latter may yield misleading results from
Because the onset of AH is insidious, its diag- binding with thyroid-binding proteins. The investiga-
nosis is often delayed for months after a prolonged tion should also include examination of the neck for an
­period of abnormal linear growth. Moreover, because enlarged thyroid, measurement of linear growth and
children with AH are generally well behaved and achiev- growth velocity, assessment for signs and symptoms of
ing satisfactorily at school in the hypothyroid state, hypothyroidism, and determining a family history of
concern may be minimal. However, in rare cases where thyroid disease. Additionally, serum levels of gonado-
the disorder does develop in infancy, these children tropins, morning cortisol, and prolactin should be
often show many of the same features as late-­treated measured in patients with delayed puberty or concern
CH including deceleration of growth, coarse facial fea- of central hypothyroidism. Bone age, which is typically
tures, dry skin, wiry hair, hoarse cry, large tongue, an delayed, is often used as a marker of the onset of AH.
umbilical hernia, delayed dentition, delayed closure of Computed tomography and magnetic resonance imag-
the fontanelles, and lethargy. ­Toddlers and preschool- ing (MRI) of the brain may reveal an enlarged sella
ers with AH may also show regression of intellectual turcica caused by pituitary thyrotroph hypertrophy.52
and motor development following the onset of hypo- An empty sella and other CNS dysmorphic features,
thyroidism as well as engage in severe temper tantrums such as septo-optic dysplasia, may also be apparent.
and show increased irritability.50 Because of the brain’s
high need for ­thyroid hormone up to 3 years of age, TREATMENT
these children will likely be permanently affected and The treatment of hypothyroidism is relatively easy and
show neurodevelopmental delays. inexpensive and the treatment of choice for infants and
children is levothyroxine (l-T4). Although the total dose
DIAGNOSIS increases about three- to fivefold from infancy to adult
life, the daily dose per body weight steadily decreases
Congenital Hypothyroidism to an adult dose in adolescence. Treatment must be
The diagnosis of CH should be made as soon as pos- individualized because thyroxine absorption and ­
sible after the newborn screening results are avail- metabolism differ among individuals, making careful
able. Diagnostic tests should include a serum free monitoring essential. Because certain foods (e.g., soy
T4 (FT4), serum thyroglobulin if the thyroid gland is formulas, fiber-containing foods) can block intestinal
not palpable, and thyroid ultrasonography or tech- absorption of l-T4, these should be limited or closely
netium scan to establish the cause of hypothyroid- monitored. Similarly, because medications containing
iron or calcium can also block l-T4 absorption, these
should be given at different times of day than l-T4.
There are no complications from l-T4 therapy if
the proper dose is taken and blood tests are ­monitored
on a regular basis. Complications can be associated
with unrecognized or inadequately treated hypothy-
roidism, the worst being delayed treatment in infancy.
A B C Premature craniosynostosis following a high dose level
Figure 10–2  Child before hypothyroidism (A), after onset for many weeks in infancy is generally not seen, as long
of acquired hypothyroidism (B), and after treatment (C). as thyroid hormone levels are closely monitored.


Adapted from Germak JA.43 conveyed broadly.. one-and-a-half. Food facilities are typically treated by primary physicians and Drug Administration (FDA) has deemed that sev. two. the dose of ­Subtle dosage adjustments can also be achieved by the l-T4 should be reduced until the TSH is measurable addition or omission of one tablet/wk or by 12. or iron and the dose should be adjust. the recom- weight is normal and the baby was born full term. who may not be cognizant of the American Academy eral l-T4 products are bioequivalent to some current of Pediatrics guidelines.5 mg/day should be sufficient if the birth In managing a child with CH. overtreatment. Congenital Hypothyroidism allow for normalization of serum T4 and TSH within The American Academy of Pediatrics recommends a 3 days and 2 weeks.43 In patients for whom compliance is suspected until growth has ceased.5 μg.g. For infants with a TSH higher set the thyroid insufficiency56 because mother’s milk than 20 mU/L and normal T4 values. infants with athyreosis set of children who are refractory to treatment54 and who have very low or undetectable FT4 and highly may have a less sensitive than normal hypothalamic- ­elevated TSH levels are prescribed to start with 13 to pituitary-thyroid axis. initial and ongoing coun. We are aware of a number of cases If a parent misses a dose or thinks the dose was of children who received inadequate care for CH missed. ated with poor compliance.58 dose of 37. age when treatment is initiated. up. 25-μg tablets els in the upper end of the normal range for at least should be prescribed and children should be given. breast milk.5-μg and the clinical symptoms subside.52 Children showing serum to be poor. thyroid-stimulating hormone. and because of the major sequelae associ. may require dose retitration. However. or ­improper As a rule. the dosage on the next day should be doubled. thyrotropin-releasing hormone. The pill should be crushed in a sus. 75-μg. mended protocol is to evaluate the children at 2 and Thereafter. respectively. a starting l-T4 contains small amounts of thyroxine.59 In follow- l-T4 is available for infants in 25-.0 mU/L and T4 and/or FT4 in the upper monthly or quarterly between 6 months and 3 years half of the reference range for the first 3 years of of age. or two-and-a-half be undetectable despite normal FT4 levels. if the increments daily. or 62. monthly to age 6 months.5 and 2. and dosage of of therapy is to normalize T4 within 2 weeks and replacement hormone. hypothyroidism with a particular cause may need seling of parents is recommended. Hypothyroidism Table 10–3  Thyroid Function Test Results Hypothalamic Thyroid Function Test Primary Hypothyroidism Hypothyroidism Pituitary Hypothyroidism TSH Elevated Normal or low Low Free T4 Low Low Low TSH response to TRH Exaggerated Normal or delayed Absent and exaggerated T4. tri- 0.S. 1990.5. fiber.43 The U. Thus. although there is a small sub- TSH within 1 month. TSH elevations should receive a dose increment. Any change in source of l-T4. the first 3 years of life. no dose increments. normal FT4 with a measurable TSH. 50.57. associated with clinical thyrotoxicosis. Care should the dose slightly by half to one tablet/wk to retain be taken to avoid concomitant administration of soy. more frequent adjustments than others. thyroxine. (e. During infancy. J Pediatr 117:211-219. and semiannually or annually from 3 years life. especially if not tion about treatment and management of CH be a standard brand.53 The exact duration starting dose of l-T4 from 10 to 15 μg/kg/day taken of hypothyroid therapy usually reflects disease sever- at least 30 minutes before food intake. Foley TP Jr: Longitudinal assessment of l-thyroxine therapy for congenital hypothyroidism. TRH. TSH levels may for ­ example.55 Breast feeding can mildly off- 15 mg/kg/day of l-T4. Occasionally. or water. it is important that informa- brands. it is important to maintain TSH between 4 weeks after diagnosis. it is advisable to decrease pension of formula. starting dose levels of 10 to 15 μg/kg can parental education) from uninformed primary health 129 . 50-. child is clinically euthyroid. If this is tablets to get daily dosages of 37. calcium. The goal ity. TSH. a dose should be provided that maintains FT4 lev- and higher tablets. Because children from rural communities or ed according to the infant’s clinical response and who live in small cities that lack academic health care serum FT4 and TSH concentrations.

tion. initiation of replacement therapy. If the initial scan dotumor cerebri. episodic hip or knee sal in the developed world and is also seen in many pain caused by unilateral or bilateral slipped capi. developing nations (see Chapter 8). The rec. Serial objective measurements of vision determine and 2 to 3 μg/kg from 11 to 20 years. 6 μg/kg from 1 to 5 years. these children often showed significant tion. els in the middle or upper range of normal for age. then a trial off therapy should be considered also been reported in an infant with AH following at age 351. and on the need for invasive inter- ventions that rarely are seen in patients on l-T4 ther- Acquired Hypothyroidism apy for AH. this usu- nence of CH. these guidelines for clinical and thyroid function monitor. determined by the child’s size.64. Children missed by euthyroidism. ally disappears following treatment in most. however. the final adult height may be less than and more serious damage occurring if hypothyroid- expected. patients. standing hypothyroidism. and familial causes of CH. up to 250 mg three times daily.61 The opti. spo. improvement.60.. despite appropriate treatment. In obese serum TSH and maintain serum FT4 or total T4 lev. Excessive dosages should most children diagnosed clinically with CH were be avoided to prevent accelerated skeletal maturation at risk for mental retardation. with severity of the and consequently compromised final adult height impairment reflecting the length of delay in treat- and hyperthyroidism as well. In addition to in food. celiac disease. Confirmation of the cause can be accom. i­ntervention.62 or 123I-iodine scans and ultrasound using ­ standard ­ A small proportion of children may also expe- protocols for the evaluation of the permanent. 4 μg/kg from 6 to 10 years. the CH is perma. newborn screening and treated late often show the If diagnosis is delayed or treatment is inad. 6 to 8 μg/kg from 6 to 12 months. Cerebral venous sinus thrombo- mal maintenance dosage should normalize levels of sis should be excluded by MRI examination. formance in the hypothyroid state.63 Although these nent. This Congenital Hypothyroidism approach is optimal for children with severe and long.66 Treatment of the pseudotumor is usu- CH can be considered permanent and the individual ally based on expert opinion. The diagnostic lumbar puncture may cause daily dose. cases. A prudent approach based on our earlier studies is PROGNOSIS to provide a low dosage initially and gradually titrate the dose upward until euthyroidism is achieved. with visual function as will need to continue l-T4 therapy throughout life. but not plished by thyroid imaging using 99mTc-technetium all. the key to severity.67-69 As a rule. show slowing of mental function and poor school per- It is also important to assess for the perma. with severe headaches following shows an ectopic or absent gland. the prognosis for tal femoral epiphysis that often requires ­ surgical children with CH is far better than in the ­prescreening 130 . rience visual impairment with papilledema and pseu- radic. weight loss is an important intervention. because these can impair thyroxine absorp.g.73 hypothyroidism is also associated with high levels of Because newborn screening is almost univer- cholesterol. and chronic constipation. Similarly. ­abnormalities usually disappear with appropriate ing and at the prescribed intervals for infants and treatment. children with malabsorptive disorders neurobehavioral impairments. same characteristics as those prior to screening.60 Except fore essential that there be strict adherence to the for ­ attenuation in expected adult height. a few children consequences for the affected child.52 three divided doses.65 pseudotumor cerebri has period.70-72 as well need an increase in their thyroxine dose to maintain as ophthalmologic difficulties. It is there. If the initial TSH level is lower than 50 mU/L effects are especially evident in children between 8 and there is no increase in TSH after the newborn and 13 years of age.Part II  Pediatric Thyroid Disease care physicians and their professional staff. slowing of activity. inflammatory bowel disease) may deficits. Temporary reduction in dose should be Treatment of AH involves oral l-T4 taken in a single helpful. and neurologic abnormalities. treatment past 3 months of age note that the l-T4 dose may need to be increased if an was associated with frank and severe mental retarda- infant is on a soy-containing formula or a child is tak. Prior to the advent of newborn thyroid screening. retardation. It is also important to ment. Although most children are well behaved children with CH to avoid permanent detrimental and achieve satisfactorily at school. the treatment. whereas treatment before this age was ­associated ing iron and calcium medications or high dietary fiber with a lesser degree of retardation. treatment decisions. The cornerstone of medical manage- ommended daily dosage by age is 8 to 10 μg/kg at ment is dosage of acetazolamide of 25 mg/kg/day in 3 to 6 months. neuropsychological (e. Prolonged ism was not treated until 3 months of age. if the TSH level increases off therapy. with equate for several years in late childhood or early neurologic damage appearing to originate prenatally adolescence.

80. standards. which was ing dose of L-T4 12. median weights country of residence. ethnic and socioeconomic were found to be heavier when compared with background. dosage). and 17. period of thyroid hormone insufficiency.76 Subjects were categorized based on the cause children with CH results in the attainment of normal of CH—athyreosis.76 hormone at diagnosis. arche occurring at 12. age at assessment.3 years. breast development reached Tanner stage 2 at severity of CH. Another theory is that there As a rule. was normal when com- pared to Tanner and Whitehouse growth standards. the subsequent treatment is adequate. Across both genders.9 ± 2 μg/kg/day.0 cm above refer- tified by screening show normal growth and develop.82 although still in the normal SD at 3 years and significantly predicted height. linear ity of CH at diagnosis. the severity of CH at diagnosis was not found to analyses revealed that onset of pubertal development be an associated risk factor for linear growth. 0. child’s thyroid hormone levels at time of testing. depending on the avail- 3 years of age and no differences were observed able guidelines for treatment at the time the children between boys and girls. First-generation studies. low IQs were also A third prospective study from Australia has associated with the length of time to achieve euthy- followed the physical development of a cohort of 152 roidism. which depended on several treatment fac- children with CH to age 12 years. and dyshormonogenesis.81.2 days with an initial start. Most children iden. pubertal development and final height of patients malizes unless treatment is excessively delayed.86 shortened cranial base. Throughout the 3-year study period.87 low-up period. ectopia. Also.84 a difference compensatory growth of the calvarium as a result of a maintained into adolescence85 and adulthood. Consistent with other studies. from diagnosis until 3 years of indicate that timely identification and treatment of age. with the mean age of men- of treatment was 16. children with athy. However. final height and pubertal development.4 cm above.5 years in males. pared with British reference standards.75 The mean age at diagnosis and start a mean age of 10. In boys. and they had a the Netherlands78. the findings from these four studies 125 children with CH. One with CH has reported that pubertal development longitudinal study followed a cohort of 74 children occurs at normal ages in both genders.74 bone age lagged narrowly behind the chronologic age across all age groups. children with CH had normal heights com. median value in boys was 1.. tes- with congenital hypothyroidism until 3 years of age ticular volume of 4 mL was seen at 11. linear growth was normal in the factors influencing intelligence scores included the children with CH and persisted throughout the fol.77 and was most pronounced in Physical Development the group with athyreosis. and when the study U. Other previous studies.1 to 2.5 years.3 years. A 1996 meta-analysis of seven studies from the was postulated that the larger head circumference in first cohort reported a 6. It range.3-point IQ differential from children with the athyreotic variant might reflect a sibling or closely matched controls. par. physical A retrospective study from Italy examining recovery is generally good and stature usually nor..83. In addition. c­ ircumferences were larger in affected children at all ticularly if thyroxine therapy is initiated promptly and ages compared with Australian reference data77.78 In and measured linear growth and its association to the girls. age at starting treatment. Mean ment and attain IQs within the normal range.g. Hypothyroidism era and the risk of mental retardation is very low.6 to 1. and final heights are independent of cause and sever- In another retrospective cohort study. reported mean IQ levels were diagnosis and 3 years of age. the mean length standard deviation (SD) was within 1 SD of normal Psychological Development population standards and did not differ among the The psychological follow-up studies of children with three groups. the lowest scores were attained by chil- is an increase in neuronal mass following thyroxine dren with athyreosis or the lowest levels of thyroid replacement in those with thyroid athyreosis.80) and with dosages of thyroxine significant increase in head circumference between from 5 to 10 mg/kg.77 As with the two tors (e.9 ± 5. no difference was found among CH identified by screening can be categorized accord- the three variants as to length SD at diagnosis and ing to eras or generations.5 ± 0. in girls. significantly below expectation and below ­unaffected sis was negatively correlated with head circumference sibling controls.76 The total T4 at diagno.S. growth and head circumference were examined in Overall. ence values and.g. and was least pronounced Although children often fail to grow during the in the ectopic group.75 By the age of evaluated at a mean age of 16. head was conducted in relation to the derivation of the test 131 . when chil- reosis between 1 to 3 years of age showed significantly dren tended to be treated toward the end of the first larger head circumferences compared with children month of life (e. were diagnosed. 27 days in Quebec and 29 days in with ectopia and dyshormonogenesis.79 Further Also.5 years in females 3 years. Final height.5 ± 0.

(3) visual. both the American Academy of Pediatrics98.102 a finding that continues into a 50% gain in T4 or lowering of TSH level.90 A surprising finding from and may signify further improvement in scores.101 particularly if they have the athyreotic cause. tial impairments. when the starting dose level selected deficits in the visual domain appear to be most by some groups was relatively low (typically less than apparent and evident very early in life. showed improved outcome and neuromotor deficits. time to Expressive grammar ­normalization Word comprehension Time to normalization Understanding grammar Visual Contrast sensitivity Disease severity Visual acuity Blue-yellow color vision Disease severity Red-green color vision Visuospatial Object location and Initial disease severity Object identification.99.94 Comparisons contributing disease and/or treatment factors.93 At the beginning of the newborn Among the various deficits seen in these children. Language testing reveals weak expressive ommended starting dose levels to 10 to 15 μg/kg. controlled attention 132 . specific cognitive domains are affected to a greater ism or duration of hypothyroidism is highly depen. with and receptive skills. euthyroidism memory. visuomotor. screening era.95-97 and the difference was largest in chil.100 Furthermore certain abilities within dose level of l-T4.88 3 years of age100. given the upward drift in scores over time in standards decreased the time for achieving normal a population. These new adulthood. most children show later and the European Pediatric Society47 raised the rec. Across studies.92 efforts to improve treatment time should still clumsiness. face orientation discrimination Attention Focus. Delayed speech acquisition is often evident around 1990s. lists some of the specific deficits that have been ism often ranged from days to several months for T4 described in these children to date. those with more hypothyroidism. place learning. sustain Initial disease severity. working learning. however. decision normalization making. children with born a decade apart. levels Inhibit. children levels revealed higher IQ levels in the higher dose with CH may show subtle speech and language defi- subgroups. of children stratified according to their starting dose Regarding language development. catch-up. divide at time of testing Memory Span size. cits. cases treated more individually are now under way91 less of treatment age. regard. the usual time to achieve euthyroid. findings only in the children with mild thyroid hormone have revealed the following: (1) delays in speech insufficiency. associative Time to achieve Face recognition. Nevertheless. story recall everyday memory Executive function Delay in treatment and Working memory.103 Table 10–4  Specific Deficits in Congenital Hypothyroidism in Relation to Disease and Treatment Factors Domain Ability Affected Contributing Factor Nonaffected Ability Language Expressive speech Athyreosis. and visuospa- continue. dent on dosage. given that time to achieve euthyroid. the Netherlands comparing cohorts of CH children In addition to lower IQ scores.43 Studies to identify third-generation severe presentation at birth had reduced IQs.88 serum T4 levels to 3 days and for normal TSH to 2 Children with CH from the second wave of weeks.89. along with the and from weeks to months for TSH. verbal ability. particularly for word knowledge the normalization time defined as the time to achieve but not grammar.82 dren with the most severe hypothyroidism.Part II  Pediatric Thyroid Disease norms. shift. In the mid.91 Because the cost of a 4. degree than others and some may be totally spared. CH may experience a number of specific cognitive ing superior treatment. (2) weak motor skills and general cant. with the later cohort receiv. taking into account the severity of the initial first-generation cases.53 The most recent guidelines of the American follow-up studies appeared to achieve a smaller decline Academy of Pediatrics now recommend 10 to 15 μg/ in IQ of approximately 4 points74 compared with the kg of l-T4.to 6-point acquisition with catch-up and subsequently reduced loss in IQ in the general population is not insignifi. and (4) attention and memory Another major treatment variable is the starting problems. Table 10-4 8 μg/kg/day).

physiotherapy.55. difference in volume between CH and controls.105 and abilities in manipulating and social maturity are frequent. including contrast detec. ues into adulthood86 and the CH group is also less likely Because prolonged hypothyroidism is associated with to graduate from high school than siblings.100. their weak attentional skills reflect factors relat.108-111 scans in CH relative to controls127 and abnormal spec- Memory is a further area of vulnerability in troscopy results in the hippocampus.116 In addition. including attention-deficit and adults with CH and reflect reduced strength hyperactivity disorder. which are unaffected. of 10. In summary. ease severity factors. Factors contributing born screening generally perform satisfactorily. of children may experience a delay in diagnosis of ties are usually normal. difficulties with attention. in focusing and sustaining attention in contrast to as well as delayed myelination.106 starting dose level.112 Deficits in these campal size did correlate with memory performance memory skills appear to reflect the delay in achieving in the CH but not the control group..125. show fine motor deficits in visuomotor integration. introversion. More- On tests assessing specific aspects of cerebellar func. they are at risk for Selective motor deficits are seen in children severe behavioral problems. children with CH identified by new.104 color vision. shifting. and social awkwardness. Although studies of small samples of late-treated in life. and ball throwing. they may and time to TSH normalization. In addition. although CH children identi- manual dexterity. unless treatment particularly in language.130 In addition. and ­dividing scale studies of infants detected by screening have attention.114.107 In children with shown no morphologic defects. hippo- and associative learning skills. dysdiadochokinesia.g. and exec- is significantly delayed. locating objects in space. nitive and behavioral deficits. A recent study fied by newborn screening and treated in a timely has reported an association between postural control manner show a relatively good outcome. Particularly preliminary hippocampal measurements revealed no affected are their digit span. These chil- timing).82.119 Their learning profile contin.120 At and visuospatial function. of the ­ possibility of missed detection and therefore mental difficulty in infancy. tor the children closely to prevent overtreatment. due to elevated ­ arousal may need to diagnose CH clinically. children with CH and special class placements. attention. implicating a gestational need Only a few studies have as yet examined neuro- for thyroid hormone in the neural substrates sup. difficulties in Children with a delayed diagnosis of CH typi- attention and everyday memory functioning seem to cally attain IQs about 2 SDs below their parents and affect the child’s daily functioning. Hypothyroidism Deficits are seen in multiple aspects of visual levels and increased environmental sensitivity. Autopsy findings reveal extensive neuropathology in Attentional skills may also be problematic in children with late diagnosis or who died for other rea- children with CH who are identified and treated ­early sons. their adaptive skills are weak and they are unable tioning (e.. which affects primarily their arithmetic abilities.106 utive function skills.124 comparable small- abilities involved in inhibiting. over. anxiety. memory.101 der. tive to controls but showed no evidence of cerebel.80 School permanent brain damage and poor psychological success has also been correlated with initial l-T4 dose. dysmetria. forming of the behavior problems are ­positively correlated with block constructions. CH because of an error in screening or sampling. One variable that has received area.129 Although children with CH who are treated early.80.to 16-year olds with CH diagnosed via screen- ing to both initial disease severity and abnormal ing found an increased incidence of abnormal MRI ­thyroid hormone levels at the time of testing. tion.113 Executive func. their reading abili.117 still have a slight lowering of IQ and subtle neurocog- At school.123 this suggests the need to moni- These deficits are typically associated with initial dis. Particularly affected appear to be the abilities cases reported atrophy in the frontal and ­parietal lobes. disease severity and the delay in achieving euthyroid- lings or classmates. children with CH are ism. 133 . porting these abilities.122 Because some mental images. tenance dose. an older age. outcome. a small proportion which is seen in about 20% of cases.121.118 Moreover. motor to function independently in adulthood. According to parents. and solving puzzles. occupational therapy) lar involvement. children with CH performed atypically rela.126 However. depression. a study CH. ­siblings and also show marked cognitive deficiencies.127 euthyroidism. reflecting when treatment was initiated and the at greater risk of a learning disability in the nonverbal starting dose levels.103. anatomy and neurologic function in children with CH. pervasive developmental disor- and balance80. tion skills are generally unaffected.112 limited attention so far is the adequacy of the main- Unless the children have an associated hearing deficit.128. but to the different specific deficits in CH include initial their levels of achievement are lower than their sib.g. speech therapy. dren have a high need for professional services (e. memory for locations. it is important that all physicians be aware Behavior problems reflect increased tempera.115 and increased clumsiness.

most severely affected experienced significant growth moodiness. however.135 We described three ado. In the entire pliant behavior and reduced activity levels. as well as an (but not l-T4) and a psychotic relapse suggested that increased ­ incidence of academic problems. which subsequently abated following diagno. following a 3-year period of growth failure. he sexually assaulted an older neighbor gence lower than normal if AH develops at a ­relatively and subsequently suffered significant school and young age. organization. psychosis and petit mal seizures and subsequently sustained severe concentration. mild behavioral problems. Although no major changes Older children are frequently described as were noted in overall intelligence. a teen. One of these patients also experienced a improved behavior because of increased energy lev- persistent neurosensory deficit. achieved euthyroidism quickly and whose thyroid lescents with AH who demonstrated ­ significant hormone levels were high. about one third of the children showed appropri- tor. and tinuous and appropriate therapy. aggression. findings revealed that features of organic brain syndrome and an inability skeletal maturation exceeds expectation for statural to concentrate and acquire new information. all boys. with 17% devel- or developed it earlier in infancy. irritability) and 17% devel- deceleration and a long delay before treatment was oping attention problems.50 The two cases oping de novo behavior problems (temper tantrums. mental retardation or significant language delays Our experience with these three adolescents were observed in three of four cases presenting with prompted a prospective study in which 23 newly acquired primary hypothyroidism in infancy. After school achievement may be subnormal and intelli. he developed an acute in adult stature. none of 134 .62 Results showed either sustained a longer period of hypothyroidism considerable variability in response. Shortly of treatment was significantly related to the decrease after initiation of treatment. who also to myxedema madness. integration ability was seen over the 2-year period. 22% showed initiated. treatment. and spelling abilities. the children were approximately second case involved a 12-year-old boy who was diag- 2 SDs below the normal adult stature for gender as nosed with AH after a 2-year history of slow growth. and Neuropsychological Development behavioral difficulties and was failing at school. another third failed to make any gains in reading In adults. and 24 months postdiagnosis.136 One was a 13½-year-old girl who went Growth from being an above-average student with superior Children with prolonged and severe AH may fail to mathematics ability and advanced artistic talents to achieve their predicted final height. Children with un­common after initiation of treatment for AH133.132 A follow-up their children showed significant declines in writ- after discontinuation of psychotropic medication ing. The The severe mental deficiency typically seen in late. The diagnosed children and adolescents with AH were least affected child was a girl who acquired her hypo. 6.134 the worst outcome were those with the more severe and a case of a murder after T4 treatment was ascribed and long-standing hypothyroidism initially. no gain at 3 months but caught up after 1 year. However. 26% showed a well behaved and high achievers at school when they significant decline. if ever. In a study of the a student whose work deteriorated significantly and long-term growth of children with severe primary was not able to concentrate. behavioral problems are not or arithmetic over the 2-year period. parents reported on questionnaires that sis and treatment of hypothyroidism. and that his AH and psychosis needed con. whereas a further 26% showed are in the hypothyroid state. whereas the other three children. whereas one third showed originally. perform at school. 12. arithmetic. third case was a 16-year-old boy diagnosed with AH treated CH is seldom. Only his hypothyroidism was probably an aggravating fac. She showed of normal thyroid function.Part II  Pediatric Thyroid Disease Acquired Hypothyroidism and marked behavior abnormalities following l-T4 therapy. Although group. a significant overall decline in visuomotor behavior problems are rare before treatment. Nevertheless. els and a better attitude. ager described in 1993 presented with psychosis Although achievement testing revealed only a slight (new-onset auditory hallucinations and severe obses. The growth. ­evaluated with neuropsychological tests right after thyroidism past 1 year of age and was treated shortly diagnosis and prior to onset of L-T4 therapy as well at thereafter. rather than the primary cause of the psychosis ate school-related gains. He had been an honor student with no signs of Duration of hypothyroidism prior to the institution hyperactivity or major behavior problems. 10-3). well as below their predicted midparental heights. possibly because of their significant improvement (Fig. seen in AH. In a study of very young AH patients. and nonsignificant decline in scores over the 2-year sions). or hypothyroidism treated with l-T4 for maintenance draw following the onset of l-T4 therapy. period.131 As a result.

gene therapy for the familial forms of dysgenesis. early.138. tion of TSH release can also result from constant lems in the hypothyroid state. dosing regimen. only Alabama and Delaware). some programs have chosen to ­sufficient regions. Hypothyroidism 140 interfere with iodine synthesis and/or thyroid pro- duction and transport. especially if iodine levels are deficient. cardiovascular abnormalities. in iodine. who have more severe and debilitating phenotypes.140. children with a low total T4 and normal TSH profile because of hypothalamic immaturity. despite definite benefits in other gestational iron deficiencies. fail to diagnose a small subset of children. as long as the disease is diagnosed early and Although screening for both hormones is ideal and treatment (which is relatively inexpensive) is provided performed by a few programs (in the United States. transient hypothy- could help prevent iodine-induced transient hypothy. example. or thyroxine-binding globulin (TBG) these children showed behavioral problems as severe deficiency may be missed on TSH screening. given the findings that adverse effects because the thyroidal response to iodine supplemen. time of screening. 60 PITFALLS. In rare as the three patients described earlier. of treatment were seen in selected gestational age sub- tation is attenuated in the presence of selenium and groups. However. this approach adds dren with receptor and transporter defect disorders. Similarly. these programs may problems following l-T4 therapy. they would have been identified on TSH screening. it age subgroups.141 At an environmental level. essential for normal first screen. some children with primary In summary. 40 AND CONTROVERSIES 4 6 8 10 12 14 16 18 Age (years) Congenital Hypothyroidism Figure 10–3  Individual pretreatment (square) and As noted. are capable of producing low lev- els of thyroid hormone. for various rea- ­posttreatment (circle) IQ scores in sample of children sons. Selenium. treat these infants. unneces. whereas a small pro. portion of children will experience severe learning Similarly. significantly to the cost of the screening program. which is increasing 100 in the pediatric population.145 Additional issues ­ concerning is also important to reduce. 135 . roxinemia from immaturity of the hypothalamic- roidism. such as lith- ium therapy for bipolar disease. COMPLICATIONS. Pediatric patients undergoing 120 therapy for certain psychiatric illnesses. For with juvenile hypothyroidism.139 should sient hypothyroxinemia of prematurity is whether to be tested. hypothyroxinemia of prematurity include identify- sary exposure to the chemical compounds that may ing the optimal dosage of treatment.144. roidism in the fetus and infant. cases (1 in 100. In 6 weeks of age or at 36 weeks projected gestation to addition. children older than 3 years of hypothyroidism have a delayed rise in TSH. T4 determination by tandem mass spectrometry will Discontinuing the excessive use of iodine-containing obviate the cost issue. which are sufficiently high to PREVENTION pass the neonatal screening program. illness. other trace metal deficiencies often coexist capture possible false-negative cases missed on the with iodine deficiency. gene therapy may be unnecessary except for chil. Inhibi- age generally show few behavioral or learning prob. especially if the miss children with milder forms of CH who. Iodine supplementation during pregnancy ­pituitary axis or nonthyroidal illness is not uncommon. although T4 screening programs can diag- and memory deficits and behavior and attention nosis central hypothyroidism. at the period of hypothyroidism was prolonged. if not eliminate. and lactation is critical in iodine-deficient countries Because of the delayed rise in TSH associated with to prevent iodine deficiency–associated hypothy. infusions of dopamine or high-dose glucocorticoids. extreme prematurity.137 it is still necessary to supplement repeat the neonatal screening in these infants at 2 and iodine intake during pregnancy and lactation.142. Possibilities in the future might involve sating for their low (but recognizable) levels of T4. screening programs can.000). and severe illness. A major controversy surrounding tran- activity of the monodeiodinase enzymes. Because many Prevention of thyroid disease in children is essentially of the latter group of children would be compen- nonexistent. prema- turity.143 drugs or cutaneous applications of iodine in infancy In many preterm infants. should have their TSH levels monitored regularly during therapy to prevent IQ 80 iatrogenic hypothyroidism.

..g.g. germline mutations in the TSH overdosing just prior to testing. Because the vast majority of mon form of CH. In this case. • Persistent elevations in serum TSH caused by Because of the possibility of a missed or false. associated with variable potency of the medica- Another persisting and controversial issue tion. healthy full-term infants as a result of intrauterine • Intermittent elevations of serum TSH levels asso- exposure to maternal antithyroid drugs. with or without dase 2 deficiency. FT4. appro. Additional genetic counseling for families planning to have testing and dose changes may be necessary at times more children. including adult endocrinol- with partial thyroid function at diagnosis.147 because of inconsistent compliance with treat- Transient hypothyroidism may also occur in ment and overdosing just prior to testing.146. gray-scale ultrasonography mal. When transitioning the dose. some children with CH may spurt. despite ism is now a rare phenomenon. TSH and FT4 tests. In these cases. and possibly increase the iodinated contrast materials).g. it is important If a genetically mediated thyroid synthetic enzyme for treating physicians to be fully informed of the deficit is identified. and retesting the child. it receptor. cally euthyroid and FT4 and T3 levels are nor- able alternative. priate education and training regarding the disorder • Intermittent elevations of serum TSH levels should continue to be provided. ogy clinics. Thus. it may be necessary to some hospitals may not having scanning facilities reduce the dose of l-T4 until the child is clini­ available. levothyroxine and determine whether the med- Although a thyroid scan will help determine whether ication is fresh by checking the date of produc- a condition is permanent. should be made regarding compliance.Part II  Pediatric Thyroid Disease duration of therapy. or prenatal or postnatal may be necessary to arrange for more frequent exposure to excess iodides (e. povidone iodine. and T3 caused by is heritable and the risk for subsequent offspring. Careful inquiry cannot be distinguished clinically from true hypothy. iodine deficiency. and mode of administration. know how to diagnose CH clinically. If problems (usually about 3 years) whether the hypothyroidism are suspected. Because cretin. particularly reproduction have not been conducted in the CH because prolonged hyperthyroidism can lead population. heterozygous thyroid oxi. These causes should be dose despite episodes of thyrotoxicosis during evaluated by careful history taking and. education and counseling of the is permanent by discontinuing the medication briefly parents are necessary. dren of their own. however. detailed studies of puberty and This may require a dose reduction. certain foods). may be missed. ectopic tion of the specific lot number. it may be necessary to increase the dose. maternal ciated with normal or high T4 and FT4 values TSH receptor antibodies. from inconsistent compliance. to premature craniosynostosis. with CH is also critical. iron. dos- roidism. it is important to determine at a later age ing. such as the pubertal growth Occasionally. Color Doppler these children are not followed throughout child- ultrasonography may provide a suitable alternative. it is important to take into account the cause port groups and informational meetings for parents of the CH and disease severity when assigning and patients are often helpful. gland versus aplasia). Good continued management of children ning and an ectopic thyroid gland. its severity (e. of increased growth. so sup- l-T4. In this case. and/or whether the condition • Elevated levels of TSH. Ultrasound is safe and provides a reason. calcium. compound. it is important to arrange for condition and the child’s special needs. which may be too high for children to adult health facilities. or eliminate the ­suspected symptoms to make a clinical diagnosis.. is less sensitive than iodine 123 or technetium scan. hood by pediatric endocrinologists. if possible. it is still necessary to (e. the abnormal feedback control of pituitary TSH tests may expose the child to ionizing radiation and secretion. Although it has been established that growth encounter problems associated with treatment of and pubertal onset are normal in this population hypothyroidism because of the following: and that some of these patients are now having chil- • Thyrotoxicosis from dose levels that are too high. It may be necessary to change brands of concerns the benefit of thyroid imaging at diagnosis. it is important that all physicians be well 136 . it is essential that episodes of thyrotoxicosis during periods of physicians remain prudent of the critical signs and improved absorption. and appropriate biochemical • Undetectable TSH levels with normal FT4 markers to use for monitoring of therapy. regardless of the serum TSH level. Despite recent Children and parents have frequent con- guidelines for relatively high starting doses of cerns about the disease and its impact on life. the most com. problems in absorption or metabolism of l-T4 negative screening test result. because they periods of good compliance.

roiditis with hypothyroidism. will be missed by each screening method or because to ensure that proper interventions are provided. physicians must addition. Because a few children at critical time points in their education. Another tral nervous system development. it is References important that physicians recognize the hallmarks of    1. The dosage. physician be aware of this possibility when seeing a ing adverse reactions to therapy need the additional child who fails to grow and/or shows an unexplained resources of psychologists and psychiatrists. et al: ­Families and their physicians must be aware of the Early maternal hypothyroxinemia alters histogen- association of other autoimmune diseases. it is important that the children be assessed childhood and adolescence. In AH. Because infants and very young children with AH would have passed the newborn screening test. In dealing with the commonly distinct conditions from hypothyroidism in the adult. Shapiro S: Metabolic and maturational effects of windows of development. 2001. Bernal J. brain development resulting from severe dietary other autoimmune diseases may be present or ­develop iodine deficiency in sheep. thus. Legrand J: Effects of thyroid hormones on cen- showing an adverse effect to AH treatment. par. Neuropath Appl Neu- subsequently in a patient with autoimmune AH. particularly if the hypothyroidism was long-standing. their causes seen in the newly diagnosed AH patient.    3. Congenital and acquired hypothyroidism represent related problems. It is also important by a preexisting illness. Provisions for special edu. if needed. Elsevier. Children show. such as family disturbance and stressful events. Hypothyroidism informed about the special needs of these patients. treat as soon as possible after the positive newborn trolled trial. AH can also occur in infants who Acquired Hypothyroidism might have passed the newborn screening test but Controversies surrounding AH concern adequacy of also could be vulnerable to brain damage associated treatment and titration of the dose. Although associated learning disabilities screening levels have been determined. On the other hand. Eur J Endocrinol 133:390-398. et al: Protracted Because some acute psychiatric illnesses. so it is critical that the dren have the disorder for a long time. progeny. Mano M. particularly with regard to diagnosis. because hearing and vision should be routinely tested. a number of children with CH CONCLUSIONS may evidence subtle to severe cognitive and school. treatment. quickly to prevent any brain damage during critical    2. Simi. atively high to achieve euthyroidism quickly and thus tification and remediation because they are caused reduce the risk of brain damage.148 history be taken in the diagnostic process. and cians may consider psychostimulant medications. it is essential to diagnose and however. their nosis of CH and timely treatment. Amsterdam. Cases O. García-Velasco JV. and some decline in neurodevelopment. et al: Retarded fetal In AH caused by an autoimmune process.    6. 1984. 1966. Ausó E. it larly. to manage these children appropriately throughout Thus. it is important that a careful nancy and during the early months of pregnancy. 1995. ­expression of serotonin transporter and altered ticularly during adolescence. because some children with CH will be at still be prudent about the need for the clinical diag- risk for certain auditory and visual problems. Potter B. J Clin Invest 111:1073-1082. will require special education or outside tutoring. physi. in micrograms per unit of body weight. should be rel- these children may not qualify for traditional iden. management. according to some criteria. reported difficulties in focusing attention. For example. pothyroid rats. Endocrinology 78:527- cation and counseling should be made for children 532.    4. pp 331-363. some children with persisting clumsiness may is important to titrate the dosage slowly to prevent need physiotherapy and/or occupational therapy. In Yanat J (ed): pitfall is the failure to diagnose other problems or Neurobehavioral Teratology. with a lack of TH in infancy. Follow-up studies have shown that despite IQs in the normal range. a dose deviance were ever noted. Eur J Neurosci 14:1968-1980. children may also need psychostimulant medications. which esis and cerebral cortex cytoarchitecture of the occur more often in patients with autoimmune thy. these should be administered under a con. In of an error in the screening process. Fouquet C. In CH. some increment of about 150% should be considered in forms of AH may be caused by exposure to psycho- women of reproductive age contemplating preg­ tropic medications. robiol 8:303-313. 2003. Nunez J: Thyroid hormones and brain de- this disorder and be able to make a clinical diagnosis velopment. Belling G. Ausó E.    5. it is thalamocortical projections in the barrel field of hy- important to evaluate thyroid status in these children. adverse reactions. especially if chil. severe problems following therapy may occur. 137 . Lavado-Autric R. thyroxine in the infant rat. are caused by AH. especially if no previous signs of mental illness or including reproductive issues. 1982.

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J Pediatr 136:273-274. Morissette J. Victo. Rovet J: Long-term neuropsychological sequelae 1978. 199.   87. Wong SC. ism. Di Maio S. Coakley JC: Newborn Sanden RW. 2001. Kempers MJ. et al: Starting dose Sanden MW. 2006. Acta Paediatr 432:88-95. Metab 15:973-977. Apezteguia M. Nijhuis-van der   95. Sundet K. J Pediatr 117:211-219. and motor outcome at 10 years of age. 2003. et al: Intellectual and motor devel. J Pediatr Endocrinol Germany. 2002. Germak JA. 1979. Fisher DA: The importance of early management   81. Amsterdam. pp 259-272.   91. 2003. J Pediatr 147:768-774. 2007. et al: Con. Mayayo E. Gilbert R. et al: Neurologi. tion. Curr Opin Endocrinol Diabetes diatr Drugs 5:141-149. Labarta J.   80. Puga B: Psychomotor devel-   75. Santavuori P. 1996. Ann En- genital hypothyroidism: Age at start of treatment docrinol (Paris) 64:58-61. In Morreale de Escobar G. Foley TP Jr: Longitudinal assessment by neonatal screening. Elsevier. Dussault JH. Leger J. Parkin JM: A comparison between the l-thyroxine treatment on intellectual.   83. Micillo M. 2002. 1992. Giumarey L. Kase BF. Selva KA.   96. Kempers MJ. Muir T. et al: Follow. J Clin En- ress and outcome. 61:155-159. early: A longitudinal study. Touati G. 1994. genital hypothyroidism diagnosed by neonatal   97. J Pediatr 147:775-780.   84. Thyroid 13:1029-1038. Glorieux J. Clin Endocrinol tal ­hypothyroidism. Harper A.   90. substances: Economic and health costs of four case up at ages 5 and 7 years on mental development studies that are candidates for environmental causa- in children with hypothyroidism detected by Que. 2003. De Cock P. Ng SM. et al: Longitudi. Developmental outcome in relation to levothyroxine cal abnormalities in patients treated for hypothy. Morin A. 2005. 14:1611-1634. chol 17:187-213. Logan S. et al: Neonatal screening for congeni- screening for congenital hypothyroidism. ism. J Pediatr Psy. Dhondt JK (eds): New Horizons in ing for congenital hypothyroidism. et al: Congenital Paediatr Scand Suppl 277:41-46. 1992. sexual maturation and final height in target T4 and TSH. roidism: Analysis of literature data. logical study in treated thyroid dysgenesis. Hrystiuk K. prog. Glorieux J. J Child Psychol Psychiatry development in early-treated congenital hypothy- 24:629-635. J Pediatr 107:913-915. 2001. Macfaul R. Toublanc JE. Environ Health Perspect 109:885-903. mental outcomes in congenital hypothyroidism:   79. and neurological and intellectual abnormalities in school-associated outcomes in young adults. de Vijlder J. Bongers-Schokking JJ. 1983. Van Vliet G: Intellectual in optimizing IQ in infants with congenital hypo- development at age 12 years of children with con. Didi M: Head circumference SM: Influence of timing and dose of thyroid hor- and linear growth during the first 3 years in treated mone replacement on mental. Verkerk PH: ­Neuropsychologic logical development. 2004. dosage of 8 μg/kg is appropriate for the vast ma-   82. atrics 112:923-930. Stuttgart. versus outcome. of early-treated congenital hypothyroidism: Effects   71.   93. Virtanen M. van der Sluijs Veer L. Eur J Endocrinol 145: of L-thyroxine therapy for congenital hypothyroid- 377-383. 1986. Daneman D: Congenital hypothyroidism: 1983. 39:561-566. Pe- and outcome. hypothyroidism: A systematic review. 2003. Neonatal Screening. Nijhuis-van der   77. Brett EM. 2005. Heyerdahl S.Part II  Pediatric Thyroid Disease   68. Noel P. Dorner S. 1990. et al: An initial screening.   92. experience.   88. Rovet J: Congenital hypothyroidism: Treatment tices in relation to neuropsychologic outcome. Salerno M. Derksen-Lubsen G. roidism from early life.   85. van der Sluijs Veer L. 1977-1997. Acta   86. motor. Downs A. Rickards AL. pp 145-148. Acta Paediatr Scand 72:197-201. Klein RZ: Neonatal screening for hypothyroidism. 2005. Maenpaa J. and preschool children following newborn screen. thyroidism [editorial]. Oerbeck B. Dussault J. 2003. in adolescence. Frost GL. Pedi- children and adults with congenital hypothyroid. Schattauer. patients with congenital hypothyroidism ­detected   94. with sporadic congenital hypothyroidism. Eur J Pediatr 145:480-484. Part 2: Treatment. J Pediatr Endocrinol Metab docrinol Metab 92:919-924. et al: Neuropsycho. Endocrinol Metab 91:418-424. Wolter R. 2001. J Clin Adol Med 156:485-491. Arch Dis Child 53:611-619. Comparison of initial T4 dose and time to reach nal growth. Rovet J: Long-term follow-up of children born   73. hypothyroidism: Influence of disease severity and   72. de Muinck Keizer-Schrama   76. In Farriaux JP.   89. Obes 12:42-52. Arch Pediatr roidism diagnosed by neonatal screening.

cits in children with ADHD and congenital hypo. Rovet J: Neuromotor deficiencies in six-year-old deficits and associated factors. 123. Pedi. Lewandowski L: Subtle Eighth National Neonatal Screening Sympo- speech and motor deficits of children with con. Rovet J: Congenital hypothyroidism: Persisting 114. ­hypothyroid children identified by newborn chol 8:150-162. 112. In Morreale de Escobar G. Hepworth S: Attention problems in ado. 1996. J Child Psychol Behavioural correlates of early-treated congenital Psychiatry 42:1049-1056. Gauchard GC. In Stabler B. 2007. van der Meere JJ. J Int Neuropsychol Soc therapy for congenital hypothyroidism. 2000. Arch Dis Child 90:132-137. 1995. et al: Brain me- tained attention problems in children with early tabolite changes on in vivo proton magnetic reso- treated congenital hypothyroidism. Dev Med Child Neurol tal and neonatal thyroid hormone ­insufficiencies. Eur Stuttgart. Germany. Kooistra L. fication in Childhood. Ehrlich R. 110. University of Toronto. tion. screening. 113. Efficacy. screening. 116. American Academy of Pediatrics. New York. 100. Gottschalk B. and Quality of Life. Alvarez M: Thyroid hormone and atten. cognitive development in children with congeni- 103. 2005. Hepworth SL: Dissociating attention defi. In Pass K (ed): Proceedings of the 101. Westall C. Wash- genital hypothyroidism treated early. congenital hypothyroid children. tal hypothyroidism. 1996. J Pediatr 126:389-392. and learning disabilities. et al: Effect 2005. 122. of age at thyroid-stimulating hormone normaliza- 104. Public Health: Newborn screening for congenital Disorder. Working Group on Congenital Hypothyroid. treated congenital hypothyroidism following ism of the European Society for Paediatric En. 120. DC. 115. J Pediatr 127:776-783. Rovet J. peutic Outcome of Endocrine Disorders. Rovet J. van der Meere J. 1995. hypothyroidism. Deviterne D. Master’s thesis. et al: Neu- velopment and neuropsychological functioning. 2001. 1999. newborn screening. Vulsma T. J Pediatr 124: thyroxine treatment on adult memory. 118. Butz S (eds): The Thyroid and Brain. Oerbeck B. J Int Neuropsychol Soc 121. Siragusa V. Ehrlich RM: Long-term effects of l-thyroxine ticomponential analysis. Springer- 109. ism. Genetic and biochemical influences on brain de. pp 242- J Pediatr 152:974-975. Acta Paediatrica 90:1141-1146. Leheup B. 1997. screening. 2003. Poptani H. Acta Paediatr nance spectroscopy in children with congenital Scand 85:425-429. 1993. 146:107-113. Pediatr Res 37: velopmental Disorders: Manifestation and Identi. 736-740. et al: Sus. J Pediatr 7:734-744. 1993. Ross J (eds): Neurogenetic De. lour vision capabilities of children. et al: Long-term sequelae Department of Psychology. Ehrlich RM: The psychoeducational char- 105. J Pediatr En. sium and XXI Birth Defects Symposium. pp 255-281. Rondanini GF. Association of State and Territo- Child Neurol 36:216-220. Rovet JF: Neurobehavioral consequences of con- 7:734-744. MIT Press. Sundet K. 2003. J Pediatr 114:63-69. and Dysfunction. et al: Motor and pp 266-295. Bhatia V. of hearing impairment in congenital hypothyroid- Toronto. et al: The devel. Section on En. roid hormone on temperament in infants with 107. Child Neuropsy. Pediatrics 105:515-522. Berscu B (eds): Thera- tion in congenital hypothyroidism. rophysiologic studies and cognitive function in In Mazzocco M. Walker W. Innovation. Rovet J. Press. 106. 124. Vulsma T. 2001. 2006. 1994. 141 . 1992. Kooistra L. tion on postural control in children with con- opment of contrast sensitivity in infants with prena. et al: thyroidism using multiple CPTs. Hepworth S: Attention problems in ado. 119. rial Public Health Laboratory Directors. Kase BF. docrinology: Guidelines for neonatal screening de Vijlder J. Laane C. ­programmes for congenital hypothyroidism. Sorbara D: The effect of thy- Thyroid 9:741-748. Stemerdink N. docrinol Metab 9:63-66. 1989. Pediatr Res 57:902-907. pp 235-254. Rovet J. 1995. Rovet J. Richman R. Rovet J. ticomponential analysis. Gupta RK. Dev Med ington. atten. 258. Rovet J: Neuropsychological follow-up of early-   99. Verlag. 903-909. Brown R: Congenital hypothyroidism: pp 378-381. Rovet JF. genital hypothyroidism. and behaviour. Rovet JF: Outcome in congenital hypothyroidism. 2001. In Rourke B (ed): Syndrome American Thyroid Association Committee on of NLD: Manifestations in Neurological Disease. 126:380-386. 102. 2000. 111. lescents with congenital hypothyroidism: A mul. Schattauer. Asztalos E. 1995. Rovet J. Mirabella G. Guilford hypothyroidism: Recommended guidelines. 1994. et al: Congenital tal hypothyroidism: A long-term evaluation of hypothyroidism: No adverse effects of high-dose the effects of neonatal treatment. atrics 91:1203-1209. Rovet J: Congenital hypothyroidism and nonverbal docrinology and Committee on Genetics. Kooistra L. 117. 2001. Rovet JF. Boston. Weber G. Borkowski S: The effects of an early life transient acteristics of children with early-treated congeni- thyroid hormone deficiency on the subsequent co. 2005. New York. hypothyroidism. Hypothyroidism   98. Bliss B. genital hypothyroidism identified by newborn 108. congenital hypothyroidism detected by newborn lescents with congenital hypothyroidism: A mul.

2006. development in infants born at less than 30 weeks’ 131. Care Companion J Clin Psychiatry 5:260-266. 1988. Sheard E. gesta- 129. with hypothyroidism. Br J Psychiatry et al: Neonatal thyroxine supplementation for 137:222-228. Thyroid 16:949-951. ­Ontario. J Perinatol 28:270-274. Siragusa V. ing as psychosis: Myxedema madness revisited. growth in juvenile acquired hypothyroidism: The 145. et al: Using mag. et al: Ef- tices in relation to neuropsychologic outcome. Wegmueller R. J Pediatr 122:543-549. 1993. Presented at the International 322. et al: Brain mag. 127. Neuropsychological Society 34th Annual Meeting. et al: Ab. 128. Williamson M. Williamson M. 1993. Kelleher AS. Hamilton. 2004. Bode HH.Part II  Pediatric Thyroid Disease 125. 2003. 133. Chace DH: Mass spectrometry in newborn and Network of Ontario Symposium. Presented at the Fifth Annual Imaging 143. and netic resonance imaging in congenital hypothy. Pe. Lawrence J. et al: Changes in 138. ing and magnitude of increases in levothyrox- cal consequences of thyroxine therapy for juvenile ine requirements during pregnancy in women acquired hypothyroidism. et al: The Boston. Thyroid 7:761-764. et al: Tim- 136. 2002. Rovet JF. Bhatara VS. et al: Abnormal tional age and time on thyroxine levels in prema- MRS profiles in children with congenital hypothy. in preterm infants. Engle H. 2008. Thyroid 16:919-920. Prim 2006. Houtzager BA. Mackenzie TB: Thyroid-induced 146. Kok JH. Ontario. 2005. Heinrich TW. N Engl J Med 336:21-26. Zeder C. Am J Clin Nutr 80:1283- ment. Delange F. ture neonates. 1290. 144. Daneman D: Congenital hypothyroidism: 2009. Rovet J. Grahm G: Hypothyroidism present. Eidson M. Josephson AM. future directions. Vanderpas J: Nutritional epidemiology and thy- normal MRS profiles in children with congenital roid hormone metabolism. failure to achieve normal adult stature. Alves C. N Engl J Kok JH: Ten-year follow-up of children born at Med 318:599-602. Rivkees SA. 44:163-170. N Engl J Med 351:241-249. 139. Boffelli S. J Clin Psychiatry 41:316-318. Pediatrics 116:e613-e618. 1989. Williamson M. 115:600-603. McMaster University. 141. A review of current diagnostic and treatment prac. J Pediatr 123:840-841. et al: netic resonance spectroscopy (MRS) to study Triple fortification of salt with microcapsules of io- thyroid hormone’s role in hippocampal develop. Bianco AC. cellular and molecular biology. Bandettini F: Behavioral ­thyroxine in the neonatal period in a random- manifestations of hypothyroidism versus thyrox. Weber G. Bianco AC. 1980. 137. 140. 148. Rovet J. Asztalos EV: Thyroid hormone supplementation 135. Gereben B. Salvatore D. 142 . and vitamin A. 142. Clark RN. J Mass Spectrom. Westera J. Crawford JD: Long-term gestation. Endocrinol Rev 23:38-89. Master’s of science thesis. fense in homicide. Bailey J: Adverse psychologi. 2006. van Wassenaer AG. iodinases. Nash K. Zimmermann MB. Public Health Committee of the American Thyroid Association. 130. Easson WM: Myxedema psychosis—insanity de. 2002. <30 weeks’ gestational age supplemented with 132. chemistry. metabolic screnning: Historical perspective and March 2007. 2003. Steinbach M. J Pediatr Invest 116:2571-2579. Kim BW: Deiodinases: Implications of brain maturation detected by magnetic resonance the local control of thyroid hormone action. transient hypothyroxinemia of prematurity: Bene- 134. February 2006. 2006. Braverman LE. dine. ized. influence of amino-acid supplementation. 2004. mania in hypothyroid patients. La Gamma EF. ficial or detrimental? Treat Endocrinol 5:335-346. Becker DV. physiological roles of the iodothyronine selenode- roid infants at diagnosis. et al: Iodine supplementation for pregnancy and lactation—United States and Canada: Recom- mendations of the American Thyroid Association. roidism. 147. fects of thyroxine supplementation on neurologic diatr Drugs 5:141-149. Alexander EK. Golombek SG. 2006. McMillin J. controlled trial. Daneman D. ine effects. de Vijlder JJ. iron. van Wassenaer AG. Toronto. Maqusee E. 1980. Rovet JF. Nash K. J Clin imaging in congenital hypothyroidism. 1997. 1997. Ann Rev Nutr 26:293- hypothyroidism. Desrocher M. van Wassenaer AG. et al: Bio- 126.

It may occur at any age dur- leukocyte antigen (HLA) gene on chromosome 6p. For unknown reasons. men. but is believed in both the development of GD and its severity. the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene ­peaking during adolescence (Fig. ring most frequently as a consequence of Graves’ dis. destruction. the GD is a rare disease in children. Acute or sub. An imbalance between patho- Pathogenesis genic and regulatory T cells is thought to be involved The cause of GD remains unclear. mostly in their teens and 20s. GRAVES’ DISEASE leading to B-cell dysregulation and an increase in auto- antibody production. and the PTPN22 (lymphoid dence is thought to be rising and is about 0. with causes of thyrotoxicosis. Genetic suscepti. TSH) this disease than in controls suggest that about 80% receptor stimulation by autoantibodies. Chapter Hyperthyroidism 11 Juliane Léger Key Points n Thyrotoxicosis is a rare disorder in childhood. T cells activate local inflammation and tis- sue remodeling by producing and releasing cytokines. n Overall frequency of relapse is higher in children than in adults. The inci- on chromosome 2q33. this disease tor antibody) that stimulates the thyroid gland to affects approximately 2% of women and 0. about 30% of children achieve ­lasting remission after about 24 months of ATD. Thyrotoxicosis is a rare disorder in childhood. environmental factors. Data from twin studies and the higher prevalence of ease (GD). to 5% of all patients with GD. n Pregnant women with GD or euthyroid with a history of GD should undergo thyrotropin receptor ­antibody (TRAb) determinations at the beginning of pregnancy. chronic lymphocytic thyroiditis.4 to result from a complex interaction among genet- ic background (heredity). lack of compliance. tyrosine phosphatase) gene on chromosome 1p13. and antithyroid drug toxicity. but it increases in frequency with age.2.2% of produce excess thyroid hormone. the fetus should be considered at risk of developing thyrotoxicosis����������������������������������� ������������������������������������������������� and monitored accordingly. occurring most frequently as a consequence of Graves’ disease (GD). as are TSH-secreting pituitary T-lymphocyte abnormality and an absence of follicular tumors and thyroid hormone resistance (Table 11-1). and factors. Incidence and the immune system. (TSI) binds to and stimulates the TSH receptor on cosis. resulting in follicular cell somatic gain-of-function mutations of the TSH recep. GD and children. an increase in vascularity. accounting for 1% immune system produces an antibody (TSH recep. and the excessive syn- tor gene. If TRAbs are detected.1/100.3 acute or chronic administration of thyroid hormones The thyroid-stimulating immunoglobulin and/or iodides may also result in transient thyrotoxi. ing childhood. The thyroid of diffuse hyperplasia and toxic nodules. n Indications for radical treatment (thyroidectomy or radioactive iodine) include relapse after ­appropriate course of ATD. McCune-Albright syndrome and germline and the thyroid cell membrane. n Antithyroid drug (ATD) is usually recommended as initial treatment for hyperthyroidism in children. 11-1). which may be associated with the presence thesis and secretion of thyroid hormone. GD is much more frequent in female has been reported to be associated with the human than in male subjects. are also rare gland typically displays lymphocytic infiltration. of the susceptibility to GD is determined by genetic acute thyroiditis.6 In both adults bility to the disease is thought to be polygenic. In adults. growth.1 occur.5.000 143 . an autoimmune disorder resulting from Graves’ disease in first-degree relatives of patients with thyrotropin (thyroid-stimulating hormone.

30 Clinical Manifestations 25 Most patients present the classic symptoms and signs Girls of hyperthyroidism. m. height velocity decreased and height normalized and followed its previous course. Increases in height velocity. an increase in appetite accom- panied by no weight gain or even weight loss. 11-2). Once euthyroidism had been ­established hormone.000 mitral valve. with advanced patient-years has been reported in Hong-Kong. and in children with a famil- ial history of autoimmune thyroid disease. meters.Apalpablethrillmaybepresent. Figure 11–1  Distribution of age at diagnosis of andnottender.7. 144 . An increase in growth TSH-secreting pituitary tumors velocity with advanced bone age can clearly be seen. are related to the duration of hyperthyroid- no relationship to differences in iodine nutritional ism (Fig. nervousness. Hyper- thyroidism went unrecognized for 1 year before the initiation TRAbs. irritability. with staring eyes. Other signs include tachycardia. and 10 diarrhea. thalmic abnormalities are less severe in children than peaking in adolescence.Part II  Pediatric Thyroid Disease person-years in young children to 3/100. palpitations. A decline in academic performance and 5 deteriorations in attention are often associated.reflecting ­thyrotoxicosis in childhood in 155 patients with Graves’ the increase in blood flow through the gland. The frequency of this condition increases with age. emotional labil- ity. TSH.1 A frequency of up to 14/100. through ATD treatment. uniformly smooth. The size of the thyroid gland is highly variable 0 and the goiter may go unnoticed in patients with a 0 2 4 6 8 10 12 14 16 18 slightly enlarged thyroid gland. Oph. precordial thrill. an increase in blood pressure. As in adults.000 person.8 GD is more frequent in children with other a lower than normal bone mass. and an 140 m +2 DS –2 DS 130 Table 11–1  Causes of Thyrotoxicosis in Children 120 Graves’ disease Autoimmune neonatal hyperthyroidism (passage of Height (cm) 110 ­maternal TRAbs across the placenta) Thyroiditis   Subacute thyroiditis 100   Chronic lymphocytic thyroiditis (Hashimoto’s disease) Exogenous causes 90   Exogenous thyroid hormone (acute or chronic)  Iodine-induced hyperthyroidism—iodine. children with GD may have status. than boys. fatigue. and a wide palpebral aperture. radiocontrast agents. before and during the course Selective pituitary resistance to thyroid hormones of antithyroid drug (ATD) therapy.9 Pretibial myxedema autoimmune conditions. thyroid-­stimulating of ATD treatment. disease. with bone age. Boys 20 Number of patients with changes in behavior. The thyroid gland is Age (years) usually symmetrically enlarged. insomnia. e­ jectionmurmurcausedbyfunctionalinsufficiencyofthe years in adolescents. amiodarone 80 Autonomous functioning nodules  Somatic activating mutation of Gsα—McCune-Albright 70 syndrome   Somatic activating mutation of the TSH receptor gene 0 2 4 6 8 10 12   Toxic adenoma Age (years)   Hyperfunctioning papillary or follicular carcinoma Congenital activating mutations of the TSH receptor gene Figure 11–2  Height curve of a child with Graves’ disease (hereditary or de novo)—congenital hyperthyroidism diagnosed at the age of 5 years. thyrotropin receptor antibodies. True exophthalmos is rare in children. 15 excessive perspiration. The early symptoms are subtle. Girls are more frequently affected in adults. retraction of the upper lid. firm.

Various symptoms are observed. or large. rare side effects include drug- and long-term side effects of the different therapeutic induced hepatitis and the production of cytoplasmic options. As in many rare diseases.10 Duration of antithyroid drug therapy Laboratory Diagnosis Radical treatment options: near-total thyroidectomy or The diagnosis is confirmed by thyroid hormone mea- radioiodine therapy surements.13 and prospective lems) in about 5% to 25% of cases. in whom the disease is more frequent. sine residues in thyroglobulin. a TRH test may be carried out. The thyroid gland is diffusely Antithyroid Drug Therapy enlarged. psychiatrists.15 inhibition of TSH release in response to TRH stimu. in some cases. which may be observed at diagnosis or at compliance on the part of the patient or the parents.16 MMI also presents a major achieve long-term compliance and the rate of relapse advantage over PTU in terms of compliance. There is no specific cure for side effects may be dose-related and is very small for the disease and each therapeutic option has associated severe side effects in patients receiving MMI at a dos- complications.14. The most commonly used ATDs are ity is observed. and inhibit thyroid hormone synthesis by interfering with the goiter may be small. for the diagnosis of GD and has been replaced by ultrasound scans. drugs and other major. subtotal or near-total thyroidectomy. tests for antibodies against (except in patients with asthma or cardiac failure) thyroglobulin. TSH is undetectable in the serum (less than 0. PTU can also block the conversion of T4 to T3. Most children with hyperthyroidism have high serum free thyroxine gland or destruction of the gland by radioiodine treat- (FT4) and free triiodothyronine (FT3) concentrations. The frequency of randomized long-term clinical studies are required to agranulocytosis is between 0. occurs only in exceptional cases. Current treatment options include antithyroid antineutrophil antibodies. and stopped when the patient Thyroid imaging with radioisotopes is not required becomes ­euthyroid. The gland may dis. and radio. with highly variable titers. to reduce the patient’s symptoms. between countries and depends on local traditions and Thyrotropin receptor antibodies (TRAbs) are resources. Antibody-positive vasculitis drugs.2% and 0. some patients may have normal FT4 levels tions for radical treatment in children include relapse and high FT3 levels — a condition termed triiodothyro. In this test. times of relapse during the course of the disease. This treatment (propanolol) can be given orally twice daily. it is difficult to the short term than PTU. gastrointestinal prob- a matter of debate (Table 11-2).5% for both compare treatment failure frequencies and the short. High-grade hypervascularization is not carbimazole and its active metabolite. Indica- However. ment are therefore often used as alternatives. Diffuse parenchymal hypervascular­ and adolescents. In and ATD toxicity. the age and preference of the patient. there is cur- some patients with mild hyperthyroidism and serum rently no evidence-based strategy for the management FT4 and FT3 levels close to the upper limit of normal of this disease in children.11 In rare the thyroid peroxidase–mediated iodination of tyro- cases. and children may initially be referred to cardiologists. These drugs autoimmune thyroiditis. methimazole observed to the same extent in patients with chronic (MMI).3 mU/L) in all patients. the detected in most patients. GD treatment policy varies considerably within and lation confirms the diagnosis of ­hyperthyroidism. because is high in children. Goiter size is variable.15 MMI is more effective in antithyroid drugs (ATDs). However. in contrast to the situation values. and/or gastroenterologists before being referred to an endocrinologist. thyroid volume is normal. at a dos- Thyroid Imaging age of 2 mg/kg/day. Surgical removal of the thyroid MMI has a longer half-life and is effective when given 145 . and often homogenous. whereas MMI cannot. a lack of nine toxicosis. ophthalmolo. Hyperthyroidism is rare. size of the goiter. moderate. after an appropriate course of drug treatment. Determinations of circulating thyroid peroxidase Additional treatment with beta blockers levels and. Antithyroid drug treatment is usually recommended as play normal echogenicity or may be hypoechogenic. The frequency of active iodine (iodine 131). Most patients are initially treated with age of less than 10 mg/day. and propylthiouracil (PTU). Table 11–2  L ist of Controversies for Optimal Management of GD in Childhood gists. Treatment Both MMI and PTU are associated with minor reac- The optimal treatment of GD in childhood remains tions (rash. and the severity of the disease.12. the initial treatment for hyperthyroidism in children as in thyroiditis. the in adults. may be useful for the confirmation of during the first 2 weeks of management may help thyroid autoimmune disease. arthralgia. urticaria.

administered with replacement doses of levo. patients with a large goiter or with ophthalmopathy. Complications hormone secretion is effectively blocked and thyroid such as hypoparathyroidism. No additional ben.Part II  Pediatric Thyroid Disease as a single daily dose. corresponding to about 250 Gy) may experience ­ gradual remission of the disease. there is still some debate about whether remission on ATD therapy is linked to the restoration RAI treatment or surgical ablation should be preferred of euthyroidism rather than the immunosuppressive as the definitive treatment for pediatric GD.25 More prolonged use of ATD (at least 2 years) in chil. trol study with long-term follow-up to settle this issue als of this treatment are currently required. the remaining patients. dysfunction or higher frequencies of abnormalities bition of autoantibodies obtained by treatment is dif. Methods for identifying the patients who Total (or near-total) thyroidectomy is often currently are unlikely to have remission after drug treatment preferred to subtotal (or partial) thyroidectomy to would greatly improve patient management. RAI should also be avoided in very young cytes are important self-antigen–presenting cells and children because of an increased potential risk of precursors of antibody-secreting plasma cells. whereas only 10% relapse after Surgical Treatment 18 months. and hormone levels have normalized. efit accrues from the maintenance of a high dose of For patients with recurrent hyperthyroidism after ATD.28 Consequently. 75% of patients relapse within 6 months of the end of drug treatment. whereas ATD treat- ized trials are still lacking to evaluate the efficacy of ment results in long-term remission in about 40% short. because the for a second operation. Euthyroidism caused by the radioiodine-mediated dren than in adults may be required to achieve remis. About ment in children. and most patients can be suc- ism. the patient (220 to 275 μCi/g. Once this cycle is broken by ATD treatment ren. remission lasting at least 2 years. the remission rate in children. Large clinical tri. B lympho. bination with ATDs to enhance remission rates. There is no evidence of reproductive improved by educational strategies.and long-term ATD therapy to increase the to 60% of adult patients.13 effects of the drugs. than in adults. because sion.15 GD For other cases.24 l-T4 replacement therapy should ­carbimazole) is 0. The initial starting dose of PTU vascularity of the gland is decreased by adding iodine is 5 to 10 mg/kg/day. and mortality rates have antibody rituximab may therefore efficiently decrease highlighted the need for a large.13 The they would facilitate the identification of patients 146 .11.12. and appropriate doses of l-T4 must there- remission after about 24 months of ATD.19 definitively.20-23. Larger doses dering the patient euthyroid or by surgery. cessfully treated with a single oral dose. surgery. feeding.18. and further studies are overall frequency of relapse is higher in children required to increase our knowledge of ATD treat.20-23 For fore be administered throughout the patient’s life. Compliance is therefore an important issue in radioiodine therapy has a particular effect on thyroid the management of these children and should be autoimmunity.13 frequency of side effects is dose-dependent. After 2 to 4 weeks. hyperparathyroidism. with a maximum of 300 mg/ to ATD (5 to 10 drops of Lugol’s solution) for 1 week day in three equal doses. when thyroid should undergo long-term follow-up. whereas that of MMI (or before surgery. There is This radical option is often recommended for also currently no rationale for the use of l-T4 in com. probably because the treatment does lutely contraindicated during pregnancy and breast- not target B cells or autoantibodies directly. with a maximal be initiated within days of surgery and the patient dose of 30 mg/day. by a pediatric surgeon with extensive experience.11. because reduce the risk of recurrent hyperthyroidism. and may reach 70% to 80%. However. Long-term Outcome tic options.17 should be preferred over smaller doses of 131I. roidism caused by GD. but both carry a high risk of permanent Less than 30% of children treated with ATDs achieve hypothyroidism. vocal cord palsy. Unfortunately. Hyperthyroidism itself has been shown to worsen the autoimmune aberration. prospective random. the initial dose is keloid formation are rare for operations performed gradually reduced by 30% to 50%. Concerns about potential thyroid malig- porary B-lymphocyte depletion with the monoclonal nancy. Recent studies have even suggested mended because the risk of complications is higher that high-dose therapy may be harmful.26 RAI is abso- ficult to predict. near-total thyroidectomy or radioiodine therapy are the definitive therapeu. neoplasia. the inhi. randomized con- or abolish the production of TRAbs. and Iodine Treatment autoimmunity leads to the generation of more TSH RAI treatment is effective in children with hyperthy- receptor antibodies and a worsening of hyperthyroid. in the offspring of treated patients. Tem.27 Hypothyroidism is likely to occur after Less than 30% of children achieve lasting treatment. radioactive iodine (RAI) treatment is recom- thyroxine (l-T4). destruction of the thyroid gland is different.5 to 1 mg/kg/day.

ism caused by a mutant thyrotropin receptor hyper- ioural functioning. sever. ity of biochemical hyperthyroidism at onset.40 In maternal gesta- of medical treatment as predictive markers of GD tional autoimmune GD. tion of the TSH receptor gene is a rare disease. Surgical removal of the mole cures the hyperthyroidism in childhood over the longer term hyperthyroidism. Germline mutations are found in ity of life during and after treatment. congenital fetal and postnatal Negative consequences for health-related qual. surgical. have been demonstrated in adult congenital hyperthyroidism.43-45 health-related quality of life in the long term. The clinical course of patients with GD. generally transient.35-37 Large prospective random. which stimulate the adenylate ated with a mortality rate of up to 25% and immediate cyclase in fetal thyrocytes. and de novo mutations may cause sporadic mance and vitality. Neonatal autoimmune hyperthyroidism is caused by the passage across the placenta of mater.29-33 However. generally improves in the second half of pregnancy. rate. If TRAbs are detected. young develop when fetal TSH receptors become physi- age. second half of gestation. TRAb caused by decreases in serum TRAb concentration. decrease in body mass index. has been shown to have little impact on ectomy followed by radioiodine therapy. sensitive to human chorionic gonadotropin has also been reported in exceptional cases. leading to thyroid hor. the preservation of a normal relapse during childhood.11. Even accounted for by the patient’s thyroid hormone status with high doses of ATDs to control severe congenital during follow-up. iodine intake. levels at onset and end of treatment. Other factors. may be observed in pregnant women with a hydatidi- but it would seem prudent to monitor subjects with form mole. mostly in Conversely. and/or behav. gender. requiring subtotal thyroid- radioiodine.46 NEONATAL HYPERTHYROIDISM Clinical Manifestations Pathogenesis Fetal hyperthyroidism precedes neonatal hyperthy- Autoimmune neonatal hyperthyroidism is commonly roidism. all these fetal thyroid hormone state to ensure normal brain studies but one33 were retrospective and none has development is a complex issue. and the severity of the disease at diagnosis. roidism. emotional. It may also occur of the first course of ATD. goiter size.2% and mostly Previous studies had their limitations but evaluated results from Graves’ disease. even after 14 cases of hereditary autosomal dominant hyperthy- to 21 years. the constructed that allowed the identification of three fetus should be considered at risk of developing thy- different risk groups at diagnosis. siveness in adults. Hyperthyroidism requiring long-term ATD or early radical treatment. all pregnant women with GD and euthy- long period of primary ATD treatment on outcome roid pregnant women with a history of GD should to minimize thyroid autoimmunity and recurrence undergo TRAb determinations at the beginning and of the disease. Familial gestational hyperthyroid- for neuropsychological. Fetal and neonatal thyroid mone hypersecretion. These problems do not seem to be these diseases requires careful management. However. may be responsible resolve these issues. at around week 20.39 Graves’ thyrotoxicosis age. hyperthyroidism.41 greatly improve patient counseling and appropriate Nonautoimmune neonatal hyperthyroidism therapeutic decisions. This score would rotoxicosis and monitored accordingly. and duration but then worsens after delivery. a prognostic score was throughout pregnancy. the mode of treatment. it is associ- receptor (TRAbs). High levels of anti- led to widespread changes in clinical practice. thyrotoxicosis.39. every additional year of in the children of mothers treated years before for treatment was associated with a decrease in relapse hyperthyroidism who still have circulating ­ TRAbs. Fetal hyperthyroidism may relapse is increasing with nonwhite ethnicity. for severe.38 These During gestation. transient hyperthyroidism considerations have not been studied in children. particularly in regard to mental perfor. mutation of the Gsα gene)42 or an activating muta- have been thought to modulate individual respon. or based on the use of ment develop early in life. and smoking. occurring in only about 2% of the nal stimulating antibodies directed against the TSH offspring of mothers with GD. A body transmission are associated with the occurrence recent prospective study34 has shown that the risk of of fetal thyrotoxicosis. has a prevalence of approximately 0. These results highlight the positive impact of a Thus. lead- ized studies in children are therefore required to ing to its constitutive activation. In this study. and long-term morbidity. However. such as genetic caused by McCune-Albright syndrome (activating background. permanent. Molecular abnormalities of the TSH receptor. relapse risk decreased with duration women with high levels of TRAbs.28.23. Hyperthyroidism in pregnancy function may be disturbed to a varying degree by the 147 . as ologically responsive to TSH and TRAbs during the demonstrated by high serum TRAb and FT4 levels. thyroid nodules and goiter enlarge- whether drug-based.

and psychomotor clearance of transplacentally transmitted ATDs from disabilities may occur in severely affected infants. Thyroid function tests should therefore be repeated in the first week of life. rience of the ultrasound operator also has an impact should lead to the initiation of ATD treatment in the on the management of pregnancy in women with infant shortly after birth to prevent the development GD.55 However. infant’s circulation. poor fetal status and the results of thyroid function tests weight gain contrasting with a normal or large appetite.53. embryopathy. These enlargement is the starting point for the diagnosis of drugs may also expose the fetus to the risk of hypo- thyroid dysfunction and ultrasonography is used to thyroidism. according to thyroid hor- required and should be reserved for cases in which mone levels. bone maturation in cases of fetal hypothyroidism) During the neonatal period. Fetal thyroid width and circumference should be of clinical hyperthyroidism.. 2 to 4 days following birth (FT4 levels > 35 pmol/L). pregnancy. leading to fetal vented by administering antithyroid drugs to the hypothyroidism. which cross the for TRAbs and/or receiving ATDs. 10 to 15 mg MMI or less daily) are determination of fetal bone maturation (delayed therefore recommended to the mother. until TRAbs are eliminated from the injection is required to treat a secondary fetal hypo.47 the mother. Such scans genesis has been associated with neonatal aplasia should be taken monthly after 20 weeks of gestation cutis (a scalp defect).48 In fetuses with from the serious consequences of this condition. guiding the choice of to control tachycardia during the first 1 to 2 weeks the most appropriate treatment. mother. TRAbs titer. blood.52. but probably cannot pre- small anterior fontanelle. and dict subsequent neonatal thyroid dysfunction. TRAbs continue to be present in the neonate after the cy. mg/kg/day.Part II  Pediatric Thyroid Disease presence of TRAbs. advanced bone age. so small doses (usually 100 to 150 mg assess the presence and vascularity of the goiter. the main clinical issue is determining whether the cause is maternal treatment that is appropriate for Treatment achieving normal maternal thyroid function but inap. MMI is pre- and fetal heart rate (higher than 160/min in cases of ferred (1 mg/kg/day. The disease is transient and may last 2 the diagnosis is dubious or intra-amniotic thyroxine to 4 months. fetal hyperthyroidism can be pre- propriate and excessive for the fetus. Mothers can breast-feed while thyroid state.41. The PTU or less daily. carried out on cord blood at birth.52 retardation.53 Within 2 to in these infants. and maternal thyroid c­ riteria (e. thereby protecting infants defined from 20 weeks of gestation. The expe.49-52 A combination of maternal crite. Thyroid gland placenta and act on the fetal thyroid gland. hormone state.57 148 . are equally effective for treating hyperthyroidism in ing fetal thyroid stimulation and hyperthyroidism. Invasive fetal blood of treatment. Propanolol (2 fetal hyperthyroidism) may also facilitate the diagno. in three doses). even when nor- Diagnosis and Treatment During Pregnancy mal (or high TSH levels caused by excessive ATD in and the Neonatal Period late gestation) results have been obtained with cord The early diagnosis and treatment of fetal hyperthy. prenatal treatment strategy. ATD use and dosage) and fetal status of their infants. stare. fetal heart rate. taking ATDs. Craniostenosis.41 goiter. tracheoesophageal fistula. Remarkably. Biologic abnormalities of the liver may 5 days of birth. prematurity. may validate the goiter. eyelid retraction and/or exophthalmia. In cases in which maternal disease is and bone maturation) is used to distinguish between untreated or poorly controlled. Strong suspicion of neonatal autoimmune roidism or hypothyroidism are crucial and highlight hyperthyroidism..or hyperthyroidism.g. hyperexcitability. hyperthyroidism may develop when also be observed in the absence of cardiac insufficien. During gestation. when TRAbs are detectable in cord the importance of TRAb determination throughout blood and free thyroid hormone levels are high in the pregnancy in women with Graves’ disease. use of ATDs. or fetal thyroid stimulation by mater. and to screen for goiter and/or evidence of fetal thy. Cardiac insufficiency is one of the major risks a disturbed thyroid hormone state. with no adverse effects on the thyroid ria (e.56 The fetus benefits directly from the roid dysfunction in women with GD testing positive maternal ingestion of these drugs. oligoamnios. It is usually possible to decrease the collection and amniotic fluid sampling are usually not ATD dosage progressively. PTU and MMI both cross the placenta and nal Graves’ disease.54 hepatomegaly and/or splenomegaly are the most fre. with the presence of TRAbs caus. PTU is more commonly used Fetal ultrasound scans are a noninvasive tool because the administration of MMI during organo- for detecting fetal thyroid dysfunction. only a minority of newborns from moth- quently observed clinical features during the neonatal ers with gestational autoimmune thyroid disease have period. and fetal death The prenatal response to treatment. microcephaly. based on commonly occur.g. Tachycardia. thyroid Doppler signal. in two divided doses) can also be used sis of hypo. intrauterine growth fetal hypothyroidism and hyperthyroidism.

 Erbil Y. Hyperthyroidism References 20. 2006. 1980. 2006. 1998. density in the patients with Graves’ disease. et al: Chronic iodine ­excess tive analysis of the efficacy and safety of radioactive does not increase the incidence of hyperthyroidism: A iodine in treating young Graves’ patients. 2001. Alberti C. Lucidarme N. N Engl J Med 352: therapy. [Basedow disease in children: Clinical and evo- ease: A population-based study of two Danish twin lutive aspects. Brix TH. Hasselbalch HC. Wang SH. Christensen K. J Clin Endocrinol bone mineral recovery during treatment in chil­dren Metab 92:2190-2196. Pertzelan A. Jorgensen EV. Li Y. Eur J Endocrinol 156:403-408. Lancet 362:459-68. 1985. Noh JY. Zimmerman D. et al: Factors at 16. rotoxicosis in prepubertal children compared with thyroidism with naturally occurring CD4+ CD25+ pubertal and postpubertal patients. 25. J Clin Endocrinol Metab 93:3817-3826. J Clin Endocrinol Metab 86:930-934. 65:550-556. et al: Incidence of ju. Eur J Endocrinol 154:623. Shulman DI. 30. J Clin Endocrinol Metab venile thyrotoxicosis in Denmark 1982-88. Clin Endocrinol 54:547-50. Hegedus L: Evi. Laurberg P: Remission of Graves’ disease during ­Pediatric Endocrinologists of Northern California anti-thyroid drug therapy. Boiko J. 2007. Pediatr Clin North Am of genetic factors in the etiology of Graves’disease? 37:1273-1295. 2008. Menda Y: A 36-year retrospec-   8.] Arch Pediatr 5:722-730. 2000. J Pediatr 137:56-62. ease. Endocrinol. 1999. 2007. Cornelius EA: Influence of iodine-131   7. Cheetham T: Juvenile thyrotoxicosis. 2006. 2008. Birrell G. Léger J: diovascular and cancer mortality after radioiodine Reduced bone mineral density at diagnosis and treatment for hyperthyroidism. 2003. Kyvik KO. 32. Lavard L. multicenter study. Lippe BM. et al: Comparison of onset predictive of lasting remission in pediatric pa- methimazole and propylthiouracil in patients with tients with Graves’ disease followed for at least three hyperthyroidism caused by Graves’ disease. 2000. Landau E. Thyroid 7:755-760. Hegedus L: What is the evidence in children and adolescents. docrinol Metab 92:797-800. J Clin En- prospective community-based epidemiological survey docrinol Metab 89:4229-4233. achieve remission? Nat Clin Pract Endocrinol Metab 11. Brix TH. Ranlov I. treatment. 2000. Rivkees SA. 1997. 33. Cooper DS: Antithyroid drugs in the management 31. cal features at diagnosis and response to medical 15. Kaplan SA. Kalter-Leibovici O. Endocrinol Metab 92:2182-2189. Pediatrics pediatric Graves’ disease is radioiodine. Giriş. 26. M. Nagayama Y: Regulation of Graves’ hyper. in China. 21. Mussa GC. Yang F. study. J Clin Endo. Thyroid 8:627-634. Cooper DS: Hyperthyroidism. Rivkees SA. Hamburger JI: Management of hyperthyroidism in   1. Corrias A. Lippe BM: Remis- Metab 82:1719-1726. Tansey MJ. with Graves’ disease. Metso S. et al: Maladie de   3. tifs. J Clin Endocrinol 29. 2003. 1998. Castanet M. Styne DM: Predictors of early remission 2:2-3. Huhtala H. Saitoh O. Weetman AP: Graves’ hyperthyroidism: How long 10. 1994. 2004. 19. Styne DM: for the Organisation of 17. 60:1019-1024. Dinauer C: An optimal treatment for toxicosis treated with antithyroid drugs. et al: Autoim- of patients with Graves’ disease: An evidence-based mune hyperthyroidism in prepubertal children and approach to therapeutic controversies. Perrild H. Glaser NS. Endocrinology 147:4559-4560. Hegedües 34. Raux-Demay MC. dicting the likelihood of remission in children with 18. Basedow chez l’enfant: Aspects Cliniques et évolu- dence for a major role of heredity in Graves’ dis. J Clin En. Léger J. Cheng PS: Increasing incidence of child. Twenty-five percent remission every two years. et al: Effect of lugol solu-   5. 2001. 2007. 23. children and adolescents. Landaw EM. Cooper DS: Antithyroid drugs. J Clin years. Glaser NS. Endocrinol Metab 64:1241-1245. Eur J Endocrinol 130:565-568. Muhar I. N Engl J Med 343: tion on thyroid gland blood flow and microvessel 1236-1248. Gan-Gaisano M: Hyperthyroidism   2. Jaatinen P. cohorts. J Clin   6. et al: Predic- L: The rationale for B lymphocyte depletion in tors of autoimmune hyperthyroidism relapse in Graves’ disease. Lazar L. Grumbach MM. 2006. J Clin J Clin Endocrinol Metab 92:801-803. Endocrinol Metab 92:2157-2162. Pediatrics 121:e481-e488. 2006. of hyperthyroidism in children. 2007. et al: Increased car-   9. 905-17. Teng X. 1987. 1990. 24. Monoclonal anti-CD20 antibody as children after discontinuation of antithyroid drug a novel treatment option. Itoh K. 28. dose on the outcome of hyperthyroid children. Lee JA. 632. 149 . nol Metab 85:3678-3682. Kaguelidou F. Read CH. adolescents: Comparison of clinical and biochemi- crinol Metab 88:3474-3481. Nakamura H. 2007. Kaplan SA: Hyperthyroidism 13. Silvestro L. Graves’ disease: A prospective. 14. 1997. J Clin Endocri- regulatory T cells in a mouse model. ogy 147:417-2422. et al: Thy-   4. Collen RJ. 22. 2004. A brief review. A nation. Shan Z. Clark OH: The optimal in children treated with long term medical ­therapy: treatment for pediatric Graves’ disease is surgery. Czernichow P. 27. 2007. can should antithyroid drug therapy be continued to we do better? Arch Dis Child 89:745-750. J Pediatr Endocrinol Metab 12:537-541. hood Graves’ disease in Hong Kong: A follow-up Pediatrics 111:745-9. El Fassi D. Wong GW. Nielsen CH. 2003. Ruiz JC. Baker JR: Targeting B cells in Graves’ dis. wide study. Kyvik KO. Time to reconsider the Collaborative Graves’ Disease Study Group: Pre- mechanism? Eur J Endocrinol 155:783-786. sion rates of children and adolescents with thyro- 12. 2005. Ozluk Y. Weetman AP: Graves’ disease.

2001. J Clin Endocrinol Metab 88:117-124. rionic gonadotropin. of Graves’ disease. Ito K: Effects of 150-154. thyroid drugs.Part II  Pediatric Thyroid Disease 35. 1997. 2003. Ranzini AC. Volumenie JL. severe neonatal hyperthyroidism. Eur J Endocrinol 156:173-179. Van den Abbeele AD. Kempers MJE. 36. 2000. Hidaka Y. 1995. 51. Wallin G. Le Gac I. N Engl J Med 339:1823-1826. of outcome and comparison of different drug 47. 1997. 1991. Polak M. 2003. agement of fetal thyroid goitres: A report of 11 cases 40. Van Tijn DA. Yoshimoto M. 48. Mansour S: Carbim- Metab 81:2023-6. Abraham-Nordling M. later years. et al: Man- 1997. Baba T. Luton D. Vuillard E. J Clin Endocrinol Metab pregnancy: Pathways of endocrine adaptation from 88:4175-4179. Noh JH. Polak M. Daykin J. sampling in the diagnosis and the treatment of fe- 38. ­thyrotropin-receptor gene. Prenat Diagn 20:799-806. N Engl J Med 332: 55. et al: Med Genet 132:130-135. 2002. 1996. of the thyroid-stimulating hormone receptor in a J Clin Endocrinol Metab 82:3633-3636. Van Trotsenburg SP. Skuza KA. of neonatal McCune-Albright syndrome with Cush. ing syndrome and hyperthyroidism. Lundell G. Endocrinol 53:177-181. et al: A case mothers with Graves’ disease. Acta Paediatr 54. J Clin Endocrinol Metab thyrotropin receptor hypersensitive to human cho- 85:1038-1042. mothers take high doses of propylthiouracil. 2000. J Ultra- term outcome in Graves’ patients treated with anti. J Clin Endocrinol Metab 88:5851-5857. 1980. propylthiouracil and methimazole on fetal thyroid 44. Clin 2007. disease. 13 years’ follow-up of severe congenital nonautoim. Gelwane G. of reference intervals for markers of fetal thyroid 39. azole embryopathy: An emerging phenotype. 57. Elmslie F. Daneman D. 49. De Roux N. Ishikawa N. tion of neonatal hyperthyroidism in infants born to 42. De Roux N. blocking type anti-thyrotropin receptor antibodies 2000. J Pediatr 128:264-267. Gronowski AM: Establishment 2007. Yamashita R. Luton D. 50. Amito N. J Clin Endocrinol 56. Holder RL. 2005. Bremont C. Rodien P. J Clin Endocrinol tal thyroid function in relation to maternal Graves’ Metab 90:6093-6098. Parma J. Makino F. J Pediatr 97:257-259. Am J 45. Ann Endocrinol 58:338-342. Van Sande J. 2004. Singh PK. Guibourdenche J. Best Pract Res Clin Endocrinol Metab 53. al: Central congenital hypothyroidism due to gesta- 43. Tör­ tal hyperthyroidism in the offsprings of a euthyroid ring O: Thyroid hormone state and quality of life mother. et al: Fetal and neona. Eur J Endocrinol 147:583-589. et al: Predictors 1998. Graves’ disease during pregnancy: The key role of 41. Léger J. et al: A neomutation status in mothers with Graves’ hyperthyroidism. Izumi Y. Vuillard E. 1996. Park YJ. Sanson ML. Nedrebo B. et al: Thyroid mune hyperthyroidism due to an activating neomu. Walpole I. Stene M. Ananth CV. Glinoer D: The regulation of thyroid function in status in amniotic fluid. Momotani N. sound Med 20:613-617. Park DJ. Polak M. 150 . Smulian JC. during pregnancy in patients with Graves’ disease. 52. et al: Congenital tional hyperthyroidism: Detection where prevention hyperthyroidism caused by a mutation in the failed. Foulds N. Momotani N. Kopp P. Sills IN. producing thyroid stimulating immuno- at long term follow-up after randomized treatment globulins. et al: Age and 46. Kim TY. Couet J. Le Gac I. 2003. physiology to pathology. et Scand 80:984-987. et al: Epitope heteroge. et al: Familial gender predict the outcome of treatment for gestational hyperthyroidism caused by a mutant Graves’ hyperthyroidism. function in wholly breast-feeding infants whose tation of the TSH receptor gene. Parvin CA. 2005. Endocrinol Rev 18:404-433. et al: No increase of in a single perinatal unit. et al: Ultraso- 37. nography of the fetal thyroid: Normograms based neity of thyroid-stimulating antibodies predicts long on biparietal diameters and gestational age. Howard NJ: Neonatal thyrotoxicosis: regimens for the prevention of relapse in patients Intellectual impairment and craniosynostosis in with Graves’disease. Holm PI. Rapaport R: Predic- 18:289-302. et al: Fetal cord blood 2003. fetal thyroid gland monitoring. et al: Management of J Clin Endocrinol Metab 88:5871-5874. Allahabadia A. Polak M. Nakayama M. Horm Res 68:220. Uhlving S.

9 stimulate thyroid growth and function by mimicking pituitary TSH.7 As is true of a thyroid-stimulating factor offered a cause for the of most autoimmune diseases.6 A historical cohort from continues to bear the name of Robert Graves. goiter. Ophthalmopathy may rarely occur alone or of iodine sufficiency in the region in question. n Radioiodine is contraindicated in moderate to severe Graves’ ophthalmopathy whose primary ­therapy remains corticosteroids.5 indistinguishable from other forms of thyrotoxicosis and those that are unique to GD—specifically EPIDEMIOLOGY ­orbitopathy. is also inti. although less well defined. and rheumatoid arthritis.1 The disease. When there is a ­recurrence. at the same time. or after the onset 153 . outnumbering Caleb Hillier Parry was the first to describe the features other common disorders. men are affected at a disease. autoimmune thyroid disease is the presents before. In with Hashimoto’s thyroiditis. who in the United Kingdom has found the incidence of GD 1835 proposed an association between exophthalmos. but most commonly it the United States. ophthalmopathy. The signs and symptoms of GD can be divided into those mately involved with the TSH receptors on orbital and that manifest a state of hyperthyroidism (Table 12-1) dermal fibroblasts and adipocytes. however. in women over a 20-year period to be about 1 in 1000. accounting for 60% to 80% of receptor is the causative factor in GD. These antibodies cases. it is clear that the binding of these than about 40 years. and palpitations. Over a century later. patients may opt to continue antithyroid drugs or receive radioiodine ablation therapy. Davies Key Points n Graves’ disease is the commonest cause of hyperthyroidism in young women. such as diabetes mellitus of Graves’ disease (GD) in 1825.4. and occasionally der- The prevalence of GD depends largely on the level mopathy. n Treatment can be non-thyroid ablative with antithyroid drugs or ablative with radiodioine or ­surgery. Hollander and Terry F. Section A Hyperfunction Chapter Graves’ Disease 12 Jason M. n TSH receptor antibody measurements may help predict recurrence after antithyroid drugs. HISTORY most prevalent autoimmune disease. The cause of Graves’ ophthalmopathy CLINICAL PRESENTATION AND DIAGNOSIS and dermopathy. and methimazole is the drug of choice. GD is the most common cause antibodies to the thyroid-stimulating hormone (TSH) of ­ hyperthyroidism. evidence with a prevalence of approximately 2%. the stimulator was identified as an IgG much lower rate than women.2 In 1964.3 Currently. Most patients are best treated first with antithyroid drugs.8 In patients younger antibody.

thyroidologists have two commonly suppressed TSH with elevated levels of triiodothyro. in unclear cases. but not document the diagnosis and possibly offer prognostic MMI. directed against the TSH receptor.18 but convincing data of immunosuppres- provide. however. ter for debate. decreases peripheral T4 deiodination. the measurement of TSH possess a number of other salutary effects (see later). Increased appetite Lid lag Antithyroid Drugs Thionamides of thyroid hyperfunction. The thionamides have proved to 50% of patients. disrupting the cases. Hyperkinesias Tremor Diarrhea Atrial fibrillation TREATMENT Excessive sweating Muscle weakness The main treatment options for GD include ATDs. thereby information. It was first choice of therapy is often dictated by the needs and argued by some that observed changes in the immune preference of the individual patient rather than by system could be attributed to normalization of thyroid evidence-based outcome data. In practice. access to a qualified thyroid surgeon. when rapid control of thyrotoxicosis is This chapter will review the mainstays of necessary. Whether these immunomodulatory effects are caused ities. Ultimately.19-23 Furthermore. thyroglobulin. In severe the enzyme thyroid ­peroxidase (TPO).13 The second half of the chapter will focus on Symptoms Signs the therapeutic options for the infiltrative ­orbitopathy Palpitations Tachycardia and ophthalmopathy of GD. Graves’ glands are typical. tion of iodination leads to decreased intrathyroidal ily history of autoimmune disease. and surgery. First.11. propylthio- nine (T3) and thyroxine (T4). which is ­present in stores of T4 and T3. mostly soft but The thionamides are actively concentrated by the thy- varying to firm and rubbery. the management of GD Nervousness Goiter in pregnancy. including the use of antithyroid drugs Immunosuppression. Heat intolerance Stare radioiodine. but there is no dispute that a number the decision to pursue one form of therapy rather of immunologically important events accompany than another represents a complex interplay of facts thionamide treatment. a number of 154 . considering measurable end points such as cure by the intrathyroidal actions of thionamides or by a (remission) and weighing them against the real and direct effect on local immune elements may be a mat- theoretical risks of each form of treatment.  PTU in large doses. Ultimately. with iodination of tyrosine residues on the thyroglobulin an associated bruit. PTU and MMI are known as thionamides. age of patient.17. previous reaction to ATDs. over the years surrounding the importance of the im- ity has proven efficacy in the treatment of GD. including disease severity. roid gland15 and subsequently act by interfering with ly smooth but occasionally may feel nodular. is used widely in England and other countries. Mechanism of Action Laboratory data will invariably reveal a low or In the United States.10 In areas of relative iodine defi. a normal decreasing T3 levels more rapidly than MMI. and surgery. enlarged glands of variable consistency. frequently in a ratio uracil (PTU) and methimazole (MMI). the specific ­ diagnosis of molecule. Often. a thrill may be felt over the upper poles. prescribed ATDs in their armamentarium. Certainly. Fortunately. ingested.Part III  Adult Thyroid Disease compliance.14 a pattern known as T3 thyrotoxicosis. and patient’s wishes in regard to child- Table 12–1  C  ommon Manifestations bearing. the serum ­ antibodies and factors. when they occur simultaneously. ­ presence of and thyroid peroxidase all decrease with thionamide ­ophthalmopathy. sive effects have been found by many investigators. once ciency.12 The goal here is to function. and an evidence-based approach to Easy fatigability Weight loss treating so-called thyroid crises. an evidence-based ratio. radioiodine (RAI). more than 90% of patients of Thyrotoxicosis express satisfaction with their chosen therapy. GD. Carbimazole higher than 20:1. as much as possible.  There has been some controversy (ATDs). GD therapy. T3 may be elevated in the face of a normal T4. carbimazole is rapidly ­ converted to MMI. most patients have diffusely drugs capable of inhibiting thyroid hormone synthesis. this property of PTU can be exploited. patient treatment (Fig. 12-1).16 This is or elevated radioiodine uptake can corroborate the probably of little clinical importance in most cases of diagnosis by excluding subacute ­thyroiditis. and the munomodulatory properties of thionamides. the diagnosis of GD is straightforward.19-29 nale for the use of each of the three treatment modal. this thionamide-induced inhibi- GD can be deduced from the clinical picture and fam. receptor antibodies (TSH-R Abs) is routinely made to Inhibition of Deiodination. Each modal. Additionally. a class of On presentation.

et al: Antithyroid peroxidase autoantibodies in thyroid diseases. a between 30 minutes and 3 hours after ingestion.31 After a single oral dose. however.21 ues to exert its effect on thyroid hormone metabolism. B. 1990. Petersen MM.33 number of changes have been observed in immune and the half-life is much longer than PTU. thionamides appear to upregulate the Both PTU and MMI are readily absorbed from the expression of Fas ligand (Fas-L) in thyrocytes. Assays were performed after 6 to 8 months of MMI therapy in the Graves’ disease patients. gastrointestinal tract and have a bioavailability that ducing Fas-L–mediated apo­ptosis of infiltrating lym. HLA-DR. remains unclear. ingestion and has a half-life of 40 to 120 minutes.05 p <0.29 Furthermore. J Clin Endocrinol Metab 71:661-669. believed to be a factor in the Peak plasma concentrations of MMI are achieved perpetuation of the autoimmune process. Antibody activity toward the thyroid-stimulating hormone (TSH) receptor during treatment of 16 patients with hyperthyroidism from Graves’ disease with propranolol followed by ­carbimazole and thyroxine (T4).24 suggests an effect much greater than the inhibition Similarly. McLachlan SM. Variation in thyroid peroxidase (TPO) antibodies after treatment with ­methimazole (MMI). It follows that the drug contin- decrease during thionamide therapy.27 Thionamides also inhibit the aberrant a maximum concentration approximately 1 hour after follicular cell expression of the major histocompati.31 To illustrate logic observations remains unclear.26 Pharmacokinetics Additionally. Whether immune this.25.28 Finally. It is clear that both MMI and PTU are concentrated ing ATD-induced remission. even after serum concentrations wane. modulation or simply the restoration of a euthyroid Soluble intracellular ­adhesion molecule-1 (sICAM-1) state accounts for the efficacy of thionamide therapy was found to be elevated in newly diagnosed GD pa. However. natural by the thyroid and remain partly unmetabolized for killer cells30 and intrathyroidal lymphocyte numbers long periods of time. Graves’ Disease 100 TSH receptor anitbody activity (% Inhibition of TSH binding) 90 80 p <0. A. soluble interleukin-2 (IL-2) receptor and of iodination and organification discussed earlier. PTU reaches phocytes. Piccolo P. whereas helper T-cell numbers return to normal dur. B from Mariotti S. hours. N Engl J Med 303:302-307. suppressor-­inducer T-cell subsets are upregulated ing when discussing the activity of these medications. In particu. from 3 to 6 cell subsets during treatment with ATDs. in. The clinical significance of these immuno. (A adapted from ­McGregor AM. et al: Carbimazole and the autoimmune response in Graves’ disease. exceeds 80%. Jansson and colleagues34 have demonstrated that 155 .31 The plasma half-lives.05 70 105 60 50 40 104 Anti-TPO Ab (U/mL) 30 20 103 10 0 300 Serum T4 –10 200 (mean 102 100 �SEM –20 0 nmol/L) 0 2 4 6 8 8 10 12 14 16 18202224 Time (weeks) 10 Thyroxine <10 UT T UT T Propranolol Addition Hashimoto’s Graves’ disease or placebo of carbimazole thyroiditis A B Figure 12–1  Thyroid antibodies after thionamide treatment.32 bility complex. soluble IL-6 levels were significantly lower in patients treated with MMI than untreated individuals. the breadth of evidence tients and was noted to fall with thionamide therapy. can be deceiv- lar.) other immune molecules decrease with treatment. Caturegli P. 1980.

When they do manifest. In fact. elevations do not preclude thionamide therapy. injury during PTU therapy may be common. MMI and PTU are excreted in the urine. MMI.Part III  Adult Thyroid Disease intrathyroidal concentrations of MMI are identical in c­ linician must be mindful of the toxicities associated surgically resected thyroids.37 Alternatively.50 Marked elevations in amino- those exposed to PTU. liver enzyme levels normalize while on con- 90% bound to albumin. there appears to be no significant differ- ence in pharmacokinetics relating to age38 or degree Hepatotoxicity of ­thyrotoxicosis.5%) Fulminant ANCA-positive vasculitis (rare) Urticaria Cholestasis (MMI) Arthralgias ANCA. indicating the idiosyn- Side Effects cratic nature of such reactions.39 These properties suggest that MMI but not PTU at the start of therapy to establish a baseline and on would readily cross the placenta as well as enter the a regular basis thereafter.46.49 We suggest checking liver function ity.5% of the trations of the drug were ­ significantly higher in the time. most cutaneous reactions do not neces- Some authors have suggested a sensible empirical sitate termination of ATD therapy. tinued ­therapy. upset to severe. current evidence occur at any time. PTU has been demonstrated to reduce MMI. ATD to another may provide relief. because serious effects may lacteals of lactating women. antineutrophil cytoplasmic antibody. propylthiouracil.39 with the hours prior to surgery. and those that do not. although MMI appears to exert better control on those toxicities that require cessation of therapy at this dose frequency. subclinical liver MMI and PTU share many similarities but have impor. with a very low lipid solubil. Others have contended that no rash or pruritus. ­However. whereas PTU is 80% to patients. although cross- est dose possible of ATD is used in all such patients.45 have suggested little relationship between hepatic necrosis and dose of PTU. Both drugs can therefore be given on a daily in a number of ways.51 In contrast to Side effects associated with ATDs range from benign PTU. most severe reactions occurring less than 0. the serum concen. regardless of whether the with thionamide therapy. DIL. Finally. It is reasonable dosage adjustment in advanced hepatic dysfunction to coadminister an antihistamine provided neither because elimination half-life increases with degree angioedema nor bronchospasm accompanies the of liver impairment.40 More importantly. extant data than PTU43) and are considered safe in lactation. but in practice one must be clear basis. Unlike hepatic failure or agranulocytosis. A recent study has demon.48 Moreover. In most and is highly lipid-soluble. but available evidence suggests that no dosage adjustment Cutaneous Effects is required for renal insufficiency35 or renal failure. reactivity may be as high as 50%. methimazole. MMI circulates unbound in serum ing almost 30% of patients by 2 months. the likelihood a patient will last dose of MMI was taken 3 to 6 hours versus 17 to 20 experience any side effect is merely 5%. To strated equal placental transfer kinetics for PTU and the contrary. It is important to note that baseline debunks this assertion.47 Side effects (Table 12-2) can be ­categorized former. Additionally. 156 .44.36 In general.41 Both medications appear in transferase levels developing after the start of thera- breast milk at very low concentrations (MMI42 more py warrant cessation of the drug. life-threatening reactions such as the process is typically ­cholestatic in nature. thyroid studies in infants mortality and improve liver function in patients with exposed to MMI in utero are indistinguishable from alcoholic hepatitis.31 This is a more complex topic because elevations in transaminase levels frequently accompany the Differences Between Propylthiouracil and Methimazole hyperthyroid state itself. reports of MMI hepatotoxicity are infrequent nuisance reactions such as rash or gastrointestinal in the medical literature. the low. changing from one dosage adjustment is necessary. affect- tant differences. PTU.37 In practice. Although the PTU-induced hepatocellular injury. drug-induced lupus. which appears Table 12–2  Side Effects of Antithyroid Drugs Hypersensitivity Hematologic Liver Rheumatologic Rash Leukopenia Hepatitis (PTU) DIL (rare) Pruritus Agranulocytosis (<0.

61 Moreover. 3. in the iodine content of the local diet. However. at least as initial therapy.12 ATDs remain a viable. definitive evidence is lacking at this time. 30% to 50% of patients. in the literature meeting strict diagnostic criteria. studies have shown a greater frequency ­function in pretreated individuals following RAI of agranulocytosis in this age group (6. There are a handful of circumstances that deserve mention when thionamides are clearly pre- Agranulocytosis ferred. MMI also been identified in GD patients treated with MMI.58 Of note. ATDs are first-line therapy in pregnancy.56 If agranulocytosis does cations.11.52 Resolution of MMI-induced cho. Overall. will be reviewed in detail later in this chapter. Although euthyroid for over 10 years.37 Most cases of 2.63 toms develop. granulocyte ­ colony-­stimulating factor older individuals.45 to 114. gression is observed during ATD therapy.62 to the safe administration of these medications.54 was well tolerated and. 12. Perhaps trials. Should these symp.64 Whether pre- ATD provided that the number does not represent a treatment actually prevents worsening of cardiac precipitous fall from a previous cell count and that a status has not been demonstrated in prospective follow-up test can be done within 1 to 2 days. their use has increased but remains in contrast to the culoskeletal symptoms predominated and resolution of practice in Europe. most American thy- Drug-induced lupus (DIL) associated with PTU has roidologists preferred radioiodine therapy to ATDs been described. ATDs effectively induced remission in a less favorable prognosis.57 although lestasis is the rule once the medication is stopped.65 P < . mus. As would be vasculitis require immunosuppressive therapy. Depend- cytoplasmic antibody (ANCA)–positive vasculitis carries ing on the study.4 times higher. (G-CSF) may hasten ­ marrow recovery. while just 39% of patients most case reports have implicated PTU. 1. a recent ran- pulmonary symptoms occur primarily in ANCA-positive domized controlled trial has demonstrated the safety vasculitis. probably reflecting differences lap in symptomatology between ANCA-positive vascu. 5% to 95% confidence questions in regard to the optimal use of these medi- interval [CI]. where ATDs tend to be used as the illness required nothing more than withdrawal of first-line therapy. the cholestasis associated with u occur. the clinician is next challenged with other than 65 years (odds ratio. A level between 1000 rise in plasma hormone levels that follows thy- and 1500/mm3 will likely be approached differently roid cell breakdown induced by RAI ablation by each physician. this confusion during therapy because a mild leukope. renal dysfunction and serious destructive therapy must be used. A granulocyte count less lished coronary artery disease to deplete intra- than 1000/mm3 dictates that thionamide therapy thyroidal T3 and T4 stores. whereas no pro- common presenting symptoms. MMI occurs more commonly at higher doses and in Additionally. rather. nia can be associated with GD itself. there is a clear reduction in post- greater caution should be exercised with those older treatment biochemical parameters of thyroid than 40 years.55 Moreover.9. However. including mucocutaneous lesions. rationale. surpris- Prompt recognition of these syndromes is paramount ingly cheaper than RAI and its consequences. the ATD in most patients. It is probably safe to continue the can have serious consequences. litis and DIL.12 Since then.60. over 90% of MMI-treated patients remained most severe cases requiring plasmapheresis. Graves’ Disease ­ nrelated to dose. fever. Of the 12 cases and surgery for the treatment of GD. Making the Choice to Use Antithyroid Drugs Autoimmune Phenomena When surveyed in the early 1990s.53 In contrast.56 Fever and sore throat are the most RAI in about 15% of patients. ANCAs have treated with RAI remained euthyroid.001). Which ATD is “best”? At what dose? For how 157 . These include the This remains the most feared complication of ATD following: therapy. there is no compelling reason that and serositis. but is exceedingly rare. necroinflammatory liver disease has been reported with MMI therapy albeit rarely. although often transiently. thionamide therapy should be dis. because the rapid be permanently discontinued. broad-spectrum ­antibiotics should be ­initiated. one study has found the risk When the decision to use ATDs is finally of a fatal reaction to be much higher in those older reached. with than 1 year. in this particular study. There is considerable over. At least 50% of patients with PTU-induced and efficacy of long-term MMI therapy. with the expected.92). in those who recur. ATDs are encouraged prior to RAI in older continued immediately and a cell blood count and patients and in those with suspected or estab- differential determined. compared with those who were not pretreated. Current evidence also suggests that moderate agranulocytosis occur within weeks to months of the to severe active Graves’ ophthalmopathy (GO) initiation of ATD therapy but can occur after more may worsen. A pretreatment white cell count can prevent 1. antineutrophil and cost-effective59 first-line therapy for GD.55.

PTU 255 ± 85 mg). there is a strong suggestion in the literature that the ­antithyroid treatment. in our opin- free T4 achieved within 3 months of the ­initiation of ion. likely because of its PTU. Finally. A study by Pearce56 a low dose. patient achieved a euthyroid state. (2) neutropenia (P = 0. Overall.0018). 10 mg every 8 hours. Older and per.67 Both In contrast.0002). agranulocytosis occurred at all doses of studies strongly favored MMI. must be taken in context. one study com- PTU. Finally. Which drug is more efficacious? ed by Cooper and colleagues. were euthyroid 158 .66For this reason alone. (P = 0. was euthyroid versus 34 of paring daily MMI with PTU three times daily found 66 patients on MMI. both high (MMI 60 ± 19 mg. They found no significant ­ difference in adverse events between the medications. These data. at least two important conclusions can markers detected between these groups. in exchange for an increased likelihood of adverse haps less reliable studies do not support these findings. Which drug is safer? records of 50 patients treated with ATDs who devel- 3. events. although most side Propylthiouracil or Methimazole effects reported occurred in the high-dose MMI To determine which should be used. This dose-response effect was also not- 1. Which drug is associated with greater compliance? oped agranulocytosis were compared with those of 50 patients treated with ATDS with no untoward Unfortunately.3% in the PTU group. When considering an initial dose of medi- ders. high-quality evidence does not sup. By 3 months. (5) gastrointestinal disorders er the dose of ATD influences the remission rate. 6. In conclusion.0310). and compli- port the routine use of one ATD over the other.55 In this study. troversies surrounding the use of ATDs. and (2) rare but serious reactions. Furthermore. 8. Two of the trials compared sis when the dose exceeded 40 mg daily (P < . low-dose ATDs (MMI 23 ± 10 mg. are hours.01). safety.68 Another be drawn: (1) serious adverse events are unlikely at study randomized 94 patients to 100 mg PTU every low doses of MMI.0038). cosis pose to this patient? A euthyroid state can be tarily reported to a national registry compared with achieved more rapidly with higher doses of ATDs the number of prescriptions written. except those in the Compliance has never been a primary out- every 12-hour dosing arm. PTU. PTU 728 ± 216 mg) and 68.68 PTU much less rospective study. (4) renal and urinary of ATDs render patients euthyroid sooner. drug-induced hepatitis and some of the longer half-life and greater efficacy when dosed once rarer rheumatologic manifestations of ATD toxicity daily.6-fold increase in agranulocyto- compared PTU with MMI. (3) respi. MMI is effective when dosed daily.0016). or 12 including hepatitis and ANCA-positive vasculitis.70 Although compliance (assessed by pill count) to be 83. excluding hypothyroidism (P = 0. including 73 Japanese GD patients. There were no cases of agranulocytosis answer these questions definitively. the 2. ance favor the routine use of MMI in the treatment Safety is another important consideration of GD.3% in the preponderance of the data available favors the the MMI group versus 53.0190). A total of four in those taking less than 30 mg of MMI daily. 8. one would infer superior found that by 5 weeks. almost every MMI is a safer medication.66. although provocative.69 efficacy of MMI. suggesting that side effects are dose-related must be considered: with MMI. efficacy.4% of patients on MMI. and wheth- disorders (P = 0. there are few head to head trials to reactions. and cation. the clinical scenario must be carefully evalu- (7) psychiatric disorders (P = 0. there was an 8. the following group. a ret. 15 mg of MMI daily to 150 mg of PTU daily.Part III  Adult Thyroid Disease long? The following sections address the clinical con. lowing must also be addressed—whether higher doses ratory disorders (P = 6 × 10−5). the fol- (P = 0. ated. more- prospective trials and one retrospective trial have over. and MMI demonstrate similar efficacy. This how severe is the disease? What risk does thyrotoxi- was a retrospective study using adverse events volun. 10 mg daily. How symptomatic is the patient? Biochemically. has found that the per prescription event rate for the following occurred at a significantly higher Dosing Considerations rate in PTU-treated individuals: (1) agranulocytosis When considering the dose of ATD to be used. It was concluded that PTU come measure in studies comparing PTU with MMI. so. only 1 of 17 patients receiving compliance with MMI.72 Although the evidence in regard to safety is There was no difference in thyroid indices or clinical not definitive. 100 mg every 8 hours. or 12 hours or 10 mg of MMI every 6. (6) endocrine and reproductive disor.69 The primary outcome measure was the lowest more often associated with PTU. Reinwein and associates73 have demonstrat- Werner and coworkers71 have examined patients on ed in a randomized controlled trial that at 6 weeks. A third trial randomized 22 patients with GD to occurred almost exclusively in patients treated with 30 mg of MMI daily or 100 mg of PTU every 8 hours. particularly if a patient can be maintained on when choosing a treatment.

4% experi. the recurrence rate at of prospective randomized controlled trials have 3 years was just 1.7% recurrence rate after ATD treatment. much greater risk of side effects.78.3%. Patients were treated for just over 1 year and fol- lowed for almost 2 years after drug discontinuation.001). was discontinued.. P < .7% compared with 34.. Additional studies have confirmed the ers have tested the concept of suppressing TSH with efficacy of initiating ATD therapy at a decidedly low exogenous l-T4 to prevent the recurrence of GD. Finally. in patients uation of TSH-R Ab concentrations by stimulating with more severe disease or in those for whom more the release of thyroid antigens. The The second question to be considered is TSH-R Ab concentrations were significantly lower whether ATD dose influences remission. plus MMI. MMI. however. twice daily.6 ± 5. moreover.84-90 At least between initial dose and remission rate. Grebe and associates79 remains sparse and inconclusive. however.91 There is. and 29% on PTU. 35. At 12 months.6% in the low-dose arm addition of a small amount of l-T4 to an ATD instead (P < 0.1 vs.02).9 In this scenario. by 24 months. suggest. 83 After an additional year. be in remission (42. in their study. therefore. 100 μg. symptom score) between the groups. clin. MMI. patients in on ATDs alone. MMI was and especially useful in patients difficult to control stopped after 6 months. for the use of l-T4 therapy after discontinuation of dard therapy (PTU. the goal is to nor- the high-dose arm were significantly more likely to malize the TSH rather than suppress it.79 These data daily (about 30 mg MMI) had significantly lower free imply that there is no role for prolonged courses of T4 values at 4 weeks compared with those random. MMI.2 pmol/L. patients treated with high-dose carbimazole plus l-T4 response effect for PTU and MMI.1% on 40 mg daily.9 mg). Despite these biochemical differences. but most clini- have confirmed this observation. 10 mg every 6 hours. ATD therapy. high-dose thionamides. compared with those treated with a traditional dose. Beginning in 1991. Unfortunately. A number in the l-T4 group. MMI 15 mg daily) in most patients with theory was that TSH itself contributed to the perpet- mild to moderate GD. Jorde and colleagues78 block and replace discussed earlier.76 Conversely. research- many patients. these results have not tion of one study (by Romaldini and associates). 10 mg twice daily. placebo group. 100 mg recurrence rate. the evidence supports initiating ATD therapy at a Nevertheless.77.5 mg MMI) plus supplemen. the remission rate was no longer dif. in most studies. this theory was tested by randomizing higher dose (e.79 one would of titrating the ATD to bring the patient to euthyroid- hypothesize that relapse rates in the Romaldini study ism.001). Block-Replace Of the patients in the high-dose arm.75. approach has been touted as simple and predictable tion regimen using methimazole alone. The dose (e. have con- achieved a euthyroid state by 6 weeks but only 14% firm that high-dose ATD therapy does not influence on MMI. Based on other studies. P < . A rational argument. 60 ± 14. with a study by Hashizume and pulse.g. ATDs for the GD treatment. advantage in achieving greater remission rates. the been replicated. Duration ferent. Additional studies. currently no role tal T3 or T4 (so-called block-replace therapy) or stan. No less than seven additional trials data have consistently demonstrated no relationship have failed to corroborate these results.7% in the attempted to answer this question. 180 ± 58 mg. almost every patient in the highest dose group (MMI.g. Although of no randomized patients to 60 mg MMI (with levothyrox. the more traditional approach referred to as would converge over time. 13. can be made for the enced a remission versus 41. Graves’ Disease compared with 83. 77. Even patients after 6 months of MMI to placebo plus MMI higher doses are unlikely to be of benefit and carry a or l-T4. Their study77 one trial has demonstrated an increased rate of recur- randomized patients to either high-dose ATD therapy rence with l-T4 administration following successful (693 ± 73 mg PTU. PTU. How this could occur rapid normalization of thyroid function is required. this ine [l-T4] to maintain a euthyroid state) or a titra. coworkers83 demonstrating an astonishingly low ing that lower doses of ATDs may be preferable in 1. Block-Replace-Replace ical response was not significantly different (weight. With the excep. 2-year relapse rates were the same. but not l-T4 or placebo. suggesting that higher doses of ATDs delay The evidence in regard to duration of therapy but do not prevent relapse. demonstrating a cians have supported the concept that the longer the 159 . 75. ized to 20 mg of carbimazole (19. 100 mg every 6 hours) with follow-up ranging from 2 to 4 years. Page and colleagues74 have found patients randomized to high-dose ATDs experienced that patients randomized to 40 mg of carbimazole a greater number of adverse events.4 vs. in the presence of TSHR-Abs was never explained. Kallner and s­ ignificantly longer median relapse-free interval in coworkers69 have similarly demonstrated a dose.80-82 Furthermore. 20 mg twice daily).73.

TSH-R Ab levels in the prediction of outcome after cantly more patients in the 18-month arm remained ATDs. affirming what is already known— larger goiters predict recurrence. ­quantification of ­thyroidal blood flow with Doppler women are more likely to achieve remission than ultrasound has demonstrated its potential as a tool men and individuals older than 40 years are more to predict outcome following ATD treatment. Predicting response to ATDs remains imper- fect and often frustrating.111 A strong correlation lihood of remission. P < 0. Nevertheless. the gender lack sensitivity and specificity but. 41.and 24-month. signifi. with little additional benefit from treat. demonstrating that high levels predict failure to paring 12. it is often diffi. in general. a smaller goiter and raphy could predict recurrence with a sensitivity of milder hyperthyroidism at baseline increase the like.93 but a more recent study by relapse. highly sensitive assays for TSH-R Abs may improve fore. Two d After 12 to 18 months of ATDs. once roglobulin may also provide important information patients have completed a course of ATDs. Larger stud- from ATDs as primary therapy—that is. 71% and a specificity of 100%.96). although its specificity is poor.92. if a patient ies are needed to confirm the importance of the is certain to relapse. Quad- sought to identify laboratory and clinical predictors beck and associates105 have found that a low TSH to stratify patients as being likely to respond to ATDs level 4 weeks after ATD withdrawal has a positive pre- or unlikely to respond (Table 12-3). the lower the relapse rate.79 to 0. long-term use of ATDs can be discussed with the patient. at present offer prognostic information term thionamide therapy is contemplated. Female Male About 75% of relapses occur in the 3 months fol- Age > 40 yr Age < 40 yr lowing ATD withdrawal. suggests that ATDs be continued for at least these results. py.104 multiple studies have affirmed the signifi- in remission compared with those in the 6-month cance of TSH-R Ab levels at the end of ATD thera- arm (61. Unfortunately.95 18.108. However. Khanna and colleagues107 have found and 50% of individuals. More recently. the test is worth performing at the time of ATD withdrawal. Two years after drug withdrawal. there is a cult to predict which patients are likely to benefit more than an 80% chance of relapse.and 12-month97 treatment durations have been generally unhelpful.110 One likely than those younger than 40 to evidence a last. Likely to Remit Unlikely to Remit all patients must be followed closely for relapse.and 42-month. there.102. Moreover.103 was found between thyroid volume and blood flow (r = 0. therefore. Therefore. The evidence. When combined with other indices. A number of studies have sought to identify Allannic and colleagues94 has refuted this assertion. it remains and may be the most sensitive index of relapse avail- unclear in many of them who will relapse and when. small prospective trial has found that Doppler sonog- ing response to ATDs. that when the T3/T4 ratio exceeds 20. Predictors of Remission The T3/T4 ratio has also been suggested as a predic- ATDs induce a sustained remission in between 30% tor of relapse. ment extending to 18 months or longer unless long. able. destructive therapy would be a T3/T4 ratio. thyroid-stimulating hormone receptor antibody. in only a minority of people. Inevitably. TSH-R Ab. thy- more appropriate early intervention. predictors of relapse upon cessation of ATD therapy.96 and achieve remission whereas undetectable levels are 6. TSH-R Ab levels nor- 12 months. malize in most people during ATD treatment and. Following Mild hyperthyroidism More severe thyrotoxicosis a relapse. more than 50% of patients will 18 months of therapy. most thy- small uncontrolled studies have concluded that short. Alternatively. most patients Table 12–3  P  redictors of Antithyroid desiring a therapeutic trial of ATDs should be Drug–induced Remission afforded that chance. roidologists will begin withdrawal therapy and term (4 months) ATD therapy is as effective as 12 to observe.Part III  Adult Thyroid Disease ­ uration of therapy.105. serious consideration should be given to Low TSH-R Ab titers High TSH-R Ab titers destructive therapy because a second course of ATDs is unlikely to induce a lasting remission. Other studies com. even when the clinical predic- tors are unfavorable. After thionamide withdrawal.7%. The study randomized patients to 6 and 18 months of Since the first study to observe the usefulness of ATD therapy.05).98-102 Age and dictive value of 70% for relapse. Finally.106 The new generation of unable to confirm these data. A low TSH level will often Small goiter Large goiter be the earliest harbinger of recurrence.8% vs.109 TSH itself A number of retrospective studies have has been shown to be predictive of relapse. 160 .

3%. studies have identified specific characteristics of non- responders. despite the half-century of experience with dose of RAI with the intention of treating them more RAI. some patients 1.86 tions in gland size. study of over 2000 patients treated with a fixed 7-mCi inducing necrosis and ultimately fomenting a potent dose. er than as an adverse event. RAI will cure (euthyroid or hypo- thyroid) 75% to 90% of individuals with GD after a RAI dose = 80 to 160 μCi × thyroid tissue (g)/ single treatment.125 amenable to non- tional doses of RAI (two to six) to achieve control steroidal anti-inflammatory drugs. and (5) concomi- To discuss efficacy. ma. chromosomal damage. ­suggesting 161 . tant ATD therapy (see later). ing a single treatment of RAI. chronic of hyperthyroidism.112 Within 10 years. respec.119 In patients with eated. At this dose. Hertz and Roberts published a study evaluat. In one large prospective cohort After ingestion.113 Today. ablative doses 160 μCi × 30 g ÷ 0.114. Finally.121 Thyroid volume may be estimated or mea. the cumulative incidence of hypothyroidism at inflammatory response. including the following: (1) male gender. 5. RAI is one of the preferred of dosing strategy.81 and 14. and thyroid carcino- inevitable and have strived to ablate the gland. A common meth.120 particularly when higher. following sections will review the best evidence in an and expense of additional treatments. A number of attempt to resolve outstanding controversies. Graves’ Disease Radioiodine these patients.117 Of in fine-needle aspiration (FNA) specimens. consideration should be given avoid post-therapy hypothyroidism using dosimetry to to delivering larger doses of RAI (approximately 20 deliver a set number of millicuries (mCi) to the gland mCi) to ensure resolution of hyperthyroidism with a (80 to 160 μCi/gram thyroid tissue).124 As a result.11 on identifying those less likely to respond to a single However. will experience transient anterior neck pain and ten- tively. the require- ment of additional doses of RAI must be viewed as Radiation Thyroiditis a treatment failure. a number much greater than the uptake (%) 30% to 50% of remissions induced by ATDs. 78.3%.126 Of note. a greater focus should be placed treatments for GD because of its safety and efficacy.118 thyroid. to distort nuclear architecture and promote cellular ism of 47.9%. With time. The aggressively at the outset to save the time. A recent prospective ing the thyroidal absorption of radiolabeled iodine trial has confirmed these numbers. 67. Because hypothyroidism will eventually occur offering patients ablative thyroid therapy without the in at least 75% of those treated with RAI. demonstrating a in 12 GD patients. Others have long accepted hypothyroidism as kemia. akin to the dramatic rise in childhood thyroid by obviating the need for long-term close follow-up. RAI has been used to treat en difficult. section will review studies on the safety of RAI for the thyroidism must be viewed as a measure of cure rath. remarking that 80% to 90% of a 2-year incidence of hypothyroidism of 74. 131I is concentrated in thyrocytes. (3) severe hyperthyroid- Efficacy ism. 82.2% and a small dose of RAI was concentrated in the Graves’ treatment failure rate of 12. experience with RAI grew.123 This regardless of the physician’s intentions. regardless risks of surgery. the goal of therapy must be delin.1%.122 no such In practice. Side Effects sured using ultrasonography. thyroidologists have aimed to these characteristics. For more than 50 years. 59%. and 10 years. Traditionally. this has prov. respectively. maximizing potential for cure. single treatment. However. probably because of the unpredictable hyperthyroid conditions. derness (radiation thyroiditis). and 82%. to deliver 160 μCi/g of thyroid tissue to a 30-g follow-up period has found RAI to be the most cost- thyroid with a 60% uptake: effective therapy when compared with surgery or thi- onamides. most patients will end up hypothyroid adverse events have been observed in adults. there. Despite concern that the variables in the measurements used to determine radiation exposure might predispose patients to leu- dose. 3.2% at 6 atypia leading to erroneous diagnoses of malignancy months and 1. and 88. a number of clinical conundrums persist. A retrospective analysis of 186 inflammation and fibrosis result in substantial reduc- GD patients treated with between 10. RAI has been shown mCi found a cumulative incidence of hypothyroid.6 = 8 mCi of RAI were used. Conversely. od for determining radioiodine dose is as follows: In general. (2) younger than 40 years.1%. discomfort. at least one large retrospective study with a 24-month So. 10. treatment of GD. 9. and 25 years was 24%. 25% of patients required addi.114-116 so hypo. (4) medium to large goiter.7% remained hyperthyroid follow- In 1942. cancer following the Chernobyl disaster.

does not support this assertion. including over 7000 hyperthyroid indi- with minimal disease in this uncontrolled study expe. although the likelihood lowing administration of RAI is potential worsening is small with inactive or mild GO. ilarly.144 (MRI). that RAI be avoided in patients with moderate to formed thyroid hormone. a population-based months following 131I therapy. Tallstedt and associates129 have dem.127 patients with GD considering RAI should be coun- Perhaps the most immediate concern fol. the doses of RAI used in reexamined the association between RAI and dete. Genetic Changes Furthermore.129 ­Bartalena Thyroid Cancer and colleagues63 have demonstrated that in GD patients The potential for RAI to induce carcinogenesis contin- with slight or no GO randomized to RAI alone. reports from the 1960s demonstrating chro- systems differed by protocol. has demonstrated increased rienced an exacerbation of GO. in other words. presumably dosed by titration. the subjective ophthalmologic grading Finally. then and.130. the rise Ab production rises dramatically. TSH-R ing the administration of 131I.132.137. based on the observation that following RAI. sure to radioiodine in childhood caused an epidemic onstrated that in individuals between 35 and 55 years of thyroid cancer. Multiple studies have inferior. There was no significant change Decreased Spermatogenesis in TMV following RAI therapy in this small group. the treatment of GD do not appear to be carcinogenic.64 have occurred follow.63 therapy consisted of 4 months of MMI. 13 of 39 patients (33%) doses of radioiodine. in great contrast to the relatively large doses used or developed eye disease de novo. most (60 all-cause mortality and mortality caused by cardiovas- of 72) patients in their study had been on months cular disease. If RAI coronary disease (see later).134 However. Fortunately. increases in TSH-R Abs following 131I could herald and those with ­ coronary disease or at high risk for exaggeration of the orbital immune response. pretreatment with ATDs should roid and retro-orbital antigens. a number of stud- ies have warned that GO may worsen. and fracture.142 The literature measure total muscle volume (TMV) in the superior. rarely. Except for a handful of case reports.Part III  Adult Thyroid Disease that nodular disease should be adequately addressed In light of the disparity in these data. 12 cer mortality in patients with GD. 10 patients (50%) showed evi- dence of mild GO.140 of high-dose MMI therapy with replacement l-T4 Whether these findings are attributable to the disease (block-replace) prior to RAI.136 the worsening eye disease in the RAI arm was significantly weight of the evidence refutes an association between greater (P = . seled that GO may worsen.139 In general. whereas in the original itself or to the RAI is unknown.141. viduals treated with RAI.143. there mosomal abnormalities in leukocytes from patients are significant factors that preclude comparison treated with 131I raised concern that RAI may lead to among studies. all prior to 131I therapy. cerebrovascular disease. 23 of ues to trouble some. most evidence suggests the use of concomitant high- Exacerbation of Graves’ Ophthalmopathy dose glucocorticoids (see later). Transient thyrotoxicosis128 severe GO. such exposure was to low old treated with RAI for GD. if not based on the data presented. whereas it likely has little impact on can- evaluated 72 patients with minimally active GO.133 Because GO in hormone concentrations is clinically silent in most is likely driven by crossover specificity between thy- patients. ment of thyroid cancer. Although changes in spermatogenesis have been although the sensitivity of this technique to change reported after large doses of RAI used in the treat- in volume or degree of inflammation is unclear. despite years of experience and 150 patients (15%) experienced new-onset or worsen. none of the subjects cohort study. rioration of GO.135. In addition.131 Perros and coworkers130 have Interestingly.63 In the days to months following RAI. opting to offspring of treated individuals. and medial rectus muscles of newly diag. those with arrhythmias. Prudence dictates of thyroid function as the necrotic cells release pre. a combination therapeutic RAI and cancer-related mortality.138 Sim- of surgically treated and medically treated patients. Gupta and coworkers131 eliminated chromosomal damage and pose a genetic risk to the the subjective measurement of eye disease. The incidence of in GD. reassuring data refutes an association between 131I A number of other investigators have also and leukemia. already known to be thyrodanger- experienced exacerbations of existing eye disease ous. At baseline. demonstrated healthy offspring born to individuals nosed GD patients with magnetic resonance imaging previously treated with RAI.63.02) than in the other arm. thyroid storm. The Cherno­ ing GO compared with 4 of 148 (3%) treated with MMI byl experience provided irrefutable evidence that expo- alone. However.145 there is no evidence to 162 . Similarly. study by Bartalena and associates. it follows that sudden be the rule in older patients. mounting evidence attesting to its safety. is to be administered in more severe cases of GO.

A number of studies have ­demonstrated impres.11 This practice raises a strategy based on a 24-hour thyroid 123I uptake. more than 50 years of experi.156 However. The dose of 131I per 5. with a larger thyroid gland. the effect volume ­measurement and 24-hour uptake.145.153 Leslie treated with MMI have significantly lower free T4 and and associates154 randomized 88 individuals with GD T3 levels at all time points after RAI adminis­tration to four dosing strategies: 5 mCi fixed. to reduce post-RAI exacerbation of thyrotoxicosis. After a mean follow-up sive increases in thyroid hormone concentrations.147-150 Doses between therapy (see later).risk individuals. No signifi- is transient and of no physiologic significance. thionamides are and colleagues152 have evaluated a unique dosing frequently restarted after RAI. no clinically significant events occurred. these patients were 3. 226 2.1% were euthyroid or hypothyroid. What is the net effect of ATDs on cure rates fol- estimated gram of thyroid tissue was significantly low.5% euthyroid or hypothyroid). who derives the most benefit from pre- patients (86%) were euthyroid or hypothyroid and treatment ATDs? 36 (14%) remained hyperthyroid. ately for selected patients. Higher doses may also be considered for those roidism in the largest number of GD patients at the who have already failed a dose of RAI and those who lowest possible dose. Clinical Approach to Dosing Dosing Considerations In general. were associ. 163 . more traditional approach using an accurate thyroid es used to treat GD. When can ATDs be resumed following RAI? and higher prevalence of GO. a small subset in both had progres- adjusted for 24-hour uptake). Even with high doses. Should individuals with GD be pretreated with gland. Thionamides ated with a greater number of treatment failures Thionamides are frequently used to restore a euthy- (48. Jarlov and coworkers155 have pretreated individuals. Patients pretreated with thionamides may also to provide definitive treatment for GD at the lowest require larger doses because the failure rate has been cost. Two randomized No data exist demonstrating an advantage for dosime. Without exception. a corollary to the goal of therapy could be ure. demonstrated.5% to 97.5% of GD patients euthyroid or hypothyroid after a single dose. 10 mCi fixed.157 Although most people in both stud- low-adjusted (80 μCi/g of thyroid adjusted for 24-hour ies experienced a gradual decline in free T4 and T3 uptake). Adjunctive Treatments Lower doses. reported to be higher in these patients unless the sive efficacy data when 131I is administered in fixed ATDs are discontinued for 4 to 7 days prior to RAI doses ranging from 5 to 15 mCi. Graves’ Disease suggest that this occurs after the relatively small dos. The average 24-hour uptake was 58% and ATDs? the average dose of 131I was 15. the goal of a larger goiter and more severe disease at diagno- therapy must be to achieve euthyroidism or hypothy. sis. with number of important questions: the goal of delivering a fixed 8 mCi to the thyroid 1. leading the authors to conclude that a ence with RAI have confirmed its safety and efficacy semiquantitative approach to 131I dosing is likely to be in the treatment of adult GD when used appropri. and high-adjusted (120 μCi/g of thyroid following RAI. When should ATDs be withdrawn prior to RAI younger. higher 24-hour uptake. of 80 months. higher serum T4 therapy? concentration at diagnosis. there is an evidence-based rationale to use Dosimetry this strategy in high. If so. and simplicity of fixed-dose regimens. There is still. (Fig.151 ­ Alexander roid state prior to RAI. 76. 12-2). a fixed dose between 15 and 20 mCi will Fixed Dosing cure (hypothyroid or euthyroid) almost all patients. pre- the study could not identify any advantage to using an treated patients had lower hormone levels than non– adjusted-dose method.6 mCi. With spiraling per capita health may suffer untoward effects from a treatment fail- care costs. At 1 year. trials have clearly demonstrated that individuals pre- try over fixed dosing in the treatment of GD. an ongoing debate as to The literature also supports the cost-effectiveness whether 131I is best delivered in fixed doses or if elab.148. after 50 years. The participants in both studies compared an inexpensive practical dosing strategy were not older patients and. lowing RAI? er in the treatment failure patients compared with Pretreatment with ATDs has not been proven those who evidenced cure.65. 10 and 15 mCi rendered 88. Ultimately.146 cant difference in outcome between groups could be In conclusion. as effective as more complicated dosing strategies.11 Moreover. even in this small subset. despite rises in thyroid based on thyroid volume as assessed by palpation to a hormone.120 Larger dos- orate calculations based on thyroid size and uptake es should be reserved for younger individuals with (dosimetry) improve outcome. particularly 5 mCi or less. 4.

treat. Further studies are needed to clarify treatment. The final study randomized 149 patients to data on pretreatment with PTU are much clearer post-therapy MMI beginning 7 days after RAI ­versus and support a marked reduction in RAI treatment no treatment. MMI needs to be withdrawn is relatively weak.) Extrapolating these data to older at-risk individuals. of RAI. 8 weeks.0005 (compared with T = 0). 2001. Is this an evidence-based practice controversial. One One study demonstrated no difference in thyroid study randomized 30 patients with GD to continue function 6 weeks after the administration of RAI in MMI until 4 weeks after RAI or to stop MMI 8 days a group of patients treated with PTU (beginning 5 prior to RAI. Three prospective studies have consid. ††.005. the day of antithyroid drug discontinuation). that this effect disappeared when MMI was discon- ment with MMI did not affect the one-dose cure rate tinued 4 to 6 days prior to RAI therapy. and a subgroup of 19 nonpretreated patients not experiencing worsen- ing thyrotoxicosis after radioiodine (RAI). Solomon BL. Cooper DS. ***. Values shown represent the mean and the bars indicate standard error of the mean (SEM). *. 21 nonpretreated patients. even when discontinued 15 days prior to RAI in rate of cure. P < . antithyroid drug. A. In the MMI group.05.165-167 Santos and coworkers165 compared reduced goiter shrinkage. The second study randomized In contrast. ††.02). P < . but MMI slightly but significantly therapy. P < . P < .164 The with RAI.71). P < . post-treatment exacerbations of thyrotoxicosis. Moreover. and no arm (P < .005 (compared with day 6). arm. the day of RAI treatment). P < 0. pretreatment should be considered to blunt the rise although the clinical situation may drive the decision in thyroid hormone post-RAI.Part III  Adult Thyroid Disease 120 18 Free T3 (pmol/L) 16 100 Free T4 (pmol/L) 14 ** ** * 80 * 12 ** ** *** ** ** * 10 60 ** †† †† ** *** 8 * † **** 40 *** 6 ATD †† †† †† † 4 20 stopped ATD I-131 2 stopped I-131 0 –6 –4 –2 0 2 4 6 8 10 12 14 –6 –4 –2 0 2 4 6 8 10 12 14 Time (days) Time (days) A B Figure 12–2  Changes in serum free thyroxine (T4) (A) and free triiodothyronine (T3) (B) levels in 21 antithyroid drug–­pretreated patients. another small but retrospective study 159 patients to RAI alone or RAI followed by MMI found that treatment failures were significantly more and l-T4 (block-replace). or a theory driven anachronism? The evidence that ered the effect of post-RAI ATDs on thyroid function. ****.158 Of inter. ATDs were withdrawn 15 days before RAI 164 . It is customary to stop ATDs 4 to 7 days pri- The effect of post-treatment ATDs remains or to RAI therapy. P < .0005 (compared with T = 0. B.159 The time to achieve likely in individuals taking carbimazole at the time euthyroidism was significantly shorter in the treat. treatment failure rate. †. the role of ATDs following the administration of RAI.005. thereby preventing making in some patients. P < .161 Of 19 patients in the MMI-positive days after RAI) versus the control group. et al: The effect of antithyroid drug pretreatment on acute changes in thyroid levels after 131I ablation for Graves’ disease.163. ATD. MMI. free T4 100 GD patients treated with 10 mCi of RAI. 12 recurred and 6 of 11 patients in the MMI est. P < .0005 (compared with day 6.160 There was no significant difference success.01.162 and two randomized clinical trials found ment group (2 vs. †.001). *. J Clin Endocrinol Metab 86:3016-3021. PTU.005. P < . **. **. P < 0. (Adapted from Burch HB. Patients was significantly lower at 3 weeks than in the control were randomized into the groups. a nonsignificant difference (P = . those randomized to PTU experienced a higher arm recurred.

and T3 from the thyroid and may actually inhibit RAI adrenergic symptoms. respectively (P = NS [not signifi. including sup. they are probably of little benefit. the exact mechanism of action is not patients undergoing RAI. it can be resumed 5 to 7 glucocorticoids started after RAI are not radioprotec- days after RAI. contrast. Do these actions affect the outcome of to lithium and RAI: (1) Lithium prevents the rise in RAI treatment for GD? thyroid hormone that follows thionamide withdrawal Little prospective data exist to answer this in preparation for RAI. Lithium However. beta blockers should be clearly defined. glucocorticoids already impressive cure rate of GD with RAI. considered in those individuals whose condition may ing that glucocorticoids may have a radioprotective deteriorate after thionamide withdrawal. and (2) to prevent the worsen. (3) 2 weeks of randomized patients to betamethasone 3 weeks before lithium therapy significantly reduces post-RAI eleva- RAI and 4 weeks after RAI or placebo.168 control of post-RAI hyperthyroidism. corticosteroids. with the discov- with marked ophthalmopathy.171 thus lowering and the MMI arm demonstrated similar rates of cure.3% and 77.001). thyroid hormone levels effects on the pituitary-thyroid axis.172. had no impact on the final outcome of GD patients treated with RAI. their formation. However.05). further. can be 20 patients in the placebo group (P < . Graves’ Disease administration. In younger patients with no cardiac disease. discontinued at least 4 days prior to therapy but. Finally. ATDs tend to have a prolonged effect. this may be preferable to restart- or persistent hyperthyroidism. However. Lithium can strated that steroids started after RAI have no appre. hormone levels can increase pression of TSH and reduced peripheral monodeio. and (4) lithium may result in only 9 of 20 betamethasone-treated patients required more rapid and effective reduction in goiter size. demon. available evidence implies that very high-risk individuals. studies have demonstrated the following with respect sive action.173 This is not to say that illness develops GD. a large retro. the RAI uptake in the gland and reducing its effec- 73.169 Corticosteroids ery of ATDs and RAI. although effect.172. Following RAI.8%. tions in thyroid hormone. lithium is without potential usefulness.169 however. longed. increase.63. in high-risk documented. a dose of lithium. surgery in the United States 165 . there are no theoretical reasons why beta Although the antithyroid effects of lithium are well blockade should interfere with cure and. ATDs are warranted in high-risk induce apoptosis in the local immune infiltrate and individuals prior to RAI. Glucocorticoids have a number of direct amides are held prior to RAI. (2) lithium results in prompter question. in Therefore. the no-treatment arm may reduce the levels of TSH-R Abs. Interestingly. The PTU group showed a rate of cure of 32%. tive and therefore no dosage adjustment is required. High-quality dination of T4 in addition to their immunosuppres. Bartalena and colleagues. In this study. The role of the immunosuppressive Thyroidectomy effects of corticosteroids has been widely recognized For many years. MMI should be mediated thyroid cell destruction. an effect that theo- Glucocorticoids retically could augment the actions of RAI. but there are only limited No prospective studies exist evaluating the use of data to support this. thyroidectomy represented the only and is the reason for their use with RAI in patients treatment available for GD. When thion- ing of GO. can In summary. which are lympholytic. the evidence does beginning 2 days prior to RAI compared with patients not support the routine use of lithium to augment the not receiving steroids. ing a thionamide in high-risk patients because some spective study by Jensen and associates170 reviewed evidence has suggested that post-RAI ATD therapy outcome in GD patients treated with prednisolone may reduce the cure rate. by Gamstedt and Karlsson. also be continued after 131I to prevent a rise in thy- ciable impact on the prevalence of hypothyroidism roid hormone level. There are two scenarios in which glucocorticoids randomized controlled trials have generally been might be administered concomitantly with RAI: (1) a unable to demonstrate that lithium used concomi- patient with a concurrent glucocorticoid-dependent tantly with RAI affects cure. Lithium prevents the release of T4 added to MMI to ameliorate the potential for post. One study. indicat. However. However. exposing frailer patients to risk. lithium enhances the intrathyroidal retention of iodine. because the half-life of IgG is pro- cant]). tiveness. beta blockers with RAI. this effect is not seen in the short term. Additionally.174 thyroid replacement at 1 year compared with 17 of Hence. Glucocorticoids started prior to RAI may theoreti- Beta Blockers cally reduce the cure rate. In significantly lower than in the other arms (P < . The evidence supports the reduce the effectiveness of RAI-induced immune- use of MMI over PTU in this case. 300 mg every 8 hours. At 12 months.

or more specifi.183 and presence or absence of thyroid also been reported. and Hypoparathyroidism 0. versus subtotal thyroid- gery effects cure of an autoimmune disease is unclear.6 100 thyroidologists worldwide concur that there is little RLN injury role for thyroidectomy in mild GD patients. safer. Miltenburg DM: The efficacy of effective therapy. one could expect 90:161-165.185 Preoperative therapy is aimed at restoring a euthyroid RLN injury and hypoparathyroidism are the state prior to surgery. All patients will require l-T4 replace- removal of most of the gland.Part III  Adult Thyroid Disease has been relegated to select situations: (1) patient Table 12–4  Cure and Complication Rates preference.192 These procedures are not cur- antibodies. and extremely Data from Palit TK. but 85% of patients are cured. with or without compressive symp. come following a total thyroidectomy is no different than that of a subtotal thyroidectomy.7 0 (7) the presence of suspicious nodules. as the surgical community continues to perfect Temporary 2. (6) severe Graves’ ophthalmopathy175. many continue to be cautious Complicaton/Cure Thyroidectomy Thyroidectomy because of the fear of neoplasia formation123.191 Minimally thyroid remnant left by the surgeon. hypothyroidism.174). The rate of permanent hypoparathyroidism away the vast majority of thyroid-specific T cells and B was similarly low. making the surgery faster. dict and is surgeon-dependent.8 7. When one considers that as many as The prevention of hypothyroidism.186 The rate of permanent RLN injury was It has been suggested that removal of the gland takes 0.182 The incidence of recurrence depends rently performed routinely in the United States. the risk of recurrence is zero following a total A subtotal thyroidectomy is typically defined as the thyroidectomy.7%. recurrent laryngeal nerve. There were no perioperative cells177 and that thyroid-specific clonal suicide of the mortalities reported. on the size of the thyroid remnant as well as the pre- operative TSH-R Ab concentration184 and can be as Preparing for Surgery high as 15%.7 the procedure. This occurs in up to 15% of patients.187-189 Further- Total Versus Subtotal Thyroidectomy more. including the skill and preference damage. How such sur. for whom the surgeon tries drops twice daily) several days prior to the procedure 166 . A growing body of evidence sup- remaining thyroid-specific immune cells is induced ports the assertion that in an experienced endocrine by the large amount of thyroid antigen released into surgeon’s hands. the TSH-R Abs in GD to induce thyroid cell growth and disease recurrence. (5) large goiter. cally the establishment of a euthyroid state following we suggest that total thyroidectomy be considered subtotal thyroidectomy. Permanent 0. sparing about 2 g from ment indefinitely. thyroidectomy is an underused. (2) urgent control of thyrotoxicosis.9 1 less invasive. because this might a subtotal versus a total thyroidectomy will involve a minimize the risk of recurrent laryngeal nerve (RLN) number of factors. depending on the size of the for GD using a subclavicular approach. safe. 1%.178-182 duration invasive thyroidectomy via an axillary approach has of follow-up. a salient argument can be made that RLN. this is best accomplished with antithyroid medica- over 7000 surgically treated GD patients has found tions titrated as discussed earlier. J Surg Res is removed. the absolute risk of an adverse out- the circulation at the time of surgery.7 0. Inorganic iodide is typi­ that the rate of hypoparathyroidism and RLN injury cally initiated (saturated solution of potassium iodide is not significantly different in those patients treated [SSKI].9 ever. Available evidence suggests case series has demonstrated the efficacy and safety that the rate of hypothyroidism ranges from less than of video-assisted subtotal or near-total thyroidectomy 10% to almost 80%. Miller CC. and Euthyroid 59. the decision to pursue the posterior portion bilaterally. In general. 3 to 5 with total thyroidectomy. Hypothyroid 25. When thyroidectomy is truly elec- two major risks of surgery. Recurrence 7. has proven difficult to pre. (4) child or adolescent intolerant of ATDs (although RAI is Subtotal Total used in this age group. the treatment of choice for GD.190 A recent procedure (Table 12-4). of the surgeon. and hypoparathyroidism. to remove all thyroid tissue.9 0 toms. ectomy. of Thyroidectomy (%) (3) pregnant patient intolerant of ATDs. A meta-analysis including tive.176 Because not all the thyroid tissue thyroidectomy for Graves’ disease: A meta-analysis. even in the best hands. 1 drop twice daily or Lugol’s solution. 15% of patients recur following a subtotal procedure.12 How. its pursuit explains Newer minimally invasive procedures are the unacceptably high recurrence rate following this being developed to improve cosmesis. Ultimately. 2000.

216 despite other statements in the literature.09 to 5.205 be indistinguishable from that of Graves’ thyroid dis- Eye disease is usually bilateral and frequently asym. but nicotine is known to influence nitric OTHER MANIFESTATIONS OF THYROID oxide formation. ease. which 167 . Smoking increases the risk of GD (odds ratio [OR]. eye disease. 22% of patients (13) improved substantially. gression of GO after RAI and decreases the efficacy of erated hyperthyroidism and thyroid storm. Pharma- GO represents the most common extrathyroidal cotherapy (e.204 Severe ophthalmop. smoking cessation must be aggressively Epidemiology addressed in GD patients with eye disease. the GD patients.206 The disease tends to be orbits. somewhat reminiscent of the patients with newly diagnosed GD. worsened. The genetics of Graves’ ophthalmopathy appears to athy accounts for no more than 3% to 5% of cases. for a median of 12 months. Of these patients. affecting those in their fifth as smoking. including sive disease may be even lower.217 metrical.212 In contrast. smoking does level fell from 500 ± 48 (normal range. varenicline. A discussion of accel.195 ros and colleagues208 followed a cohort of 59 patients Some small studies have evaluated the use of with GO. as well as orbital radiation and glucocorticoid therapy. likely because (13) did not change. as or surgical treatment. 95% CI. Smoking and Graves’ Ophthalmopathy If an urgent or emergent thyroidectomy is warranted.3 to 13. 2. and iodinated radiographic blunts the efficacy of proven therapies. 42. cigarette smoking increases the risk of pro- euthyroid at the time of surgery.. although newer imaging modalities can demonstrate anatomic changes consistent with GO Cause in more than 75% of patients.7).214 Patient education is paramount. SSKI. dexamethasone this risk. smok- strated in an uncontrolled prospective study involv. encountered postoperative problems. 143 ± 13 ng/dL in 7 days.203 Approximately 50% of replacement) as well as counseling may be necessary patients will have some degree of clinically evident to overcome the inertia of nicotine addiction.215 Despite the frustrations of tobacco addiction. possibly exacerbating any inflam- HYPERFUNCTION matory response.2% rally. and nicotine manifestation of GD. with the worst GO smoke the most. 49% state prior to surgery with ATDs forestalls this sort of improved substantially.3. the sole preoperative treatment modality. and 13. trauma. who had not received immunosuppressants beta blockers. tive management in patients with GO. and 53 patients (65%) received no therapy other tion of thyroid surgery. The peak incidence of GO demonstrates Hence.198 Restoring a euthyroid than supportive local care.22). Graves’ Disease to decrease the vascularity of the gland. and beta blockers.211 Hence.203 The result is that autoreactive T lympho- more aggressive in older individuals and in men. A small number of patients. bupropion.5% of patients (8) dete- of the younger age and milder disease of most of riorated. ing greatly increases the risk of developing GO (OR.210 Stopping ameliorates combination of thionamides.202 The with individuals with thyrotoxicosis alone and patients usefulness of this combination was recently demon. unfortunately. can be found later in this chapter. 4. Overall. outcome was good. 50% did not change. all subjects were clinically Moreover. ing 17 severely hyperthyroid patients. with or without inorganic iodide.193. iodine. invited by an developing severe GO. 60 to 180) to not appear to be related to other thyroid disorders.7. 81 had GO (41%) profound thyroid crises that followed the introduc. there is concern about external insults such a bimodal distribution. nism whereby smoking exacts this effect has yet to be elucidated. or pressure buildup in smaller and seventh decades. A Swiss study has suggested that the rate of progres- ever. Per- the benefit of this maneuver is unproven. and 1% postoperative complication. operative euthyroidism with ATDs.194 although care will be all that most patients will require. we always strive to achieve pre. rapid control of thyroid status can be achieved with a 3. 95% CI.196-200 Natu. 22% of surgery.201. These data support the merits of conserva- In our practice.213 Smok- the mechanism of action and clinical application of ing thus profoundly affects the course of GO and corticosteroids. The average T3 7. The mecha- contrast agents. ultimately requiring medical intervention.207 The natural history of the antigen shared by the thyroid and orbit.209 Of 196 consecutive tachycardia and fever. these patients remain hyperthyroid at the time of patients (25) showed minor improvement. cytes infiltrate orbital tissues and the perimysium and with men older than 60 years at the highest risk for endomysium of extraocular muscles.210 More patients with GO smoke compared (1 to 2 mg twice daily). education alone is unlikely to deter Graves’ Ophthalmopathy most smokers.197.g.218 The cul- disease is such that watchful waiting and supportive prit antigen appears to be the TSH receptor. Inorganic iodide is then added 1 week prior to the planned procedure. how.

cyto. the damaged extraocular muscles become TSH-R Ab levels. promoting edema and fibril disruption and rather than the influence of a particular treatment. as inflammation decreases and the disease tion of thyroid autoimmunity and an elevation of burns out. promoting edema and sitivity to radiation. as the the restoration of euthyroidism favorably influences orbital fat and muscle volumes increase. Additionally. preadipocytes. extraocular Graves’ eye disease. tive randomized trials have demonstrated that GO 168 . gery. the immune system is locally upregulated. by the natural history of untreated GO in that most mulate in the extracellular matrix.222 The trouble with ATD therapy muscle impairment and/or proptosis may develop. particularly interferon-γ. the immune response fibril disruption. description of TSH-R Ab.221 In more severe cases.232 As ­ noted. The large increase in TSH- In response to the putative antigen. in response to the local immune response. which accu. which may affect extra- preadipocytes. remains the high rate of recurrence. thyroidal activity of this immune response in the eyes mature into adipocytes. GO remains controversial.224.227. some prospec- upregulating the aberrant immune response. and pretibial myxedema has also been shown disease by reducing regulatory T-cell function.219 After antigen recognition. provides patients with the greatest protection against worsening GO. there are abundant data to show the loss of GAG thyroid autoantibodies after thyroid surgery. A subset of orbital fibroblasts. The literature is not kines. impairing muscle function (Fig. the extent of the thyroid resection (total versus subtotal) appears to have no impact on the progression of GO. the immune evaluated the course of GO following the three treat- system is locally upregulated by the release of a num. most studies have suggested that surgery has ing the thyroid and thus eliminating the source of auto. R Ab levels after RAI treatment is well documented stimulating hormone (TSH) receptor.226 Some have contended that a thyroidectomy Cytokines followed by a remnant ablation. stimulate fibroblasts definitive. the discussion is complicated to secrete glycosaminoglycans (GAGs). Trauma and smoking likely worsen the and skin.229 This is reflective of disease dissipation and why many suggest that thyroid surgery is the best way to manage Graves’ patients with severe eye disease. the thyroid. There is a well-known relation- fibrosed. thionamides. including Orbital fibroblast GAG Orbital adipocytes the loss of TSH-R Abs.Part III  Adult Thyroid Disease is overexpressed in retro-orbital fibroblasts and result in regression of GO? A number of ­studies have ­adipocytes. and RAI. However. 12-3). with reactiva- With time. A subset of fibroblasts. matures into adipocytes.231 Hence. effectively eliminat- ing the culprit antigen along with the source of the Immune TSH-receptor infiltrate culpable T cells.223 Whether the antibodies Management of Underlying are the cause or merely a reflection of ongoing T-cell Hyperthyroidism and Progression activity is unclear. although there is a suggestion that pressure buildup. little effect on the course of the disease. coerced by the inflamma. Cytokines stimulate orbital fibroblasts to and thought to be secondary to regulatory T-cell sen- secrete glycosaminoglycans (GAGs). Thionamides tory milieu.220 Subsequent patients stabilize or improve whereas only a small fibroblast stimulation results in further accumulation minority progress. Thus. causing permanent disability necessitating ship between TSH-R Ab and GO. Trauma/ smoking Radioiodine Therapy The association between RAI and the progression of Figure 12–3  Pathophysiology of Graves’ ophthalmopathy. ever since the first corrective surgery. Furthermore. of Graves’ Ophthalmopathy Should the presence of GO influence the choice of