Thyroid Disorders with Cutaneous Manifestations

Thyroid Disorders with Cutaneous Manifestations

Thyroid Disorders with Cutaneous Manifestations

Edited by Warren R. Heymann University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School at Camden Marlton, NJ, USA

Editor Warren R. Heymann, MD University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School at Camden Marlton, NJ, USA

ISBN 978-1-84800-186-2 e-ISBN 978-1-84800-187-9 DOI: 10.1007/978-1-84800-187-9 British Library Cataloguing in Publication Data Thyroid disorders with cutaneous manifestations 1. Thyroid gland – Diseases 2. Cutaneous manifestations of general diseases I. Heymann, Warren R. 616.4′4 ISBN-13: 9781848001862 Library of Congress Control Number: 2008921764 © Springer-Verlag London Limited 2008 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com

Foreword

Jacques Barzun, the noted Columbia University historian of ideas and culture, once described the feeling that some people experience when they come upon a new reference book. He wrote: “Hand over to one of us a new Dictionary, “Companion,” or Guide, and our eyes first light up and then turn dreamy: we have seized the volume and are off, arm in arm with the guide or companion.…”i The book now in your hands made my eyes light up. Thyroid Disorders with Cutaneous Manifestations is that kind of book. Heymann, who has been fascinated by this sometimes controversial subject for decades, has brought not only his own expertise, but that of many experts from the fields of the skin and the thyroid gland. Steven Jay Gould wrote about overlapping and nonoverlapping magisteria—this book demonstrates just how much important overlap there is. But it also covers the basics in such a way that dermatologists can find what they need to know about the thyroid and thyroidologists can find what they need to know about the skin. Thyroid Disorders with Cutaneous Manifestations falls neatly into the tradition of medical monographs that become standards. They fulfill the roles of gathering, digesting, and synthesizing current knowledge, and they do so in a way that review articles cannot approach and that the scientific literature is not designed to accomplish. Practicing clinicians as well as investigators will, when confronted by a clinical challenge or scientific inquiry, start with this book, and, in many cases, end with it as well. From reading on the well-known pretibial myxedema to genetic disorders, such as Pendred syndrome, from itch as a manifestation of hyperthyroidism to Plummer’s nails to the cutaneous manifestations of Williams-Beuren syndrome, those who need to know about the skin/thyroid axis will find this book enjoyably engaging and surprised to learn just how much the topic includes. Jeffrey D. Bernhard, MD, FRCP Edin Professor of Medicine and Physiology, emeritus University of Massachusetts Medical School Editor emeritus Journal of the American Academy of Dermatology

i Jacques Barzun, "Not All are O.O.O." in A Company of Readers, by W.H. Auden, Jacques Barzun, and Lionel Trilling. New York: Free Press, 2001, pp 74–79.

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Preface and Acknowledgments

The interactions between the thyroid gland and the skin are of profound clinical importance in health and disease. The cutaneous manifestations of thyroid disease are protean and involve all age groups. Given the prevalence of thyroid disease worldwide, especially in women, it is imperative that primary care physicians, endocrinologists, and dermatologists appreciate the scope of these associations so that thyroid disease may be diagnosed and treated expediently. The purpose of this text is to provide a single resource that will enable the physician to comprehend the basic science, laboratory evaluation, epidemiology, and clinical aspects of thyroid diseases and their cutaneous manifestations. Specific disorders such as the thyroglossal duct cyst and cutaneous metastases, nonspecific features of the skin and its appendages seen in hyperthyroidism and hypothyroidism, and the multiple associations with other dermatologic and systemic diseases are surveyed. Specific chapters are devoted to certain syndromal diseases, alopecia in thyroid disease, thyroid dermopathy (pretibial myxedema), and the relationship of autoimmune thyroid disease to chronic idiopathic urticaria and angioedema. Potential therapeutic uses for thyroid hormone are considered. It is hoped that the reader will be inspired to learn more about this dynamic discipline as our understanding of pathophysiology, diagnostic techniques, clinical features, and therapeutic approaches continues to evolve. Internationally recognized authorities have graciously contributed their expertise for this text. Each author has been dedicated to the project and has done superlative work in bringing it to fruition. At the beginning of each chapter, I have written a brief “editorial perspective” offering my thoughts on the importance of the specific topics. As this textbook is meant to serve as a reference and is likely to be utilized intermittently as a source for information on specific issues relevant to the clinician, I would encourage the reader to spend a few moments reading each of these minieditorials—it is hoped that the scope, complexity, and relevance of this text will be appreciated. In any such endeavor, acknowledgments are in order to thank those individuals who have allowed this textbook to become a reality. Hannah Wilson and Grant Weston at Springer have been enthusiastic about this project from its inception; they have been the backbone of the textbook throughout the entire process. I must offer a very special thank you to Chad Hivnor, MD. Chad approached me with a request that I serve as his mentor for the leadership program of the American Academy of Dermatology. I was honored that he thought of me in this capacity. I asked him if he would consider working with me on this text, and he willingly agreed. Dr. Hivnor has been indefatigable in his quest for excellence; indeed, his insights have greatly improved the clarity vii

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Preface and Acknowledgments

and focus of the text. Finally, this textbook would never have been possible without the unwavering support and love of my wife, Ronnie, and children, Andrea and Deborah. This book is dedicated to them. Warren R. Heymann, MD

Contents

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Preface and Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1 Anatomy and Embryology of the Thyroid Gland . . . . . . . . . . . . . . Gabriel Wong and Scott Schaffer

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Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Airani Sathananthan, Kimberly A. Placzkowski, and John C. Morris

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3 Classification and Epidemiology of Thyroid Disease . . . . . . . . . . . Ghada Haddad and Steven Kaufman

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4 Laboratory Diagnosis of Thyroid Disease . . . . . . . . . . . . . . . . . . . . Reagan Schiefer and Vahab Fatourechi

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5 Thyroglossal Duct Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lisa M. Reid

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6 Thyroid Cancer and the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert A. Somer and Nati Lerman

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7 Chromosomes, Genes, and the Thyroid Gland. . . . . . . . . . . . . . . . . Analisa V. Halpern and Rhonda E. Schnur

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8 Cutaneous Manifestations of Hyperthyroidism . . . . . . . . . . . . . . . . Clara-Dina Cokonis, Carrie W. Cobb, Warren R. Heymann, and Chad M. Hivnor

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9 Cutaneous Manifestations of Hypothyroidism . . . . . . . . . . . . . . . . . Sandra A. Kopp, Pascal G. Ferzli, Chad M. Hivnor, and Warren R. Heymann

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10 Pretibial Myxedema (Thyroid Dermopathy) . . . . . . . . . . . . . . . . . . 103 Vahab Fatourechi

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Contents

11 Alopecia and Thyroid Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Michelle Babb-Tarbox and Wilma F. Bergfeld 12 Chronic Idiopathic Urticaria and Thyroid Disease. . . . . . . . . . . . . . 145 Jeffrey S. Rumbyrt and Alan L. Schocket 13 Dermatologic Disorders Associated with Thyroid Disease . . . . . . . 157 Joslyn Sciacca Kirby and William D. James 14

Potential Therapeutic Uses of Thyroid Hormone. . . . . . . . . . . . . . . 181 Joshua D. Safer and Michael F. Holick

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

Contributors

Michelle Babb-Tarbox, MD Department of Dermatology, Cleveland Clinic, Cleveland, OH, USA Wilma F. Bergfeld, MD Department of Dermatology, Cleveland Clinic, Cleveland, OH, USA Carrie W. Cobb, MD Division of Dermatology, Cooper University Hospital, Camden, NJ, USA Clara-Dina Cokonis, MD, RPh Division of Dermatology, Cooper University Hospital, Camden, NJ, USA Vahab Fatourechi, MD Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA Pascal G. Ferzli, MD, MSc, BA Department of Dermatology, University of Medicine and Dentistry of New Jersey, Camden, NJ, USA Ghada Haddad, MD Division of Endocrinology, Cooper University Hospital, Camden, NJ, USA Analisa V. Halpern, MD Division of Dermatology, Cooper University Hospital, Camden, NJ, USA Warren R. Heymann, MD Division of Dermatology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Marlton, NJ, USA Chad M. Hivnor, MD Department of Dermatology, SAUSHEC—Wilford Hall Medical Center, Lackland, TX, USA Michael F. Holick, PhD, MD Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, MA, USA

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William D. James, MD Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Steven Kaufman, MD Cooper University Hospital, Camden, NJ, USA Sandra A. Kopp, MD Division of Dermatology, Cooper University Hospital, Camden, NJ, USA Nati Lerman, MD Department of Haematology and Medical Oncology, Cooper University Hospital, Camden, NJ, USA John C. Morris, MD Department of Endocrinology, Mayo Clinic, Rochester, MN, USA Kimberly A. Placzkowski, MD Department of Endocrinology, Mayo Clinic, Rochester, MN, USA Lisa M. Reid, MD Cooper University Hospital, Camden, NJ, USA Jeffrey S. Rumbyrt, MD Department of Medicine, University of Colorado Health Sciences Center, Lakewood, CO, USA Joshua D. Safer, MD Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, MA, USA Airani Sathananthan, MD Department of Endocrinology, Mayo Clinic, Rochester, MN, USA Scott Schaffer, MD The ENT Specialty Center, Gibbsboro, NJ, USA Reagan Schiefer, MD Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA Rhonda E. Schnur Department of Pediatrics, Cooper University Hospital, Camden, NJ, USA Alan L. Schocket, MD, MSHD Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA

Contributors

Contributors

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Joslyn R. Sciacca Kirby, MD Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Robert A. Somer, MD Department of Medicine, Division of Haematology and Medical Oncology, Cooper University Hospital, Voorhees, NJ, USA Gabriel Wong, MD The ENT Specialty Center, Gibbsboro, NJ, USA

1 Anatomy and Embryology of the Thyroid Gland Gabriel Wong and Scott Schaffer

Editorial Perspective George Orwell said that “Men are only as good as their technical development allows them to be.” The same could be said for the embryology and anatomy of any organ, including the thyroid gland. Understanding normal development of the thyroid and its gross and microscopic anatomy allows for comprehension of the presentation and complications of thyroglossal duct cysts compared to other cysts of the neck, such as branchial cleft cysts or bronchogenic cysts. Embryology also explains the diversity of certain thyroidal conditions, ranging

Introduction An understanding of the embryology and anatomy of the thyroid gland is essential for clinical-pathologic correlation, especially for the management of thyroglossal duct cysts, thyroid nodules, and tumors. Endocrinologists, dermatologists, radiologists, pathologists, and surgeons all should be familiar with the structure and function of the thyroid gland as it relates to appropriate diagnosis and management of these conditions.

Anatomy The mature thyroid gland is an H- or U-shaped endocrine organ located in the base of the neck.

from the lingual thyroid to the superior v ena cava syndrome due to a mediastinal goiter. Expertise in the gross anatomy of the thyroid gland is essential for any head and neck surgeon, whether they are excising a benign thyroglossal duct cyst or a thyroid malignancy. Understanding the histology of the thyroid gland explains how medullary thyroid cancer differs from other thyroid malignancies. These are just a few examples suggesting that knowledge of the embryology and anatomy of the thyroid gland will improve one’s diagnostic and therapeutic acumen related to disorders that affect the skin and the thyroid gland.

The left and right lobes cover the lower sides of the larynx and upper trachea and are connected by a central isthmus. In certain individuals, thyroid tissue extends superiorly along the midline from the thyroid isthmus. This tissue is known as the pyramidal lobe and represents remnants of the embryonic thyroglossal duct. Despite sharing common nomenclature, the thyroid cartilage and thyroid gland do not anatomically overlap significantly. The naming of these two structures was derived from the Greek root meaning “shield-shaped.”1 In the adult, the normal thyroid weighs 20 to 25 g.2 The average dimension by ultrasonography of each lobe is 4 cm long vertically, 1–1.5 cm wide, and 1 cm in thickness. The isthmus is usually less than 5 mm high and 3 mm deep3 (Figure 1.1).

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Figure 1.1. Anatomy of the thyroid gland. I, isthmus; LL, left thyroid lobe; RL, right thyroid lobe; PL, pyramidal lobe

The thyroid isthmus typically overlaps the third tracheal ring and is firmly attached to it by a pretracheal fascia also known as Berry’s ligament. This firm attachment causes the thyroid gland to move superiorly in response to tracheal elevation during swallowing. This helps differentiate thyroid masses such as thyroid nodules and thyroglossal duct cysts, which move during swallowing, from lymphadenopathy or branchial clefts cysts, which remain stationary.4 The thyroid gland lies deep to the strap muscles of the neck. The carotid sheath is located lateral and deep to the thyroid gland and is separated by distinct facial layers. The left lateral portion of the esophagus borders the deep surface of the left thyroid lobe. The parathyroid glands are typically located along the deep surface of each thyroid lobe. The number and location of the parathyroid glands can be extremely variable; this may prove to be frustrating for surgeons intraoperatively. The thyroid gland receives a rich arterial blood supply from bilateral superior and inferior thyroid arteries. Per gram of tissue, it has one of the highest blood flows of any organ in the body. The superior thyroid artery is the first branch of the external carotid artery above, while the inferior thyroid artery comes from the thyrocervical trunk below. The inferior thyroid artery also supplies both the inferior and superior parathyroid glands. Some research suggests that the superior thyroid artery

G. Wong and S. Schaffer

may also contribute to the perfusion of the superior parathyroid gland. Although the thyroid gland has two pairs of supplying arteries, venous outflow is accomplished through three pairs of veins, termed the superior, middle, and inferior thyroid veins. The superior and middle thyroid veins carry blood back to the internal jugular vein. The inferior thyroid vein has a nearly vertical course inferiorly, until it reaches the brachiocephalic vein. Lymphatic vessels arise from both lateral thyroid lobes. They extend inferiorly in the central neck compartment before emptying into the thoracic duct. Pretracheal lymph nodes may also become enlarged with thyroid pathology. A single pretracheal node may sometimes be palpated in the midline of the neck and is referred to as the Delphian node. This was named for the Oracle of Delphi of ancient Greece because this single node may portend an underlying malignancy. The thyroid gland is innervated by the autonomic nervous system. The parasympathetic branches arise from the vagus nerves, while the sympathetic fibers descend from the superior, middle, and inferior sympathetic ganglia of the sympathetic trunk. The actual effect of the autonomic nervous system on the gland is poorly understood, although it is theorized that most of the effect is to regulate arterial and venous perfusion. The recurrent laryngeal nerve and external superior laryngeal nerve are paired structures that innervate the intrinsic muscles of the larynx, which allow for phonation and respiration. The recurrent laryngeal nerve lies within the tracheoesophageal groove and may even lie within pretracheal fascia as it courses superiorly into the cricothyroid membrane. The external branch of the superior laryngeal nerve may be found near the superior thyroid artery until it innervates the cricothyroid muscle. Both nerves may be damaged during thyroid surgery, leading to temporary or permanent hoarseness. Risk of injury to the laryngeal nerves is estimated at 1% during thyroid surgery. Minor variations of thyroid anatomy are common, especially as the presence of goiters and nodules can distort the overall structure. Inferior hypertrophy of the gland behind the sternum is called a retrosternal thyroid. When severe, a retrosternal thyroid may cause significant tracheal compression and airway compromise.1,4,5 Histologically, the architecture of the thyroid gland is composed of many spherical hollow sacs called thyroid follicles. The follicles are lined by a simple

1. Thyroid Anatomy and Embryology

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Figure 1.2. Thyroid histology with hematoxylin and eosin staining. C, colloid; fc, follicular cells; pfc, parafollicular cells

cuboidal epithelium and contain colloid centrally. The colloid lumen stains uniformly pink with hematoxylin and eosin (Figure 1.2). Thyroid colloid, which consists of thyroglobulin and iodide, is produced by the follicular cells and extruded in the lumen for future use. Subsequently, thyroid-stimulating hormone (TSH) stimulates the follicular cells to synthesize mature thyroid hormone from the colloid precursor. These surrounding follicular cells are single layered and usually cuboidal in shape; however, the overall architecture is affected by the general metabolic state of the thyroid gland. During periods of increased production, the amount of colloid is decreased as it is being converted into mature thyroid hormone. The follicular cells also become columnar in shape, reflecting increased metabolic activity. When the thyroid is relatively inactive, the lumen is larger as more colloid is stored in preparation for future use. The follicular cells become flattened and smaller, indicating decreased metabolic activity. Parafollicular (C cells) that produce calcitonin can be found in stroma between thyroid follicles. They are often better visualized with immunoperoxidase staining.3,6,7

Embryology The thyroid gland is the first endocrine gland to develop, starting on approximately the 24th day of gestation.1 The principle cells of the thyroid gland, which form thyroid follicles and produce thyroglobulin, arise from an endodermal bud between the first and second branchial arches, known as the foramen

Figure 1.3. The foramen cecum and branchial arches at 28th day of development. Roman numerals indicate the 1st through 4th branchial arches

cecum (Figure 1.3) The foramen cecum can be found as a blind pit in the midline of the tongue and is located between the anterior two-thirds and posterior one-third of the tongue. In adults, this border is delineated by the circumvallate papillae and corresponds to the ectodermal-endodermal boundary of the tongue. The initial thyroid primordium thickens and invaginates inferiorly, forming a tubular structure called the thyroid diverticulum. As it continues to descend, it becomes bilobed and solidifies until it reaches its eventual position in the inferior aspect of the anterior neck.5 By the seventh week, the thyroid gland lies immediately inferior to the larynx and around the front and lateral sides of the trachea8 (Figure 1.4). Initially, the thyroglossal duct connects the primordial thyroid gland to the foramen cecum in the tongue. Typically, the thyroglossal duct atrophies, and the foramen cecum regresses into a vestigial pit that is visible in the base of tongue in approximately 60% of adults.9 An understanding of this development helps to explain congenital disorders and anatomic variations of the thyroid gland.

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Figure 1.4. The descent of the foramen cecum

Occasionally, the thyroglossal duct fails to atrophy. As a result, accessory or ectopic thyroid tissue can be found anywhere along the migratory course of the duct. In fact, the pyramidal lobe, found in approximately 50% of the population, is actually failure of the inferior portion of the thyroid duct to involute.5 These foci of accessory thyroid tissue can be metabolically active, although the amount of thyroid hormone is usually insufficient without the main gland. Ectopic thyroid remnants have also been known to development malignancy, although this is uncommon4,8 (Figure 1.5). If the thyroid gland fails to descend into the neck, a lingual thyroid is formed. A mass is noted in the posterior tongue, and a patient may complain of dysphagia, a globus sensation, or airway difficulties if the lingual thyroid is large. Excision may be necessary to alleviate these symptoms. It is essential to remember that a lingual thyroid may be the only functional thyroid tissue present. If removed, either intentionally or inadvertently, subsequent thyroid supplementation may be nec-

essary. Computed tomographic scans, ultrasound, or nuclear imaging is helpful in differentiating between an ectopic lingual thyroid remnant versus complete failure of descent of the thyroid gland4,12,13 (Figure 1.6). Failure to atrophy can also lead to thyroglossal duct cysts and sinuses. These lesions typically present as midline masses and are usually centered below the hyoid bone, although they may be located superiorly as well. Thyroglossal duct cysts may become infected, leading to erythema, swelling, and occasional purulent drainage if the overlying skin ruptures. Treatment consists of systemic antibiotics and possible excision. If excision is considered, removal of duct remnants is important to prevent recurrences. As the thyroglossal duct is intimately involved with the hyoid bone, removal of the central portion of the hyoid decreases the risk of recurrence to 1%. Some authors profess that the hyoid may be left intact if the duct is clearly noted to travel away from the bone.4,10–12 (Figure 1.7).

1. Thyroid Anatomy and Embryology

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Figure 1.7. Thyroglossal duct cyst

Figure 1.5. Locations of ectopic thyroid tissue

The principle cells of the thyroid function to regulate metabolism by the production and secretion the thyroid hormones thyroxine (T4) and triiodothyronine (T3). These hormones play a significant role in growth and development in addition to increasing the metabolic activity of the cardiac, gastrointestinal, and neuromuscular systems.

Figure 1.6. Lingual thyroid

Biosynthesis of thyroid hormone occurs by the iodination of the amino acid tyrosine. Worldwide, iodine deficiency is the most common cause of hypothyroidism, goiter, and preventable mental retardation. Fortunately, iodine deficiency is extremely uncommon in the United States due to supplemented foods and table salt; however, some authors believe that the dietary iodine surplus may cause hypothyroidism as well. Iodine excesses may lead to the development of chronic thyroiditis (Hashimoto’s thyroiditis, lymphocytic thyroiditis), which often leads to eventual hypothyroidism. An estimated 90% of hypothyroid cases are attributed to chronic thyroiditis. Therefore, it is possible that both iodine deficiency and surplus may lead to hypothyroidism.4,14,15 During the descent, the thyroid gland also incorporates a second cell type that lies in the parafollicular spaces. These cells are known as parafollicular, clear, or C cells of the thyroid gland. These cells produce calcitonin, which participates in the regulation of calcium and phosphorus metabolism. Calcitonin is a peptide made of 32 amino acids. Its secretion is stimulated through increasing serum calcium ion concentrations. The main biologic effect of calcitonin is to inhibit osteoclastic bone resorption, in opposition to parathyroid hormone, which promotes bone resorption. Interestingly, patients who undergo

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total thyroidectomy do not need calcitonin supplementation as they have no recognizable abnormalities and no increased incidence of osteoporosis.14 Increased serum calcitonin measurements may useful to differentiate medullary thyroid carcinomas (MTCs) from other thyroid malignancies as MTCs secrete excess calcitonin. Sudden increases in serum calcitonin may also signal a recurrence in patients with a known history of previously treated MTC.4 Some researchers suggested elevated serum procalcitonin levels may also be used as a negative predictor of survival in sepsis as seen in animal models.16 The parafollicular C cells were originally thought to be derived from endoderm of the ultimobranchial body. The ultimobranchial body is a caudal pharyngeal complex, arguably comprised of portions of the fourth, fifth, or sixth pouch. Cytochemical evidence led to the realization, however, that the C cells are actually ectodermal in origin and are derived from the neural crest.17 It has been demonstrated that during development neural crest cells infiltrate the ultimobranchial body, which in turn is enveloped by the larger foramen cecum derivatives.1,4,6

References 1. Hollinshead WH. Anatomy for Surgeons: The Head and Neck. Vol. 1. Philadelphia: Harper and Row; 1982:382–384. 2. Baskin HJ. Thyroid Ultrasound and UltrasoundGuided FNA Biopsy. Norwell, MA: Kluwer; 2000. 3. Cotran RS, Kumar V, Robbins SL. Robbins Pathologic Basis of Disease. 5th ed. Philadelphia: Saunders; 1994.

G. Wong and S. Schaffer 4. Cummings CW, Frederickson JM, Harker LA, et al. Otolaryngology Head and Neck Surgery. 3rd ed. St. Louis, MO: Mosby-Year Book; 1998. 5. Warwick R, Williams PL. Gray’s Anatomy. 36 ed (British). Philadelphia: Saunders; 1980. 6. Larsen PR, Ingbar SH. The thyroid gland. In: Wilson JD, Foster DW, eds. Williams Textbook of Endocrinology. 8th ed. New York: Saunders; 1992. 7. Braverman LE, Utiger RD, ed. Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text. 6th ed. New York: Lippincott; 1991. 8. Sadler TW. Langman’s Medical Embryology. Baltimore: Lippincott Williams & Wilkins; 1990. 9. Bailey BJ, Calhoun KH. Head and Neck Surgery: Otolaryngology. 2nd ed. Philadelphia: LippincottRaven; 1998. 10. Marshall SF, Becker WF. Thyroglossal cysts and sinuses. Ann Surg 1949;129: 642. 11. Organ GM, Organ CH Jr. Thyroid gland and surgery of the thyroglossal duct: exercise in applied embryology. World J Surg 2000;24:886–890. 12. Pemberton J. Stalker: cysts, sinuses, and fistulae of the thyroglossal duct. Ann Surg 1940;111:950. 13. Skolnik EM, Yee KF, Goden TA. Transposition of the lingual thyroid. Laryngoscope 1976;86:785. 14. Andreoli TE, Bennett JC, Carpenter CC, Plum F. Cecil Essentials of Medicine. 4th ed. Philadelphia: Saunders; 1997. 15. Kasper DL. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005. 16. Steinwald PM, Whang KT, Becker KL, et al. Elevated calcitonin precursor levels are related to mortality in an animal model of sepsis. Crit Care 1999;3:11–16. 17. Pearse AGE, Polak JM. Cytochemical evidence for the neural crest origin of mammalian ultiobranchial C cells. Histochemie 1971;27:96.

2 Hormones Airani Sathananthan, Kimberly A. Placzkowski, and John C. Morris

Editorial Perspective As a physician, it is essential to comprehend normal physiology before one can grasp the concepts of pathophysiology. This is especially true for the thyroid gland and its disorders related to the skin. In this chapter, the synthesis, regulation, transport, metabolism, and actions of thyroid hormones are detailed. Understanding thyroid physiology will enable the clinician to utilize thyroid function tests appropriately. In addition, practitioners will gain an appreciation regarding why disorders that affect the dynamics of thyroid hormone have such profound and diverse clinical

Introduction Iodide is an essential component of thyroid hormone, and active transport of iodide into the thyroid gland is a crucial rate-limiting step in its biosynthesis.1 Thus, normal thyroid hormone synthesis requires adequate iodide intake. Minimum dietary requirements for iodide are approximately 75 µg/day.2 The World Health Organization (WHO), however, recommends 150 µg/day as the minimum daily intake of iodide, with even higher levels recommended during pregnancy. Iodine in its organic form is converted mostly to iodide prior to absorption.3 Inorganic iodide is concentrated by the thyroid from that derived from extracellular fluid. The iodide carrier is a transport protein known as the sodium iodide symporter (NIS), which is located on the basolateral membrane of thyroid follicular cells

effects. The skin is a complex organ with vascular, neural, and muscular components. Aside from its role as protective barrier to infectious and noninfectious insults from outside world, it is a metabolically active organ that is vital in maintaining homeostasis. The skin is intimately involved in thermoregulation. Disorders that result in either hyperthyroidism or hypothyroidism will adversely affect how the skin performs its functions in maintaining homeostasis. Having knowledge of normal thyroid physiology will enable the clinician to recognize when abnormalities exist, allowing efforts to be made to return to the euthyroid state.

(see Figure 2.1).2 It cotransports two sodium and one iodide ion, with the transmembrane sodium gradient serving as the driving force for iodide uptake into follicles.1 Thyroid-stimulating hormone (TSH), as well as other follicular cell autoregulatory systems responsive to intracellular and intrathyroidal iodide concentrations, influences NIS expression in the thyroid.2 Pituitary-derived TSH stimulates iodide transport into the thyroid gland by inducing NIS expression.1 In general, an increasing glandular content of organic iodide diminishes iodide transport and its response to TSH.2 Pendrin is another protein involved in iodide transport. It appears to be involved in iodide transport across the apical membrane of the follicular cell into the follicular lumen, where it can be incorporated into thyroglobulin.2 Tetraiodothyronine (thyroxine, T4) and 3,5,3′triiodothyronine (T3) are the primary thyroid

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Figure 2.1. Schematic of the thyroid follicular cell showing the key aspects of thyroid iodine transport and thyroid hormone synthesis. ADP, adenosine diphosphate; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; NIS, sodium iodide symporter; PDS, pendrin; T3, triiodothyronine; T4, thyroxine; Tg, thyroglobulin; TPO, thyroid peroxidase; TSHR, thyroid-stimulating hormone receptor

hormones.4 They differ in chemical structure by one iodide atom present at the 5′ position in T4, which is absent in T3 (see Figure 2.2).4 Thyroglobulin, a high molecular weight glycoprotein, is the primary protein synthesized by follicular cells and serves as the backbone for thyroid hormone synthesis.5 Thyroid peroxidase (TPO) enzyme oxidizes iodide that covalently attaches to specific tyrosine residues I

in the thyroglobulin backbone to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) in a process called organification.1 The TPO-catalyzed iodination of tyrosine residues and coupling within the thyroglobulin molecules occur in the follicular lumen. Two DITs forms T4, and one DIT and one MIT form T3.4,5 T4 and T3 are stored as part of the thyroglobulin molecule

I NH2

HO

CH2 CH

O

I

COOH

I 3⬘,5⬘,3,5, Tetraiodothyronine (Thyroxine, T4)

5 Deiodinase

5⬘ Deiodinase

I

I NH2

NH2 O

HO

CH2 CH

O

HO

CH2 CH

COOH

I

I 3⬘,5⬘,3-Triiodothyronine (rT3)

COOH

I

I 3⬘,3,5-Triiodothyronine (T3)

Figure 2.2. Thyroxine (T4) is the primary hormonal product of the thyroid. Up to 80% of triiodothyronine (T3) in circulation is formed though peripheral conversion of T4 by 5′-deiodinase with removal of an iodine molecule from the outer ring. A portion of T4, however, is enzymatically converted to the biologically inactive reverse T3 (rT3) by 5-deiodinase, which cleaves an iodine molecule from the inner ring

2. Hormones

in the colloid portion of the follicle.5 Through endocytosis, colloid is taken up by the follicular cell at the apical membrane.4 Lysosomes migrate from the basal end of the follicular cell to fuse with the colloid droplets. Lysosomal proteases cleave iodothyronines from thyroglobulin, releasing thyroid hormone, which is then taken up into capillaries adjacent to the basal cell membrane.4 As large quantities of iodinated thyroglobulin are present within the normal thyroid, it contains several weeks’ supply of thyroid hormones.2

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transcription of the TSH α- and β-genes as well as the pro-TRH gene.2 Thyroid-stimulating hormone-releasing hormone reaches the anterior pituitary via the hypothalamic pituitary portal circulation.2 It interacts with specific receptors on pituitary thyrotrophs to release TSH and on mammotrophs to release prolactin.2 The thyroid also demonstrates autoregulation.2 In a state of iodide excess, iodide transport is decreased, whereas in the presence of iodide deficiency it is increased.2 As noted, much of this effect is mediated by changes in NIS expression.1

Regulation of Thyroid Function The function of the thyroid gland is regulated mainly by TSH, which acts on the thyroid to increase the production of thyroid hormone.6 TSH is synthesized and secreted by thyrotrophs in the anterior pituitary gland6,7 in response to stimulation by TSH-releasing hormone (TRH) produced in the hypothalamus. TSH is one of the family of pituitary glycoprotein hormones with a structure that is characterized by the presence of two distinct subunits, α and β. The α-subunit is common to TSH, luteinizing hormone, follicle-stimulating hormone, and the placental gonadotropin human chorionic gonadotropin (hCG). The β-subunits, however, are unique for each hormone and confer biological specificity.6 By interacting with G protein-linked receptors on thyroid follicular cells, TSH stimulates the thyroid to enhance the activity of adenylyl cyclase and thus stimulates the generation of cyclic adenosine monophosphate (cAMP) as a second messenger inside the cell.2 Regulation of TSH secretion is under control of both hypothalamic TRH and thyroid hormone.2 Excessively high concentrations of thyroid hormone feedback at the level of the pituitary gland to suppress synthesis and secretion of TSH. This “negative feedback” mechanism serves as the most important physiologic regulator of circulating TSH levels.6 Both T4 and T3 are capable of inhibiting TSH secretion by the pituitary, although intrapituitary T3 appears to mediate more feedback inhibition than peripheral T3.2 In addition, negative feedback by T3 occurs at the level of the pituitary as well as at paraventricular nucleus of the hypothalamus.2 This feedback decreases the

Transport of Thyroid Hormone and Tissue Delivery Thyroid hormone in the circulation is largely bound to thyroid hormone-binding globulin (TBG), transthyretin, and albumin, with approximately 70% bound to TBG, 20% to albumin, and 10% to transthyretin.8 Lipoproteins carry a minor fraction of thyroid hormones.2 Thus, the total quantity of T4 and T3 measured in the blood is affected by conditions altering concentrations of these binding proteins.8 Only about 0.03% of T4 and 0.3% T3 is free or unbound.2 Thyroxine has a lower metabolic clearance rate and longer serum half-life than T3 because it binds more tightly to serum-binding proteins than T3. The half-life of T3 is less than a day; where as the half-life of T4 is about 7 days.2 Most T4 and T3 assays will report the total hormone concentration in plasma or serum samples.8 Only free thyroid hormone concentrations are biologically important as only unbound hormones can transit cellular membranes and exert their effect on nuclear receptors. Estrogen therapy, pregnancy, congenital anomalies in binding protein production, acute liver disease, or hypothyroidism frequently increase the concentration of one or more thyroxine binding protein.8 Often, women taking oral contraceptives demonstrate high total T4 concentrations but have normal free T4 levels due to the increase in TBG synthesis by the liver.8 These altered binding protein concentrations have no clinical consequences for patients. Hypothalamic and pituitary control of thyroid function is also regulated by free hormone rather than by total hormone concentrations.8

10

A. Sathananthan et al.

Metabolism of Thyroid Hormone

Thyroid Hormone Action

Thyroxine (T4) is the primary hormone synthesized by the thyroid and accounts for at least 90% of thyroid hormone production. Approximately 5% of hormone produced is T3, with the remainder less-active iodothyronines. T4 is converted in the thyroid, pituitary, and peripheral tissues to the biologically more active T3 through the action of 5′-deiodinase enzymes (see Figure 2.2). Two types of 5′-deiodinase are present, although levels of each enzyme vary from one tissue to another.9 Type I 5′-deiodinase (TI-5′D) is found in the highest concentrations in the liver and kidney but may be found in lower concentrations in several tissues throughout the body, including the thyroid. It is the most abundant deiodinase and functions to maintain plasma levels of T3. Activity of TI-5′D is elevated in hyperthyroidism and suppressed in hypothyroidism.10 Increased activity accounts for the elevated T3 levels, even with normal T4 levels, which may be seen in thyrotoxicosis. Type II 5′-deiodinase (TII-5′D) is primarily present in the brain and pituitary and is responsible for maintaining intracellular T3 levels.9 As T4 concentrations decrease, TII-5′D activity increases, protecting the brain and thyroid from the effects of hypothyroidism. T4 may also be converted to the biologically inert hormone reverse T3 by 5-deiodinase, also known as Type III deiodinase (see Figure 2.2).

Cardiovascular System

Thyroid Hormone Receptors Many actions of thyroid hormone are mediated through nuclear thyroid hormone receptors (TRs), although some hormone effects may be nongenomic. Two types of TRs, α and β, modulate the actions of free hormone. Receptor response elements also play key roles in the binding of thyroid hormone to TR. Genes coding for the different receptor types are found on separate chromosomes. At least two subtypes have been found for each TR; these are products of alternate splicing. TRα1 and TRβ1 are expressed at various levels throughout the body and differ in potency and affinity for T3 analogs. TRβ2 also binds thyroid hormone but is only present in the brain.9 TRα2, however, does not bind T3 and is thought to inhibit T3 action.11

Thyroid hormone is important for maintenance of heart rate and plays a role in determining cardiac output, systemic vascular resistance, and oxygen consumption. The association between hyperthyroidism and tachycardia or atrial fibrillation is well documented. T3 indirectly acts on the heart by increasing β-adrenergic receptors, thereby increasing β-adrenergic action.12 Increased sympathetic tone and decreased parasympathetic tone lead to the increased heart rate of hyperthyroidism. Conversely, bradycardia may be seen in severe hypothyroidism. Cardiac output depends on heart rate and stroke volume, for which contractility plays an important role. Contractility of the heart is indirectly controlled by T3 through changes in peripheral oxygen consumption. Hyperthyroidism increases peripheral oxygen consumption, thereby causing increased cardiac contractility and increased cardiac output. Contractility is also directly affected by T3 action on cardiac muscle. Animal studies have shown that increases in T3 concentrations augment the transcription of α-myosin heavy chains,13 which may improve cardiac output. In addition, T3 increases activity of calcium-activated adenosine triphosphatase (ATPase), phospholamban, and sarcoplasmic reticulum proteins of cardiac myocytes in animals, leading to changes in both systolic and diastolic heart function.14 In hyperthyroidism, systolic and diastolic functions are both increased. In thyroid hormone deficiency, however, systolic function may be reduced, and diastolic relaxation may be prolonged. Nongenomic effects in the heart include changes in ion channel flux, which can lead to increased inotropy and chronotropy.15 Finally, thyroid hormone decreases systemic vascular resistance through relaxation of the vascular smooth muscle, which also contributes to increased cardiac output.16 Hypothyroidism, however, is associated with decreased cardiac output, which together with bradycardia may contribute to congestive heart failure.

Neuromuscular System Thyroid hormone is crucial in the development of the central nervous system. TRα1 is preferentially expressed very early in development and may

2. Hormones

be important for mediating appropriate neuronal development.11 Congenital hypothyroidism, when undiagnosed and untreated very early in life, is associated with profound changes in cognitive development. Animal studies have shown that myelin basic protein,17 Purkinje cell protein 2,18 and TRH19 genes are thyroid hormone dependent. These genes may be important for the action of T3 on normal brain development, although several other genes likely also contribute. As in cardiac muscle, skeletal muscle is also influenced by thyroid hormone concentrations. Deep tendon reflexes are prolonged in hypothyroidism and tend to be brisk in thyrotoxicosis. Muscle relaxation is dependent on the calciumactivated ATPase activity, which has action that is increased by thyroid hormone.14

Skeletal System and Growth Thyroid hormone, together with growth hormone (GH) and insulin-like growth factor 1 (IGF-1), is an important hormone for growth and bone development. In children with hypothyroidism, short stature and growth retardation are seen due to delayed bone maturation and decreased linear bone growth.20 Changes in linear growth, however, are at least partially reversible if children are treated with thyroxine replacement prior to fusion of the growth plates. Thyrotoxicosis, conversely, is associated with increased bone turnover and accelerated growth rate. Accelerated growth maturations may lead to short stature in hyperthyroidism despite changes in growth rate.21 Thyroid hormone indirectly influences growth through stimulation of GH synthesis and secretion.22 IGF-1 levels increase under GH stimulation, but T3 also increases the tissue actions of IGF-1.23 Thyroid hormone also interacts directly with osteoblasts and osteoclasts through the TRs in bone. It appears that osteoblast stimulation by T3 is important for osteoclasts bone resorption.24

Lipid and Cholesterol Metabolism Thyroid hormone has important effects on hepatocytes and adipocytes, influencing metabolism. Thyroid hormone initially stimulates lipogenesis by inducing fatty acid synthetase, among other enzymes, in adipocytes.25 Lipolysis is subsequently

11

stimulated, however, and the fatty acids formed are used in calorigenesis needed for the increased metabolism seen in hyperthyroidism.26 Hypothyroidism alters lipoprotein metabolism in the liver and is associated with increased cholesterol levels, specifically intermediate-density (IDL) and low-density (LDL) lipoproteins.9 Decreased concentrations of thyroid hormone lead to lower levels of LDL receptors in the liver, which in turn leads to decreased cholesterol clearance with a subsequent rise in serum lipid levels. In addition, hypothyroidism decreases hepatic lipase and lipoprotein lipase concentrations, which reduce the conversion of IDL to LDL and clearance of triglycerides, respectively.27 Normalization of thyroid hormone levels reverses the adverse effects on cholesterol metabolism. To date, however, thyroxine therapy, at doses lower than those that induce thyrotoxicosis, has not been shown to improve cholesterol levels in euthyroid patients.

Thermogenesis and Energy Metabolism Thyroid disease is associated with changes in the balance between energy intake and energy expenditure, thereby influencing body weight. Thyroid hormone excess increases the basal metabolic rate, although the physiology of this effect remains poorly understood in humans. Thermogenesis plays a large role in energy expenditure. In rodents, brown fat is the site of facultative thermogenesis. In humans, however, brown fat has only been found in neonates.9 Weight loss and increased body temperature are well-recognized effects of hyperthyroidism. Changes in body temperature may contribute to heat intolerance. Thyroid hormone influences many biochemical pathways, including protein synthesis,28 and when combined with increased oxygen consumption and alterations in cardiac function, these factors likely contribute to increased energy expenditure. Lipolysis helps provide substrate for the increased overall metabolic need. Hypothyroidism, on the other hand, is associated with modest weight gain and a sensation of cold intolerance.

References 1. Spitzweg C, Heufelder A, Morris JC. Thyroid iodine transport. Thyroid 2000;10:321–330.

12 2. Griffen JE. The thyroid. In: Griffin JE, Ojeda SR, eds. Endocrine Physiology. New York: Oxford University Press; 2004:294–318. 3. Cavalieri R. Iodine metabolism and thyroid physiology: current concepts. Thyroid 1997;7:177–181. 4. Surks MI. Thyroid hormone formation, secretion, transport, metabolism and action. In: Surks MI, Korenman SG, eds. Atlas of Clinical Endocrinology. Volume 1: Thyroid Diseases. Philadelphia: Current Medicine Blackwell Science; 1999:1–13. 5. Kettyle WM, Arky R. The thyroid. In: Kettyle WM, Arky R, eds. Endocrine Pathophysiology. Philadelphia: Lippincott-Raven; 1998:71–98. 6. Shupnikm MA, Ridgeway EC, Chin W. Molecular biology of thyrotropin. Endocr Rev 1989;10:459– 475. 7. Manger J. Thyroid stimulating hormone: biosynthesis, cell biology, and bioactivity. Endocr Rev 1990;11:354–385. 8. Neal JM. Thyroid gland. In: Neal JM, ed. Basic Endocrinology: An Interactive Approach. Malden, MA: Blackwell Science; 2000:51–87. 9. Brent GA. The molecular basis of thyroid hormone action. N Engl J Med 1994;331:847–853. 10. Bianco AC, Salvatore D, Gereben B, et al. Biochemistry, cellular and molecular biology, and physiologic roles of iodothyronine selenodeiodinases. Endocr Rev 2002;23:38–89. 11. Bradley DJ, Towle HC, Young WS III. Spatial and temporal expression of α- and β-thyroid hormone receptor mRNAs, including the β2-subtype, in the developing mammalian nervous system. J Neurosci 1992;12:2288–2302. 12. Hoit BD, Khoury SF, Shao Y, et al. Effects of thyroid hormone on cardiac beta-adrenergic responsiveness in conscious baboons. Circulation 1997;96:592–598. 13. Ojamaa K, Klemperer JD, MacGilvary SS, et al. Thyroid hormone and hemodynamic regulation of beta-myosin heavy chain promoter in the heart. Endocrinology 1996;137:802–808. 14. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344: 501–509. 15. Walker JD, Crawford FA, Kato S, et al. The novel effects of 3,5,3′-triiodo-L-thyronine on myocyte contractile function and beta-adrenergic responsiveness in dilated cardiomyopathy. J Thorac Cardiovasc Surg 1994;108:672–679. 16. Ojamaa K, Klemperer JD, Klein I. Acute effects of thyroid hormone on vascular smooth muscle. Thyroid 1996;6:505–512.

A. Sathananthan et al. 17. Farsetti A, Desvergne B, Robbins J, et al. Characterization of myelin basic protein thyroid hormone response element and its function in the context of native and heterologous promoter. J Biol Chem 1992;267:15784–15788. 18. Strait KA, Zou L, Oppenheimer JH. β1 Isoformspecific regulation of a triiodothyronine-induced gene during cerebellar development. Mol Endocrinol 1992;6:1874–1880. 19. Lezoualch F, Hassan AH, Giraud P, et al. Assignment of the β-thyroid hormone receptor to 3,5,3′-triiodothyronine-dependent inhibition of transcription from the thyrotropin-releasing hormone promoter in chick hypothalamic neurons. Mol Endocrinol 1992;6:1797–1804. 20. Fisher D, Polk D. Thyroid disease in the fetus, neonate and child. In: DeGroot LD, ed. Endocrinology. Philadelphia: Saunders; 1995:783–798. 21. Riggs WJ, Wilroy RJ, Etteldorf J. Neonatal hyperthyroidism with accelerated skeletal maturation, craniosynostosis and brachydactyly. Radiology 1972;105:621–625. 22. Brent GA, Harney JW, Moore DD, et al. Multihormonal regulation of the human, rat and bovine growth hormone promoters: differential effects of 3,5-cyclic adenosine monophosphate, thyroid hormone, and glucocorticoids. Mol Endocrinol 1988;2:792–796. 23. Weiss RE, Refetoff S. Effect of thyroid hormone on growth: lessons from the syndrome of resistance to thyroid hormone. Endocrinol Metab Clin 1996;25:719–730. 24. Britto J, Fenton AJ, Holloway WR, Nicholson GC. Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone resorption. Endocrinology 1994;134:169–176. 25. Oppenheimer JH, Schwartz HL, Mariash CN, et al. Advances in our understanding of thyroid hormone action at the cellular level. Endocr Rev 1987;8:288– 308. 26. Oppenheimer JH, Schwartz HL, Lane JT, et al. Functional relationship of thyroid hormone-induced lipogenesis, lipolysis and thermogenesis in the rat. J Clin Invest 1991;87:125–132. 27. Packard CJ, Shepherd J, Lindsay GM, et al. Thyroid replacement therapy and its influence on postheparin plasma lipases and apolipoprotein-B metabolism in hypothyroidism. J Clin Endocrinol Metab 1993;76:1209–1216. 28. Davies AG. Thyroid physiology. BMJ 1972;2:206– 209.

3 Classification and Epidemiology of Thyroid Disease Ghada Haddad and Steven Kaufman

Editorial Perspective Thyroid diseases are exceedingly common. The thyroid gland, by virtue of its effect on tissue metabolism, affects every organ system. The cutaneous manifestations of thyroid disease are protean and include all age groups. The spectrum of the cutaneous manifestations of thyroid disease includes specific lesions such as cutaneous metastases from thyroid malignancies and thyroglossal duct cysts; nonspecific alterations of the skin, hair, and nails reflecting both the hyperthyroid and hypothyroid states; and the multiple

Introduction Thyroid diseases are common, preventable, and treatable. The US National Health and Nutrition Examination Survey (NHANES III) screened 13,344 individuals with no known thyroid disease by measuring serum thyroid-stimulating hormone (TSH), thyroxine (T4), thyroglobulin antibodies, and thyroid peroxidase antibodies and found that 4.6% had hypothyroidism (0.3% overt and 4.3% subclinical) and 1.3% had hyperthyroidism (0.5% overt and 0.7% subclinical). In addition, 10% of individuals had positive serum thyroglobulin antibody concentrations, and 11% had positive serum thyroid peroxidase antibody concentrations.1 Thus, with the high proportion of the US population having laboratory evidence of thyroid disease, it would support the usefulness of routine screening. Environmental factors are major determinants

associations of thyroid disease with other cutaneous and systemic diseases. In this chapter, Drs. Haddad and Kaufman classify thyroid disorders and provide information regarding their prevalence. It is abundantly clear that dermatologists will be seeing patients with a thyroid disorder on a daily basis and that endocrinologists will be managing patients with dermatologic issues. It behooves dermatologists and endocrinologists to have knowledge of the breadth and epidemiology of thyroid diseases and their attendant dermatologic manifestations to ensure early diagnosis and treatment of these diseases.

of thyroid disease; iodine deficiency is the most common cause of thyroid disorders worldwide. In 2005, the World Health Organization estimated that 2 billion individuals (35% of the world’s population) are iodine deficient, including 60% of the population in Europe.2,3 Iodine is an essential component for thyroid hormone synthesis. Iodine deficiency results in inadequate thyroid hormone production and clinical manifestations of hypothyroidism, such as endemic goiter. If the deficiency is severe during infancy it could cause irreversible mental retardation, cretinism, and increased neonatal mortality.4 Iodine repletion in western China lowered neonatal mortality by 65%,5 and iodine repletion in most parts of the world resulted in decreased incidence of endemic goiter and cretinism.6 Just as iodine deficiency causes serious disease, iodine excess also causes autoimmune thyroid disease, both hyperthyroidism and hypothyroidism. Follicular

13

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thyroid cancer is more prevalent in iodine-deficient areas, while papillary thyroid cancer is more prevalent in the population with high iodine intake. Other environmental factors also contribute to thyroid disease. Radiation exposure during childhood, such as after the fallout from Chernobyl, increases the incidence of papillary thyroid cancer. Studies of survivors of the atomic bomb in Japan and studies of children treated with radiation therapy for Hodgkin disease established a definite relationship of radiation exposure with thyroid cancer.7 This knowledge has potential application in case of nuclear accidents. Potassium iodide (KI) given daily decreases the thyroid uptake of radioactive iodine and provides protection against thyroid cancer in later years. The protection is best when KI is given before a nuclear event; its efficacy decreases to 80% when it is administered within 2 h following the nuclear event and is significantly less effective in decreasing the cancer risk if given after 8 h.8

Hypothyroidism Subclinical Primary Hypothyroidism Mild or subclinical hypothyroidism refers to a state in which the serum TSH concentration is elevated, but the serum free T4 and triiodothyronine (T3) concentrations remain normal.9 Subclinical hypothyroidism is common; its prevalence has been reported to be between 3% and 17% in various populations, especially in older women.10 In the NHANES III study, as noted, the prevalence of subclinical hypothyroidism among 13,444 subjects was 4.3%.1 The Whickham survey, a large cross-sectional study conducted over 20 years in a mixed urban and rural area in northeast England, revealed a prevalence of 4%–5% among women aged 18–44 years, 8%–10% among women aged 45–74 years, and 17.4% among women older than 75 years. The prevalence among men older than 65 years was 6.2%.11 The causes of subclinical hypothyroidism are the same as those of overt hypothyroidism. The risk factors for progressing to overt hypothyroidism include (1) age older than 60 years; (2) prior history of thyroid surgery or irradiation; (3) having a TSH concentration above 10 mIU/L; and (4) demonstrating high titers of antithyroid antibodies, indicating autoimmune thyroid disease.12 In this same study,

G. Haddad and S. Kaufman

subjects with subclinical hypothyroidism with both elevated TSH and antithyroid antibodies developed overt hypothyroidism at a rate of 4.3%. It is uncertain whether treatment of asymptomatic individuals with mildly elevated TSH and a normal free T4 is beneficial.13

Overt Primary Hypothyroidism Overt hypothyroidism, as opposed to subclinical hypothyroidism, is defined by an elevated serum TSH concentration and a low serum free T4 concentration. This state indicates a more pronounced degree of hypothyroidism; patients usually have symptoms and signs of hypothyroidism.9

Etiology Chronic Autoimmune (Hashimoto) Thyroiditis Hashimoto thyroiditis is the most common cause of hypothyroidism in an iodine-sufficient population. It presents with either an atrophic form or a goiter. Thyroid injury is caused by both humoral and cellular factors. The disease is characterized by diffuse lymphocytic infiltrate of the thyroid parenchyma and follicular destruction, leading to progressive thyroid failure. Over 90% of patients have detectable antithyroid antibodies. Hashimoto thyroiditis is more prevalent in women, with a sex ratio of 7:1; children can also be affected. In the mild form of the disease with only a slightly elevated TSH and positive antithyroid antibodies, the rate of progression to overt hypothyroidism is about 5% per year.12,14 Not all patients with goiter or circulating antithyroid antibodies have hypothyroidism. In the NHANES III survey of patients with no known disease, 10% had high serum thyroglobulin antibodies, and 11% had high thyroid peroxidase antibodies.1 The latter has predictive value for development of hypothyroidism in the future, while the former does not.

Thyroidectomy Thyroid surgery causes variable rates of hypothyroidism depending on the amount of remnant tissue. Thyroxine has a half life of 7 days; therefore, thyroid function tests may remain within the normal range during the initial postsurgical period. Patients who develop hypothyroidism after hemithyroidectomy tend to have a higher preoperative TSH level.15

3. Classification and Epidemiology of Thyroid Disease

15

Radioiodine Therapy

Industrial and Environmental Agents

Radioactive iodine is commonly used in the United States for treatment of hyperthyroidism. One of its major expected consequences is the onset of hypothyroidism. Most people with Graves disease become hypothyroid in the first 6–12 months following the radioactive iodine treatment.16,17 The incidence of hypothyroidism is less frequently seen after treatment of toxic multinodular goiter or toxic adenoma.

There are naturally occurring antithyroid agents. Thiocyanate consumed directly from cabbage and related plants or from the breakdown of compounds in the cassava root may cause goiter and hypothyroidism. Some synthetic pollutants, including pesticides and herbicides, are associated with goiter and hypothyroidism.25

External Neck Irradiation

Additional Etiologies of Primary Hypothyroidism

The onset of hypothyroidism usually occurs many years following exposure to external beam radiation (x-ray therapy, XRT). In a large study of 1677 patients treated with radiotherapy for Hodgkin disease followed for 20 years, the incidence of hypothyroidism was 30%.18 The incidence of hypothyroidism was even higher, 48%–67% in patients with head and neck cancer treated with XRT, with a mean time to develop hypothyroidism of 1.4 years.19

Riedel (fibrous) thyroiditis is a rare condition causing infiltration of the thyroid and surrounding tissue. While 30%–40% of patients have hypothyroidism, most present with an enlarging neck mass and symptoms of tracheal or esophageal compression.26,27 Other infiltrative diseases and infections may cause hypothyroidism. These include hemochromatosis, amyloidosis, sarcoidosis, AIDS, cystinosis, and primary thyroid lymphoma.28

Drug-Induced Hypothyroidism Several drugs are known to cause hypothyroidism. Up to 20% of patients treated with amiodarone can develop hypothyroidism in iodine-sufficient areas. Normal thyroid autoregulation of iodine uptake will prevail in those patients with normal underlying thyroid function. However, the already impaired autoregulation of chronic autoimmune (Hashimoto) thyroiditis becomes overwhelmed, and hypothyroidism ensues.20 Of patients treated with lithium, 20%–30% develop hypothyroidism, usually in the first 2 years of therapy.21 The risk of hypothyroidism is increased in women22 and those with underlying autoimmune thyroid disease.23 Other medications, such as interferon alfa and interleukin 2, are also known to induce thyroid dysfunction. Tyrosine kinase inhibitors such as sunitinib, an antiangiogenic agent used in the treatment of gastrointestinal malignancy and renal cell carcinoma, caused hypothyroidism in 36% of patients in one study.24 A baseline TSH level should be drawn prior to starting a medication that may affect thyroid function. If normal, TSH should be rechecked every 6–12 months. If the patient has a first-degree relative with hypothyroidism, a TSH level should be measured more frequently.

Central Hypothyroidism Secondary and tertiary hypothyroidism result from a deficiency of pituitary TSH or hypothalamic TSHreleasing hormone (TRH), respectively. Pituitary mass lesions, in particular pituitary adenomas, are the most common cause of central hypothyroidism. Hypothyroidism occurs if TSH secretion from the pituitary thyrotroph cells is impaired due to either direct compression of pituitary thyrotrophs or interruption of the hypothalamic-pituitary portal blood flow.29 Central hypothyroidism presents with symptoms and signs similar to primary thyroid failure. However, the laboratory evaluation will be different. Patients will have a low free thyroxine level, while the TSH level is inappropriately normal or low. Immediately after an acute event (i.e., hypophysectomy or apoplexy), the free thyroxine level may remain normal given the long half-life of thyroxine. Often, the patient has a deficiency of other pituitary hormones. Common symptoms include headache, visual disturbances, or symptoms of pituitary hormone excess or deficiency. Other etiologies of central hypothyroidism include sellar lesions such as meningioma, craniopharyngioma, dysgerminoma, and metastatic disease and infiltrative processes such as sarcoido-

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Table 3.1. Clinical manifestations of hypothyroidism. Symptoms Fatigue Cold intolerance Weight gain Constipation Depression Mental impairment Hoarseness Dry skin Decreased appetite Paresthesia Arthralgia

Signs Bradycardia Hoarseness Slow movement Slow speech Dry skin Delayed relaxation phase of reflexes Edema Goiter Central hypothyroidism Headache Visual field impairment Pituitary hormone deficiency/excess

sis, hemochromatosis, or histocytosis.29 Surgery,30 radiation,31 trauma,32 or pituitary apoplexy33 may also impair secretion of TRH or TSH.

Clinical Manifestations The clinical presentation of hypothyroidism may be ambiguous for several reasons. First, no symptom is pathognomonic for hypothyroidism. Second, symptoms of hypothyroidism such as weight gain and fatigue are often nonspecific. Third, the signs and symptoms of hypothyroidism are similar regardless of the cause. Fourth, the severity of the symptoms often does not correlate with the degree of biochemical abnormality. Fifth, the onset of symptoms may be insidious. The most common signs and symptoms of hypothyroidism are listed in Table 3.1.

Hyperthyroidism Subclinical Primary Hyperthyroidism Subclinical hyperthyroidism, occasionally referred to as early or mild hyperthyroidism, is defined as a low serum TSH concentration and normal serum free T4 and T3 concentrations. One should exclude drugs that can inhibit TSH secretion, such as glucocorticoids and dopamine, nonthyroidal illness, and pituitary disease, all of which can result in a low TSH value. In the NHANES study, the incidence of hyperthyroidism among 16,533 subjects with no known thyroid disease was 0.7%, using a TSH cutoff value of 0.1 mU/L.1 The highest rate was seen in subjects aged 20–39 years and in those older than

79 years. In the Framingham heart study of 2575 unselected ambulatory persons older than 60 years, 4% had a low serum TSH level(< 0.1 mU/ml); about half of them were taking thyroid hormone.34 Only 4.3% of subjects in this study progressed to overt hyperthyroidism after 4 years.34 Subjects with a low, but not undetectable, TSH value may spontaneously recover when retested. After a 1-year follow-up study of subjects over 60 years of age, 76% of those who had an initially low TSH level(0.05–0.5 mU/L) had a normal TSH value, up while 87% of those with completely undetectable TSH remained the same.35

Overt Primary Hyperthyroidism The prevalence of overt hyperthyroidism from large population studies has varied between a range of < 0.1 to 1 per 1000 year. In the Whickham study of 2779 subjects, the prevalence of undiagnosed hyperthyroidism among women was 4.7 per 1000 women and only 1.6–2.3 per 1000 men.11 The presence of a goiter or serum antithyroid antibodies was not a predictor of development of thyrotoxicosis in follow-up. In a larger study from England, among 1,641,949 subjects, the incidence per 1000/ year was 0.1 in men and 0.6 in women.36 Graves disease was more prevalent among women aged 20 to 49 years, and toxic multinodular goiter was more prevalent among older subjects. In a crosssectional survey of 25,682 subjects attending a health fair in Colorado, the presence of a TSH level < 0.01 mU/L was found in only 1 per 1000 of those not taking thyroid hormone.37 In the NHANES III study, among 16,533 subjects aged over 12 years with no previous history of thyroid disease, only 2 per 1000 had thyrotoxicosis, defined as a serum T4 concentration > 13 µg/dL and a serum TSH < 0.1 mU/L.1 When studying older individuals, such as in a recent US cross-sectional study of 2799 healthy adults between the ages of 70 and 79 years, the incidence of overt hyperthyroidism was also found to be low; only 1 man and 4 women had a serum TSH below 0.1 mU/mL and a serum free T4 above 1.8 ng/dL.38

Etiology Most etiologies of thyrotoxicosis present with a low TSH level from negative feedback at the hypo-

3. Classification and Epidemiology of Thyroid Disease

17

thalamus and pituitary. The exception is a TSH-producing adenoma. The causes of hyperthyroidism may be divided into those conditions causing increased versus decreased iodine uptake. Increased uptake denotes increased endogenous overproduction of thyroid hormone, while decreased iodine uptake is caused by inflammation of the gland or excess exogenous thyroid hormone.

Exogenous Thyroid Hormone

Low Iodine Uptake

Increased Iodine Uptake

Thyroiditis

Graves Disease

Thyroiditis is a spectrum of diseases caused by an inflammatory process with subsequent release of stored thyroid hormone. The initial hyperthyroid phase may progress to hypothyroidism before thyroid function recovers to normal.39 Subacute thyroiditis is typically preceded by a viral prodrome of fever, myalgia, and malaise in the days to weeks preceding the hyperthyroidism. The thyroid gland is often tender to palpation.39 In contrast, a silent painless thyroiditis, which includes postpartum thyroiditis, may present with symptoms of thyroid hormone excess.40

Robert Graves originally described the constellation of hyperthyroidism, goiter, and ophthalmopathy.46 Graves disease is an autoimmune disease caused by TSH receptor (TSHR) antibodies (Abs) stimulating the thyroid gland.47 The TSHR Abs are derived from intrathyroidal lymphocytes48 and are specific to Graves disease.49 The ability of the TSHR Abs to be a causal factor, and not a marker of disease, was demonstrated when TSHR Abs were infused into healthy human volunteers.50 Although ophthalmopathy and pretibial myxedema are classical manifestations of Graves disease, the most common dermatologic features of Graves disease are the nonspecific findings attributable to the hyperthyroid state (see chapter 8 on the cutaneous manifestations of hyperthyroidism). Ophthalmopathy may present independently in 10% of cases; it rarely occurs with pretibial myxedema.47,51

Iodine-Induced Hyperthyroidism The use of iodinated contrast, dietary supplements, over-the-counter medications,41 or prescription drugs such as amiodarone20 may cause hyperthyroidism. Normally, thyroid hormone production is not directly tied to the amount of dietary iodine as thyroid cell autoregulation can temporarily impair thyroid hormone production.42 Changes in thyroid hormone level are seen after exposure to iodine even in normal individuals.43 The changes will correct as the patient’s thyroid hormone production resumes even after 2–4 weeks of continued iodine exposure.44 However, patients with autonomously functioning thyroid tissue are likely to develop hyperthyroidism after exposure to iodine. Amiodarone Amiodarone, an iodine-rich molecule, can cause thyrotoxicosis by increasing iodine load to the thyroid. The increased iodine interferes with normal thyroid autoregulation.20 Other possible mechanisms include the induction of thyroid antibodies20 or an inflammatory or cytotoxic effect on thyroid cells.45

By surreptitious use of thyroid hormone supplements, some individuals hope to control weight or decrease fatigue. The risk of osteoporosis and atrial fibrillation cannot be overlooked. Iatrogenic hyperthyroidism from overreplacement with thyroid hormone occurs often but is readily corrected by adjustment of the levothyroxine dose.

Toxic Multinodular Thyroid and Toxic Adenoma A toxic multinodular thyroid or a toxic adenoma represents autonomously functioning thyroid nodules. Toxic adenomas represent well-defined autonomously functioning thyroid tissue that is independent of TSH.52 Hyperthyroidism develops as the adenoma grows. Nodules often begin as nonfunctional and may later develop autonomous function. While the pathogenesis of this process is unclear, activating mutations of TSH receptor and Gs[alpha] genes may play a role.53,54 Thyroid-Simulating Hormone-Secreting Pituitary Adenoma The TSH-secreting pituitary adenomas account for less than 1% of pituitary adenomas.55 Signs and symptoms are accompanied by elevated free

18

G. Haddad and S. Kaufman

T4 level with an inappropriately normal-to-elevated TSH level. Measurement of the α-subunit is important in the diagnosis of this condition.55,56 Most patients have clinical hyperthyroidism and a goiter. Many TSH-secreting pituitary adenomas are macroadenomas with extrasellar extension at the time of diagnosis. Thus, a mass effect causing visual disturbances or headache is common. Treatment often includes surgical resection and pituitary irradiation. Methimazole or Propylthiouracil (PTU) can be used in the perioperative period to control the hyperthyroidism.56

Clinical Manifestations Common symptoms and signs of thyrotoxicosis are listed in Table 3.2. A patient’s clinical presentation depends on the severity of the disease and underlying comorbid conditions. Most patients present with classical symptoms of hyperthyroidism. However, elderly patients often present with depression or failure to thrive, a condition known as apathetic hyperthyroidism. Chronic hyperthyroidism may cause osteoporosis or atrial fibrillation and, in severe cases, high-output heart failure. Atrial fibrillation or osteoporosis may be the initial clinical presentation in otherwise asymptomatic patients.57

Thyroid Nodules The detection of thyroid nodules has significantly increased over the last few years in part due to the widespread use of imaging studies. Clinically palpable thyroid nodules are present in 4%–7% of the US population.58 By contrast, the Table 3.2. Clinical manifestations of hyperthyroidism. Symptoms Palpitation Tremor Heat intolerance Hyperactivity Weakness Increased appetite Weight loss Hyperdefecation Increased perspiration Menstrual disturbances

Signs Tachycardia Tremor Systolic hypertension Muscle weakness Warm skin Moist skin Hyperactivity Lid retraction Ophthalmopathy Goiter

prevalence of nodules detected by high-resolution ultrasonography has ranged between 20% and 65% in unselected subjects.59,60 In patients with a single palpable nodule, ultrasonography detected additional nodules in 20%–48% of patients.61 In subjects older than 65 years, more than 50% will have a detected thyroid nodule by imaging.58 The rate of developing a thyroid carcinoma within a thyroid nodule is only 5%–8%.62 However, when a thyroid nodule is discovered in a child, it is twice as likely to be a carcinoma than in an adult.63 Differentiated papillary and follicular thyroid carcinomas are the most common type of thyroid carcinomas (90%–95% of all thyroid cancer) and have an excellent prognosis. Medullary thyroid carcinoma arising from parafollicular (C) cells accounts for 3%–5% of thyroid carcinoma; thyroid lymphoma accounts for 3%–5% of thyroid cancer and generally occurs in older individuals with a background of chronic lymphocytic thyroiditis.64 Anaplastic thyroid carcinoma is fortunately rare; it is an aggressive solid tumor occurring mostly in older women, presenting as a rapidly growing painless mass in the neck. Anaplastic cancer usually develops from a more differentiated thyroid carcinoma, usually papillary. The median survival is only 4–6 months, with an overall cause-specific mortality rate of 68.4% at 6 months and 80.7% at 12 months.65 The incidence of thyroid carcinoma in the United States increased from 12,200 in 1996 to 20,700 in 2002,66 particularly in women, with a female-tomale ratio of 3:1. The increase in surveillance and detection likely accounts for the higher incidence of thyroid cancer documented. It is unclear, however, whether other environmental factors are also contributing to the increased incidence. A study, based on a retrospective cohort evaluation of patients using the Surveillance, Epidemiology, and End Results (SEER) program and database on thyroid cancer mortality, revealed that the incidence of papillary thyroid cancer increased from 2.7 per 100,000 in 1973 to 7.7 per 100,000 in 2002, a 2.9-fold increase (95% confidence interval [CI] 2.6–3.2). In contrast there was no significant increase in the incidence of follicular, medullary, or anaplastic cancer.67 Between 1988 and 2002, of the increase, 49% consisted of papillary cancer measuring 1 cm or smaller; 87% consisted of cancer measuring 2 cm or smaller. Mortality from thyroid cancer was stable between 1973 and 2002.

3. Classification and Epidemiology of Thyroid Disease

The well-known existence of papillary microcarcinoma (< 1 cm) reported in 6%–37% of autopsies series68 combined with stable mortality suggest that the increase in thyroid cancer in the United States may be due to increased detection of small papillary cancer rather than true occurrence of thyroid cancer.

Screening for Thyroid Disease There are situations and conditions for which screening for thyroid disease is widely accepted, such as in diabetic patients because of their increased incidence of developing thyroid disease and proven cost-effectiveness of the screening.69 Women with a previous history of postpartum thyroiditis should be screened yearly because of their long-term risk of permanent hypothyroidism. Subjects with Turner syndrome70 and Down syndrome71 should also be screened annually due to the high prevalence of hypothyroidism in these patients. In addition, patients presenting with newonset atrial fibrillation should have their thyroid status checked to exclude the possibility of thyrotoxicosis causing the arrhythmia.72 Hyperlipidemic patients should be screened for hypothyroidism,73 as well as patients with strong family history of thyroid dysfunction, especially if symptomatic. There is a controversy, however, regarding whether healthy adults would benefit from routine screening for thyroid disease. As the prevalence of unsuspected overt thyroid disease is rare, as noted, screening usually reveals subclinical disease. To date, there are no convincing trials demonstrating that treatment of subclinical hypothyroidism results in long-term benefit. A consensus panel from the American Thyroid Association, the American Association of Clinical Endocrinologists (AACE), and the Endocrine Society recommended against routine screening of the general population.57 They believe there is no sufficient evidence to prove potential benefit of treatment in subclinical hypothyroidism. In addition, since 20% of patients with hypothyroidism in the community are overtreated by physicians,37 the treatment of subclinical hypothyroidism may have more potential harm than benefit. After the guidelines of the panel were published in 2004, two members of each of these organizations formed another panel to review the

19

consensus conference recommendation and disagreed with the previous recommendations.74,75 At present, the American Thyroid Association recommends routine screening for thyroid dysfunction beginning at age 35 years and every 5 years thereafter76; the AACE recommends screening older patients, especially women.77 The US Preventive Services Task Force stated that the available data are “insufficient to recommend for or against routine screening for thyroid disease in adults.”78

References 1. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489–499. 2. De Benoist B, Anderson M, Takkouche B, et al. Prevalence of iodine deficiency worldwide. Lancet 2003;362:1859. 3. Anderson M, Takkouche B, Egli I, et al. Current global iodine status and progress over the last decade towards the elimination of iodine deficiency. Bull World Health Organ 2005;83:518–525. 4. Delange F. Iodine deficiency. In: Braverman LE, Utiger RD, eds. The Thyroid. A Fundamental and Clinical text. 8th ed. Philadelphia: Lippincott Williams and Wilkins; 2000:295–316. 5. DeLong GR, Leslie PW, Wang SH, et al. Effect on infant mortality of iodination of irrigation water in a severely iodine deficient area of China. Lancet 1997;350:771–773. 6. Delange F, de Benoit B, Pretell E, et al. Iodine deficiency in the world: where do we stand at the turn of the century? Thyroid 2001;11:437–447. 7. Sklar C, Whitton J, Merkes, et al. Abnormalities of the thyroid in survivors of Hodgkin’s disease: data from the childhood cancer survivor study. J Clin Endocrinol Metab 2000;85:3277–3232. 8. Zanzonico PB, Becker DV. Effect of time of administration and dietary iodine levels on potassium iodide (KI) blockade of thyroid irradiation by 131I from radioactive fallout. Health Physician 2000;78:660–667. 9. McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab 2001;86:4585–4590. 10. Tunbridge WH, Vanderpump MP. Population screening for autoimmune thyroid disease. Endocrinol Metab Clin North Am 2000;29:239–253.

20 11. Tunbridge WH, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickman survey. Clin Endocrinol (Oxf) 1977;7:481. 12. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a 20-year follow-up of the Whickham survey. Clin Endocrinol (Oxf) 1995;43:55–68. 13. Helfand M. Screening for subclinical thyroid dysfunction in non pregnant adults: a summary of the evidence for the US preventive services task force. Ann Intern Med 2004;140:128–141. 14. Huber G, Staub JJ, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab 2002;87:3221–3226. 15. McHenry CR, Slusarczyk SJ. Hypothyroidism following hemithyroidectomy: incidence, risk factors, and management. Surgery 2000;128:994–998. 16. Franklin JA, Daykin J, Drolc Z, et al. Long term follow-up of treatment of thyrotoxicosis by three different methods. Clin Endocrinol (Oxf) 1991;34:71–76. 17. Ross DS, Daniel GH, Destefano P, et al. Use of adjunctive potassium iodide following radioactive iodine (I131) treatment of Graves’ hyperthyroidism. J Clin Endocrinol Metab 1983;57:250–253. 18. Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin’s disease. N Engl J Med 1991;325:599–605. 19. Mercado G, Adelstein DJ, Saxton JP, et al. Hypothyroidism: a frequent event after radiotherapy with chemotherapy for patients with head and neck carcinoma. Cancer 2001;92:2892–2897. 20. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997;126:63–73. 21. Perrild H, Hegedus L, Baastrup PC, et al. Thyroid function and ultrasonically determined thyroid size in patients receiving long term lithium treatment. Am J Psychiatry 1990;147:1518–1521. 22. Kirov G, Tredget J, John R, et al. A cross-sectional and a prospective study of thyroid disorders in lithium-treated patients. J Affect Disord 2005;87:313. 23. Berens SC, Bernstein RS, Robbins J, Wolff J. Antithyroid effects of lithium. J Clin Invest 1970;49:1357. 24. Desai J, Yassa L, Marqusee E, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006;145:660– 664. 25. Brucker-Davis F. Effects of environmental synthetic chemicals on thyroid function. Thyroid 1998;8:827– 856. 26. Lo JC, Loh KC, Rubin AL, et al. Riedel’s thyroiditis presenting with hypothyroidism and hypoparathy-

G. Haddad and S. Kaufman roidism: dramatic response to glucocorticoid and thyroxine therapy. Clin Endocrinol 1998;48:815–818. 27. Beahrs OH, McConahey WM, Woolner LB. Invasive fibrous thyroiditis (Riedel’s struma). J Clin Endocrinol Metab 1957;17:201–220. 28. Singer PA. Primary hypothyroidism due to other causes. In: Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text. 9th ed. Philadelphia: Lippincott Williams and Wilkins; 2005:746–753. 29. Samuels MH, Ridgway EC. Central hypothyroidism. Endocrinol Metab Clin North Am 1992;21:903–919. 30. Sudhakar N, Ray A, Vafidis JA. Complications after trans-sphenoidal surgery: our experience and a review of the literature. Br J Neurosurg 2004;18:507–512. 31. Lam KS, Tse VK, Wang C, Yeung RT, Ho JH. Effects of cranial irradiation on hypothalamicpituitary function—a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q J Med 1991;78:165–176. 32. Agha A, Thompson CJ. Anterior pituitary dysfunction following traumatic brain injury (TBI). Clin Endocrinol 2006;64:481–488. 33. Sheehan HL, Davis JC. Pituitary necrosis. Br Med Bull 1968;24:59–70. 34. Sawin CT, Geller A, Kaplan MM, et al. Low serum thyrotropin (thyroid-stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med 1991;151:165–168. 35. Parle JV, Franklyn JA, Cross KW, et al. Prevalence and follow up of abnormal thyrotropin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991;34;77–83. 36. Barker DJB, Philips DIW. Current incidence of thyrotoxicosis and past prevalence of goiter in 12 British towns. Lancet 1084;2:567. 37. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526–534. 38. Kanaya AM, Harris F, Volpato S, et al. Association between thyroid dysfunction and total cholesterol level in an older biracial population: the Health, Aging and Body Composition Study. Arch Intern Med 2002;162:773–779. 39. Farwell AP. Subacute thyroiditis and acute infectious thyroiditis. In: Werner and Ingbar’s Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text. 9th ed. Philadelphia: Lippincott Williams and Wilkins; 2005:538–547. 40. Lazarus JH. Sporadic and postpartum thyroiditis. In: Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text. 9th ed. Philadelphia: Lippincott Williams and Wilkins; 2005;525–535. 41. Nuovo J, Wartofsky, L. Adverse effects of iodide. In: Becker: Principles and Practice of Endocrinology

3. Classification and Epidemiology of Thyroid Disease and Metabolism. 3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2001. 42. Wolff J, Chaikoff IL. Plasma inorganic iodide as a homeostatic regulator of thyroid function. J Biol Chem 1948;174:555. 43. Saberi M, Utiger RD. Augmentation of thyrotropin responses to thyrotropin-releasing hormone following small decreases in serum thyroid hormone concentrations. J Clin Endocrinol Metab 1975;40:435–441. 44. Wolff J, Chaikoff IL, et al. The temporary nature of the inhibitory action of excess iodine on organic iodine synthesis in the normal thyroid. Endocrinology 1949;45:504. 45. Lambert M, Unger J, De Nayer P, Brohet C, Gangji D. Amiodarone-induced thyrotoxicosis suggestive of thyroid damage. J Endocrinol Invest 1990;13:527– 530. 46. Graves RJ. Newly observed affection of the thyroid. London Med Surg J 1835;7:515. 47. Ginsberg J. Diagnosis and management of Graves’ disease. CMAJ 2003;168:575–585. 48. Paschke R, Bruckner N, Eck T, Schaaf L, Back W, Usadel KH. Regional stimulation of thyroid epithelial cells in Graves’ disease by lymphocytic aggregates and plasma cells. Acta Endocrinol (Copenh) 1991;125:459–465. 49. Bolton J, Sanders J, Oda Y, et al. Measurement of thyroid-stimulating hormone receptor autoantibodies by ELISA. Clin Chem 1999;45:2285–2287. 50. Adams DD, Fastier FN, Howie JB, et al. Stimulation of the human thyroid by infusions of plasma containing LATS protector. J Clin Endocrinol Metab 1974;39:826. 51. Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves disease (pretibial myxedema): review of 150 cases. Medicine (Baltimore) 1994;73:1–7. 52. Corvilain B, Van Sande J, Dumont JE, Vassart G. Somatic and germline mutations of the TSH receptor and thyroid diseases. Clin Endocrinol 2001;55:143–158. 53. Holzapfel HP, Fuhrer D, Wonerow P, Weinland G, Scherbaum WA, Paschke R. Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiters. J Clin Endocrinol Metab 1997;82:4229–4233. 54. Fuhrer D, Holzapfel HP, Wonerow P, Scherbaum WA, Paschke R. Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab 1997;82:3885–3891. 55. Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC, Weintraub BD. Thyrotropin-secreting pituitary tumors. Endocr Rev 1996;17:610–638. 56. Magner JA. Thyroid-stimulating hormone-mediated hyperthyroidism. Endocrinologist 2004;14:201–211.

21 57. Surks M, Ortiz E, Daniels G, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228– 238. 58. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993;328:553–559. 59. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas: prevalence by palpation and ultrasonography. Arch Intern Med 1994;154:1838–1840. 60. Marqusee E, Benson CB, Frates MC, et al. Usefulness of ultrasonography in the management of nodular thyroid disease. Ann Intern Med 2000:696–700. 61. Tan GH, Gharib H. Thyroid incidentaloma: management approaches to non palpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 1997;126:226–231. 62. Werk EE Jr, Vernon BM, Gonzalez JJ, et al. Cancer in thyroid nodules. A community hospital survey. Arch Intern Med 1984;144:474–476. 63. Belfiore A, Giuffrida D, La Rosa GL, et al. High frequency of cancer in cold thyroid nodules occurring at young age. Acta Endocrinol (Copenh) 1989;121:197–202. 64. Sisson JC. Medical treatment of benign and malignant thyroid tumors. Endocrinol Metab Clin North Am 1989;18:359–387. 65. Kebebew E, Greenspan FS, Clark OH, et al. Anaplastic thyroid carcinoma. Cancer 2005;103:1330–1335. 66. American Cancer Society. Cancer facts and figures 1997, 1998, 1999, 2000, 2001, 2002. Available at: http://www.cancer.org/. 67. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 2006;10:2164–2167. 68. Yamamoto Y, Maeda T, Isumi K, et al. Occult papillary carcinoma of the thyroid: a study of 408 autopsy cases. Cancer 1990;65:1173–1179. 69. Perros P, McCrimmon RJ, Shaw G, et al. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 1996;12:622–627. 70. Livadas S, Xekouki P, Fouka F, et al. Prevalence of thyroid dysfunction in Turner’s syndrome: a long term follow up study and brief literature review. Thyroid 2005,15:1061–1066. 71. Van Vliet G. How often should we screen children with Down’s syndrome for hypothyroidism? Arch Dis Child 2005;90:557–558. 72. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 2006;295(9):1033–1041. 73. Pirich C, Mullner M, Sinzinger H, et al. Prevalence and relevance of thyroid dysfunction in 1922 cholesterol screening participants. J Clin Epidemiol 2000;53:623–629.

22 74. Gharib H, Tutle RM, Baskin HJ, et al. 2005 consensus statement: subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Association. J Clin Endocrinol Metab 2005;90:581–585. 75. Matthew R, Mazzaferri E. Subclinical thyroid dysfunction—can there be a consensus about the consensus? J Clin Endocrinol Metab 2005;90: 588–590.

G. Haddad and S. Kaufman 76. Ladenson P, Singer PA, Ain KB, et al.2000 American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med 2000;160:1573–1575. 77. American Association of Clinical Endocrinologist. 2002 clinical guidelines for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002;8:457–467. 78. US Preventive Services Task Force. 2004 screening for thyroid disease: recommendation statement. Ann Intern Med 2004;140:125–127.

4 Laboratory Diagnosis of Thyroid Disease Reagan Schiefer and Vahab Fatourechi

Editorial Perspective From a dermatologist’s vantage point, there are two major reasons to order thyroid function studies: to confirm a clinical suspicion of either hyperthyroidism or hypothyroidism. This is done by checking a thyroid-stimulating hormone (TSH) level with thyroxine (T4) level (or on occasion, triiodothyronine [T3]) or by screening for thyroid autoantibodies in an effort to ascertain if a patient is at risk for the development of autoimmune thyroid disease. For example, a 52-yearold woman presents with mild keratoderma and alopecia. A determination of TSH and T4 levels will rapidly determine if she is hypothyroid. In another typical case, an 8-year-old boy with alopecia areata is found to have elevated thyroperoxidase antibodies and a normal TSH. This child may have the potential to develop autoimmune

Introduction Diseases of the thyroid gland are the most common among endocrine disorders.1 As many as 1 in 10 people in the United States may be affected by autoimmune thyroid disease (AITD), goiter, or nodular thyroid.2 Despite the high prevalence of thyroid disease, many cases of thyroid disorders go undiagnosed. The reasons for missed diagnoses are many. However, the most likely reasons are the nonspecific symptoms associated with thyroid disease and the lack of accepted national guidelines for routine testing.

thyroid disease and should be followed periodically with a TSH level to be certain that neither Graves disease (GD) nor Hashimoto thyroiditis ensues. The appropriate use of thyroid function studies depends on a fundamental knowledge of thyroid hormone physiology. Many tests are now considered historical; however, their designs offer insights into thyroid physiology. On occasion, the dermatologist may order imaging studies of the thyroid gland, such as for the evaluation of thryoglossal duct cysts or for assessing the gland for thyroid adenomas or carcinomas in patients with Cowden syndrome. In this chapter, the clinician reviews the utility and limitations of thyroid function tests and imaging studies so that they may be used appropriately in the diagnosis of thyroid disease, risk assessment for associated disorders, and as tools for monitoring response to treatment for those patients receiving thyroid hormone.

Thyroid diseases are usually detected by abnormalities in the results of thyroid function tests. However, the interpretations of these tests are not always straightforward. Proposed changes in laboratory reference ranges and increased test sensitivity have led to earlier detection of thyroid disorders and have uncovered more subclinical thyroid diseases. The objective of this chapter is to guide clinicians in the interpretation of thyroid function tests and increase their knowledge regarding which thyroid tests are appropriate in different clinical scenarios. Before interpretation of these tests can be done, we must first understand the evolution of

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the differing assays. We review the biochemical tests and follow with clinical scenarios.

Biochemical Tests Thyroid-Stimulating Hormone Since the early 1970s, most of the following laboratory tests have been available for physicians to use to diagnose thyroid dysfunction: triiodothyronine (T3) uptake test, free thyroxine (T4) index (FTI), total T4 (TT4), total T3 (TT3), TT4/thyroxinebinding-globulin (TBG) ratio, free T4 (FT4), free T3 (FT3), and basal thyroid-stimulating hormone (TSH) by radioimmunoassay (RIA).3 Since its introduction in the mid-1980s, the sensitive TSH immunometric assay (IMA) has replaced the lesssensitive TSH radioimmunoassay (RIA) methods.4 As the years have progressed, improvement in assay sensitivity for serum TSH has demonstrated a major milestone in thyroid assessment.5 The improved sensitivity assays have allowed distinction between suppressed TSH values typically seen in hyperthyroidism from normal TSH levels found in euthyroid states. The reason for the increased sensitivity seen in these TSH IMAs stems from the IMA sandwich assay configuration. In the IMA assay, two anti-TSH antibodies are used rather than the single antibody used in RIAs. One or both of these antibodies are monoclonal, which increases the specificity of these antibodies for the TSH epitopes. The first antibody is targeted at the TSH β-subunit, and the second antibody is geared toward the TSH α-subunit. The first antibody is present in abundance and selectively extracts out nearly all of the TSH from the sample. The second antibody is used to quantify this bound TSH. This method allows not only increased assay sensitivity but also faster turnaround time with a wider working range as compared to prior RIAs.4 Improvement in assay sensitivity for serum TSH led to the use of a generation nomenclature system to distinguish these newer IMAs from the less-sensitive RIAs. Basically, each generation represents a 10-fold improvement in functional sensitivity.4 First-generation TSH assays, such as RIAs, have a functional sensitivity limit between 1.0 and 2.0 mIU/L. The second-generation TSH IMAs have a functional sensitivity limit between 0.1 and 0.2 mIU/L, with the third generation having a functional sensitivity limit between 0.01 and 0.02 mIU/L.6

R. Schiefer and V. Fatourechi

The use of second-generation TSH assays has shown that below-normal TSH values are not limited to overt hyperthyroidism. Subnormal TSH levels can be seen in geriatric patients, nonthyroidal illnesses, treated hyperthyroidism, and those on thyroid hormone replacement who may have normal peripheral thyroid hormone levels.7–11 Thus, a group of patients, including subclinical hyperthyroid patients, who have normal laboratory range circulating thyroid hormone levels but abnormally low serum TSH can now be diagnosed. Important to note is that poor laboratory quality control can lead to inaccurate values.4 Therefore, laboratories using IMAs have to determine their own functional sensitivity limit independent of the manufacturer’s claims of “generation.”6 Third-generation TSH assays are currently in wide use. The third-generation assays are able to differentiate completely suppressed, undetectable TSH values characteristic of thyrotoxicosis from suppressed but detectable TSH results seen in patients with mild hyperthyroidism, on slightly excessive thyroid hormone replacement, or with nonthyroidal illnesses.4,12 Due to high sensitivity of the assay, serum TSH values in overt hyperthyroidism are readily distinguished from serum TSH values in euthyroidism.13 Now, the current focus has changed from establishing more sensitive assays to distinguishing between overt thyrotoxicosis and euthyroidism to focusing on the appropriate upper limit of normal for serum TSH. Much controversy surrounds this debate, and we only mention this to raise awareness of upcoming challenges that face clinicians. The majority of laboratories have used the upper limit of normal values of 4.5–5.0 mU/L. If the upper limit of normal for TSH is lowered to values of 2.5 or 3.0 mU/L, as proposed by some national organizations, the number of patients diagnosed with subclinical hypothyroidism will substantially increase.14,15 With the background of TSH assays reviewed, we can focus on the physiological principals of TSH testing. Measurement of serum TSH is the most sensitive and specific indicator of the biologic effects of tissue concentration of active thyroid hormone, namely T3, assuming steady-state conditions and an intact pituitary and hypothalamus. TSH is an indirect but more accurate and more sensitive measure of thyroid function, whereas serum FT4 serves as a measure of T4 secretory activity by the thyroid gland. Thus, these two tests in conjunction provide complementary information regarding the normality of thyroid gland T4 production and biological

4. Laboratory Diagnosis of Thyroid Disease

Hypothalamus TRH +

−

Anterior Pituitary

T3 and T4

TSH

+

Thyroid

−

TRH: Thyrotropin-releasing hormone TSH: Thyroid stimulating hormone T4: Thyroxine T3: Triiodothyronine

Figure 4.1. Hypothalamic-pituitary-thyroid axis with negative-feedback pathway

action.4 The reason is due to the negative log-linear relationship between serum FT4 and TSH. Simply stated, very small changes in serum FT4 result in very large reciprocal changes in serum TSH.12 (See Figure 4.1 for negative-feedback diagram.) Low TSH is seen in suspected hyperthyroidism, and high TSH is seen in suspected hypothyroidism. However, it is known that the TSH level alone cannot be trusted in the setting of acute illness (physical or mental) or hypothalamic-pituitary disease. As stated, TSH level is an indirect measure of thyroid function. Therefore, it should be emphasized that the diagnosis of thyroid disease will require measurement of peripheral thyroid hormones when the screening serum TSH level is abnormal.

Appropriate Use of Serum Thyroid-Stimulating Hormone The following are appropriate uses of measurement of serum TSH: 1. Screening for primary thyroid disease or exclusion of thyroid disease. 2. Monitoring during maintenance therapy of primary hypothyroidism.

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3. Monitoring thyroid hormone suppressive therapy in differentiated thyroid cancer. (In most cases of differentiated thyroid cancer, suppressive T4 therapy is needed; the goal is achievement of low normal or undetectable TSH.) 4. For differential diagnosis of primary from secondary hypothyroidism (of pituitary origin) when peripheral thyroid hormones are low, serum TSH is also low, and the patient is clinically hypothyroid. The following are conditions for which serum TSH measurement without measurement of peripheral thyroid hormone levels is not helpful: 1. Screening thyroid function in hypothalamic or pituitary disorders. 2. Screening thyroid function in hospitalized patients with acute psychotic or nonthyroidal illnesses. 3. Screening thyroid function in patients receiving acute dopamine or glucocorticoid therapy. 4. Monitoring thyroid status during transitional phases of treatment for hyper- or hypothyroidism.4

Free Thyroxine For the diagnosis of thyroid disease, the “free hormone” hypothesis is the accepted appropriate measure.16–18 This in essence means that the free, or non-protein-bound, form of the hormone is what is available for uptake into the cells and interaction with nuclear receptors. Only about 0.02% of T4 is unbound. The majority is bound hormone, mostly to TBG, which is not readily available to the cells and serves as a circulating storage pool.16 Because FT4 is not affected by alterations in TBG or other thyroid hormone-binding proteins, FT4 is a better indicator of thyroid hormone function than TT4. Certain drugs, illnesses, and physiologic conditions are known to affect binding protein concentrations or alter the binding of proteins to their free hormones. Thus, the free and total hormone concentrations may not be concordant, necessitating the need for measurement of free hormone concentrations. FT4 is elevated in hyperthyroidism and low in hypothyroidism. There are four main tests that have been used to determine the FT4 levels: equilibrium dialysis, “direct” free hormone measurements, calculated

26

FTI, and calculated levels of total thyroid hormone to TBG.19 TBG also can be directly measured, but this is rarely needed. However, none of these assays measure FT4 directly. Another difficult challenge of these assays is performance without bias despite large variations in the concentrations and affinities of serum T4-binding proteins in the population. Marked improvements to the performance of FT4 assays have been seen19 since the first attempt in 1965. In addition to these improvements, many approaches have been done to measure FT4 due to the effect of quantitative and qualitative variations in thyroid hormone-binding proteins on TT4 and for that matter TT3.1 However, this binding protein dependence interferes with the diagnostic accuracy of free hormone methods subject to these interferences. Currently, the two most common FT4 assays are dialysis and ultrafiltration. Of these two, equilibrium dialysis is the gold standard. Equilibrium dialysis is occasionally needed when the FT4 level with routine measurements does not fit the clinical picture. The difficulty is that equilibrium dialysis methods are not readily available in routine laboratories. Equilibrium dialysis separates FT4 from serum proteins and from protein-bound T4 prior to the use of sensitive tandem mass spectrometry to measure FT4. Thus, this method is independent of TBG concentrations. The future of FT4 measurement lies in the field of advanced mass spectrometry for quantifying hormones.20

Free Triiodothyronine Triiodothyronine is protein bound 99.7% of the time. Therefore, only a minute amount is circulating free and biologically active.21 FT3, like FT4, is usually high in hyperthyroidism, low in hypothyroidism, and within normal limits in euthyroidism.1 In nonthyroidal illness, FT3 is low due to favored peripheral conversion of T4 to reverse T3 (rT3), which is biologically inactive.22 Free T3 is usually measured in the small subset of hyperthyroid patients in whom T3 toxicosis is suspected. In T3 toxicosis, only T3 is elevated but not T4. Usually, FT3 measurement is not required. In most laboratories, a reliable FT3 may not be available, and it is acceptable to obtain TT3. However, like TT4, TT3 is affected by abnormalities of binding proteins. FT3 may be required in

R. Schiefer and V. Fatourechi

euthyroid patients who have altered binding proteins.23 As with FT4, FT3 is measured with equilibrium dialysis, which makes it more technically demanding and expensive.1

Total Thyroid Hormones Thyroxine (T4) is the primary thyroid hormone produced by the thyroid gland, with essentially all of the T4 in circulation secreted by the thyroid gland. On the other hand, 80% of T3 is primarily produced enzymatically in nonthyroidal target tissues by 5′-monodeiodination of T4. Only 20% of T3 is produced by the thyroid.24 Most (99.98%) of T4 is bound to specific plasma proteins, prealbumin, transthyretin, TBG, and albumin.12, 16 In contrast, only 99.7% of T3 is bound to plasma proteins, with a higher affinity for albumin than T4 but 10-fold weaker protein binding than T4.12 Several methods for measuring total thyroid hormones have evolved since the 1950s. However, since the early 1970s, RIA methods have been employed to measure both TT4 and TT3. Due to the significant amount of bound T4 and T3 in the circulation, alterations in binding proteins result in changes in TT4 and TT3 concentrations. The TT4 levels are low in hypothyroidism and elevated in hyperthyroidism. The serum level of TT4 is not altered with age.4,6,12,17,25–32 The drawback of TT4 levels is that elevated or decreased values can occur in euthyroid patients due to alterations in binding proteins, presence of T4-antibody binding, increases in T4-albumin binding, effects of medications, or nonthyroidal illness.22,33–36 For instance, an increase in binding globulins is seen in pregnancy, estrogen and oral contraceptive use, acute hepatitis, porphyria, and congenital hereditary elevated TBG. On the other hand, TT4 is lower in nephrotic syndrome and androgen therapy and in use of glucocorticoids, some anticonvulsant drugs (e.g., dilantin), and high doses of aspirin. With the measurement of free hormones, all of these factors are eliminated.

Triiodothyronine-Resin Uptake The T3-resin uptake is used to calculate the FTI. The T3-resin uptake is determined by incubating a patient’s serum with radiolabeled T3. During the incubation, the radiolabeled T3 tracer occupies the thyroid hormone-binding sites that were

4. Laboratory Diagnosis of Thyroid Disease

27

empty. An insoluble resin, such as charcoal, is then added. Any remaining unbound radiolabeled T3 adsorbs to the resin, which is separated, then quantified. The T3-resin uptake is the percentage of radiolabeled T3 absorbed to the resin. The T3-resin uptake is inversely related to the available thyroid hormone-binding sites. The availability of unoccupied binding sites depends on binding protein levels, endogenous thyroid hormone production, and exogenous thyroid hormone replacement dosage.24 In the absence of binding abnormalities, it is high in hyperthyroidism and low in hypothyroidism. With availability of the FT4 test, most laboratories have abandoned the T3-resin uptake test.

nervosa, severe trauma and hemorrhagic shock, hepatic failure, postoperative state, sepsis, and burn patients. The mechanism is by 5′-monodeiodinase inhibition, which reduces T3 production by directing the pathway of T4 peripheral conversion to increased production of rT3 at the expense of T3.37 In nonthyroidal illness, the clearance of rT3 to diiodothyronine (T2) is also reduced, leading to increased levels of rT3, except in renal failure38,39 and AIDS.40,41 Reverse T3 is often measured in hospitalized patients to distinguish sick euthyroid from central hypothyroidism.

Free Thyroxine Index

Measurement of serum thyroglobulin (Tg) levels is usually limited for follow-up of thyroid cancer. Occasionally, it may be used to distinguish thyroiditis from exogenous factitious hyperthyroidism as Tg is high in the former and low in the latter. Tg is a large (molecular weight 660,000) glycoprotein prohormone of T3 and T4; it is secreted only by the thyroid gland. Tg is involved in thyroid hormone synthesis, storage, and release. T4 and T3 are synthesized from tyrosine residues of Tg. Tg is not biologically active but is rather the stored portion of thyroid hormone, which forms colloid in the follicular lumen. When the colloid is reabsorbed and proteolyzed, thyroid hormone is released.42 The amount of Tg released into circulation depends on several factors, including

Initially, the FTI methods, which combine two measurements (TT4 by immunoassay and T3 uptake), were accepted as proportional to actual FT4 status until it was recognized that these assays were also, although to a lesser degree, influenced by TBGs.19 The FTI is calculated as the TT4 multiplied by the percentage T3-resin uptake. This aspect is advantageous in that a potential binding protein abnormality is easily revealed since in changes of T4-binding capacity, T3-resin uptake and TT4 change in opposite directions. The disadvantages include not only the inaccurate results in cases of significant binding protein abnormalities but also the confusion surrounding the calculation. In our institution, we have replaced use of the FTI with measurement of FT4.

Reverse Triiodothyronine Measurement of rT3 is rarely needed except in complex cases of nonthyroidal illness. Its interpretation may be difficult requiring a specialist consultation. We do not recommend its routine use. Reverse T3 differs from T3 in the positions of the iodine atoms attached to the aromatic rings. Reverse T3 is formed from removal of an iodine atom of T4 via the 5′-monodeiodinase enzyme. As with T4 levels, rT3 is low in hypothyroidism and high in hyperthyroidism. Reverse T3 is thought to be metabolically inactive. Elevated levels of rT3 can been seen in cases of nonthyroidal illnesses, such as starvation, anorexia

Thyroglobulin

1. Thyroid cell mass.43–45 2. TSH receptor stimulation by TSH, human chorionic gonadotropin (hCG), or thyroidstimulating antibody (TSAb)/thyroid-stimulating immunoglobulin (TSI).46 3. Presence of inflammation in or physical damage to the thyroid (by biopsy, surgery, hemorrhage, radioactive iodine, external irradiation, or inflammation such as thyroiditis).1,45–47 As mentioned, Tg is routinely used as a tumor marker for monitoring patients with differentiated thyroid cancers.46 However, serum Tg measurement is technically challenging.48 The greatest limitation is interference by anti-Tg autoantibodies.49 Most laboratories use IMA methods in preference to RIAs due to the practical advantages of IMAs of shorter incubation times and automation.46,50 However, serum Tg concentration can be falsely lowered or

28

elevated by autoantibodies and heterophilic antibody interference.51,52 It is usually falsely low in IMA and high in RIA. In the presence of Tg antibodies, measurement of Tg is unreliable. Autoantibodies to Tg are present in 20% of patients with differentiated thyroid cancer, 10% of normal subjects, and the majority of patients with AITDs.53–56

Antithyroid Antibodies Antibodies to various thyroid autoantigens are frequently seen in AITD.57–59 Changes in thyroid function seen in AITD result from the stimulatory or blocking effects of autoantibodies on cell membrane receptors. Three principal antithyroid antibodies are discussed. Tg autoantibodies and their clinical usefulness have previously been detailed. Here, we describe the utility of measuring antibodies to thyroperoxidase (TPO) and antibodies to thyroid receptor (TR).

Thyroperoxidase Antibodies The TPO antibody (TPO-Ab) is the most sensitive lab test for detecting AITD.60 In the past, TPOAb was called antimicrosomal antibody. TPO-Ab elevation is usually the first abnormality to occur in the development of hypothyroidism due to Hashimoto thyroiditis. TPO-Ab occurs in more than 95% of patients with Hashimoto thyroiditis and approximately 85% of patients with GD.61 TPO-Ab detection early in pregnancy may predict those women at risk for postpartum thyroiditis.62 In addition to these clinical settings, TPO-Ab positivity is a risk factor for developing thyroid disease in patients treated with amiodarone, lithium, interleukin 2, or interferon alfa.63–67

Thyroid-Stimulating Hormone Receptor Autoantibodies Initially reported in 1956, TSH receptor autoantibodies (TRAbs) have had many different nomenclatures (TSI, TBII, TSH-R, and TRAb), but the international recommendation is TRAb. Measurement of TRAbs is not required in the routine evaluation of GD. However, there are some clinical situations for which the determination of TRAb presence seems helpful. TRAbs may aid in predicting the course of GD. High titers of TRAbs at the time of diagnosis predict the likelihood of

R. Schiefer and V. Fatourechi

persistent or recurrent disease if radioactive iodine ablation is not performed.68 Also, TRAbs can be used to predict fetal or neonatal GD in pregnant women with a previous history of AITD.69,70 An elevated TRAb titer in early pregnancy is a significant risk factor for fetal hyperthyroidism, whereas an elevated titer during the third trimester is used to evaluate for neonatal hyperthyroidism.69 In the case of questionable pretibial myxedema, measurement of TRAbs is very useful since this condition does not occur in the absence of these antibodies.

Clinical Applications of Thyroid Function Tests This section provides clinical scenarios and discussion of which laboratory tests are appropriate in select clinical situations. Tables 4.1 and 4.2 provide quick reference sources.

Screening The American Thyroid Association guidelines for detection of thyroid dysfunction recommends screening with serum TSH measurements in adults at the age of 35 and every 5 years thereafter. Routine screening in all newborns for hypothyroidism is already a widely accepted practice and is mandated by law. However, persons with risk factors for thyroid disease should be screened more frequently, especially when they present with nonspecific symptoms that could be attributed to thyroid disease. Persons at higher risk for thyroid disorders are those with the following: 1. Prior history of thyroid disorder (including goiter) or family history of thyroid disease. 2. Prior history of head or neck irradiation. 3. Prior surgery or radiotherapy affecting the thyroid gland. 4. Family history or personal history of autoimmune disorders, including, but not limited to, thyroid disease. 5. Infertility or anovulation. 6. Certain medications (lithium and iodinecontaining compounds: amiodarone, radiocontrast agents, expectorants containing potassium iodide, and kelp). 7. Postpartum women.

High N

Less than 0.1

Less than 0.1 Less than 0.3

Thyroiditis (subacute, silent, or postpartum) hyperthyroid Nodular toxic goiter Subclinical hyperthyroid

N

N N

N

High

High

N

N N

N

Less than 0.1

Less than 0.1

High

High

N

N N

N

High N

High

Low Low N High

2.0–3.5 pg/ mL

FT3

High

High

N

High Low

High

High N

High

Low Low N High

5.0–12.5 µg/dL

TT4

Thyroid RAI uptake

High

N

N

High Low

High

High N

High

Low Low N High

Low

Low

Low

N N

N

N V

Low

V/NI Low/NI N High

80–190 24-h uptake ng/dL

TT3

May be positive V

N

N N

Negative May be positive N

Positive Negative NI May be positive V

*< 9.0 IU/mL

TPO-Ab

Negative

Positive

N

N N

Negative + if due to Graves N

Negative

*< 16% is negative; ≥16% is positive NI Negative NI Positive

TRAb

Low

V

N

N N

N

NI NI

High

< 33 ng/mL; < 0.1 ng/mL (in athyrotic patients) NI V NI NI

Tg

High

High

N

Low High

Low

High N

High

*Male 27%– 37%; female 20%–37% Low Low N High

T3 R uptake

High

High

N

N N

N

High N

High

Low Low N High

1.5–3.0

FTI

Bold indicates essential tests suggestive of that particular condition. +, positive; FT3, free triiodothyronine; FT4, free thyroxine; FTI, free thyroxine index; N, normal; NI, not indicated; RAI uptake, radioactive iodine uptake; Rx, therapy; Tg, thyroglobulin; TPO-Ab, thyroid peroxidase antibodies; TRAb, thyroid receptor antibodies; T3 R uptake, triiodothyronine resin uptake; TSH, thyroid-stimulating hormone; TT3, total triiodothyronine; TT4, total thyroxine; V, variable. * These are Mayo laboratory normal values. For TRAb and T3 R uptake, different scales and indexes may be used in different laboratories.

Normal on oral contraceptives Normal on estrogen Rx Normal on androgen therapy Normal on iodine or contrast Graves hyperthyroid and iodine or contrast Exogenous hyperthyroid

High

High Low or N High Less than 0.1

Primary hypothyroid Secondary hypothyroid Subclinical hypothyroid Graves hyperthyroid

Low Low N High

0.3–5.2 mIU/L 0.8–1.8 ng/ dL

FT4

Normal

TSH

Table 4.1. Thyroid function tests in different conditions.

4. Laboratory Diagnosis of Thyroid Disease 29

30

R. Schiefer and V. Fatourechi

Table 4.2. Suggested initial tests to order when different thyroid conditions are suspected. TSH

FT4

T3

RAI uptake

TPO-Ab

TRAb

Thyroid scan

Screening for thyroid disease Hypothyroid suspected

Yes Yes

* *

— —

— —

— —

— —

Hyperthyroid suspected

Yes

*

#

Yes Yes

Yes Yes

— —

— —

Yes, in some cases — —

Yes, in some cases

Pituitary problem suspected High possibility of thyroid disease Follow-up hypothyroid Rx with thyroxine Follow hyperthyroidism on antithyroidal medications

Yes, if hyperthyroid biochemically — —

— Yes, to establish etiology —

— —

Yes

—

—

—

—

—

—

Yes

Yes

—

—

—

—

—

FT4, free thyroxine; RAI uptake, radioactive iodine uptake; Rx, therapy; T3, triiodothyronine; TPO-Ab, thyroid peroxidase antibodies; TRAb, thyroid receptor antibodies; TSH, thyroid-stimulating hormone; —, not indicated. *Yes, if TSH abnormal. #Yes, if TSH abnormal and FT4 normal.

In addition to these personal and family risk factors for thyroid disease, abnormalities in some routinely obtained laboratory values can suggest thyroid dysfunction. These include hypercholesterolemia, hyponatremia, anemia, elevated creatinine phosphokinase, lactate dehydrogenase elevation, alkaline phosphatase elevation, hypercalcemia, and elevated hepatic transaminases. These abnormalities may prompt screening for thyroid dysfunction, especially if they are new and persistent.71 Due to the improved sensitivity of TSH assays, TSH measurement is recognized as the better screening test for detecting thyroid dysfunction than FT4 determination.71 If TSH is within the normal reference range, no further thyroid tests are required. However, as mentioned, TSH level is an indirect measurement of thyroid function. FT4 should be checked when the serum TSH is abnormal. High TSH and low FT4 levels are characteristic of hypothyroidism. Low TSH and high FT4 levels are characteristic of hyperthyroidism. There are certain situations for which TSH cannot be used as a reliable test to evaluate thyroid function. TSH measurement can be misleading in persons with pituitary or hypothalamic disorders. In the presence of suspected pituitary or hypothalamic disorder, a FT4 level should be used to evaluate thyroid function. Also, TSH level is unreliable in the setting of nonthyroidal illnesses, including

acute physical or mental illnesses, certain drugs, and physiologic conditions. In the presence of certain medications, TSH levels may be discordant. For example, dopamine and glucocorticoids can suppress TSH secretion. Examples of physiologic conditions that alter TSH are discussed in following sections. In addition, serum TSH values can be misleading during transition periods that occur in the early phase of treating hyperthyroidism or hypothyroidism and after changes are made in the dosage of thyroid hormone replacement. There is a lag period from 6 to 9 weeks before the pituitary secretion of TSH reequilibrates to the new thyroid hormone status.72 These transition periods can also be seen following thyroiditis of any type.

Suspicion of Hypothyroidism Levels of TSH and FT4 should be checked in patients presenting with clinical symptoms of hypothyroidism. If TSH is elevated and FT4 is low, the diagnosis of hypothyroidism is made. However, a subset of patients falls in the category of having subclinical hypothyroidism. Most often, these patients are asymptomatic. In the Whickham study, the prevalence of subclinical hypothyroidism was 8%.73 Subclinical hypothyroidism refers to mildly elevated serum

4. Laboratory Diagnosis of Thyroid Disease

TSH and normal levels of serum T4 in the absence of other causes of elevated TSH. Usually, subclinical hypothyroidism is due to an underlying AITD or inadequate thyroid hormone replacement in treated hypothyroidism. TPO-Ab would reveal an AITD with the likelihood of progressing to overt hypothyroidism. Different etiologies of subclinical hypothyroidism include prior treatment for hyperthyroidism, prior neck radiation, medication effects (cytokines, iodine, lithium, and amiodarone), and the hypothyroid phase of thyroiditis.74 Treatment of subclinical hypothyroidism is controversial. No controversy exists for treating patients with TSH levels greater than 10 mIU/L. For patients with TSH levels between 5 and 10 mIU/L, observation or treatment is recommended on an individualized basis.74

Suspicion of Hyperthyroidism Levels of TSH and FT4 should be checked in patients with suspected hyperthyroidism. If TSH is suppressed and FT4 is high, then the diagnosis of hyperthyroidism is made. If TSH is suppressed but FT4 is normal, then FT3 needs to be checked to evaluate for T3 toxicosis, for which only T3 is elevated in the setting of suppressed TSH. Although the third-generation TSH assays are able to differentiate completely suppressed, undetectable TSH values characteristic of thyrotoxicosis from suppressed but detectable TSH results seen in patients with mild hyperthyroidism, on thyroid hormone replacement, or with nonthyroidal illnesses4,12, the peripheral thyroid hormone levels are helpful in determining the degree of biochemical hyperthyroidism. Once the diagnosis is made by biochemical evidence, then the etiology of the hyperthyroidism must be determined. The clinical scenario and physical exam can help direct the physician toward the etiology of the hyperthyroidism but at times can be misleading. In GD, patients usually present with a diffuse goiter and ophthalmopathy. If the patient has a nodular goiter, then a toxic multinodular goiter (MNG) should be considered. In thyroiditis, the symptoms may be preceded by a recent viral illness with a painful neck, or individuals may be clinically asymptomatic, depending on the type of thyroiditis. Recent exposure to iodine-containing contrast dye also needs to be investigated. A 24-h thyroid

31

radioiodine uptake is frequently necessary to confirm the diagnosis of Graves hyperthyroidism and exclude other etiologies. If a toxic MNG is considered, then thyroid radioiodine uptake and scan should be performed if the physical exam findings are not helpful in differentiating these two disorders. Thyroid radioiodine uptake entails an oral administration of either iodine 123 or iodine 131 followed by a 6-h or a 24-h determination of radioactivity over the thyroid. The normal range of radioactivity is inversely proportional to dietary iodine intake. Therefore, the reference range is lower in the United States, an iodine-repleted region, as compared to relative iodine-deficient areas, such as western European countries. If the uptake is high or inappropriately normal in the setting of suppressed TSH, GD and toxic MNG can be considered. If the uptake is low in the setting of thyrotoxicosis, the differential diagnoses include thyroiditis, exogenous thyroid hormone, or iodinemediated thyrotoxicosis. If the physical exam is not optimal for differentiating GD from toxic MNG, thyroid ultrasound can be used to evaluate for the heterogeneity and increased vascularity that is seen in GD as compared to nodularity seen in MNG. Radionuclide thyroid scan helps to differentiate between diffuse uptake seen in GD and asymmetric uptake seen in toxic MNG. The treatment for GD includes surgery, radioactive iodine ablation, and antithyroidal medications. Each of these treatments has advantages and disadvantages. However, radioactive iodine ablation is most frequently used in the United States. On the other hand, treatment for toxic MNG includes surgery or radioactive iodine. The dose of radioactive iodine used to treat toxic MNG is higher than the doses required in ablating GD. Antithyroidal medications are not used to treat toxic MNG. Regarding thyroiditis, the treatment is aimed at alleviating symptoms of hyperthyroidism. βBlockers are used to slow the heart rate, decrease tremors, and decrease peripheral conversion of T4 to T3. Rarely, antithyroidal medications are used. The clinical course consists of a few weeks of hyperthyroidism followed by an equally long period of hypothyroidism, with a subsequent recovery phase in most cases.

32

Suspicion of Hypothalamic-Pituitary Problem For the measurement of TSH to be reliable, an intact hypothalamus and pituitary are essential. If a hypothalamic-pituitary disorder is suspected, an FT4 level is needed to evaluate thyroid function. TSH levels are misleading in this case, and thyroid function must be followed by FT4 level measurement. If FT4 levels are low, then thyroid hormone replacement is required. The dose of thyroid hormone should be adjusted based on the patient’s symptomatology, and the FT4 goal should be within the reference range for that population.

Suspicion of Autoimmune Disease It is well known that a person with one autoimmune disorder is more prone to develop another autoimmune process. This association should be kept in mind when thyroid disease is suspected in a person with known autoimmune disorder or with a strong family history of autoimmunity. In this case, checking TPO-Ab in addition to TSH is reasonable. Although the TSH level may well be within the normal range, a positive TPO-Ab level can be the first abnormality to appear in the progression to hypothyroidism. It has been estimated that positive TPO-Ab patients in the setting of elevated TSH can progress to overt hypothyroidism at a rate of 5% per year. Measurement of antibodies is only for diagnosis and is not needed for follow-up of therapy for hypothyroidism due to Hashimoto thyroiditis.

Pregnancy During pregnancy, estrogen production increases progressively. This increase in estrogen production leads to an increase in thyroid-binding globulin concentration with levels at two to three times the prepregnancy level by 20 weeks of gestation.75 Since the majority of TT4 and TT3 are protein bound, then the levels of TT4 and TT3 also rise, shifting the reference range for TT4 and TT3 to 1.5 times the nonpregnant level by 16 weeks of gestation.62 All of these changes in the first trimester are associated with a decrease in serum TSH. Subnormal serum TSH can be found in

R. Schiefer and V. Fatourechi

approximately 20% of normal pregnancies.75 The subnormal TSH is attributed to the thyroid-stimulating activity of hCG, which is structurally similar to the TSH molecule.76 FT4 measurement is more reliable in pregnancy. During the first trimester of pregnancy, lower levels of FT4 are noted, and lower levels of TSH are physiologic. Increased thyroid hormone replacement up to 30%–40% can be required in pregnant women who are already on thyroid hormone replacement for hypothyroidism.75 In patients on T4 therapy, the TSH level should be checked each trimester and more frequently if a dose change is required. Screening all pregnant women for TSH and TPO-Abs in the first trimester is now recommended by some (but not all) national societies due to recent reports that suggest compromised neuropsychological development in the offspring of women with elevated TSH and positive TPO-Abs.77,78 As mentioned elsewhere, high TPO-Ab levels during the first trimester are a risk factor for postpartum thyroiditis.

Imaging Studies Among the several imaging modalities that provide clinically useful anatomic information about the thyroid gland, sonography is the most commonly used technique.

Sonography Ultrasound provides a graphic representation of the regional thyroid anatomy. Sonography has high resolution with the ability to detect nodules greater than 3 mm in diameter. Features of nodules, such as cystic regions, nodular margins, echo pattern, internal consistency, and calcifications, can be demonstrated.79 Ultrasonography is able to differentiate multiple nodules when only one nodule is clinically palpable.80 In a majority of patients, ultrasound has replaced isotope scanning due largely to its higher resolution, noninvasiveness, lower cost, lack of radioisotope administration, and shorter time to complete. Ultrasound can be performed in a matter of minutes instead of hours. Ultrasound is also used to guide fine-needle aspiration (FNA) biopsies of nonpalpable thyroid nodules.

4. Laboratory Diagnosis of Thyroid Disease

Isotope Scan The thyroid isotope scan received much attention in the past as an aid in the differential diagnosis of thyroid lesions. Before the advent of FNA biopsy, “cold nodules” on thyroid isotope scan were selected for surgery. However, the specificity of this approach for thyroid cancer was low since the majority of cold nodules were benign. The two isotopes most commonly used are iodine 123 (123I) and technetium 99 [99 mTc] pertechnetate, the latter being preferable because of lower cost and greater availability. However, isotope imaging is no longer needed for the majority of thyroid nodules. For evaluation of a thyroid nodule, serum TSH concentration should be measured. If serum TSH is suppressed, FNA biopsy may not be needed, and a hyperfunctioning nodule may be confirmed by isotope scanning. The likelihood of thyroid malignancy is extremely low if the scan demonstrates a hyperfunctioning nodule. In addition to evaluation of thyroid nodules, a thyroid isotope scan is still used in the hyperthyroid patient to differentiate GD versus MNG versus thyroiditis. Also, a thyroid isotope scan is used in follow-up of thyroid cancer patients to detect iodine uptake after thyroidectomy.

33

situations based on clinical presentation, sonographic characteristics, and risk factors.

Other Imaging Modalities Magnetic resonance imaging (MRI) and computed tomography (CT) may be used to evaluate thyroid regional anatomy in a few incidences. MRI and CT are helpful in evaluating substernal extension of goiters. In addition, MRI and magnetic resonance angiography are helpful in cases of large malignant thyroid lesions and goiters to assess the relationship of the mass to vascular structures in that region.82 CT may be useful in certain cases of thyroid goiter and invasive malignant nodules prior to surgery to evaluate for tracheal invasion. However, we do not advocate MRI or CT for routine evaluation of thyroid nodules.

Conclusion The judicious use of thyroid function studies, imaging techniques, and pathology should enable the clinician to render accurate diagnoses and manage therapeutic decisions regarding the thyroid precisely.

Positron Emission Tomographic Scan 18 F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) delineates areas of increased metabolic activity by producing a map of FDG uptake. FDG-PET imaging has emerged as an accepted modality for detection, staging, and surveillance of a wide variety of malignant tumors.81 Although FDG-PET is not indicated for evaluation of thyroid nodules, incidentally discovered FDG-PET-positive thyroid nodules may be found on scans performed for detection and staging of other malignant lesions. Approximately 3% of FDG-PET scans have incidentally detected abnormalities in the thyroid gland.82 Approximately 30% prove to be malignant.83 However, a variety of benign conditions, including AITD, inflammatory and granulomatous processes, benign follicular neoplasms, and Hurthle cell adenomas may be FDG-PET positive.84 Unilateral FDG-PET positivity warrants pursuit of a cytological diagnosis. FNA biopsy is not needed in the presence of known AITD with bilateral FDG-PET positivity.81 Thyroid FNA biopsy should be considered in other

References 1. Kane L, Gharib H. Thyroid testing a clinical approach. In: Braverman L, ed. Contemporary Endocrinology: Diseases of the Thyroid. 2nd ed. Boston: Humana Press; 2003:39–52. 2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988–1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87: 489–499. 3. Caldwell G, Gow S, Sweeting, V. A new strategy for thyroid function testing. Lancet 1985;325:1117– 1119. 4. Nicoloff J, Spencer C. Clinical review 12: the use and misuse of the sensitive thyrotropin assays. J Clin Endocrinol Metab 1990;71:553–558. 5. Franklyn J, Black E, Betteridge J, et al. Comparison of second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy, and those with nonthyroidal illness. J Clin Endocrinol Metab 1994;78: 1368–1371.

34 6. Spencer C, Takeuchi M, Kazarosyan M, et al. Interlaboratory/Intermethod differences in functional sensitivity of immunometric assays of thyrotropin (TSH) and impact on reliability of measurement of subnormal concentrations of TSH. Clin Chem 1995;41: 367–374. 7. Spencer C, Eigen A, Shen D, et al. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem 1987;33:1391–1396. 8. Franklyn J, Black E, Wilson E, et al. Limitations of a sensitive assay for TSH in the management of thyroid disease. Clin Chem 1988;34:991. 9. Ross D, Ardisson L, Meskell M. Measurement of thyrotropin in clinical and subclinical hyperthyroidism using a chemiluminescent assay. J Clin Endocrinol Metab 1989;69:684–688. 10. Parle J, Franklyn J, Cross K, et al. Prevalence and follow-up of abnormal TSH concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991;34:77–85. 11. Davies P, Franklyn J, Daykin J, et al. The significance of TSH values measured in a sensitive assay in the follow-up of hyperthyroid patients treated with radioiodine. J Clin Endocrinol Metab 1992;74:1189–1194. 12. Spencer C, LoPresti J, Patel A, et al. Applications of a new chemiluminescent thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990;70:453–460. 13. Spencer C, Takeuchi M, Kazarosyan M. Current status and performance goals for serum thyrotropin (TSH) assays. Clin Chem 1996;42:140–145. 14. Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:1. 15. Kratzsch J, Fiedler G, Leichtle A, et al. New reference intervals for thyrotropin and thyroid hormones based on National Academy of Clinical Biochemistry criteria and regular ultrasonography of the thyroid. Clin Chem 2005;51:1480. 16. Elkins R. The free hormone hypothesis and measurement of free hormones. Clin Chem 1992;38:1289– 1293. 17. Ekins R. Measurement of free hormones in blood [review]. Endocr Rev 1990;11:5–46. 18. Elkins R. The free hormone hypothesis and measurement of free hormones. Clin Chem 1993;39: 1343–1344. 19. Midgley J. Direct and indirect free thyroxine assay methods: theory and practice. Clin Chem 2001;47:1353–1363. 20. Soldin S, Soukhova N, Janicic N, et al. The measurement of free thyroxine by isotope dilution tandem mass spectrometry. Clin Chim Acta 2005;358:113–118.

R. Schiefer and V. Fatourechi 21. Stockigt J. Free thyroid hormone measurement. A critical appraisal. Endocrinol Metab Clin North Am 2001;30:265–289. 22. Chopra I, Hershman J, Pardridge W, et al. Thyroid function in nonthyroidal illnesses. Ann Intern Med 1983;98:946–957. 23. Hay I, Klee G. Thyroid dysfunction. Endocrinol Metab Clin North Am 1998;17:473–509. 24. Balock Z, Carayon P, Conte-Devolx B, et al. Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:3–126. 25. Spencer C, Nicoloff J. Serum TSH measurement—a 1990 status report. Thyroid Today 1990;13:1–4. 26. Klee G, Hay I. Biochemical thyroid function testing. Mayo Clin Proc 1994;69:469–470. 27. Stockigt J. Serum thyrotropin and thyroid hormone measurements and assessment of thyroid hormone transport. In: Braverman L, Utiger R, ed. Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text. 7th ed. Philadelphia: LippincottRaven; 1996:377–396. 28. Kaptein E. Clinical application of free thyroxine determinations. Clin Lab Med 1993;13:653–672. 29. Kaye T. Thyroid function tests. Application of newer methods. Postgrad Med 1993;94:81–82, 87–90. 30. Braverman L, Dawber N, Ingbar S. Observations concerning the binding of thyroid hormones in sera of normal subjects of varying ages. J Clin Invest 1966;45:1273–1279. 31. Kaiser F. Variability of response to thyroidreleasing hormone in normal elderly. Age Ageing 1987;16:345–354. 32. Sawin C, Chopra D, Azizi F, et al. The aging thyroid. Increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA 1979;242:247–250. 33. Hay I. Euthyroid hyperthyroxinemia. Mayo Clin Proc 1985;60:61–63. 34. Kaplan M. Interactions between drugs and thyroid hormone. Thyroid Today 1981;4:1–6. 35. Moses A, Lawlor J, Haddow J, et al. Familial euthyroid hyperthyroxinemia resulting from increased thyroxine binding to thyroxine-binding prealbumin. N Engl J Med 1982;306:966–969. 36. Tibaldi J, Surks M. Effects of nonthyroidal illness on thyroid function. Med Clin North Am 1985;69:899–911. 37. Chopra I. An assessment of daily turnover and significance of thyroidal secretion of reverse T3. J Clin Invest 1975;58:32–40. 38. Kaptein E, Feinstein E, Nicoloff J, et al. Serum reverse triiodothyronine and thyroxine kinetics in patients with chronic renal failure. J Clin Endocrinol Metab 1983;57:181–189.

4. Laboratory Diagnosis of Thyroid Disease 39. Kaptein E. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr Rev 1996;17:45–63. 40. LoPresti J, Fried J, Spencer C, et al. Unique alterations of thyroid hormone indices in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989;110:970–975. 41. Ricart-Engel W, Fernandez-Real J, Gonzalez-Hulx F, et al. The relation between thyroid function and nutritional status in HIV-infected patients. Clin Endocrinol 1996;44:53–58. 42. Torrens J, Burch H. Serum thyroglobulin measurement. Utility in clinical practice. Endocrinol Metab Clin North Am 2001;30:429–467. 43. Dralle H, Schwarzrock R, Lang W, et al. Comparison of histology and immunohistochemistry with thyroglobulin serum levels and radioiodine uptake in recurrences and metastases of differentiated thyroid carcinomas. Acta Endocrinol (Copenh) 1985;108:504–510. 44. Pineada J, Lee T, Robbins J. Treating metastatic thyroid cancer. Endocrinologist 1993;5:433–442. 45. Spencer C, Takeuchi M, Kazarosyna M. Current status and performance goals for serum thyroglobulin. Clin Chem 1996;42:164–173. 46. Refetoff S, Lever E. The value of serum thyroglobulin: measurement in clinical practice. JAMA 1983;250:2352–2357. 47. Spencer C, Wang C. Thyroglobulin measurement: techniques, clinical benefits and pitfalls. Endocrinol Metab Clin North Am 1996;24:841–864. 48. Schlumberger M, Van Herle A. Critical analysis of I-131 and I-125 thyroglobulin labels for radioimmunoassay use. J Clin Endocrinol Metab 1982;54:581–586. 49. Spencer C, Bergoglio L, Kazarosyan M, et al. Clinical impact of thyroglobulin (Tg) and Tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas. J Clin Endocrinol Metab 2005;90:5566–5575. 50. Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:3–126. 51. Preissner C, O’Kane D, Singh R, et al. Phantoms in the assay tube: heterophile antibody interferences in serum thyroglobulin assays. J Clin Endocrinol Metab 2003;88:3069–3074. 52. Spencer C. Challenges of thyroglobulin (Tg) measurement in the presence of Tg autoantibodies (TgAb). J Clin Endocrinol Metab 2004;89:3702–3704. 53. Spencer C, Takeuchi M, Kazarosyan M, et al. Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998;83:1121–1127.

35 54. Hollowell J, Staehling N, Hannon W, et al. Serum thyrotropin, thyroxine, and thyroid antibodies in the United States population: NHANES III. J Clin Endocrinol Metab 2002;87:489–499. 55. Chung J, Park Y, Kim T, et al. Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiated thyroid cancer after thyroid ablation. Clin Endocrinol (Oxf) 2002;57: 215–221. 56. Pacini F, Mariotti S, Formica N, et al. Thyroid autoantibodies in thyroid cancer: incidence and relationship with tumor outcome. Acta Endocrinol 1988;119:373–380. 57. Amino N, Hagen S, Yamada N, et al. Measurement of circulating thyroid microsomal antibodies by the tanned red cell haemagglutination technique: its usefulness in the diagnosis of autoimmune thyroid diseases. Clin Endocrinol 1976;5:115–125. 58. Cayzer I, Chalmers S, Doniach D, et al. An evaluation of two new haemagglutination tests for the rapid diagnosis of autoimmune thyroid diseases. J Clin Pathol 1978;31:1147–1151. 59. Chiovato L, Bassi P, Santini F, et al. Antibodies producing complement-mediated thyroid cytotoxicity in patients with atrophic or goitrous autoimmune thyroiditis. J Clin Endocrinol Metab 1993;77:1700–1705. 60. Mariotti S, Caturegli P, Piccolo P, et al. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990;71:661–669. 61. Feldt-Rasmussen. Anti-thyroid peroxidase antibodies in thyroid disorders and non-thyroid autoimmune diseases. Autoimmunity 1991;9:245–251. 62. Nohr S, Jorgensen A, Pedersen K, et al. Postpartum thyroid dysfunction in pregnant thyroid peroxidase antibody-positive women living in an area with mild to moderate iodine deficiency: is iodine supplementation safe? J Clin Endocrinol Metab 2000;85:3191–3198. 63. Martino E, Bartalena L, Bogazzi F, et al. The effects of amiodarone on the thyroid. Endocr Rev 2001;22:240–254. 64. Johnston A, Eagles J. Lithium-associated clinical hypothyroidism. Prevalence and risk factors. Br J Psychiatry 1999;175:336–339. 65. Bell T, Bansal A, Shorthouse C, et al. Low titre autoantibodies predict autoimmune disease during interferon alpha treatment of chronic hepatitis C. J Gastroenterol Hepatol 1999;14:419–422. 66. Ward D, Bing-You R. Autoimmune thyroid dysfunction induced by interferon-alfa treatment for chronic hepatitis C: screening and monitoring recommendations. Endocr Pract 2001;7:52–58. 67. Phan G, Attia P, Steinberg S, et al. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 2001;19:3477–3482.

36 68. Zakarija M, McKenzie J, Banovac K. Clinical significance of assay of thyroid-stimulating antibody in Graves’ disease. Ann Intern Med 1980;93: 28–32. 69. Laurberg P, Nygaard B, Glinoer D, et al. Guidelines for TSH-receptor antibody measurements in pregnancy: results of an evidence-based symposium organized by the European Thyroid Association. Eur J Endocrinol 1998;139:584–586. 70. Radetti G, Persani L, Cortelazzi D, et al. Transplacental passage of anti-thyroid autoantibodies in a pregnant woman with auto-immune thyroid disease. Prenat Diagn 1999;19:468–471. 71. Ladenson P, Singer P, Ain K, et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med 2000;160:1573–1575. 72. Uy H, Reasner C, Samuels M. Pattern of recovery of the hypothalamic-pituitary thyroid axis following radioactive iodine therapy in patients with Graves’ disease. Am J Med 1995;99:173–179. 73. Vanderpump M, Tunbridge W, French J, et al. The incidence of thyroid disorders in the community: a 20-year follow up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43:55–68. 74. Fatourechi V. Subclinical thyroid disease. Mayo Clin Proc 2001;76:413–417. 75. Glinoer D, De Nayer P, Bourdoux P, et al. Regulation of maternal thyroid function during pregnancy. J Clin Endocrinol Metab 1990;71:276–287. 76. Nissim M, Giorda G, Ballabio M, et al. Maternal thyroid function in early and late pregnancy. Horm Res 1991;36:196–202.

R. Schiefer and V. Fatourechi 77. Pop V, De Vries E, Van Baar A, et al. Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol Metab 1995;80:3561–3566. 78. Haddow J, Palomaki G, Allan W, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549–555. 79. Marqusee E, Benson CB, Frates MC, et al. Usefulness of ultrasonography in the management of nodular thyroid disease. Ann Intern Med 2000;133:696–700. 80. Tan, GH, Gharib H. Thyroid incidentalomas: management approaches to non-palpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 1997;126:226–231. 81. Chen YK, Chen YL, Cheng RH, Yeh CL, Lee CC, Hsu CH. The significance of FDG uptake in bilateral thyroid glands. Nucl Med Commun 2007;28: 117–122. 82. Karantanis D, Bogsrud TV, Wiseman GA, et al. Clinical significance of diffusely increased 18FFDG uptake in the thyroid gland. J Nucl Med 2007;48:896–901. 83. Kim TY, Kim WB, Ryu JS, Gong G, Hong SJ, Shong YK.18F-Fluorodeoxyglucose uptake in thyroid from positron emission tomogram (PET) for evaluation in cancer patients: high prevalence of malignancy in thyroid PET incidentaloma. Laryngoscope 2005;115:1074–1078. 84. Higgins CB, Auffermann W. MR Imaging of thyroid and parathyroid glands: a review of current status. AJR Am J Roentgenol 1988;151:1095–1106.

5 Thyroglossal Duct Cysts Lisa M. Reid

Editorial Perspective The evaluation of cysts on the neck requires an appreciation of the embryological development of this region. Differentiating thryoglossal duct cysts from branchial and bronchogenic cysts is based predominantly on clinical criteria; increasingly, however, imaging studies are being utilized in evaluating these lesions. Although thyroglossal duct cysts are characteristically observed in

Introduction There are several congenital lesions that develop in the neck, with the etiology primarily determined by their position. In the midneck, the most commonly encountered lesion is a thyroglossal duct cyst (TGDC). Although seen more commonly in children, these can present at any age. They are created from failed involution of the tract formed by the thyroid as it begins its descent from the base of the tongue to its final position in the lower neck.

the pediatric population, they may also present in adults as infected cysts, sinus tracts, or rarely as malignancies. It is essential that clinicians be certain that these cysts are distinguished from ectopic thyroid tissue, which on occasion may be the only functioning thyroid tissue present. Knowledge of the presentation, complications, and issues regarding surgical excision of these lesions is essential for endocrinologists, dermatologists, and head and neck surgeons.

bone forms on either side of the tract after the downward migration of the thyroid tissue. When the cells of the tract do not involute, a TGDC can develop at the site. These become apparent when there is an infection from an upper respiratory illness or a fistula to the skin develops.

Presentation Cysts can present as an asymptomatic swelling in the midline of the neck or as an infected neck mass in the setting of an upper respiratory infection (Figure 5.1).

Embryology The thyroid tissue develops in the third brachial pouch in the foramen cecum. During the fourth week of gestation, it descends in the midline of the neck via a tract, the thyroglossal duct, that usually resolves by the sixth week of gestation. The hyoid

Diagnosis Most cysts can be diagnosed based on clinical history.1 The lesions move upward with swallowing and with tongue protrusion. This may not occur if

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Figure 5.1. Three-year-old boy with midline neck mass

there has been complete involution of embryonic thyroid remnants. Anatomic location is important in making a clinical diagnosis as there are several other cystic lesions that arise in the neck of children. Bronchogenic cysts are characteristically in a suprasternal position, and branchial cysts are located laterally. The location of the TGDC in the midline or just off center is usually diagnostic along with the provocative maneuvers mentioned. It is important to differentiate a TGDC from a thyroid lesion, for which the treatment is completely different. An ultrasound can help in defining normal anatomic position of the thyroid. Many surgeons believe preoperative ultrasound is important in preventing hypothyroidism postoperatively, from inadvertent removal of the patient’s only thyroid tissue. Less commonly, a malignancy, usually thyroid cancer, can be found in the tract.

Figure 5.2. Computed tomographic scan showing classic position of thyroglossal duct cyst in midline of neck

Radiology Radiologic imaging is often used to support the clinical diagnosis. The diagnostic modalities include ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and thyroid scans2 (Figures 5.2–5.5). These are not routinely indicated. An ultrasound will reveal a cystic structure in close approximation to the hyoid bone. The lesion is usually above or may be within the strap muscles. The ultrasound can also rule out ectopic thyroid as the source of the lesion.3 Ultrasound is painless, cheaper than other modalities, and avoids radiation exposure.

Figure 5.3. Computed tomographic scans showing thyroglossal duct cyst slightly off midline with proximity to hyoid bone

5. Thyroglossal Duct Cysts

39

Treatment The primary treatment for a TGDC is surgical excision. Surgical treatment should be delayed until infected cysts have been adequately treated with antibiotics. Resection is recommended to prevent infection and rare cases of malignancy. The surgical technique has evolved as the understanding of the embryology of these cysts has been elucidated.4 This has dramatically reduced the recurrence rates after surgery to between 0% and 8%.4,5 The surgical method now used is named after Walter Sistrunk of the Mayo Clinic after his landmark 1920 article.6

History

Figure 5.4. Computed tomographic scans showing thyroglossal duct cyst slightly off midline with proximity to hyoid bone

Initial treatment of TGDCs involved incision and drainage, which led to recurrence rates of 50%. Schlange was then able to reduce this rate to 20% by excising the central portion of the hyoid bone along with the cyst. Sistrunk developed the surgical procedure still used today.6 This has reduced the recurrence rates to between 0% and 8%.7,8 In addition to taking the central portion of the hyoid bone, he also recommended taking out a core of tissue 1/8 inch radius from the hyoid bone to the foramen cecum.

Preoperative Preparation As with any surgery, the best outcomes are in patients who are suitable for surgery. In older patients with comordities such as hypertension or diabetes, these conditions should be controlled prior to surgery. As mentioned, infected cysts should be treated with antibiotics prior to surgical excision. The possibility that this midline mass is the patient’s only site of thyroid tissue should be assessed preoperatively with either an ultrasound or radionuclide uptake scan. Figure 5.5. Magnetic resonance imaging appearance of thyroglossal duct cyst

Anesthesia Surgery is usually done using general anesthesia.

As CT scanning has become more commonplace, it is now often used to support the diagnosis of a TGDC. It gives more anatomic detail regarding the extent of the lesion and its relation to surrounding structures. MRI has also been used in aiding diagnosis. Thyroid scans are used to determine the location of normal thyroid tissue.

Surgical Procedure A small incision is made in the upper neck above the cyst. The cyst is circumferentially dissected up to the level of the hyoid bone, which is then cut on either side. A core of tissue up to the level of the foramen cecum is then excised (Figures 5.6A–C). The wound is closed with absorbable sutures.

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Hyoid bone Sternohyoid m.

Cyst

Cyst Hyoid bone

A

Incision site

B

Hyoid bone Mylohyoid m.

Tract

Cyst

C Figure 5.6. Surgical steps in the Sistrunk procedure for removal of thyroglossal duct cyst (TGDC). (A) Site of surgical incision. (B) Dissection of cyst. (C) Removal of central portion of hyoid bone and tract to base of tongue. (Illustration courtesy of Paul Rogers, CMI.)

5. Thyroglossal Duct Cysts

Postoperative Care Surgery is generally a same-day procedure. Eating and talking are not restricted, although a sore throat for a few days postoperatively can be expected.

Complications Reported complications for TGDC surgery include hematoma, seroma, wound infection, abscess, recurrence, paralysis of the hypoglossal nerve, and hypothyroidism.4,7 Most of these can be avoided with meticulous dissection, attention to anatomy, and complete preoperative preparation.

Recurrence With use of the Sistrunk procedure, recurrence is rare but may present as a recurrent midline neck cyst. Reoperation is necessary to remove residual ductal tissue.8–10

Special Considerations Most thyrogossal duct cysts are benign, but malignancies have been found in resection specimens. The occurrence of malignancy in a TGDC is only 1%. The most commonly found malignancy is thyroid cancer,11,12 with papillary thyroid cancer the most frequently encountered type. There is controversy regarding the necessary extent of surgery for the finding of thyroid cancer. Some authors believe excision of the duct is adequate, while others argue that a total thyroidectomy and nodal dissection for clinical nodes is necessary for adequate oncologic care.13–15 Squamous cell cancer has also been found in TGDC.16 These are rarely recognized on preoperative imaging but can be diagnosed with fine-needle aspiration (FNA).17 Acknowledgments. Illustrations by Paul Rogers, CMI, medical illustrator, Cooper Hospital Department of Surgery. Radiologic images courtesy of the collection of Joshua Brody, DO, Cooper Hospital Department of Radiology.

References 1. Dedivitis R, Camargo D, Peixoto G. Thyroglossal duct: a review of 55 cases. J Am Coll Surg 2002;194: 274–277.

41 2. Tunkel D, Domenech E. Radioisotope scanning of the thyroid gland prior to thyroglossal duct cyst excision. Arch Otolaryngol Head Neck Surg 1998;124: 597–599. 3. Gupta P, Maddalozzo J. Preoperative sonography in presumed thyroglossal duct cysts. Arch Otolaryngol Head Neck Surg 2001;127:200–202. 4. Wagner G, Medina J. Excision of thyroglossal duct cyst: the Sistrunk procedure. Oper Tech Otolaryngol 2004;15:220–223. 5. Allard RH. The thyroglossal cyst. Head Neck Surg 1982;5:134–146. 6. Sistrunk WE. The surgical treatment of cysts of the thyroglossal tract. Ann Surg 1920;71:121–126. 7. Maddalozzo J, Venkatesan TK, Gupta P. Complications associated with the Sistrunk procedure. Laryngoscope 2001;111:119–123. 8. Hewitt K, Pysher T, Park A. Management of thyroglossal duct cysts after failed Sistrunk procedure. Laryngoscope 2007;117:756–758. 9. Kim M, Pawel B, Isaacson G. Central neck dissection for the treatment of recurrent thyroglossal duct cysts in childhood. Otolaryngol Head Neck Surg 1999;121:543–547. 10. Marianowski R, Ait Amer JL, Morisseau-Durand MP, Manach Y, Rassi S. Risk factors for thyroglossal duct remnants after Sistrunk procedure in a pediatric population. Int J Pediatr Otolaryngol 2003;67:19– 23. 11. Heshmati HM, Fatourechi V, Van Heerden JA, et al. Thyroglossal duct carcinoma. Report of 12 cases. Mayo Clin Proc 1997;72:315–319. 12. Kim W, Souillard R, Brandwein M, et al. Follicular adenoma in a juxtathyroidal thyroglossal duct cyst with papillary carcinoma in the adjacent thyroid gland. Am J Otolaryngol 2005;26:348–350. 13. Pribitkin E, Friedman O. Papillary carcinoma in a thyroglossal duct remnant. Arch Otolaryngol Head Neck Surg 2002;128:461–462. 14. Myssiorek D. Total thyroidectomy is overly aggressive treatment for papillary carcinoma in a thyroglossal duct cyst. Arch Otolaryngol Head Neck Surg 2002;128;464. 15. Persky M. Total thyroidectomy as appropriate treatment for papillary carcinoma in a thyroglossal duct cyst. Arch Otolaryngol Head Neck Surg 2002;128:463. 16. Hanna E. Squamous cell carcinoma in a thyroglossal duct cyst (TGDC). Clinical presentation, diagnosis, and management. Am J Otolaryngol 1996;17: 353–357. 17. Branstetter B, Weissman J, Kennedy T, et al. The CT appearance of thyroglossal duct carcinoma. AJNR Am J Neuroradiol 2000;21:1547–1550.

6 Thyroid Cancer and the Skin Robert A. Somer and Nati Lerman

Editorial Perspective “Doctor, is this lump anything important?” This is a question that dermatologists face on a daily basis. Most frequently, lesions are usually benign cysts, nevi, or adnexal tumors. On occasion, however, they may be cutaneous metastases. Although such lesions usually occur in patients with a known history of malignancy, they may be the initial presentation of a cancer. Thyroid cancers may metastasize to the skin; when routine histology is equivocal, immunohistochemical stains may allow for a precise diagnosis. Although the

Introduction Benign thyroid diseases are remarkably prevalent, yet thyroid malignancies are relatively uncommon. It was estimated that 33,550 people in the United States (8,070 men and 25,480 women) would be diagnosed with cancer of the thyroid in 2007. Of those, 1,530 cases would die of the disease.1 The median age at diagnosis was 47 years of age for 2000–2004, with an incidence rate of 8.5 per 100,000 people per year. The incidence is higher in women compared to men, with a ratio of three to one. Of note, on January 1, 2004, in the United States, there were approximately 366,466 men and women who had a history of thyroid carcinoma.1 These data contrast to skin cancer, for which more than a million cases of basal cell and squamous cell carcinomas of the skin were expected2 to be newly diagnosed in 2007. Although the incidence

presentation of cutaneous metastases is associated with advanced disease, the dermatologist, has the unique opportunity to recognize rare syndromes associated with thyroid malignancies before they develop. By diagnosing these entities, notably multiple endocrine neoplasia type 2, the Carney complex, and Cowden syndrome, clinicians may be able to prevent thyroid tumors from developing in these patients and their kin. This chapter details the spectrum of thyroid cancers, their propensity to metastasize, the association with fine-needle aspiration, and the genetic syndromes associated with thyroid tumors.

of thyroid carcinoma has increased by over 250% since 1950, the 5-year survival from thyroid malignancies has improved from 93% to 97%.2 Treatment for thyroid cancer, either surgical or pharmacological, almost invariably results in hypothyroidism, which, if untreated, can result in several dermatological phenomena described widely elsewhere. Hyperthyroidism, with its characteristic skin manifestations, can result from excessive intake of thyroid hormone, which is usually prescribed for patients with thyroid cancer at some point during their course. Thyroid cancer itself has few dermatological manifestations: It sometimes metastasizes to the skin and may be spread through the fine-needle aspiration (FNA) needle track. Certainly, development of cutaneous metastasis is typically associated with metastasis to other distant tissues and eventual death of the patient from overwhelming malignancy.3

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Dermatologic manifestations of thyroid malignancies are unusual given the relative rarity of thyroid cancer coupled with its indolent nature. Cutaneous metastases from thyroid malignancies are extremely rare. In a minority of cases, thyroid malignancies are known to be associated with several rare genetic syndromes that also have dermatologic aspects and characteristics.

R.A. Somer and N. Lerman Table 6.1. Thyroid carcinoma in the United States, 1973–1991. Subtype Papillary Follicular Medullary Anaplastic Other (i.e., lymphoma)

Percent 76 17 3 2 3

Source: From ref. 16.

Etiology It has been clearly documented that external radiation to the neck causes thyroid malignancies, whether there had been thymic radiation in childhood, radiation treatments for acne as a teenager, treatment of other malignancies such as Hodgkin disease or head and neck cancers, and of course external exposures to environmental radiation such as the Chernobyl accident.4–10 Although ionizing radiation is a known risk factor for developing thyroid carcinoma, other risks have not been clearly established. Given that the incidence of thyroid malignancies is higher in women than men,1 it has been hypothesized that hormonal factors may be involved in increasing the risk of developing a thyroid malignancy. Furthermore, cigarette smoking and increased alcohol consumption may be inversely associated with thyroid cancer risk.11,12 Unfortunately, a recent prospective cohort study provided little support for associations with hormonal factors, smoking, or alcohol consumption between each of these factors and the risk of developing thyroid cancer.13 A rare entity, thyroid lymphoma, may be associated with autoimmune thyroiditis or Hashimoto thyroiditis.14 Follicular thyroid cancers are more common in countries that have diets that are low in iodine. Furthermore, a diet low in iodine may also increase the rate of papillary thyroid cancer when the person is exposed to radioactivity.15 In the United States, iodine is added to table salt and other foods to avert this risk. Finally, approximately 20% of medullary thyroid carcinomas result from a genetic disorder discussed separately in this chapter.

Classification and Prognosis The most common thyroid cancers are papillary, mixed papillary, and follicular carcinomas

(see Table 6.1).16 Several studies documented that mixed tumors that contain papillary features have the same natural history and prognosis as papillary thyroid cancer without follicular characteristics.17 Papillary and follicular carcinomas of the thyroid are often grouped together as “differentiated” thyroid carcinomas and account for approximately 90% of all thyroid malignancies. Whereas papillary thyroid carcinoma has an excellent prognosis with only 5% of patients having recurrence with distant metastasis, pure follicular carcinoma spreads hematogenously, with up to 20% of patients developing distant metastases.18 A variant of follicular neoplasms of the thyroid is the Hürthle cell subtype. Although all lesions were once considered to be malignant, only approximately one-third show evidence of invasive growth and metastasis. In fact, many Hürthle cell tumors are benign and may potentially be treated conservatively.19–21 Medullary thyroid carcinoma (MTC) accounts for a minority of all thyroid cancers and arises from the parafollicular or C cells that produce calcitonin. It is hereditary in approximately 25% of cases.22 Although differentiated thyroid cancers occur more commonly in women than in men, MTC has an approximately equal sex distribution. Because medullary thyroid cancers arise from the parafollicular C cells that produce calcitonin, serum calcitonin levels may be used as a tumor marker for following patients with this malignancy.23 This is especially important: As opposed to the differentiated tumors, MTCs do not concentrate iodine, thus iodine 131 thyroid scans may be ineffective for monitoring this subtype of thyroid cancer. In some cases, however, MTC has been shown to concentrate iodine.24 Finally, anaplastic thyroid carcinoma is extremely aggressive and one of the most lethal forms of thyroid malignancy, with a median survival of approximately 5 months. Most patients present with a rapidly enlarging thyroid

6. Thyroid Cancer and the Skin

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Table 6.2. Tumor, Node, Metastasis (TNM) definitions. Primary tumor (T) Note: All categories may be subdivided into (a) solitary tumor or (b) multifocal tumor (the largest determines the classification). TX: Primary tumor cannot be assessed T0: No evidence of primary tumor T1: Tumor 2 cm or less in greatest dimension, limited to the thyroid T2: Tumor larger than 2 cm but 4 cm or smaller in greatest dimension, limited to the thyroid T3: Tumor larger than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues) T4a: Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve T4b: Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels All anaplastic carcinomas are considered T4 tumors: T4a: Intrathyroidal anaplastic carcinoma—surgically resectable T4b: Extrathyroidal anaplastic carcinoma—surgically unresectable Regional lymph nodes (N) Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes. NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Regional lymph node metastasis N1a: Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes) N1b: Metastasis to unilateral or bilateral cervical or superior mediastinal lymph nodes Distant metastases (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis

Figure 6.1. Metastatic papillary thyroid carcinoma to skin (×2). (Courtesy of Hong Wu, MD PhD, Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA.)

papillary (Figures 6.1 and 6.2) or follicular, medullary, and anaplastic carcinoma, as outlined in Table 6.3.26 Prognosis is established based on pathologic subtype and clinical staging, with more advanced disease having a worse prognosis.

Cutaneous Metastases from Thyroid Malignancies Cutaneous metastases from nondermatologic malignancies are an uncommon finding in dermatology.27 Only a minority of patients with such malignancies develop metastases to the skin. In a study that

Source: Adapted from ref. 26.

mass, and 50% have distant disease at the time of diagnosis. The vast majority of patients present with regional lymph node involvement. There is no effective treatment known.25 Other malignancies of the thyroid account for 2% or less and may include lymphoma, sarcoma, and metastasis from other sites of malignancy. Because of the unique differences in the biology and behavior of thyroid malignancies, establishing a prognosis needs to be performed on an individual basis and may be difficult. To achieve uniformity in assessing results of therapy, a clinical staging system is used utilizing the tumor, node, metastasis (TNM) method (Table 6.2).26 Furthermore, separate stage groupings are recommended for

Figure 6.2. Metastatic papillary thyroid carcinoma to the skin (×40). (Courtesy of Hong Wu, MD PhD, Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA.)

46

R.A. Somer and N. Lerman

Table 6.3. Clinical staging of thyroid cancer. Papillary or follicular Stage I Stage II Stage III Stage IVa

Stage IVb Stage IVc

Younger than 45 years old Any T, any N, M0 Any T, any N, M1 n/a T1–3, N1a, M0 n/a T4a, N1a, M0 T1–4a, N1b, M0 n/a n/a

Older than 45 years old T1, N0, N0 T2, N0,M0 T3, N0, M0 T1–3, N1a, M0 T4a, N0, M0 T1–4a, N1b, M0 T4b, any N, M0 Any T, any N, M1

Medullary

Anaplastic*

T1, N0, M0 T2, N0, M0 T3, N0, M0 T4a, N0–1a, M0

T4a, any N, M0

T4b, any N, M0 Any T, any, N, M1

T4b, any N, M0 Any T, any N, M1

n/a: not applicable. *Note: All anaplastic carcinomas are considered stage IV. Source: From ref. 26.

included 3848 patients with metastatic carcinomas, only 343 (9%) had clinically recognized skin metastases during the course of their disease.28 Many different malignancies can give rise to cutaneous metastases, with the more common cancers, such as lung, colon, and breast, accounting for most cases.27,29 Cutaneous metastases usually represent progression of a known primary malignancy, but in the minority of cases they are the first presentation of an otherwise-occult disease. Cutaneous metastases from thyroid malignancies represent only a small fraction of all skin metastases28,29 and occur in a small minority of thyroid cancer cases. In a study of 731 patients with papillary thyroid cancer, 91 (12%) had metastases outside regional lymph nodes at some point in the course of their disease, but only 6, fewer than 1% of all patients with papillary carcinoma, had cutaneous metastases.30 In another series of 1800 patients with papillary cancer treated at one institution, distant metastases developed in 100 (6%), and in only 1 patient (0.06%) was the skin the presenting site of distant spread.31 It is apparent from these studies that papillary thyroid cancer rarely metastasizes to the skin. Some authors have suggested that follicular carcinoma may have a greater preponderance for cutaneous metastasis than papillary carcinoma.32 In a literature review from 1997, Dahl and colleagues summarized 43 reports of cutaneous metastases from thyroid malignancies between 1964 and 1997. Of the 43 reports, 16 were papillary, 11 follicular, 6 medullary, and 6 anaplastic, and the remaining 4 were not characterized.33 These data might support the notion that follicular carcinoma has a greater preponderance to metastasize to the skin

since follicular carcinoma accounted for a much higher proportion of the cutaneous metastases than expected from its relative incidence among all cases of thyroid cancer. Despite the generally good prognosis of the welldifferentiated thyroid carcinomas, it appears that development of cutaneous metastases portends a deterioration in the disease course and is frequently associated with widely disseminated disease.33,34 Thus, it can be hypothesized that thyroid tumors that obtain the ability to metastasize to the skin possess or acquire a more aggressive biologic profile. Some clinical, pathological, biochemical, and molecular features found in cutaneous metastases support the notion of a biologically more aggressive tumor. For example, Erickson et al. reported a series of 16 patients with well-differentiated thyroid carcinomas metastasizing to the skin. Most of the patients’ metastases had high-risk clinical features, such as large size, local invasion, or foci of anaplastic transformation.34 In 2 cases, the cutaneous metastases exhibited uncharacteristic cytoplasmic clearing that was not apparent in the original tumor, and a subset of the tumors contained the BRAF mutation, thought to be associated with a more aggressive clinical course. Loureiro et al. described a case in which the original tumor produced thyroglobulin, but the skin metastasis did not. Smit et al. detailed a case of metastatic thyroid carcinoma presenting with skin lesions that was found to have some novel cytogenetic abnormalities.35,36 Molecular abnormalities associated with particular clinical features have been described in many other types of cancer, and it remains to be seen if such abnormalities are also consistently found in thyroid cancer.

6. Thyroid Cancer and the Skin

47

The more aggressive variants of thyroid cancer— anaplastic and medullary—are responsible for a larger proportion of the cutaneous metastases reported in the literature than their incidence alone might suggest. As already mentioned, these variants accounted for 12 of the 43 cases (28%) compiled by Dahl et al., a far higher proportion than their share of all thyroid malignancies. This is not surprising since these tumors tend to metastasize much more readily than the well-differentiated types and carry a much poorer prognosis.33 Cutaneous metastases from thyroid cancer tend to localize in the head and neck region or in the upper chest, although isolated reports exist of more distant locations, even as far as the fingers or toes.33,34,37 They usually appear as a firm subcutaneous nodule, either flesh colored or violaceous, sometimes ulcerated,38 and sometimes highly vascularized.39 In the vast majority of cases, a prior history of thyroid cancer suggests the diagnosis, but only in a minority of cases are cutaneous metastases the first presentation of the disease.34,40–56 In these cases, the disease may present a diagnostic challenge. Metastases from follicular cell malignancies can usually be diagnosed by their characteristic histological appearance and by staining for thyroglobulin and thyroid transcription factor 1 (TTF-1).57,58 Medullary carcinomas are readily identified by neuroendocrine markers, including synaptophysin, chromogranin, and CD56, in addition to the specific tumor marker of this entity, calcitonin. They may be difficult to distinguish from other neuroendocrine malignancies (see Table 6.4). Hürthle cell carcinomas and anaplastic thyroid carcinomas can present a challenge to the pathologist as they can sometimes be difficult to differentiate from

other high-grade malignancies, such as melanoma, neuroendocrine carcinomas, large cell lymphomas, and other anaplastic carcinomas.37 In summary, cutaneous metastases from thyroid carcinomas are an uncommon event, usually suggestive of a poor prognosis and limited survival. Rarely, metastases to skin are the first presentation of an occult thyroid cancer and should be in the differential diagnostic workup for a skin nodule of an unknown primary neoplasm.

Dissemination Through the Biopsy Needle Track Fine-needle aspiration biopsy (FNAB) plays a central role in the diagnostic workup of thyroid nodules59 and has been established as reliable, accurate, and safe, with false-negative and false-positive rates of 4% and 2%, respectively.60 Dissemination of tumor cells through the biopsy track is a known, albeit rare, complication of needle biopsies in several types of cancer, among them breast cancer61,62] and various abdominal malignancies.63 Considering the numbers of thyroid FNAB procedures performed since it came into widespread use, there have been only a few case reports suggesting needle track dissemination as a mechanism for recurrence.64–67 In most of them, the tumors involved were follicular or papillary, although one report described the recurrence of Hürthle cell carcinoma along a surgical drain track.68 There have been no reports of high-grade thyroid malignancies, such as anaplastic and medullary carcinomas, recurring in the biopsy tracks, but given the aggressive nature of these tumors and their fast progression, local or distant recurrences

Table 6.4. Characteristic immunohistochemical stains for thyroid malignancies.

Follicular thyroid Papillary thyroid Medullary thyroid Anaplastic thyroid Lymphoma Melanoma Neuroendocrine Ca

Thyroglobulin

TTF-1

Calcitonin

+ + − +/− − − −

+ + +/− +/− − − +/−

− − + − − − −

Synaptophysin/ chromogranin/ CD 56 − − +/− − − − +

CD45LCA

CK19

− − − − + − −

+/− + +/− − − − −

TTF-1, thyroid transcription factor 1; +, positive; -, negative; +/-, positive or negative or equivocal.

HMB45, S100 melan A + + − − − + −

− − − − − + −

48

are expected to occur in the majority of cases, so that needle-track seeding is not usually a concern. This is not the case with the lower-grade thyroid malignancies, the vast majority of which are quite indolent. In these otherwise-curable malignancies, needle-track dissemination is a possible mechanism of recurrence. In the reported cases, suspicious lesions appeared several (2–11) years after the biopsy was performed, or the drain placed in the case of the Hürthle cell carcinoma. They are described mostly as pea-size subdermal hard nodules appearing along the track of the biopsy or drain. All recurrences were treated with surgical reexcision, and at the time of publication were without relapse. It is believed that using the proper technique and a high-gauge needle can reduce the risk of needle track dissemination. Guidelines call for the use of a 23-gauge or smaller needle and for the release of suction prior to needle withdrawal.69 Due to the dearth of data, it remains unclear whether other factors, related to the mechanics of the procedure or to the biology of the tumor involved, affect the risk of developing needle track recurrence. In conclusion, FNAB remains a cornerstone of the diagnostic workup for thyroid nodules. With proper technique, the risk of needle track dissemination is very low. However, clinicians should be aware of the rare possibility of this complication since early diagnosis and complete reexcision likely provide a high probability of cure.

Genetic Syndromes Associated with Thyroid Cancer and Skin Abnormalities Multiple Endocrine Neoplasia Type 2 Multiple endocrine neoplasia type 2 (MEN 2A, MEN 2B, and familial medullary thyroid carcinoma [FMTC]) is a group of rare autosomal dominant disorders, all caused by mutations in the RET proto-oncogene. The three subtypes are characterized by mutations in different parts of the gene.70 The hallmark of these syndromes is the development of MTC, which has a penetrance of 100%. Patients with MEN 2 usually develop multifocal, bilateral tumors at a young age. Family members of patients with one of the MEN 2 syndromes

R.A. Somer and N. Lerman

must be referred for genetic counseling and can be diagnosed as a carrier by analysis of the RET gene mutations in peripheral blood. Carriers of the mutations should undergo prophylactic surgery to prevent the development of MTC.71 The MEN 2A disorder includes MTC in all patients, pheochromocytomas in about half, and parathyroid hyperplasia in a quarter of patients.71 Cutaneous macular (or lichen) amyloidosis can occur in association with MEN 2A.72 It can also occur sporadically or as a familial disease. In the setting of MEN 2A, cutaneous amyloidosis is usually localized to the interscapular area. Lesions consist of pruritic, scaly, lichenoid papules with hyperpigmentation. Histopathologic features are similar to isolated lichen amyloidosis,73 with altered keratin as the source of the amyloid deposits. Several reports described a clear genotypephenotype correlation between a mutation in codon 634 of the RET gene and the development of cutaneous lichen amyloidosis,74,75 but it has also been described in association with other RET mutations.76 In MEN 2B, all patients develop MTC, usually in infancy. MTC in MEN 2B appears to follow a particularly aggressive course, with early metastatic spread. About half the patients also develop pheochromocytomas. All affected individuals develop ganglioneuromas or neurofibromas, particularly in the mucosa of the digestive tract, conjunctiva, lips, and tongue.39,71,77

Carney Complex (NAME Syndrome, LAMB Syndrome) Carney complex is a rare disease, with about 500 patients reported worldwide.78 The genetic abnormality underlying the syndrome is one of several known inactivation mutations in the PRKAR1A gene.79 The term NAME syndrome is an acronym for nevi, atrial myxoma, myxoid neurofibomas, ephelides. LAMB syndrome is an acronym for lentignes, atrial myxoma, mucocutaneous myxomas, and blue nevi. The syndrome is characterized by a combination of various types of dermatological abnormalities, myxomas, and multiple endocrine neoplastic lesions. Typical skin findings include multiple lentigenes, which usually become apparent around puberty but may be present at birth. These lentigenes

6. Thyroid Cancer and the Skin

are small, brown-to-black macules usually located around the upper and lower lips, on the eyelids, ears, and the genital area. Other pigmented lesions, including blue and other nevi, café-au-lait spots and depigmented lesions may also be present at birth or appear later.80 Skin myxomas can occur anywhere, but certain sites are affected more frequently, notably the eyelid, external ear canal, breast, and nipples. Myxomas may also be found in the oropharynx, the female genital tract, and the pelvis. Other tumors that should not be confused with myxomas may also occur in Carney complex, including trichofolliculoepitheliomas, lipomas, collagenomas, angiomas, and others.78 The characteristic thyroid lesions found in 75% of individuals with Carney complex are multiple follicular cystic adenomas, which progress to carcinoma in 10%.81 In addition to skin and thyroid lesions, patients may also have adrenal hyperplasia, acromegaly, testicular and breast adenomas, multiple schwannomas, and more.78

Cowden Syndrome (Multiple Hamartoma Syndrome) Cowden syndrome was named after Rachel Cowden, a patient with multiple gingival and cutaneous hamartomas and bilateral breast cancer. First described in 1963 in Cowden and her family, the syndrome is characterized by multiple benign and malignant lesions in tissues derived from all three germ layers: the endoderm, mesoderm, and ectoderm.82 Patients develop lesions in the skin and mucous membranes, breasts, thyroid, digestive and genitourinary tracts, and central nervous system.83,84 The syndrome shows a dominant inheritance pattern, with a variable penetrance. Various germ line mutations in the PTEN gene have been found in more than 80% of patients.83 The PTEN gene product plays a central role in regulating the PIK3/Akt pathway. Mutations inactivating PTEN allow constitutive and unregulated activation of this signaling pathway, resulting in uncontrolled proliferation.85 Germ line mutations in the PTEN gene have also been found in other hamartomatous syndromes involving the skin (but not the thyroid),86 such as BannayanRiley-Ruvalcaba syndrome and Proteus syndrome. These have all been grouped under the heading PTEN hamartoma tumor syndrome.83 Interestingly,

49

somatic mutations in the PTEN gene, with resultant overactivity of the PIK3/Akt pathway, have also been found in a variety of malignancies, including gliomas; melanoma; prostate cancer; and endometrial, renal, and breast malignancies, and it may serve as a target for novel therapeutics.87,88 Patients with Cowden syndrome present with a variety of mucocutaneous findings, which are the most constant features of the disease and are present in nearly 100% of patients.84,86 Trichilemmomas, the characteristic lesions, are usually the presenting feature. They typically appear in the late teens or twenties as multiple skin-colored or yellowish 1- to 4-mm smooth and keratotic facial papules clustered around the eyes, mouth, ears, and nose; these papules may coalesce and then resemble common warts. Acral verrucous keratotic papules, most commonly located on the dorsal aspect of hands, forearms, and feet, are another prominent finding.89,90 Translucent keratotic papules with central depression are found over palms and soles. Mucosal lesions consisting of small whitish or pink papules may involve any mucosal surface but appear mostly on the gingival, palatal, and labial mucosa. They often coalesce, imparting a cobblestone appearance to the oral cavity. A scrotal tongue is another frequent finding.84 Additional cutaneous manifestations in patients with Cowden syndrome include lipomas and angiomas, xanthomas, dermal fibromas, skin tags, café-au-lait spots, and neuromas.91 Squamous cell carcinoma of the skin, lips, and tongue; basal cell carcinoma; malignant melanoma; Merkel cell carcinoma; and trichilemmomal carcinoma have also been reported in patients with Cowden syndrome.84 Thyroid involvement is common in Cowden syndrome, with as many as 60% developing benign thyroid lesions, such as multinodular goiter, and follicular adenomas.92 The risk for thyroid cancer (typically follicular, but occasionally papillary) is approximately 10%.83,84,86 Thyroglossal duct cysts and thyroiditis have been described.84 In addition to thyroid malignancies, breast cancer is a major risk in Cowden syndrome and may develop in 30%–50% of affected individuals.93 Given the high risk of malignancies developing at a young age, patients with a PTEN hamartomatous syndrome should be screened for breast, colon, and thyroid malignancies starting in their early twenties or thirties.83

50

R.A. Somer and N. Lerman

Table 6.5. Selected characteristics of genetic syndromes involving the thyroid. Gene involved MEN 2

RET protooncogene

Carney complex

PRKAR 1A

Cowden’s syndrome

PTEN in 80% of patients

Thyroid manifestations

Other findings

Medullary carcinoma in all patients

• Pheochromocytomas • Parathyroid hyperplasia • Ganglioneuromas/neurofibromas • Cutaneous amyloidosis Multiple follicular cystic • Multiple lentigenes around lips, eyes, genitals adenomas, with • Multiple myxomas of skin, genital tract, oropharynx progression to carcinoma • Lipomas, angiomas, trichofolliculoepitheliomas, schwannomas in 10% of patients • Other endocrine neoplastic lesions: acromegaly, adrenal hyperplasia, testicular and breast adenomas Multiple adenomas or • Multiple verrucous keratotic papules on face, hands, and feet multinodular goiter; • Multiple mucosal papular lesions carcinoma in 10% • Lipomas, angiomas, xanthomas, dermal fibromas, skin tags, of patients café-au-lait spots, and neuromas • Increased incidence of various cutaneous malignancies • Breast cancer in 30%–50% • Increased risk of colon cancer

Conclusion In summary, cutaneous manifestations of thyroid malignancies are relatively uncommon in the general population given the low incidence of thyroid malignancies and favorable biology of the most common thyroid malignancies. Dermatological manifestations of thyroid cancers may be seen as metastasis to the skin and spread through the FNA needle track. It is important to be aware of the genetic syndromes that have characteristic dermatologic manifestations that may be associated with increased risk of developing thyroid cancers and other malignancies (Table 6.5). It is the prompt diagnosis of these syndromes by dermatologists that may ultimately lead to improved surveillance and therapeutic options for this patient population who are at risk for thyroid cancer.

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51 a retrospective study of 4020 patients. J Am Acad Dermatol 1993;29:228–236. 29. Saryia D, Ruth K, Adams-McDonnell, et al. Clinicopathologic correlation of cutaneous metastases. Arch Dermatol 2007;143:613–620. 30. Hoie J, Stenwig AE, Kullmann G, Lindegaard M. Distant metastases in papillary thyroid cancer: a review of 91 patients. Cancer 1988;6l:1–6. 31. Dinneen SF, Vallimaki MJ, Bergstralh EJ, et al. Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during five decades. J Clin Endocrinol Metab 1995;80:2041–2045. 32. Koller EA, Tourtelot JB, Pak HS, et al. Papillary and follicular thyroid carcinoma metastatic to the skin: a case report and review of the literature. Thyroid, 1998;8:1045–1050. 33. Dahl PR, Brodland DG, Goellner JR, Hay ID. Thyroid carcinoma metastatic to the skin: a cutaneous manifestation of a widely disseminated malignancy. J Am Acad Dermatol 1997;36:531–537. 34. Erickson LA, Jin L, Nakamura N, et al. Clinicopathologic features and BRAFV600E mutation analysis in cutaneous metastases from well-differentiated thyroid carcinomas. Cancer 2007;109:1965– 971. 35. Loureiro MM, Leite VH, Boavida JM, et al. An unusual case of papillary carcinoma of the thyroid with cutaneous and breast metastases only. Eur J Endocrinol 1997;137:267–269. 36. Smit JW, Van Zelderen-Bhola S, Merx R, et al. A novel chromosomal translocation t(3;5)(q12;p15.3) and loss of heterozygosity on chromosome 22 in a multifocal follicular variant of papillary thyroid carcinoma presenting with skin metastases. Clin Endocrinol 2001;55:543–548. 37. Alwaheeb S, Ghazarian D, Boerner SL, Asa SI. Cutaneous manifestations of thyroid cancer: a report of four cases and review of the literature. J Clin Pathol 2004;57:435–438. 38. Capezzone M, Giannasio P, DeSanctis D, et al. Skin metastases from anaplastic thyroid carcinoma. Thyroid 2006;16:513–514. 39. Burman KD, McKinley-Grant L. Dermatologic aspects of thyroid disease. Clin Dermatol 2006;24:247–255. 40. Brownstein MH, Helwig EB. Metastatic tumors of the skin. Cancer 1972;29:1298–1307. 41. Barr R, Dann F. Anaplasrlc thyroid carcinoma metastatic to skin. J Cutan Pathol 1974;1:201–206. 42. Auty RM. Dermal metastases from a follicular carcinoma of the thyroid. Arch Dermatol 1977;113:675– 676. 43. Hamilton D. Cutaneous metastases from a follicular thyroid carcinoma. J Dermatol Surg Oncol 1980;6:116–117.

52 44. Pitlik S, Kitzes R, Ben-Bassat M, et al. Thyroid carcinoma presenting as a solitary skin metastasis. Cutis 1983;31:532–536. 45. Horiguchi Y, Takahashi C, Imamura S. Cutaneous metastasis from papillary carcinoma of the thyroid gland: report of two cases. J Am Acad Dermatol 1984;10:988–992. 46. Bevilacqua G, Mariotti S, Castagna M, et al. Cutaneous metastasis of a radiation-associated thyroid medullary carcinoma. J Endocrinol Invest 1984;7:653–657. 47. Rico MJ, Penneys NS. Metastatic follicular carcinoma of the thyroid to the skin: a case confirmed by immunohistochemistry. J Cutan Pathol 1985;12:103– 105. 48. Orddfiez NG, Samaan NA. Medullary carcinoma of the thyroid metastatic to the skin: report of two cases. J Cutan Pathol 1987;14:251–254. 49. Doulre MS, Beylot C, Baquey A, et al. Cutaneous metasiasis from papillary carcinoma of the thyroid: a case confirmed by monoclonal antithyroglobulin antibody. Dermatologica 1988;177:241–243. 50. Paglidis NA, Sourla AD, Nikolaou NG, et al. Neglected cases of papillary and follicular thyroid carcinoma: occurrence of subcutaneous scalp metastases. Eur J Surg Oncol 1990;16:175–179. 51. Elgart GW, Patterson JW, Taylor R. Cutaneous metastasis from papillary carcinoma of the thyroid gland. J Am Acad Dermatol 1991;25:404–408. 52. Vives R, Valcayo A, Menendez E, et al. Follicular thyroid carcinoma metastatic to the skin [letter]. J Am Acad Dermatol 1992;27:276–277. 53. Caron P, Moreau-Cabarrot A, Gorguet B, et al. Cutaneous metastasis from follicular carcinoma of the thyroid gland. Thyroid 1993;3:235–237. 54. Toyota N, Asaga H, Hirokawa M, et al. A case of skin metastasis from follicular thyroid carcinoma. Dermatology 1994;188:69–71. 55. Quinn TR, Duncan LM, Zembowicz A. Cutaneous metastases of follicular thyroid carcinoma. A report of four cases and a review of the literature. Am J Dermatopathol 2005;27:306–312. 56. Avram AM, Gielczyk R, Su L, et al. Choroidal and skin metastases from papillary thyroid cancer: case and a review of the literature. J Clin Endocrinol Metab 2004;89:5303–5307. 57. Lau SK, Luthringer DJ, Eisen RN. Thyroid transcription factor-1: a review. Appl Immunohistochem Mol Morphol 2002;10:97–102. 58. Bejarano PA, Nikiforov YE, Swenson ES, et al. Thyroid transcription factor 1, thyroglobulin, cytokeratin 7, and cytokeratin 20 in thyroid neoplasms. Appl Immunohistochem Mol Morphol 2000;8:189–194. 59. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993;328:553–559.

R.A. Somer and N. Lerman 60. Agrawal S. Diagnostic accuracy and role of fine needle aspiration cytology in management of thyroid nodules. J Surg Oncol 1995;58:168–172. 61. Stolier A, Skinner J, Levine EA. Prospective study of seeding of the skin after core biopsy of the breast. Am J Surg 2000;180:104–107. 62. Thurfjell MG, Jansson T, Nordgren H, et al. Local breast cancer recurrence caused by mammographically guided puncture. Acta Radiol 2000;41:435– 440. 63. Smith EH. Complications of percutaneous abdominal fine needle biopsy: review. Radiology 1991;178:253– 258. 64. Naotaka U, Takako S, Tomoko I, et al. Needle tack dissemination of follicular thyroid carcinoma following fine-needle aspiration biopsy: report of a case. Surg Today 2007;37:34–37. 65. Hales MS, Hsu FS. Needle tract implantation of papillary carcinoma of the thyroid following aspiration biopsy. Acta Cytol 1990;34:801–304. 66. Karwowski JK, Nowels KW, McDougall IR, et al. Needle track seeding of papillary thyroid carcinoma from fine needle aspiration biopsy. A case report. Acta Cytol 2002;46:591–595. 67. Shogo S, Etsuo Y, Makito T, et al. Implantation metastasis of head and neck cancer after fine needle aspiration biopsy. Auris Nasus Larynx 2001;28;377– 380. 68. Chadwick DR, Harrison BJ, Manifold IHM. Solitary drain-site metastasis from Hurthle-cell carcinoma of the thyroid. Eur J Surg Oncol 2000;26:10. 69. Guidelines of the Papanicolaou Society of Cytopathology for the examination of fine-needle aspiration specimens from thyroid nodules. The Papanicolaou Society of Cytopathology Task Force on standards of practice. Mod Pathol 1996;9: 710–715. 70. Kouvaraki MA, Shapiro SE, Perrier ND. RET ProtoOncogene: a review and update of genotype–peenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid 2005;15:6. 71. Guillem JG, Wood WC, Moley JF. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 24:4642–4660. 72. Gagel RF, Levy ML, Donovan DT, et al. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med 1989;111(10):802–806. 73. El-Hajj Fuleihan G, Rubeiz N. Dermatologic manifestations of parathyroid-related disorders. Clin Dermatol 2006;24:281–288. 74. Ceccherini CR, Romei C, Barone V, et al. Identification of the Cys634®Tyr mutation of the RET

6. Thyroid Cancer and the Skin proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous amyloidosis. J Endocrinol Invest 1994;17:201–204. 75. Verga U, Fugazzola L, Cambiaghi S et al. Frequent association between MEN 2A and cutaneous lichen amyloidosis. Clin Endocrinol 2003;59:156–161. 76. Baykal C, Buyukbabani N, Boztepe H, et al. Multiple cutaneous neuromas and macular amyloidosis associated with medullary thyroid carcinoma. J Am Acad Dermatol 2007;56:S33–S37. 77. Holloway KB, Flowers FP. Multiple endocrine neoplasia 2B (MEN 2B)/MEN 3. Dermatol Clin 1995;13:99–103. 78. Boikos SA, Stratakis CA. Carney complex: the first 20 years. Curr Opin Oncol 2007;19:24–29. 79. Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 2001;86:4041– 4046. 80. Carney JA, Stratakis CA. Epitheliod blue nevus and psammomatous melanotic schwannoma: the unusual pigmented skin tumors of the Carney complex. Semin Diagn Pathol 1998;15:216–224. 81. Stratakis CA, Courcoutsakis NA, Abati A, et al. Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas (Carney complex). J Clin Endocrinol Metab 1997;82:2037–2043. 82. Lloyd KM 2nd, Dennis M. Cowden’s disease. A possible new symptom complex with multiple system involvement. Ann Intern Med 1963;58:136–142. 83. Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 2000;37:828–830.

53 84. Fistarol SK, Anliker MD, Itin PH. Cowden disease or multiple hamartoma syndrome—cutaneous clue to internal malignancy. Eur J Dermatol 2002;12:411–421. 85. Agrawal S, Eng C. Differential expression of novel naturally occurring splice variants of PTEN and their functional consequences in Cowden syndrome and sporadic breast cancer. Hum Mol Genet 2006;15:777–787. 86. Burgdorf WHC. Cancer-associated genodermatoses: a personal history. Exp Dermatol 2006;15:653–666. 87. Goswami A, Ranganathan P, Rangnekar VM. The phosphoinositide 3-kinase/Akt1/Par-4 axis: a cancer-selective therapeutic target. Cancer Res 2006;66:2889–2892. 88. Chow LML, Baker SJ. PTEN function in normal and neoplastic growth. Cancer Letters 2006;241: 184–196. 89. Weary PE, Gorlin RJ, Gentry WC, et al. Multiple hamartoma syndrome (Cowden’s disease). Arch Dermatol 1972;106:682–690. 90. Brownstein MH, Mehregan AH, Bikowski JB, et al. The dermatopathology of Cowden’s syndrome. Br J Dermatol 1979;100:667–673. 91. Schaffer V, Kamino H, Witkiewicz A, et al. Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome. Arch Dermatol 2006;142:625–632. 92. Lachlan KL, Lucassen AM, Bunyan DJ, et al. Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome represent one condition with variables expression and age-related penetrance: a clinical study of 42 individuals with PTEN mutations. J Med Genet 2007 May 25 [epub ahead of print]. 93. Schweitzer S, Hogge JP, Grimes M, Bear HD, et al. Cowden disease: a cutaneous marker for increased risk of breast cancer. Am J Roentgenol 1999;172:349–351.

7 Chromosomes, Genes, and the Thyroid Gland Analisa V. Halpern and Rhonda E. Schnur

Editorial Perspective As molecular genetics advances at breakneck speed, unraveling genetic mysteries via genomics, proteomics, and microarray analysis, we are at the cusp of the era of “personalized” medicine, by which knowledge of our unique genetic blueprint will allow us to anticipate, and hopefully obviate, a host of heritable diseases. The genetic aspects of thyroid diseases are manifest in all age groups, from the neonate with congenital hypothyroidism due to a newly defined mutation in thyroid hormonogenesis, to the adult who is genetically predisposed to autoimmune thyroid disease because of aberrations of autoregulatory genes. The recognition of thyroid disease is of paramount importance, especially in the neonatal period. A failure to diagnose these diseases will have a profoundly adverse effect on the growth and development of the child. It is essential that practitioners are cognizant of how common thyroid diseases are in patients with certain genetic syndromes. Addressing these issues

Introduction This chapter focuses on selected disorders caused by chromosome or single-gene changes that affect thyroid function. Most are detectable in the infant or young child but continue to have an impact on health throughout life. The elucidation of specific transcription factors that affect thyroid organogenesis and the biochemical pathways leading to thyroid hormone production and regulation within the thyroid gland are also contributing to

is essential for proper care. I recall seeing a patient with Down syndrome who was frequently treated for repeated bouts of secondarily infected nummular eczema. Recognizing that approximately one-third of patients with Down syndrome have thyroid disorders, a thyroid-stimulating hormone (TSH) level was checked. The patient was found to be hypothyroid; once she was placed on thyroid hormone, the xerotic skin that predisposed her to developing eczema resolved, and secondary infection was no longer an issue. This chapter offers current insights into the pathogenesis and dermatologic features of a host of chromosomal, mosaic, and inborn errors of metabolism that also affect the thyroid gland. When confronted with syndromal patients, thoughtful clinicians will entertain the possibility that there may be coexistent thyroid gland disorders and will research this by utilizing resources such as OMIM (the Online Mendelian Inheritance of Man database). It is a worthwhile endeavor to do so as maintaining a euthyroid state is crucial for optimal health.

a better understanding of mechanisms leading to congenital hypothyroidism (CH). Common chromosomal disorders and microdeletion syndromes that are associated with thyroid dysfunction are reviewed. Advances in the ability to detect subtle chromosome dosage abnormalities using the techniques of comparative genomic hybridization or microarray analysis (CGH/CMA) are likely to lead to the recognition of new genetic mechanisms for thyroid organogenesis and hormonal regulation.

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Syndromic and Nonsyndromic Forms of Congenital Hypothyroidism Congenital hypothyroidism (CH) is common, affecting 1 in 3000–4000 newborns. Newborn screening for CH is mandatory in all 50 US states, Canada, and the United Kingdom. There are seldom few physical variations at birth, but in about 5% of affected infants, usually those with more severe deficits, features such as large fontanels and widely split sutures, macroglossia, skin mottling, abdominal distention, and umbilical hernia may be seen.1 True macroglossia (Figure 7.1A) is usually readily distinguishable from the protruding tongue that accompanies disorders with oral hypotonia, including Down syndrome (DS) (Figure 7.1B). The majority of children with CH represent sporadic cases, with about 15% of cases hereditary; most of the latter category are caused by enzymatic

Figure 7.1. (A) True macroglossia. (B) Protruding tongue associated with oral hypotonia in Down syndrome

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deficiencies in thyroid hormonogenesis. In this group, most disorders are autosomal recessive conditions, with the exception of a thyroid hormone receptor defect, which is dominant. The most common inborn error of thyroid production is a deficiency of thyroid peroxidase.2,3 Additional hereditary deficiencies in thyroid hormonogenesis are caused by mutations of the thyroglobulin (Tg) gene, NIS (sodium iodide symporter), and DUOX2/THOX24 and DUOXA2.5 The SLC26A4 gene causes Pendred syndrome (goiter and deafness), a disorder of thyroid organification (discussed separately). Congenital hypothyroidism may be secondary to pituitary insufficiency or associated with clefting and other midline defects.6 It may also be associated with other multiple-malformation syndromes, particularly with cardiac malformations.7–14 In addition, premature infants may have a delay in the maturation of their hypothalamic pituitary axis, leading to insufficiency of thyroid-stimulating hormone (TSH). Repetition of newborn screening between 2 and 6 weeks of age has been suggested to detect hypothyroidism in preterm infants who may have had a normal first screen.15 Short-term treatment of these infants remains controversial. The largest group of patients with CH have thyroid “dysgenesis”: thyroid hypoplasia, aplasia, or ectopy. Ectopy is the most frequent malformation. The vast majority of patients in this group are sporadic cases, lacking a family history or obvious genetic cause. Traditionally, about 2% of these cases are thought to be familial,16 although at least one recent review suggested that up to 7.9% of thyroid dysgenesis cases may be familial.17 Since the disorder is so common, the search for factors that contribute to CH has been a major focus of investigation, beginning with several developmental genes that have directly been implicated in the rarer genetic forms of CH.3,18 Homozygous mutations in TSHR can cause nonsyndromic CH, and heterozygous mutations are found in some cases of subclinical hypothyroidism. For example, Camilot et al.19 studied 14 newborns with CH, 116 individuals with subclinical hypothyroidism, and 120 healthy controls for mutations in the TSH receptor gene. Among hypothyroid subjects, one patient was heterozygous for a novel missense variation, and two others were homozygous or heterozygous for P162A, a previously reported

7. Chromosomes, Genes, and the Thyroid Gland

mutation. In patients with subclinical hypothyroidism, only heterozygous substitutions were found, including several novel as well as previously published mutations (P162A, R109Q, L252P, and C41S). In general, mutations that would be predicted to be more deleterious were associated with more significant thyroid dysfunction. TTF-1 causes dominant CH and neurologic phenotypes associated with gene deletion; PAX-8 causes syndromic and nonsyndromic CH, and MCT8 is an X-linked gene that encodes a membrane thyroid hormone transporter. The MCT8-related phenotype, also known as the Allan-Herndon-Dudley syndrome, includes microcephaly and craniofacial variations, central hypotonia, peripheral hypertonicity, dystonia, nystagmus and disconjugate eye movements, and severe feeding problems and reflux, with the eventual development of spastic quadriplegia and severe developmental delay. Heterozygotes have only milder thyroid phenotypes without neurologic dysfunction.20 Males with MCT8 mutations have low levels of free thyroxine (T4), high free triiodothyronine (T3), and high TSH. The thyroid dysfunction is detectable in early infancy but not at birth. Thus, these patients could easily be missed in newborn screening. An interesting syndrome with dermatologic features, in addition to those intrinsically associated with CH, is the Bamforth Lazarus syndrome. This is an autosomal recessive condition characterized by CH due to thyroid agenesis or ectopy with the additional feature of spiky hair. The syndrome has been linked to mutations in TTF-2 (also known as TITF2, FKHL15, or FOXE1). TTF-2 is a member of the forkhead/winged helix domain protein family.21 This gene is expressed in the developing thyroid, palate, choanae, and Rathke’s pouch in mice, as well as in the human hair follicle, thyroid, and prepubertal testes.22,23 More variable features of the Bamforth Lazarus syndrome include choanal atresia and pharyngeal anomalies, including cleft palate. In the original Welsh family reported by Bamforth et al.,24 two affected brothers were later found to have a homozygous missense mutation, A65V, in TTF2, causing thyroid agenesis, hypoplastic bifid epiglottis, and bilateral choanal atresia.25 In another reported family, two affected siblings with homozygosity for S57N, another missense mutation within the conserved forkhead DNA-binding domain of TTF2, lacked choanal atresia, but had thyroid agen-

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esis, cleft palate, and spiky hair.26 More recently, a third individual with thyroid ectopy, but not agenesis, was homozygous for a TTF2 loss-of-function missense mutation (R102C).27 The patient also had a cleft palate, spiky hair, and bilateral choanal atresia. These reports suggest that TTF2 loss of function should particularly be considered in syndromic forms of either thyroid dysgenesis or ectopy. Investigators have studied whether polymorphisms within the TTF2/FOXE1 gene contribute to the risk for CH. Carré et al.28 studied the possible association of CH with a polymorphic polyalanine tract of 16 or 14 repeats within FOXE1. The authors found that FOXE1 alleles with 16 repeats had higher transcriptional activity than alleles with 14 repeats. The 14/14 genotype was associated with an increased risk of thyroid dysgenesis (odds ratio [OR] 2.59, 95% confidence interval [CI] 1.56–4.62, p = .0005), leading to the conclusion that the alanine repeat of FOXE1 may modulate the risk of CH, although it is not a diseasecausing mutation. However, other investigators, such as Santarpia et al.,29 concluded that the homozygous Ala14 polymorphism (Ala14/14) was less frequent in patients with CH than in controls. Carré et al.28 suggested that ethnicity-related deviations in allele frequency and differences in study design might account for the apparently discrepant results. Clearly, additional studies are needed. NKX2-5 is a homeobox gene that has also been implicated in thyroid dysgenesis (TD). Dentice et al.30 found three heterozygous NKX2-5 missense changes in four patients with TD. This gene also underlies cardiovascular malformations, including tetralogy of Fallot and atrial septal defects. A child with severe CH was associated with maternal isodisomy of chromosome 2p.31 The disomy created homozygosity for a thyroid peroxidase (TPO) mutation that was present in the child’s mother in heterozygous form but absent in the father. This case is only one example of potentially novel genetic mechanisms that can lead to CH as our screening methodology continues to evolve.

McCune-Albright Syndrome and Albright Hereditary Osteodystrophy McCune-Albright syndrome (MAS) is a sporadic disease classically defined as the triad of polyostotic fibrous dysplasia (Figure 7.2), café-au-lait (CAL)

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Figure 7.2. Polyostotic fibrous dysplasia

macules, and polyendocrinopathy, especially precocious puberty. Thyrotoxicosis, pituitary gigantism, and Cushing syndrome are also commonly associated, but virtually any hormone can be secreted in excess. Precocious puberty, particularly in girls with MAS, is due to autonomous ovarian function, independent of luteinizing hormone-releasing hormone (LHRH), luteinizing hormone (LH), or folliclestimulating hormone (FSH). Other MAS manifestations include hyperplastic adrenal nodules, pituitary or parathyroid adenoma and hyperplasia.32 MAS is caused by somatic mosaicism for an activating mutation in GNAS1. GNAS1 encodes the a-subunit of the trimeric guanosine triphosphatebinding protein that stimulates adenylate cyclase, which is involved in signal transduction from stimulated transmembrane receptors to effector proteins. The variability in MAS clinical features directly correlates with the tissue-to-tissue distribution of the mutation.33 Most MAS mutations involve the replacement of arginine by histidine at position 201 of the mature Gs a-protein.34 Because the mutation arises postzygotically, the disorder is

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not generally heritable. Molecular testing is available; however, blood studies may be normal, with the mutation detectable only in an affected tissue. Typical MAS CAL macules (Figure 7.3) are 0.5 to 20 cm, light brown/tan smooth patches that have an irregular “coast of Maine” border. This description is in contrast to the regular, nonjagged “coast of California” border of CAL macules seen in neurofibromatosis. CAL macules in MAS tend to occur on the forehead, nape of the neck, and buttocks and tend not to cross the midline. Thyroid dysfunction in MAS tends to present with a nodular or diffuse goiter, with or without hyperthyroidism.35 GNAS1-activating mutations within the thyroid gland result in local cyclic adenosine monophosphate (cAMP) overproduction. This in turn stimulates growth of thyrocytes and excess hormone secretion. A large study of 113 patients36 found that only 24% of MAS patients had the complete clinical triad, while 33% showed two signs, and 40% had one sign. The same authors found that a significant proportion of affected patients (46% overall) had a detectable GNAS1 mutation in blood. The yield increased to 90% when an affected tissue was studied (except for skin, where the yield was lower). Interestingly, even 33% of 39 cases of isolated peripheral precocious puberty had detectable GNAS1 mutations, leading the authors to conclude that partial forms of MAS may be more frequent than previously thought. Bhat et al.35 described a patient with polyostotic fibrous dysplasia and asymptomatic hyperthyroidism without CAL macules but with areas of vitiligo on her back and lower extremities. Serum laboratory

Figure 7.3. A typical café-au-lait spot in McCuneAlbright syndrome

7. Chromosomes, Genes, and the Thyroid Gland

values revealed an elevated T4 and depressed TSH with negative antithyroid antibody (ATA) tests. The patient received carbimazole and b-blockers and underwent a partial thyroid lobectomy. At 2-year follow-up, the patient remained euthyroid. Unlike hyperthyroidism due to Graves disease, for which remission can be induced with methimazole or propylthiouracil, the GNAS1 mutation cannot be “shut off ”; therefore, remission with medical treatment alone is unsuccessful. Ablative therapy with radioactive iodine 131 or thyroidectomy is necessary in most cases. Two MAS patients with thyroid carcinoma (papillary and clear cell) have also been reported in MAS.37 Also, MAS should be differentiated from the Carney complex. The Carney complex is an autosomal dominant disorder characterized by abnormal pigmentation of the skin and mucosa, primary pigmented nodular adrenocortical disease (PPNAD), cardiac and cutaneous myxomas, growth hormone (GH) and prolactin (PRL) pituitary adenomas, testicular tumors, thyroid adenoma or carcinoma, and ovarian cysts. The Carney complex is genetically heterogeneous but may be caused by mutation in the protein kinase A regulatory subunit-1-a gene (PRKAR1A) on chromosome 17q.38 In contrast to MAS, Albright hereditary osteodystrophy (AHO) is often caused by constitutional (nonmosaic) downregulating GNAS1 mutations, although this phenotype can also be caused by alterations at other genetic loci. Interstitial deletions of chromosome 2q37 have also been associated with a partial phenocopy of AHO lacking the endocrinologic manifestations.39 Resistance to parathyroid hormone (PTH) is the hallmark of GNAS1-related AHO, but hypothyroidism due to resistance to TSH is also commonly associated. Short stature, brachydactyly, developmental delay and cognitive dysfunction, obesity, cataracts, and bony abnormalities also comprise the syndrome. A common cutaneous manifestation is the presence of subcutaneous calcifications. Pseudohypoparathyroidism (PHP) has been divided into subtypes Ia and Ib. PHP type Ia is more severe, with features of AHO and multihormone resistance, while type Ib disease is not associated with AHO, with hormone resistance usually limited to PTH. Molecular correlations suggest that tissue-specific imprinting of Gs-a plays a major determining role in the phenotype, with maternally

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inherited mutations causing the more severe manifestations.40,41

Pendred Syndrome The SLC26A4 gene, encoding pendrin, a transmembrane iodide and chloride transporter, underlies the autosomal recessive Pendred syndrome. The hallmarks of this disorder are goiter, with or without thyroid dysfunction, and deafness. The syndrome maps to chromosome 7q21-34.42 Pendred syndrome is thought to be the most common syndromal form of deafness, possibly accounting for as many as 10% of cases of hereditary deafness.43 The estimated population incidence is 7.5–10 per 100,000. In Pendred syndrome, developmental abnormalities of the cochlea, particularly enlargement of the vestibular aqueducts with a Mondini malformation, are associated with sensorineural hearing loss, which can be progressive. Diffuse thyroid enlargement and dyshormonogenesis are due to a mild congenital organification defect. Cutaneous abnormalities in Pendred syndrome are related directly to the thyroid dysfunction. Clinically, the degree of thyroid dysfunction is highly variable. The perchlorate discharge test may be abnormal, thryoglobulin levels may be increased, and there may be overt hypothyroidism.44 Although Pendred syndrome has been only occasionally detected in newborn screening programs for thyroid function,45,46 the disorder may be more commonly detected through newborn screening programs for deafness. The proportion of infants found to have SLC26A4 mutations increases significantly in the group of deaf infants with enlarged vestibular aqueducts.47 These infants may have elevated serum Tg levels and increased free T3. Interestingly, thyroid carcinomas may be associated with decreased pendrin expression48,49 and with impaired targeting to the apical cell membrane.50 Epigenetic modification (hypermethylation) of SLC26A4 may also be an early event in thyroid tumors of various types, including benign adenomas.51

Down Syndrome The average incidence of Down syndrome (DS) is approximately 1 in 700 live births, and the prevalence of all thyroid disorders in DS is about 30%.52

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The majority of DS patients (95%) have trisomy 21, with three free copies of chromosome 21. About 5% of patients have DS due to a translocation of chromosome 21 to one of the other acrocentric chromosomes (usually chromosome 14 or 21).53,54 A smaller percentage of cases are associated with mosaicism for trisomy 21 and a normal cell line, with a potentially milder phenotype.55 Various cutaneous findings unrelated to thyroid dysfunction are more frequently seen in DS patients, including syringomas, milia-like calcinosis, acanthosis nigricans, and elastosis perforans serpiginosa.56 There are characteristic dermatoglyphic patterns, such as displaced axial triradial patterns of the palm and “open-field” patterns on the soles of the feet. Often, a single palmar crease and clinodactyly may be a clue to the clinician of the diagnosis (Figure 7.4). Autoimmune and endocrine abnormalities, including insulin-dependant diabetes mellitus, celiac disease, alopecia areata, vitiligo, Addison disease, pernicious anemia, autoimmune hepatitis, and thyroid disease have all been reported in DS patients, with autoimmune thyroiditis the most common association.57–59 Early in its course, it is often difficult to differentiate the clinical symptoms of thyroid dysfunction from other intrinsic manifestations of the DS phenotype. Constipation may be due to Hirschprung disease or hypothyroidism. Protruding tongue (due to hypotonicity in DS) can mimic the macroglossia of hypothyroidism. Hair loss may be due to alopecia areata, and growth delay is both intrinsic and aggravated by cardiac disease as well as

Figure 7.4. The hand in Down syndrome: a single palmar crease and clinodactyly

A.V. Halpern and R.E. Schnur

hypothyroidism. Slowing of the growth rate in a child with DS may be one of the most commonly detected changes suggesting hypothyroidism. A pericardial effusion and bradycardia can suggest congenital or acquired hypothyroidism as well as congenital heart disease (CHD) but will completely resolve after T4 therapy. Any child with DS who presents with dyspnea and cardiomegaly should be evaluated immediately with both thyroid function studies and echocardiography.60 The incidence of CH in DS is about 2%– 3%; hyperthyroidism is seen less often.61,62 The most frequently observed thyroid condition in DS is autoimmune subclinical hypothyroidism. In this condition, elevated and transient TSH levels with normal or low T4 levels are frequently detected, and patients are commonly asymptomatic. Subclinical hypothyroidism (also called compensated hypothyroidism, subacute hypothyroidism, mild hypothyroidism, isolated raised thyroid-stimulating hormone [IR-TSH], and isolated hyperthyrotropinemia) is detected in approximately 80%–90% of screened DS patients in early infancy and 30%–50% thereafter.63,64 The majority of the patients with elevated IR-TSH are under age 6 years.65 The cause of subclinical hypothyroidism has not been elucidated, but it has been suggested that young DS patients may be predisposed to a self-limited autoimmune process without clinical symptoms. Suggested mechanisms for self-limited subclinical disease include inappropriate release of TSH related to a central disorder, the production of a less-active form of TSH, or some form of TSH insensitivity in the thyroid gland.66 Despite the absence of classic hypothyroidism or ATAs, Oliveira et al.67 noted elevated basal TSH and prolactin levels in their DS patients and hypothesized that the abnormality was related to central hypothalamic dysfunction. van Trotsenburg et al.68 examined 284 DS children and found the mean T4 concentrations were significantly decreased yet normally distributed—a left shift on the Gaussian curve—and mean TSH was significantly increased. They concluded that these findings supported a DS-specific thyroid regulation disorder. Konings et al.69 found normal TSH bioactivity in the plasma of a subset of DS children, indicating that the primary etiology of subclinical hypothyroidism was intrinsic to the thyroid gland.

7. Chromosomes, Genes, and the Thyroid Gland

van Trotsenburg et al.70 agreed with the theory of thyroidal etiology (rather than central hypothalamic) for subclinical hypothyroidism in DS. They pointed out that plasma TSH in DS patients with CH responds to therapeutic T4 replacement in the same way as non-DS patients with CH of thyroidal (as opposed to central) origin. In addition, they noted that in central hypothyroidism, plasma TSH is rarely elevated and practically never exceeds 20 mIU/L. In their study, a cohort of DS neonates was followed over 24 months to examine the incidence of persistent hypothyroidism beyond the neonatal period. The mean TSH concentrations in 97 placebo-treated DS infants were persistently shifted higher (than T4-treated counterparts), and the treated infants needed relatively higher free T4 concentrations to normalize the plasma TSH level. They concluded that DS infants have a novel type of persistent mild CH and hypothesized that, due to the trisomic state of chromosome 21, genomic dosage imbalance of dosage-sensitive genes may interfere with thyroid hormone production. For example, in DS there may be hyperresponsiveness to interferon due to overexpression of IFNAR1 or IFNAR2, the genes encoding interferon receptors 1 and 2 (gene map loci 21q22.1 and 21q22.1–q22.2, respectively). A connection is suggested by a study of interferon therapy in multiple sclerosis patients. Caraccio et al.71 found that in vitro type I interferons were able to downregulate the TSH-stimulated gene expression of several proteins involved in T4 synthesis (i.e., sodium iodide symporter, thyroid peroxidase, and Tg), as well as T4 secretion. Although not the standard of care for DS infants, some authors have proposed that replacement T4 during the first few weeks of life in all DS babies with IR-TSH (even those without symptoms) might prevent developmental abnormalities associated with congenital thyroid dysfunction.63,64 To examine the role of empiric T4 treatment in the developmental outcomes of DS newborns, a randomized, double-blind, 24-month trial compared T4 therapy with placebo in 196 DS neonates.63 Treated children were found to have a smaller delay in motor and mental development at 24 months than the placebo-treated babies, although the latter failed to reach statistical significance. Neonates treated with T4 showed statistically significant gains in length and weight over the control babies during the treatment period.

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A subset of patients with subclinical hypothyroidism at birth subsequently develop clinically relevant thyroid dysfunction. There are no specific clues to predict which subset will follow this course. These patients may pass undetected in neonatal screens and therefore go untreated. Currently, the Committee on Genetics of the American Academy of Pediatrics72 recommends screening all DS patients for thyroid disorders every 6 months until 1 year of age and annually thereafter. Gibson et al.66 aimed to define thyroid function characteristics in the first decade that might predict subsequent hypothyroidism in the second decade and therefore be able to more appropriately target subgroups for more specific screening recommendations. They analyzed thyroid function in 122 DS children aged 6–14 years and repeated the analysis 4–6 years later in 103 DS adolescents aged 10–20 years. The likelihood ratio was 20 for a positive result on second testing, when raised TSH and positive antibody status of first testing are combined, and 14 when autoantibody levels alone were assessed. In their report, they showed that a DS neonate’s basic probability at birth of requiring T4 treatment in the second decade is 2%. After testing positive for autoantibodies alone, the probability of hypothyroidism in the second decade rises to 28% and to 34% if elevated TSH is also identified. They concluded that early positive results for ATAs or IR-TSH could be used as a basis to select a subgroup for testing at regular intervals for overt hypothyroidism, and that yearly screening for otherwise normal DS infants might not be economically or logistically justifiable. Several other independent studies have shown that the presence of anti-TPO antibodies detected early in life in DS babies may be a marker for a higher risk of developing of thyroid dysfunction later. In one study, progression to overt thyroid disease was always related to the development of ATAs. Gruñiero de Papendieck et al.62 and Dias et al.73 found that increased TSH had a statistically positive relationship with anti-TPO but not with gender, abnormal ultrasound, or iodine 131 scintigraphy findings. The autoimmune regulator gene AIRE encodes a 545-amino acid protein transcription factor, and AIRE mutations are associated with autoimmune polyendocrine syndrome I (APS I). AIRE maps to chromosome 21q22.3, a region considered critical

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in the development of DS. In mouse models, targeted inactivation of this gene suggests that it is involved in the regulation of central tolerance.74,75 Söderbergh et al. found that 4 of 48 DS patients had autoantibodies previously thought to be specific for APS I. They acknowledged that the relevance of these antibodies for the future development of clinical disease is uncertain.75

Turner Syndrome Thyroid dysfunction, especially hypothyroidism secondary to Hashimoto autoimmune thyroiditis, is more frequent in girls with Turner syndrome than in chromosomally normal females. TS is observed in approximately 1 in 2500 females at birth. Complete loss of one X chromosome is observed in about half of all cases, with the remainder showing mosaicism or structural abnormalities of the X chromosome. The range of clinical manifestations is broad and highly variable among patients. The most common problems are short stature and infertility due to streak gonads. Other phenotypic abnormalities include facial variations (Figure 7.5) such as a triangular face; hypertelorism; low-set ears; low posterior hairline; pterygia colli; widespaced nipples; cubitus valgus; short fourth metacarpals; cardiac defects, particularly involving the aorta; renal anomalies; lymphedema (Figure 7.6); and frequent episodes of otitis media. Because of the wide variability in manifestations, karyotyping of any girl with unexplained short stature or primary amenorrhea is warranted.

Figure 7.5. Turner syndrome: broad neck, relatively narrow chin/triangular face, low-set ears

Figure 7.6. Congenital lymphedema

In a recent study of 84 patients with TS (ages 0.5–19 years), Livadas et al.76 detected hypothyroidism in 24% of the total group and 65% of those with ATAs. They also found hyperthyroidism in 2.5%. Hashimoto thyroiditis manifesting as acquired hypothyroidism is the most common autoimmune disorder in TS patients. Hypothyroidism can potentially aggravate the poor growth that is intrinsic to TS. Similar to DS patients, TS patients are more susceptible to autoimmune disorders in general. They also show a higherthan-average frequency of alopecia, psoriasis, and nevi, in addition to thyroid dysfunction.77–80 The relationship between thyroid disease and TS was first suggested in 1948 by Atria et al.81 The incidence of the thyroid abnormalities ranges from 0% to 40% in the literature, with most sources stating an average of around 25%, and the annual incidence of autoimmune hypothyroidism has been estimated at 3.2%.76,82 Thyroid peroxidase autoantibodies or anti-Tg antibodies were detected in 42% of TS patients in one study.76 The majority of the ATA-positive girls (65%) had either Hashimoto thyroiditis (elevated TSH and ATA+) or subclinical/compensated hypothyroidism (elevated TSH; normal T4, T3). The prevalence of hypothyroidism in ATA− patients was only 10%. El-Mansoury et al.82found the prevalence of clinical and subclinical hypothyroidism in a 5-year study of TS patients to be 37% (25% in year 1 of the study). The frequency of ATA in all TS patients with hypothyroidism was 43% and was evenly distributed between 45,X karyotype and mosaic

7. Chromosomes, Genes, and the Thyroid Gland

patients. In their population, high body mass index (BMI) was also associated with hypothyroidism. Similar to Livadas et al.,76 they found positive correlation between elevated anti-TPO and elevated TSH levels in their TS patient population—nearly half of patients with hypothyroidism were antiTPO+. They speculated that TS patients who are euthyroid but anti-TPO+ are at a much higher risk of developing clinical hypothyroidism over time and should be followed more closely. Livadas et al.76 found an evenly distributed annual incidence (no increase in rate of diagnosis per year) up to age 19 years, while El-Mansoury et al.82 found the incidence of hypothyroidism increased with increasing age. Hyperthyroidism is less common in TS, and studies in younger patients are lacking. According to Radetti et al.,83 6% of TS patients found to be hyperthyroid were actually in the hyperthyroid phase of Hashimoto thyroiditis and did not have Graves disease. The incidence of true hyperthyroidism in young girls with TS is not well described but is estimated at 1.3%–2.6%, and in older women it is considered to be approximately 0.5%–1.4%.76,84 The influence of karyotype on thyroid autoimmunity in TS patients has been somewhat controversial. Early studies suggested that isochromosome X Turner syndrome patients were significantly more likely to develop clinical hypothyroidism and require replacement therapy than those with other karyotypes.85 However, several analyses disputed this assertion.76,82 Since many girls with TS are treated with GH, several groups have studied the effects of GH treatment on thyroid function. Susperreguy et al.86 noted that GH treatment lowers peripheral thyroid hormone function in girls with TS. A proposed mechanism is that GH treatment induces somatomedin C (insulin-like growth factor I [IGF-1]), which subsequently reduces the thyroid hormone receptor (TR). This mechanism was supported by experiments in peripheral blood mononuclear cells of TS patients. Assays of messenger RNA for the TR showed reduced levels, and biochemical markers of thyroid hormone action, including TSH, were increased. Similarly, patients with Prader Willi syndrome (PWS) are routinely treated with GH. Festen et al.87 detected normal baseline free T4 levels in most PWS children. However, during

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GH treatment, levels decreased significantly, while TSH levels remained normal. Interestingly, T3 levels were relatively high or normal, suggesting that PWS children have increased T4-to-T3 conversion. A greater concern was raised by Cabanas et al.88 about the potential risk of thyroid neoplasia associated with GH treatment. Papillary thyroid carcinoma developed in two Spanish girls with TS who were treated with recombinant GH therapy, with the tumor cells testing positive for GH receptor expression. Since thyroid carcinoma is also associated with acromegaly and elevated GH levels,89 there may be a significant long-term risk of thyroid cancer in GH-treated TS girls. Clearly, additional long-term studies will be helpful in ascertaining the risk of developing thyroid malignancies.

Williams-Beuren Syndrome Williams-Beuren or Williams syndrome (WS) is a multisystemic contiguous gene deletion disorder caused by microdeletions of the long arm of chromosome 7 (7q11.23) that include the elastin gene. Diagnostic testing via fluorescent in situ hybridization (FISH) or CGH is readily available. Distinctive facial features include midface hypoplasia, a depressed nasal bridge, anteverted nostrils, a long philtrum, full lips, and a wide mouth. Typically, there is a medial flare of the eyebrows, pale blue or green irides, stellate irides, short palpebral fissures, and periorbital fullness.90–93 Children with WS often have a harsh or “brassy” hoarse voice,94 likely due to abnormal vocal cord elastin. Of interest to the dermatologist, WS may also be associated with premature graying of the hair, dental anomalies including enamel hypoplasia, hypoplastic nails, and connective tissue laxity. Cardiovascular defects, particularly supravalvular aortic stenosis, peripheral pulmonary artery stenosis, and hypertension, are the most serious risks to health. Developmental delay with a characteristic loquacious personality, short stature, specific behavioral phenotype, and hypercalcemia are other unique features of the syndrome. Hypercalcemia may be seen in adults as well as infants95 and has been attributed to a deficient endogenous response of calcitonin to a calcium load.96 The current health care guidelines for Williams syndrome proposed by the American Academy of

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Pediatrics97 suggests that thyroid screening should be performed via newborn screening and every 4 years thereafter. Thyroid anomalies and dysfunction, however, may be more frequent than generally recognized. TD, hemigenesis/hypoplasia, and functional dyshormonogenesis were described in several early studies of WS patients.98–101 Selicorni et al.102 found that approximately75% of the patients with WS in their study had hypoplasia of the thyroid, and 37.9% had elevated TSH with normal T3 and T4 levels (defined as subclinical hypothyroidism). No patients had ATAs. The same authors found that the incidence of subclinical hypothyroidism decreased with age from 69% to 6% (from age under 1 year to over 18 years). None of the patients over age 13 in another study103 had an elevated TSH. In both studies,102,103 elevated TSH correlated with hypoplasia of the thyroid gland. It is hypothesized that the infantile requirement for thyroid hormone is relatively higher than in the adult, and that the hypoplastic gland is insufficient in producing adequate amounts of thyroid hormone to meet the demand. However, with age, the body’s need for thyroid hormone declines relatively, and the thyroid gland can accommodate at that point, lowering the TSH and eliminating subclinical hypothyroidism.102 Cambiaso et al.104 studied a group of 92 patients with WS with respect to thyroid gland structure and function. No patient in their group had overt hypothyroidism, and none had thyroid antibodies, but 31.5% had subclinical hypothyroidism. This was more prevalent in the younger patients. In addition, 67.5% had ultrasonographic changes in thyroid morphology or volume. The authors suggested yearly screens of thyroid function, and that at least a baseline thyroid ultrasound should be performed in all patients with WS. As in other syndromes associated with CH, there is some controversy regarding whether patients with WS with subclinical hypothyroidism should be treated. Cambiaso et al.104 suggested that treatment be initiated if the patient is symptomatic or if thyroid function seems to be deteriorating. Several groups have studied whether hemizygosity for the elastin gene in patients with WS has effects on the skin, either clinically or at an ultrastructural level. Ghomrasseni et al.105 found decreased diameter of elastic fibers in the dermis of patients with WS. Urbán et al.106 noted subtle

A.V. Halpern and R.E. Schnur

textural changes in the skin of patients with WS as well as reduced amounts of elastin in elastic fibers within the dermis, affecting the elastic fiber ultrastructure. Dridi et al.107 also found disorganized elastic fibers in the dermis of 10 WS patients. Interestingly, myxedema itself may be associated with elastic fiber alterations, including reduced amounts, variable elastic fiber diameter, and reduced microfibrils.108 Thus, WS patients with hypothyroidism may be particularly prone to the complications of reduced skin and vascular wall resiliency.

22q11.2 Deletion Syndrome (DiGeorge Syndrome, Velocardiofacial Syndrome) With an incidence of 1 in 4000–5000 live births, the 22q11.2 microdeletion syndrome is the most common interstitial deletion syndrome.109 The syndrome is a neurocristopathy, or abnormality of cranial neural crest cell development, and is characterized by the complete or partial absence of derivatives of the third and fourth pharyngeal pouches.110 Associated defects in the third, fourth, and sixth aortic arches lead to abnormal development of the thymus, parathyroid glands, palate, and cardiovascular system. Additional aberrations in immunologic and endocrine function may be observed. Several phenotypic subsets fall under the umbrella of the 22q11.2 microdeletion and are distinguished by wide variability in clinical findings. DiGeorge syndrome (DGS), velocardiofacial syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome and autosomal dominant Opitz G/BBB syndrome, and Cayler cardiofacial syndrome are all phenotypes associated with deletions of chromosome 22q11.2 but with partially distinctive yet overlapping manifestations.111,112 Common dermatologic manifestations of the microdeletion include severe acne in greater than 23% and seborrhea/dermatitis in 34.6% of 78 adult patients in one study.113 Patients also suffer from dental enamel hypoplasia and, presumably, the secondary effects of their endrocrinologic and immune dysfunction. One of the most common types of anomalies seen in individuals with 22q11.2 deletions is CHD, particularly involving the outflow tract

7. Chromosomes, Genes, and the Thyroid Gland

Figure 7.7. 22q11.2 deletion syndrome: a broad nasal root, bulbous nasal tip, and micrognathia related to Pierre Robin syndrome

(e.g., truncus arteriosis, tetralogy of Fallot, and type B interrupted aortic arch). More than 75% of patients with the microdeletion syndrome have CHD.112 Other features are aplasia or hypoplasia of the thymus, hypoparathyroidism, cleft palate, developmental problems such as speech and learning disability, short stature, obesity, and craniofacial anomalies (broad nasal root or bulbous nose, cleft palate, and variable Pierre Robin anomalad) (Figure 7.7). Psychiatric problems, including schizophrenia, are also seen in greater than 20% of individuals with 22q11.2 deletions.113 Short stature has been reported in 39%–67% of patients and may be the result of intrauterine growth retardation, feeding difficulties, or GH deficiency.114 Endocrine anomalies are commonly seen in DGS, especially hypoparathyroidism, hypothyroidism, and short stature.114–116 Hypoparathyroidism is the most common of these, with a prevalence of 32% in one study of patients with DGS.114 Thyroid dysfunction is also frequent and may be related

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to developmental thyroid anomalies as well as autoimmune dysfunction. Transient hypocalcemia and tetany are common in the newborn with the syndrome, although later onset of hypocalcemia, as well as relapse of hypoparathyroidism, has also been described.117,118 Surveillance in these patients throughout life is recommended. Thymic dysplasia or aplasia can cause clinical or subclinical immunodeficiency in patients with DGS. Although seemingly counterintuitive, these patients are also prone to autoimmune disorders.119,120 Approximately 9% of all patients with the deletion syndrome are known to have associated autoimmune disorders, including thyroid disorders such as Graves disease and Hashimoto thryoiditis.114,121–123 Less-frequent autoimmune conditions include hemolytic anemia, idiopathic thrombocytopenic purpura, type I diabetes mellitus, and juvenile rheumatoid arthritis. It is thought that the dysregulation of the cellular immune system allows for both inadequate normal immunity and destabilized inappropriate immunity to self-antigens. The 22q11.2 deletion region (Figure 7.8) contains approximately 35 genes, with the TBX1 gene now thought to be the most critical in determining the major phenotypic malformations.112,124,125 The TBX1 gene is a T-box transcription factor gene, a downstream target of sonic hedgehog, and has long been thought to be pivotal in pharyngeal arch development.126,127

Figure 7.8. Fluorescence in situ hybridization: The normal copy of chromosome 22 has two sets of signals. The deleted homolog has only one hybridization signal corresponding to a “control” probe and is missing the probe from the critical segment of 22q11.2

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Fagman et al.128 studied mice that were homozygously deleted for the critical region of chromosome 22q11.2, including Tbx1. The same group had previously postulated that murine thyroid development depends on inductive signals arising from embryonic vessels of the cardiac outflow tract.129 They also noted again the relatively high frequency of TD in all patients with cardiac anomalies (not limited to those with the 22q11.2 microdeletion) and suggested that the association is due to the dependence of thyroid gland morphogenesis on proper cardiovascular development. Tbx1 was found to be expressed in the developing mesenchyme surrounding the thyroid gland, although not in the thyroid gland itself. In the Tbx1−/− mice, the migration of thyroid precursor cells was much delayed, and the thyroid failed to form symmetric lobes. The resultant, mostly unilateral, hypoplastic thyroid gland resembled thyroid hemiagenesis. In humans, researchers have determined that the average number of calcitonin-producing cells in children with DGS is significantly reduced.130,131 Other authors have found gross structural variations in the thyroid gland itself. Scuccimarri et al.132 reported a case of CH with DGS and reviewed previous studies demonstrating structural thyroid anomalies in DGS. Similarly, Preece and Smith133 reported a child with 22q11.2 deletion and CH whose thyroid gland was found to be hypoplastic by ultrasound, suggesting thyroid dysplasia. The authors suggested that thyroid disease may be an intrinsic part of the 22q11.2 deletion syndrome, and that thyroid screening is warranted in all affected individuals. Indeed, Bassett et al.113 found that 20.5% of 78 adults with 22q11.2 deletions had evidence of hypothyroidism, with another 5.1% having hyperthyroidism, lending additional support for a thyroid-screening protocol in the 22q11.2 deletion syndrome.

Conclusion In conclusion, it is apparent that genetics, thyroid disease, and dermatology are intimately related in a host of heritable disorders. Particular vigilance is necessary in considering thyroid disease in the disorders reviewed in this chapter. Appropriate screening for thyroid disease may

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have a profound influence on the health of these patients.

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67 ated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 1998;19:399–401. 26. Castanet M, Park SM, Smith A, et al. A novel lossof function mutation in TTF2 is associated with congenital hypothyroidism, thyroid agenesis, and cleft palate. Hum Mol Genet 2002:11:2051–2159. 27. Baris I, Arisoy AE, Smith A, et al.. A novel missense mutation in human TTF-2 (FKHL15) gene associated with congenital hypothyroidism but not athyreosis. J Clin Endocrinol Metab 2006;91:4183–4187. 28. Carré A, Castanet M, Sura-Trueba S, et al. Polymorphic length of TTF2/FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis. Hum Genet 2007;122:467–476. 29. Santarpia L, Valenzise M, Di Pasquale G, et al. TTF2/FOXE1 gene polymorphisms in Sicilian patients with permanent primary congenital hypothyroidism. J Endocrinol Invest 2007 30:13–19. 30. Dentice M, Cordeddu V, Rosica A, et al. Missense mutation in the transcription factor NKX2-5:a novel molecular event in the pathogenesis of thyroid dysgenesis. J Clin Endocr Metab 2006;91:1428–1433. 31. Bakker B, Bikker H, Hennekam RCM, et al. Maternal isodisomy for chromosome 2p causing severe congenital hypothyroidism. J Clin Endocrinol Metab 2001:86:1164–1168. 32. Jabbour SA. Endocrinology in dermatology. Clin Dermatol 2006;24:235–236. 33. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991;325:1688–1695. 34. Schwindinger WF, Francomano CA, Levine MA. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G-protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci 1992;89:5152–5156. 35. Bhat MH, Bhadada S, Dutta P, Bhansali A, Mittal BR Hyperthyroidism with fibrous dysplasia: an unusual presentation of McCune-Albright syndrome. Exp Clin Endocrinol Diabetes 2007;115:331–333. 36. Lumbroso S, Paris F, Sultan C, European Collaborative Study. Activating Gs alpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome—a European Collaborative Study. J Clin Endocrinol Metab 2004;89:2107–2113. 37. Collins MT, Sarlis NJ, Merino MJ, et al. Thyroid carcinoma in the McCune-Albright syndrome: contributory role of activating Gs alpha mutations. J Clin Endocrinol Metab 2003;88:4413–4417. 38. Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type Ialpha regulatory subunit in patients with the Carney complex. Nat Genet 2000;26:89–92.

68 39. Wilson LC, Leverton K, Oude Luttikhuis C, et al. Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localized to 2q37. Am J Hum Genet 1995;56:400–407. 40. Liu J, Erlichman B, Weinstein LS. The stimulatory G protein alpha-subunit Gs-alpha is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metab 2003;88:4336–4341. 41. Mantovani G, Bondioni S, Linglart A, et al. Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 2007;9:3738–3742. 42. Sheffield VC, Kraiem X, Beck JC, et al. Pendred syndrome maps to and is caused by an intrinsic defect in thyroid iodine organification. Nat Genet 1996;12:424–426. 43. Reardon W, Trembath RC. Pendred syndrome. J Med Genet 1996;33:1037–1040. 44. Bogazzi F, Russo D, Raggi F, et al. Mutations in the SLC26A4 (pendrin) gene in patients with sensorineural deafness and enlarged vestibular aqueduct. J Endocrinol Invest 2004;27:430–435. 45. Banghova K, Taji EA, Cinek O, et al. Pendred syndrome among patients with congenital hypothyroidism detected by neonatal screening: identification of two novel PDS/SLC26A4 mutations. Eur J Pediatr 2007 Sept 18 [epub ahead of print]. 46. Gaudino R, Garel C, Czernichow P, Léger J. Proportion of various types of thyroid disorders among newborns with congenital hypothyroidism and normally located gland: a regional cohort study. Clin Endocrinol 2005;62:444–448. 47. Iwasaki S, Tsukamoto K, Usami S, Misawa K, Mizuta K, Mineta H. Association of SLC26A4 mutations with clinical features and thyroid function in deaf infants with enlarged vestibular aqueduct. J Hum Genet 2006;51:805–810. 48. Bidar J, Mian C, Lazar V, et al. Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues. J Clin Endocrinol Metab 2000;85:2028–2033. 49. Bashir EA, Ahmed S, Murtaza B, et al. Follicular carcinoma thyroid in Pendred syndrome. J Coll Physicians Surg Pak 2004;14:679–680. 50. Skubis-Zegadło J, Nikodemska A, Przytula E, et al. Expression of pendrin in benign and malignant human thyroid tissues. Br J Cancer 2005;93: 144–151. 51. Xing M, Tokumaru Y, Wu G, Westra WB, Ladenson PW, Sidransky D. Hypermethylation of the Pendred syndrome gene SLC26A4 may also be an early event in thyroid tumorigenesis. Cancer Res 2003;63:2312–2315.

A.V. Halpern and R.E. Schnur 52. Prasher VP. Down syndrome and thyroid disorders: a review. Downs Syndr Res Pract 1999;6:25–42 53. Thuline HC, Pueschel SM. Cytogenetics in Down syndrome. In: Pueschel SM, Rynders JE, eds. Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Cambridge, UK: Ware Press; 1982:133. 54. Hook EB Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA 1983;249:2034–2038. 55. Mikkelsen M. Down’s syndrome cytogenetic epidemiology. Hereditas 1977;86:45–59. 56. Schepis C, Barone C, Siragusa M, Pettinato R, Romano C. An updated survey on skin conditions in Down syndrome. Dermatology 2002;205:234–238. 57. Ivarsson SA, Ericsson UB, Gustafsson J, Forslund M, Vegfors P, Annaren G. The impact of thyroid autoimmunity in children and adolescents with Down syndrome. Acta Paediatr 1997;86:1065–1067. 58. Reid AH, Adamson DG, Browning MC, Donald JM. A case of idiopathic Addison’s disease and probable autoimmune thyroiditis in a mongol. J Ment Defic Res 1975;19:205–208. 59. McCulloch AJ, Ince PG, Kendall-Taylor P. Autoimmune chronic active hepatitis in Down’s syndrome. J Med Genet 1982;19:232–234. 60. Dinleyici EC, Ucar B, Kilic Z, Dogruel N, Yarar C. Pericardial effusion due to hypothyroidism in Down syndrome: report of four cases. Neuro Endocrinol Lett 2007;28:141–144. 61. Tonacchera M, Perri A, De Marco G, et al. TSH receptor and Gs(alpha) genetic analysis in children with Down’s syndrome and subclinical hypothyroidism. J Endocrinol Invest 2003;26:997–1000. 62. Gruñeiro de Papendieck L, Chiesa A, et al. Thyroid dysfunction and high thyroid stimulating hormone levels in children with Down’s syndrome. J Pediatr Endocrinol Metab 2002;15:1543–1548. 63. van Trotsenburg AS, Vulsma T, van RozenburgMarres SL, et al. The effect of thyroxine treatment started in the neonatal period on development and growth of 2-year-old Down syndrome children: a randomized clinical trial. J Clin Endocrinol Metab 2005;90:3304–3311. 64. Tüysüz B, Beker DB Thyroid dysfunction in children with Down’s syndrome. Acta Paediatr 2001;90: 1389–1393. 65. Hasanhodzic´ M, Tahirovic´ H, Lukinac L. Down Syndrome and thyroid gland. Bosn J Basic Med Sci 2006;6:38–42. 66. Gibson PA, Newton RW, Selby K, Price DA, Leyland K, Addison GM. Longitudinal study of thyroid function in Down’s syndrome in the first two decades. Arch Dis Child 2005;90:574–578.

7. Chromosomes, Genes, and the Thyroid Gland 67. Oliveira AT, Longui CA, Calliari EP, Ferone Ede A, Kawaguti FS, Monte O. [Evaluation of the hypothalamic-pituitary-thyroid axis in children with Down syndrome]. J Pediatr (Rio J) 2002;78:295–300. 68. van Trotsenburg AS, Vulsma T, van Santen HM, Cheung W, de Vijlder JJ. Lower neonatal screening thyroxine concentrations in down syndrome newborns. J Clin Endocrinol Metab 2003;88:1512–1515. 69. Konings CH, van Trotsenburg AS, Ris-Stalpers C, Vulsma T, Wiedijk BM, de Vijlder JJ. Plasma thyrotropin bioactivity in Down’s syndrome children with subclinical hypothyroidism. Eur J Endocrinol 2001;144:1–4. 70. van Trotsenburg AS, Kempers MJ, Endert E, Tijssen JG, de Vijlder JJ, Vulsma T. Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin. Thyroid 2006;16:671–680. 71. Caraccio N, Dardano A, Manfredonia F, et al. Longterm follow-up of 106 multiple sclerosis patients undergoing interferon-{beta} 1a or 1b therapy: predictive factors of thyroid disease development and duration. J Clin Endocrinol Metab 2005;90: 4133–4137. 72. American Academy of Pediatrics, Committee on Genetics. American Academy of Pediatrics: health supervision for children with Down syndrome. Pediatrics 2001;107:442–449. 73. Dias VM, Nunes JC, Araújo SS, Goulart EM. [Etiological assessment of hyperthyrotropinemia in children with Down’s syndrome]. J Pediatr (Rio J) 2005;81:79–84. 74. Mathis D, Benoist C. A decade of AIRE. Nat Rev Immunol 2007;7:645–650. 75. Söderbergh A, Gustafsson J, Ekwall O, et al. Autoantibodies linked to autoimmune polyendocrine syndrome type I are prevalent in Down syndrome. Acta Paediatr 2006;95:1657–1660. 76. Livadas S, Xekouki P, Fouka F, et al. Prevalence of thyroid dysfunction in Turner’s syndrome: a longterm follow-up study and brief literature review. Thyroid 2005;15:1061–1066. 77. Auada MP, Cintra ML, Puzzi MB, Viana D, Cavalcanti DP. Scalp lesions in Turner syndrome: a result of lymphoedema? Clin Dysmorphol 2004;13:165–168. 78. Dacou-Voutetakis C, Kakourou T. Psoriasis and blue sclerae in girls with Turner syndrome. J Am Acad Dermatol 1996;35:1002–1004. 79. Watabe H, Kawakami T, Kimura S, Fujimoto M, et al. Childhood psoriasis associated with Turner syndrome. J Dermatol 2006;33:896–898. 80. Rosina P, Segalla G, Magnanini M, Chieregato C, Barba A. Turner syndrome associated with psoriasis and alopecia areata. J Eur Acad Dermatol Venereol 2003;17:50–52.

69 81. Atria A, Sanz R, Donoso S. Necropsy study of a case of Turner’s síndrome. Case report. J Clin Endocrin Metab 1948;8:397–405. 82. El-Mansoury M, Bryman I, Berntorp K, Hanson C, Wilhelmsen L, Landin-Wilhelmsen K. Hypothyroidism is common in Turner syndrome: results of a 5-year follow-up. J Clin Endocrinol Metab 2005;90:2131–2135. 83. Radetti G, Mazzanti L, Paganini C, et al. Frequency, clinical and laboratory features of thyroiditis in girls with Turner’s syndrome. The Italian Study Group for Turner’s Syndrome. Acta Paediatr 1995;84: 909–912. 84. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a 20-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43:55–68. 85. Elsheikh M, Wass JA, Conway GS. Autoimmune thyroid syndrome in women with Turner’s syndrome—the association with karyotype. Clin Endocrin 2001;55:223–226. 86. Susperreguy S, Miras MB, Montesinos MM, et al. Growth hormone (GH) treatment reduces peripheral thyroid hormone action in girls with Turner syndrome. Clin Endocrinol (Oxf) 2007;67:629–636. 87. Festen DA, Visser TJ, Otten BJ, Wit JM, Duivenvoorden HJ, Hokken-Koelega AC. Thyroid hormone levels in children with Prader-Willi syndrome before and during growth hormone treatment. Clin Endocrinol (Oxf ) 2007;67:449–456. 88. Cabanas P, García-Caballero T, Barreiro J, et al. Papillary thyroid carcinoma after recombinant GH therapy for Turner syndrome. Eur J Endocrinol 2005;153:499–502. 89. Tita P, Ambrosio MR, Scollo C. High prevalence of differentiated thyroid carcinoma in acromegaly. Clin Endocrinol (Oxf ) 2005;63:161–167. 90. Mass E, Belostoky L. Craniofacial morphology of children with Williams syndrome. Cleft Palate Craniofac J 1993;30:343–349. 91. Preus M. The Williams syndrome: objective definition and diagnosis. Clin Genet 1984;25:422–428. 92. Holmström G, Almond G, Temple K, Taylor D, Baraitser M. The iris in Williams syndrome. Arch Dis Child 1990;65:987–989. 93. Winter M, Pankau R, Amm M, Gosch A, Wessel A. The spectrum of ocular features in the WilliamsBeuren syndrome. Clin Genet 1996;49:28–31. 94. Gosch A, Städing G, Pankau R. Linguistic abilities in children with Williams-Beuren syndrome. Am J Med Genet 1994;1;52:291–296. 95. Cherniske EM, Carpenter TO, Klaiman C, et al. Multisystem study of 20 older adults with Williams syndrome. Am J Med Genet A 2004;131:255–264.

70 96. Culler FL, Jones KL, Deftos LJ. Impaired calcitonin secretion in patients with Williams syndrome. J Pediatr 1985;107:720–723. 97. Committee on Genetics. American Academy of Pediatrics: Health care supervision for children with Williams syndrome. Pediatrics 2007;107:1192–1204. 98. Cammareri V, Vignati G, Nocera G, Beck-Peccoz P, Persani L. Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome. Am J Med Genet 1999;85:491–494. 99. Stagi S, Bindi G, Neri AS, et al. Thyroid hypoplasia of the left lobe in two girls affected by Williams syndrome. Clin Dysmorphol 2003;12:267–268. 100. Bini R, Pela I. New case of thyroid dysgenesis and clinical signs of hypothyroidism in Williams syndrome. Am J Med Genet A 2004;127:183–185. 101. Cappa M, Galasso C, Boscherini B. Aspetti auxologici ed endocrinologici. In: Giannotti A, Vicari S eds. Il bambino con sindrome di Williams. Milan: Franco Angeli; 1994:59–64. 102. Selicorni A, Fratoni A, Pavesi MA, Bottigelli M, Arnaboldi E, Milani D. Thyroid anomalies in Williams syndrome: investigation of 95 patients. Am J Med Genet A 2006;140:1098–1101. 103. Stagi S, Bindi G, Neri AS, et al. Thyroid function and morphology in patients affected by Williams syndrome. Clin Endocrinol (Oxf) 2005;63:456–460. 104. Cambiaso P, Orazi C, Digilio MC, et al. Thyroid morphology and subclinical hypothyroidism in children and adolescents with Williams syndrome. J Pediatr 2007;150:62–65. 105. Ghomrasseni S, Dridi M, Bonnefoix M, et al. Morphometric analysis of elastic skin fibres from patients with: cutis laxa, anetoderma, pseudoxanthoma elasticum, and Buschke-Ollendorff and Williams-Beuren syndromes. J Eur Acad Dermatol Venereol 2001;15:305–311. 106. Urbán Z, Peyrol S, Plauchu H, et al. Elastin gene deletions in Williams syndrome patients result in altered deposition of elastic fibers in skin and a subclinical dermal phenotype. Pediatr Dermatol 2000;17:12–20. 107. Dridi SM, Ghomrasseni S, Bonnet D, et al. Skin elastic fibers in Williams syndrome. Am J Med Genet 1999;87:134–138. 108. Matsuoka LY, Wortsman J, Uitto J, et al. Altered skin elastic fibers in hypothyroid myxedema and pretibial myxedema. Arch Intern Med 1985;145:117–121. 109. Yamagishi H. The 22q11.2 deletion syndrome. Keio J Med 2002;51:77–88. 110. Hutson MR, Kirby ML. Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations. Semin Cell Dev Biol. 2007;18:101–110.

A.V. Halpern and R.E. Schnur 111. McDonald-McGinn DM, Emanuel BS, Zackai EH. 22q11.2 deletion syndrome. Updated December 16, 2005. In: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. 1997–2007. Available at: http://www.genetests.org. Accessed December 9, 2007. 112. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet 2007;370(9596):1443–1452. 113. Bassett AS, Chow EW, Husted J, et al. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet A 2005;138:307–313. 114. Choi JH, Shin YL, Kim GH, et al. Endocrine manifestations of chromosome 22q11.2 microdeletion syndrome. Horm Res 2005;63:294–299. 115. Weinzimer SA. Endocrine aspects of the 22q11.2 deletion syndrome. Genet Med 2001;3:19–22. 116. Kitsiou-Tzeli S, Kolialexi A, Mavrou A. Endocrine manifestations in DiGeorge and other microdeletions related to 22q11.2. Hormones 2005;4:200–209. 117. Greig F, Paul E, DiMartino-Nardi J, Saenger P. Transient congenital hypoparathyroidism: resolution and recurrence in Chromosome 22q11 deletion. J Pediatr 1996;128:563–567. 118. Cuneo BF, Driscoll DA, Gidding SS, Langman CB. Evolution of latent hypoparathyroidism in familial 22q11 deletion syndrome. Am J Med Genet 1997;69:50–55. 119. Jawad AF, McDonald-Mcginn DM, Zackai E, Sullivan KE. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr 2001;139:715–723. 120. McLean-Tooke A, Spickett GP, Gennery AR. Immunodeficiency and autoimmunity in 22q11.2 deletion syndrome. Scand J Immunol 2007;66:1–7. 121. Kawamura T, Nimura I, Hanafusa M, et al. DiGeorge syndrome with Graves’ disease: a case report. Endocr J 2000;47:91–95. 122. Kawame H, Adachi M, Tachibana K, et al. Graves’ disease in patients with 22q11.2 deletion. J Pediatr 2001;139:892–895. 123. Brown JJ, Datta V, Browning MJ, Swift PG. Graves’ disease in DiGeorge syndrome: patient report with a review of endocrine autoimmunity associated with 22q11.2 deletion. J Pediatr Endocrinol Metab 2004;17:1575–1579. 124. Liao J, Kochilas L, Nowotschin S, et al. Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage. Hum Mol Genet 2004;13:1577–1585.

7. Chromosomes, Genes, and the Thyroid Gland 125. Zweier C, Sticht H, Aydin-Yaylagül I, Campbell CE, Rauch A. Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. Am J Hum Genet 2007;80:510–517. 126. Lindsay EA, Vitelli F, Su H, Morishima M, et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 2001;410:97–101. 127. Baldini A. Dissecting contiguous gene defects: TBX1. Curr Opin Genet Dev 2005;15:79–284. 128. Fagman H, Liao J, Westerlund J, Andersson L, Morrow BE, Nilsson M. The 22q11 deletion syndrome candidate gene Tbx1 determines thyroid size and positioning. Hum Mol Genet 2007;16:276–285. 129. Fagman H, Anderson L, Nilsson M. The developing mouse thyroid: embryonic vessel contacts and parenchymal growth pattern during specifica-

71 tion, budding, migration, and lobulation. Dev Dyn 2006;235:444–455. 130. Palacios J, Gamallo C, García M, Rodríguez JI. Decrease in thyrocalcitonin-containing cells and analysis of other congenital anomalies in 11 patients with DiGeorge anomaly. Am J Med Genet 1993;46:641–646. 131. Pueblitz S, Weinberg AG, Albores-Saavedra J. Thyroid C cells in the DiGeorge anomaly: a quantitative study. Pediatr Pathol 1993;13: 463–473. 132. Scuccimarri R, Rodd C. Thyroid abnormalities as a feature of DiGeorge syndrome: a patient report and review of the literature. J Pediatr Endocrinol 1998;11:273–276. 133. Preece JM, Smith RA. Thyroid disease in children with 22q11.2 deletion syndrome. J Pediatr 2002;141:297.

8 Cutaneous Manifestations of Hyperthyroidism Clara-Dina Cokonis, Carrie W. Cobb, Warren R. Heymann, and Chad M. Hivnor

Editorial Perspective The key to diagnosing hyperthyroidism from a dermatologic perspective is based on having a high index of suspicion that excess thyroid hormone is responsible for the patient’s signs and symptoms. As there are no definitive cutaneous manifestations of hyperthyroidism, a careful review of systems may yield important clinical clues to the diag­ nosis: Is the patient intolerant of heat? Has there been weight loss? Has the patient experienced any palpitations? Have the bowel habits changed? The unique challenge lies in when systemic symptoms are absent or vague, and the skin manifestations are subtle. Should one routinely check a thyroid­ stimuating hormone (TSH) level when the only dermatologic finding is onycholysis? Should one obtain a TSH level before administering botulinum toxin for axillary hyperhidrosis with an otherwise unremarkable review of systems? Should you check thyroid function studies for patients present­ ing with alopecia areata? There are no definitive answers to these questions. Obviously, the yield will be higher in those patients who have several signs and symptoms referable to a hyperthyroid state. It is my opinion that for isolated findings, such as onycholysis or palmoplantar hyperhid-

Introduction Thyrotoxicosis is commonly encountered in clini­ cal practice. In the United States, clinical hyper­ thyroidism occurs in 0.5% of the population and

rosis, with an unremarkable review of systems, screening for hyperthyroidism is not mandatory. On the other hand, I believe that it is appropri­ ate to check a TSH level in a woman presenting with alopecia, even if there are no associated constitutional symptoms. When patients present with other autoimmune diseases (i.e., chronic idi­ opathic urticaria, dermatitis herpetiformis, lichen sclerosus, etc.) in which there is an increased risk for autoimmune thyroid disease, I think it is rea­ sonable to check for thyroid autoantibodies (anti­ thryroglobulin, antithyroid peroxidase), especially if there is a positive family history for autoimmune diseases (notably diabetes mellitus or autoimmune thyroid disease). If positive, these patients may be at a greater risk for the development of autoim­ mune thyroid disease and should be screened periodically (every 3–5 years) with a TSH assay unless clinical circumstances dictate otherwise. In this era of evidence-based medicine, diagnosing hyperthyroidism is still founded on clinical acu­ men. Fortunately, a clinician’s suspicions are easily confirmed or refuted by straightforward laboratory testing. Maintaining an appropriate index of suspi­ cion for hyperthyroidism will allow patients to be diagnosed and treated expediently, thereby greatly increasing their quality of life.

subclinical hyperthyroidism in 0.7%, amounting to 1.3% of the total population.1 Gender comparison displays a 10:1 female predominance, and geo­ graphic variations exist, with a higher prevalence of hyperthyroidism in areas of iodine deficiency.2,3

73

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Autoimmune processes top the list of causes of thyroid disease in the iodine-replete regions. Thyrotoxicosis is defined as the result of elevated thyroid hormones and represents a hypermetabolic state. Hyperthyroidism, more specifically, is the persistent increase in the production of thyroid hormones by the thyroid gland. Thus, a common cause of thyrotoxicosis, namely overingestion of exogenous thyroid medication, is not an example of hyperthyroidism. Subclinical hyperthyroidism is defined by laboratory parameters occurring when thyroid-stimuating hormone (TSH) levels are decreased in the presence of normal levels of triiodothyronine (T3) and thyroxine (T4). The multisystem effects of elevated thyroid hor­ mones (T3 and T4) often result in a multidiscipli­ nary approach to patient care. Dermatologists are among those consulted for management of these patients. Cutaneous involvement is substantiated by demonstration of thyroid hormone deiodinases in the skin as well as expression of TSH recep­ tors on several cells found in the epidermis and dermis.4,5 Aberrations in their function may be responsible for many of the cutaneous manifesta­ tions of thyroid disease.

C.-D. Cokonis et al. Table 8.1. Etiologies. Autoimmune Graves disease Inflammatory/destructive Postpartum thyroiditis Painless thyroiditis Subacute thyroiditis Thyroid infarction Radiation thyroiditis Ectopic production Struma ovarii Hypothalamic-pituitary axis dysregulation Thyroid-stimuating hormone-secreting adenoma Thyrotropic resistance to thyroid hormone Trophoblastic tumor Hyperemesis gravidarum Gestational thyrotoxicosis Autosomal-dominant hyperthyroidism Extrinsic consumption Exogenous thyroid consumption Dietary iodine excess Drug-induced thyroiditis Intrinsic overproduction Thyroid carcinoma Toxic adenoma Toxic multinodular goiter

Etiologies

Dermatologic Signs of Hyperthyroidism

Causes of thyrotoxicosis are vast and include autoimmune processes, inflammatory disorders, ectopic production of thyroid hormone, extrin­ sic consumption of thyroid hormone or hormone products, hypothalamic pituitary axis dysregu­ lation, and thyroid gland overproduction. The most common cause of overt hyperthyroidism is Graves disease, accounting for 60%–90% of hyper­ thyroidism, while overconsumption of extrinsic thyroid hormone is the most common cause of subclinical thyrotoxicosis.6 In Graves disease, autoantibodies are found to thyroglobulin, thyroperoxidase, the TSH receptor, or several other smaller antigens. It is likely that only anti-TSH receptor antibodies are responsible for disease.7 The result is unregulated and sus­ tained release of thyroid hormone. Graves disease is unique among the causes of hyperthyroidism because of its distinctive cutaneous features: pretibial myxedema and acropachy.8 Table 8.1 lists the causes of hyperthyroidism.

As with the majority of signs and symptoms of thyroid disease, the cutaneous findings are similarly nonspecific. One of the few studies in hyperthyroidism showed that the two most common complaints were itching and alopecia.9 Pruritus had a 6.4% prevalence with a 2.6% prevalence of alopecia. One important note clinically is that the authors believed that the diagnosis of hyperthyroidism was delayed if pruritus alone was the major complaint. Thus, hyperthyroidism should be considered as a potential cause of pruritus in the absence of other symptoms or signs of the condition. In general, the skin is warm, moist, and smooth but not atrophic. Exam of the scalp hair may reveal soft and fine hair, occasionally found alongside dif­ fuse, nonscarring alopecia. Diffuse thinning may also occur. Nail changes often include distal ony­ cholysis, and Plummer’s nail changes (onycholysis accompanied by a concave appearance) can be seen. Hyperpigmentation may be noted in a localized, dif­ fuse, or Addisonian pattern. Hyperhidrosis, flushing,

8. Cutaneous Manifestations of Hyperthyroidism

and palmar erythema (Figure 8.1) are often observed in a hyperthyroid state.10,11 Men with hyperthy­ roidism may develop gynecomastia as a result of sec­ ondary increase in estrogen production.12 See Table 8.2 for a summary of cutaneous manifestations. Special mention must be given to findings that have been characteristically associated with Graves disease. However, they are not pathognomonic for Graves disease as they may rarely be observed in euthyroid patients or those with Hashimoto thy­ roiditis. Pretibial myxedema, which may occur on any part of the body, may have varied presenta­ tions. Most commonly, lesions begin as bilateral, raised plaques or nodules with varying hues, which have a classic “woody” induration typically in the “pretibial” location (Figure 8.2). Acropachy consti­ tutes a triad of digital clubbing, soft tissue swelling of the hands and feet, and periosteal new bone for­ mation. This rare manifestation of Graves disease is asymptomatic and usually occurs in the setting of

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Figure 8.2. Pretibial myxedema in a patient with Graves disease

coincident exophthalmos or pretibial myxedema.13 Please refer to chapter 10 for greater detail regarding pretibial myxedema and thyroid acropachy. The sometimes subtle cutaneous findings of hyperthyroidism should prompt further investiga­ tion, especially when found in conjunction with classic systemic and constitutional symptoms of thyrotoxicosis: palpitations, heat intolerance, unin­ tentional weight loss, and generalized fatigue or with stigmata of other autoimmune processes.13

Epidermis and Sweat/Sebaceous Glands

Figure 8.1. Palmar erythema as seen in hyperthyroidism Table 8.2. Cutaneous manifestations. Skin

Hair

Nails

Warm Moist Smooth Flushed Palmar erythema Hyperpigmentation Localized Diffuse Addisonian Soft Fine Diffuse, nonscarring alopecia Diffuse thinning Onycholysis Plummer’s nails

The major changes in epidermal structure in hyper­ thyroidism are thinning and a more pronounced rete pattern.14,15 These paradoxical changes are attributed to an overall anabolic effect of thyroid hormone. Specific effects of thyroid hormone include increased oxygen consumption and protein synthesis with stimulation of mitosis.8 A recent article by Safer et al. proposed T3-mediated fibrob­ last proliferation with resultant production of trans­ forming growth factor-b1 as the mechanism for epidermal thickening. The article also suggested an opposite effect on epidermal proliferation when thyroid hormone was applied topically.4 Hyperhidrosis is a frequent complaint of patients suffering from thyrotoxicosis and is attributed to increased metabolic activity and activation of the sympathetic arm of the autonomic nervous system. By contrast, external heat does not appear to have an impact on the secretion of sweat, as discussed by Gibinski et al.14 Hyperhidrosis may be diffuse but is often localized to the palms and scalp.11

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Kim et al. described a case of a woman presenting with signs and symptoms of Graves disease accom­ panied by multiple eccrine hidrocystomas. The skin lesions resolved with treatment of the underlying thyroid dysfunction. While eccrine hidrocystomas have been reported in patients with hyperhidrosis, it remains unclear why this phenomenon has not been seen more frequently in patients with hyper­ thyroidism. The authors suggested a direct effect of thyroid hormone as a causative factor.15 Although the effect in hyperthyroidism on seba­ ceous glands has not been studied in detail, it has been shown that in hypothyroid animals there is a decrease on sebum production.16,17 Both TSH and T4 have been demonstrated to have effects on sebo­ cytes.18 The exact effect in hyperthyroidism has not been reported.

Hair Examination of hair, as described, may demonstrate a soft, fine texture with or without nonscarring alopecia. The demonstration of thyroid hormone receptors (primary b1) on the dermal papilla and outer root sheath substantiates the changes observed.19,20 In fact, measurement of T4 content in hair has been proposed as a method for noninvasive estimation of systemic thyroid status.21 The clinical changes observed are believed to be due to altera­ tions of the anagen/telogen ratio.11 Eyelash loss has also been reported with hyperthyroidism, respond­ ing to treatment of the underlying endocrinologic disease. Loss of axillary hair has also been reported in up to 60% of patients.22 One important report showed in murine models that intraperitoneal T3 resulted in 48% fewer hairs (p < .001), yet topical application demonstrated 160% more hairs (p< .01).4 This study was some­ what reinforced by another that showed increased hair length in topically applied T3 versus control (1180% longer; p < .001).23 Why there is such a stark contrast between systemic and topical application seems counterintuitive, yet a similar study showed similar results in epidermal thickening.4 Human clinical implications of this phenomenon require further elucidation. There is a higher incidence of alopecia areata in hyperthyroid patients as well, especially in patients with autoimmune thyroid diseases. Up to 8% of patients with alopecia have associated thyroid dis-

C.-D. Cokonis et al.

Figure 8.3. Onycholysis seen in hyperthyroidism

orders, most commonly thyroiditis.24 Please refer to chapter 11, which is devoted to alopecia and thyroid disease.

Nails Nail growth is enhanced in hyperthyroidism, and nail changes are seen in approximately 5% of hyperthyroid patients.25 While not specific for hyperthyroidism, concave nails with distal onychol­ ysis, termed Plummer’s nails, is the most frequent finding (Figure 8.3).24,25 For unknown reasons, this distal separation from the nail plate often begins on the fourth digit and may spread to involve toenails as well.10 The name “dirty nails” has been used to describe onycholysis, which predisposes to dirt trap­ ping beneath the nail bed.26 Nail findings are less frequent in older patients.10 Beau’s ridge, a transver­ sal thick ridge, may also be present.24 Additional nail findings seen in the context of hyperthyroidism are caused by overlap with other autoimmune diseases. For example, nail pitting and trachyonychia can be seen with associated alopecia areata.11

Dermis Dermal changes associated with hyperthyroidism are less well defined compared with epidermal changes. In a study by Safer et al.,4 no significant difference of dermal thickness compared to con­ trols is appreciated with systemic thyroid admin­ istration, but topical effects of thyroid hormone result in a significantly thicker dermis.

8. Cutaneous Manifestations of Hyperthyroidism

Pretibial myxedema results primarily from changes in the dermis. The characteristic plaques of pretibial myxedema result from dermal accu­ mulation of hyaluronic acid.27 In addition, altera­ tions in quantity and quality of elastic elements are seen.28 One report looked at glycosaminoglycans (GAGs) in Graves disease. Dermatan sulfate and heparin sulfate/heparin (HS/H) were both elevated in Graves patients versus controls, sevenfold higher in HS/H in fact. Antithyroid treatment led to a decrease to normal values in HS/H and below normal values with dermatan sulfate.29 The authors contended that the changes in GAGs reflected systemic changes in extracellular matrix proper­ ties. This hypothesis, however, fails to explain why normalization of thyroid status does not improve thyroid dermopathy (pretibial myxedema).

Vascular Changes The effects of thyroid hormones on the cardiovas­ cular system have been extensively studied. In the hyperthyroid state, there is a 30% increase in car­ diac output; increases in heart rate, pulse pressure, and blood pressure; and a decrease in peripheral vascular resistance.30–32 T3 causes smooth muscle relaxation; therefore, it inhibits vascular smooth muscle contractility and decreases peripheral vas­ cular resistance.33 T3 also suppresses vascular smooth muscle cell proliferation by inhibiting angi­ otensin II-induced activation of cyclic adenosine monophosphate (cAMP) response element-binding protein.34 The skin feels warm in hyperthyroidism as an effect of these vascular changes. Palmar erythema and facial flushing may occur due to the same mechanism.25 Cutaneous vessels may show calcifications. In a small study evaluating 14 specimens of calci­ fied cutaneous blood vessels, 3 of the patients had hyperthyroidism.35 Hyperthyroidism may be associated with tel­ angiectasia formation. Generalized essential tel­ angiectasia has been reported to occur in a patient with Graves disease.36 In another case, unilateral nevoid telangiectasia developed in a hyperthyroid patient.37 Hyperthyroidism may be associated with anticardiolipin antibodies.38–40 Liel reported a case of a woman who developed livedo reticularis

77

and anticardiolipin antibodies associated with hyperthyroidism. Treatment of her thyroid disease with methimazole resulted in resolution of livedo reticularis and normalization of anticardiolipin antibodies.38 In one case report, purpura fulmi­ nans occurred after starting propylthiouracil for Graves disease. A serologic workup revealed the presence of anticardiolipin antibodies, antineu­ trophilic cytoplasmic antibody, a false-positive VDRL test, and activated protein C resistance, which all resolved within 6 months of discontinu­ ing propylthiouracil and treatment with radioac­ tive iodine (RAI).39 Thyrotoxicosis has been associated with arteri­ tis. One study of 59 women with giant cell arteritis found that 8.5% had a history of thyroitoxicosis.41 When giant cell arteritis involves the aorta, patients may present with aortic insufficiency.42 In addi­ tion, two cases of concomitant hyperthyroidism, Crohn disease, and Takayasu arteritis have been reported.43

Thyroid Ophthalmopathy Thyroid ophthalmopathy develops in 20%–50% of patients with Graves disease.44,45 It most com­ monly occurs in the hyperthyroid state; however, it may occur in euthyroid and hypothyroid patients as well.31,44 Graves ophthalmopathy manifests as con­ junctival irritation, eyelid retraction, von Graefe sign (a dynamic “lid lag” sign), exophthalmos (bulging of the eye anteriorly out of the orbit as seen with endocrinopathies), lagophthalmos (inability or poor closure of the upper eyelid), optic nerve dysfunction, or extraocular muscle involvement in one or both eyes.44,46,47 One study found that eyelid retraction occurred in 38%, von Graefe sign in 36%, and lagophthalmos in 16% of Graves ophthalmopathy patients.47 Only 3%–5% of patients with Graves ophthalmopathy have severe symptoms such as intense pain, chemosis (conjunc­ tival edema), proptosis (anterior displacement of the eye due to any cause), diplopia (double vision), or loss of vision.31,45 Most patients experience mild discomfort.45 The physical disfigurement, eye discomfort, and impaired vision caused by Graves ophthalmopathy can result in depression, anxiety, and decreased psychological well-being even in euthyroid patients.48

78

The pathogenesis of Graves ophthalmopathy involves enlargement of orbital fat or extraocular muscles. This causes the globe to project for­ ward and compression of ocular venous outflow. Fibroblasts within the orbit are stimulated in thy­ roid ophthalmopathy to produce hyaluronic acid or differentiate into mature adipocytes. Insulin-like growth factor 1 receptors on fibroblasts are acti­ vated by the immunoglobulins of Graves disease patients. This causes an increase in hyaluronic acid within ocular muscle connective tissue, resulting in edema, myositis, fibrosis, and potentially ocular misalignment.45 Ocular fibroblasts display an increased expression of TSH receptors in Graves disease.45,49 Cases of palpebral edema with or without pruritus or erythema have been described in hyperthyroid patients due to Graves disease. Dermatopathology reveals edema of the dermis and dilated lymphatics without evidence of increased mucopolysaccharides by alcian blue stain. The eti­ ology of the edema is thought to be due to obstruc­ tion of venous return in these cases.50

Skeletal System Elevations in thyroid hormone can affect the skeletal system by decreasing bone mineral den­ sity, resulting in osteoporosis and pathologic frac­ tures.51,52 Vitamin D levels are decreased, leading to a negative calcium balance. Fortunately, patients who have been treated for hyperthyroidism seem to experience normalization of bone density51 and a decrease in fracture risk.52 In untreated pediatric hyperthyroidism, the most common site of bone loss is in the cortex.53 In patients with severe Graves disease, the skeletal system may be affected with thyroid acropachy.54 Thyroid acropachy is the triad of finger clubbing, swelling of the digits, and perio­ steal reaction in the long bones.55 Of patients with Graves disease, 30% develop exophthlamos, 4% have thyroid dermopathy and 1% develop thyroid acropachy.54–56 At the time of diagnosis, most with acropachy patients are hyperthyroid, but it may present in euthyroid and hypothyroid patients as well. One study of 40 patients showed thyroid acropachy to be more common in females (ratio of men to women 3.4:1), and the average age was 50 years old (range 32–82). Patients may have arthral-

C.-D. Cokonis et al.

gias in the distal small bones.54 Plain radiographs classically show lacy subperiosteal new bone in the diaphysis of the short tubular bones of the hands and feet.55 The most common bones to be affected are the first, second, and fifth metacarpals; the proximal and middle first, second, and fifth phalanges of the fingers; and the first metatarsals and the first proximal phalanges of the toes.44,55 Infrequently, the long bones of the forearms and legs may show these radiographic changes.44,55 Bone scans demonstrate increased radionucleotide uptake in affected areas.44 Histologically, there is nodular fibrosis of the periosteal area, subperiosteal bone formation, and fibrosis of the marrow space.44 There may be a potential association with smoking; in one study, 79% were smokers, which is 3.7 times higher than women and 2.6 times higher then men in the US population.54

Pregnancy and Congenital Hyperthyroidism Pregnancy is associated with significant changes in maternal thyroid physiology, such as moderate thyroid enlargement, glandular hyperplasia, and increased vascularity. In the first trimester, thyroid hyperplasia may be due to the homology between hCG (human chorionic gonadotropin) and TSH. An increase in estrogen in pregnancy leads to increases in thyroid binding globulin.57 Overt hyperthyroidism affects 2 in 1000 preg­ nancies.57,58 Clinically, patients may present with nervousness, heat intolerance, palpitations, thyromegaly, weight stabilization, weight loss, heart failure, and exophthalmos.57 Some of these symptoms may easily be confused with expected symptoms of pregnancy. In mothers with hyper­ thyroidism, there is an increased risk of spontane­ ous pregnancy loss,59–61 congestive heart failure, thyroid storm, preterm birth, preeclampsia, fetal growth retardation, and perinatal morbidity and mortality. Graves disease is the most common cause of hyperthyroidism in pregnancy; however, women with a history of Graves disease prior to preg­ nancy may experience normalization of thyroid hormone levels. Women with Graves disease may deliver a baby with hypothyroidism57 or hyperthy­ roidism.62,63 One case report described a Graves

8. Cutaneous Manifestations of Hyperthyroidism

disease mother delivering dichorionic, diamniotic twins; one developed hypothyroidism and the other hyperthyroidism.64 Hyperthyroidism in pregnancy may also be due to toxic nodular goiter, thyroid storm, thyroiditis, T3 thyrotoxicosis, or excessive thyroid intake. Unique to pregnancy is gestational transient thyrotoxicosis, which is usually associated with hyperemesis gravidarum, molar pregnancies, and high hCG levels.57 Congenital hyperthyroidism most commonly occurs in infants born to mothers with Graves dis­ ease.62,65,66 This is due to transplacental passage of TSH receptor antibodies (TRAbs)62 and occurs in 0.6%–1% of babies born to mothers with Graves disease or previously treated Graves disease.62,63 The risk of congenital hyperthyroidism is directly proportional to the level of TRAbs in the newborn’s blood.67,68 Antibodies may persist after maternal ablation of thyroid by surgery, radioiodine, or Hashimoto thyroiditis.62 Neonatal hyperthyroidism due to maternal Graves disease may persist up to 3 months.63 Rarely, congenital hyperthyroidism may be due to genetic defects such as in McCuneAlbright syndrome62,69 and activating mutations in the TSH receptor gene.62,65,66 In the newborn, signs of hyperthyroidism include congestive heart failure, arrhythmias, hepatosplenomegaly, jaundice, thrombocytopenia, and hyperviscosity syndrome. Neonates may be flushed, diaphoretic, and hyperkinetic. Clinically, as in adults, they may have a goiter, exophthalmos, or periorbital edema.62

Other Systemic Manifestations Neuropsychiatric manifestations of hyperthy­ roidism include anxiety, depression, dysphoria, restlessness, emotional lability, and paranoia.31,70,71 Cognitive dysfunction may be seen, especially in the elderly. Signs of mania, such as euphoria and pressured speech, may also be present.71 Although routine screening for thyroid disease is common in depressed patients, one study of 277 patients hos­ pitalized for depression or dysthymia found only 2 cases of hyperthyroidism and 8 with subclinical hypothyroidism.72 The gastrointestinal system is affected during a hyperthyroid state. Patients experience frequent bowel movements, diarrhea, and malabsorption

79

with steatorrhea.31,73 Small and large intestinal transit time is decreased in hyperthyroid cases.73 In both men and women, the reproductive sys­ tem may be affected in hyperthyroidism. Menstrual irregularities occur in 20%–60% of females, with hypomenorrhea and oligomenorrhea occurring most often.74 Some women experience anovulatory cycles75,76 and, among women with autoimmune thyroid disease, infertility.60,61 Male patients with hyperthyroidism have an increase in peripheral conversion of androgen to estrogen. They may present with clinical signs of high-estrogen states such as gynecomastia, spider angiomas, and a decreased libido.77 Sperm motility tends to be lower in thyrotoxicosis and improves following treatment of hyperthyroidism.77

Diagnosis Laboratory studies are the primary diagnostic tool in diagnosis of hyperthyroidism. TSH levels are used for primary screening in asymptomatic patients. Free T4 and T3 should be ordered in addition to TSH if thyrotoxicosis is suspected.31 Hyperthyroid patients will have a suppressed TSH level and elevated levels of T4 and T3.30,78 In 95% of patients with thyrotoxicosis, TSH is suppressed (< 0.05 µU/mL), and T4 is elevated. Free thyroid hormone levels should be ordered instead of total T4 and T3 levels since the total level is a factor of free and protein-bound thyroid hormone. Protein binding may be affected by multiple medications (phenytoin, carbamazepine, heparin, diazepam, nonsteroidal anti-inflammatory drugs, salicylates, furosemide, estrogen, and opiates) and disorders/ conditions (hepatitis and pregnancy).31 The presence of TRAbs indicates Graves dis­ ease. The TSH-binding inhibitor immunoglobulin (TBII) assay is used to detect TRAbs; however, it is not specific for antibodies that cause thy­ roid stimulation.31 The thyroid-stimulating immu­ noglobulin (TSI) assay measures the presence of TSH receptor antibodies by detecting thyroid hormone production.78 Calculating the T3-to-T4 ratio can aid in diagnos­ ing the etiology of hyperthyroidism. T3 toxicosis occurs when free T3 is increased and T4 is within normal range. The T3/T4 ratio is typically greater than 20 in Graves disease and toxic multinodular

80

goiter as they are predominantly T3 processes. In thyroiditis, iodine exposure, or exogenous levothy­ roxine intake, the T3/T4 ratio is usually less than 20.31 Radioactive iodine uptake and scanning utilizing RAI (iodine 123 or iodine 131) are useful tools for diagnosing hyperthyroidism. In general, increased uptake indicates de novo synthesis of thyroid hor­ mone. Diffuse uptake is seen in Graves disease, whereas toxic multinodular goiter has focal nodules of increased uptake. A solitary toxic nodule has only one focus of uptake. Increased uptake may also be observed in iodine deficiency, Hashimoto thyroiditis, nephritic syndromes, chronic diarrhea, and ingestion of bile acid-binding resins. Decreased uptake may be seen in exogenous thyroid intake, thyroiditis, iodine intoxication, and ingestion of iodine-rich drugs or food (amiodarone, radiographic contrast agents, and kelp [seaweed]). Technetium 99 m pertechnetate imaging is used similarly to RAI scanning to detect iodine uptake.31 A thyroid sonogram is a useful tool in aiding in the diagnosis of hyperthyroidism. Ultrasounds can detect solitary thyroid nodules or diffuse enlarge­ ment as seen in Graves disease. Graves disease may demonstrate an increase in blood flow by Doppler studies.31 Diagnosing fetal hyperthyroidism may be crucial in preventing fetal death. In mothers with elevated TRAb at 26–28 weeks of gestation, a fetal thyroid ultrasound should be performed.63 Enlarged fetal thyroid glands may signify either hyperthyroidism or hypothyroidism. Hyperthyroidism is presumed in the presence of intrauterine growth retardation, arrhythmias, tachycardia (>160 beats per minute), congestive heart failure, advanced bone age, cranio­ synostosis, and hydrops.62,63 Umbilical cord blood sampling may be used for definitive diagnosis.63 For more details on the laboratory diagnosis of thyroid disease, please refer to chapter 4.

Treatment The management of hyperthyroidism is aimed at reducing thyroid hormone production and manag­ ing systemic symptoms, such as tachycardia. The most commonly used class of antithyroid medication is the thionamides. Propylthiouracil, methimazole, and carbimazole constitute this class

C.-D. Cokonis et al.

of medications and act by decreasing the out­ put of thyroid hormone from the thyroid gland. They inhibit thyroid peroxidase-mediated iodina­ tion of thyroglobulin, propylthiouracil reversibly and methimazole irreversibly. Propylthiouracil also inhibits the peripheral conversion of T4 to T3. Carbimazole, which is not currently available in the United States, is rapidly converted to methi­ mazole, the active drug moiety. The starting dose of propylthiouracil is 300 mg/day in three divided doses; methimazole is given 15–30 mg/day as a single daily dose. Adverse effects include abnormal taste sensation, pruritus, arthralgias, and urticaria, occurring in 1%–5% of cases. Rare but serious adverse effects include hepatitis in 0.1%–0.2% and agranulocytosis in 0.2%–0.5%, leading to fever, sore throat, and sepsis in some cases.31 There are reports of vasculitis, including vasculitis associated with antineutrophil cytoplasmic antibodies after treatment with propylthiouracil.79,80 Management of cardiovascular symptoms of hyperthyroidism is with the use of b-adrenergic­ blocking agents. Propranolol is commonly used in doses greater than 160 mg/day. It has been shown to decrease T3 levels in addition to adren­ ergic blockade. Other b-blockers, like atenolol (50–200 mg/day in two divided doses), metoprolol (100–200 mg/day), and nadolol (40–80 mg/day), can be used successfully.31 Many other medications are used to treat hyper­ thyroidism when thionamides are not warranted. Inorganic iodine at high concentrations blocks the release of prestored thyroid hormone, decreases iodine transport, and prevents oxidation in follicu­ lar cells. The Wolff-Chaikoff effect, or the inhibi­ tion of thyroid metabolism by iodine, is transient, and increasing doses of iodide are necessary for treatment.31 Inorganic iodine is available as satu­ rated solution of potassium iodide (SSKI) and Lugol’s solution. Dosage of SSKI (38 mg/drop) is 1 drop daily, and for Lugol’s solution (8 mg/drop) it is 3–5 drops per day. Potassium perchlorate is useful in the treatment of amiodarone-induced thyrotoxicosis; however, one serious side effect is aplastic anemia. Lithium is also a useful secondline agent in doses of 300 mg every 8 h. Lithium levels must be monitored. In addition to reducing cholesterol levels, cholestyramine binds thyroid hormone in the intestine, thereby reducing entero­ hepatic circulation of thyroid hormone.

8. Cutaneous Manifestations of Hyperthyroidism

Radioactive iodine (RAI) is used to cause thyroid ablation. The most common side effect, which is essentially also the goal of therapy, is permanent hypothyroidism. Secondary malig­ nancy risk is considered either negligible or vir­ tually nonexistent, but reports vary. One recent report noted that after RAI therapy there was an increase in cerebrovascular mortality as well as malignancy, particularly in those above the age of 60 years. A limitation of this study is that it was unclear if all the confounding vari­ ables were taken into account.81 Thyroidectomy is potentially curative for patients with toxic multinodular goiters and solitary toxic adenomas. Patients with thyroiditis are usually symptomati­ cally treated with b-adrenergic-blocking agents and nonsteroidal anti-inflammatory medications for pain.31 There is some controversy over the treatment of subclinical hyperthyroidism, with differing opin­ ions in many texts and articles. One author sug­ gested that because there is an associated increased risk of atrial fibrillation, mortality, and decreased bone mineral density, especially in elderly women, there may be a subset of patients in whom treat­ ment should be considered.82 A contrasting view was presented by Surks et al.,83 who looked at this issue from an evidence-based medicine approach. The authors noted, however, that aggressive inves­ tigation/screening would be appropriate in preg­ nancy, women older than 60 years, and others at high risk for thyroid abnormalities. Dermatologic manifestations of thyroid disease such as onycholysis, Plummer’s nails, and pruritus fortunately improve with the treatment of thyroid disease.78 Unfortunately, the treatment of pretibial myxe­ dema is difficult and does not seem to improve with correction of thyroid function.78 However, since thyroid dermopathy is rarely symptomatic, no treatment may be appropriate. In patients with limited mobility, cosmetic concerns, or discom­ fort, treatment may be initiated.44 Patients should be encouraged to stop smoking due to an associ­ ated risk of ophthalmopathy, dermopathy, and acropachy. Since the severe elephantastic form of thyroid dermopathy is seen in obese patients, weight reduction may be recommended, although it has not been proven to be effective. The most common treatment modality for thyroid dermopa­

81

thy is topical steroids under occlusion.44 Several studies have shown improvement of pretibial myxedema with the use of mid- to high-potency topical corticosteroids under occlusion.44,84 One study revealed partial remission of pretibial myxe­ dema in 38% of patients with the use of topical corticosteroids as opposed to 17% in the group receiving no treatment.85 A patient had complete resolution of pretibial myxedema and improve­ ment in Graves ophthalmopathy with the use of oral pentoxifylline and topical clobetasol oint­ ment.86 Patients may benefit from compression stockings or bandages.44 One case of elephantastic pretibial myxedema received 6 weeks of intensive complete decongestive physiotherapy and had sustained skin softening at a 2-year follow-up.87 The use of intravenous immunoglobulin initially showed promise in treatment; however, results could not be duplicated.44,88 Surgical excision of skin nodules and skin grafting can result in tem­ porary improvement of pretibial myxedema, but an exuberant reoccurrence in the site of surgical scar may occur. Intralesional glucocorticoids and hyaluronidase are not recommended because they may cause an uneven skin texture. Octreotide acetate has also showed promise; however, it was not beneficial in a long-term follow-up.44 Treatment of Graves ophthalmopathy ranges from supportive therapy in the mildest cases to corticosteroid therapy or surgery in patients with more severe disease.44 Spontaneous improvement is seen in 60%–80% of patients with thyroid ophthalmopathy.89 Preventive measures include smoking cessation and avoidance of second-hand smoke.76 Mild disease is controlled with lubricat­ ing eye drops, punctual plugs, taping the eye shut to sleep, and corrective lenses.89 Radiotherapy may be used to treat ophthalmopathy; however, a study only showed a statistically significant improvement in motility. In addition, only 25% of the irradiated group was able to avoid addi­ tional strabismus surgery.90 Corticosteroid therapy is effective in 66.9% of moderately to severely affected patients. Pulsed weekly intravenous cor­ ticosteroids are more effective than daily oral corticosteroids.91 Local corticosteroids injected inside the septum near the orbital rim have shown improvement in ophthalmopathy. Although the improvement was not as great as with systemic corticosteroids, there were fewer adverse effects

82

with localized treatment.89 The adjunctive use of radiotherapy to corticosteroids tends to be more effective than steroids alone.91 The use of radio­ iodine therapy in the treatment of Graves disease may worsen or induce thyroid ophthalmopathy, and corticosteroid therapy may be used prophy­ lactically in these patients.76,89 Other immunosup­ pressive agents used include cyclosporine and methotrexate.89 Pentoxifylline, allopurinol, nico­ tinamide, infliximab, etanercept. and rituximab have also been used to treat thyroid ophthalmopa­ thy.85,88,92 Surgical techniques to improve thyroid ophthalmopathy and prevent optic neuropathy include orbital fat decompression, strabismus sur­ gery, and repair of lagophthalmos and eyelid malposition.93 In pregnancy, first-line therapy for hyperthy­ roidism is thionamide drugs.57,63 The goal of treat­ ment is to maintain the T4 level at or just above the upper limit of normal using the lowest possible dose of antithyroid medication.63,94 Free T4 should be measured every 4 weeks.94 Propylthiouracil is preferred over methimazole because it partially inhibits the peripheral conversion of T4 to T3, and it crosses the placenta 75% less than methimazole.57,58 In addition, methimazole has been associated with aplasia cutis.57,58,95–97 Other reported congenital defects attributed to methimazole include cho­ anal atresia, esophageal atresia, tracheoesopha­ geal fistula, minor facial and skin dysmorphic features, growth restriction, and developmental delay.63,96 Congenital goiter, hypothyroidism, or both may occur with all thionamides.96 Other treat­ ment options for hyperthyroidism in pregnancy include propranolol, iodide, ipodate, iopanoic acid, and thyroidectomy, which are rarely used due to obstetric and fetal risks.57,63,94 Amiodarone can be used to treat supraventricular and ventricular arrhythmias.94 RAI ablation is contraindicated in pregnancy,57,63 and pregnancy should be avoided for 6 months after its use.57 Neonatal hyperthyroidism may be treated with the same modalities as for older patients. These include propylthiouracil, methimazole, carbimazole, saturated potassium iodide, Lugol’s iodine solution, iopanoic acid, sodium ipodate, propranolol, prednisone, digoxin, and thyroid­ ectomy.62,98 Treatment usually lasts 1 month on average.98 Fetal hyperthyroidism may be treated by treating maternal disease with propylthiouracil.62

C.-D. Cokonis et al.

Hyperthyroidism and Associated Cutaneous Diseases Many dermatologic diseases have been associated with hyperthyroidism, mainly immune-mediated processes. Please refer to chapter 13 for a detailed discussion on dermatologic disorders associated with thyroid disease. As mentioned, an association between thyroid disease and alopecia areata has been described. There is an increased incidence of antithyroid antibodies demonstrated in alopecia areata patients as well, reported as high as 24%.99 Other studies, however, have not shown an association with thy­ rotoxicosis and alopecia areata.100,101 Graves disease has been associated with blis­ tering diseases, especially pemphigus vulgaris and pemphigus foliaceous, as well as Sweet’s syndrome and urticaria.8 Cases of thyrotoxicosis occurring with dermatitis herpetiformis102 and her­ pes gestationis102 have also been reported. Many connective tissue diseases have been associated with thyrotoxicosis. Graves disease has been reported with dermatomyositis and the sclero­ derma-dermatomyositis overlap syndrome.104–106 Conflicting data exist regarding the association of systemic sclerosis (SSc) and thyrotoxicosis. In a study of 24 patients with SSc, 12.5% had T3 toxicosis.107 A larger study of 202 SSc patients with gender- and age-matched controls revealed 3 cases of Graves disease (p = .0140).108 In contrast, another study of 79 women with SSc with agematched controls with osteoarthritis did not find an association with thyroid dysfunction.109 Miyagawa et al. described two pediatric patients with erythema annulare associated with Sjögren syndrome with coincident findings of antithyroid antibodies110 (Table 8.3).

New Insights Into and Reports on Skin Manifestations of Hyperthyroidism In comparison to hypothryoidism, there is an overall paucity of data in reference to hyperthyroidism, yet there are some recent literature reports that may be of interest and clinically relevant in the near future.

8. Cutaneous Manifestations of Hyperthyroidism

83

Table 8.3. Thyrotoxicosis and associated cutaneous diseases.

Conclusion

Alopecia areata Bullous disorders Dermatitis herpetiformis Epidermolysis bullosa aquisita Herpes gestationis Pemphigus vulgaris Pemphigus foliaceous Connective tissue diseases Dermatomyositis Discoid lupus erythematosus Scleroderma Sjögren syndrome Systemic lupus erythematosus Erythema annulare centrifugum Pustulosis palmoplantaris Sweet’s syndrome Urticaria Vitiligo

Dermatologists, endocrinologists, and primary care providers need to be cognizant of the myriad presentations of hyperthyroidism. Although there are no pathognomonic dermatologic features, awareness of the varied presentations will allow astute clinicians to diagnose the hyperthyroid state so that appropriate therapy may be instituted expediently.

Source: From references 25 and 111–115.

Although most characteristically hyperthy­ roidism manifests with weight loss due to the increased metabolism and lipolysis, patients with anorexia nervosa many have an increased appe­ tite. This may be responsible for involuntary weight gain in this population.116 Thyroid hor­ mones are well documented in their relationship with lipid metabolism. This is partially related to an increase in metabolic rate (defined as oxygen consumption). There is also recent documentation of regional variation of lipid and fat metabolism in hyperthyroid patients. Riis et al. found that femoral and abdominal adipose tissue contribute equally to the excessive rate of lipolysis and appear to be associated with insulin resistance.117 Nedvidkova et al. showed that lipolysis in the abdominal sub­ cutaneous tissue is strongly modulated by thyroid function.118 The clinical relevance of these factors have yet to be determined. With the advent of more in vivo monitoring techniques, more data may soon be available in the field, as editorialized by Mariash in reference to Haluzik et al.119,120 Although atrial myxomas are the most common primary cardiac neoplasm, of which 5%–10% can be attributed to Carney complex, there was a report of a patient with newly diagnosed Graves disease who had an atrial myxoma.121

References 1. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489–499. 2. Leese GP, Flynn RV, Jung RT, Macdonald TM, Murphy MJ, Morris AD. Increasing prevalence and incidence of thyroid disease in Tayside, Scotland: the Thyroid Epidemiology Audit and Research Study (TEARS). Clin Endocrinol (Oxf) 2007 Oct 29 [epub ahead of print]. 3. Stanbury JB, Ermans AE, Bourdoux P, et al. Iodineinduced hyperthyroidism: occurrence and epidemiol­ ogy. Thyroid 1998;8:83–100. 4. Safer JD, Crawford TM, Fraser LM, et al. Thyroid hormone action on skin: diverging effects of topi­ cal versus intraperitoneal administration. Thyroid 2003;13:159–165. 5. Gout S, Morin C, Houle F, Huot J. Death receptor­ 3, a new E-Selectin counter-receptor that confers migration and survival advantages to colon carci­ noma cells by triggering p38 and ERK MAPK acti­ vation. Cancer Res 2006;66:9117–9124. 6. Braverman LE, Utiger RD. Introduction to thyro­ toxicosis. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s: The Thyroid. 7th ed. Philadelphia: Lippincott-Raven; 1996:453–455. 7. Davies TF, Larsen PR. Thyrotoxicosis. In: Wilson GM, Foster D, Kronenberg M, Larsen PR, eds. Williams Textbook of Endocrinology. Philadelphia: Saunders; 2002, 333–368. 8. Heymann WR. Cutaneous manifestations of thyroid disease. J Am Acad Dermatol 1992;26:885–902. 9. Ramanathan M, Abidin MN, Muthukumarappan M. The prevalence of skin manifestations in thyro­ toxicosis—a retrospective study. Med J Malaysia 1989;44:324–328. 10. Jabbour SA. Cutaneous manifestations of endocrine disorders: a guide for dermatologists. Am J Clin Dermatol 2003;4:315–331.

84 11. Heymann WR. The skin in thyrotoxicosis. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid: A Functional and Clinical Text. Philadelphia: Lippincott Williams and Wilkins; 2000, 593–595. 12. Carlson HE. Gynecomastia. N Engl J Med 1980;303 795–799. 13. Dabon-Almirante CL, Surks MI. Clinical and labora­ tory diagnosis of thyrotoxicosis. Endocrinol Metab Clin North Am 1998;27:25–35. 14. Gibinski K, Powierza-Kaczynska C, Zmudzinski J, Giec L, Dosiak J. Thyroid control of sweat gland function. Metabolism 1972;21:843–848. 15. Kim YD, Lee EJ, Song MH, Suhr KB, Lee JH, Park JK. Multiple eccrine hidrocystomas associ­ ated with Graves’ disease. Int J Dermatol 2002;41: 295–297. 16. Goolamali SK, Evered D, Shuster S. Thyroid disease and sebaceous function. Br Med J 1976;1(6007):432– 433. 17. Thody AJ, Shuster S. Control and function of seba­ ceous glands. Physiol Rev 1989;69:383–416. 18. Ebling FJ. Hormonal control and methods of meas­ uring sebaceous gland activity. J Invest Dermatol 1974;62:161–171. 19. Ahsan MK, Urano Y, Kato S, Oura H, Arase S. Immunohistochemical localization of thyroid hor­ mone nuclear receptors in human hair follicles and in vitro effect of L-triiodothyronine on cultured cells of hair follicles and skin. J Med Invest 1998;44:179– 184. 20. Billoni N, Buan B, Gautier B, Gaillard O, Mahe YF, Bernard BA. Thyroid hormone receptor beta1 is expressed in the human hair follicle. Br J Dermatol 2000;142:645–652. 21. Zamboni G, Camilot M, Francia G, et al. Thyroxine hair content in congenital hypothyroidism and hyper­ thyroidism. J Pediatr Endocrinol Metab 2003;16:379– 382. 22. Alonso LC, Rosenfield RL. Molecular genetic and endocrine mechanisms of hair growth. Horm Res 2003;60:1–13. 23. Safer JD, Fraser LM, Ray S, Holick MF. Topical triiodothyronine stimulates epidermal proliferation, dermal thickening, and hair growth in mice and rats. Thyroid 2001;11:717–724. 24. Niepomniszcze H, Amad RH. Skin disorders and thyroid diseases. J Endocrinol Invest 2001;24:628– 638. 25. Leonhardt JM, Heymann WR. Thyroid disease and the skin. Dermatol Clin 2002;20:473–481, vii. 26. Ghayee HK, Mattern JQ 3rd, Cooper DS. Dirty nails. J Clin Endocrinol Metab 2005;902428.

C.-D. Cokonis et al. 27. Lambert WC. Cutaneous deposition disorders. In: Farmer ER, Hood AF, eds. Pathology of the Skin. Norwalk, CT: Appleton and Lange; 1990:432. 28. Matsuoka LY, Wortsman J, Uitto J, et al. Altered skin elastic fibers in hypothyroid myxedema and pretibial myxedema. Arch Intern Med 1985;145:117–121. 29. Komosinska-Vassev K, Winsz-Szczotka K, Olczyk K, Kozma EM. Alterations in serum glycosaminoglycan profiles in Graves’ patients. Clin Chem Lab Med 2006;44:582–588. 30. Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007;116:1725–1735. 31. Nayak B, Hodak SP. Hyperthyroidism. Endocrinol Metab Clin North Am 2007;36:617–656, v. 32. Vargas F, Moreno JM, Rodriguez-Gomez I, et al. Vascular and renal function in experimental thyroid disorders. Eur J Endocrinol 2006;154:197–212. 33. Ojamaa K, Balkman C, Klein IL. Acute effects of triiodothyronine on arterial smooth muscle cells. Ann Thorac Surg 1993;56(1 suppl):S61–S66; discus­ sion S66–S67. 34. Fukuyama K, Ichiki T, Imayama I, et al. Thyroid hormone inhibits vascular remodeling through suppression of cAMP response element binding protein activity. Arterioscler Thromb Vasc Biol 2006;26:2049–2055. 35. Kossard S, Winkelmann RK. Vascular calcifica­ tion in dermatopathology. Am J Dermatopathol 1979;1:27–34. 36. Buckley R, Smith KJ, Skelton HG. Generalized essential telangiectasia in a patient with Graves’ disease: should the spectrum of autoimmune dis­ eases associated with generalized telangiectasia be expanded? Cutis 2000;65:175–177. 37. Kavak A, Kutluay L. Unilateral nevoid telangiectasia and hyperthyroidism: a new association or coinci­ dence? J Dermatol 2004;31:411–414. 38. Liel Y. Livedo reticularis: a rare manifestation of Graves hyperthyroidism associated with anticardioli­ pin antibodies. South Med J 2004;97:601–603. 39. Ligier S, Pham CD, Watters AK, Kassis J, Fortin PR. Purpura fulminans and anticardiolipin antibodies in a patient with Grave’s disease. Scand J Rheumatol 2002;31:371–373. 40. Nakayama T, Yamamoto T, Kanmatsuse K, Kokubun S. Graves’ disease associated with anticar­ diolipin antibody positivity and acquired protein S deficiency. Rheumatol Int 2003;23:198–200. 41. Thomas RD, Croft DN. Thyrotoxicosis and giantcell arteritis. Br Med J 1974;2(5916):408–409. 42. Tandon R, Fahy R. Giant cell arteritis in a patient with acute aortic insufficiency with thyrotoxicosis. Clin Rheumatol 2006;25:254–257.

8. Cutaneous Manifestations of Hyperthyroidism 43. Kettaneh A, Prevot S, Biaggi A, et al. Hyperthyroidism in two patients with Crohn disease and Takayasu arteritis. Scand J Gastroenterol 2003;38:901–903. 44. Fatourechi V. Pretibial myxedema: pathophysiol­ ogy and treatment options. Am J Clin Dermatol 2005;6:295–309. 45. Garrity JA, Bahn RS. Pathogenesis of graves ophthalmopathy: implications for prediction, pre­ vention, and treatment. Am J Ophthalmol 2006;142: 147–153. 46. Bartley GB, Gorman CA. Diagnostic criteria for Graves’ ophthalmopathy. Am J Ophthalmol 1995;119:792–795. 47. Gaddipati RV, Meyer DR. Eyelid retraction, lid lag, lagophthalmos, and von Graefe’s sign quantifying the eyelid features of Graves’ ophthalmopathy. Ophthalmology 2007 Sept 25 [epub ahead of print]. 48. Coulter I, Frewin S, Krassas GE, Perros P. Psychological implications of Graves’ orbitopathy. Eur J Endocrinol 2007;157:127–131. 49. Bahn RS, Dutton CM, Natt N, Joba W, Spitzweg C, Heufelder AE. Thyrotropin receptor expression in Graves’ orbital adipose/connective tissues: poten­ tial autoantigen in Graves’ ophthalmopathy. J Clin Endocrinol Metab 1998;83:998–1002. 50. Higuchi T, Satoh T, Yokozeki H, Katayama I, Nishioka K. Palpebral edema as a cutaneous mani­ festation of hyperthyroidism. J Am Acad Dermatol 2003;48:617–619. 51. Wexler JA, Sharretts J. Thyroid and bone. Endocrinol Metab Clin North Am 2007;36:673–705, vi. 52. Vestergaard P, Mosekilde L. Fractures in patients with hyperthyroidism and hypothyroidism: a nation­ wide follow-up study in 16,249 patients. Thyroid 2002;12:411–419. 53. Numbenjapon N, Costin G, Gilsanz V, Pitukcheewanont P. Low cortical bone density meas­ ured by computed tomography in children and ado­ lescents with untreated hyperthyroidism. J Pediatr 2007;150:527–530. 54. Fatourechi V, Ahmed DD, Schwartz KM. Thyroid acropachy: report of 40 patients treated at a single institution in a 26-year period. J Clin Endocrinol Metab 2002;87:5435–5441. 55. Tran HA. Thyroid acropachy. Intern Med J 2004;34:513–514. 56. Anderson CK, Miller OF 3rd. Triad of exoph­ thalmos, pretibial myxedema, and acropachy in a patient with Graves’ disease. J Am Acad Dermatol 2003;48:970–972. 57. Casey BM, Leveno KJ. Thyroid disease in preg­ nancy. Obstet Gynecol 2006;108:1283–1292.

85 58. Kalb RE, Grossman ME. The association of aplasia cutis congenita with therapy of maternal thyroid dis­ ease. Pediatr Dermatol 1986;3:327–330. 59. Anselmo J, Cao D, Karrison T, Weiss RE, Refetoff S. Fetal loss associated with excess thyroid hormone exposure. JAMA 2004;292:691–695. 60. Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female reproduction. Clin Endocrinol (Oxf) 2007;66:309–321. 61. Trokoudes KM, Skordis N, Picolos MK. Infertility and thyroid disorders. Curr Opin Obstet Gynecol 2006;18:446–451. 62. Zimmerman D. Fetal and neonatal hyperthyroidism. Thyroid 1999;9:727–733. 63. Chan GW, Mandel SJ. Therapy insight: management of Graves’ disease during pregnancy. Nat Clin Pract Endocrinol Metab 2007;3:470–478. 64. O’Connor MJ, Paget-Brown AO, Clarke WL. Premature twins of a mother with Graves’ disease with discordant thyroid function: a case report. J Perinatol 2007;27:388–389. 65. Kopp P, van Sande J, Parma J, et al. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 1995;332:150–154. 66. Nishihara E, Fukata S, Hishinuma A, et al. Sporadic congenital hyperthyroidism due to a germline mutation in the thyrotropin receptor gene (Leu 512 Gln) in a Japanese patient. Endocr J 2006;53(735– 740. 67. Fu J, Jiang Y, Liang L, Zhu H. Risk factors of primary thyroid dysfunction in early infants born to mothers with autoimmune thyroid disease. Acta Paediatr 2005;94:1043–1048. 68. Skuza KA, Sills IN, Stene M, Rapaport R. Prediction of neonatal hyperthyroidism in infants born to moth­ ers with Graves disease. J Pediatr 1996;128:264– 268. 69. Yoshimoto M, Nakayama M, Baba T, et al. A case of neonatal McCune-Albright syndrome with Cushing syndrome and hyperthyroidism. Acta Paediatr Scand 1991;80:984–987. 70. Bunevicius R, Prange AJ Jr. Psychiatric manifesta­ tions of Graves’ hyperthyroidism: pathophysiol­ ogy and treatment options. CNS Drugs 2006;20: 897–909. 71. Peiris AN, Oh E, Diaz S. Psychiatric manifestations of thyroid disease. South Med J 2007;100:773–774. 72. Ordas DM, Labbate LA. Routine screening of thyroid function in patients hospitalized for major depression or dysthymia? Ann Clin Psychiatry 1995;7:161– 165.

86 73. Wegener M, Wedmann B, Langhoff T, Schaffstein J, Adamek R. Effect of hyperthyroidism on the transit of a caloric solid-liquid meal through the stomach, the small intestine, and the colon in man. J Clin Endocrinol Metab 1992;75:745–749. 74. Krassas GE. Thyroid disease and female reproduc­ tion. Fertil Steril 2000;74:1063–1070. 75. Doufas AG, Mastorakos G. The hypothalamicpituitary-thyroid axis and the female reproductive system. Ann N Y Acad Sci 2000;900:65–76. 76. Krassas GE, Perros P. Prevention of thyroid associatedophthalmopathy in children and adults: current views and management of preventable risk factors. Pediatr Endocrinol Rev 2007;4:218–224. 77. Krassas GE, Pontikides N. Male reproductive func­ tion in relation with thyroid alterations. Best Pract Res Clin Endocrinol Metab 2004;18:183–195. 78. Burman KD, McKinley-Grant L. Dermatologic aspects of thyroid disease. Clin Dermatol 2006;24:247–255. 79. Tan F, Nam TQ, Lee KO, Cheah WK, Mukherjee JJ. Recurrent episodes of arthritis in a hyperthyroid patient. Singapore Med J 2006;47:163–165. 80. Erem C, Yucel Y, Ya Z, Reis A, Kocak M, Hacihasanoglu A. Leukocytoclastic vasculitis: a rare manifestation of propylthiouracil hypersensitivity. Med Princ Pract 2005;14:366–369. 81. Metso S, Jaatinen P, Huhtala H, Auvinen A, Oksala H, Salmi J. Increased cardiovascular and cancer mor­ tality after radioiodine treatment for hyperthyroidism. J Clin Endocrinol Metab 2007;92:2190–2196. 82. Cooper DS. Approach to the patient with sub­ clinical hyperthyroidism. J Clin Endocrinol Metab 2007;92:3–9. 83. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291(2): 228–238. 84. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydro­ colloid occlusive dressing. Acta Derm Venereol 1992;72:69–71. 85. Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves disease (pretibial myxedema). Review of 150 cases. Medicine (Baltimore) 1994;73:1–7. 86. Pineda AM, Tianco EA, Tan JB, Casintahan FA, Beloso MB. Oral pentoxifylline and topical clobeta­ sol propionate ointment in the treatment of pretib­ ial myxoedema, with concomitant improvement of Graves’ ophthalmopathy. J Eur Acad Dermatol Venereol 2007;21:1441–1443. 87. Susser WS, Heermans AG, Chapman MS, Baughman RD. Elephantiasic pretibial myxedema: a novel treatment for an uncommon disorder. J Am Acad Dermatol 2002;46:723–726.

C.-D. Cokonis et al. 88. Terheyden P, Kahaly GJ, Zillikens D, Brocker EB. Lack of response of elephantiasic pretibial myxoedema to treatment with high-dose intra­ venous immunoglobulins. Clin Exp Dermatol 2003;28:224–226. 89. Modjtahedi SP, Modjtahedi BS, Mansury AM, et al. Pharmacological treatments for thyroid eye disease. Drugs 2006;66:1685–1700. 90. Mourits MP, van Kempen-Harteveld ML, Garcia MB, Koppeschaar HP, Tick L, Terwee CB. Radiotherapy for Graves’ orbitopathy: randomised placebocontrolled study. Lancet 2000;355(9214):1505– 1509. 91. Zoumalan CI, Cockerham KP, Turbin RE, et al. Efficacy of corticosteroids and external beam radia­ tion in the management of moderate to severe thyroid eye disease. J Neuroophthalmol 2007;27:205–214. 92. Nielsen CH, El Fassi D, Hasselbalch HC, Bendtzen K, Hegedus L. B-cell depletion with rituximab in the treatment of autoimmune diseases. Graves’ ophthalmopathy the latest addition to an expanding family. Expert Opin Biol Ther 2007;7:1061–1078. 93. Della Rocca RC. Thyroid-related orbitopathy: con­ cepts and management. Facial Plast Surg 2007;23: 168–173. 94. Bach-Huynh TG, Jonklaas J. Thyroid medica­ tions during pregnancy. Ther Drug Monit 2006;28: 431–441. 95. Iwayama H, Hosono H, Yamamoto H, Oshiro M, Ueda N. Aplasia cutis congenita with skull defect in a monozygotic twin after exposure to methima­ zole in utero. Birth Defects Res A Clin Mol Teratol 2007;79:680–684. 96. Diav-Citrin O, Ornoy A. Teratogen update: antithy­ roid drugs-methimazole, carbimazole, and pro­ pylthiouracil. Teratology 2002;65:38–44. 97. Karg E, Bereg E, Gaspar L, Katona M, Turi S. Aplasia cutis congenita after methimazole exposure in utero. Pediatr Dermatol 2004;21:491–494. 98. Polak M, Legac I, Vuillard E, Guibourdenche J, Castanet M, Luton D. Congenital hyperthyroidism: the fetus as a patient. Horm Res 2006;65:235–242. 99. Milgraum SS, Mitchell AJ, Bacon GE, Rasmussen JE. Alopecia areata, endocrine function, and autoan­ tibodies in patients 16 years of age or younger. J Am Acad Dermatol 1987;17:57–61. 100. Nanda A, Alsaleh QA, Al-Hasawi F, Al-Muzairai I. Thyroid function, autoantibodies, and HLA tis­ sue typing in children with alopecia areata. Pediatr Dermatol 2002;19:486–491. 101. Puavilai S, Puavilai G, Charuwichitratana S, Sakuntabhai A, Sriprachya-Anunt S. Prevalence of thyroid diseases in patients with alopecia areata. Int J Dermatol 1994;33:632–633.

8. Cutaneous Manifestations of Hyperthyroidism 102. Callen JP, Weston WF, Chanda JJ. Dermatitis herpetiformis and thyrotoxicosis. Int J Dermatol 1979;18:219–221. 103. Holmes RC, Black MM. Herpes gestationis. A possible association with autoimmune thyrotoxi­ cosis (Graves’ disease). J Am Acad Dermatol 1980;3:474–477. 104. Selva-O’Callaghan A, Mijares-Boeckh-Behrens T, Solans-Laque R, Molins-Vara T, Olive G, VilardellTarres M. Dermatomyositis and Graves’ disease. Clin Exp Rheumatol 2001;19:595–596. 105. Zingrillo M, Errico M, Simone P, Bosman C, Fusilli S. A case of dermatomyositis associated with hypothyroidism and hypoparathyroidism after surgery for Graves’ disease. J Endocrinol Invest 1990;13:949–950. 106. Kamei N, Yamane K, Yamashita Y, et al. AntiKu antibody-positive scleroderma-dermatomyositis overlap syndrome developing Graves’ disease and immune thrombocytopenic purpura. Intern Med 2002;41:1199–1203. 107. Shahin AA, Abdoh S, Abdelrazik M. Prolactin and thyroid hormones in patients with systemic scle­ rosis: correlations with disease manifestations and activity. Z Rheumatol 2002;61:703–709. 108. Antonelli A, Ferri C, Fallahi P, et al. Clinical and subclinical autoimmune thyroid disorders in systemic sclerosis. Eur J Endocrinol 2007;156:431–437. 109. Marasini B, Ferrari PA, Solaro N, Selmi C. Thyroid dysfunction in women with systemic sclerosis. Ann N Y Acad Sci 2007;1108:305–311. 110. Miyagawa S, Kitamura W, Sakamoto K. Skin lesions associated with Sjogren’s syndrome and anticytoplasmic antibodies in SLE patients. J Dermatol 1983;10:495–500. 111. Strakosch CR, Joyner D, Wall JR. Thyroid-stimu­ lating antibodies in patients with autoimmune disorders. J Clin Endocrinol Metab 1978;47:361– 365.

87 112. Rodrigue S, Laborde H, Catoggio PM. Systemic lupus erythematosus and thyrotoxicosis: a hitherto little recognised association. Ann Rheum Dis May 1989;48:424–427. 113. Rosen K, Lindstedt G, Mobacken H, Nystrom E. Thyroid function in patients with pustulosis palmo­ plantaris. J Am Acad Dermatol 1988;19:1009–1016. 114. Bakar O, Demircay Z, Ergun T. Epidermolysis bullosa acquisita associated with vitiligo, Graves’ disease and nephrotic syndrome. Int J Dermatol 2004;43:378–380. 115. Weiss GR, Fehrenkamp SH, Tokaz LK, Sunderland MC. Vitiligo and Graves’ disease following treatment of malignant melanoma with recombinant human interleukin 4. Dermatology 1996; 192:283–285. 116. Birmingham CL, Gritzner S, Gutierrez E. Hyperthyroidism in anorexia nervosa: case report and review of the literature. Int J Eat Disord 2006;39:619–620. 117. Riis AL, Gravholt CH, Djurhuus CB, et al. Elevated regional lipolysis in hyperthyroidism. J Clin Endocrinol Metab 2002;87:4747–4753. 118. Nedvidkova J, Haluzik M, Bartak V, et al. Changes of noradrenergic activity and lipolysis in the sub­ cutaneous abdominal adipose tissue of hypo- and hyperthyroid patients: an in vivo microdialysis study. Ann N Y Acad Sci 2004;1018:541–549. 119. Mariash CN. Thyroid hormone and the adipocyte. J Clin Endocrinol Metab 2003;88:5603–5604. 120. Haluzik M, Nedvidkova J, Bartak V, et al. Effects of hypo- and hyperthyroidism on noradrenergic activity and glycerol concentrations in human sub­ cutaneous abdominal adipose tissue assessed with microdialysis. J Clin Endocrinol Metab 2003;88: 5605–5608. 121. Kumar G, Chow JT, Klarich KW, Dean DS. Hyperthyroidism and atrial ayxoma—an intrigu­ ing cardio-endocrine association. J Am Soc Echocardiogr 2007;20:1413, e5–e7.

9 Cutaneous Manifestations of Hypothyroidism Sandra A. Kopp, Pascal G. Ferzli, Chad M. Hivnor, and Warren R. Heymann

Editorial Perspective On any given day, in any given bustling dermatology practice, it is highly likely that at least one patient has clinically overt or subclinical hypothyroidism. The cutaneous manifestations of hypothyroidism are protean, affecting the skin and its appendages, as outlined in this chapter. Hypothyroidism literally affects all organ systems and has a profound effect on a patient’s overall health and quality of life. While it is not necessary to check a thyroid-stimuating hormone (TSH) level

on every individual with dry skin in the wintertime, when recognizing any cutaneous feature of hypothyroidism, we should ask ourselves the following questions: Are any other cutaneous findings present to suggest the diagnosis? Does the patient have any systemic symptoms consistent with the diagnosis of hypothyroidism? A simple screening for TSH and free thyroxine (FT4) levels can change a person’s life. If the diagnosis of hypothyroidism is confirmed and treated, clinicians must remain alert for the many associations that accompany this diagnosis over the course of a lifetime.

Introduction

Etiologies

Hypothyroidism has been termed the “great imitator” because of thyroid hormones’ numerous systemic functions and manifestations. It may result from either inadequate circulating levels of thyroid hormone or end-organ target cell resistance. According to the National Health and Nutrition Examination Survey (NHANES) III study, 4.6% of the population in the United States suffers from hypothyroidism (0.3% clinical and 4.3% subclinical).1 The leading cause of hypothyroidism worldwide is iodine deficiency; however, in regions where intake is sufficient, chronic autoimmune lymphocytic thyroiditis (Hashimoto thyroiditis) predominates.2 It has been estimated that patients with subclinical hypothyroidism secondary to an autoimmune process (normal thyroxine [T4], elevated thyroid-stimuating hormone [TSH]) will develop frank hypothyroidism at a rate of 5% per year.3

Primary hypothyroidism is caused (Table 9.1) by failure of the thyroid gland to produce adequate amounts of thyroid hormone. In addition to autoimmune processes and iodine deficiency, primary hypothyroidism can result from a myriad of other insults, including previous radioiodine (iodine 131) or radiation therapy (x-ray therapy [XRT]), thyroid surgery, and drug-induced (lithium, amiodorone, etc.) thyroiditis. Other etiologies of primary hypothyroidism include viral and infiltrative destruction of the gland and heritable thyroid enzyme defects.4 Secondary hypothyroidism develops as a result of pituitary dysfunction resulting in the release of inadequate levels of TSH. Possible causes of secondary hypothyroidism include tumor, infarction, trauma, radiation, or surgical manipulation of the pituitary gland. It is commonly associated with other pituitary-related endocrinopathies.5

89

90

S.A. Kopp et al.

Table 9.1. Causes of hypothyroidism. Primary

Central (pituitary/ hypothalamic)

Defects in thyroid hormone biosynthesis Congenital defects in hormone synthesis Inheritable enzyme defects Iodine deficiency Iodine excess Antithyroid medications (lithium, amiodorone, goitrogens, bexarotene) Decreased functional thyroid tissue Hashimoto thyroiditis (chronic autoimmune thyroiditis) Thyroid surgery Radioiodine (iodine 131) therapy Radiation to head and neck Infiltrative diseases: sarcoidosis, hemochromatosis, systemic sclerosis, amyloidosis, Riedel thyroiditis, cystinosis Viral infections: subacute thyroiditis Postpartum thyroiditis Thyroid dysgenesis/agenesis Decreased pituitary/hypothalamic tissue Tumors: pituitary adenoma, craniopharyngioma, meningioma, glioma, metastases Vascular-ischemic necrosis, hemorrhage (Sheehan syndrome), internal carotid artery aneurysm, compression of pituitary stalk Trauma: head injury, radiation, surgery Infectious: brain abscess, tuberculosis, syphilis, toxoplasmosis Infiltrative: sarcoidosis, hemochromatosis, histiocytosis Chronic lymphocytic hypophysitis Congenital abnormalities: pituitary hypoplasia, basal encephalocele Genetic mutations in TRH receptor, TSH receptor, and Pit-113

TRH, TSH-releasing hormone; TSH, thyroid-stimulating hormone.

Hypothalamic dysfunction may result in tertiary hypothyroidism, which shares similar etiologies with secondary hypothyroidism. Although infrequent, primary idiopathic hypothalamic hypothyroidism has been reported.5 In the rare event of isolated thyroid-releasing hormone deficiency, other pituitary functions remain normal, and subsequent hypothyroidism may be transient.6 Pregnancy can induce a transient hypothyroid state due to the thyroid gland’s inability to adjust to physiologic changes associated with pregnancy.7 Postpartum thyroiditis is also a common transient hypothyroid state, occurring within 1 year following delivery. Postpartum thyroiditis has been shown to be present after approximately 5%–7% of pregnancies, most likely due to an autoimmune process.8 Presence of HLA-DRB, -DR4, and -DR5, as observed in Hashimoto thyroiditis, increases the likelihood of autoimmune-related hypothyroidism after delivery.9 Particularly relevant to dermatologists, medications such as bexarotene and potassium iodide can induce a hypothyroid state. Bexarotene induces central hypothyroidism in 29%–40%10,11 of cases via a reversible retinoid X receptor (RXR)-mediated independent suppression of the TSH gene expression.

Thus, it is important to monitor free T4 rather than TSH for patients taking bexarotene.12

Dermatologic Signs of Hypothyroidism Adult-onset hypothyroidism may be insidious in onset and often occurs over the course of many years. A wide range of signs and symptoms affecting multiple organ systems may comprise the nonspecific clinical manifestations, including bradycardia, hypotension, fatigue, malaise, constipation, decreased memory, inability to concentrate, muscle cramps, depression, weight gain, decreased appetite, voice deepening, menorraghia, and cold intolerance, which patients sometimes falsely attribute to aging (Table 9.2).14 The dermatologic manifestations are variable, depending on the duration of the disease and the ethnicity of the patient.15

Epidermis and Sweat Gland Dry skin (xerosis) and pruritus are hallmarks of hypothyroidism.17 In the elderly, dry skin was

9. Cutaneous Manifestations of Hypothyroidism

91

Table 9.2. Cutaneous manifestations of hypothyroidism. Surface alterations Vascular signs Hair alterations

Nail changes Dermal pathology Pigmentary change

Associations with other autoimmune disorders with cutaneous features (see chapter 13, this volume) Miscellaneous associations

Cool, dry, pale Keratoderma Vasoconstriction Purpura, ecchymosis Dry, coarse, brittle Diffuse or partial alopecia, alopecia areata (associated) Loss of lateral third of eyebrow hair (madarosis) Thick, brittle, slow growing Pits and trachyonychia (if associated with alopecia areata) Generalized myxedema Sallow color secondary to myxedema and possible anemia Carotenemia Vitiligo (associated) Melasma Systemic and discoid lupus, scleroderma, Sjogren, dermatomyositis, mixed connective tissue disease, rheumatoid arthritis, blistering diseases (pemphigus, bullous pemphigoid, pemphigoid gestationis, dermatitis herpetiformis), Addison disease, pernicious anemia, lichen sclerosus et atrophicus Palmoplantar pustulosis

Source: Adapted from reference 16.

found to be the most useful symptom leading to a possible diagnosis of hypothyroidism18 (Figure 9.1). Xerosis may present with a severity mimicking acquired icthyosis.17 The etiology of xerosis in hypothyroidism is unknown; however, several theories have been proposed, including hypohydrosis related to cytologic alterations in the eccrine apparatus,19 diminished sebaceous gland secretion,17 and diminished epidermal sterol biosynthesis, predominantly cholesterol and its esters.20 The periodic acid-schift (PAS)-positive, diastase-resistant granules in the pale cells of the secretory coil of the eccrine apparatus may be altered.19 Thyroid hormone (triiodothyronine, T3) is an important regulator of epidermal growth and dif-

Figure 9.1. Xerosis, in the right clinical setting and in conjunction with other physical findings, increases the suspicion for hypothyroidism

ferentiation as well as keratin gene expression. Keratin gene expression has been shown to be constitutively activated by the T3 receptor (T3R) in the absence of its ligand, T3. Keratin gene expression is inhibited by T3-liganded T3R via direct binding of T3R to the response elements of the keratin promoters on DNA.21 T3 has also been shown to alter cornification and lipogenesis.22,23 Isseroff et al. reported an increased level of transglutaminase, a cross-linking enzyme involved in the formation of cornified envelopes during keratinocyte differentiation, as well as a decreased level of protease plasminogen activator, an enzyme involved in desquamation, in cultured keratinocytes devoid of T3.22 These alterations in keratinocyte differentiation may explain the increase in desquamation associated with hypothyroidism.22 Rosenberg et al. demonstrated a decreased rate of synthesis of cholesterol and its esters in two different hypothyroid models, the epidermis of thyroidectomized rats and human keratinocytes cultivated in a medium devoid of thyroid hormone.23 Thyroid hormone has been shown to modulate cholesterol metabolism by inducing the key enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase.24 Previous studies have demonstrated that peroxisome proliferator-activated receptors are involved in lipid metabolism though its effects on thyroid hormone expression.25 Thyroid hormone may also serve as an important regulator of the stratum corneum by affecting lamellar granules (Odland

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Figure 9.2. Acquired palmoplantar keratoderma secondary to hypothyroidism. (Courtesy of Jeffrey Miller, MD.)

bodies), which are vital to the establishment of a normal stratum corneum.26 Hoath et al. studied the effects of thyroid hormone on epidermal growth factor (EGF) concentration in neonatal mouse skin. Their study revealed a possible physiologic relation between thyroid hormone and cutaneous responses to EGF in postnatal cutaneous development in mice.27 The authors suggested that the epidermal maturation following thyroid hormone administration may be mediated by local tissue levels of EGF.27 Acquired ichthyosis and hypertrichosis have been reported secondary to autoimmune thyroiditis, with complete remission on treatment with thyroxine replacement.24,28 Less than 10% of hypothyroidism due to central causes, pituitary or hypothalamic, present with these classic dermatologic signs.29 In these cases, the skin is more likely to have fine wrinkles, with a parchment-like quality.30 Hypohidrosis, possibly accompanied by diminished epidermal sterol biosynthesis, may also lead to acquired palmoplantar keratoderma5 (Figure 9.2). There are several reports of keratoderma associated with hypothyroidism; these were resistant to topical corticosteroids and keratolytics, but showed a rapid (10 days to 3 months) response to thyroid hormone replacement therapy.31–34

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roidism have an increased percentage of telogen hairs, demonstrating the effect of thyroid hormone on initiation as well as duration of hair growth.36 DNA flow cytometry studies of dissected anagen hair follicles from hypothyroid patients demonstrated a significant (15%) decrease in the S and G2 + M phases of the cell cycle compared to controls, as well as a significant (30%) increase in hyperthyroid patients, demonstrating the effects of thyroid hormone on the cell cycle.37 In a follow-up study, a correlation was noted between the percentage of time spent in S phase and plasma T3 levels.38 Thyroid hormone replacement therapy has been shown to restore the normal telogen–anagen relationship and reverse the resulting alopecia.36 Initiation of replacement therapy may also result in shedding of scalp hair secondary to loss of club hairs from telogen follicles that are entering the anagen phase.39 Billoni et al. reported detection of thyroid receptorb1 in human pilosebacous units using reverse transcriptase polymerase chain reaction (PCR) and reported on effects of 3,3',5-triiodo-l-thyronine (T3) on the survival of human hair follicles in vitro.40 Using a physiological level of free T3, the authors were able to significantly enhance human hair survival but were unsuccessful in increasing the rate of hair growth.40 Despite these advances in genetics, the exact mechanisms behind thyroid hormone-mediated alopecia still remain unclear. Madarosis, or loss of hair from the lateral third of the eyebrow or eyelash, is also a common finding in hypothyroidism41 (Figure 9.3). Periocular

Hair Hypothyroidism classically manifests with dry, coarse, brittle hair with a decreased diameter of the shaft and increased tendency to fall out, resulting in diffuse, partial alopecia.35,36 Patients with hypothy-

Figure 9.3. This patient exhibits three classical features of hypothyroidism: madarosis, alopecia, and periorbital puffiness

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alopecia mandates that special caution be taken to protect the affected eye.42 Axillary and pubic hair may also be sparse in hypothyroid patients. Although uncommon, children with hypothyroidism may paradoxically present with characteristic hypertrichosis on the back, shoulders, and lateral aspects of the extremities.43–45 A case of neonatal hypertrichosis in an infant with congenital hypothyroidism that resolved after thyroid hormone replacement has been reported.46 Thyroid function should therefore be evaluated in all neonates with hypertrichosis, hypotrichosis, or abnormal distribution of body hair.46

Nails Nails are also affected by low levels of thyroid hormone, characteristically appearing as thin, dry, brittle, and slow growing.47 Plummer’s nails are characterized by a concave contour with distal onycholysis. These nail changes have been reported to be associated with hypothyroidism; however, they are more commonly associated with hyperthyroidism and may also be seen in psoriasis, traumatic injury, or allergic contact dermatitis.17 Several case reports have demonstrated onycholysis as the presenting symptom of undiagnosed hypothyroidism.48 Although onycholysis may have many etiologies, patients with unexplained onycholysis should be screened for asymptomatic thyroid disease.48 Patients with hypothyroidism may be at increased risk for Candida nail infections as well as folliculitis. It has been suggested that because sebaceous glands of hypothyroid patients secrete less sebum than euthyroid patients, their hair follicles may have decreased amounts of lipophilic organisms and a higher concentration of Candida albicans.48 Macura et al. studied the nail susceptibility to fungal infections in patients with altered thyroid states, finding a significantly increased frequency and severity of Candida infections in hyper- and hypothyroid patients as compared to the control group.49

Dermis The most characteristic clinical sign of hypothyroidism is generalized myxedema, resulting from the deposition of hydrophilic mucopolysaccharides in the dermis, particularly hyaluronic acid and

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chondroitin sulfate.17 The hygroscopic nature of hyaluronic acid allows the molecule to swell to 1000 times its dry weight on hydration. Mucin deposition affects not only the skin but also virtually all organs of the body except the stomach. The skin may appear “doughy” or swollen, dry, pale, waxy, and firm to the touch.50 Although it may appear edematous, the skin does not pit on pressure. Typically, the facial appearance, often appearing as a dull affect, may include swollen lips, a broad nose, macroglossia, and puffy, drooping eyelids.50 Ptosis has been attributed to decreased sympathetic stimulation of the superior palpebral muscle.30 Hashimoto thyroiditis, the most prevalent form of hypothyroidism, can manifest with features similar to Graves disease. Pretibial myxedema, which is classically associated with hyperthyroidism has been reported in Hashimoto thyroiditis.51 In contrast to the fibroblast hypertrophy and hyperplasia observed in scleroderma and scleromyxedema, hypothyroidism is characterized by normal or inactive dermal fibroblasts, suggesting a systemic infiltration of glycosaminoglycans.52 Hypothyroidism is also associated with an absence of new collagen deposition.16 Tissue deposits of mucoproteins accumulate in the subendothelial layers of vascular capillaries and lymphatics, leading to subsequent loss of plasma proteins into the interstitial space.53 Inadequate lymphatic drainage leads to edema of the hands, face, and eyelids and can explain the formation of exudates in the serous cavities that are apparent in the myxedematous state.54 Studies examining the skin ultrastructure in myxedema, due to both hyper- and hypothyroid mechanisms, have demonstrated a wide variability of elastic fiber diameter and decreased microfibrils associated with both quantitative and qualitative defects of dermal elastic fibers.55 Cutaneous vasoconstriction and increased deposition of water and mucopolysaccharides in the dermis alter the refraction of light, resulting in pallor. A yellowish hue may be imparted on the skin, particularly on the palms, soles, and nasolabial folds. This occurs as the result of carotenemia due to the diminished hepatic conversion of b-carotene to vitamin A and decreased levels of low-density lipoprotein (LDL), which carries carotene,56 in concert with an associated anemia and myxedema.17 Carotene is excreted in sweat

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and deposited mainly in areas rich in sebaceous glands.57 Scleral sparing can differentiate carotenemia from jaundice.58 The anemia and vasoconstriction may also enhance the pallor and impart an appearance of livedo reticularis.17 If hypercholesterolemia and hypertriglyceridemia result from poorly controlled hypothyroidism, other associated findings can be present, such as tuberous and eruptive xanthomas.59

Vascular Changes The decreased metabolic rate of hypothyroidism causes a reflexive vasoconstriction to maintain core body temperature, resulting in the characteristic cool, pale appearance of the skin.48 The alterations in skin perfusion have been documented by nailfold capillaroscopy.60 Pazos-Moura et al. studied microvascular autoregulation in patients with hypothyroidism compared to euthyroid controls.60 Hypothyroid patients had disturbed microvascular autoregulatory mechanisms that resolved following thyroid hormone replacement.60 Similar results have been documented by laser Doppler techniques.61 Purpura may be observed secondary to the decreased level of clotting factors and vascular injury from dermal mucin accumulation. As a result, wound healing is greatly impaired.62 Increased ecchymoses may also be observed due to the decreased concentration of factor VII, von Willebrand factor, decreased platelet adhesion, and prolonged bleeding time.63 Approximately half of the hypothyroid population may have a malar flush.64 As mentioned, tissue deposits of mucoproteins accumulate in the subendothelial layers of vascular capillaries and lymphatics, leading to subsequent loss of albumin and formation of edema that can exacerbate the myxedematous state.53,54

Other (Nerves, Eyes) Entrapment syndromes such as carpal tunnel syndrome and facial nerve palsy have been reported in patients with hypothyroidism.65 Several mechanisms have been proposed to explain peripheral nerve abnormalities associated with hypothyroidism. The most common theory attributes the mononeuropathy to compression caused by mucinous deposits in the soft tissues surrounding the affected nerve.66,67

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Previous studies have also reported structural alterations of myelin and axonal-oligodendroglial dysfunction responsible for neuropathy in hypothyroidism.68,69 Despite increasing research in this area, the etiology of polyneuropathy in hypothyroidism still remains unclear.67 In hypothyroid patients with peripheral nerve abnormalities, surgical intervention should not be attempted until thyroid replacement therapy has proven inadequate.67 The prevalence of ophthalmopathy is noted in only 2% of patients with Hashimoto thyroiditis.70 Ptosis, conjunctival injection, diplopia, lagopthalmos, and decreased vision have all been reported.71 Although there is no clear explanation for the similarities in the ophthalmopathy and dermopathy of these two disorders, there is thought to be a cross-specificity between thyroid peroxidase (TPO) and thyroglobulin antibodies with orbital and dermal fibroblasts.71 Lymphocyte-mediated cytokines induce fibroblasts to secrete hydrophilic glycosaminoglycans that ultimately accumulate in the dermis and extraocular muscles, producing fibrosis.71 As discussed, patients with hypothyroidism and associated madarosis should increase protective measures of affected eyes.

Congenital Hypothyroidism Congenital hypothyroidism (cretinism, congenital athyrosis) occurs when insufficient quantities of thyroid hormone are produced, from primary, secondary, or tertiary causes, either in utero or during the early perinatal period.17 Primary congenital hypothyroidism occurs in approximately 1 of 4000 live births, affecting females twice as often as males.72 In over 90% of these births, a permanent thyroid gland abnormality is identified. Of these abnormalities, 10%–15% are due to dyshormonogenesis, whereas 80%–85% are caused by thyroid gland dysgenesis.72 Thyroid ectopia is more common than aplasia or hypoplasia.73 Hypothalamic or pituitary causes of congenital hypothyroidism are much rarer, occurring in 1 of 50,000–100,000 births.72 Congenital hypothyroidism may be transient due to transplacental transfer of maternal thyroid-blocking antibodies,74 maternal antithyroid medications,9 or iodine deficiency in utero in endemic areas of the world.17 If the lack of thyroid hormone goes unrecognized, a unique syndrome of dwarfism, mental retardation, cutaneous changes,

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and systemic features of hypothyroidism may occur.5 Transient hypothyroidism has also occurred while using topical iodine preparation in treating delayed-closure wounds75 or an omphalocele76; however, there are conflicting reports when topical iodine preparations are used as disinfectants.77,78 Routine newborn screening for congenital hypothyroidism is mandatory in the United States. Approximately 33% of infants with congenital hypothyroidism present with no abnormal signs or symptoms.5 All infants should be screened for hypothyroidism before leaving the nursery, optimally between 2 and 4 days of age. Specimens collected prior to 48 h of age may show a falsepositive TSH result due to the physiologic increase in TSH postnatally.79 The myxedema in congenital hypothyroidism classically presents as characteristic periorbital puffiness,5 increased skin creases,4 thick lips, acral swelling, macroglossia, or a smooth, red tongue.5 A pronounced clavicular fat pad may also be apparent.17 These manifestations result from the same mechanism as adult hypothyroidism, as discussed. Cutis marmorata may be accentuated in this setting.5 The skin may also appear yellow secondary to carotenemia from diminished hepatic conversion of b-carotene to vitamin A as well as prolonged physiologic jaundice, anemia, and myxedema.17 Hair is usually coarse, dry, and brittle.5 Patchy alopecia or persistent lanugo hairs may be present.5 Nails tend to be brittle and have slow growth.17 A case of congenital hypothyroidism in a collodion baby has been reported.80 As the disease worsens, the infant may show signs of poor feeding, bradycardia, hypothermia, and an enlarged posterior fontanelle.81 Other anomalies reported in association with congenital hypothyroidism include cardiovascular abnormalities (ventricular septal defect, patent ductus arteriosus, and pulmonary stenosis); gastrointestinal abnormalities (colic duplication with hypertrophic pyloric stenosis); umbilical hernia; and musculoskeletal abnormalities (unilateral clubfoot and congenital dislocation of the hip).80

Diagnosis A diagnosis of hypothyroidism requires a detailed history and physical examination as well as measurements of the serum levels of TSH and free T4.

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In most cases of hypothyroidism, the decreased function of thyroid hormone is due to a peripheral mechanism, which elevates the TSH level to compensate for the low levels of circulating thyroid hormone. In the early stages of hypothyroidism, the free T4 level may be normal due to the delay in the decline of free T4; however, this should not deter the physician from entertaining a diagnosis of hypothyroidism.82 The best diagnostic test for primary hypothyroidism is an elevated TSH. In the rare occurrence of central hypothyroidism, the TSH level can be low or even normal.15 Antithyroid peroxidase (anti-TPO) antibodies and antithyroglobulin antibodies may help confirm the diagnosis of Hashimoto thyroiditis.

Treatment Thyroid hormone replacement therapy with L-thyroxine is essential for the treatment of the skin manifestations of hypothyroidism. An adequate daily starting dose of 1.6 or 1.7 mg/kg is recommended.15 In patients with comorbid cardiac disease or the elderly, however, the starting dose should be adjusted to 25 mg per day and increased weekly by 25 mg until the optimal dose is reached.82 Further adjustments in the L-thyroxine dose should be made after repeating thyroid function serum studies 4–6 weeks later. The desired TSH level is between 0.5 and 2.5 mg/mL, with many hospitals opting for a range of 1–2 mg/ mL as the “normal range.”15 As mentioned, xerosis can be so severe in hypothyroidism that it may be initially diagnosed as ichthyosis. Frequent and meticulous dry skin care can alleviate the symptoms of xerotic skin as an adjunct to thyroid replacement therapy. Myriad topical agents are available for the treatment of xerosis related to hypothyroidism, including ahydroxyl acids,83 ointments with unctuous materials such as petrolatum or lanolin, liquid emulsions, oils,84 and urea.85 These agents provide temporary relief in some cases. In a preliminary, open, nonblinded trial, it has been shown that topical thyroid hormone at a concentration of 0.0167 mg/cm2 is effective in the treatment of xerosis in euthyroid patients. In this study, there were no significant systemic effects. The optimal formulation of topical thyroid hormone is yet to be determined.86 As mentioned, although the vast majority of patients

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with pretibial myxedema have hyperthyroidism, it has been reported in patients with hypothyroidism. The cornerstone of treatment in these patients is the use of topical or intralesional corticosteroids. Plasmapheresis has helped improve several lesions transiently, while surgical approaches have not shown promising results.

Hypothyroidism and Associated Cutaneous Diseases Hypothyroidism may be associated with various other dermatologic or systemic diseases, many of which are autoimmune (Table 9.3). An entire chapter in this text (chapter 13) addresses this in detail, although some aspects are particularly mentioned in this chapter. Although the evidence relies on a small number of case reports and the pathophysiologic mechanisms are yet to be elucidated in most instances, physicians should be aware of the following links. Alopecia areata has been associated with hypothyroidism secondary to Hashimoto thyroiditis. In a study of 45 children with alopecia areata, almost a quarter had an abnormality of thyroid function, all appearing clinically asymptomatic.87 Hashimoto thyroiditis was 2.5 times more frequent among children with vitiligo.88 Autoimmune hypothyroidism has also been associated with pernicious anemia secondary to B12 deficiency as a result of the antibody-mediated atrophic gastritis. Wolf and Feuerman first described an association of pemphigus with thyroid dysfunction, with their first patient having both pemphigus foliaceus and primary hypothyroidism.89 Bullous pemphigoid has also been observed in patients with autoimmune hypothyroidism. Cunningham and Zone reported hypothyroidism associated with dermatitis herpetiformis.90 Middermal elastosis (resulting from elastophagocytosis and granuloma formation), reticular erythematous mucinosis, and acral papulokeratotic lesions have been associated with Hashimoto thyroiditis.91,92 These associations rapidly regressed after thyroid replacement therapy.91,92 Also, friction-induced intraepidermal bullae may develop in patients with hypothyroidism. Le Brun et al. reported a case of pretibial epidermolysis bullosa and hypothyroidism, regressing after thyroid hor-

S.A. Kopp et al. Table 9.3. Cutaneous Manifestations of Thyroid Disease. I. Specific lesions A. Thyroglossal duct cyst B. Cutaneous metastases from thyroid malignancies II. Nonspecific lesions A. Hyperthyroidism (general) 1. Alopecia 2. Plummer’s nails 3. Textural alterations 4. Hyperpigmentation B. Graves disease 1. Opthalmopathy 2. Dermopathy (pretibial myxedema) 3. Thyroid acropachy C. Hypothyroidism 1. Congenital hypothyroidism 2. Generalized myxedema a. Textural alterations b. Xerosis/keratoderma c. Carotenemia d. Alopecia e. Brittle nails 3. Miscellaneous disorders III. Thyroid disorders associated with other dermatologic or systemic diseases A. Immunologically mediated disorders 1. Alopecia areata 2. Anemias 3. Bullous disorders a. Pemphigus b. Bullous pemphigoid c. Herpes gestationis d. Dermatitis herpetiformis 4. Connective tissue diseases a. Dermatomyositis b. Lupus erythematosus c. Scleroderma 5. Endocrinopathies a. G protein disorders i. McCune-Albright syndrome ii. Albright’s hereditary osteodystrophy b. Multiple endocrine neoplasia, types 2a and 2b c. Acanthosis nigricans 6. Pustulosis palmoplantaris 7. Sweet syndrome 8. Urticaria/angioedema 9. Vitiligo B. Miscellaneous disorders C. Complications related to the treatment of thyroid disease Source: Adapted from reference 116.

mone therapy.93 The authors recommended that all patients presenting with pretibial bullae be evaluated for thyroid dysfunction.93 Both discoid lupus erythematosus and systemic lupus erythematosus have been associated with an

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autoimmune-mediated hypothyroidism. In a series of 139 patients with progressive systemic sclerosis (PSS), DeKeyser et al. found 2 clinically hypothyroid patients and 7 patients with subclinical hypothyroidism.94 An autopsy series of 56 fatal cases of PSS demonstrated histologic evidence of severe fibrosis of the thyroid gland in 14% of cases as opposed to 2% of the matched control autopsy series. Five of the seven patients had the Calcinosis, Raynaud syndrome, Esophageal dysmotility, Sclerodactyly, and Telangiectasia (CREST) syndrome variant of PSS.87 A report by Antonelli et al. demonstrated a significantly higher prevalence of thyroid dysfunction, antithyroid-peroxidase autoantibodies, and ultrasonographic evidence of thyroid autoimmunity in patients with systemic sclerosis than controls with similar iodine status. The authors suggested that thyroid function and ultrasonographic imaging be included in the clinical profiling of systemic sclerosis patients because of the impact thyroid function has on the manifestations of scleroderma and its treatment.95 A controversy still exists regarding the relation between acanthosis nigricans (AN) and thyroid disease. Matsuoka et al. described three patients who presented with primary hypothyroidism and AN. All of these patients had insulin resistance, but correction of the hypothyroidism did not change the appearance of the AN.96 On the other hand, Ober reported a case of an obese 15-year-old boy with primary hypothyroidism, AN, and subclinical insulin resistance. In this case, thyroid hormone replacement resulted in weight loss, reversal of hyperinsulinemia, and resolution of the AN.97 Finally, Dix et al. reported a 13-year-old girl with Hashimoto thyroiditis, hypertrichosis, and AN without signs of insulin resistance. Both the AN and hypertrichosis resolved with thyroid replacement therapy.98 There is also an association between idiopathic chronic urticaria or angioedema and hypothyroidism (addressed in detail in chapter 12). In most patients, treatment with thyroxine does not improve the urticaria or angioedema, but a few patients demonstrated an impressive response. Lanigan et al. studied 25 patients with chronic urticaria or angioedema and found 5 patients with biochemical evidence of hypothyroidism, 3 of whom had clinical features of myxedema.99 In a review of nine cases of reticular erythematous mucinosis, two patients had thyroid dysfunction: One was

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hyperthyroid, while the other was hypothyroid. A few cases of hypothyroidism have also been associated with pseudoxanthoma elasticum.17

New Insights and Reports into Skin Manifestations of Hypothyroidism A number of associations between hypothyroidism and other previously unrelated disease entities are surfacing. Although the importance of these reports and the pathogenic nature of the purported associations remain to be determined, clinicians should be cognizant of their existence. A number of reports have linked congenital hemangiomas to hypothyroidism. Huang et al. reported on a 3-month-old infant with massive hepatic hemangiomas and severe primary hypothyroidism.100 They identified high levels of expression of type 3 iodothyronine deiodinase activity in the hemangioma tissue that was responsible for the increased rate of degradation of thyroid hormone. Type 3 iodothyronine deiodinase inactivates T4 and T3 by conversion into inactive reverse T3 and diiodothyronine (T2), respectively. The authors suggested that an endocrine or paracrine induction of type 3 iodothyronine deiodinase in endothelial cells by basic fibroblast growth factors, or other growth factors, is responsible for the increased rate of enzyme expression in hemangiomas.100 Subsequent case reports have confirmed this association with cutaneous and hepatic hemangiomas and have thus linked hypothyroidism to syndromes involving hemangiomas.101 It is interesting to note that in all reports, patients required very high doses of thyroid hormone replacement to restore euthyroidism. These reports highlight the importance of thyroid function testing on children with hemangiomas to avoid the potentially devastating effects of hypothyroidism on their growth and development. In addition, it is also essential to search for vascular tumors in infants with consumptive hypothyroidism not explained by other processes.100 Hypothyroidism has been observed in patients with cutis verticis gyrata. A 62-year-old woman with a decade-long history of hypothyroidism presented after the development of increasingly large asymptomatic grooves in the scalp.102 The pathogenesis

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of this association is unknown; however, it may involve a combination of factors leading to the activation of fibroblasts in hypothyroidism. As discussed in chapter 14 on the potential uses of thyroid hormone, it has become evident that thyroid hormone is important in wound healing.103 Indeed, researchers have noted that T3 is necessary for keratinocyte proliferation in wounds. Hypothyroid patients who need to undergo surgery that cannot be delayed might benefit from receiving T3 in the perioperative period. Chronic mucocutaneous candidiasis (CMC) is a rare disorder characterized by recurrent Candida infections of the skin, nails, and oropharynx. It has been associated with endocrinopathies in 50% of cases and has been termed the Candida endocrinopathy syndrome. Further studies have demonstrated two subsets of hypothyroid patients with CMC: one group of CMC patients with hypothyroidism or hypoadrenalism in an autosomal recessive inheritance pattern and another group of CMC/hypothyroid patients with autosomal-dominant inheritance.104 The authors urged that genetic counseling be offered to all affected members. A report of a 15-year-old girl linked severe hypothyroidism to psoriasiform lesions and multiple abscesses.105 The temporal relationship of the development of hypothyroidism with the appearance of these psoriasiform lesions and their near resolution with treatment of the hypothyroid state was noteworthy. The authors suggested that hypothyroidism may induce epidermal proliferation in a similar way to the ichthyosiform eruptions discussed. There are few reports that link hypothyroidism to abscess formation. Some investigators have noted the decreased ability of polymorphonuclear cells to eliminate Staphylococcus aureus in hypothyroid patients.105 There are numerous drugs implicated in the development of hypothyroidism. In recent reports, sunitinib, an inhibitor of tyrosine-kinase used in the treatment of cancer, has been linked to a high prevalence of hypothyroidism during its use.106 The authors suggested that an underlying mechanism in impaired iodine uptake is responsible for the hypothyroidism. They recommended that patients treated with sunitinib be monitored closely for the development of hypothyroidism.106 Another agent, denileukin diftitox, used in treatment of mycosis fungoides, has been reported

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to cause thyrotoxicosis during therapy, leaving several patients in a transiently hypothyroid state following cessation of the drug.106 It had been suggested that because the uptake of iodine is inhibited by denileukin diftitox, perhaps patients should be screened for thyroid disease before and during treatment.107 Thyroid dysfunction is a common complication of interferon therapy in patients suffering from hepatitis C. A case of central hypothyroidism and hypophysitis during treatment of hepatitis C with pegylated interferon alfa with ribavirin has been reported, adding central hypothyroidism to the potential side effects of combination treatment for hepatitis C.108 In another report, three euthyroid patients with Hashimoto thyroiditis developed hypothyroidism after the administration of rifampin, which resolved after rifampin was discontinued.109 Possible explanations are the increased hepatic clearance of T4 and excretion of iodothyronine conjugates stimulated by rifampin.110,111 Studies in control patients without thyroid disorders indicated that rifampin decreased circulating thyroid hormone without affecting TSH.112 Patients taking rifampin who appear to be at risk for becoming hypothyroid should be aware of this consequence of the drug.112 Dermatologists should be cognizant of two reports stating that hypothyroidism was more common in melanoma patients.113,114 In an in vitro study it has been demonstrated that melanoma cells, and not melanocytes, are induced to proliferate at physiologic concentrations of TSH.115 If shown to be valid in vivo, this may have profound implications for melanoma patients, and a TSH level would therefore become a crucial component in the workup of a patient with a newly diagnosed melanoma. Correction of the underlying hypothyroidism could lead to suppression of the TSH level, potentially decreasing the rate of melanoma cell proliferation. This intriguing work requires further studies to validate these findings. These miscellaneous case reports demonstrate how the interface between the skin and the thyroid gland continues to expand. Further research may allow us to comprehend the nature of these associations, thereby leading to new insights and paradigms that will ultimately benefit our patients with hypothyroidism.

9. Cutaneous Manifestations of Hypothyroidism

References 1. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4 and thyroid antibodies in the United States population (1988–1994): National Health and Nutrition Survey (NHANES III). J Clin Endocrinol Metab 2002;87:486–488. 2. Braverman LE, Utiger RD. Introduction to hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid. 7th ed. Philadelphia: Lippincott-Raven; 1996:736–737. 3. Topliss DJ, Eastman CJ. Diagnosis and management of hyperthyroidism and hypothyroidism. Med J Aust 2004;180:186–193. 4. Wolff K, Johnson RA, Suurmond D. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. 5th ed. New York: McGraw-Hill; 2005:444. 5. Leonhardt JM, Heymann WR. Thyroid disease and the skin. Dermatol Clin 2002;20:473–481. 6. Gharib H, Abboud C. Primary idiopathic hypothalamic hypothyroidism. Am J Med 1987;83:171–174. 7. Glinoer D, Riahi M, Grün JP, Kinthaert J. Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 1994;79:197–204. 8. Muller AF, Drexhage HA, Berghout A. Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care. Endocr Rev 2001;22:605–630. 9. Stagnaro-Green A, Roman SH, Cobin RH, ElHarazy E, Wallenstein S, Davies TF. A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction. J Clin Endocrinol Metab 1992;74:645–653. 10. Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatment of refractory advancedstage cutaneous T-cell lymphoma: multinational phase II–III trail results. J Clin Oncol 2001;19:2456–2471. 11. Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent earlystage cutaneous T-cell lymphoma. Arch Dermatol 2001;137:581–593. 12. Sherman SI. Etiology, diagnosis, and treatment recommendations for central hypothyroidism associated with bexarotene therapy for cutaneous T-cell lymphoma. Clin Lymphoma 2003;3:249–252. 13. Brown MR, Parks JS, Adess ME, et al. Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene. Horm Res 1998;49:98–102. 14. Levy EG. Thyroid disease in the elderly. Med Clin North Am 1991;75:151–167.

99 15. Burman KD, McKinley-Grant L. Dermatologic aspects of thyroid disease. Clin Dermatol 2006;24: 247–255. 16. Heymann, WR. The skin and connective tissue in hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid: A Functional and Clinical Text. 8th ed. Philadelphia: Lippincott Williams and Wilkins; 2000:774–776. 17. Heymann WR. Cutaneous manifestations of thyroid disease. J Am Acad Dermatol 1992;25:885–906. 18. Barnes DJU, O’Conner JD, Bending JJ. Hypothyroidism in the elderly: clinical assessment versus routine screening. Br J Clin Pract 1993;47: 123–127. 19. Means MA, Dobson RL. Cytologic changes in the sweat gland in hypothyroidism. JAMA 1963;186:113–115. 20. Rosenburg RM, Isseroff RR, Ziboh VA, et al. Abnormal lipogenesis in thyroid hormone-deficient epidermis. J Invest Dermatol 1986;86:244–248. 21. Tomic-Canic M, Day D, Samuels HH, Freedberg IM, Blumenberg M. Novel regulation of keratin gene expression by thyroid hormone and retinoid receptors. J Biol Chem 1996;271:1416–1423. 22. Isseroff RR, Chun KT, Rosenberg RM. Triiodothyronine alters the cornification of cultured human keratinocytes. Br J Dermatol 1989;120: 503–10. 23. Rosenberg RM, Isseroff, Ziboh VA, et al. Abnormal lipogenesis in thyroid hormone-deficient epidermis. J Invest Dermatol 1986;86:244. 24. Kippers LE, Palumbo PJ. Lipid disturbances in endocrine disorders. Med Clin North Am 1972;56: 1013–1020. 25. Hunter J, Kassam A, Winrow CJ, Rachubinski RA, Capone JP. Crosstalk between thyroid hormone and peroxisome proliferators-activated receptors in regulating peroxisome proliferators-response genes. Mol Cell Endocrinol 1996;116:213–221. 26. Hanley K, Devaskar UP, Hicks SJ, et al. Hypothyroidism delays fetal stratum corneum development in mice. Pediatr Res 1997;42:610–614. 27. Hoath SB, Lakshmanan J, Scott SM, Fisher DA. Effect of thyroid hormones on epidermal growth factor concentration in neonatal mouse skin. Endocrinology 1983;112:308–314. 28. Brazzelli V, Prestinari F, Barbagallo T, et al. Acquired ichthyosis and hypertrichosis due to autoimmune thyroiditis therapeutic response to thyroxine replacement. Pediatr Dermatol 2005;22:447–449. 29. Boelaert K, Franklyn JA. Thyroid hormone in health and disease. J Endocrinol 2005;187:1–15. 30. Freinkel RK, Freinkel N. Cutaneous manifestations of endocrine disorders. In: Fitzpatrick TB, Eisen AZ,

100 Wolf K, et al., eds. Dermatology in General Medicine. 3rd ed. New York: McGraw-Hill; 1987:2036–2081. 31. Miller JJ, Roling D, Spiers E, Davies A, Rawlings A, Leyden J. Palmoplantar keratoderma associated with hypothyroidism. Br J Dermatol 1998;139:741–742. 32. Good JM, Neill SM, Payne CM, Staughton RC. Keratoderma of myxoedema. Clin Exp Dermatol 1988;13:339–341. 33. Hodak E, David M, Feuerman EJ. Palmoplantar keratoderma in association with myxedema. Acta Derm Venereol 1986;66:354–357. 34. Tan OT, Sarkany I. Severe palmar keratoderma in myxoedema. Clin Exp Dermatol 1977;2:287–288. 35. Rook A. Endocrine influences on hair growth. Br Med J 1965;1:609–614. 36. Freinkel RK, Freinkel N. Hair growth and alopecia in hypothyroidism. Arch Dermatol 1972;106:349–352. 37. Schell H, Kiesewetter F, Seidel C, von Hintzenstern J. Cell cycle kinetics of human anagen scalp hair bulbs in thyroid disorders determined by DNA flow cytometry. Dermatologica 1991;182:23–26. 38. Kiesewetter F, Schell H. Cell kinetics of anagen scalp hairs under physiological and pathological conditions. Skin Pharmacol 1994;7:55–60. 39. Alonso LC, Rosenfield RL. Molecular genetic and endocrine mechanisms of hair growth. Horm Res 2003;60:1–13. 40. Billoni N, Buan B, Gautier B, Gaillard O, Mahe YF, Bernard BA. Thyroid hormone receptor β1 is expressed in the human hair follicle. Br J Dermatol 2000;142:645–652. 41. Donnelly A. Skin signs of systemic disease. Aust Fam Physician 1999;28:1217–1222. 42. Khong JJ, Casson RJ, Huilgol SC, Selva D. Madarosis. Surv Ophthalmol 2006;51:550–560. 43. Diven DG, Gwinup G, Newton RC. The thyroid. Dermatol Clin 1989;7:547–558. 44. Stern SR, Kelnar CJH. Hypertrichosis due to primary hypothyroidism. Arch Dis Child 1985;60:763–766. 45. Perloff WH. Hirsutism: a manifestation of juvenile hypothyroidism. JAMA 1955;157:651–652. 46.Akcakus M, Koklu E, Kurtoglu S, Koklu S, Keskin M, Buyukkayhan D. Neonatal hypertrichosis in an infant of a diabetic mother with congenital hypothyroidism. J Perinatol 2006;26:256–258. 47. Mullin GE, Eastern JS. Cutaneous signs of thyroid disease. Am Fam Physician 1986;34:93–98. 48. Dekio S, Imaoka C, Jidoi J. Candida folliculitis associated with hypothyroidism. Br J Dermatol 1987;117:663–664. 49. Macura AB, Gasinska T, Pawlik B. Nail susceptibility to fungal infections in patients with hypothyroidism and hyperthyroidism. Przegl Lek 2005;62:218–221. 50. Lever WF, Schaunberg-Lever G. Metabolic diseases. In: Lever WF, Schaumburg-Lever G, eds.

S.A. Kopp et al. Histopathology of the Skin. 7th ed. Philadelphia: Lippincott; 1990:452–487. 51. Cannavo SP, Borgia F, Vaccaro M, Guarneri F, Magliolo E, Guarneri B. Pretibial myxoedema associated with Hashimoto’s thyroiditis. J Eur Acad Dermatol Venereol 2002;16:625–627. 52. Matsuoka LY, Wortsman J, Carlisle KS, Kupchella CK, Dietrich JG. The acquired cutaneous mucinoses. Arch Intern Med 1984;144;1974–1980. 53. Hierholzer K, Finke R. Myxedema. Kidney Int Suppl 1997;59:S82–S89. 54. Parving HH, Hansen JM, Nielsen SL, Rossing N, Munck O, Lassen NA. Mechanisms of edema formation in myxedema—increased protein extravasation and relatively slow lymphatic drainage. N Engl J Med 1979;301:460–465. 55. Matsuoka LY, Wortsman J, Uitto J, et al. Altered skin elastic fibers in hypothyroid myxedema and pretibial myxedema. Arch Intern Med 1985;145:117–121. 56. Mazzaferri EL. Adult hypothyroidism 1. Manifestations and clinical presentation. Postgrad Med 1986;79: 64–74. 57. Niepomniszcze H, Amad RH. Skin disorders and thyroid diseases. J Endocrinol Invest 2001;24: 628–638. 58. al-Jubouri MA, Coombes EJ, Young RM, McLaughlin NP. Xanthoderma: an unusual presentation of hypothyroidism. J Clin Pathol 1994;47:850–851. 59. Stephens CJ, McKee PH, Black MM. The dermal mucinoses. Adv Dermatol 1993;8:201–206. 60. Pazos-Moura CC, Moura EG, Breitenbach MM, Bouskela E. Nailfold capillaroscopy in hypothyroidism and hyperthyroidism: blood flow velocity during rest and postocclusive reactive hyperemia. Angiology 1998;49:471–476. 61. Weiss M, Milman B, Rosen B, Zimlichman R. Quantitation of thyroid hormone effect on skin perfusion by laser doppler flowmetry. J Clin Endocrinol Metab 1993;76:680–682. 62. Feingold KR, Elias PM. Endocrine-skin interactions. J Am Acad Dermatol 1987;17:921–940. 63. Wiersinga WM. Hypothyroidism and myxedema coma. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: Saunders; 2001:1491–1506. 64. Bernhard JD, Freedberg IM, Vogel LN. The skin in hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid. 7th ed. Philadelphia: Lippincott-Raven; 1996:792–795. 65. Diven DG, Gwinup G, Newton RC. The thyroid. Dermatol Clin 1989;7:547–557. 66. Khedr EM, El Toony LF, Tarkhan MN, Abdella G. Peripheral and central nervous system alterations in hypothyroidism: electrophysiological findings. Neuropsychobiology 2000;41:88–94.

9. Cutaneous Manifestations of Hypothyroidism 67. Kececi H, Degirmenci Y. Hormone replacement therapy in hypothyroidism and nerve conduction study. Neurophysiol Clin 2006;36:79–83. 68. Ferreira AA, Nazario JC, Pereira PJ, Azevedo NL, Barradas PC. Effects of experimental hypothyroidism on myelin sheath structural organization. J Neurocytol 2004;33:225–231. 69. Nemni R, Bottachi E, Fazio R. Polyneuropathy in hypothyroidism: clinical, electrophysiological and morphological finding in four cases. J Neurol Neurosurg Psychiatry 1987;50:1454–1460. 70. Simon LL, Justen JM, Giraldo AA, Krco CJ, Kong YC. Activation of cytotoxic T cells and effector cells in experimental autoimmune thyroiditis by shared determinants of mouse and human thyroglobulin. Clin Immunol Immunopathol 1986;39:345–356. 71. Singh SK, Singh KK, Sahay RK. Images in medicine: Hashimoto’s thyroiditis with orbitopathy and dermopathy. J Postgrad Med 2000;46:286–287. 72. Brown RS, Demmer LA. The etiology of thyroid dysgenesis—still an enigma after all these years. J Clin Endocrinol Metab 2002;87:4069–4071. 73. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid 1999;9:735– 740. 74. Dussault JH, Fisher DA. Thyroid function in mothers of hypothyroid newborns. Obstet Gynecol 1999;93:15–20. 75. Kovacikova L, Kunovsky P, Lakomy M, et al. Thyroid hormone status after cardiac surgery in infants with delayed sternal closure and continued use of cutaneous povidone-iodine. Endocr Regul 2003;37:3–9. 76. Cosman BC, Schullinger JN, Bell JJ, Regan JA. Hypothyroidism caused by topical povidone-iodine in a newborn with omphalocele. J Pediatr Surg 1988;23:356–358. 77. Linder N, Davidovitch N, Reichman B, et al. Topical iodine-containing antiseptics and subclinical hypothyroidism in preterm infants. J Pediatr 1997;131:434–439. 78. Gordon CM, Rowitch DH, Mitchell ML, Kohane IS. Topical iodine and neonatal hypothyroidism. Arch Pediatr Adolesc Med 1995;149:1336–1339. 79. Rose SR, Brown RS, Foley T, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006;117:2290–2303. 80. Kurtoglu S, Caksen H, Erdogan R, et al. Collodion baby concomitant with congenital hypothyroidism: a patient report and review of the literature. J Pediatr Endocrinol Metab 1998;11:569–573. 81. Foley TP. Congenital hypothyroidism. In: Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia: Lippincott Williams and Wilkins; 2000:977–982.

101 82. Jabbour SA. Cutaneous manifestations of endocrine disorders; a guide for dermatologists. Am J Clin Dermatol 2003;4:315–333. 83. Kempers S, Katz S, Wildnauer R, Green B. An evaluation of the effect of an alpha hydroxyl acid-blend skin cream in the cosmetic improvement of symptoms of moderate to severe xerosis, epidermolytic hyperkeratosis, and ichthyosis. Cutis 1998;61:347–350. 84. Lazar A, Lazar P. Dry skin, water, and lubrication. Dermatol Clin 1991;9:45–51. 85. Loden M. Urea-containing moisturizers influence barrier properties of normal skin. Arch Dermatol Res 1996;288:103–107. 86. Heymann WR, Gans EH, Manders SM, Green JJ, Haimowitz JE. Xerosis in hypothyroidism: a potential role for the use of topical thyroid hormone in euthyroid patients. Med Hypotheses 2001;57:736–739. 87. Milgraum SS, Mitchell AJ, Bacon GE, et al. Alopecia areata, endocrine function, and autoantibodies in patients 16 years of age or younger. J Am Acad Dermatol 1987;17:57–61. 88. Kakourou T, Kanaka-Gantenbein C, Papadopoulou A, Kaloumenou E, Chrousos GP. Increased prevalence of chronic autoimmune (Hashimoto’s) thyroiditis in children and adolescents with vitiligo. J Am Acad Dermatol 2005;53:220–223. 89. Wolf R, Feuerman EJ. Pemphigus in association with autoimmune thyroid disease. Cutis 1981;27: 423–424. 90. Cunnigham MJ, Zone JJ. Thyroid abnormalities in dermatitis herpetiformis: prevalence of clinical thyroid disease and thyroid autoantibodies. Ann Intern Med 1985;102:194–196. 91. Gambichler T, Linhart C, Wolter M. Mid-dermal elastolysis associated with Hashimoto’s thyroiditis. J Eur Acad Dermatol Venereol 1999;12:245–249. 92. Velasco JA, Santos JC, Villabona V, Santana J. Reticular erythematous mucinosis and acral papulokeratotic lesions associated with myxoedema due to Hashimoto thyroiditis. Dermatology 1992;184:73–77. 93. Le Brun V, Boulinguez S, Bouyssou-Gauthier ML, et al. Pretibial epidermolysis bullosa and hypothyroidism. Ann Dermatol Venereol 2000;127: 184–187. 94. DeKeyser L, Narhi DC, First DE, et al. Thyroid dysfunction in a prospectively followed series of patients with progressive systemic sclerosis. J Endocrinol Invest 1990;13:161–169. 95. Antonelli A, Ferri C, Fallahi P, et al. Clinical and subclinical autoimmune thyroid disorders in systemic sclerosis. Eur J Endocrinol 2007;156:431–437. 96. Matsuoka LY, Wortsman J, Gavin JR, Kupchella CE, Dietrich JG. Acanthosis nigricans, hypothyroidism, and insulin resistance. Am J Med 1986;81:58–62.

102 97. Ober KP. Acanthosis nigricans and insulin resistance associated with hypothyroidism. Arch Dermatol 1985;121:229–231. 98. Dix JH, Levy WJ, Fuenning C. Remission of acanthosis nigricans, hypertrichosis, and Hashimoto’s thyroiditis with thyroxine replacement. Pediatr Dermatol 1986;3:323–326. 99. Lanigan SW, Adams SJ, Gilkes JJ, Robinson TW. Association between urticaria and hypothyroidism. Lancet 1984;1:476. 100. Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000;343:185–189. 101. Goddard DS, Liang MG, Chamlin SL, Svoren BM, Spack NP, Mulliken JB. Hypopituitarism in PHACES Association. Pediatr Dermatol 2006;23:476–480. 102. Corbalan-Velez R, Perez-Ferriols A, Aliaga-Bouiche A. Cutis vertices gyrate secondary to hypothyroid myxedema. Int J Dermatol 1999;38:781–783. 103. Safer JD, Crawford TM, Holick MF. A role for thyroid hormone in wound healing through keratin gene expression. Endocrinology 2004;145:2357–2361. 104. Coleman R, Hay RJ. Chronic mucocutaneous candidosis associated with hypothyroidism: a distinct syndrome? Br J Dermatol 1997;136:24–29. 105. Winter JK, Weinstein M, Bargman H. Psoriasiform lesions and abscesses as initial manifestations of severe hypothyroidism in a previously healthy 15year-old girl. Pediatr Dermatol 2007;24:321–323. 106. Mannavola D, Coco P, Vannucchi G, et al. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 2007 [epub ahead of print]. 107. Ghori F, Polder KD, Pinter-Brown LC, et al. Thyrotoxicosis after denileukin diftitox therapy in

S.A. Kopp et al. patients with mycosis fungoides. J Clin Endocrinol Metab 2006;91:2205–2208. 108. Ridruejo E, Christensen AF, Mando OG. Central hypothyroidism and hypophysitis during treatment of chronic hepatitis C with pegylated interferon alpha and ribavirin. Eur J Gastroenterol Hepatol 2006;18:693–694. 109. Takasu N, Takara M, Komiya I. Rifampin-induced hypothyroidism in patients with Hashimoto’s thyroiditis. N Engl J Med 2005;352:518–519. 110. Ohnhaus EE, Burgi H, Burger A, Studer H. The effect of antipyrine, phenobarbitol and rifampicin on thyroid hormone metabolism in man. Eur J Clin Invest 1981;11:381–387. 111. Finke C, Juge C, Goumaz M, Kaiser O, Davies R, Burger AG. Effects of rifampicin on the peripheral turnover kinetics of thyroid hormones in mice and in men. J Endocrinol Invest 1987;10:157–162. 112. Ohnhaus EE, Studer H. A link between liver microsomal enzyme activity and thyroid hormone metabolism in man. Br J Clin Pharmacol 1983;15:71–76. 113. Shah M, Orengo IF, Rosen T. High prevalence of hypothyroidism in male patients with cutaneous melanoma. Dermatol Online J 2006;12:1. 114. Ellerhorst JA, Cooksley CD, Broemeling L, Johnson MM, Grimm EA. High prevalence of hypothyroidism among patients with cutaneous melanoma. Oncol Rep 2004;10:1317–1320. 115. Ellerhorst JA, Sendi-Naderi A, Johnson MK, Cooke CP, Dang SM, Diwan AH. Human melanoma cells express functional receptors for thyroid-stimulating hormone. Endocr Relat Cancer 2006;13: 1269–1277. 116. Heymann WR. Advances in the cutaneous manifestations of thyroid disease. Int J Dermatol 1997;36:641–645.

10 Pretibial Myxedema (Thyroid Dermopathy) Vahab Fatourechi

Editorial Perspective Pretibial myxedema (thyroid dermopathy) is the sine qua non of the dermatologic manifestations of thyroid disease. Although any medical student can reflexively state that pretibial myxedema is a hallmark of Graves disease, how many clinicians realize that the term is a misnomer? That thyroid dermopathy is not necessarily limited to the pretibial region and is not exclusively seen in patients with Graves disease are just two facts frequently misconceived about this condition. The reality is that much has been learned about the immunologic pathogenesis of thyroid der-

Introduction Autoimmune thyroid disease including Graves disease is a systemic process with several target tissues.1,2 Graves ophthalmopathy is the most common and pretibial myxedema or thyroid dermopathy, the least common extrathyroidal manifestation.3 About 0.5%–4.3% of patients with a history of Graves thyrotoxicosis and 13% of patients with severe Graves ophthalmopathy have thyroid dermopathy.4–6 We prefer the general term of extrathyroidal manifestations of autoimmune thyroid disease because of occasional occurrence of dermopathy and ophthalmopathy in Hashimoto hypothyroidism and euthyroid Graves disease.3 The term thyroid dermopathy is more appropriate than pretibial myxedema because involvement of the upper parts of body is also docu-

mopathy, a condition that results from the accumulation of the glycosaminoglycans, hyaluronic acid, and chondroitin sulfate in the dermis. A precise understanding of its pathogenesis, however, remains to be determined. This chapter surveys the clinical, biological, and therapeutic landscape of thyroid dermopathy. By understanding its natural history, eliminating or reducing predisposing factors such as smoking and obesity, appreciating the complexities of the immunologic aberrations leading to mucin deposition, and having a logical approach to therapy, clinicians should be able to at least ameliorate this chronic, occasionally severe, recalcitrant disorder.

mented.7,8 Thyroid dermopathy in the upper parts of the body exposed to trauma is also a proof of a systemic process.3,9,10 A subclinical form of the disorder identified by skin biopsies that show activated fibroblasts and deposition of glycosaminoglycans (GAGs) in patients with Graves disease without clinically evident skin changes has also been proposed.11 Skin grafts harvested from other areas and grafted to the lower extremity may develop dermopathy.12 Thus, thyroid dermopathy is a generalized condition that becomes clinically apparent in the lower extremity because of local factors such as dependent position and mechanical stress. Twenty percent of patients with significant dermopathy have acral changes called acropachy.13 Clubbing is the most common form of acropachy.13 In rare cases, there is thickening of digits and

103

104

V. Fatourechi 20-40%

AITD Acropachy Ophthalmopathy Graves (rarely Hashimoto thyroiditis)

20% Hypo 5%

Hyper 95%

4-13%

Dermopathy

Figure 10.1. Various systemic manifestations of Graves disease and autoimmune thyroid disease. AITD, autoimmune thyroid disease

changes similar to pulmonary osteoarthropathy13 (Figure 10.1). Thyroid dermopathy is almost always associated with Graves ophthalmopathy.14–17 Both conditions of ophthalmopathy and dermopathy are characterized by accumulation of GAGs. GAGs accumulate in dermis and subcutaneous tissues in the case of dermopathy and in the orbital connective tissues and interstitial substance in the case of ophthalmopathy.18–20 Histologic similarities between fibroblast activation and GAG accumulation in the retro-orbital tissue of patients with Graves ophthalmopathy and in the dermal tissue of patients with localized myxedema favor a systemic connective tissue process.21,22 Both the severity of the autoimmune process and longer duration of disease play a role in the development of pretibial myxedema. That is why dermopathy usually occurs 1 year after the presentation of the ophthalmopathy of Graves disease.15,17

Thyroid Function Status in Patients with Thyroid Dermopathy A history of hyperthyroidism is present in 90% of the patients with thyroid dermopathy.5,15,17,23 The remaining 10% have either hypothyroidism or

are euthyroid.5,15,17,23 In all these patients, laboratory evidence of autoimmune thyroid disease is present,13,23,24 including the presence of antibodies against the thyroid-stimuating hormone (TSH) receptor.25 These antibodies can be measured either by a receptor assay (TSH receptor antibody) or by a bioassay based on generation of cyclic adenosine monophosphate (cAMP) in a thyroid cell line. Antithyroid antibodies such as antithyroid peroxidase (TPO antibody) are often present in the serum of the patients.25

Clinical Symptoms and Signs of Thyroid Dermopathy Thyroid dermopathy is usually asymptomatic and is only of cosmetic concern.17 Many patients are so overwhelmed by symptoms of hyperthyroidism and associated ophthalmopathy that they may not be aware of the pretibial skin changes. An observant clinician usually diagnoses early stages of the condition. Occasionally, severe dermopathy causes impairment of function, such as difficulty wearing shoes or entrapment neuropathy. Foot drop may occur in severe cases.26 When dermopathy is associated with thyroid acropachy, bone pain may

10. Pretibial Myxedema (Thyroid Dermopathy)

be present due to a periosteal reaction. Rarely, dermopathy lesions may be painful or pruritic.17 Thyroid dermopathy commonly begins with raised waxy lesions in the pretibial area. The lesions may be flesh colored or yellowish brown. Lesions may be indurated. The hair follicles are prominent, resulting in an orange peel (peau d’orange) or pigskin appearance and texture.15 In early stages, a yellowish or light reddish discoloration and localized nonpitting thickness of the skin is present. The lesions in the pretibial areas and the feet are usually symmetrical.15 Toes may be involved early in the process because of trauma from shoes.17 Hyperpigmentation and hyperkeratosis may be present.17 Sweat over the lesions may be visible as a result of sympathetic nerve stimulation by excess mucin.27,28

105

Pretibial myxedema may appear in several distinct clinical forms (Figure 10.2): The most common is diffuse, nonpitting edema, occurring in 43% of patients. It should be noted that the hyperthyroidism of Graves disease might occasionally result in lower extremity edema not due to dermopathy. This may occur either because of congestive heart failure or, in some cases, because of increased vascular permeability. Pretibial myxedema differs from edema of the lower extremity by its nonpitting nature and its flesh or orange color.17 Another clinical presentation is the plaque form, which consists of raised plaque lesions on a background of nonpitting edema. This form occurs in 27% of cases of dermopathy. The nodular form presents itself as sharply circumscribed tubular or nodular lesions. The nodular form occurs in 18%.17 The most

Figure 10.2. Thyroid dermopathy (pretibial myxedema) in five patients. (A) Nonpitting edema form in pretibial area. (B) Plaque form in pretibial area. (C) Nodular form in ankle and foot. (D) Elephantiasis form. (E) Occurrence of dermopathy in scar tissue. (Reproduced from reference 17 with permission from Journal of Clinical Endocrinology and Metabolism.)

106

Figure 10.3. Thyroid dermopathy in shoulder area at the site of pressure of shoulder straps.

severe form is elephantiasis, which occurs in 5% of patients who have pretibial myxedema 17 (Figure 10.2). It consists of nodular lesions along with sig-

V. Fatourechi

nificant lymphedema. Rarely, the lesions are polypoid or fungating. They usually do not ulcerate.17 The elephantiasis form of pretibial myxedema is the most symptomatic form and creates mechanical and functional disability. Patients are prone to all of the morbidity and complications that can be seen in lymphedema.12,15,29–32 Obesity may be a risk factor for more severe forms of dermopathy, presumably because of an augmentation of effects of dependency and mechanical factors. Isolated cases of involvement of the upper extremities, shoulders, upper back, pinnae, and nose have been reported.8,33 Occurrence in unusual areas usually relates to local trauma such as surgical scars, burns, and vaccination sites (Figure 10.3).8,34–38 I personally have seen involvement of the umbilicus at the site of a laparoscopy scar (Figure 10.4).

Clinical Symptoms and Signs of Thyroid Acropachy

Figure 10.4. Thyroid dermopathy at a patient’s umbilicus at the site of laparoscopy scar. This patient with Graves disease had severe pretibial myxedema and dermopathy at the buttocks

Acropachy is the least common manifestation of Graves disease.13,39–47 Thyroid acropachy does not usually occur in the absence of dermopathy and ophthalmopathy. Diagnosis of thyroid acropachy should be doubted in the absence of these associated conditions. Although a report suggested subtle acropachy in autoimmune thyroid disease in the absence of dermopathy and ophthalmopathy, the results of this study should be interpreted with caution.48 Similar to dermopathy, acropachy is a marker of a severe autoimmune process and of the severity of the associated ophthalmopathy.23 The most common manifestation of acropachy is clubbing of the fingernails and toenails, which occurs in 20% of patients who have thyroid dermopathy (Figure 10.5).13 There may be swelling and tightness of the skin of fingers and toes. A complete picture occurs in 3% of dermopathy patients; it is somewhat similar to pulmonary osteoarthropathy and consists of edema and thickening of the fingers and hands (Figure 10.6) and a periosteal reaction of distal bones. Radiography shows fusiform soft-tissue swelling of the digits and subperiosteal bone formation, usually involving the metacarpals, the proximal and middle phalanges of the fingers, and the metatarsal and proximal phalanges of the toes.13 The subperiosteal reaction is unusual in the

10. Pretibial Myxedema (Thyroid Dermopathy)

107

Graves Ophthalmopathy, a more Common Extrathyroidal Manifestation of Graves Disease

Figure 10.5. Clubbing of the fingers as the most common form of thyroid acropachy

long bones of the forearms or the legs, in contrast to pulmonary osteoarthropathy.13 The periosteal reaction is distinct from pulmonary arthropathy by characteristic spiculated, leathery frothy or lacy appearance on radiographs. The periosteal reaction is most marked in the midportion of the diaphysis. There may be involvement of the metacarpals, middle phalanges of the fingers, and metatarsal and proximal phalanges of the toes. Occasionally, radiography is normal, and bone scans show an accumulation of the radionucleotide in affected areas.13,49 Thyroid acropachy is usually asymptomatic, although it is occasionally painful.13 The histopathology of acropachy has not been studied. One can speculate that the process involves autoimmune activation of periosteal fibroblasts.

Figure 10.6. Severe form of thyroid acropachy associated with dermopathy of the forearm

Almost all patients with dermopathy have clinical ophthalmopathy. Few rare exceptions have been reported; however, dermopathy in the absence of ophthalmopathy should be considered very unlikely. Clinically demonstrable ophthalmopathy occurs in 20%–40% of patients with Graves hyperthyroidism50–52 (Figure 10.1). However, like dermopathy, it can occur in euthyroid or hypothyroid patients.4,5 Diagnostic criteria for Graves ophthalmopathy include eyelid retraction with the retraction of the upper lid at or above the superior corneoscleral limbus, exophthalmos with an exophthalmometer measurement greater than 20 mm, or optic nerve dysfunction or extraocular muscle involvement in the form of a restrictive myopathy. Muscle enlargement on imaging studies such as computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography53 confirms the diagnosis in questionable cases. The ophthalmic signs may be either unilateral or bilateral. In unilateral disease, subtle signs are usually present on the contralateral eye as well. In early stages, symptoms and signs may be trivial; the patient may complain of vague discomfort or eye irritation, leading to misdiagnosis, such as an allergic conjunctivitis.4,54 The majority of cases of ophthalmopathy are mild, requiring only supportive therapy.4 However, the ophthalmopathy is usually severe if it is associated with thyroid dermopathy.23 The frequency of optic neuropathy in Graves and the need for corticosteroid therapy or surgical intervention are very high for cases of ophthalmopathy associated with dermopathy and acropachy.23 Classic signs of Graves ophthalmopathy are almost always present in thyroid dermopathy.17,23,55 In a review of l78 consecutive patients with pretibal myxedema, only 4 patients did not have any evidence of Graves ophthalmopathy at the time of diagnosis, and there was no previous history of clinical ophthalmopathy.17,23 Similar cases with localized myxedema as the presenting symptom have been reported.56–58 In all of these cases, subclinical ophthalmopathy, or previous unnoticed and resolved eye disease, might have been present. Only rarely does dermopathy precede ophthalmopathy.

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Chronology of Manifestations of Graves Disease The usual sequence of development of systemic manifestation of Graves disease is thyroid dysfunction followed by Graves ophthalmopathy in the first year and dermopathy several months to about a year after the development of the ophthalmopathy.59 Thyroid acropachy indicates more severe disease and usually occurs in a later stage, following thyroid dermopathy.13,17,23The most common time of onset of the ophthalmopathy is within 12 months following the diagnosis of thyrotoxicosis; the skin manifestations appear months or about a year later.6,17,57

Histopathology of Dermopathy Biopsy specimens of lesions of thyroid dermopathy demonstrate large amounts of GAGs. GAG is a mucin-like substance in the reticular part of the dermis but is not usually present in the papillary dermis.60,61 A few lymphocytes may be seen in the perivascular spaces. Extensive infiltration with lymphocytes is unusual; however, more than the usual number of lymphocytes may be present in association with an increased number of mast cells.62 With hematoxylin and eosin staining,

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fragmentation and fraying of collagen fibers are demonstrated.61 Mucinous material, with and without connective tissue separation, is seen when the tissue is stained with alcian blue and periodic acidSchiff stain (Figure 10.7).17 Ultrastructural studies show dilated endoplasmic reticulum in fibroblasts, which is indicative of active GAG synthesis and secretion. The epidermis is usually normal except for widened intercellular spaces. Amorphous electron-dense material is seen close to the surface of the fibroblasts.63–65 The deposited mucin promotes dermal edema by retention of fluid, which in turn causes compression or occlusion of small peripheral lymphatics, resulting in the development of lymphedema.66 In general, there are similarities between connective tissue involvement of the extraocular muscles in Graves ophthalmopathy and the pathology of dermopathy.12,22 Lymphocyte infiltration is more abundant in ophthalmopathy and edema and mucin deposition more prominent in thyroid dermopathy. The structural changes of localized myxedema can be distinguished from hypothyroid myxedema by hyperkeratosis, a greater abundance of mucin, and the presence of mononuclear cells.61,63–65 The characteristics that distinguish localized myxedema from mucinosis associated with stasis dermatitis and other causes of pretibial mucinosis include the preservation of a zone of normal-appearing

Figure 10.7. Photomicrographs of skin specimen from a patient with pretibial myxedema showing mucin deposition, edema, fraying of connective tissue fibers, mild fibrosis, and lymphocytic infiltration. Epidermis is normal. (A) Hematoxylin and eosin. (B) Alcian blue. Magnification ×40

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collagen in the superficial papillary dermis, mucin deposition in the reticular dermis, a lack of angioplasia, and the relative absence of hemosiderin.62

Pathogenesis of Dermopathy Graves disease is multigenic and develops as a result of susceptibility genes and environmental factors.67,68 To date, no unique susceptibility genes specific to pretibial myxedema or Graves ophthalmopathy have been identified.69 Hyperthyroidism of Graves disease is an autoimmune condition caused by binding of thyroid-stimulating autoantibodies to the TSH receptor.22,70,71 Activation of the TSH receptor by the autoantibody results in excessive production of thyroid hormones.22 As opposed to our clear knowledge of the pathogenesis of hyperthyroidism, the pathophysiology of Graves ophthalmopathy and dermopathy is less well understood.7,22,70–73 For the development of extrathyroidal manifestations of Graves disease, a more severe autoimmune process and longer duration of disease is needed.74 All patients with localized myxedema have high serum concentrations of TSH receptor-stimulating antibodies.25,75 Of patients with the hyperthyroidism of Graves disease, 90% have positive antibodies; the levels are usually higher in patients with extrathyroidal manifestations.25,75 The development of the extrathyroidal manifestation of Graves disease has been attributed to three major pathogenic mechanisms: immunologic, cellular, and mechanical.22,70

Immunologic Process There is recruitment of certain classes of lymphocytes in dermal tissues of patients with pretibial myxedema. This infiltration is not as diffuse as it is in ophthalmopathy.76 The majority are T lymphocytes; however, some B cells are also present. Subsequently, cytokines are produced, contributing to a cascade of immune processes.22,70 Hyperthyroidism, ophthalmopathy, and dermopathy are the clinical manifestations of the same systemic autoimmune disease.22,70 This is suggested by the presence of a subclinical form of ophthalmopathy in the majority of Graves patients, as detected by sensitive imaging techniques and

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tonometry.77 Subclinical involvement of dermal tissues has been detected by ultrasonography in 76% of patients with Graves hyperthyroidism.78,79 Since the major antigen in hyperthyroidism is the TSH receptor and the antibody is TSH receptor antibody, the logical candidate antigen for all of the systemic manifestations is the TSH receptor. By using polymerase chain reaction (PCR), RNA encoding the extracellular domain of the TSH receptor has been demonstrated in cultured orbital tissue, abdominal skin, and peripheral skin fibroblasts from patients with ophthalmopathy or localized myxedema. It has also been found in the skin from normal subjects.12,79 In addition, it has also been clearly demonstrated that pretibial myxedema tissue and normal skin both express TSH receptor protein.12 TSH receptor immunoreactivity and transcripts have been demonstrated in fibroblast cultures of orbital and pretibial myxedema and normal skin.12,80,81 Not all studies have demonstrated TSH receptor immunoreactivity in normal skin. In one study, TSH receptor immunoreactivity was demonstrated in the pretibial hypodermis of two patients with thyroid dermopathy but not in pretibial tissues of normal controls. The immunoreactivity was in the fibroblasts.82 These results implicate TSH receptor-stimulating antibodies and TSH receptors in the pathogenesis of localized myxedema.18,19 It is likely that in Graves disease the receptor is overexpressed in pretibial tissues, possibly induced by certain cytokines or local factors.18,19 Another proof for an immune process is that serum of patients with localized myxedema may stimulate GAG production by fibroblasts in vitro.83,84 In summary, the most likely initiator of the immune process in thyroid dermopathy and Graves ophthalmopathy is interaction of a common antigen, most likely the TSH receptor with TSH receptor antibodies.18,22

Cellular Process Fibroblasts synthesize GAGs and all of the enzymes needed for metabolism of GAGs.21,85 Recent investigations showed that the fibroblast population may be heterogeneous in different tissues. There may be heterogeneity even within a specific tissue.85–87 Also, differences in tissue expression of TSH receptor may be a contributing factor leading to the clinical manifestations in the orbit and pretibial

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areas.88–90 Activation of fibroblasts resulting in excessive production of GAGs is the main pathologic process in thyroid dermopathy. The systemic activation of fibroblasts is suggested by the demonstration of increased urinary GAGs in patients with Graves disease without clinical dermopathy or ophthalmopathy.91 The fibroblast activation in localized myxedema could be indirect, through sensitized T lymphocytes to antigen(s) shared by thyroid follicular cells and fibroblasts, one candidate antigen being a portion of the TSH receptor. In the immune cascade, cytokines, including interleukin and transforming growth factor-β, stimulate synthesis of GAGs and activate immunomodulatory proteins in dermal fibroblasts.22,70,92,93 There is evidence of accumulation of thyroid-specific T cells in the retroorbital and pretibial tissues in patients with Graves ophthalmopathy and localized myxedema, respectively.22 Thus, in both extrathyroidal manifestations of Graves disease, similar antigens may be responsible for recruitment and expansion of T cells. Whatever causes increased dermal production of GAGs, the local accumulation of these substances leads to edema and expansion of dermal connective tissue and thus the characteristic skin change.22

to the site of trauma. Secondarily, obstruction of the lymphatic microcirculation may aggravate the immune process.22,94 Although evidence for differences in the regulation of synthesis of GAGs by fibroblasts from various anatomic sites has been presented as an alternative hypothesis, at the present time, the mechanical theory seems to be a more plausible explanation for the localization of thyroid dermopathy in the lower extremity.22,94 In summary, with the demonstration of TSH receptor transcripts and proteins in fibroblasts, the recognition of the role of various cytokines in stimulation of fibroblast synthetic activity, the demonstration of high concentrations of TSH receptorstimulating antibodies in the serum of patients with localized myxedema, and the role of mechanical factors, our understanding of pathogenesis of thyroid dermopathy is improving.

Mechanical Contribution

There is strong association between tobacco use and Graves ophthalmopathy. Both ex-smokers and current smokers are more likely to have the disorder.97–102 The association between smoking and ophthalmopathy is strong, and the odds ratio, relative to controls, is as high as 20.2 for current smokers and 8.9 for previous smokers.103 Among patients with ophthalmopathy, smokers are more likely to have severe eye disease.104 The frequency in both current and ex-smokers is much higher in patients who have Graves dermopathy and acropachy.17 Patients with Graves disease, acropachy, and dermopathy are three times more likely to have a history of tobacco use and are five times more likely to be current smokers compared to those with Hashimoto thyroiditis (M.M. Fatourechi et al., unpublished data). Tobacco is also linked to other autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease. The exact mechanism of this association is unknown, but it is likely that tobacco products may cause stimulation of autoimmune process.105–107 A direct effect of tobacco products on fibroblasts from the orbit has been reported.105

If the TSH receptor is expressed in normal skin, then why is the pretibial area most commonly involved? There is a mechanical contribution to its pathogenesis.22,94 Dependency and mechanical factors in the lower extremity certainly play a role. Also, it has been suggested that dependency and dependent edema, because of a lower return of lymphatic fluid, might reduce the clearance and increase the half-life of disease-related cytokines within the affected tissue.22 Another proof for importance of dependency and mechanical factors is that grafts of skin to the lower extremity, from areas that are not usually involved, develop localized myxedema in the recipient site.94–96 In addition, localized myxedema develops in the upper extremity in areas exposed to repetitive trauma34 and at sites of immunization.36 There is some evidence to show that trauma and injury may lead to activation of T cells and initiation of an antigenspecific response, in this case fibroblast activation and production of GAGs. Trauma to cells releases a danger signal that in itself attracts immune cells

Tobacco as a Risk Factor of Severity of Extrathyroidal Manifestation of Graves Disease

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Diagnosis of Thyroid Dermopathy

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rogenic systemic fibrosis) has a different clinical picture.116–122 This serious entity has been partially linked to use of gadolinium for MRI in patients with renal failure. Scleromyxedema also has similarities, but other systemic manifestations and the absence of thyroid dysfunction are helpful in differentiation.123–125 Fibrosing dermopathy has some similarities with thyroid dermopathy, but the clinical picture and manifestations are different.117,121

The diagnosis of localized myxedema is usually obvious because of the typical pretibial lesions, the presence of Graves ophthalmopathy, and a history of thyrotoxicosis. A biopsy may be necessary in some cases.17 In a report of large series from a referral center, 58% of 178 cases had biopsy confirmation of the condition.17 However, in most cases when typical lesions of thyroid dermopathy and Graves ophthalmopathy are present, a biopsy is not needed. In rare cases, the dermopathy can be the initial presentation of Graves disease,17 as mentioned. The diagnosis should be considered doubtful in the absence of Graves ophthalmopathy. Serologic evidence of thyroid autoimmunity, specifically TSH receptor antibodies that are always present in active thyroid dermopathy,17 and the TSH receptor antibody test may be needed for confirmation of the diagnosis. Imaging studies such as bone x-rays and isotope bone scan may be helpful for diagnosing associated acropachy by the demonstration of periosteal reaction in distal bones.26 MRI features of thyroid dermopathy and acropachy have been reported but do not add any information other than what can be obtained by physical examination alone.39

Because of the proven association of tobacco use with the severity of autoimmune manifestations of Graves disease such as ophthalmopathy, dermopathy, and acropachy, patients should be strongly advised to stop tobacco use if they are smokers.97,126 Obesity is a contributing factor to lower-extremity dependent edema and increased mechanical pressure, which aggravates pretibial myxedema. The elephantiasic form may occur in significantly obese individuals.127 Although benefits of weight reduction in obese patients with thyroid dermopathy are anecdotal, it should be strongly recommended.

Differential Diagnosis

Management of Thyroid Dysfunction

Skin changes somewhat similar to those of thyroid dermopathy can occur in patients with simple edema as a result of fluid retention or venous insufficiency. In generalized myxedema, chronic or lichenified dermatitis, hypertrophic lichen planus, and the urticarial phases of certain blistering eruptions, such as bullous pemphigoid skin lesions, may have similarities to thyroid dermopathy.108 Cutaneous mucinoses, such as lichen myxedematosus (papular mucinosis), reticular erythematous mucinosis, and follicular mucinosis, are relatively rare dermatologic conditions in which accumulation of mucin in the dermis is a prominent feature.62,108–115 Most of these mucinoses involve the upper extremities, and thyroid dysfunction and ophthalmopathy are absent (although they may be rarely associated with autoimmune thyroid disease; see chapter 13). Mucin deposition in recently recognized nephrogenic fibrosing dermopathy (neph-

There is evidence to indicate that normalization of thyroid function has a beneficial effect for Graves ophthalmopathy.128,129 Hypothyroidism, by increasing soft tissue edema and mucin deposition, aggravates ophthalmopathy.129 Because of rarity of dermopathy and acropachy, the beneficial effect of achieving euthyroidism on these conditions has not been evaluated. However, since both manifestations have similar pathogenesis, it is recommended to normalize thyroid function as soon as possible, avoiding prolonged hypothyroidism or hyperthyroidism. The mode of therapy for associated hyperthyroidism in the presence of Graves ophthalmopathy is the subject of controversy.129–132 Isolated cases of rapid development of dermopathy, ophthalmopathy, and acropachy after radioactive iodine therapy have been reported, but these may be coincidental.44 In a randomized study, transient aggravation of ophthalmopathy after radioactive iodine therapy in 10% and

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persistent aggravation in another 5%, compared to an antithyroid drug therapy group, were reported.133 However, in the same study, concomitant corticosteroid therapy prevented worsening of the ophthalmopathy.133,134 The authors suggested that their studies should not be used as an argument against use of radioactive iodine therapy. They advocated the use of concomitant corticosteroids when clinical ophthalmopathy is present and, for those without eye disease, in the presence of known risk factors such as smoking.134 TSH receptor antibodies increase immediately after radioactive iodine therapy, and this may theoretically be a reason for transient worsening of extrathyroidal manifestations.135 Ablation of the thyroid by surgery and radioactive iodine results in disappearance of thyroid antibodies after several years. If it is assumed that the presence of thyroid tissue plays a role in persistence of autoimmunity, elimination of antigen after total ablation of thyroid, in the long term, may be beneficial for extrathyroidal manifestations.135,136 However, studies demonstrating benefits of total thyroid ablation in Graves ophthalmopathy or dermopathy are scarce.136–138 Future research is needed to clarify this issue. Meanwhile, despite absence of a clear-cut benefit, the practice in our institution has been to use relatively large doses of radioactive iodine for therapy of Graves hyperthyroidism. In cases of severe ophthalmopathy or dermopathy, we ablate the thyroid remnant with radioactive iodine while using concomitant corticosteroids.133 It can be advised that if radioactive iodine is given for therapy of Graves hyperthyroidism in the presence of significant ophthalmopathy, a short course of corticosteroids be administered, particularly if risk factors such as tobacco use are present.128 Although studies related to preventive effects of corticosteroid therapy on development of dermopathy are lacking, it is reasonable to apply the same approach to dermopathy and acropachy prevention.

Management of Associated Ophthalmopathy Ophthalmopathy, if moderately severe, is usually treated with systemic corticosteroids as the first choice of medical therapy.139–141 Other forms of systemic immunomodulatory therapy for ophthalmopathy also improve the associated dermopathy.17 When ophthalmopathy overshadows

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the localized myxedema, as is often the case, systemic glucocorticoids or other immunosuppressive therapies such as cyclosporine, in association with corticosteroids,142 intravenous immunoglobulin (IVIG),143–146 and plasmapheresis147–151 or octreotide,15,152–158 are used, depending on the severity of disease. Evidence for effectiveness of corticosteroid therapy is stronger.142

Local Corticosteroid Therapy Most patients require no therapy for dermopathy because the lesions are usually asymptomatic and not particularly unsightly. Dermopathy can be covered by clothing to the patient’s satisfaction.17 In addition, the lesions usually progress little and may partially or completely regress with time.17 When treatment becomes necessary because of cosmetic concerns, functional impairment, or local discomfort, topical application of a glucocorticoid is the treatment of choice.17,159–161 The likelihood of success of therapy decreases as the extent of the lesions increases. The glucocorticoid is applied directly to the lesions, and for optimal results, occlusive therapy with a plastic film such as Saran Wrap is recommended. In a group of 11 patients treated by application of a midpotency corticosteroid (0.2% fluocinolone acetonide cream) to the lesions under occlusive plastic film dressings, nightly or every other night, all patients demonstrated substantial improvement.159,160 The improvement persists after the frequency of treatment is gradually reduced. High-potency steroids, such as clobetasol propionate, can also be used under an occlusive patch (DuoDERM).17,161 A trial of 4–10 weeks, followed by intermittent maintenance therapy, is usually required.17 Hydrocolloid or plastic wrap occlusive dressings can enhance the absorption of topical corticosteroids.17,161 The occlusive dressing is kept on for 12 h. The skin should be watched for signs of adverse effects from the topical steroids, such as atrophy, telangiectasia, and ecchymosis. Similar local corticosteroid therapy for acropachy has been used with apparent success.162 Because of fluid accumulation, use of compressive bandages or a Jobst stocking during the day results in an additional benefit, especially in patients with the elephantiasic form of the disorder. Patients may require many months of therapy, the goal of which is to limit the degree of disfigurement,

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improve function, and avoid tissue breakdown and compressive complications. Intradermal injections of a glucocorticoid163 and hyaluronidase have been used, but these are not recommended because their efficacy is limited, and they may cause irregular lumpy skin.

physiotherapist, is a combination of manual lymphatic drainage gentle massage, followed by the application of a multilayered low-stretch bandaging, exercise, and scrupulous skin care.30

Systemic Immunomodulation

Local excision of pseudotumorous localized myxedema of the dorsum of the foot resistant to medical therapy has been reported with apparent success.166,169,170 There is a report of a patient with long-standing pretibial myxedema who underwent surgical excision. Significant improvement was sustained for 12 months.171 Because of the chronicity of thryoid dermopathy, the benefit of surgery in this case report is unclear because follow-up for only a year may be considered too short. Despite these isolated case reports, we do not recommend surgical excision of nodules or skin grafting because of the possibility of exuberant recurrence of localized myxedema at the site of a surgical scar.

Systemic immunomodulation measures are rarely, if ever, needed for localized myxedema. They are usually indicated for associated severe ophthalmopathy. Treatments that have been beneficial when used solely for dermopathy in a few patients, include corticosteroid therapy starting at 60–80 mg of oral prednisone daily for 4 weeks with gradual tapering over 3 months. Plasmapheresis and IVIG have been used in isolated cases. A lack of benefit from high-dose IVIG in a case of elephantiasic pretibial myxedema was reported.164,165 Evaluation of the effects of these therapies is difficult because of the small number of reported patients, short follow-up periods, and lack of controlled studies.

Octreotide Therapy The rationale for a beneficial effect of octreotide is the presence of somatostatin receptors in lymphocytes that are present in the pretibial myxedema tissue.166–168 Octreotide is a potent somatostatin analog with potent inhibitory properties. It has been used in thyroid dermopathy with anecdotal success.158,166–168 A report, however, did not show benefit from long-term octreotide therapy in four severe cases of pretibial myxedema.127Whether it is effective in milder cases is not clear; because of the cost of the drug and its equivocal benefit, it is not a recommended therapy for thyroid dermopathy.

Compressive Therapy and Complete Decompressive Physiotherapy For severe cases of pretibial myxedema such as the elephantiasic form, aggressive management, similar to that used for lymphedema, may be required. In one report, complete decompressive physiotherapy (CDP) resulted in significant sustained improvement in a case of elephantiasic pretibial myxedema. This treatment, given by a certified

Surgical Excision of Lesions

Long-Term Outcome of Thyroid Dermopathy In a report, 46% of patients did not require any therapy for dermopathy.17 In mild cases not requiring therapy, 50% had complete remission in 17 years. Severe cases that received local corticosteroids did not fare better than milder cases not receiving any specific therapy. After 25 years of follow-up, 70% of milder untreated cases and 58% of severe forms that received local therapy achieved either partial or complete remission (Figure 10.8).17 It appears that the long-term remission was dependent on degree of severity of initial disease rather than the effect of therapy. Milder cases without therapy had a better chance of complete remission than the severe cases despite therapy. Present modalities of therapy for thyroid dermopathy and acropachy are palliative at best. There is a need for new forms of immune modulation for all extrathyroidal manifestations of autoimmune thyroid disease. New therapies currently used for other autoimmune conditions such as rheumatoid arthritis and monoclonal antibodies against T cells and B cells should be considered for trials in autoimmune thyroid disease.

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acropachy manifests commonly as digital clubbing, sometimes accompanied by thickening of the skin of digits and by a periosteal reaction. Acropachy, despite its similarities, is distinguishable from pulmonary osteoarthropathy. No specific therapies are available for acropachy.

References Figure 10.8. Percentage of patients who had complete remission according to treatment group (Kaplan Meier method). (Reproduced from reference 17 with permission from Journal of Clinical Endocrinology and Metabolism.)

Conclusion Pretibial myxedema is an extrathyroidal manifestations of Graves disease not related to thyroid dysfunction. It occurs in patients with a history of hyperthyroid Graves disease and less commonly in the background of thyroid autoimmunity with hypothyroidism or euthyroidism. Its diagnosis should be doubted in the absence of laboratory evidence of thyroid autoimmunity. It almost always occurs with, or follows, thyroid ophthalmopathy. All patients with thyroid dermopathy have high titers of thyroid receptor antibodies, indicating the severity of the autoimmune process. The majority of the cases can be diagnosed clinically, and skin biopsy is only needed in questionable cases for confirmation of the clinical diagnosis. Most cases are of cosmetic concern and are transient. If systemic corticosteroid therapy is used for the associated ophthalmopathy, the dermopathy may also resolve. Local corticosteroid therapy is the standard treatment for localized dermopathy. Half of the cases do not require local corticosteroid therapy and resolve over time. Moderately severe cases require local corticosteroid therapy and will have a partial response. The elephantiasis form is very difficult to treat, and most therapies fail. Future therapies should aim at inhibiting the basic pathogenic immune process. In some severe cases of thyroid dermopathy, involvement of upper and lower extremities may be associated with thyroid acropachy. Thyroid

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119 158. Stan MN, Garrity JA, Bradley EA, et al. Randomized, double-blind, placebo-controlled trial of long-acting release octreotide for treatment of Graves’ ophthalmopathy. J Clin Endocrinol Metab 2006;91:4817–4824. 159. Kriss JP. Pathogenesis and treatment of pretibial myxedema. Endocrinol Metab Clin North Am 1987;16:409–415. 160. Kriss JP, Pleshakov V, Rosenblum A, Sharp G. Therapy with occlusive dressings of pretibial myxedema with fluocinolone acetonide. J Clin Endocrinol Metab 1967;27:595–604. 161. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Derm Venereol 1992;72:69–71. 162. Parker LN, Wu SY, Lai MK, et al. The early diagnosis of atypical thyroid acropachy. Arch Intern Med 1982;142:1749–1751. 163. Engin B, Gümüsel M, Ozdemir M, Cakir M. Successful combined pentoxifylline and intralesional triamcinolone acetonide treatment of severe pretibial myxedema. Dermatol Online J 2007;13:16. 164. Antonelli A, Palla R, Casarosa L, et al. In vitro solubilization of deposits of IgG immune complexes by gamma-globulins in patients with Graves’ disease, Graves’ ophthalmopathy, pretibial myxoedema and Hashimoto’s thyroiditis. Pharmacol Res 1992;26(suppl 2):170–171. 165. Antonelli A, Saracino A, Alberti B, et al. High-dose intravenous immunoglobulin treatment in Graves’ ophthalmopathy. Acta Endocrinol 1992;126:13–23. 166. Felton J, Derrick EK, Price ML. Successful combined surgical and octreotide treatment of severe pretibial myxoedema reviewed after 9 years. Br J Dermatol 2003;148:825–826. 167. Kuyvenhoven JP, van der Pijl JW, Goslings BM, Wiersinga WM. Graves’ dermopathy: does octreotide scintigraphy predict the response to octreotide treatment? Thyroid 1996;6:385–389. 168. Priestley GC, Aldridge RD, Sime PJ, Wilson D. Skin fibroblast activity in pretibial myxoedema and the effect of octreotide (Sandostatin) in vitro. Br J Dermatol 1994;131:52–56. 169. Pingsmann A, Ockenfels HM, Patsalis T. Surgical excision of pseudotumorous pretibial myxedema. Foot Ankle Int 1996;7:107–110. 170. Shaw SJ, Kamdar V, Bughi S. Elephantiasic form of severe pseudotumorous pretibial myxedema: a case report. Endocrinologist 2000;10:433–436. 171. Derrick EK, Tanner B, Price ML. Successful surgical treatment of severe pretibial myxoedema. Br J Dermatol, 1995;133:317–318.

11 Alopecia and Thyroid Disease Michelle Babb-Tarbox and Wilma F. Bergfeld

Editorial Perspective Hair has an intimate relationship with thyroid hormone. Although the precise physiologic effects remain to be determined, it is clear that fluctuations in the level of thyroid hormone may result in alopecia. These findings may be noted throughout life, appearing in congenital hypothyroidism in the neonate and apathetic hyperthyroidism in the elderly. The spectrum of hair disorders associated with thyroid disease includes cycling defects seen with either hypothyroidism or hyperthyroidism, cycling

Introduction Alopecia and alterations of hair growth are common complaints for a significant percentage of patients presenting to dermatologic, pediatric, gynecologic, and internal medicine clinics. Patients present with their concerns about the hair loss and its effect on their appearance and self-esteem. All forms of hair loss can cause significant psychological distress, which can result in anxiety or depression.1 Many patients address concerns that the hair loss might be associated with a medical disorder.2 The accessible nature of hair for examination and the relative vulnerability of the growing hair follicle to changes in the internal environment support a careful examination of the hair, which can provide important diagnostic insights. The anagen follicle cells, with their active metabolism, are among the most rapidly dividing

problems related to drugs that affect the thyroid gland, syndromal disorders, inflammatory conditions such as lichen planopilaris or lupus that could lead to scarring alopecia, or associations with other autoimmune disorders such as alopecia areata. I follow the credo that if there is hair loss, an evaluation for thyroid disease, either as a cause or as an association, should routinely be part of any workup. As more is learned about the genuine function of thyroid hormone on hair, perhaps we will bear witness to a future in which thyroid hormone may be used therapeutically as an adjunctive agent for alopecic disorders.

cells in the human body, along with those in the gastrointestinal (GI) tract and the bone marrow.3 Due to high metabolic needs, these rapidly dividing cells are exquisitely vulnerable to nutritional deficiencies, medications, medical disorders, and physical stresses. In times of crisis, which can include all of the above situations and myriad others, the hair can shut down its growth to redirect energy and resources to more essential tissues.4,5 With this generalized impact on actively proliferating cells, all forms of thyroid disease can be associated with abnormalities of hair growth and alopecia. Aberrations of hair growth may serve a sentinel function for potential damage to more indispensable tissues supporting the need for medical evaluation. Because hair loss may be sign of an internal disease, investigation of hair loss disorders should be considered a medical necessity and not just a cosmetic concern.

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Table 11.1. Types of thyroid disease, associated hair disease, and basic science. Type of thyroid disease Hair changes Hypothyroidism

Basic science

- Trichodystrophies

- Thyroid hormone receptors and thyroid hormone-binding protein in hair follicle - Telogen effluvium - Increased percentage of hairs in telogen - Slow growing hair - Decreased sebum production - Telogen effluvium - Thyroid hormone receptors and thyroid hormone-binding protein in hair - Fine, sparse hair follicle - Decreased axillary hair - Decreased hair follicles in experimental animals with increased systemic triiodothyronine - Associated with - Immune changes secondary to stress may predispose patients to alopecia areata autoimmune thyroid disease and alopecia areata - Telogen effluvium - Trichodystrophies - Premature graying - Premature graying - Premature graying may indicate increased risk of low bone mineral - Associated with density alopecia areata - Thyroid hormone receptors and thyroid hormone-binding protein in hair follicle - Telogen effluvium

Hyperthyroidism

Hashimoto thyroiditis

Graves disease

Table 11.2. Hair diseases, associations with thyroid disease, and thyroid screening. Hair disease Telogen effluvium Madarosis Alopecia areata Lichen planopilaris Discoid lupus Morphea Hirsuitism Hypertrichosis, adult Hypertrichosis, infant

Association with thyroid disease Stress of thyroid disease causes shift of abnormal percentage of hair to telogen Characteristic sign of hypothyroidism Association with autoimmune thyroid disease (Hashimoto thyroiditis and Graves disease) Associated with thyroid disease Associated with DLE in the setting of coexistent SLE or Sjögren syndrome Associated with autoimmune thyroid disease (Hashimoto thyroiditis and Graves disease) Associated with hypothyroidism in the setting of PCOS Associated with hypothyroidism Associated with congenital hypothyroidism

Should thyroid testing be performed? Yes, once other causes of hair loss are excluded Yes, if other signs or symptoms are present Yes, at the time of diagnosis and once to twice yearly thereafter Yes, if other signs or symptoms are present Yes, if patient has coexistent SLE or Sjögren syndrome Yes, in all patients at diagnosis Yes, in women with PCOS, irregular menses, or anovulation Yes, once other potential causes are excluded Yes, all neonates with hypertrichosis

DLE, discoid lupus erythematosus; PCOS, polycystic ovarian syndrome; SLE, systemic lupus erythematosus.

Table 11.3. Types of thyroid disease and thyroid screening. Type of thyroid disease Hypothyroidism

Hyperthyroidism

Initial thyroid screening - TSH - T3 - T4 - Microsomal - TSH - T3 - T4 - Microsomal - TRAb if any of the above are abnormal

Follow-up thyroid screening TSH

TSH

Microsomal, antimicrosomal antibodies; T3, triiodothyronine; T4, thyroxine (free and total); TRAb, anti-TSH receptor antibody; TSH, thyroid-stimuating hormone.

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Table 11.4. Thyroid screening for specific hair disorders. Hair disorder

Initial thyroid screening

Telogen effluvium

Follow-up thyroid screening

- TSH - T3 - T4 - Microsomal Madarosis - TSH - T3 - T4 - Microsomal Androgenic alopecia, women - TSH in all women Androgenic alopecia, men - TSH in men with atypical pattern alopecia Seborrheic dermatitis - TSH if associated with other symptoms of hypothyroidism Alopecia areata - TSH - T3 - T4 - Microsomal Lichen planopilaris - TSH - T3 - T4 - Microsomal Discoid lupus - TSH - T3 - T4 - Microsomal Morphea - TSH - T3 - T4 - Microsomal Hirsuitism - TSH - DHEAs and testosterone (free and total) - HbA1C Hypertrichosis, adult - TSH if nutritional deficiencies and medications ruled out Hypertrichosis, infant - TSH in all infants with hypertrichosis

- TSH yearly

- TSH yearly

- TSH (if previously abnormal or new symptoms) - TSH (if previously abnormal or new symptoms) - TSH (if previously abnormal or new symptoms) - TSH yearly

- TSH yearly

- TSH yearly

- TSH yearly

- TSH(if previously abnormal or new symptoms)

- TSH(if previously abnormal or new symptoms) - TSH(if previously abnormal or new symptoms)

DHEA, dehydroepiandrosterone; microsomal, antimicrosomal antibodies; T3, triiodothyronine; T4, thyroxine (free and total); TSH, thyroid-stimuating hormone.

In this chapter, we review the different ways that thyroid disease, disorders of hair growth, and alopecia are interrelated (Tables 11.1 and 11.2) and introduce guidelines for thyroid function screening (Tables 11.3 and 11.4).

Thyroid and the Hair Follicle Thyroid Receptor and the Hair Follicle Thyroid hormone plays a central role in regulating the growth, differentiation, metabolism, and development of many of the tissues in the body, including the hair. Thyroid receptors have been

demonstrated in hair follicles, suggesting that thyroid hormone may directly affect hair cell cycling and hair growth.6,7 The thyroid receptor is a nuclear receptor that acts as a hormonally modulated transcription factor through binding to short regulatory sequences of DNA known as thyroid response elements (TREs), resulting in up- or downregulation of the expression of different target genes. When bound to thyroid hormone, the thyroid hormone receptor acts as a transcriptional activator, and when not bound to thyroid hormone it typically acts as a repressor of transcription.8 Thyroid receptors are found in hair follicles, and multiple studies reinforce the role that thyroid

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hormone plays in regulating hair growth. Animal studies demonstrate that thyroid hormone acts in concert with estradiol and testosterone to regulate follicular activity and the rate of hair growth. Thyroid hormone acts on the hair follicle in mammals to hasten the commencement of follicular activity as well as seasonal molting. In contrast, when a hypothyroid state is induced in experimental animals with either thyroidectomy or propylthiouracil (PTU), the onset of follicular activity is delayed.9 There are two different isoforms of the thyroid receptor in humans, α and β. In the hair follicle, the thyroid receptors, predominantly of the β1 isoform, have been localized to the nuclei of cells of the outer root sheath and the dermal papillae10,11 (Figure 11.1). Addition of thyroxine (T4) to the growth media of hair cells in culture results in proliferation of outer root sheath and dermal papillae cells, suggesting a trophic effect for thyroid hormone in these cells.12 In the future, studies of the different effects of mutations of the human isoforms of the thyroid receptor may give added insight into the mechanism by which thyroid hormone effects hair cycling and growth.

Inner root sheath

Outer root sheath

Dermal papilla

Figure 11.1 *Thyroid hormone receptor, present in the outer root sheath and the dermal papilla. +Thyroid hormone-binding protein, present in the inner root sheath

Thyroid-Binding Protein and the Hair Follicle A thyroid-binding protein, µ-crystallin, has also been localized to the hair follicle, where it is abundantly expressed in the inner root sheath cells of murine hair follicles, especially in late anagen (Figure 11.1). Thyroid hormone-binding proteins such as µ-crystallin act in intracellular transport of thyroid hormone and help to regulate its concentration within the cell.13 This exuberant expression of a thyroid hormone-binding protein within the hair follicle, with levels that vary with the hair cycle, suggests that this might be another mechanism by which thyroid hormone affects hair growth. Along with the direct effects described, the metabolic derangements incurred with imbalance in thyroid hormone can indirectly affect hair growth as well.6,7 Thyroid hormone controls the basal metabolic rate. The catabolic state induced by hyperthyroidism can affect the balance of calcium, iron, and zinc.14,15 Deficiencies of these nutrients can impede hair follicle growth. Conversely, imbalances in iron and zinc may also influence thyroid function.15,16

Thyroid and Sebaceous Gland The interactions between the thyroid gland and the sebaceous glands are complex. A decrease in sebum production is observed in hypothyroid humans and animal models.17,18 Interestingly, therapeutic thyroid hormone supplementation increases but does not normalize sebum production in treated human patients.17 In hypothyroid animal models, thyroid hormone supplementation rapidly normalizes sebum production independent of testosterone or other hormones that affect sebum production.18,19 Both thyroid-stimuating hormone (TSH) and T4 have effects on sebocytes. TSH increases both sebaceous gland mitosis and sebum secretion in hypophysectomizedcastrated rats.20 Thyroxine administered to castrated rats also receiving testosterone increases sebum secretion while simultaneously decreasing sebaceous gland mitosis, apparently acting by increasing intracellular synthesis.19,20 The complex interplay between the thyroid and sebaceous glands may help produce the characteristic changes of skin and hair texture that are commonly observed in thyroid disease states.

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Specific Thyroid Diseases Related to Hair Loss Hypothyroidism The most common type of thyroid disease is hypothyroidism. In the National Health and Nutrition Examination Survey (NHANES) III study, TSH, total serum T4, antithyroid peroxidase (TPO-Ab), and antithyroglobulin (TgAb) antibodies were measured from a sample of 17,353 people selected to represent the US population. Hypothyroidism was discovered in 4.6% of those sampled. The majority of hypothyroidism detected in this study was subclinical (4.3%), indicating the need for a high index of suspicion to detect thyroid disease.21 Hypothyroidism has multiple effects on the skin, hair, and nails. It can present with dry flaky skin; puffiness of the face, hands, and feet; thick, brittle nails; dry, sparse hair; and increased hair shedding, which is typically the result of telogen effluvium.22,23 Patients with hypothyroidism often complain of increased hair shedding. In animal models, untreated hypothyroid animals have been found to have a greater number of follicles in telogen (shedding phase) and fewer hair shafts than control animals or treated hypothyroid animals.24 In contrast, treated hypothyroid animals were found to have more hair follicles in anagen (growing phase) than either control or untreated hypothyroid animals. The greater percentage of telogen follicles in the hypothyroid state results in a greater percentage of hairs susceptible to shedding at any given time, a condition described as telogen effluvium. As a result, patients shed more hairs than normal. These patients also have fewer hairs in anagen phase, resulting in decreased density of growing hairs, which is perceived as thinning. A reduced need for haircuts and slow hair regrowth are other common complaints among hypothyroid patients. In experimental animals, untreated hypothyroid dogs demonstrated a slower rate of hair regrowth 2 months after clipping.24 Patients complaining of increased hair shedding, or hair that does not grow, should be carefully interviewed for symptoms of hypothyroidism; when other symptoms are present, thyroid screening should be performed. Thyroid screening for a new patient should consist of TSH, free T4, triiodothyronine (T3), and either microsomal antibody or

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antithyroid peroxidase antibody. Patients can be followed with TSH levels (Table 11.3). Patients with hypothyroidism also often complain of fragile, broken hairs, which is the clinical representation of trichodystrophy. When trichograms from the parietal and occipital area of patients with thyroid disease and hair loss were examined, increases of dysplastic and broken hairs were noted compared to trichograms from normal scalp. These differences were accentuated in the occipital scalp.25 Hypothyroid patients often complain of dry skin and thinning hair, raising the question of sebaceous dysfunction. As described, the hypothyroid state adversely affects sebum production. Sebum serves to condition, lubricate, and waterproof the hair shaft. Conceivably, the decreased sebum production associated with hypothyroidism could result in a dryer, more fragile hair shaft. Complaints of a change in the hair texture, thickness, or fragility or increased hair shedding (telogen effluvium) could be the first diagnostic clue to developing hypothyroidism. Such patients should be carefully questioned for additional symptoms of hypothyroidism. If one or more is present; screening for thyroid dysfunction as described may be warranted (Table 11.3). Women over 50 years of age are especially vulnerable to thyroid disease. Symptoms suggestive of hypothyroidism should be carefully considered in these patients.26 The prevalence of hypothyroidism increases with age, particularly in women.27 Geriatric patients should be carefully screened, as symptoms of hypothyroidism, which could be falsely attributed to the aging process, are often subtle (Table 11.3).

Hyperthyroidism Hyperthyroidism, although less common than hypothyroidism, affects a significant percentage of patients within the United States. In the NHANES III trial, thyroid screening as described of 17,353 people selected to represent the US population revealed hypothyroidism in 1.3% of this study population. In contrast to hypothyroidism, the percentage of patients presenting with clinical versus subclinical hypothyroidism was much more similar (0.5% clinical vs. 0.7 % subclinical); however,

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since over half of hyperthyroid patients presented subclinically, symptoms suggestive of hyperthyroidism deserve serious consideration.21 Patients suspected of hyperthyroidism should be screened for TSH as well as free T4 and T3 levels. If any of these values are abnormal, tests for anti-TSH receptor antibody and antimicrosomal antibody should be performed (Table 11.3). Hyperthyroidism also has multiple effects on the skin, hair, and nails. It can present with warm, moist skin; brittle nails; sparse, fine hair; or hair loss.22,23 Short, scant, thin, or fine hair has been observed in 20% to nearly 50% of hyperthyroid patients; however, the severity of thyroid disease does not appear to correlate with the degree of hair loss.28–30 Decreased axillary hair has been reported in conjunction with thyrotoxicosis in up to 60% of patients.31 The effects of hyperthyroidism on the skin, hair, and nails have not been as extensively evaluated as the effects of hypothyroidism, and much of our current knowledge on this topic derives from animal research.32 In murine models, intraperitoneal T3 resulted in 48% fewer hairs (p < .001) than controls.33 Elevated levels of systemic thyroid hormone in humans could have a similar effect, resulting in sparse hair and diffuse hair loss, which have been observed in hyperthyroid human patients.34 Mice within the same study treated with topically applied T3 demonstrated 160% more hairs (p < .01) by contrast.33 In a similar study, mice treated with topically applied T3 demonstrated an increase in hair length, which was 1180% longer (p < .001) than control mice.32 Topical application of thyroid hormone has also been found to increase wound closure by 58% in experimental animals versus application of the vehicle alone.35 The differences between topically applied and systemically administered T3 may be due to the other changes that occur in metabolism and hormonal regulation with systemic hyperthyroidism. In a randomized controlled study involving 48 male patients with androgenetic alopecia, topically applied T4 compounded with insulin, growth hormone, and three nonsteroidal anabolic hormones resulted in cessation hair loss in 80% of participants, as confirmed by a hair count. An increase of the hair count of 17.1% signifying increased scalp hair density was observed in the patients treated with the T4-containing compound versus 8.9% increase in hair counts in the control population.36

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While it is difficult to isolate the role of the T4 in this complex compounded topical preparation, future studies of topical T4 for the treatment of hair loss could be promising.

Autoimmune Thyroid Disease Autoimmune thyroid disease (AITD) is one of the most common manifestations of autoimmunity, affecting approximately 1.5% of the population. This is associated with a female predominance.37 The etiology of AITD is multifactorial, including genetic and environmental influences. AITD can take the form of either Hashimoto thyroiditis or Graves disease,38,39 both of which can occur concurrently in the same patient.40 Epidemiologic and case-control studies suggest a role for stress in the development of AITD. It is proposed that physical or psychological stress can induce immunologic changes that may predispose patients toward autoimmunity.38,39 AITD can occur as either a dysfunction of humoral immunity, as is the case with Graves disease, or as a misdirection of cellular immunity, as occurs in Hashimoto thyroiditis. Although Graves disease and Hashimoto thyroiditis are typically defined as two separate clinical entities, they frequently occur within the same family, and some individuals have been known to progress from one form of AITD to the other.41 There are case reports of patients presenting with concomitant Graves disease and Hashimoto thyroiditis. These patients can present with the characteristic physical findings of Graves disease, and the systemic symptoms of hypothyroidism. Laboratory workup in these patients typically reveals both a positive anti-TSH receptor antibody and a positive antimicrosomal antibody.40 There are also multiple case reports of Graves disease and Hashimoto thyroiditis occurring in sets of monozygotic twins, with one twin having Graves disease and the other Hashimoto thyroiditis.41–44 Because monozygotic twins have identical genetic makeup and similar environmental exposure, studies of monozygotic twins expressing different types of AITD are of particular interest in unraveling the complex genetic and environmental interactions that act together to produce the different phenotypes of thyroid autoimmunity.41 There is a 30% concordance rate for Graves disease in monozygotic

11. Alopecia and Thyroid Disease

twins versus only a 3%–9% concordance rate in dizygotic twins.45 The differences in concordance rates between monozygotic and dizygotic twins demonstrates the importance of genetics in the pathogenesis of AITD; however, there are other influences. The fact that two genetically identical individuals have a 60% discordance rate in development of Graves disease emphasizes the importance of nongenetic environmental and hormonal factors in the development of thyroid autoimmunity. There is still much to be learned about the genetic and environmental basis of AITD. Patients presenting with hair loss who complain of elevated levels of psychological or physical stress should be thoughtfully examined for other signs or symptoms suggestive of thyroid disease. If AITD is present in these patients, it could present with either hypothyroidism or hyperthyroidism, or they may be euthyroid in the case of Hashimoto thyroiditis.

Hashimoto Thyroiditis Hashimoto thyroiditis is a lymphocyte-driven autoimmune attack on the thyroid gland. It can present with physical findings, including a diffuse or nodular goiter. Patients may be euthyroid, transiently hyperthyroid, or hypothyroid or can present with subclinical hyperthyroidism or hypothyroidism. Most cases of Hashimoto thyroiditis eventually progress to permanent hypothyroidism. Screening with antimicrosomal antibody can be helpful to detect disease in patients with subtle clinical presentations. Occasionally, Hashimoto thyroiditis can cause acute cell-mediated destruction of thyroid cells, resulting in the release of stored thyroid hormones. When this occurs, a transient thyrotoxic state ensues, referred to as Hashitoxicosis.38,39 In both Hashimoto thyroiditis and Graves disease, the histopathology demonstrates a lymphocytic infiltration of the parenchyma of the thyroid gland.39 The balance of Th1 to Th2 cells within this lymphocytic infiltrate partially determines which type of AITD is likely to develop.38 Hashimoto thyroiditis involves a predominantly Th1 lymphocytic infiltrate. This results in a cellmediated autoimmune attack on thyroid cells with epithelial cell destruction and fibrosis. Typically, the entire thyroid gland is involved. The size of

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the thyroid follicles diminishes, and colloid may be sparse or absent. Characteristic Hürthle or Askanazy cells, which are slightly larger, more acidophilic staining cells packed with mitochondria, may be apparent.39 The lymphoid infiltration within the thyroid interstitial tissue may form follicles and germinal centers with plasma cells.38,39 Although Hashimoto thyroiditis is predominantly a cell-mediated autoimmune attack on the thyroid gland, autoantibodies to thyroid peroxidase and thyroglobulin are produced as well. Immunoglobulin G (IgG) deposits can be identified on electron microscopy of thyroid tissue from patients with Hashimoto thyroiditis as dense deposits along the basement membrane. Although these antibodies are known to be complement fixing, it is unclear if they are cytotoxic or if they play a significant role in thyroid destruction. Transplacental exposure to maternal antithyroid globulin or antithyroid peroxidase antibodies in the unborn children of women with Hashimoto thyroiditis does not typically result in thyroid damage. Prevalence rates of antithyroglobulin and antithyroid peroxidase antibodies in the blood of newborn children of women with Hashimoto thyroiditis have been reported to range from 6% to 10%. One study of these children determined the overall incidence of antithyroid peroxidase antibodies in cord blood to be approximately 8%. There was no statistical difference in T4, T3, or TSH levels in the children with versus the children without the antithyroid peroxidase antibodies.31 There is an increased rate of spontaneous abortion in pregnant women with positive antithyroid peroxidase antibodies. This is believed to be attributable to the autoimmune nature of Hashimoto thyroiditis and maternal hypothyroidism and not directly to the pathogenic effects of autoantibodies on the fetal thyroid gland.31 Hashimoto thyroiditis can present in association with a variety of hair disorders, including telogen effluvium, trichodystrophies, and premature graying. As an autoimmune disease, Hashimoto thyroiditis can also be associated with alopecia areata. Patients with alopecia areata are more likely to have a positive family history of AITD than controls and are also more likely to manifest thyroid autoimmunity themselves.46 In one study, 16%–25% of patients with alopecia areata also had thyroid disease, with the higher percentage representing patients with more extensive alopecia.47 Similar to

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Hashimoto thyroiditis, alopecia areata has also been associated with psychological or physical stress.46 The proposed mechanism for this association is an upregulation of corticotrophin-releasing hormone (CRH) receptors in the hair follicle, inducing a local inflammatory response.46 Hashimoto thyroiditis can also present either as hypothyroidism or hyperthyroidism (due to either Hashitoxicosis or concomitant Graves disease as described); this may be associated with the different trichodystrophies and hair loss associated with the thyroid states discussed (Tables 11.1 and 11.2).

Graves Disease Graves disease typically presents as part of a syndrome that includes hyperthyroidism, goiter, ophthalmopathy, and characteristic dermopathies. It occurs when anti-TSH receptor antibodies artificially overstimulate the thyroid gland to produce thyroid hormone, resulting in thyrotoxicosis. This overstimulation results in parenchymal hypertrophy with a change from cuboidal to columnar epithelium and the formation of papillary infoldings of the follicular wall, with increased colloid space. In Graves disease, the lymphocytic infiltrate is less intense than in Hashimoto disease; it is dominated by Th2 lymphocytes, which pathologically induce B cells to produce stimulating anti-TSH receptor antibodies.38,39 The infiltrate typically presents as a focal thyroiditis with aggregates of lymphocytes that occasionally form germinal centers. As with Hashimoto thyroiditis, plasma cells are often present. Occasionally, the lymphocytic infiltrate can be mild and diffuse throughout the thyroid gland and may even overlap with the pattern of Hashimoto thyroiditis. Graves disease is an autoimmune disease that, similar to Hashimoto thyroiditis, is associated with alopecia areata; however, the association is not as well documented. Graves disease is also associated with premature graying of the hair (canities). This could represent a deleterious affect of autoimmunity, or elevated levels of thyroid hormone, on the melanocytes of the hair follicles. Patients with excess thyroid hormone, whether endogenously produced or exogenously supplied, are at increased risk for decreased bone mineral density due to direct stimulation of osteoclasts by thyroid hormone.48 In the hyperthyroid state, excess thyroid hormone increases

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osteoclastic bone resorption, leading to a negative bone balance, decreased bone mineral density, and eventually osteoporosis. Interestingly, a study analyzing the link between the premature graying observed in patients with Graves disease and reduced bone mineral density demonstrated that women with Graves disease and premature graying had significantly lower bone mineral density scores of the lumbar spine compared to patients with Graves disease who were not prematurely gray.49 This difference was not demonstrated in prematurely gray patients who were not hyperthyroid. In the same study, a higher percentage of patients with Graves disease were affected by premature graying than control patients; this finding, however, did not reach statistical significance.49 Patients complaining of premature graying with other symptoms of thyroid disease should be screened for thyroid dysfunction. In those patients with known thyroid dysfunction, the presence of premature graying may warrant special consideration of other risk factors for osteoporosis, necessitating a lower threshold for bone mineral density screening.

Types of Hair Loss and Hair Disease Related to Thyroid Disease Telogen Effluvium In the postnatal period, all hair follicles cycle independently through a growing phase (anagen), a period of involution secondary to apoptosis (catagen), and a resting phase during which the hair is shed (telogen).6,50 Normally, only 5%–15% of hair follicles on the human scalp are in telogen phase at any given time.51 The general health of the patient, the patient’s nutritional status, and levels of various hormones that have receptors in the hair follicle, including thyroid hormone, can affect the timing of this cycle. Telogen effluvium (Figure 11.2) is a common cause of diffuse hair loss in which a stressful event such as pregnancy, childbirth, medication changes, severe weight loss, surgery, major illness, or extreme psychological distress triggers a shift of an abnormal percentage of hairs from anagen into telogen. This shift results in subsequent shedding of mature, telogen hairs approximately 3 months after the inciting event.51,52 Telogen effluvium may be triggered by

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Madarosis The term madarosis is derived from the Greek word madao, which means “to fall off.” In its classical usage, it describes loss of the eyelashes; however, it is commonly used to describe the loss of eyebrow hair as well.53 The majority of patterns of hair loss that may present with thyroid disease are nonspecific; however, loss of the outer third of the eyebrows is a relatively characteristic sign of hypothyroidism.22,23 Patients presenting with loss of the lateral third of the eyebrow should be carefully interviewed for other symptoms of hypothyroidism and carefully examined for other signs of hypothyroidism; if any concerning symptoms or signs are present, thyroid screening as described for hypothyroidism should be performed (Tables 11.3 and 11.4).

Androgenetic Alopecia

Figure 11.2. Telogen effluvium

both hypothyroidism and hyperthyroidism. The ratio of telogen to anagen hairs is increased in both hypothyroidism and hyperthyroidism.22,24 It may also occur in euthyroid patients with Hashimoto thyroiditis, in which case it may be the result of more complex interplay between the immune system and the hair follicle (Tables 11.1 and 11.2). A diagnostic workup of telogen effluvium begins with a detailed history, evaluating for potential triggering events, and by excluding other potential causes of alopecia, such as androgenetic alopecia or traumatic alopecia. The next step is a thorough physical exam, including examination of the scalp and nails as well as palpation of the thyroid gland. The scalp must be carefully examined to exclude other causes of increased shedding, including alopecia areata, cicatricial alopecia, seborrheic dermatitis, and tinea capitis.51,52 Once other causes of hair loss are excluded, testing of thyroid function as described for hypothyroidism is appropriate51,52 (Tables 11.3 and 11.4).

The term androgenetic alopecia (Figure 11.3) is generally employed to describe hereditary patterned hair loss in both men and women. Androgenetic alopecia is incredibly common, affecting over half of men and a similar proportion of postmenopausal women. The condition affects Caucasian patients more severely than other racial groups.54,55 The most important hormones involved in androgenetic alopecia include testosterone and dihydrotestosterone (DHT). Both act through the androgen receptor, which, like all steroid hormone receptors, is a nuclear receptor. The androgen receptor is encoded on the X chromosome and is activated by the binding of testosterone or DHT, allowing it to act at androgen response elements in the promoter region of genes regulated by androgenic hormones.28 Polymorphisms of the androgen receptor have been observed in androgenetic alopecia. Androgen effect on the skin seems to be mediated by types 2–5 alpha reductase and the androgen receptor. The actions of male hormones on the hair follicles depend largely on the location of the hair follicles. Hair follicles in androgen-dependent areas such as the beard, axilla, and groin respond to androgenic stimulation with enlargement of the hair follicles. Hair follicles on the scalp in patients susceptible to androgenetic alopecia respond to androgenic stimulation with follicular miniaturization and eventual alopecia.28 It has been suggested that an interaction between thyroid hormones and androgens could play a role in

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Figure 11.3. Androgenetic alopecia

the development of androgenetic hair loss, especially when an underlying abnormality of thyroid function is present. DNA flow cytometry studies have suggested that thyroid hormone may affect the cell cycle of anagen hair cells.56 Hyperthyroid patients in this study demonstrated an increased percentage of anagen hair cells in S phase, while hypothyroid individuals demonstrated a lower percentage of anagen hair cells in S phase.56 Interestingly, DNA flow cytometry preformed on dissected anagen hairs from androgensensitive areas of the scalp demonstrated an increase of anagen hair cells in S phase in patients with male pattern baldness versus healthy controls.57

Metabolic Syndrome and Polycystic Ovarian Syndrome Metabolic syndromes affecting multiple organ systems can have complex effects on hair growth and hair loss. Polycystic ovarian syndrome (PCOS) is one of the most common endocrinopathies in

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women, affecting 5%–10% of women of reproductive age. PCOS describes a syndrome in which typically overweight or obese women become both hyperandrogenic and insulin resistant, resulting in a characteristic phenotype. The clinical definition of PCOS includes dermatologic criteria, specifically hirsutism, acne, and androgenetic alopecia, which are all sequelae of hyperandrogenism.58,59 Recognition of this syndrome is important both in managing the dermatologic manifestations of PCOS and in preventing the cardiovascular, neoplastic, and metabolic diseases for which these patients are at increased risk. Similar to patients with the metabolic syndrome, patients with PCOS are at increased risk for hypertension, coronary artery disease, obesity, sleep apnea, type 2 diabetes, and dyslipidemia. It has been suggested that PCOS is a gender-specific expression of the metabolic syndrome.58 Patients with PCOS are also at increased risk of both endometrial and breast cancer and frequently suffer from infertility due to menstrual irregularities.58 Androgenetic alopecia or facial hirsutism may be the presenting complaint of undiagnosed patients with PCOS. These early opportunities for diagnosis and treatment of PCOS should be taken full advantage of and may represent opportunities for intervention in the course of PCOS before the patient develops heart disease or diabetes. PCOS should be considered in any female patient presenting with androgenetic alopecia, especially if concomitant obesity, hirsutism, severe acne, or irregular menstruation are present. Early recognition of PCOS and the institution of medical therapy and behavioral modification could have significant effects on the long-term health of these patients. Proper management of PCOS includes weight loss, oral contraceptives, and insulin sensitizers.58 In their review on the evaluation and treatment of male and female pattern hair loss, Olsen et al. recommended that TSH screening be performed in all women presenting with hair loss and in men in whom the hair loss is diffuse or not in a typical pattern for male pattern hair loss.60 Women presenting with signs of PCOS should also be screened for diabetes, especially if they are obese59 (Table 11.4).

Seborrheic Dermatitis Interestingly, patients with hypothyroidism often have seborrheic dermatitis (Figure 11.4). Seborrheic

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the immune system due to the hypothyroidism itself. Macrophages in experimental animals treated with the antithyroid drug methimazole demonstrated a decreased ability to phagocytose and kill yeast.63 It is possible that decreased immune-mediated control of P. ovale in hypothyroid patients allows the yeast to grow beyond the density of normal flora, thereby producing an overcolonization, with resultant seborrheic dermatitis. Hypothyroid patients with seborrheic dermatitis of the scalp may present with hair loss, not only contributed to by hypothyroidism as described, but also as a result of the subacute chronic inflammation that accompanies seborrheic dermatitis. In such patients, addressing both the underlying hypothyroidism and the seborrheic dermatitis are important in treating associated alopecia. Patients presenting with seborrheic dermatitis and alopecia should be carefully examined and interviewed for other signs of hypothyroidism, and when present, thyroid screening with TSH should be performed. Patients with persistent, treatment-resistant seborrheic dermatitis may warrant consideration of thyroid function testing as well (Table 11.4).

Alopecia Areata Figure 11.4. Seborrheic dermatitis demonstrating scalp erythema and greasy scale

dermatitis is a chronic dermatitis characterized by erythematous skin with overlying greasy scale concentrated in the seborrheic areas of the face and scalp. Despite the name, seborrheic dermatitis is not associated with increased sebum production. It has been associated with the yeast Pityrosporum orbiculare, which is part of the normal flora of the skin.61 The growth of this yeast may cause increased epidermal proliferation and desquamation. The causative role of Plasmodium ovale in seborrheic dermatitis is illustrated by the condition’s response to antifungal therapy as well as an observed correlation between the clinical severity of seborrheic dermatitis and the density of P. ovale on affected skin.62 As discussed, the interactions between the thyroid gland and the sebaceous gland are complex, but in general the hypothyroid state results in decreased sebum production. Seborrheic dermatitis in hypothyroid patients may be due to changes in

Alopecia areata (Figures 11.5 and 11.6) is a relatively common form of nonscarring, patchy hair loss that is largely believed to be autoimmune in nature. Alopecia areata is fairly common and affects 1.7% of the population at some point in life.64 An oligoclonal autoreactive T-cell response predominantly affecting the peribulbar region of the hair shaft is the characteristic pathologic finding in alopecia areata

Figure 11.5. Patchy alopecia areata in an ophiasis pattern

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personal or family history of thyroid disease range from 8% to 47%, with an average 8% for a personal history and from 4% to 15% for family history.68 Children with alopecia areata have an increased rate of a positive family history for thyroid disease. Several studies have demonstrated a statistically significant increased prevalence of a positive family history for thyroid disease in patients versus controls, 14.6% versus 3% in one study.47,68 Screening of patients with alopecia areata generally includes assessment of thyroid function due to the relatively strong association of alopecia areata with thyroid disease. Some authors have suggested restricting thyroid screening in acute alopecia areata to those patients who have a positive family history of thyroid disease.46 In their review of thyroid disease and alopecia areata in children and adolescents, Kurtev and Iliev identified AITD in 47.8% of their study population; they recommended thyroid screening at the time of diagnosis of alopecia areata and twice yearly thereafter69 (Table 11.4). Figure 11.6. Alopecia totalis

Alopecia Areata in Down Syndrome

and is felt to be central to the pathology of this disease.47,65,66 Alopecia areata patients have increased rates of a personal or family history of other autoimmune diseases, particularly AITD, vitiligo, and type 1 diabetes. This strengthens the argument that alopecia areata is itself a manifestation of autoimmunity.47,67 As with most dermatologic diseases, alopecia areata presents as a spectrum from mild to severe, ranging from a single localized patch of alopecia (Figure 11.5), to alopecia affecting 100% of the scalp hair (Figure 11.6), to alopecia affecting all of the hairs on the body.47,65,66 Total or near-total loss of all scalp hair is referred to as alopecia totalis (AT).47,65,66 Total or near-total loss of all body hair is referred to as alopecia universalis (AU). Increased rates of AITD have been observed in patients with all forms of alopecia areata; however, patients with AU and AT are significantly more likely to have thyroid disease than patients with patchy alopecia areata.47,66 In one study of 513 alopecia areata patients, 25% of patients with AU and AT had thyroid disease versus 15.59% of patients with patchy alopecia areata.47,66 The reported percentages of patients with alopecia areata and a

Alopecia areata is more common in patients with Down syndrome than in the general population, with a reported prevalence rate ranging from 2.4% to 11%.70–72 Intriguingly, two candidate genes for alopecia areata have been localized to the region of chromosome 21 affected by Down syndrome.73 One of the genes implicated is the autoimmune regulator (AIRE) gene, which is mutated in autoimmune polyglandular syndrome type I.73 AITD is one of the less-common clinical manifestations of polyglandular syndrome type I; however, it occurs frequently enough for consideration of thyroid screening to be prudent in patients affected by this syndrome, especially in patients who also have alopecia areata.74 A second candidate gene for alopecia areata called MX1 is also located within the region of chromosome 21 affected in Down syndrome. MX1 encodes an interferon-induced p78 protein called MxA, which participates in resistance to influenza viruses.75 Chromosome 21 is only one of many chromosomes containing candidate genes for alopecia areata; other implicated chromosomes68 include 6, 10, 16, and 18 as well as loss of function mutations of filaggrin.76 In otherwise healthy patients, the association between alopecia areata and thyroid

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disease has long been suspected and has been demonstrated in multiple studies.47,69 Down syndrome patients are known to have an increased risk of autoimmune disease, with AITD the most common. A study of female Down syndrome patients with alopecia areata revealed a 35% prevalence of antithyroid antibodies (including both antimicrosomal and antithyroglobulin antibodies) versus only 9% of female Down syndrome patients without alopecia areata.77 A similar study examining autoimmunity in patients with Down syndrome and alopecia areata had a similar frequency of hypothyroidism, affecting approximately 33% of their study population.78 The frequency of thyroid disease in patients with Down syndrome is reported to be greater than 15%. It is standard of care to screen patients with Down syndrome for thyroid disease at birth, 6 months of age, and then yearly thereafter.79 Given the even greater frequency of antithyroid antibodies in Down syndrome patients with alopecia areata, even more aggressive monitoring of these patients is warranted (Table 11.4).

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of patients with lichen planopilaris suffered from thyroid disease, with 7% of the study population affected by Hashimoto thyroiditis.87 Patients diagnosed with lichen planopilaris should be carefully questioned and examined for signs and symptoms of thyroid disease. Patients with a physical exam or history that raises concern of thyroid disease merit evaluation of thyroid function as described for hypothyroidism80 (Tables 11.3 and 11.4).

Lupus Erythematosus Up to 14% of patients with systemic lupus erythematosus (SLE) (Figure 11.9) may have discoid scalp lesions. Patients with discoid lupus erythematosus (DLE) patients are reported to have scalp involvement 34%–56% of the time.89 When it affects the scalp, discoid lupus erythematosus can cause a scarring alopecia that presents

Cicatricial Alopecias Lichen Planopilaris Lichen planopilaris (Figures 11.7 and 11.8) occurs when lichen planus affects hair follicles of the scalp.80 It is a form of scarring alopecia that presents with perifollicular erythema and progressive scarring. The pathology of lichen planopilaris is similar to that of lichen planus, with a lichenoid infiltrate of activated CD8+ T cells, resulting in the destruction of the follicular epithelium.81 It is typically a disease of adults, afflicting mainly middle-aged women; however, it can occasionally occur in children.82–84 Lichen planopilaris is suspected to be autoimmune in origin and could thus be expected to demonstrate an increased association with other autoimmune diseases. The observation of Langerhans cells in early lesions of lichen planopilaris, along with case reports of disease onset following vaccination or infection with hepatitis B and C, raises the question of a possible antigenic trigger for this disease.81,85,86 Several studies have demonstrated a statistically significant association between thyroid disease and lichen planopilaris.80,87,88 In one study, 24%

Figure 11.7. Lichen planopilaris demonstrating perifollicular erythema and the characteristic “footprints-inthe-snow” pattern

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Figure 11.8. Chronic lichen planopilaris with prominent central scarring demonstrating the characteristic pattern of footprints in the snow

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centrifugally, resulting in the classic “discoid” appearance.90 When these lesions occur on the scalp, scarring alopecia results with notable loss of follicular ostia in the involved skin. Long-standing lesions of DLE appear hypopigmented, often with a peripheral rim of hyperpigmentation and central atrophic scarring.90 Despite the noninflammatory appearance of long-standing lesions of DLE, active inflammation may still be present in the deep dermis or subcutis.91 Patients with SLE can also demonstrate “lupus hairs,” which are short, fine hairs involving the frontal hairline. A generalized telogen effluvium may occur in patients with SLE.92 Autoimmune thyroid disease, manifesting with both hypothyroidism and hyperthyroidism, is common among patients with SLE, with reported rates ranging from 2.4% to 11.4% (relative risk); however, with carefully matched controls, an excess of thyroid disease is not observed in patients with SLE.93,94 In the subset of patients with SLE and symptoms of Sjögren syndrome, patients had a statistically significant increase in thyroid disease.95 Routine evaluation of thyroid function in patients with SLE and discoid scalp lesions, or with DLE resulting in alopecia, may be low yield; however, in patients with coexistent SLE, especially if they also have symptoms of Sjögren syndrome, thyroid screening should be preformed (Table 11.4).

Morphea with follicular plugging, atrophy, telangiectasia, and mottled hyper- and hypopigmentation. Active lesions may appear as plaques of erythematous, firm, indurated, hyperkeratotic skin that expand

Figure 11.9. Discoid lupus erythematosus affecting the scalp with scarring alopecia

Scleroderma is a disease presenting with hardening and stiffening of the skin due to extensive fibrosis. This process results in eventual loss of the adnexal structures, including the hair. Morphea (Figure 11.10) is a form of localized scleroderma that causes scarring alopecia when it affects the scalp. Linear scleroderma of the frontal or frontoparietal scalp is referred to as en coup de sabre and has a typical clinical appearance. The cause of scleroderma and morphea is unknown; however, an autoimmune mechanism is highly suspected. As is often observed in suspected autoimmune disorders, patients with morphea display an increased risk of autoimmune diseases, including cutaneous disorders such as lichen sclerosus et atrophicus, alopecia areata, and vitiligo,96 which are reported to occur with AITD.97,98 In their presentation of two patients with morphea and AITD, Hyun-Jeong et al. recommended that patients with morphea undergo

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Figure 11.10. Morphea of the scalp causing scarring alopecia

thyroid screening as described for hypothyroid patients97 (Tables 11.3 and 11.4).

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Experimental mice with null mutations of the mouse homolog/hairless (hr) gene develop normal first coats of fur; however, when the first coat is shed, the mice fail to grow a second coat.99 The human hairless (hr) gene on chromosome 8p12 has been implicated as a cause of both congenital atrichia and atrichia with papular lesions in multiple studies of several large families worldwide.100,101 The hr gene is predominantly expressed in the skin and brain, where it encodes a 127-kDa protein, a putative multifunctional transcription factor that appears to participate in the transition of hair cells into the first adult cycle.100 This suspicion is reinforced by the typical history in these patients of shedding early in life without subsequent regrowth of the hair.100,102 The upstream regulatory region of the hr gene contains a powerful thyroid hormone response element, and the hr gene is strongly upregulated by thyroid hormone, with a greater than 10-fold increase in its expression.103 The hr gene product (Hr) has been demonstrated to interact with the thyroid hormone receptor in part of a proposed autoregulatory mechanism. The complex interactions among thyroid hormone, the thyroid receptor, and the hr gene with its proposed role in hair cycle regulation provide an insight into one pathway through which thyroid disorders could potentially affect hair growth.

Congenital Syndromes with Thyroid Disorders and Hair Disease Congenital Hypothyroidism Much of our current understanding of the biology of the human body derives from studying the pathologic consequences of disruptions of normal physiology. There are multiple congenital syndromes with alopecia as a central component; thyroid disorders are variably present in a subset of these disorders.

Congenital Atrichia Congenital atrichia is an autosomal recessive form of inherited alopecia in which patients are born with normal-to-sparse hair. In the first weeks to months of life, the patients shed most of their hair, which never regrows. In some families, patients also develop papular lesions, in which case the disorder is referred to as atrichia with papular lesions.99,100

Congenital hypothyroidism presents with a characteristic syndrome that includes macroglossia; lethargy; dry, coarse, brittle hair; and the typical cutaneous changes of hypothyroidism. Patchy alopecia and persistent lanugo hairs can also be part of the presentation of congenital hypothyroidism. Paradoxically, although hypothyroidism is associated with hair loss in adults, in infants hair loss seemingly associated with the treatment of congenital hypothyroidism with T4 has also been described. It is proposed that the hair loss observed in these case reports might actually be a late manifestation of congenital hypothyroidism rather than a direct effect of T4, especially since hair regrowth is typically observed in these patients within 4 months of beginning thyroid replacement therapy.5 It is also possible that treatment with T4 hastens the transition of the hair follicle from the increased number of telogen follicles already present due

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to the hypothyroid state into anagen resulting in release of the club hair from the follicle.31 Cessation of thyroid replacement therapy in an infant with congenital hypothyroidism on the basis of hair loss temporally related to T4 treatment could have catastrophic consequences. In one case report, an infant with congenital hypothyroidism developed alopecia while on T4 replacement therapy, prompting her parents to discontinue the T4. Within a month, the infant developed lethargy, macroglossia, and a delayed relaxation phase of the deep tendon reflexes.5 Parents of children with congenital hypothyroidism must be forewarned about the potential for hair loss in their child and of the necessity to continue thyroid supplementation under the guidance of the pediatrician. Although the etiology of hair loss in this circumstance is unclear and requires further investigation, it is clear that these patients eventually do achieve hair regrowth and should be treated through their alopecic episode.5

Disorders of Excessive Hair Growth Hirsutism Hirsutism (Figure 11.11) describes the condition of excessive terminal hair growth in androgen-sensitive areas, especially on a woman. It is typically the result of increased androgen action on hair follicles, which can result from increased levels of either endogenous or exogenous androgens or from increased sensitivity of the hair follicles to normal levels of androgens.104 The majority of women with hirsutism (60%–80%) have increased systemic androgen levels; however, the severity of hirsutism has not been demonstrated to correlate with the degree of androgen excess.105 Women with hirsutism beginning around puberty with regular menses, no signs of virilization, and an otherwise normal physical appearance have a low risk of severe hormonal dysregulation or endocrine neoplasm. Women with irregular menses, PCOS, or anovulation merit a workup that may include prolactin level and thyroid screening to exclude pituitary tumors or thyroid dysfunction106 (Table 11.4).

Hypertrichosis In contrast to hirsutism, hypertrichosis, which is defined as generalized, excessive growth of vellus hairs, is not influenced by sex hormones.

Figure 11.11. Hirsutism demonstrated on a woman’s cheek

Hypertrichosis can be part of several congenital syndromes, such as trisomy 18 or Hurler syndrome, or it can be associated with metabolic derangements, including porphyrias, anorexia nervosa, malnutrition, and hypothyroidism. Hypertrichosis may also be acquired following severe head trauma, skin injury, or use of medications such as cyclosporine, diazoxide, minoxidil, hydrocortisone, and phenytoin.107 If hypertrichosis is present and other potential causes such as poor nutrition or medication effect are excluded, thyroid screening should be considered. Hypertrichosis may also aid in the diagnosis of congenital hypothyroidism. Akcakus et al. described hypertrichosis in a female infant with congenital hypothyroidism. The child, born to a diabetic mother, demonstrated both neonatal hyperinsulism and elevated testosterone levels. The patient’s hypertrichosis resolved following 3 months of thyroid replacement therapy. They recommended that thyroid function should be evaluated

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in newborns demonstrating hypertrichosis or abnormally distributed body hair108 (Table 11.4).

Medications Drug Therapy for Thyroid Disease Hypothyroidism Hypothyroidism has multiple causes. The most common cause of hypothyroidism in the United States and other iodine-sufficient countries is Hashimoto thyroiditis, accounting for nearly 90% of noniatrogenic causes.109 Therapy for hypothyroidism typically consists of providing exogenous thyroid hormone. The dose of thyroid hormone, usually given as levothyroxine, is determined by monitoring the patient’s TSH level. Despite the fact that most normal ranges for TSH are from 0.5 to 4.5 mU/L, the patient’s TSH should be maintained in a range between 1 and 2.5 mU/L. Recent studies have led to questions regarding whether liothyronine LT3 provides additional benefit to the patient compared to supplementation with levothyroxine. Some argued that in normal physiology 20% of the thyroid hormone produced by the thyroid gland is liothyronine, and that thyroid hormone supplementation should mirror this endogenous pattern.110 Some suggested that thyroid supplementation using organic sources, such as Armour thyroid, which is desiccated pig thyroid, may be more physiologic and therefore more likely to restore normal functioning to thyroid-responsive tissues in hypothyroid individuals.111 In our experience, some hypothyroid patients continue to have symptoms of hypothyroidism, including fatigue, cold intolerance, alopecia, and trichodystrophy, despite pharmacologically adequate thyroid supplementation with levothyroxine. Some of these patients benefit from the addition of Armour thyroid to the management of their disease. Another option for thyroid replacement therapy is Cytomel, which is synthetically manufactured liothyronine sodium, an analog of T3.111 This medication is sometimes used in combination with levothyroxine; however, several studies have failed to demonstrate improvement in neuropsychological or physiologic parameters with combination liothyronine and levothyroxine treatment over levothyroxine alone.112–114 There has also been a question regarding whether there is a difference in therapeutic efficacy between

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generic and brand name levothyroxine. Some studies have indicated that generic levothyroxine can differ from brand name levothyroxine by 25%–33%.110 In our experience, some hypothyroid patients with previously stable hair loss will experience increased shedding if they are switched from trade to generic levothyroxine at equivalent doses. This may reflect the difference in the bioavailability of the different preparations. In some of these patients, switching them back to the trade medicine can stabilize the increased shedding. Further efforts are required to evaluate the physiologic effects of different thyroid replacement hormones on the hair. Any changes in the management of thyroid supplementation should be carefully followed by both laboratory and clinical parameters.

Hyperthyroidism Surgical Excision and Radioactive Iodine In cases of hyperthyroidism caused by Graves disease, toxic adenoma, and goiter, patients can be treated by removal of all or part of the thyroid or by destruction of the thyroid using radioactive iodine, which is selectively taken up by thyroid follicular cells. This treatment frequently results in hypothyroidism, making iatrogenic thyroid damage the second most common cause of hypothyroidism. Profound hair loss may be associated with treatment using radioactive iodine (Table 11.5). In a study of 203 patients treated with radioiodine for thyroid carcinoma, 28% reported alopecia. The episodes of alopecia typically began within 1 week to several weeks following administration of the radioiodine and lasted 1–12 weeks before returning to normal. Of the patients in this study, 13 reported moderate alopecia lasting more than 1 year, which was not dependent on the dose of radioiodine administered.115

Antithyroid Drugs Antithyroid drugs were accidentally discovered with the administration of thiocyanate to treat hypertension. Some patients treated with thiocyanate for hypertension developed hypothyroidism, leading to the discovery of this drug class. Since that time, the thioamides PTU and methimazole have been developed. Both of these agents concentrate in the thyroid, where they act by inhibiting iodination of tyrosyl groups and coupling of

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Table 11.5. Medications affecting thyroid function. Medication

Effect on thyroid function

Association with alopecia

Radioiodine

- Frequently results in permanent hypothyroidism

PTU

- Inhibits thyroid hormone formation - Inhibits peripheral conversion of T4 to T3 - Inhibits thyroid hormone formation - Iodine-induced hyperthyroidism - Destructive thyroiditis - Inhibits peripheral conversion of T4 to T3 - Inhibits thyroid hormone formation - Prevention of thyroid hormone release - Suppresses TSH secretion - Increases peripheral degradation of T4 - Inhibits peripheral conversion of T4 to T3 - Inhibits thyroid hormone formation - Inhibits peripheral conversion of T4 to T3

Methimazole Amiodarone

Lithium Bexarotene Propranolol Prednisone

- Common transient alopecia (28%) - Occasional persistent alopecia - Significant percentage of patients may develop alopecia - Delays onset of follicular activity in animals - Significant percentage of patients may develop alopecia - Patients may occasionally develop alopecia

- Significant percentage of patients may develop alopecia - Frequent treatment-related alopecia (4%–11%) - Significant percentage of patients may develop alopecia - Significant percentage of patients may develop alopecia

PTU, propylthiouracil; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimuating hormone.

iodotyrosines to form T4 and T3.116 In vitro studies have demonstrated that both of these medications can suppress the thyroid hormone receptor and T3-mediated transcriptional activities in a dosedependent manner through the recruitment of a nuclear corepressor protein (Table 11.5).116 PTU is also one of many medications that are able to inhibit the peripheral conversion of T4 to T3 (Table 11.5). Neither of the thioamides is able to affect already-synthesized thyroglobulin, meaning that therapeutic efficacy and reduction in symptoms might not be observed until the patient’s preexisting thyroglobulin stores are depleted.116 Alopecia is listed as a significant adverse effect of both PTU and methimazole. PTU administered to experimental animals delays the onset of follicular activity.9 Patients treated with either of these medications for thyroid disease should be forewarned of the possibility of hair loss associated with their treatment.

Drugs Affecting the Thyroid Gland and Thyroid Hormone The level of thyroid hormones available to interact with thyroid receptors in target tissues is dependent on the rate of production of thyroid hormone; the rate of conversion of T4 to the more biologically active T3; the rate of delivery to the tissues, which is dependent on circulation; and the rate of degradation of thyroid hormone. A medication that interferes with any of these factors could alter the

normal homeostasis of thyroid hormone relative to the hair follicle and adversely affect hair growth. Patients presenting with new onset of hair loss should be carefully questioned for new medications or dosage changes of old medications with special attention to those medications known to affect the thyroid gland or thyroid hormone metabolism.

Amiodarone Amiodarone is an antiarrythmic medication that is very effective in maintaining sinus rhythm in patients with atrial fibrillation. It is also used to control tachyarrhythmias and in ischemic heart disease. Amiodarone is 37% iodine by molecular weight, and it can cause thyroid dysfunction in 14%–18% of patients taking the drug.117 Both amiodaroneinduced hyperthyroidism (AIH) and amiodaroneinduced thyrotoxicity (AIT) are recognized clinical entities, and both can occur in patients with or without preexisting thyroid disease.117 When AIT occurs in patients with preexisting thyroid disease, such as latent Graves disease or nodular goiter, it is referred to as type I AIT, thought to be due to iodine-induced hyperthyroidism. AIT in a patient without preexisting thyroid disease is referred to as type II AIT. It is caused by destructive thyroiditis due to the amiodarone itself or the high iodine content of the drug.118 Amiodarone also has direct effects on thyroid hormone, including prevention of peripheral conversion of T4 to T3 and inhibition of thyroglobulin and free T3 production in the thyroid

11. Alopecia and Thyroid Disease

follicle.118 Alopecia is listed as an occasional adverse effect of amiodarone therapy (Table 11.5).

Lithium Lithium is a mood-stabilizing medication that is often used by bipolar patients. It can cause hypothyroidism by preventing thyroid hormone release. Patients on lithium are more likely to develop hypothyroidism during their first year of therapy. Middle-aged women, patients with iodine deficiency, and those with preexisting thyroid autoimmunity are also particularly vulnerable to developing hypothyroidism.119 It is recommended to perform thyroid screening with serum TSH on patients prior to starting lithium therapy and then yearly thereafter. In patients who present with symptoms of thyroid disease, including alopecia, more extensive testing may be indicated, including levels of free T4, T3, and microsomal antibody. Alopecia is listed as a severe adverse effect of lithium therapy (Table 11.5).

Bexarotene Bexarotene is a retinoid X receptor antagonist that is used in the treatment of cutaneous T-cell lymphoma. It is known to cause hypothyroidism by suppressing TSH secretion. It has also been demonstrated to increase peripheral degradation of thyroid hormone.120 The degree of suppression of TSH secretion is greater in patients on higher doses of bexarotene. Bexarotene seems to act by suppressing the activity of the TSH β-subunit gene promoter by up to 50% in the same region involved in the negative-feedback loop with T3. The retinoid 9-cis-retinoic acid also acts at this promoter.121 Alopecia occurs in 4%–11% of patients treated with bexarotene (Table 11.5).

Drugs Affecting the Peripheral Conversion of T4 to T3 The thyroid gland produces two types of thyroid hormone, T4 and T3. The thyroid produces significantly more T4 than T3, in a ratio of approximately14:1. T3 is the more biologically active form of thyroid hormone, with three to four times greater potency than T4. While all the T4 in the body is produced in the thyroid gland, the peripheral conversion of T4 to T3 accounts for 80% of the

139

T3 in the body. Several medications decrease the peripheral conversion of T4 to T3, including propranolol, corticosteroids, PTU, ipodate/iopanoic acid, and amiodarone (Table 11.5). Interestingly, both propranolol and amiodarone can also decrease production of thyroglobulin and free T3 in the thyroid follicle.122 Patients presenting with alopecia often complain of increased shedding following a change in medication. Special attention should be paid to medications known to be associated with thyroid abnormalities.

Conclusion The hair is both directly and indirectly affected by all forms of thyroid disease, with both specific and nonspecific forms of alopecia and hair disorders. Molecular diagnostic tools are just now allowing us to scratch the surface of the complex interactions between hormonal regulation of tissue growth and development. Much still remains to be elucidated about the relationship between thyroid hormone and the hair follicle. Since hair is external and easily accessible for examination, abnormalities of hair growth may be an important first clue to underlying thyroid disease. Patients with alopecia or hair disorders should be carefully evaluated for other signs or symptoms of thyroid disease; if present, thyroid screening is indicated.123

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11. Alopecia and Thyroid Disease thyroiditis, presenting as primary hypothyroidism. Ir Med J. 1996;89:141–142. 41. Aust G, Krohn K, Morgenthaler NG, et al. Graves’ disease and Hashimoto’s thyroiditis in monozygotic twins: case study as well as transcriptomic and immunohistological analysis of thyroid tissues. Eur J Endocrinol 2006;154:13–20. 42. Jayson MI, Doniach D, Benhamou-Glynn N, et al. Thyrotoxicosis and Hashimoto goitre in a pair of monozygotic twins with serum long-acting thyroid stimulator. Lancet 1967;215–218. 43. Chertow BS, Fidler WJ, Fariss BL. Graves’ disease and Hashimoto’s thyroiditis in monozygous twins. Acta Endocrinol 1973;72:18–24. 44. Ilicki A, Marcus C, Karlsson FA. Hyperthyroidism and hypothyroidism in monozygotic twins: detection of stimulating and blocking THS receptor antibodies using the FRTL5-cell line. J Endocrinol Invest 1990;13:327–331. 45. Heward J, Gough SCL. Genetic susceptibility to the development of autoimmune disease. Clin Sci (Colch) 1997;93:479–491. 46. Kakourou T, Karachristou K, Chrousos G. A case series of alopecia areata in children: impact of personal and family history of stress and autoimmunity. J Eur Acad Dermatol Venereol 2007;21:356–359. 47. Goh C, Finkel M, Christos PJ, et al. Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history. J Eur Acad Dermatol Venereol 2006;20:1055–1060. 48. Numbenjapon N, Costin G, Gilsanz V, et al. Low cortical bone density measured by computed tomography in children and adolescents with untreated hyperthyroidism. J Pediatr 2007;150:527–530. 49. Leary AC, Grealy G, Higgins TM, et al. Premature hair greying may predict reduced bone mineral density in Graves’ disease. Ir J Med Sci 2001;170:117–119. 50. Rook A. Endocrine influences on hair growth. BMJ 1965;1:609–614. 51. Rebora A. Telogen effluvium. Dermatology 1997;195:209–212. 52. Harrison S, Sinclair R. Telogen effluvium. Clin Exp Dermatol 2002;27:389–385. 53. Duke-Elder S, MacFaul P. The ocular adnexa, part I: diseases of the eyelashes. In: Duke-Elder S, ed. System of Ophthalmology. Vol. 13. St Louis, MO: Mosby; 1974:373–390. 54. Hamilton JB. Patterned hair loss in man: types and incidence. Ann N Y Acad Sci 1951;53:708–728. 55. Olsen EA. Female pattern hair loss. J Am Acad Dermatol 2001;45:S70–S80. 56. Schell H, Kiesewetter F, Seidel C, et al. Cell cycle kinetics of human anagen scalp hair bulbs in

141 thyroid disorders determined by DNA flow cytometry. Dermatologica 1991;182:23–26. 57. Kiesewetter F, Schell H. Cell kinetics of anagen scalp hairs under physiological and pathological conditions. Skin Pharmacol 1994;7:55–60. 58. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223–1236. 59. Heward J, Gough SCL. Genetic susceptibility to the development of autoimmune disease. Clin Sci (Colch) 1997;93:479–491. 60. Olsen EA, Messenger AG, Shapiro J, et al. Evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol 2005;52:301–311. 61. Schwartz RA. Superficial fungal infections. Lancet 2004;364:1173–1182. 62. Heng MC, Henderson CL, Barker DC, et al. Correlation of Pityosporum ovale density with clinical severity of seborrheic dermatitis as assessed by a simplified technique. J Am Acad Dermatol 1990;23:82–86. 63. Liu WK, Ng TB. Effect of methimazole-induced hypothyroidism on alveolar macrophages. Virchows Arch B Cell Pathol Incl Mol Pathol 1991;60:21–26. 64. Wasserman D, Guzman-Sanchez DA, Scott K, et al. Alopecia areata. Int J Dermatol 2007;46:121–131. 65. Gilhar A, Kalish RS. Alopecia areata: a tissue specific autoimmune disease of the hair. Autoimmun Rev 2006;5:64–69. 66. Hordinsky M, Ericson M. Autoimmunity: alopecia areata. J Investig Dermatol Symp Proc 2004;9:73–78. 67. Sipetić S, Vlajinac H, Kocev N, et al. Family history and risk of type 1 diabetes mellitus. Acta Diabetol 2002;39:111–115. 68. Kakourou T, Karachristou K, Chrousos G. A case series of alopecia areata in children: impact of personal and family history of stress and autoimmunity. J Eur Acad Dermatol Venereol 2007;21:356–359. 69. Kurtev A, Iliev E. Thyroid autoimmunity in children and adolescents with alopecia areata. Int J Dermatol 2005;44:457–461. 70. Schepis C, Barone C, Siragusa M, et al. An updated survey on skin conditions in Down syndrome. Dermatology 2002;205:234–238. 71. Carter DM, Jegasothy BV. Alopecia areata and Down syndrome. Arch Dermatol 1976;112:1397–1399. 72. Daneshpazhooh M, Nazemi TM, Bigdeloo L, et al. Mucocutaneous findings in 100 children with Down syndrome. Pediatr Dermatol 2007;24:317–320. 73. McDonagh AJ, Tazi-Ahnini R. Epidemiology and genetics of alopecia areata. Clin Exp Dermatol 2002;27:405–409. 74. Joshi RR, Rao S, Prabhu SS. Polyglandular autoimmune syndrome-type I. Indian Pediatr 2006;43: 1085–1087.

142 75. Tazi-Ahnini R, di Giovine FS, McDonagh AJ, et al. Structure and polymorphism of the human gene for the interferon-induced p78 protein (MX1): evidence of association with alopecia areata in the Down syndrome region. Hum Genet 2000;106:639–645. 76. Betz RC, Pforr J, Flaquer A, et al. Loss-of-function mutations in the filaggrin gene and alopecia areata: strong risk factor for a severe course of disease in patients comorbid for atopic disease. J Invest Dermatol 2007 Jun 21 [epub ahead of print]. 77. Du Vivier A, Munro D. Alopecia areata, autoimmunity, and Down’s syndrome. BMJ 1975;25;1(5951): 191–192. 78. Schepis C, Barone C, Lazzaro Danzuso GC, et al. Alopecia areata in Down syndrome: a clinical evaluation. J Eur Acad Dermatol Venereol 2005;19: 769–770. 79. Roizen NJ, Patterson D. Down’s syndrome. Lancet 2003;361(9365):1281–1289. 80. Mehregan DA, Van Hale HM, Muller SA. Lichen planopilaris; clinical and pathologic study of 45 patients. J Am Acad Dermatol 1992;27:935–942. 81. Smith KJ, Crittenden J, Skelton H. Lichen planopilaris like-changes arising within an epidermal nevus: does this case suggest clues to the etiology of lichen planopilaris? J Cutan Med Surg 2000:4:30–35. 82. Sehgal VN Bajaj P, Srivastva G. Lichen planopilaris [cicatricial (scarring) alopecia] in a child. Int J Dermatol 2001;40:461–463. 83. Whititng DA. Cicatricial alopecia: clinicopathological findings and treatment. Clin Dermatol 2001;19:211–225. 84. Tan E, Martinka M, Ball N, et al. Primary cicatricial alopecias: clinicopathology of 112 cases. J Am Acad Dermatol 2004;50:25–32. 85. Bardazzi F, Landi C, Orlandi C, et al. Grahm LittlePiccarti-Lasser syndrome following HBV vaccination. Acta Derm Venerol (Stockh) 1998;79:93. 86. Brudy L, Janier M, Reboul D, et al. Lichen erosive du cuir chevelu. Acta Derm Venereol 1997;124: 703–706. 87. Cevasco NC, Bergfeld WF, Remzi BK, et al. A caseseries of 29 patients with lichen planopilaris: the Cleveland Clinic Foundation experience on evaluation, diagnosis, and treatment. J Am Acad Dermatol. 2007;57:47–53. 88. Rosina P, Chieregato C, Magnanini M, et al. Lichen planopilaris and autoimmune thyroiditis. J Eur Acad Dermatol Venereol 2002;16:648–649. 89. Ross EK, Tan E, Shapiro J. Update on primary cicatricial alopecias. J Am Acad Dermatol 2005;53:1–37. 90. Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestations of lupus erythematosus. Br J Dermatol 1996;135:355–362.

M. Babb-Tarbox and W.F. Bergfeld 91. Wilson CLL, George SM, Dean D, et al. Scarring alopecia in discoid lupus erythematosus. Br J Dermatol 1992;126:307–314. 92. Armas-Cruz R, Jarmecler K, Ducach G, et al. Clinical diagnosis of systemic lupus erythematosus. Am J Med 1958;25:409–419. 93. Vianna JL, Haga HJ, Asherson RA, et al. A prospective evaluation of antithyroid antibody prevalence in 100 patients with systemic lupus erythematosus. J Rheumatol 1991;18:1193–1195. 94. Kohno Y, Naito N, Saito K, et al. Antithyroid peroxidase antibody in patients with systemic lupus erythematosus. Clin Exp Immunol 1989;75:217–221. 95. Scofield R, Bruner GR, Harley JB, et al. Autoimmune thyroid disease is associated with a diagnosis of secondary Sjögren’s syndrome in familial systemic lupus. Ann Rheum Dis 2007;66;410–413. 96. Harrington CI, Dunsmore IR. An investigation into the incidence of auto-immune disorders in patients with localized morphea. Br J Dermatol 1989;120:645–648. 97. Lee H-J, Kim M-Y, Ha S-J, et al. Two cases of morphea associated with Hashimoto’s thyroiditis. Acta Derm Venereol 2002;82:58–78. 98. Tremaine R, Adam JE, Orizaga M. Morphea coexisting with lichen sclerosus et atrophicus. Int J Dermatol 1990;29:486–489. 99. Panteleyev AA, Botchkareva NV, Sundberg JP, et al. The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation. Am J Pathol 1999;155:159–171. 100. Ahmad W, Zlotogorski A, Panteleyev AA, et al. Genomic organization of the human hairless gene (HR) and identification of a mutation underlying congenital atrichia in an Arab Palestinian family. Genomics 1999;56:141–148. 101. Betz C, Indelman M, Pforr J, et al. Identification of mutations in the human hairless gene in two new families with congenital atrichia. Arch Dermatol Res 2007;299:157–161. 102. Thompson CC, Sisk JM, Beaudoin GM 3rd. Hairless and Wnt signaling: allies in epithelial stem cell differentiation. Cell Cycle 2006;5:1913–1917. 103. Thompson CC. Thyroid hormone-responsive genes in developing cerebellum include a novel synaptotagmin and a hairless homolog. J Neurosci 1996;16:7832–7840. 104. Redmond GP, Bergfeld WF. Diagnostic approach to androgen disorders in women: acne, hirsutism, and alopecia. Cleve Clin J Med 1990;57:423–427. 105. Carmina E, Lobo RA. Peripheral androgen blockade versus glandular androgen suppression in the treatment of hirsutism. Obstet Gynecol 1991;78(5 Pt 1):845–849.

11. Alopecia and Thyroid Disease 106. Gilchrist VJ, Hecht BR. A practical approach to hirsutism. Am Fam Physician 1995;52:1837–1846. 107. Leung AK, Robson WL. Hirsutism. Int J Dermatol 1993;32:773–777. 108. Akcakus M, Koklu E, Kurtoglu S, et al. Neonatal hypertrichosis in an infant of a diabetic mother with congenital hypothyroidism. J Perinatol 2006;26:256– 258. 109. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996;335:99–107. 110. Blakesley VA. Current methodology to assess bioequivalence of levothyroxine sodium products is inadequate. AAPS J 2005;30:E42–E46. 111. LeBoff MS, Kaplan MM, Silva JE, et al. Bioavailability of thyroid hormones from oral replacement preparations. Metabolism 1982;31:900–905. 112. Clyde PW, Harari AE, Getka EJ, et al. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 2003;290:2952. 113. Siegmund W, Spieker K, Weike AI, et al. Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14: 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf) 2004;60:750. 114. Walsh JP, Shiels L, Lim EM, et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 2003;88:4543.

143 115. Alexander C, Bader JB, Schaefer A, et al. Intermediate and long-term side effects of highdose radioiodine therapy for thyroid carcinoma. J Nucl Med 1998;39:1551–1554. 116. Moriyama K, Tagami T, Usui T, et al. Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription. J Clin Endocrinol Metab 2007;92:1066–1072. 117. Martino E, Bartalena L, Bogazzi F, et al. The effects of amiodarone on the thyroid. Endocr Rev 2001;22:240–254. 118. Conen D, Melly L, Kaufmann C, et al. Amiodaroneinduced thyrotoxicosis: clinical course and predictors of outcome. J Am Coll Cardiol 2007;49:2350–2355. 119. Bocchetta A, Loviselli A. Lithium treatment and thyroid abnormalities. Clin Pract Epidemol Ment Health 2006;12;2:23. 120. Smit JW, Stokkel MP, Pereira AM, et al. Bexarotene induced hypothyroidism: bexarotene stimulates the peripheral metabolism of thyroid hormones. J Clin Endocrinol Metab 2007 Apr 17 [epub ahead of print]. 121. Sherman SI, Gopal J, Haugen BR, et al. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 1999;340: 1075–1079. 122. Massart C, Hody B, Condé D, et al. Effect of amiodarone and propranolol on the functional properties of human thyroid follicles cultured in collagen gel. Mol Cell Endocrinol 1989;62:113–117. 123. Olsen EA, Messenger AG, Shapiro J, et al. Recommended guidelines for the evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol 2005;52:301–311.

12 Chronic Idiopathic Urticaria and Thyroid Disease Jeffrey S. Rumbyrt and Alan L. Schocket

Editorial Perspective Patients with chronic idiopathic urticaria or angioedema are often frustrated by their symptoms and by the inability of their physician to uncover the cause of their affliction. Detailed histories, food diaries, “routine” laboratory studies, and advanced immunologic evaluations usually offer no further insight into the pathogenesis of the disorder. Recent advances in comprehending the etiology of chronic urticaria or angioedema have supported the notion that many cases may be an indication of an underlying autoimmune

Introduction Specialists in allergy and immunology are often accused of getting mired in medical minutia. Most of us gladly accept this mantle as we believe that explanation of the mechanism of disease is as important as treatment. Moreover, unlike other physicians who focus their efforts on a specific organ system, the “immune system” tends to be more difficult to define. In addition, because immunologic manifestations can play both “good cop” and “bad cop” roles depending on the circumstances under which they occur, defining what is an appropriate versus an inappropriate response may not always be so straightforward. For example, an increase in serum immunoglobulin E (IgE) in response to a parasite infection would be appropriate; however, the same increase in IgE generated in response to an insect venom can be life

process. As discussed in this chapter, there is an increasing body of evidence to corroborate the theory that there is an association of some cases of chronic urticaria or angioedema with thyroid autoimmunity, and that a subset of these patients may respond therapeutically to the administration of thyroid hormone. Evaluating patients with chronic idiopathic urticaria or angioedema for thyroid autoimmunity should be part of their standard workup. Therapeutic use of thyroid hormone may be considered a therapeutic option in select patients who fail to respond to conventional therapy.

threatening. Numerous other examples exist, such as sepsis/cytokine storms, immune “tolerance”/graft rejection, and for the purposes of this chapter, autoimmune responses and chronic urticaria. With specific attention paid to extraglandular manifestations of thyroid disease, physicians need to be mindful of how immune reactions in one organ can result in potential reactions in others. In line with this thinking are the various dermatologic aspects of thyroid disease.1 Urticaria is defined by Dorland’s Medical dictionary as follows: urticaria (ur.ti.ca.ria) (ur”t -kar¢e-ə) [Urtica + -ia] a vascular reaction in the upper dermis, usually transient, consisting of localized edema caused by dilatation and increased capillary permeability with wheals. … It may be either acute (evolving over a few days or weeks) or chronic (continuous or persisting episodically for six weeks or more). Angioedema is the same physiological

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146 response in the deep dermis or subcutaneous or submucosal tissues.

Moreover, physical forms of urticaria are typically characterized according to the causative agent or stimulus responsible for triggering the condition. Aquagenic (due to a combination of water and sweat or sebum), cholinergic (a reaction in which acetylcholine released from parasympathetic or motor nerve terminals induces release of mediators from mast cells by exertion, stress, or increased environmental heat), contact (a localized or generalized response elicited by exposure to rapidly absorbable agents), and solar urticaria (rapidly developing urticaria occurring on brief exposure to sunlight) are examples of this.2

Background Whereas acute urticaria (with or without associated angioedema) may affect up to 15% of the US population every year, the prevalence of chronic urticaria is less.3 Kulthanan et al. referenced a study that estimated that chronic urticaria occurs in approximately 0.1% of the general population.4 Physicians treating patients with hives often invoke a routine of mental gymnastics to determine potential causes. The framework that we like to use considers the list that follows as the most common etiologies for acute or chronic urticaria. Note that in general, urticaria without associated angioedema occurs in roughly 40% of patients, urticaria with angioedema in approximately 50% of patients, and angioedema alone in 10% of patients.5 This list is by no means exhaustive or complete; rather, it simply serves as a tool for assisting in narrowing diagnostic possibilities. 1. “Ingestants” (e.g., food, drink, food colorings, flavorings, preservatives, etc.) 2. Medication (both recent and long term) 3. “Contacts” (i.e., soaps, detergents, fragrances, fabric softener, cosmetics, etc.) 4. Physical causes (e.g., heat, cold, pressure) 5. “Other” medical problems (e.g., emotional stress, infections, pregnancy, malignancy) 6. Autoimmune disease 7. Idiopathic In spite of the myriad known causes, even in the best of hands the cause in the majority of patients (>70%) with chronic hives falls into the idiopathic

J.S. Rumbyrt and A.L. Schocket

category.6 It is because of this that we, and many other investigators, began a search for alternative explanations for so-called chronic idiopathic urticaria.

Autoimmune Basis for Chronic Urticaria Many investigators have made clinical observations associating autoimmune disease with chronic urticaria. For example, the identification of autoantibodies with urticaria/angioedema has been reported to occur in the setting of hyperparathyroidism, hypoparathyroidism, systemic lupus erythematosus, gastrointestinal disease, and hematologic malignancies.7 This is true for not only adults but also children. Case reports linking chronic urticaria with celiac disease, type 1 diabetes, juvenile rheumatoid arthritis, and familial occurrences of autoimmune diseases have been published.8 In addition, observations of thyroid disease with pruritus and urticaria date back to sentinel articles9–11 beginning in 1956. The connection becomes even stronger after reports of treatment directed at the underlying autoimmune condition results in resolution of the urticarial condition. This has been observed in patients with chronic urticaria who had either underlying hypothyroidism or hyperthyroidism.12–15 That is, that resolution of the chronic urticaria did not occur until the underlying thyroid condition was treated. Furthermore, the reported improvement/ resolution of chronic urticaria in case reports using immunosuppressive therapy such as cyclosporine or the use of immunomodulating therapies such as plasmapheresis and intravenous immunoglobulin (IVIG) also speaks to the likelihood of an autoimmune pathogenesis.16 Cutaneous manifestations of thyroid disease are more thoroughly described in other chapters of this book. However, autoimmune thyroid disease (AITD) has been associated with an increased prevalence in autoimmune skin conditions as well. Subclinical thyroid autoimmunity and overt clinically important thyroid disease have been shown to occur with increased prevalence in patients with chronic urticaria as well as two other skin diseases with an autoimmune basis: alopecia areata and vitiligo. In both case-controlled and noncase-controlled studies, the prevalence of thyroid

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autoimmunity ranged from 7% to 35% of patients with alopecia areata and from 7% to 29% of patients with vitiligo.17 This association is potentially important since many of the same mediators expressed in those conditions are also seen in patients with chronic urticaria. This issue of mediators is addressed in a separate section. Interest in the link between autoimmunity and chronic urticaria grew when it was observed that a significant number of patients with chronic urticaria had a reaction to the autologous serum skin test (ASST). In brief, a so-called positive test occurs when there is the appearance of a typical wheal and pruritus after the subcutaneous injection of 0.1 mL of autologous serum.18 In 1988, Gruber et al. observed that in six patients with chronic urticaria, three had IgG directed against IgE, and that some of these patients had a positive ASST as well as in vitro tests that demonstrated histamine release from cultured basophils.19 In 1993, Hide et al. identified the presence of an IgG antibody directed against the αsubunit of the high-affinity (FcεRI) IgE receptor.20 Since then, other investigators have discovered IgG antibodies against the low-affinity IgE receptor (FcεRII/CD23) on eosinophils.18 The distinction between these two autoantibodies is centered on the inflammatory cell that is activated. In the case of antibodies against the α-subunit of FcεRI, it has recently been shown that these antibodies are directed against the unoccupied receptor. Mast cells and basophils are induced to release histamine via direct IgE binding that is enhanced in the presence of complement (probably via C3a or C5a).16 Note that the mast cells that are activated in this fashion are functionally and phenotypically distinct. Connective tissue mast cells from the skin, gastrointestinal, and respiratory submucosa, defined by the presence of both tryptase and chymase in their granules (so-called MCtc mast cells) release mediators in response to anaphylatoxins (e.g., C3a, C5a), whereas other mast cells found in the gastrointestinal and respiratory tracts that only contain tryptase (so-called MCt mast cells) do not respond to activated complement products.21 On the other hand, with the binding of anti-FcεRII IgG on eosinophils, histamine is released from basophils and mast cells via major basic protein stimulation.18 It is not known if there are any specific mast cells that are preferentially activated by this mechanism. In any case, it is estimated that as many as 40% of

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patients with chronic urticaria have one (or both) of these anti-IgE antibodies.22 Interestingly, patients with chronic urticaria and a positive ASST seem to have a slightly different clinical presentation than those without a positive ASST. Moreover, the histopathological and immunohistochemical profiles of lesional skin also differ. These issues were demonstrated in three different studies done by Caproni et al. In one study, it was observed that patients with chronic urticaria and a positive ASST had a higher wheal number, more frequent urticaria episodes, higher itch scores, and an elevated interleukin 13 (IL-13) and lower macrophage inflammatory protein 1α (MIP-1α) levels compared to chronic urticaria patients who had a negative ASST.23 In a second study, the same group described differences in immunohistochemical markers of disease activity in both spontaneous and serum-induced hives of six patients with chronic urticaria and a positive ASST. Their results showed that in the spontaneous lesions, neutrophils, adhesion molecules, IL-8, and chemokine receptors appeared to be the primary cells/substances triggering and perpetuating lesion development. On the other hand, wheals triggered by ASST showed the predominant presence of basophils and IL-4. This observation testifies to potential different mechanisms of inflammation operating even within the same patient.24 In their third study, chronic urticaria patients with ASST-induced wheals had sequential biopsies at different times as their wheals arose with subsequent immunophenotyping and immunohistochemical analysis. Compared to healthy controls, elevated levels of IL-4, IL-5, and interferon-γ (IFN-γ) were seen in lesional skin within 30 min of hive onset. Moreover, chemokine receptors CXCR3 (alpha chemokine family that promotes neutrophil attraction and Th1 responses) and CCR3 (β-chemokine family that promotes monocytes, lymphocytes, basophils, eosinophils, and primarily Th2 responses) were also found to be expressed in higher levels compared to controls.25 Having established that a large number of patients with chronic urticaria have autoantibodies, a reasonable question to ask (especially in light of the subject of this book) is whether there is an increase in the prevalence of thyroid antibodies (and possibly AITD) in patients with chronic urticaria. More specifically, is there any difference in the prevalence of thyroid antibodies in chronic urticaria

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patients with and without anti-IgE antibodies? It is worth noting that in two of the Caproni studies, AITD and circulating antithyroid antibodies were notably elevated in patients with chronic urticaria and a positive ASST.23,25 Dreskin and Andrews17 and others have stated that even though urticaria may not be a common manifestation of clinically apparent thyroid disease, there is a notable increased incidence of thyroid autoimmunity in patients with chronic urticaria (Figure 12.1). They summarized the findings of several studies and estimated that approximately 5%–34% of patients with chronic urticaria have antithyroid antibodies despite being clinically or biochemically euthyroid and also stated that between 5% and 10% of chronic urticaria patients have clinically apparent thyroid disease.17 Other authors were even more generous in their estimates when looking at whether antithyroid

Figure 12.1. Chronic idiopathic urticaria, as characterized by transient, figurate wheals, may be associated with autoimmune thyroid disease

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antibodies had any greater prevalence in chronic idiopathic urticaria versus chronic urticaria of known cause. Zauli et al.16 divided two groups of patients with chronic urticaria into “known” (n = 23) and “idiopathic” causes (n = 12 Although they did not find differences in the prevalence of patients positive for at least one thyroid antibody or the prevalence of thyroid disease between the two groups, they nonetheless noted that in either group, a shocking 40% had underlying thyroid disease, and 30% of each group had detectable thyroid antibodies.26 This is especially important given the prevalence of thyroid autoimmunity in the general population is at approximately 10%. Table 12.1 provides a summary of studies looking at the prevalence of thyroid autoimmunity in chronic idiopathic urticaria. Autoimmune thyroid disease might be broadly defined as the presence of detectable thyroid antibodies and can be said to occur even in the patient who is clinically euthyroid. Thyroid antibodies are defined as IgG antibodies directed against thyroid peroxidase (TPO) (the so-named thyroid microsomal antigen), thyroglobulin, and the thyroid-stimuating hormone (TSH) receptor. In most studies that examined the presence of thyroid antibodies in chronic urticaria, there seemed to be an increased prevalence of antibodies directed against TPO. Perhaps this is the case since anti-TPO antibodies have been referred to as “the common denominator of human thyroid autoimmunity, encompassing patients with overt hyper- or hypothyroidism as well as euthyroid individuals with subclinical disease.”31 Zauli et al., for example, stated that there is a 20% prevalence for anti-TPO antibodies alone and 29% for any type of thyroid autoantibody in patients with chronic urticaria, compared to 1%–10% (depending on age and sex) in the general population. They further stated that thyroid dysfunction or altered serum TSH levels are present in 40%–54% of thyroid antibody-positive patients with urticaria and angioedema.16 A patient with anti-TPO IgE and chronic idiopathic urticaria has also been reported; this suggests that antigen generated from autoimmune thyroid damage can be processed by antigen-presenting cells (T cells, dendritic cells, and macrophages) and presented to B cells to generate anti-TPO IgE.32 Although these antibodies may not be terribly

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Table 12.1. Prevalence of thyroid autoimmunity (TA) in chronic idiopathic urticaria (CIU). Study Leznoff et al.13 Bjoro et al. Zauli et al.16 Kikuchi et al.58 Toubi et al.59 Verneuil et al.27 Turktas et al.28 Levy et al.8 Bakos et al.29 Puccetti et al.18 Caproni et al.25 Kulthanan et al.4 O’Donnell et al.30

CIU + TA

CIU + TA, euthyroid

90/624 14.4% NR 55/122 45.1% 55/282 19.5% 17/139 12.2% 12/45 26.7% NR 8/187 4.3% 14/48* 29.2% 43/133 32.3% 15/28† 53.6% 94/337 27.9% 18/90*,† 20.0%

46/90, 46/624 51.1%, 7.4% NR 41/55, 41/122 74.5%, 33.6% NR 14/17, 14/139 82.4%, 10.1% 12/45 26.7% 15% 5/8, 5/187 62.5%, 2.7% 14/28* 29.2% NR 15/28† 53.6% 94/337 27.9% 12/90*,† 13.3%

TA in control population (%) 5.6 9.7 NR NR NR 3.3 5 0.35–1.6 estimated NR 10 (9/90) 10% NR NR NR

Thyroid autoimmunity: presence of at least one antithyroid antibody. * Antithyroperoxidase only. † Patients were autologous serum skin test positive. NR, no response.

common, it does raise the question about which type of immune response goes on in AITD, which mediators are generated, and the role that those mediators play in the development of chronic urticaria.

Immunologic Manifestations of Autoimmune Thyroid Disease A fundamental feature of AITD is the production of antibodies to one of the primary thyroid-specific antigens: thyroglobulin, the main protein of the colloid; TPO, the enzyme that catalyzes iodine organification; and the receptor for TSH (TSH-R).33 An experimental murine model for the development of autoimmune thyroiditis showed that the release of tissue antigens from necrotic thyroid epithelial cells can trigger dendritic cell maturation and subsequent thyroglobulin-specific IgG and thyroglobulin-specific CD4+ T-cell responses.34 However, the more commonly accepted theory for the development of thyroid antibodies comes from

the recruitment of peripheral lymphocytes to the site of glandular activity/injury. Thus, the source of these antibodies appears to be from the formation of ectopic or extranodal lymphoid follicles that are generated from lymphocytic infiltrates that organize themselves as follicle-like structures containing germinal centers within the thyroid gland. Intrathyroidal B lymphocytes found within these follicles have been shown to synthesize antithyroglobulin, anti-TPO, and anti-TSH-R antibodies in vitro.33 Armengol et al. also proposed that because these intrathyroidal lymphoid B cells are in a privileged location to capture large amounts of self-antigens and present them to T cells, as these centers are “outside the limits” of other lymphoid organs, normal peripheral tolerance mechanisms might be more easily bypassed and a potential robust local immune response generated.33 Like any other inflammatory disease, a plethora of cells and mediators are found with autoimmune thyroid disorders. Several investigators have postulated about which ones are most important;

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however, it is generally agreed that intrathyroidal lymphocytes are the cells that play the central role. Garcia-Lopez et al. studied thyroid follicular cells extracted from patients with autoimmune disease and found enhanced expression of several chemokines, including IFN-inducible protein (Ip) 10, Regulated Activation Normal T cell Expressed and Secreted (RANTES), and monokine induced by IFN-γ. These chemokines not only attracted T lymphocytes in vivo, but their expression correlated with the degree of inflammation found in the diseased gland. Moreover, expression of Mig and Ip-10 was not seen in normal thyroid glands.35 In addition to this, other investigators have looked at the cytokines generated by intrathyroidal lymphocytes and found a pattern that does not lend itself to the classic Th1 versus Th2 distinctions. For example, Paschke et al. found messenger RNA transcripts from IL-2, -4, -5, -6, and -10 and IFN-γ in large quantities from the glands of patients with Hashimoto thyroiditis, and IL-2 and -4 and IFN-γ in 6 of 12 patients with Graves disease.36 Watson et al., on the other hand, found increased expression of IL-1β, -6, -8, and -10 and TNF-α in six patients with Graves disease and multinodular goiter.37 What is most notable about both of these studies is the lack of evidence for the so-called allergic cytokines IL-4 and IL-13. This becomes relevant to the discussion of the association to chronic urticaria and the lack of evidence supporting a potential association with allergy/IgE. One final caveat to consider is the role (or lack thereof) that “regulatory cytokines” play in the development of thyroid disease, in particular postpartum thyroiditis (PPT). While it is recognized that PPT may not be considered an “autoimmune” thyroid condition in the same sense as Hashimoto or Graves disease, Parkes et al. showed that TPOantibody-driven complement fixation is a marker for thyroid dysfunction in TPO-antibody-positive PPT women and also demonstrated that the amount of complement activation correlated with the extent of thyroid damage seen in women with PPT.38 With that in mind, in a study done by Olivieri and colleagues, fluctuations in transforming growth factor-β1 (TGF-β1) were examined in patients with PPT. As numerous studies have implied potential “protection” from autoimmune diseases such as colitis, diabetes, and collagen-induced arthritis with enhanced TGF-β1 expression, their study

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examined whether TGF-β1 levels correlated with the risk of developing PPT. The study evaluated 63 pregnant women for thyroid antibodies and serum concentrations of total and active TGF-β1; 34 were antithyroid antibody positive, and 20 were followed in the postpartum year. Of the 20 followed, 9 developed PPT. It was observed that the presence of thyroid antibodies increased the risk of developing PPT. Decreased total TGF-β1 but increased active TGF-β1 was seen in patients with PPT. The authors speculated that enhanced activation of TGF-β1 may contribute to resolution of thyroid inflammation in the postpartum state.39 These results lend consideration to the role that this cytokine may play in conditions associated with thyroid autoimmunity (i.e., chronic urticaria). Thus, with current thinking suggesting that extranodal lymphoid tissue is specifically recruited to the thyroid gland and potentially maintained by a positive feedback of chemokine-induced inflammatory cell recruitment and potential inhibition of apoptosis,40 one is inclined to speculate about “other” influences these extranodal lymphoid follicles might have. With regard to the association with chronic urticaria, could the cytokines produced at one site (i.e., the thyroid gland) influence the development of an inflammatory condition at another site (i.e., the skin)? Is there any cytokine “overlap” between the two conditions? Is it possible that these extranodal follicles may even hone to the skin? Could this have any therapeutic implications about the role of levothyroxine affecting glandular inflammation or the suppression of urticaria? The next two sections examine this potential “thyroid–urticaria” connection.

Immunologic Manifestations of Chronic Urticaria With regard to the nature and type of mediators found in urticaria, it has long been known that histamine is responsible for the classic clinical symptoms of acute urticaria: pruritus, erythema, and localized swelling. However, many other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the variable presentation and spectrum of this disease.41 Lesional skin has been shown to contain activated T lymphocytes, eosinophils, and neutrophils but not platelets.25,42,43

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Piconi et al. confirmed the presence of activated inflammatory cells in the lesions of patients with chronic urticaria. In a study of 19 patients with chronic idiopathic urticaria and 15 healthy controls, cytokine and chemokine production, along with the expression of adhesion molecules in whole blood samples, was examined. ASST was done in the patients with chronic urticaria. Their results showed that in patients with a positive ASST, TNF-α, IL-10, MIP-1α, and RANTES production was augmented, but IL-2 and IFN-γ levels were reduced in chronic idiopathic urticaria patients. CD44, CD11a, and CD62L expression on CD4+ and CD8+ cells was augmented. In chronic idiopathic urticaria patients with a negative ASST, TNF-α and chemokine production was significantly increased. Moreover, as was the case of patients with AITD, IL-4 levels were comparable in patients and controls, suggesting that IgEdependent mechanisms are not primarily involved in the underlying pathogenesis of chronic autoimmune urticaria.44 These results distinguish not only urticarial lesions from normal skin, but also lesions from patients with and without a positive ASST. O’Donnell et al. also found differences between ASST-positive and ASST-negative patients with chronic urticaria with three other factors: HLA expression, thyroid antibody presence, and TSH level. In their study of 182 patients with chronic idiopathic urticaria, 90 were ASST positive and 92 were ASST negative. Of the 90 patients with a positive ASST, 40 showed basophil histamine release in vitro. Of 90 patients in the ASST-positive group, 18 had thyroid microsomal antibodies compared to 4/92 in the ASST-negative group. In the those with a positive ASST, 6 of 90 had elevated TSH compared to 1 of 92 in the ASST-negative group. Patients in the ASST-positive group showed a statistically significant increased frequency of HLA class II markers compared to the ASSTnegative group. HLA-D4, HLA-DQB1*0301/4, and HLA-DQB1*0302 were seen with higher frequency in the ASST-positive/positive histamine release group; HLA-DRB1*04 showed increased expression in the ASST-positive/negative histamine release group. No markers were elevated in the ASST-negative/negative histamine release group. With these findings, the authors concluded that abnormal thyroid function and the presence of

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thyroid autoimmunity provide yet another way to distinguish patients with chronic urticaria.30 This observation helps to add muster to the differences in the clinical presentation and severity of disease in patients with so-called autoimmune urticaria and “nonimmune” chronic urticaria previously addressed.

Association of Chronic Urticaria with Thyroid Disease: The Role of L-Thyroxine and Thyroid-Stimuating Hormone Having established that chronic urticaria has features similar to other inflammatory conditions, is there any way to potentially “connect the dots” insofar as its relation to AITD? An observation that potentially links these two conditions is the resolution of urticarial lesions in patients with thyroid autoimmunity who are treated with thyroid hormone. Before launching into a discussion about the role of thyroid hormone in the treatment of chronic urticaria, it is well worth a reminder that clinical experience shows that chronic urticaria can improve or remit spontaneously. Kulthanan et al. reported that in a retrospective study of 450 patients with chronic urticaria (337 with no cause identified), after 1 year from the onset of symptoms, 34.5% were free of symptoms. Of those identified as having “autoimmune urticaria,” 56.5% were free of symptoms after 1.2 years. The median duration of symptoms was 390 days for those with idiopathic urticaria and 450 days for those with autoimmune urticaria.4 Kozel et al.60 reported a spontaneous remission rate of 47% in a series of patients with chronic idiopathic urticaria.16 With those considerations, we cannot forget to communicate this very important fact to our patients with chronic urticaria: Regardless of how urticaria is treated, symptoms will most likely resolve on their own. This is a humbling tenet, but true nonetheless. Some investigators have felt that the association of thyroid autoimmunity and chronic urticaria is more of an epiphenomenon rather than anything potentially etiologic.22,32 Kandeel et al., for example, in a study looking at the histopathologic and immunohistochemistry of patients with or without

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Hashimoto thyroiditis and chronic urticaria, found no differences. They also saw no differences in patients treated with thyroid hormone insofar as the effect on the course of the urticaria.45 Similarly, Levy et al. did not see any effect on urticaria in three of eight children with underlying thyroid disease who were treated with thyroxine.8 However, in both instances, there was no comment offered about dosing, duration, or effect on TSH levels. On the other hand, several groups have reported significant improvement in urticaria for patients who had clinically evident thyroid disease as well as patients who were euthyroid. Aversano et al. treated 20 female patients with chronic urticaria and thyroid autoimmunity with L-thyroxine until total TSH suppression was seen. Eight of 20 were hypothyroid, and 12/20 were euthyroid. Within 12 weeks of treatment, 8/8 patients with hypothyroidism and 8/12 euthyroid patients had a significant decrease in urticarial symptoms. The authors also found significant reductions in antithyroglobulin, anti-TPO, and ESR (erythrocyte sedimentation rate) levels after treatment. Of note, 2 of the patients had a return of symptoms after treatment was stopped, which resolved after treatment was restarted.46 In addition, combining data from Leznoff et al.,47) Rumbyrt et al.,48) and Gaig et al.,49) Zauli et al. noted that of 23 euthyroid patients with chronic urticaria treated with L-thyroxine, 14 had complete remission of hives, 7 had partial remission, and only 2 had no remission.16 With these results in mind, some authors have suggested that screening for thyroid autoimmunity is a worthy endeavor, and that a trial of thyroid hormone would be reasonable to consider in the event that other treatment modalities fail.27,50 This has now even been taken to a different level. Heymann et al., after finding success treating chronic urticaria with oral levothyroxine,51,52 also published pilot studies looking at the role of topical thyroid hormone in euthyroid patients with xerosis.53 One is led to speculate whether this could also have a role in treating chronic urticaria.33 Moreover, Padberg et al. and others have found that prophylactic treatment of euthyroid patients with evidence of thyroid antibodies reduced both serological and cellular markers of autoimmune thyroiditis and may be useful to stop the progression or even manifestation of the disease.54

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Although their studies did not focus attention on patients with chronic urticaria, it would be worth tracking their results to see if any of those patients went on to develop urticaria.

Proposed Mechanism Several authors have published their observations of increased histamine releasibility in the setting of autoimmune chronic urticaria. Others have added to this by suggesting that thyroid glandular inflammation and the resultant generation of cytokines, chemokines, and complement activation is the actual mechanism behind that seen in patients with increased histamine releasibility.25 Schocket has been an advocate of this theory by suggesting that an active immunologic or “autoimmune” process might release histamine-releasing factors, which are capable of lowering the threshold of release of cutaneous mast cells. This would render them more susceptible to release by endogenous substances (such as vasoactive intestinal peptide [VIP], somatostatin, gastrin, and substance P). The threshold returns to normal when the immunologic process remits, resulting in the resolution of the hives.50 However, a problem remains: If histamine release was the primary end result of immune activation leading to formation of urticaria, then antihistamine treatment should, in theory, result in significant clinical relief. Although this may be true for acute urticaria, antihistamine treatment alone, even in very large doses and with H1, H2, and H3 receptor antagonists, rarely resolves the problem of chronic urticaria. True, most authors emphasized the inflammatory conditions leading to histamine release and justified their theories of resolution based on treatment of the underlying inflammatory condition. Nonetheless, one would still need to consider the fact that histamine release is more of a by-product of any inflammatory process (autoimmune or other), and that it alone does not give credence to any particular theory behind the mechanism of chronic urticaria. Since changes in thyroid antibodies do not consistently occur in patients treated with L-thyroxine, it was for this reason that we (and others) turned our focus to the role of TSH or the TSH receptor as “the marker” that warrants attention when treating potential autoimmune thyroid-associated chronic urticaria.7,48 Although antibodies to the TSH

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receptor were discovered in a patient with chronic urticaria, type 1 diabetes, and Graves disease,55 this is not likely to be a phenomenon seen in many patients. On the other hand, TSH receptor messenger RNA transcripts have been found in a number of nonthyroidal tissues, including adipocytes, skin fibroblasts, extraocular muscle, lymphocytes, and peripheral blood mononuclear cells of patients with Graves disease as well as in patients with normal thyroid glands.56,57 The primary source of these transcripts is not known, and it is not known whether they are “functional.” However, though Kandeel et al. did not see any difference in the histopathologic and immunohistochemical profiles of patients with chronic urticaria and Hashimoto thyroiditis, they did find small aggregates of Vβ8- or Vβ6-restricted T lymphocytes in the skin of some patients with chronic urticaria and Hashimoto thyroiditis and could not rule out the possibility that these cells came from the thyroid gland.45 As a way of tying this all together, Aversano et al.46) proposed a “unifying hypothesis” in which the thyroid axis has interplay with the immune system. The resulting generation of cytokines and other inflammatory mediators can have a direct effect on the hypothalamus and affect production of TSH in this manner: 1. The immune and neuroendocrine systems are totally integrated and share a common set of hormones, cytokines, and receptors. 2. Cytokines/mediators such as IL-1, IL-2, IL-6, TNF-α, INF-γ, thymic hormones, leukotrienes, and prostaglandins are able to modulate the secretion and the release of hormones by the hypothalamus, pituitary, and peripheral tissues, where specific receptors for these cytokines are present. 3. Moreover, immune cells (T and B lymphocytes, dendritic cells, monocytes, thymocytes, and splenocytes) express receptors for hormones, neurotransmitters, cytokines, and growth factors that regulate cytokine effects and secretion. In addition, several groups have documented 1. TSH, TRH (TSH-releasing hormone), HPRL, and other hormone receptors are expressed on the cellular components of the immune system. 2. Human peripheral mononuclear cells, monocytes, and splenocytes have the capability to

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release a high amount of TSH when stimulated with TRH. 3. Increased TSH levels lead to increased expression of cytokine receptors for IL-1, IL-2, IL-6, TNF-α, IFN-γ, leukotrienes, and prostaglandins. 4. There is a dose-dependent stimulatory effect of TSH on leukocytes and dendritic cells to release IL-1, IL-2, IL-6, and IL-12. The authors raise the notion that TSH itself has potential cytokine-like properties. Not only can it have a direct effect on the release of proinflammatory cytokines from leukocytes and dendritic cells, but also it has an indirect effect by increasing receptor expression for cytokines that would/could potentiate an inflammatory response. This could potentially lead to causing or aggravating inflammatory states in other target organs such as skin, muscles, central nervous system, heart, joints, eyes, and bone marrow (i.e., potential target organs affected in AITD). If this theory is correct, it flows very nicely with data about the necessity of reducing TSH levels to achieve a reduction in the urticaria brought about by AITD: Levothyroxine has a direct effect on the pituitary to reduce production of TSH. In doing so, there is an attenuation of the TSH-induced release of proinflammatory mediators—both in the thyroid gland and the skin—and hence gradual resolution of urticarial lesions. Moreover, the TSH level may have to be suppressed significantly (if not completely) to achieve a full clinical response.

Practical Considerations It is our bias that a functional assessment for thyroid disease be conducted in all patients with chronic urticaria in whom an etiology has not been determined. Of course, initially one is going to try and “round up the usual suspects,” and after conducting a thorough history and physical exam, many of the “typical” causes can hopefully be ruled out. Keeping in mind what those might be, Kulthanan and colleagues found, in their retrospective study of 450 patients with chronic urticaria, that in those in whom an etiology was determined, the “ranking” of causes was as follows: physical urticaria (dermographism, cold induced, delayed pressure, adrenergic, cholinergic, and solar) 9.5%; infection (dental caries,

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parasitic infestation, hepatitis, sinusitis, nonspecific) 3.8%; food allergy 3.6%; thyroid disease (hyperthyroidism, hypothyroidism) 3.3%; dyspepsia, atopy, medication, collagen vascular disease 1.1% each; “others” 0.4%.4 These causes do not differ substantially from the framework presented at the beginning of this chapter. However, as it has been demonstrated that chronic urticaria has a high degree of association with autoimmunity, it is the opinion of these authors as well as many others that evaluation of the thyroid axis (thyroxine [T4], TSH), as well as the presence of thyroid antibodies (antithyroglobulin, antimicrosomal/peroxidase) be performed in all patients with “chronic idiopathic” urticaria. Particularly close attention should be paid to those with strong family histories of autoimmune disease as the presence of autoantibodies is highly correlated (at least in the case of thyroid disease) with the development of clinically relevant autoimmune disease in the future. Moreover, if reports of early treatment with thyroid hormone in autoimmune euthyroid patients resulting in attenuation of future development of disease are true, screening family members of patients with autoimmune thyroid-induced chronic urticaria may also be reasonable to consider.

Suggestions for Future Studies The biologic basis for the effects of L-thyroxine in patients with chronic urticaria and AITD is not known. Although the theory proposed is quite plausible, it remains a theory. Therefore, to test whether there is any role for thyroid hormone therapy or whether thyroid antibodies actually participate in pathogenesis, several studies could be conducted. For example, if the TSH/TSH receptor interplay does have a critical role in chronic urticaria, assessment for the presence of the TSH receptor in the skin of patients with active and quiescent urticarial disease would be of interest. Moreover, assessing not only its presence but also receptor activity would be a very valuable piece of evidence linking the two conditions. Thyroid antibodies detected in the lymphoid follicles of patients with autoimmune disease could be assessed for their presence in peripheral tissues, specifically urticarial lesions. In addition, it would be important to know if L-thyroxine has any effect on inhibiting histamine release in patients with chronic urticaria. This could

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be looked at in patients who are ASST positive and ASST negative and compared to healthy controls. Dreskin and Andrews proposed looking at the way antithyroid antibodies behave in autoimmune thyroid patients (with and without disease) insofar as their ability to activate complement. They also proposed looking at whether low levels of complement activation lead to a difference in mast cell activation in patients with thyroid antibodies who do not have anti-FcεRI antibodies, implying that there may be a “threshold” level of complement activation to precipitate chronic urticaria.17

Conclusion It is somewhat amusing that there is so much jousting in the literature regarding which autoantibody, which cytokine, and which receptor are produced/activated to result in the clinical picture of urticaria. The beautifully created redundancy of the immune response makes any number of possibilities worth considering. The mere fact that mast cells can be triggered by both innate and specific/ learned immune responses makes this observation almost embarrassingly simple. However, the task that we have before us is not to debate the merit of our biases but to try to explain how our “little corner of paradise” functions. With regard to thyroid autoimmunity (our particular interest), we can see how any number of mediators are generated—simply from the autoimmune response of the gland itself. This could set in motion the entirety of the inflammatory cascade—from the release of inflammatory mediators that initiate the response, to the recruitment of inflammatory cells that perpetuate the response—that results in clinical disease. The questions that need to be answered would be: Through which inflammatory cell/receptor/tissue does this particular mechanism act? Are there certain cytokines or chemokines or “other factors” (i.e., TSH) that have a greater role in initiating or perpetuating the response? If thyroid hormone reduces glandular inflammation, is there a “global” effect on mediator production, or is there one or a group of mediators that gets attenuated? Are there any supplemental therapies that would enhance the downregulation brought about by thyroid hormone? We look forward to others contributing to this growing area of inquiry.

12. Chronic Idiopathic Urticaria and Thyroid Disease

References 1. Burman K, Mckinley-Grant L. Dermatologic aspects of thyroid disease. Clin Dermatol 2006;24:247–255. 2. Dorland’s Illustrated Medical Dictionary. Available at: http://www.mercksource.com/pp/us/cns/cns_hl_ dorlands. 3. Horan R, Schneider L, Sheffer A. Allergic disorders and mastocytosis. JAMA 1992;268:2858–2868. 4. Kulthanan K, Jiamton S, Thumpimukvatana N, et al. Chronic idiopathic urticaria: prevalence and clinical course. J Dermatol 2007;34:294–301. 5. Champion R, Roberts S, Carpenter R, et al. Urticaria and angio-oedema: a review of 554 patients. Br J Dermatol 1969;81:588–597. 6. Quaranta J, Rohr A, Rachelefsky G, et al. The natural history and response to therapy of chronic urticaria and angioedema. Ann Allergy 1989;62:421–424. 7. Rumbyrt J, Schocket A. Chronic urticaria and thyroid disease. Immunol Allergy Clin North Am 2004;24:215–223. 8. Levy Y, Segal N, Weintrob N, et al. Chronic urticaria: association with thyroid autoimmunity. Arch Dis Child 2003;88:517–519. 9. Chapman E, Maloof F. Bizarre clinical manifestations of hyperthyroidism. N Engl J Med 1956;254:1. 10. Caravati C, Richardson D, Wood B, et al. Cutaneous manifestations of hyperthyroidism. South Med J 1969;62:1127. 11. Isaacs N, Ertel N. Urticaria and pruritus: uncommon manifestations of hyperthyroidism. J Allergy Clin Immunol 1971;48:73–81. 12. Small P, Lerman S. Hyperthyroidism and polycythemia vera with chronic urticaria and angioedema with thyroid autoimmunity. Ann Allergy 1981;46:256–259. 13. Leznoff A, Josse R, Denburg J, et al. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983;119:636–640. 14. Pace J, Garretts M. Urticaria and hyperthyroidism. Br J Dermatol 1975;93:97–99. 15. Henderson C, Highet A. Urticaria associated with thyrotoxicosis. Clin Exp Dermatol 1995;20:173–174. 16. Zauli D, Grassi A, Ballardini G, et al. Thyroid autoimmunity in chronic idiopathic urticaria: implications for therapy. Am J Clin Dermatol 2002;3:525–528. 17. Dreskin S, Andrews K. The thyroid and urticaria. Curr Opin Allergy Clin Immunol 2005;5:408–412. 18. Puccetti A, Bason C, Simeoni S, et al. In chronic idiopathic urticaria autoantibodies against FcεRII/ CD23 induce histamine release via eosinophil activation. Clin Exp Allergy 2005;35:1599–1607. 19. Gruber B, Baeza M, Marchese M, et al. Prevalence and functional role of Anti-IgE autoantibodies in urticarial syndromes. J Invest Dermatol 1988;90:213–217.

155 20. Hide M, Francis D, Grattan C, et al. Autoantibodies against the high affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med 1993;328:1599–1604. 21. Castells M. Mast cell mediators in allergic inflammation and mastocytosis. Immunol Allergy Clin North Am 2006; 26:465–485. 22. Kaplan A. Chronic urticaria and angioedema. N Engl J Med 2002;346:175–179. 23. Caproni M, Cardinali C, Giomi B, et al. Serological detection of eotaxin, IL-4, IL-13, IFN-γ, MIP-1α, TARC and IP-10 in chronic autoimmune urticaria and chronic idiopathic urticaria. J Dermatol Sci 2004;36:57–59. 24. Caproni M, Gioi B, Melani L, et al. Cellular infiltrate and related cytokines, chemokines, chemokine receptors and adhesion molecules in chronic autoimmune urticaria: comparison between spontaneous and autologous serum skin test induced wheal. Int J Immunopathol Pharmacol 2006;19:507–515. 25. Caproni M, Giomi B, Volpi W, et al. Chronic idiopathic urticaria: infiltrating cells and related cytokines in autologous serum-induced wheals. Clin Immunol 2005;114:284–292. 26. Rottem M. Chronic urticaria and autoimmune thyroid disease: is there a link? Autoimmun Rev 2003;2: 69–72. 27. Verneuil L, Leconte C, Ballet J, et al. Association between chronic urticaria and thyroid autoimmunity: a prospective study involving 99 patients. Dermatology 2004;208:98–103. 28. Turktas I, Gokcora N, Demirsoy S, et al. The association of chronic urticaria and angioedema with autoimmune thyroiditis. Int J Dermatol 1997;36:187–190. 29. Bakos N, Hillander M. Comparison of chronic autoimmune urticaria with chronic idiopathic urticaria. Int J Dermatol 2003;42:613–615. 30. O’Donnell B, Francis D, Swana G, et al. Thyroid autoimmunity in chronic urticaria. Br J Dermatol 2005;153:331–335. 31. McLachlan S, Rapoport B. Autoimmune response to the thyroid in humans: thyroid peroxidase—the common autoantigenic denominator. Int Rev Immunol 2000;19:587–618. 32. Rottem M. Allergy and systemic diseases: the case of chronic urticaria and thyroid disease. Isr Med Assoc J 2002;4:889–890. 33. Armengol M, Juan M, Lucas-Martin A, et al. Demonstration of thyroid-antigen specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. Am J Pathol 2001:159;861–873. 34. Li H, Verginis P, Carayanniotis G. Maturation of dendritic cells by necrotic thyrocytes facilitates

156 induction of experimental autoimmune thyroiditis. ClinExp Immunol 2006;144:467–474. 35. Garcia-Lopez M, Sancho D, Sanchez-Madrid F, et al. Thyrocytes from autoimmune thyroid disorders produce the chemokines IP-10 and Mig and attract CXCR3+ lymphocytes. J Clin Endocrinol Metab 2001;86:5008–5016. 36. Paschke R, Schuppert F, Taton M, et al. Intrathyroidal cytokine gene expression profiles in autoimmune thyroiditis. J Endocrinol 1994;14:309–315. 37. Watson P, Pickerill A, Davies R, et al. Analysis of cytokine gene expression in Graves’ disease and multinodular goiter. J Clin Endocrinol Metab 1994;79:355–360. 38. Lazarus J, Parkes A, Premawardhana L. Postpartum thyroiditis. Autoimmunity 2002;35:169–173. 39. Olivieri A, De Angelis S, Vaccari V, et al. Postpartum thyroiditis is associated with fluctuations in transforming growth factor-β1 serum levels. J Clin Endocrinol Metab 2003;88:1280–1284. 40. Nagataki S, Eguchi K. Cytokines and immune regulation in thyroid autoimmunity. Autoimmunity 1992;13:27–34. 41. Hennino A, Berard F, Guillot I, et al. Pathophysiology of urticaria. Clin Rev Allergy Immunol 2006;30:3–12. 42. Kasperska-Zajac A, Rogala B, Nowakowski M. Assessment of platelet activity as expressed by plasma levels of platelet factor 4 and β-thromboglobulin in patients with chronic idiopathic urticaria. Exp Dermatol 2005;14:515–518. 43. Kasperska-Zajac A, Brzoza Z, Rogala B. Circulating level of the platelet-derived CXC chemokine platelet factor 4 in chronic urticaria patients with or without coexistent euthyroid Hashimoto’s thyroiditis. Autoimmunity 2006;4:265–268. 44. Piconi S, Trabattoni D, Iemoli E, et al. Immune profiles of patients with chronic idiopathic urticaria. Int Arch Allergy Immunol 2002;128:59–66. 45. Kandeel A, Zeid M, Helm T, et al. Evaluation of chronic urticaria in patients with Hashimoto thyroiditis. J Clin Immunol 2001;21:335–347. 46.Aversano M, Caiazzo P, Iorio G, et al. Improvement in chronic idiopathic urticaria with L-thyroxine: a new TSH role in immune response? Allergy 2005;60:489–493. 47. Leznoff A, Sussman G. Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients. J Allergy Clin Immunol 1989;84:66–71.

J.S. Rumbyrt and A.L. Schocket 48. Rumbyrt J, Katz J, Schocket A. Resolution of chronic urticaria in patients with thyroid autoimmunity. J Allergy Clin Immunol 1995;96:901–905. 49. Gaig P, Garcia-Ortega P, Enrique E, et al. Successful treatment of chronic idiopathic urticaria associated with thyroid autoimmunity. J Investig Allergol Clin Immunol 2000;10:342–345. 50. Schocket A. Chronic urticaria: pathophysiology and etiology, or the what and why. Allergy Asthma Proc 2006;27:90–95. 51. Heymann W. Chronic urticaria and angioedema associated with thyroid autoimmunity: review and therapeutic implications. J Am Acad Dermatol 1999;40:229–32. 52. Ai J, Leonhardt J, Heymann W. Autoimmune thyroid diseases: etiology, pathogenesis, and dermatologic manifestations. J Am Acad Dermatol 2003;48:641–659. 53. Heymann W, Gans E, Manders S, et al. Xerosis in hypothyroidism: a potential role for the use of topical thyroid hormone in euthyroid patients. Med Hypotheses 2001;57:736–739. 54. Padberg S, Heller K, Usadel K, et al. One-year prophylactic treatment of euthyroid Hashimoto’s thyroiditis patients with levothyroxine: is there a benefit? Thyroid 2001;11:249–255. 55. Asero R, Orsatti A, Tedeschi A, et al. Autoimmune chronic urticaria associated with type 1 diabetes and Graves’ disease. J Allergy Clin Immunol 2005;115:1088–1089. 56. Rapoport B, Chazenbalk G, Jaume J, et al. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev 1998;19:673–716. 57. Paschke R, Metcalfe A, Alcalde L, et al. Presence of nonfunctional thyrotropin receptor transcripts in retroocular and other tissues. J Clin Endocrinol Metab 1994;79:1234–1238. 58. Kikuchi Y, Fann T, Kaplan AP. Antithyroid antibodies in chronic urticaria and angioedema. J Allergy Clin Immunol 2003;112(1):218. 59. Toubi E, Kessel A, Avshovich N, Bamberger E, Sabo E, Nusem D, Panasoff J. Clinical and laboratory parameters in predicting chronic urticaria duration: a prospective study of 139 patients. Allergy 2004;59(8):869–873. 60. Kozel MM, Mekkes JR, Bossuyt PM, Bos JD. Natural course of physical and chronic urticaria and angioedema in 220 patients. J Am Acad Dermatol 2001;45(3):387–391.

13 Dermatologic Disorders Associated with Thyroid Disease Joslyn Sciacca Kirby and William D. James

Editorial Perspective Thyroid diseases need to be considered as contributing to the clinical picture in patients with a host of systemic and dermatologic disorders, many of which are classified as autoimmune. Imagine the following scenario: A 46-year-old woman with a known history of systemic lupus erythematosus complains of the recent development of leg weakness. The clinician needs to determine if this could be due to the lupus itself, a reaction to treatment (such as a steroidinduced myopathy), or if there is a concurrent pathologic process. Considering thyroid disease in this context should be routine; however, it is all too often forgotten as a diagnostic possibility. It is also essential to consider if a patient’s

Introduction The skin can manifest an array of signs of underlying thyroid disease or malignancy. Cutaneous signs of thyroid disease can be caused by the thyroid malady itself or be due to a primary cutaneous disease that has an associated risk of thyroid disease. For instance, changes such as exophthalmos and pretibial myxedema are skin signs of Graves disease, whereas primary diseases of the skin, such as vitiligo or lichen sclerosus et atrophicus, are associated with an increased prevalence of autoimmune thyroid disease (AITD).1 Signs of AITD are numerous and include those shared by hyper- and hypothyroidism, such as goiter,

medications may be affecting thyroid function. For example, if a patient with cutaneous T-cell lymphoma (CTCL) develops xerosis to the point of being considered as having an acquired ichthyosis, is the ichthyotic skin secondary to the lymphoma or to bexarotene-induced central hypothyroidism? This chapter emphasizes those disorders and medications that merit screening for thyroid disease in the appropriate clinical context, utilizing thyroid function studies or thyroid autoantibodies. The ability to treat thyroid disease should provide an impetus for assessing the thyroid status in patients with the maladies discussed in this chapter. Assessing thyroid function should be considered standard practice in patients with a personal or family history of any autoimmune disease. generalized nonscarring alopecia, oligomenorrhea, and nail changes. Signs of hyperthyroidism include warm, moist skin; flushing; generalized hypertrichosis; tachycardia; tremor; diarrhea; and menorrhea. Patients may complain of heat intolerance and either fatigue or hyperactivity. Hypothyroidism can manifest with signs such as cool, dry skin; constipation; bradycardia; and weight gain. These patients may complain of cold intolerance and fatigue.2 Patients with these complaints should prompt the physician to screen for a thyroid disorder. This chapter discusses systemic disorders with dermatologic manifestations, cutaneous disorders, and medications that may be associated with thyroid disease.

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Connective Tissue Disease There is a well-known association among organspecific autoimmune conditions such as Graves disease (GD) and Hashimoto thyroiditis (HT) and other organ-specific autoimmune diseases such as pernicious anemia, myasthenia gravis, immune thrombocytopenia (ITP), type 1 diabetes mellitus, and others.3–5 This constellation of diseases is sometimes referred to as autoimmune polyglandular syndrome (APS). There are multiple forms of APS (Table 13.1); for example, type 2 APS is defined by the occurrence of Addison disease with thyroid autoimmune disease or type 1 diabetes mellitus.3–6 There is less known about the overlap and frequent cooccurrence of AITD and systemic autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or systemic sclerosis (SSc).7,8 A large cohort study by Biro et al. found that 30% of patients with AITD had an associated systemic autoimmune disease. Also, patients with a known systemic autoimmune disease had about an 8% prevalence of AITD.9

Systemic and Discoid Lupus Erythematosus Lupus erythematosus (LE) is a chronic, recurrent, autoimmune inflammatory disease of unknown etiology. LE can be divided into the cutaneous and systemic forms of disease. The division does not exclude a patient from having both forms, either concurrently or serially. Cutaneous lupus erythematosus (CLE) is further divided into acute, subacute, and chronic (discoid) forms.10 The erythematous malar rash is a manifestation of acute CLE. Subacute CLE appears as pink patches, often with an annular Table 13.1. Autoimmune polyglandular syndromes. Type 1 Chronic candidiasis, chronic hypoparathyroidism, autoimmune Addison disease (at least two present) Type 2 Autoimmune Addison disease plus autoimmune thyroid diseases or type 1 diabetes mellitus (Addison disease must always be present) Type 3 Thyroid autoimmune diseases plus other autoimmune diseases (excluding autoimmune Addison disease, hypoparathyroidism, chronic candidiasis) Type 4 Two or more organ-specific autoimmune diseases (that do not fall into type 1, 2, or 3) Source: According to reference 9.

Figure 13.1. Scaling plaques of discoid lupus erythematosus (DLE) with hyperpigmentation and central hypopigmentation and scarring

configuration and fine scale, distributed on the chest and back. Discoid lupus erythematosus (DLE) is the prototype of chronic CLE. DLE initially develops as erythematous patches and plaques with thick adherent scale, commonly referred to as carpet-tack scale because of its extension down hair follicles. DLE is most commonly found on the sun-exposed areas of the scalp, face, and neck; however, the conchal bowl of the ear is also commonly affected. As the lesions of DLE evolve, hyperpigmentation develops at the edge, with central scarring and hypo- or depigmentation (Figure 13.1). About 5% of adult patients with DLE will go on to fulfill criteria for SLE. In contrast, about 90% of patients with SLE will develop any form of cutaneous disease.10 Systemic lupus erythematosus is a multisystem inflammatory disease that can involve any organ, including the skin, kidneys, lungs, joints, lymphoreticular system, heart, eyes, and nervous system. The prevalence of SLE varies from 40 to 100 cases per 100,000 people. The disease is more common in women and blacks; black women have the highest risk.11 The diagnosis is based on fulfilling four of the 1982 American College of Rheumatology (ACR) criteria: malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, and antinuclear antibodies (ANAs).12 The sensitivity of the ACR criteria ranges from 78% to 96%, and the specificity ranges from 89% to 100%.11 The hallmark of SLE is the presence of autoimmune antibodies, most commonly ANA. In addition, autoantibodies such as anti-double-stranded

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DNA (anti-dsDNA) and anti-Smith antigen (antiSm) are specific for SLE, while autoantibodies such as anti-ribonucleoprotein (anti-RNP) and anti-La are present in other autoimmune diseases. Since the 1950s, the 5-year survival rate for patients with SLE has increased from 50% to a range of 91% to 97%.11 This improvement may be due to earlier diagnosis of mild disease, better management, or improved treatment of infections, which are common in this population. Treatment of cutaneous disease includes sun avoidance and protection with physical or chemical sunscreens, antimalarials, prednisone, thalidomide, dapsone, and immunosuppressants, such as methotrexate and azathioprine.13 Management of SLE is often coordinated by a rheumatologist, using therapies such as nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials, oral or intravenous corticosteroids, azathioprine, or methotrexate. Cyclophosphamide, a nitrogen mustard derivative, is used for severe renal disease.13 Multiple studies have suggested that AITD is more common in those with SLE than in the general population.8,14–19 The prevalence of AITD in SLE patients has been reported to vary from about 4% to as high as 24%, with the most reliable estimate 5%–7%.8,15,18,19 There is some inconsistency about whether GD or HT is more common in SLE. One large study reported the risk of GD and HT to be 68- and 90-fold higher, respectively, in patients with SLE.8 Also, SLE was more prevalent in patients previously diagnosed with AITD, suggesting that symptoms in patients with AITD should not be assumed to be due to their thyroid disease but may be due to another concurrent autoimmune disease.8 AITD and DLE less commonly coexist, with only two reports of HT occurring in DLE.14,20

Scleroderma Scleroderma begins as edema of the skin that progresses to hardening and tightening. It may eventually resolve, leaving behind atrophy. Scleroderma can be characterized as localized, diffuse (generalized skin), or systemic forms. Morphea describes a localized or diffuse sclerosis limited to the skin.10,21,22 In systemic sclerosis (SSc), fibrosis can be found in the lungs, gastrointestinal tract, kidneys, vessels, joints, and heart.22–24 CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiecta-

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Figure 13.2. Sclerodactyly and scattered erosions seen in CREST (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome

sia) is considered a limited form of SSc (Figure 13.2).10,23,24 These patients have disease involving the skin and viscera but have a lower risk of renal involvement and restrictive lung disease with an overall higher rate of survival.23,24 The ACR criteria for the diagnosis of SSc includes one major criterion, diffuse proximal sclerosis, and two of three minor criteria: sclerodactyly, pitting scars or loss of the distal finger pads, and bibasilar pulmonary fibrosis.25 The prevalence of the disease is reported to be between 13 and 140 per million, with an incidence of 2.6–28 cases per million.23 Autoantibodies that may be present in scleroderma include ANAs, rheumatoid factor (RF), anticentromere antibody (ACA), antihistone antibody (AHA), antitopoisomerase I (Scl-70), and antifibrillarin antibodies. In addition, patients with anti-RNA polymerase antibodies have the worst prognosis and shortest survival times.23,26

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The autoimmune diseases such as AITD, vitiligo, pernicious anemia, and diabetes mellitus are more common in patients with morphea or SSc. The literature supports a prevalence of thyroid dysfunction in 25%–60% of patients with SSc.8,23,27,28 The etiology of the thyroid dysfunction may not be entirely due to an autoimmune etiology, although 18%–52% of SSc patients have been reported to have an antithyroid antibody.8,27,29 In another large study, the prevalence of HT or GD was approximately 220-fold and 102fold higher, respectively, in SSc patients than in the general population.8 Multiple studies have considered the relationship between pulmonary hypertension and thyroid dysfunction.30,31 These have shown pulmonary hypertension to be more prevalent in SSc patients with thyroid dysfunction than without this additional comorbidity.30 The mechanism of antithyroid antibodies in the pathogenesis of pulmonary disease in this population of scleroderma patients has not been established.

Sjögren Syndrome Sjögren syndrome (SS) is an autoimmune disorder characterized by dry eyes and dry mouth (Figure 13.3). The symptoms of dryness result from lacrimal and salivary gland destruction and dysfunction of residual glands due to lymphocytic inflammation. Primary SS occurs without other associated diseases. Secondary SS patients develop symptoms in conjunction with other autoimmune disorders such as RA, SLE, dermatomyositis (DM), SSc, or primary biliary cirrhosis. The prevalence of SS is about 0.5%–1% in the general population,

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with a female preponderance of 9:1. The onset of disease is bimodal, with the first peak during the third to fourth decades and the second peak in the sixth decade. The pathogenesis of SS is not well understood but is hypothesized to be multifactorial. Some of the factors that may trigger the disease include a genetic predisposition and environmental factors that generate inflammation in predisposed individuals.10,32 Currently, the diagnosis is made when a patient fulfills four of six criteria: dry eye; an abnormal Schirmer or Rose Bengal test; dry mouth; abnormal salivary gland function test (scintigram, sialogram, flow test); characteristic minor salivary gland biopsy findings; and positive serologic testing for SS-A or SS-B autoantibodies.33 Cutaneous manifestations of SS include dry skin and vasculitis. Topical moisturizers are utilized to treat dry skin. Patients with more serious skin findings such as vasculitis may warrant systemic management. Ocular symptoms are treated with over-the-counter preservative-free artificial tears, lubricating ointments, and methylcellulose. Prescription eyedrops containing cyclosporine or tacrolimus are also used. Oral symptoms are harder to treat; management suggestions include good dental hygiene with flossing after meals; regular professional dental hygiene treatments, including fluoride treatments as frequently as every 3 months; and avoidance of foods high in sucrose that contribute to caries.10,32 Two muscarinic agonists, pilocarpine and cevimeline, were approved as secretagogues for the treatment of xerostomia in SS. Following the trend of other connective tissue diseases (CTDs), additional organ-specific autoimmune diseases tend to co-occur with SS. SS is associated with an increased frequency of skin diseases such as vitiligo, anetoderma, alopecia, and cutaneous lymphomas.32,34 The risk of AITD in SS patients is much higher than the normal population. HT and GD are 176-fold and 74-fold more prevalent, respectively, in patients with SS.8 In multiple case series of patients with primary and secondary SS, AITD was diagnosed in 11%–30%.8,34,35 HT is found more commonly than GD.8,34–37 The diagnosis of AITD is often made prior to the diagnosis of SS.

Dermatomyositis and Polymyositis Figure 13.3. A patient with dry lips and oral mucosa due to Sjögren syndrome

Dermatomyositis (DM) and polymyositis (PM) are two distinct subsets along a spectrum of disease.

13. Dermatologic Disorders Associated with Thyroid Disease

DM is in the middle of the spectrum and includes both cutaneous and muscle disease. At either pole are amyopathic DM and PM, which manifest with disease of predominantly the skin or the muscle, respectively. The most common skin signs of DM include erythema and scale on the scalp, the classic periocular “heliotrope rash,” and Gottron papules. Gottron papules are violaceous papules overlying the dorsolateral aspect of interphalangeal or metacarpophalangeal joints (Figure 13.4). The heliotrope rash consists of a violaceous discoloration of the periorbital skin with or without edema. Other cutaneous findings in DM include periungual telangiectasia, erythema and scaling overlying extensor surfaces (Gottron sign), and scaling erythema on the upper chest and shoulders (shawl sign).10,38 Less-common findings include dry, thick scaling of the palms (mechanics hands) and linear red plaques on the trunk (flagellate erythema).39 Muscle involvement typically manifests as proximal muscle weakness without muscular pain. Signs and symptoms of DM/PM can overlap with other CTDs such as SLE, scleroderma, and mixed connective tissue disease (MCTD).10,38 Dermatomyositis and PM are associated with autoimmune antibodies, including antisynthetase, anti-Mi-2, and antinuclear antigen. Additional abnormal laboratory and diagnostic tests include elevated creatinine phosphokinase (CPK), aldolase, and lactic dehydrogenase (LDH), as well as evidence of inflammation on magnetic resonance imaging (MRI), electromyelography (EMG), and muscle biopsy.38 Treatment is dependent on the extent and severity of disease. Therapies include

Figure 13.4. Gottron papules, demonstrated as pink papules clustered over the joints of the hands in a patient with dermatomyositis

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topical and oral corticosteroids; antimalarials given singly or in combination; and immunosuppressants, including methotrexate, azathioprine, and cyclosporine, plasmapheresis, and intravenous immunoglobulin (IVIG).40 Dermatomyositis is a paraneoplastic condition in some cases.10,41,42 Patients with DM have a 6%–60% increased frequency of malignancy over the normal population, with 15% representing a good general approximation of risk. Malignancy may precede, follow, or occur simultaneously with the symptoms of DM.41,43,44 Associated neoplasms include non-Hodgkin lymphoma and ovarian, lung, pancreatic, stomach, and colorectal cancers.10,42 The association of DM and thyroid gland malignancy is rare, and only four cases have been reported.41,45–47 AITD is more common in patients with DM or PM.8,42,48–50 GD and HT are 69- and 37-fold more prevalent in this population, respectively.8 Also, DM/PM developed in twice as many people with AITD compared to a normal population.8 Juvenile dermatomyositis (JDM) is similar to DM in adults; however, there is no associated increased risk of malignancy, and calcinosis cutis is more common. The association of JDM and thyroid disease is rare, with only a single existing case report of AITD and chronic thyroiditis.51

Mixed Connective Tissue Disease Mixed connective tissue disease was first reported in 1972 and described a group of patients with overlapping features of SSc, SLE, and PM. The disease is characterized by the presence of autoimmune antibodies to the U1 ribonuclear protein component of the spliceosome (U1RNP). There is controversy about whether MCTD is a distinct clinical entity, and the term “undifferentiated connective tissue disease” has been suggested. Also, the disease was originally reported as having a benign course; however, subsequent publications have highlighted the risks of renal crises, pulmonary hypertension, and central nervous system involvement. The clinical features include Raynaud disease, sclerodactyly, arthritis, PM, and interstitial lung disease. Anemia, leukopenia, hypergammaglobulinemia, and lymphadenopathy can also occur.52,53 The course of disease tends to evolve toward signs and symptoms of either SLE or SSc. Treatment includes supportive measures, oral corticosteroids, antimalarials,

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and immunosuppressants such as methotrexate and cyclophosphamide.54 Autoimmune thyroid disease in patients with MCTD has been reported several times in adults and once in a pediatric patient.8,55–58 A cohort study found a 556-fold and 76-fold higher prevalence of HT and GD, respectively.8 Also, patients with HT and GD are at a higher risk of developing symptoms of MCTD. Twenty percent of patients with HT and 2% of those with GD were also diagnosed with MCTD.8

Rheumatoid Arthritis Rheumatoid arthritis is a systemic autoinflammatory disease that most prominently causes inflammation and destruction of the joint synovial tissue. The prevalence is about 1% and is two to three times more common in women. The peak age of onset ranges from 40–60 years old. The etiology of RA is not completely understood and is currently believed to be triggered by an unidentified antigen in a genetically predisposed host. The resultant inflammation can cause mild joint swelling and discomfort or severe destruction of the joints with extensive extraarticular inflammation of the skin, lungs, exocrine glands, heart, and kidney.

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Extraarticular disease is a marker of disease severity and is more common in those with severe involvement and hence poorer prognosis. Examples of cutaneous manifestations include Raynaud phenomenon, rheumatoid nodules (Figure 13.5), rheumatoid vasculitis, and rheumatoid neutrophilic dermatosis. Raynaud phenomenon is a reversible vasospastic event in response to cold or stress in the fingers that causes blanching, cyanosis, paresthesias, and in severe cases, necrosis of the fingerpads. Rheumatoid nodules are the most common extraarticular manifestation of RA. They are typically found on the extensor surface of joints, including the olecranon process, dorsal hands, and proximal ulna. The nodules are subcutaneous skincolored nodules that vary from firm and rubbery to soft and amorphous. Rheumatoid vasculitis manifests as erythematous papules and plaques with palpable purpura, ulcers, or gangrene. Rheumatoid neutrophilic dermatosis was described in 1978 by Ackerman as symmetric erythematous nodules and plaques. The pathogenesis of this entity is uncertain, but immune-complex deposition may play a role.10,59,60 Rheumatoid factor consists of autoantibodies directed at the Fc region of immunoglobulin IgG and is usually of the IgM isotype. RF is detectable

Figure 13.5. Subcutaneous nodules on the fingers and wrists, as well as ulnar deviation, in a patient with rheumatoid arthritis

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in up to 10% of normal individuals, 70%–80% of patients with RA, in those with other CTDs, and in many systemic infections. Additional autoantibodies found in RA include those directed against the citrullinated antigens, including antiperinuclear factor (APF), antikeratin antibody (AKA), and anticyclic citrullinated peptide (CCP) antibodies. These antigens are an overlapping group that share citrullination of arginine residues. In addition, antibodies to type II collagen (CII) are of interest given the content of CII in articular collagen. Antibodies to CII may be predictive of a more severe outcome; however, the use of this test is limited since it is also found in about 40% of normal individuals. Many RA patients do not develop an immune response to CII. Data on sensitivity and specificity are known for the better-characterized antibodies found in RA. The group of antibodies exemplified by anti-CCP testing shows a remarkable specificity for RA of greater than 95% and a sensitivity of 50%–80% that is comparable to RF testing. Antibody testing is used for diagnosing RA; in addition, there has been considerable interest in the ability of antibodies to predict disease phenotype or severity. More severe radiologic outcomes have been linked to RA patients with antiferritin and anti-interleukin-1α antibodies. Milder disease is associated with the presence of antibodies to human cartilage glycoprotein 39 and CII.61 Autoimmune thyroid disease is more common in patients with RA than in the general population.8,62 GD is 50-fold and HT is 160-fold more common in this population. The prevalence of AITD in RA patients is approximately 1%–10%. Pritchard et al. reported a possible shared pathogenetic mechanism in GD and RA involving autoantibodies activating the insulin-like growth factor receptor 1 (IGF1-R) on fibroblasts, which actives the cells to produce proinflammatory cytokines.63

Autoimmune Blistering Disease Bullous diseases are a group of cutaneous disorders that are classified according to the production of fluid-filled vesicles (< 5 mm) or bullae (> 5 mm). The etiologies of bullous diseases are diverse and include autoimmune, genetic, traumatic, allergic, metabolic, and infectious disorders. Autoimmune bullous diseases are defined by the antigen which

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correlates with the microscopic site of the blister. This separation can be subcorneal, suprabasilar, or subepidermal. Pemphigus foliaceus (PF) is distinguished from pemphigus vulgaris (PV) by subcorneal versus suprabasilar acantholysis, respectively. Bullous pemphigoid (BP), pemphigoid gestationis (PG), and dermatitis herpetiformis (DH) are characterized by subepidermal blister formation.10,64 The primary site of separation determines the clinical appearance of the autoimmune bullous disease. PF rarely presents with intact vesicles or bullae because the level of cleavage is so superficial in the epidermis that the bullae are quickly disrupted. This results in very shallow erosions that are sometimes not recognized as having once been bullae. The split in PV is deeper in the epidermis, just above the basal layer. This leaves a much more substantial roof of keratinocytes above the fluid in the bulla. Thus, intact bullae are seen in PV and are often described as being flaccid.64–66 The bullae in BP and PG are the most likely to be intact on examination and are tense compared to those in PV. In spite of this, the bullae in BP and PG are not always seen, and often healing erosions are the only sign of disease. Vesicles are rarely seen in DH due to disruption by scratching due to the intense pruritus associated with the rash.10,64 Blisters occur secondary to autoantibodies binding to specific proteins in the skin and the attendant inflammatory response. The antibodies in PF, PV, BP, and HG are directed at different antigens but are all of the IgG isotype.10,65 Other autoimmune blistering diseases are caused by different immunoglobulin subtypes. For example, DH is caused by autoantibodies of the IgA isotype.67 Diagnosis is confirmed by analysis of skin biopsies as well as blood testing. A biopsy of a blister is done for routine hematoxylin and eosin staining to identify the level of acantholysis. A second biopsy of normal skin near a blister is sent for direct immunofluorescence (DIF). DIF can identify the deposition of immunoglobulin in or beneath the epidermis. Blood can be sent for indirect immunofluorescence (IIF) or for enzyme-linked immunosorbent assay (ELISA) to identify circulating autoantibodies to proteins.10,64,66,67 Prior to the development of corticosteroids, many patients with these diseases died due to fluid and electrolyte abnormalities or secondary infection because of the loss of the skin’s barrier function.

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Today, treatment is effective and is based on the severity of disease. Topical and oral corticosteroids, tetracycline antibiotics, dapsone, as well as immunosuppressants such as mycophenolate mofetil, azathioprine, and cyclophosphamide are utilized. In particularly difficult cases, IVIG, plasmapheresis, and rituximab have been used.10,64,66

Bullous Pemphigoid and Pemphigoid Gestationis Bullous pemphigoid and PG are both autoimmune bullous diseases that are characterized by a subepidermal bulla formation that tends to spare the mucosal surfaces. The lesions tend to be pruritic and can present urticarial papules and plaques or tense bullae and circular erosions (Figure 13.6). In occasional cases, pruritus without a rash is the first finding. BP tends to occur in patients over the age of 60 years, whereas PG occurs in women of child-bearing age. The clinical lesions are identical, but the distribution is different. Lesions of BP are often generalized but have an affinity for the lower abdomen, inner thighs, groin, axillae, neck, and flexural aspects of the extremities. PG tends to present during the second trimester of pregnancy. Bullae in PG start on the abdomen and spread to the trunk and extremities. The course of the pregnancy tends to be unaffected and only rarely is the newborn affected with skin lesions that arise due to transplacental transmission of the pathogenic antibody. BP and PG share some clinical and histologic findings because the autoantibodies in both target the same epidermal antigen.10,72 On DIF, BP tends

Figure 13.6. Several tense, intact bullae and many erosions due to bullous pemphigoid

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to have more obvious deposition of autoantibodies on DIF testing; the deposition of complement is prominent in PG.10,68 BP and PG have been found to associate with other organ-specific autoimmune diseases such as psoriasis, primary biliary cirrhosis, RA, and APS.69–75 AITD is reported more often in association with PG than with BP.69,70,72 This may be due to the association of human leukocyte antigens (HLA)-B8, DR3, and DR4 with both PG and AITD, particularly GD.70,72 GD has been reported with PG in more than a dozen cases, but only twice in BP. HT has been reported in fewer than half a dozen cases of BP and PG.69–76

Pemphigus Vulgaris and Pemphigus Foliaceus Both PV and PF are rare, autoimmune blistering diseases of the skin caused by autoantibodies that disrupt the adhesion of keratinocytes to each other. The annual incidence is one to five cases per million per year, and onset is in the third to fifth decades of life. Both PV and PF are caused by IgG antibodies to transmembrane proteins, called desmogleins, which secure neighboring keratinocytes to each other. There are multiple types of desmogleins, and they are distributed in specific patterns in the epidermis. Desmoglein 1 (dsg1) is the autoantigen targeted in PF; it is found predominantly in the superficial layers of the cornified (not mucosal) epidermis, which corresponds to the superficial vesicles seen clinically and histologically. The autoantigen for PV is desmoglein 3 (dsg3). Dsg3 is distributed in the deeper layers of the cornified and mucosal epidermis, corresponding to the increased frequency of intact bullae on the skin and mucosal erosions. As discussed, biopsy, DIF, IIF, and ELISA can be used to diagnose these diseases.10,64–66 The primary lesions of PF and PV are vesicles and bullae. Intact vesicles or bullae are rarely seen in PF due to the extremely superficial location of the split in the epidermis. Patients with PF have erythematous crusted or scaling erosions predominantly on the head, neck, and upper trunk. Mucosal erosions in PF are uncommon. In contrast, patients with PV may develop painful mucosal erosions prior to the development of cutaneous disease (Figure 13.7). The vesicles and bullae in PV are flaccid and easily unroofed, leaving painful erosions.

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Figure 13.7. Many oral erosions on the underside of the tongue in a patient with pemphigus vulgaris

The lesions favor the trunk and extremities but also occur on the head and neck.10,64–66 It is generally accepted that patients with PF and PV develop AITD at a rate higher than the unaffected population; however, large cohort studies have not been reported.69,77–82 One study was done on 15 PV and 15 healthy control patients, demonstrating an overall rate of primary thyroid disorders in 7 (46.6%) PV patients and 1 (6.7%) control patient. Positive titers of TPO antibody were observed in 6 patients with PV and in 1 volunteer.82 In addition, roughly half a dozen case reports have described the association of PF and thyroid disease, including AITD.79,83 There have been single case reports of GD occurring in both PF and PV with juvenile onset.84,85

Dermatitis Herpetiformis Dermatitis herpetiformis is an autoimmune blistering disease of the skin that has an intimate relationship with celiac disease (CD), an autoimmune disease of the small intestine. Both diseases are believed to be caused by autoantibodies to transglutaminase enzymes found in the skin and gut. Transglutaminase 3 (TG3) has been shown to be the target autoantigen in the epidermis responsible for DH, while tissue transglutaminase (TG2) is the intestinal autoantigen. In both DH and CD, the autoantibodies are predominantly of the IgA subtype, and it is postulated that the IgA antibodies can cross-react to both TG2 in the gut and TG3 in the skin. This would explain the frequent cooc-

currence of DH and CD. Most patients with DH will not have symptoms of CD, such as cramping, bloating, diarrhea, or weight loss. However, 80% will have partial or complete villus atrophy consistent with CD on small bowel biopsy. Patients with DH are more likely to have first-degree family members with DH or CD, possibly due to HLA grouping within families.10,67 Dermatitis herpetiformis is intensely pruritic, and this is one of the clinical clues to the diagnosis. The lesions begin as individual erythematous vesicles or pustules; however, frequently only erosions are left after vigorous scratching by the itchy patient. The individual lesions are often grouped or clustered in a pattern reminiscent of herpes simplex, hence the name herpetiformis. The pruritic eruption is bilaterally symmetric and occurs mainly on the extensor surfaces of the arms (Figure 13.8) and legs, as well as the neck, back, and buttocks. The age of onset is most commonly in the second through fourth decades of life; however, pediatric cases as well as cases later in life have been reported.67 The differential diagnosis includes scabies, eczema, urticaria, other autoimmune bullous diseases, and prurigo nodules or other neurodermatitides, such as delusions of parasitosis. The diagnosis of DH is made considering the clinical history, physical examination, and laboratory testing. Testing often includes cutaneous biopsy of a new lesion and DIF done on perilesional skin. Additional testing that can be done includes IIF using the patient’s blood67 and serologic tests for circulating IgA autoantibody

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Figure 13.8. Pink, excoriated papules with few intact vesicles on the extensor arms of a patient with dermatitis herpetiformis

to TG2 or endomysium. Testing to for antibody to TG2 can identify patients with CD and is often positive in those cases with complete villous atrophy. However, patients with DH and occult CD can have negative TG2 serology if only partial villus atrophy is present. The endomysial autoantibody (EMA) is a more reliable serologic test and is positive in patients with partial villous atrophy.67 First-line treatment is with dapsone. Patients often have relief of their intense pruritus on the first day of treatment. The exact mechanism of action of dapsone is unknown, but it is believed to inhibit neutrophils, which are the predominant leukocyte found in the lesional skin of DH patients. Other treatments include sulfapyridine, corticosteroids, and cyclosporine.10,67 Patients should also be encouraged to start a gluten-free diet (GFD). Diet alone can treat DH and results in a slow resolution of the pruritus and rash over several months. Adding a GFD to dapsone therapy will often allow for control of the disease with minimal doses or discontinuation of the dapsone. Adopting a GFD is time-and-effort intensive, but an increasing number of resources are available, including support groups, national organizations, gluten-

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free cookbooks, and mail-order gluten-free foods. Foods containing gluten that must be removed from the diet include wheat, barley, malt, rye, oats, buckwheat, bulgur, matzo meal, millet, spelt, and other less-common grains. Both DH and CD have an increased prevalence of coexisting autoimmune diseases, such as AITD, insulin-dependent diabetes mellitus, and CTDs.69,86–90 Reunala and Collin studied over 600 patients with either DH or CD and compiled information on the cooccurrence of these diseases with AITD as well as CTD. They found that approximately 19% of patients with DH or CD, respectively, had an autoimmune endocrine disease or CTD. The prevalence of AITD in DH was 4% in this study.88 Several additional studies have investigated the prevalence of thyroid abnormalities in DH. Abnormal thyroid function tests have been found in 4%–28% of patients.69,86,87,89,90 Also, autothyroid antibodies (ATAs) occurred in 18%– 48% of DH patients.69,86,87,89,90 Hypothyroidism is slightly favored over hyperthyroidism. Although there are few studies on the association of CD and thyroid disease, two small series reported a prevalence of AITD in 6%–14% of their CD patients.88,91

Disorders of Pigmentation Melasma Melasma is a pigmentary disorder of the face, primarily the forehead, cheeks, and jaw. It was also known as chloasma, which specifically refers to its appearance with pregnancy or changes in ovarian hormones. The etiology of melasma is unknown but is known to be associated with elevation of female hormones, chronic sun exposure, darker skin types, and genetic predisposition. It presents as symmetric, irregularly shaped, tan-brown patches of hyperpigmentation on the forehead, cheeks, and jaw. Few studies have looked at the coexistence of melasma and AITD.92,93 One study showed that women with melasma were four times more likely to have thyroid autoantibodies compared to an unaffected population. The same population of women with melasma had a sixfold risk of AITD.92 Melasma is treated with multiple topical medications, including bleaching creams such

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as hydroquinone, corticosteroids, and retinoids. Patients are often treated with combination therapy rather than monotherapy. Sun protection and sunscreen application should accompany any treatment modality. Alternative treatments include chemical peels, laser treatment, and dermabrasion.94

Vitiligo Vitiligo is characterized by the loss of pigment in the skin, mucous membranes, and sometimes hair follicles. Vitiligo causes total loss of pigmentation, resulting in porcelain-white skin. This is in contrast to hypopigmented skin, which retains some pigment so is lighter than the surrounding skin but not completely depigmented. In vitiligo, patches of depigmented skin are seen periorificially, such as around the eyes, nose, mouth, and genitals. The Koebner phenomenon occurs in vitiligo, so areas of acute or chronic trauma, such as the fingers (Figure 13.9), knuckles, elbows, knees, and feet are also commonly affected. The most common form of vitiligo is the generalized form with bilaterally symmetric depigmented patches in some or all of the sites listed. There are also localized, segmental, and universal forms of vitiligo with focal, dermatomal or linear, and whole-body loss of pigment, respectively. The depigmented patches in vitiligo occur because of the loss of the melanocytes. There are several theories that attempt to explain the loss of melanocytes; these include autoimmune attack

Figure 13.9. Patches of depigmentation on the hands of a patient with vitiligo

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and metabolic or neural dysfunction.95 The most accepted and supported is the autoimmune hypothesis. Studies have shown the children, siblings, and parents of people with vitiligo are more likely to be affected; this is likely due to HLA clustering.95 Vitiligo affects 1%–2% of the world’s population, and onset is generally in the second to third decades. It is associated with significant psychosocial stress. Patients with vitiligo have problems with anxiety, embarrassment, and difficulty with intimate relationships.96 Treatments are available, but none have demonstrated a consistent ability to produce long-term repigmentation. Therapeutic options include topical corticosteroids, topical calcineurin inhibitors (pimecrolimus, tacrolimus), phototherapy using ultraviolet A (UVA) light with topical or oral administration of psoralen (PUVA), as well as narrowband ultraviolet B light (NB-UVB) to the whole body or locally using a laser.97 Surgical techniques are also used.98 The associations of autoimmune diseases such as pernicious anemia and alopecia areata with vitiligo lend strength to the autoimmune basis of vitiligo.10,95,99 AITD is also associated with vitiligo.10,93,95,99–102 It usually follows the onset of vitiligo in both adult and pediatric populations. This often allows for screening of AITD prior to the development of symptoms. AITD is approximately three times more prevalent in adults with vitiligo than in the general population.93 There is conflicting data on whether hypothyroidism or

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hyperthyroidism is favored. In the pediatric population, there have been conflicting studies regarding the association of vitiligo and AITD. However, most large case series or case-control studies have shown an increased prevalence of AITD, predominantly producing hypothyroidism, in children with vitiligo.103,104 The prevalence of ATAs in children with vitiligo ranged from 12% to 24% versus 0% to 9% in control populations.103,104 In children with vitiligo and ATA, AITD was 10 times more likely to develop versus children with positive ATA and without vitiligo.102–104 Segmental disease has not demonstrated any increased prevalence of ATA or AITD.103

Drug Effects on the Skin and Thyroid Medications given for dermatologic disease or other medical conditions can induce abnormalities of the thyroid gland. The mechanism of the effect on the thyroid may be due to upstream influence on thyroid-stimuating hormone (TSH) at the pituitary or directly on the thyroid gland. Elevated levels of iodine in the blood can trigger reductions in thyroid hormone production, also known as the Wolff-Chaikoff effect (WCE). The WCE is not completely understood and may be due to the adaptive response of the thyroid to increased levels of iodine. The thyroid gland operates under a negative-feedback loop; the hypothalamus secretes TSH-releasing hormone (TRH), which acts on the pituitary to release TSH, triggering the thyroid to release thyroid hormones. The thyroid autoregulates the level of iodine within itself to maintain an adequate level for the production of thyroid hormone. Elevated levels of iodine influence both the negative-feedback loop and the autoregulatory loop of the thyroid. Failure to compensate or overcompensation can result in hypothyroidism or hyperthyroidism, respectively.105,106 The WCE can occur with the use of potassium iodide (KI) or amiodarone, a cardiovascular medication that also has pigmentary effects on the skin.107 Bexarotene, a compound similar to other vitamin A derivatives, is used to treat CTCL and has central effects on the pituitary, causing hypothyroidism.108

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Potassium Iodide Potassium iodide is used to treat both inflammatory and infectious diseases. The neutrophilic dermatoses, including erythema nodosum, Sweet syndrome, and pyoderma gangrenosum, can be treated with KI. Infectious diseases such as sporotrichosis, human pythiosis, cutaneous cryptococcosis, and other fungal infections have also been successfully treated with preparations of KI.105,106 Potassium iodide is administered as a powder or as a saturated solution (SSKI). The mechanism of action is unknown. The WCE can occur, and some people may develop persistent hypo- or hyperthyroidism.106 Other side effects of therapy with KI include diarrhea, nausea, and vomiting. Patients treated chronically with KI may develop systemic toxicity from either the iodide molecule, also termed iodism, or the potassium component.109 Potassium iodide has also been reported to trigger or exacerbate DH and BP. Acute iododerma may occur and produce an acneiform eruption or crusted nodules (Figure 13.10) that mimic deep fungal infection.10,110

Amiodarone Amiodarone is an antiarrhythmic drug used to treat and prevent cardiac arrhythmias. It is metabolized by the liver via the cytochrome P-450 enzymes. It inhibits the P-450 enzymes; thus, it has many potential drug interactions. Medication side effects can occur in multiple organ systems due to either the deposition of the medication or the iodide

Figure 13.10. Erythematous plaque with peripheral pustules and crusting due to excessive iodine ingestion

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content. Effects on the thyroid and skin are of special interest. The main cutaneous toxicities of amiodarone include a drug exanthem, photosensitivity, and hyperpigmentation. The drug exanthem is pruritic and erythematous and located predominantly on the trunk. It usually occurs within the first few weeks of treatment. Photosensitivity is more common and has been reported to occur in 5%–20% of patients taking the medication. Hyperpigmentation in sun-exposed areas occurs in 1%–7% of patients on amiodarone (Figure 13.11). The discoloration is purple or blue-gray and is believed to be more common in patients with previous episodes of the photosensitivity. Daily doses above 800 mg and long duration of use predispose to this side effect. Pigmentation can be reversible on discontinuation but takes months to years to fade.111,112 The effects of amiodarone on the thyroid include the WCE, hypothyroidism, and hyperthyroidism. The amiodarone molecule contains two iodine atoms and has structural similarity to the thyroid hormones triiodothyronine (T3) and thyroxine (T4). A patient taking a 200-mg daily dose of amiodarone absorbs about 6 mg of free iodine, which is 20–40 times the daily recommended dose. Elevated levels of iodine at the thyroid result in the WCE or decreased production of T3 and increased levels of T4, TSH, and free T4.106 Although thyroid hormone levels are abnormal, most patients are considered euthyroid because the T3 level is low normal. After a few months of therapy, a steady state is reached, and hormone levels may approach normal, termed escape from the WCE. Some patients will not adapt to elevated serum iodine levels and may develop

Figure 13.11. Blue-grey hyperpigmentation in a photodistribution on the face due to amiodarone

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amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT). The mechanism is unknown but may be related to baseline iodide insufficiency of the diet or presence of occult AITD.106,113–115 Laboratory testing prior to starting amiodarone is not indicated unless there are signs or symptoms of thyroid disease. If signs or symptoms of thyroid disease develop while on amiodarone, thyroid function studies including T3, free T4, T4, TSH, and antithyroid antibodies should be obtained. Amiodaroneinduced hypothyroidism would result in reduced T3, free T4, and T4, with elevated TSH. Antithyroid antibody may be positive in people with HT, which can be uncovered by AIH. In contrast, AIT causes elevated T4 and free T4, normal or high T3, and low TSH. Antimicrosomal antibodies can be seen in people predisposed to develop GD.112–115 The half-life of amiodarone is approximately 100 days, mainly due to its slow release from storage in fatty tissues. Therefore, side effects from the drug can continue for some time, even after discontinuation.112 This is especially true if the person also has thyroid autoantibodies and develops persistent AITD.

Bexarotene Bexarotene is a rexinoid or retinoid X receptor (RXR) agonist. It is approved for treatment of refractory CTCL. The mechanism of action of the RXR on CTCL is unclear. The use of retinoids and rexinoids for the prevention and treatment of solid cancers is being studied in both clinical and experimental settings.116,117 The most common side effects of bexarotene are hypertriglyceridemia and hypothyroidism.118–120 Hypertriglyceridemia and hypothyroidism occurred in 79% and 40%, respectively, of CTCL patients treated in a clinical trial. The effects are dose dependent, with 28.6% and 52.6% developing hypothyroidism while on bexarotene for CTCL at 300 mg m−2 and >300 mg m−2 daily, respectively.118 The side effects are reversible with drug cessation. The symptoms of hypothyroidism in those taking bexarotene were subtle and included fatigue, depression, cold intolerance, and constipation. The mechanism of hypothyroidism associated with bexarotene is unclear. Studies in rats have

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shown decreased levels of serum TSH soon after administration of an RXR agonist. The drop in TSH levels was due to decreased synthesis of TSH messenger RNA and therefore decreased release of TSH from the pituitary.119 Levels of T4 and T3 were slower to decline. Therefore, hypothyroidism is monitored using free T4 levels, not TSH level, which will be depressed due to bexarotene therapy. A physician unaware of this mechanism and following only TSH levels may erroneously diagnosis hyperthyroidism and decrease or discontinue T4 supplementation. Expert opinion suggests screening for baseline abnormalities in fasting lipids and thyroid function, including TSH, free T4, T4, and T3 prior to starting bexarotene. If there are symptoms of thyroid disease or a family history of AITD, then antithyroid and antimicrosomal antibody studies should be performed. Pretreatment with statins or fibrates for hypertriglyceridemia and T4 for hypothyroidism prior to initiation of bexarotene has also been suggested since these conditions may be slow to respond to therapy. Expert opinion suggests monitoring thyroid function tests monthly when the dose is adjusted and every 3 months when dose is stable.121

Drug Hypersensitivity Syndrome and Hypothyroidism Drug hypersensitivity syndrome (DHS) is a rare, potentially adverse event that can occur due to a number of medications. The most common drugs associated with this syndrome include anticonvulsants, sulfonamide antibiotics, dapsone, allopurinol, and NSAIDs. DHS typically begins 4–6 weeks after starting medication. The symptoms of DHS begin as a mononucleosis-like illness with fever, fatigue, an exanthematous rash (Figure 13.12), and lymphadenopathy. In addition, systemic involvement in DHS may include hepatitis, nephritis, and bone marrow suppression with cytopenias, atypical lymphocytes, and eosinophilia. The mechanism of DHS is not well understood but is believed to be due to abnormalities in drug metabolism and detoxification.10,122–124 Treatment begins with cessation of the responsible medication; supportive measures only are often sufficient. If there is imminent or current end-organ damage, then systemic corticosteroids are started. Hypothyroidism

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Figure 13.12. Follicular accentuation and diffuse erythema on the chest of a black patient with drug hypersensitivity syndrome

has been reported to occur soon after or may be delayed by 3 or more months after an episode of DHS. These patients have low levels of T4 and elevated levels of TSH and thyroid autoantibodies, including antimicrosomal antibody.122,124 Patients should be screened for thyroid dysfunction if symptoms consistent with thyroid disease develop. Gupta et al. demonstrated that the hydroxylamine metabolite of sulfamethoxasole was toxic to thyroid cells in vitro. This may explain the development of hypothyroidism in patients unable to detoxify certain drugs.122

Other Autoimmune and Miscellaneous Disorders Addison Disease Addison disease is autoimmune adrenalitis and is distinguished from damage to the pituitary or hypothalamus that is responsible for secondary or tertiary reductions in adrenal steroid production. The most common cutaneous sign of primary adrenalitis is hyperpigmentation. The hyperpigmentation most commonly presents as a generalized, uniform, tan-brown discoloration of the skin. Hyperpigmentation may be more prominent is areas exposed to light or chronic pressure as well as the creases of the palms.125 The association of Addison disease and AITD can occur with additional organ-specific autoimmune diseases such as diabetes mellitus and pernicious ane-

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mia. This constellation is also known as APS.3 The cooccurrence of only Addison disease and AITD is known as APS type II or Schmidt syndrome, after the physician who described it in 1926. The triad of type 1 diabetes mellitus, AITD, and Addison disease is also a well-described constellation, known as Carpenter syndrome.3,126 The prevalence of type II APS is about 1.4–4.5 per 100,000 people.3 Two large case series3,127 of type II APS patients showed that all had Addison disease, and AITD was diagnosed in 69% and 89%, respectively. The types of AITD diagnosed included HT, symptomless autoimmune disease, GD, and isolated ophthalmopathy or myxedema. In one series, HT occurred twice as frequently as GD, 56% versus 21%, respectively.3,126

Nail Changes Both hyperthyroid and hypothyroid disease states can manifest as nail changes.128–132 Nail alterations can involve a few nails or all 20 nails of the hands and feet. Nail changes include onycholysis (separation of the distal nail plate from the nail bed), concavity, fragility, slow growth, longitudinal ridging, or thickening. The combination of concavity and distal onycholysis is known as Plummer’s nails and is found in about 5% of hyperthyroid patients.128–132 The prevalence of nail changes in hypothyroidism is not known. Yellow nail syndrome has also been reported to occur in thyroid disease.133 Yellow nail syndrome is the constellation of slowly growing, hyperconvex, yellow-to-green discolored nails, with absent lunulae and cuticles that usually affects all the nails (Figure 13.13). The mechanism of nail changes in thyroid disease may be due to the effect of thyroid hormone on cell metabolism and mitosis.134 In most cases, nail alteration is completely reversible after adequate treatment of the underlying thyroid disorder. Onycholysis is not specific to thyroid disease. The differential diagnosis includes psoriasis, Reiter syndrome, onychomycosis or fungal infection, eczema involving the fingertips, drug effect, and trauma.

Palmoplantar Pustulosis Palmoplantar pustulosis (PPP) is as its name describes, a dermatosis of the palms and soles. It

Figure 13.13. Thick, yellow-green nails without cuticles due to yellow nail syndrome

manifests as sterile pustules most commonly on the thenar and hypothenar eminences of the palms and on the arch and lateral aspects of the foot. The pustules recur in crops and are accompanied by erythema and scaling. Adults in the fifth and sixth decades are most commonly affected. The cause is unknown.135 In a handful of case series, the prevalence of thyroid disorders, including AITD, has been reported to be elevated in comparison to a normal population. The prevalence of abnormal thyroid testing varies from 18% to 50%. Antithyroid autoantibodies are less common and have been found in 14%–25% of patients with PPP. HT was much more common than GD in the same populations.136–139

Acquired Palmoplantar Keratoderma Palmoplantar keratoderma (PPK) is the finding of thickened skin on the palms and soles (Figure 13.14). The thickened skin may develop a scaly surface or be smooth and yellow. PPK can be a sign of inherited syndromes, which typically present at birth or in childhood and have additional signs that identify them. An acquired form has its onset in adulthood and will often have associated cutaneous

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Acquired Ichthyosis

Figure 13.14. Thick, tough skin on the soles typical of a palmoplantar keratoderma

and systemic signs of the underlying etiology. The differential for acquired PPK includes pityriasis rubra pilaris, lichen planus, psoriasis, keratoderma blenorrhagicum, and syphilis. It may also occur as a paraneoplastic condition, for example, as a sign of bronchogenic carcinoma.10 Acquired PPK has been reported to occur secondary to hypothyroidism.140,141 Six cases have been reported in the literature.140,141 A review of five of the cases by Miller et al. reported the patients were middle-aged to elderly with verrucous thickening involving the soles more extensively than the palms. A common and striking feature was the lack of response to topical corticosteroids but a total response to thyroid hormone replacement. Most people had resolution of their findings in a few weeks to months after hormone replacement. The cause of PPK in hypothyroidism is unknown and in one case was not related to intercellular stratum corneum lipid content, which can be deranged in other disorders presenting with hyperkeratosis.140

The ichthyoses are a group of congenital and acquired disorders characterized by the accumulation of visible scales on the skin. The term is derived from ichthys, the Greek word for “fish.” Congenital ichthyoses are genetic and commonly consist of a constellation of findings involving the hair, skin, and nails. They may be recessive or dominant, somatic, or sex linked. Acquired ichthyoses have their onset in adulthood and have variable involvement of the hair and nails. A person with an ichthyosis will have scaling predominantly on the trunk and extensor surfaces of the limbs, with the lower extremities more severely affected (Figure 13.15). The differential diagnosis includes the genetic ichthyoses and severely dry skin from any cause. The latter condition tends to be worse in the winter and appears as a fine, thin scaling, usually over the lower legs, sometimes with fine, shallow fissures between the scales.10 Acquired ichthyoses can be associated with malignant or nonmalignant processes. The malignancies associated with acquired ichthyosis include Hodgkin and non-Hodgkin lymphomas, CTCL, myeloma, and carcinomas of the breast, cervix, and lung. Other diseases associated with acquired ichthyosis are hypothyroidism, sarcoidosis, leprosy (Hansen disease), nutritional deficiencies, chronic renal failure, and SLE.142,143 The association of hypothyroidism and acquired ichthyosis may be due to the role of thyroid hormone in fatty acid metabolism and sterol production in the skin. Fatty acids and cholesterol metabolites are very important in the structure and function of normal skin. This is supported by reports of improvement of the ichthyosis with thyroid hormone replacement and recurrence with cessation of T4 administration.144,145 Treatment is dependent on identification and management of the underlying cause. Emollients with or without urea or lactic acid can be use for symptomatic relief. Signs of secondary infection with bacteria should be diagnosed and treated appropriately. Ichthyosis due to hypothyroidism should improve with thyroid hormone replacement in a few weeks.

Lichen Sclerosis et Atrophicus Lichen sclerosus et atrophicus (LSA) is a chronic skin disease that may affect any cutaneous surface

13. Dermatologic Disorders Associated with Thyroid Disease

but commonly occurs in the anogenital area. It is found all ages, from infancy to the geriatric population, but is most common in postmenopausal women. Lesions of LSA are light pink- to whitecolored, well-defined, symmetric papules, patches, or plaques. The surface generally appears atrophic, brittle, finely wrinkled, or shiny; however, some lesions are hyperkeratotic and rough. The Koebner phenomenon can occur in LSA. The most common symptom is pruritus, although some patients complain of a burning sensation. Complications of LSA include erosions and ulcers, with scarring, adhesions, or strictures potentially occurring in long-standing lesions. Squamous cell carcinoma can also arise within chronic areas of LSA.10,146 The mainstays of treatment include topical corticosteroids, with or without occlusion; intralesional corticosteroids; and topical calcineurin inhibitors. Other reported treatments include topical calcipotriol, topical and oral retinoids, systemic and topical sex hormones, photodynamic therapy, PUVA, and pulsed dye laser (PDL).147,148 Two large series have investigated the association of LSA and autoimmune disease. They showed that 22%–34% of women with LSA had autoimmune diseases, such as alopecia areata, vitiligo (Figure 13.16), and thyroid disease. In both studies, the prevalence of AITD was 12%. The prevalence of GD was 6%–8%, and HT was diagnosed in 4%–6% of LSA patients. Patients with LSA also had a high prevalence of autoantibodies (antithyroid, antinuclear, antigastric parietal cell, among others), and commonly had a personal or family history of autoimmune disease (60%).149,151 Several smaller studies have investigated the association of LSA and

Figure 13.15. Dry, dark scaling reminiscent of “fish scale” in a patient with acquired ichthyosis

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Figure 13.16. Pale and erythematous patches on the vulva typical of lichen sclerosus et atrophicus (LSA) in association with depigmented patches typical of vitiligo

AITD. The prevalence of AITD ranged from 12% to 17%, although a higher percentage of patients, 28%–40%, were found to have positive thyroid antibodies without evidence of thyroid disease.152–155

Scleromyxedema Scleromyxedema is an idiopathic disease that causes fibrosis and thickening of the skin. These changes are due to increased numbers of fibroblasts in the dermis that overproduce collagen as well as glycosaminoglycans (GAGs). GAGs, also called mucin, bind high volumes of water and contribute to skin volume and rigidity.154 Patients with scleromyxedema develop individual or coalescent papules and plaques predominantly on the face, neck, upper trunk, forearms, and hands. The papules and plaques are waxy, flesh colored, erythematous, or hyperpigmented and can be either pruritic or asymptomatic. Scleromyxedema is chronic and progressive and results in diffuse symmetric induration of the skin, which can cause leonine facies (thickening of the brows, forehead, nose, and cheeks so the face resembles a lion’s) and can restrict movement of the facial muscles, fingers, and joints. Of patients with scleromyxedema, 80% have a paraprotein. Additional sites of extracutaneous involvement include the gastrointestinal tract, muscle, nervous system, and lungs. The most common visceral symptom is dysphagia and can be assessed using endoscopy, which usually shows esophageal dysmotility. Peripheral nervous system manifestations include carpal tunnel syndrome and peripheral

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neuropathy, while central nervous system findings include encephalopathy, coma, stroke, seizures, and psychosis. Additional extracutaneous manifestations can include myopathy and restrictive or obstructive lung disease.153,155–157 The differential diagnosis includes other mucinous deposition diseases such as pretibial myxedema, localized or systemic scleroderma, scleredema, and nephrogenic systemic fibrosis (NSF). Skin biopsy can be suggestive but may not be able to distinguish between NSF and scleromyxedema. Immunostaining for CD34 will be positive in fibroblasts in NSF but not in scleromyxedema. NSF patients do not have a paraprotein.154 Thyroid function testing is suggested as part of baseline laboratory studies because of the clinical similarity to pretibial myxedema. Thyroid function testing would also be important to distinguish the “dermato-neuro syndrome” of fever, seizures, and coma associated with scleromyxedema from thyrotoxicosis and pretibial myxedema. Treatment options include oral steroids, oral retinoids, ultraviolet light therapy (PUVA), thalidomide, IVIG, plasmapheresis, photopheresis, and chemotherapy with bone marrow transplantation. Decisions regarding treatment are made based on the extent of cutaneous disease and presence or absence of visceral involvement.154,157,158

Conclusion In conclusion, thyroid diseases may readily be associated with a variety of systemic or cutaneous diseases, many of which are of an autoimmune nature. Considering thyroid disease in the appropriate clinical circumstances may have significant implications for the patient.

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J.S. Kirby and W.D. James 135. Hellgren L, Mobacken H. Pustulosis palmaris et plantaris. Acta Derm Venereol 1971;51:284–288. 136. Eriksson M-O, Hagforsen E, Lundin IP, et al. Palmoplantar pustulosis: a clinical and immunohistological study. Br J Dermatol 1998; 138:390–398. 137. Gimenez-Garcia R, Sanchez-Ramon S, CuellarOlmenda LA. Palmoplantar pustulosis: a clinicoepidemiologic study. The relationship between tobacco use and thyroid function. J Eur Acad Dermatol Venereol 2003;16:276–279. 138. Rosen K, Lindstedt G, Mobacken H, et al. Thyroid function in patients with pustulosis palmoplantaris. J Am Acad Dermatol 1988; 19:1009–1016. 139. Rosen K, Mobacken H, Nilson L-A, et al. Increased prevalence of antithyroid antibodies and thyroid diseases in pustulosis palmoplantaris. Acta Derm Venereol 1981;61:237–240. 140. Miller JJ, Roling D, Spiers E, et al. Palmoplantar keratoderma associated with hypothyroidism. Br J Dermatol 1998;139:741–742. 141. Salduna MD, Fux C, Albertini R, et al. Acquired palmoplantar keratoderma with hypothyroidism. Medicina 2005;65:47–48. 142. Aram H. Acquired ichthyosis and related conditions. Int J Dermatol 1984;23:458–461. 143. Schwartz RA, Williams ML. Acquired ichthyosis: a marker for internal disease. Am Fam Physician 1984;29:181–184. 144. Brazzelli V, Prestinari F, Barbagallo T, et al. Acquired ichthyosis and hypertrichosis due to autoimmune thyroiditis: therapeutic response to thyroxine replacement. Pediatr Dermatol 2005;22:447–449. 145. Heymann WR. Cutaneous manifestations of thyroid disease. J Am Acad Dermatol 1992;26: 885–902. 146. Val I, Almeida G. An overview of lichen sclerosus. Clin Obstet Gynecol 2005;48:808–817. 147. Dalmau J, Baselga E, Roe E, et al. Psoralen-UVA treatment for generalized prepubertal extragenital lichen sclerosus et atrophicus. J Am Acad Dermatol 2006;55:S56–S58. 148. Neill SM, Tatnall FM, Cox NH. British Association of Dermatologists. Guidelines for the management of lichen sclerosus. Br J Dermatol 2002;147: 640–649. 149. Meyrick Thomas RH, Ridley CM, McGibbon DH, et al. Lichen sclerosus et atrophicus and autoimmunity—a study of 350 women. Br J Dermatol 1988;118:41–46. 150. Harrington CI, Dunsmore IR. An investigation into the incidence of autoimmune disorders in patients

13. Dermatologic Disorders Associated with Thyroid Disease with lichen sclerosus and atrophicus. Br J Dermatol 1981;104:563–566. 151. Goolamali EK, Barnes EW, Irvine WJ, et al. Organspecific antibodies in patients with lichen sclerosus. Br Med J. 1974;4:78–79. 152. Poskitt L, Wojnarowska F. Lichen sclerosus as a cutaneous manifestation of thyroid disease. J Am Acad Dermatol 1993;28:665. 153. Wright AJ. Lichen Sclerosus and thyroid disease. J Reprod Med 1998;43:240. 154. Berger JR, Dobbs MR, Terhune MH, et al. The neurologic complications of scleromyxedema. Medicine 2001;80:313–319.

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155. Maize J, Maize J Jr, Metcalf J. In: Edler DE, Elenitsas R, Johson BL Jr, Murphy GF, eds. Lever’s Histopathology of the Skin. 9th ed. Metabolic Diseases of the Skin. Philadelphia: Lippincott Williams and Wilkins; 2005:435–468. 156. Dinneen AM, Dicken CH. Scleromyxedema. J Am Acad Dermatol 1995;33:37–43. 157. Pomann JJ, Rudner EJ. Scleromyxedema revisited. Int J Dermatol 2003;42:31–35. 158. Webster GF, Matsuoka LY, Burchmore D. The association of potentially lethal neurological syndromes with scleromyxedema (papular mucinosis). J Am Acad Dermatol 1993;28:105–108.

14 Potential Therapeutic Uses of Thyroid Hormone Joshua D. Safer and Michael F. Holick

Editorial Perspective At the outset, I must admit my bias and conflict of interest on this topic as I have US Patent Number 5,951,989 for the use of topical thyroid hormone in treating xerosis. Regardless of that fact, it is clear that the therapeutic use of thyroid hormone has been considered a neglected stepchild compared to hormones of the same nuclear receptor subfamily: corticosteroids, retinoids, and vitamin D. Indeed, a PubMed search performed on Independence Day (July 4th) 2007 revealed 10,081 references for topical corticosteroids and only 69 for topical

Introduction The skin manifestations of thyroid hormone dysfunction are classic and have been described since the 1800s. The name myxedema, the original name for hypothyroidism, refers to the edema-like associated skin condition caused by increased glycosaminoglycan deposition in the skin. Paradoxically, the classic observation associating hypothyroidism with the skin1 pre-dated the classic publication associating hypothyroidism with the thyroid.2 Despite the early observations of the skin manifestations of thyroid disease, the thyroid hormone receptor is the least-studied member of its superfamily with regard to skin. Ligands of other members of the retinoid/thyroid/vitamin D nuclear receptor subfamily are used to treat cutaneous pathology.3,4

thyroid hormone. As explained in this chapter, thyroid hormone has profound effects on the skin and its appendages and has the potential to treat myriad conditions, including disorders of keratinization, alopecia, wound healing, xerosis, and chronic idiopathic urticaria. This subject was chosen for the concluding chapter of this text because I hope the reader will have already come to the realization that not only are thyroid–cutaneous interactions important in health and disease but also that further research in this discipline may foster novel concepts and therapies utilizing thyroid hormone to alleviate human suffering.

The lack of interest in cutaneous responses to thyroid hormone might be attributed to the fact that most thyroid disease is controlled with existing medication. However, data from several investigators suggest that the thyroid hormone pathway can be manipulated to treat cutaneous pathology. Starting in the 1950s, there were contradictory reports regarding attempts to use local parenteral and topical triiodothyronine (T3) to treat pretibial myxedema in Graves patients.5–8 In all cases, lesions improved with topical or intralesional steroids. At the same time, it was noted that topical thyroxine (T4) stimulated hair growth and pigmentation in cows.9 After the failed attempts to treat pretibial myxedema with local T3, the study of thyroid hormone for treating skin pathology lay dormant for years.

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Background Skin findings in thyrotoxicosis are classic and numerous. Indeed, most patients with thyrotoxicosis will suffer cutaneous manifestations. In a review of thyrotoxic presentations, hyperhidrosis (heat intolerance) was the second most common finding.10 Even in cases of thyrotoxicosis in elderly patients, in whom clinical findings are often masked, 40% of patients were noted to have “fine skin.”11 Although certain signs are specific to Graves disease, thyrotoxicosis of any etiology often includes skin sequelae. Thyroid hormone is essential for optimal epidermal cell proliferation.12–15 While the increased dermal hyaluronic acid deposition in hypothyroidism is documented,16,17 the literature regarding skin in thyrotoxic states is more sparse. In 1967, Fink et al. reported skin thinning in rats that were made thyrotoxic with intraperitoneal T4. They used proline14 C uptake as a surrogate for collagen production to demonstrate decreased collagen production in the thyrotoxic animals.18 Increased collagen catabolism in thyrotoxic rats has also been reported.18,19 Clinically, the thyrotoxic epidermis is found to be thin but not atrophic. However, most thyrotoxicosis results from Graves disease, which may include autoimmune-mediated glycosaminoglycan deposition and thickened dermis. At the molecular level, thyroid hormone can act directly on cutaneous tissues, mediating its effect through the thyroid hormone receptor (TR). The TR has been identified in both epidermis and dermis. Immunohistochemical localization and quantitative polymerase chain reaction (PCR) have demonstrated that all three thyroid hormonebinding TR isoforms are expressed in skin.13,20–22 TRs have been detected in a variety of cells: epidermal keratinocytes, skin fibroblasts, hair outer root sheath, dermal papilla, fibrous sheath of the hair follicle, arrector pili muscle cells, sebaceous glands, vascular endothelial cells, smooth muscle cells, and Schwann cells. The predominant circulating thyroid hormone is the prohormone T4. T4 is converted to the active thyroid hormone T3 by intracellular thyroid hormone deiodinases.23,24 Two of the enzymes (D1, D2) are responsible for activating T4 to T3 (Figure 14.1). The primary role of the third enzyme, D3, is to convert T4 to inactive reverse T3 (rT3). Previous

Figure 14.1. Thyroid hormone is metabolized intracellularly by three iodothyronine deiodinases (D1–D3). T4 (thyroxine, the primary product of the thyroid and the primary hormone circulating) serves as the prohormone, T3 (triiodothyronine, secreted by the thyroid and circulating to a lesser degree than T4) serves as the active hormone, and the remaining iodothyronines serve as inactive metabolites. R, CH2NH3COOH T3, reverse T3

investigators have shown conversion of T4 to either T3 or rT3 in skin cultures, thus demonstrating indirectly the presence of thyroid hormone deiodinases in skin.25–27 Although inactivating deiodinase (D3) is not expressed significantly in most peripheral tissues, assays of enzyme activity have suggested that D3 is active in goat epidermis28 and human skin in vivo.29, 30 Neither D1 nor D3 was found to be active in the dermal fibroblasts, suggesting that D3 expression may be limited to epidermis. D2 activity has been demonstrated in cultured human fibroblasts.31 A small number of thyroid hormone-responsive genes have been identified in skin, including the keratin genes, the “hairless” (hr) gene, and ZAKI4.32–37 The keratin genes encode the intermediate filaments, making up about 30% of the protein of the epidermis. T3 can exert direct control over specific keratin genes at the nuclear level through thyroid hormone response elements in their upstream promoters.32,33 Although T3 stimulates expression of proliferation-associated keratin genes both in vivo and in vitro,37 to date only negative thyroid hormone response elements have been identified for these genes.32 It is not known whether this reflects thyroid hormone induction of indirect keratin gene-stimulating pathways or the existence of unidentified positive thyroid hormone response elements for the keratin genes.

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Potential Use of Thyroid Hormone in the Treatment of Cutaneous Pathology Knowledge of cutaneous manifestations of thyrotoxicosis does not predict the direct effects of T3 on skin in vivo. T3 effects on skin depend on route of delivery. In contrast to the findings with systemic thyrotoxicosis noted, topical T3 stimulates epidermal proliferation, dermal thickening, and hair growth.14,38,39 Topical application of the thyroid hormone analog TRIAC (triiodothyroacetic acid) thickens skin by stimulating production of collagen. Further, topical TRIAC has been shown to reverse the dermal atrophy associated with corticosteroids.40,41 The direct effect of T3 is as a stimulator of skin cell proliferation. In tissue culture studies using surrogates for DNA expression, T3 has been shown to stimulate growth of both epidermal keratinocytes and dermal fibroblasts.12–14 However, thyroid hormone-mediated inhibition of keratinocyte growth has been observed when the keratinocytes were cocultured with dermal fibroblasts.14 Thus, in vivo, skin proliferation directly stimulated by T3 may be offset by inhibiting factors dependent on the systemic T3. Systemically induced inhibiting factors may be bypassed with topically administered T3.

Wound Healing Topical thyroid hormone may serve as a useful means to accelerate the wound-healing rate (Figure 14.2). Topical application of supraphysiological doses of T3 accelerated wound healing in normal mice.42 A human wound-healing formulation has been described that requires T4 in addition to growth hormone and insulin.43 The importance of thyroid hormone in wound healing had been debated previously. In 1973 and 1974, Mehregan and Zamick reported that oral T3 accelerated the rate of wound healing in euthyroid rats and improved the quality of the wounds.44,45 Scars were smoother in T3-treated animals. Lennox and Johnston reported accelerated wound healing and increased tensile strength when rats were given supraphysiologic doses of T4.46 Pirk et al. reported no change in wound healing with 1.3 µg/100 mg

Figure 14.2. Topical T3 (triiodothyronine)-accelerated wound healing. Full-thickness wounds were placed on each side of the dorsum of mice. Wounds were photographed on wounding to account for variability in two-dimensional size and remeasured 4 days following injury. In each mouse, wounds on one side of the dorsum received topical T3, and wounds on the other side were left untreated. Each animal served as its own control. (A) Representative photograph of one animal at baseline and 4 days later. The right side was treated with topical T3. The left side received only vehicle. (B) Percentage of wound surface remaining open at 4 days. Data are presented as mean relative wound size (percentage of baseline ± SEM). (Adapted from reference 42.)

body weight intraperitoneal T4 in hamsters but an increased rate of fracture repair.47 Ashton and Dekel also reported an increased fracture repair rate in mice given 20 µg/100 mg body weight subcutaneous T4.48 There are also reports that several hypothyroid patients required thyroid hormone to achieve healing of radiation-induced neck fistulae.49,50 Conversely, Cannon51 reported that hypothyroidism did not diminish wound strength in pigs, and Ladenson et al.52 did not detect woundhealing deficits in hypothyroid humans.

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Hair Growth In the 1950s and 1960s, Hale and Ebling documented the impact of thyroid hormone on rat hair growth cycles.53 They demonstrated that intraperitoneal T4 decreased the resting phase of the hair growth cycle (telogen) and decreased the growth phase of the hair growth cycle (anagen). Although there was enhanced turnover, the net hair length at any given time was unchanged from that of untreated animals. The time to regrowth of hair following epilation was shortened by approximately 10%. The induction of hypothyroidism with the antithyroid drug propylthiouracil (PTU) in the drinking water increased the time to the restoration of hair by approximately 20%. Clinically, the hair in thyrotoxicosis is often fine and soft. Nail changes may also occur, characterized by a concave contour accompanied by distal onycholysis (Plummer’s nails). A diffuse, nonscarring alopecia may be observed. In vitro studies suggested an increased hair growth rate in thyrotoxicosis. DNA flow cytometry studies of dissected anagen hairs from thyrotoxic patients (compared with follicles taken from euthyroid controls) demonstrated a 30% increase in the S and G2 + M phases of the cell cycle.54 However, like with epidermal proliferation, hair changes with thyrotoxicosis are different from what can be effected with topically administered thyroid hormone. Mice and rats treated daily for 1–2 weeks with topical T3 had increased hair counts, but mice made thyrotoxic with daily intraperitoneal T3 for 1–2 weeks had decreased hair counts.14,38 Thyrotoxic goats had increased mohair length but decreased fiber diameter.55 A topical mixture including T4, insulin, and growth hormone increased hair counts over a 6-month treatment period in men with androgenic alopecia.56

J.D. Safer and M.F. Holick

Thyroid hormone may play a role in establishing the barrier function of the epidermis by increasing the activity of enzymes of the cholesterol sulfate cycle60 and by acting on the development of lamellar granules.61 T3 is reported to act on transglutaminase, the enzyme involved with the formation of the cornified envelope, and on plasminogen activator, an enzyme potentially involved in the shedding of corneocytes.62 In xerosis, expression of differentiation-associated keratins 1 and 10 may be decreased relative to expression of basal keratins 5 and 14. In a small study, there was modest improvement in xerosis treated with topical T4. Thyroid-stimulating hormone was not changed when 0.0167 µg/cm2 T4 was applied daily for a 3-week period.63 Also, it has been reported that a subset of patients with chronic urticaria and angioedema associated with thyroid autoimmunity may have their urticaria abate with the administration of thyroid hormone.64 The mechanism by which thyroid hormone may alleviate this process remains speculative.

Conclusion Although thyroid hormone is one of the most potent stimulators of growth and metabolic rate, the potential to use thyroid hormone to treat cutaneous pathology has never been subject to rigorous investigation. A number of investigators have demonstrated intriguing therapeutic potential for topical thyroid hormone. Topical T3 has accelerated wound healing in rodents. Topical T3 has accelerated hair growth in rodents. Topical T4 has been used to treat xerosis in humans. It is clear that the use of thyroid hormone to treat cutaneous pathology may be of large consequence and merits further study.

References Xerosis Thyroid hormone deficiency can manifest with findings of rough and fine superficial scales, especially on the extensor extremities.57 In fact, up to 90% of hypothyroid patients may have scaly skin.58 Xerosis may be severe enough to resemble an acquired ichthyosis. The dryness of the palms and soles may be extensive.59 This can be reversed when euthyroidism is established. Histologic examination reveals epidermal thinning and hyperkeratosis.16

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186 34. Thompson CC. Thyroid hormone-responsive genes in developing cerebellum include a novel synaptotagmin and a hairless homolog. J Neurosci 1996;16:7832–7840. 35. Thompson CC, Bottcher MC. The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors. Proc Natl Acad Sci U S A 1997;94:8527–8532. 36. Miyazaki T, Kanou Y, Murata Y, et al. Molecular cloning of a novel thyroid hormone responsive gene, ZAKI-4, in human skin fibroblasts. J Bio Chem 1996;271:14567–14571. 37. Safer JD, Crawford TM, Holick MF. A role for thyroid hormone in wound healing through keratin gene expression. Endocrinology 2004;145:2357–2361. 38. Safer JD, Fraser LM, Ray S, Holick MF. Topical triiodothyronine stimulates epidermal proliferation, dermal thickening, and hair growth in mice and rats. Thyroid 2001;11:717–724. 39. Safer JD. The skin and connective tissue in hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid. 9th ed. Philadelphia: Lippincott Williams and Wilkins; 2005:769–773. 40. Faergemann J, Sarnhult T, Hedner E, et al. Doseresponse effects of tri-iodothyroacetic acid (Triac) and other thyroid hormone analogues on glucocorticoid-induced skin atrophy in the haired mouse. Acta Derm Venereol 2002;82:179–183. 41.Yazdanparast P, Carlsson B, Oikarinen A, Risteli J, Faergemann J. A thyroid hormone analogue, triiodothyroacetic acid, corrects corticosteroid downregulated collagen synthesis. Thyroid 2004;14:345–353. 42. Safer JD, Crawford TM, Holick MF. Topical thyroid hormone accelerates wound healing in mice. Endocrinology 2005;146:4425–4430. 43. Lindenbaum ES, Har Shai Y, Ullmann Y, et al. Stimulated healing of recalcitrant wounds by topical application of enriched cell culture medium: a clinical report. Plast Reconstr Surg 2001;108;104–113. 44. Zamick P, Mehregan AH. Effect of l-tri-iodothyronine on marginal scars of skin grafted burns in rats. Plast Reconstr Surg 1973;51:71–75. 45. Mehregan AH, Zamick P. The effect of triiodothyronine in healing of deep dermal burns and marginal scars of skin grafts. A histologic study. J Cutan Pathol 1974;1:113–116. 46. Lennox J, Johnston IDA. The effect of thyroid status on nitrogen balance and the rate of wound healing after injury in rats. Br J Surg 1973;60:309. 47. Pirk FW, El Attar MA, Roth GD. Effect of analogues of steroid and thyroxine hormones on wound healing in hamsters. J Periodontal Res 1974;9:290–297. 48. Ashton IK, Dekel S. Fracture repair in the snell dwarf mouse. Br J Exp Pathol 1983;64:479–486. 49. Alexander MV, Zajtchuk JT, Henderson RL. Hypothyroidism and wound healing: occurrence

J.D. Safer and M.F. Holick after head and neck radiation and surgery. Arch Otolaryngol 1982;108:289–291. 50. Talmi YP, Finkelstein Y, Zohar Y. Pharyngeal fistulas in postoperative hypothyroid patients. Ann Otol Rhinol Laryngol 1989;98:267–268. 51. Cannon CR. Hypothyroidism in head and neck cancer patients: experimental and clinical observations. Laryngoscope 1994;104:1–22. 52. Ladenson, PW, Levin AA, Ridgeway EC, Daniels GH. Complications of surgery in hypothyroid patients. Am J Med 1984;77:261–266. 53. Hale PA, Ebling FJ. The effect of a single epilation on successive hair eruptions in normal and hormonetreated rats. J Exp Zool 1979;207:49–72. 54. Schell H, Kiesewetter F, Seidel C, et al. Cell cycle kinetics of human anagen scalp hair bulbs in thyroid disorders determined by DNA flow cytometry. Dermatologica 1991;182:23. 55. Puchala R, Prieto I, Banskalieva V, Goetsch AL, Lachica M, Sahlu T. Effects of bovine somatotropin and thyroid hormone status on hormone levels, body weight gain, and mohair fiber growth of angora goats. J Anim Sci 2001;79:2913–2919. 56. Lindenbaum ES, Feitelberg AL, Tendler M, et al. Pilot study of a novel treatment for androgenetic alopecia using enriched cell culture medium: clinical trials. Dermatol Online J 2003;9:4. 57. Heymann WR. Cutaneous manifestations of thyroid disease. J Am Acad Dermatol 1992;26:885. 58. Freinkel RK. Cutaneous manifestations of endocrine disease. In: Freedberg IM, Jisen AZ, Wolff K, et al., eds. Dermatology in General Medicine. 4th ed. New York: McGraw-Hill; 1993:2113. 59. Hodak E, David M, Feuerman EJ. Palmoplantar keratoderma in association with myxedema. Acta Derm Venereol (Stockh) 1986;66:354. 60. Isseroff RR, Chun KT, Rosenberg RM. Triiodothyronine alters the cornification of cultured human keratinocytes. Br J Dermatol 1989;120:503–510. 61. Rosenberg RM, Isseroff RR, Ziboh VA, et al. Abnormal lipogenesis in thyroid hormone-deficient epidermis. J Invest Dermatol 1986;86:244. 62. Hanley K, Jiang Y, Katagiri C, et al. Epidermal steroid sulfatase and cholesterol sulfotransferase are regulated during late gestation in the fetal rat. J Invest Dermatol 1997;108:871. 63. Heymann WR, Gans EH, Manders SM, Green JJ, Haimowitz JE. Xerosis in hypothyroidism: a potential role for the use of topical thyroid hormone in euthyroid patients. Med Hypotheses 2001;57:736–739. 64. Heymann WR. Chronic idiopathic urticaria and angioedema associated with thyroid autoimmunity: review and therapeutic implications. J Am Acad Dermatol 1999;40:229.

Index

AACE. See American Association of Clinical Endocrinologists ACA. See Anticentromere antibody Acanthosis nigricans (AN), 97 ACR. See American College of Rheumatology Addison disease, 170–171 Adenosine triphosphatase (ATPase), 10 AHA. See Antihistone antibody AHO. See Albright hereditary osteodystrophy AIH. See Amiodarone-induced hyperthyroidism AIT. See Amiodarone-induced thyrotoxicity AITD. See Autoimmune thyroid disease AKA. See Antikeratin antibody Albright hereditary osteodystrophy (AHO), 57–59 Albumin, 9 Allopurinol, 82 Alopecia androgenetic, 129–130 conclusion on, 139 introduction to, 121, 123 medications and antithyroid drugs, 137–138 peripheral conversion drugs, 139 thyroid disease drug therapy, 137 thyroid gland/hormone drugs, 138–139 Alopecia areata AT, 132

in DS, 132–133 patchy, 131 Alopecia totalis (AT), 132 Alopecia universalis (AU), 132 American Association of Clinical Endocrinologists (AACE), 19 American College of Rheumatology (ACR), 158 Amiodarone, 15, 17, 138–139, 168–169 Amiodarone-induced hyperthyroidism (AIH), 138 Amiodarone-induced thyrotoxicity (AIT), 138 AN. See Acanthosis nigricans ANAs. See Antinuclear antibodies Androgenetic alopecia, 129–130 Anticentromere antibody (ACA), 159 Anticyclic citrullinated peptide (CCP), 163 Antihistone antibody (AHA), 159 Antikeratin antibody (AKA), 163 Antinuclear antibodies (ANAs), 158 Antiperinuclear factor (APF), 163 Antithyroid antibodies, biochemical test of TPO-Ab, 28 TRAbs, 28 Antithyroid drugs, 137–138 APF. See Antiperinuclear factor APS. See Autoimmune polyglandular syndromes Aspirin, 26 ASST. See Autologous serum skin test

AT. See Alopecia totalis Atenolol, 80 ATPase. See Adenosine triphosphatase AU. See Alopecia universalis Autoimmune blistering disease, 163–166 BP/PG, 164 DH, 165–166 PV/PF, 164–165 Autoimmune polyglandular syndromes (APS), 158 Autoimmune thyroid disease (AITD), 23 hair loss and, 126–127 immunologic manifestations of, 149–150 suspicion of, 32 systemic manifestations of, 104 Autologous serum skin test (ASST), 147 Azathioprine, 159, 161 Bexarotene, 139, 169–170 Biochemical tests, for thyroid disease antithyroid antibodies, 28 FTI, 27 reverse T3, 27 T3, 26 T3 resin uptake, 26–27 Tg levels, 27–28 thyroid hormones, 26 thyroxine, 25–26 TSH, 24–25 BP. See Bullous pemphigoid Bullous pemphigoid (BP), 163, 164 187

188 Café-au-lait (CAL), 57, 58 CAL. See Café-au-lait Calcinosis Raynaud syndrome, Esophageal dysmotility, Sclerodactyly, and Telangiectasia (CREST) syndrome, 97 sclerodactyly/scattered erosions in, 159 cAMP. See Cyclic adenosine monophosphate Carbimazole, 59, 80 Cardiovascular system hyperthyroidism and, 77 hypothyroidism and, 94 thyroid hormone action and, 10 Carney complex (NAME syndrome/ LAMB syndrome), thyroid cancer and, 48–49 C-cells, of thyroid gland, 5 CCP. See Anticyclic citrullinated peptide CDP. See Complete decompressive physiotherapy CGH. See Comparative genomic hybridization CH. See Congenital hypothyroidism CHD. See Congenital heart disease Cholesterol metabolism. See Lipid/ cholesterol metabolism Cholestyramine, 80 Chronic autoimmune thyroiditis (Hashimoto thyroiditis), 14 hair loss and, 127–128 Chronic idiopathic urticaria (CIU) autoimmune basis for, 146–149 background on, 146 characteristic of, 148 conclusion on, 154 future study suggestions for, 154 immunologic manifestations of, 150–151 introduction to, 145–146 TA prevalence and, 149 thyroid disease and, 151–154 practical considerations for, 153–154 proposed mechanism of, 152–153 Chronic mucocutaneous candidiasis (CMC), 98

Index Cicatricial alopecias lichen planopilaris, 133, 134 lupus erythematosus, 133–134 morphea, 134–135 CIU. See Chronic idiopathic urticaria Clobetasol, 81, 112 CMA. See Comparative microarray analysis CMC. See Chronic mucocutaneous candidiasis Comparative genomic hybridization (CGH), 55 Comparative microarray analysis (CMA), 55 Complete decompressive physiotherapy (CDP), 113 Compressive therapy, 113 Computed tomography (CT), 33 of thyroglossal duct cysts, 38, 39 Congenital atrichia, 135 Congenital heart disease (CHD), 60 Congenital hypothyroidism (CH), 55, 94–95, 135–136 syndromic/nonsyndromic forms of, 56–57 Congenital lymphedema, TS and, 62 Connective tissue disease (CTDs) DM/PM, 160–161 MCTD, 161–162 RA, 162–163 scleroderma, 159–160 SLE/DLE, 158–159 SS, 160 Corticosteroid therapy, 112–113 Corticotrophin-releasing hormone (CRH), 128 Cowden syndrome (Multiple hamartoma syndrome), thyroid cancer and, 49 CPK. See Creatinine phosphokinase Creatinine phosphokinase (CPK), 161 CREST. See Calcinosis Raynaud syndrome, Esophageal dysmotility, Sclerodactyly, and Telangiectasia syndrome CRH. See Corticotrophin-releasing hormone CT. See Computed tomography CTCL. See Cutaneous T cell lymphoma CTDs. See Connective tissue disease

Cutaneous T cell lymphoma (CTCL), 169 Cyclic adenosine monophosphate (cAMP), 9 Cyclophosphamide, 159, 162 Cyclosporine, 82, 136, 161 Cytomel, 137 22q11.2 Deletion syndrome (DiGeorge syndrome/ Velocardiofacial syndrome), 64–66 characteristics of, 65 fluorescence in situ hybridization and, 65 Denileukin diftitox, 98 Dermatitis herpetiformis (DH), 163, 165–166 Dermatologic disorders Addison disease and, 170–171 autoimmune blistering disease and, 163–166 BP/PG, 164 DH, 165–166 PV/PF, 164–165 conclusion on, 174 CTDs and DM/PM, 160–161 MCTD, 161–162 RA, 162–163 scleroderma, 159–160 SLE/SLE, 158–159 SS, 160 ichthyosis, 172 introduction to, 157 LSA, 172–173 nail changes and, 171 pigmentation disorders and melasma, 166–167 vitiligo, 167–168 PPK and, 171–172 PPP and, 171 scleromyxedema, 173–174 Dermatomyositis (DM), 160–161 Dermis hyperthyroidism and, 76–77 hypothyroidism and, 93–94 DGS. See DiGeorge syndrome DH. See Dermatitis herpetiformis DHS. See Drug hypersensitivity syndrome DHT. See Dihydrotestosterone Diazoxide, 136

Index DIF. See Direct immunofluorescence DiGeorge syndrome (DGS), 64. See also 22q11.2 Deletion syndrome Digoxin, 82 Dihydrotestosterone (DHT), 129 Diiodotyrosine (DIT), 8 Direct immunofluorescence (DIF), 163 Discoid lupus erythematosus (DLE), 133, 134, 158–159 DIT. See Diiodotyrosine DLE. See Discoid lupus erythematosus DM. See Dermatomyositis Dopamine, 16 Down syndrome (DS), 59–62 alopecia areata in, 132–133 clinodactyly/single palmar crease and, 60 macroglossia and, 56 Drug hypersensitivity syndrome (DHS), 170 DS. See Down syndrome Electromyelography (EMG), 161 ELISA. See Enzyme-linked immunosorbent assay EMA. See Endomysial autoantibody EMG. See Electromyelography Endomysial autoantibody (EMA), 166 Energy metabolism. See Thermogenesis/energy metabolism Enzyme-linked immunosorbent assay (ELISA), 163 Epidermis/sweat glands, hyperthyroidism and, 75–76 Etanercept, 82 Eyes, hypothyroidism and, 94 FDG. See F-Fluorodeoxyglucose F-Fluorodeoxyglucose (FDG), 33 Fine-needle aspiration (FNA), 43 Fine-needle aspiration biopsy (FNAB), dissemination through, 47–48 FNA. See Fine-needle aspiration FNAB. See Fine-needle aspiration biopsy Follicle-stimulating hormone (FSH), 58

189 Foramen cecum, of thyroid gland, 3 descent of, 4 Free thyroxine index (FTI), biochemical test of, 27 FSH. See Follicle-stimulating hormone FTI. See Free thyroxine index GAGs. See Glycosaminoglycans GD. See Graves disease Genetic syndromes, thyroid cancer associated with Carney complex, 48–49 characteristics of, 50 Cowden syndrome, 49 MEN 2A/MEN 2B, 48 GFD. See Gluten-free diet GH. See Growth hormone Gluten-free diet (GFD), 166 Glycosaminoglycans (GAGs), 77 Graves disease (GD), 17 extrathyroidal manifestation of Graves ophthalmopathy and, 107 tobacco as risk factor for, 110 hair loss and, 128 manifestation chronology of, 108 pretibial myxedema and, 75 systemic manifestations of, 104 Graves ophthalmopathy, GD and, 107 Growth hormone (GH), 11 Hair excessive growth of hirsutism, 136 hypertrichosis, 136–137 follicle of thyroid-binding protein and, 124 thyroid gland and, 123–124 TREs and, 123, 124 hyperthyroidism and, 76–77 hypothyroidism and, 92–93 thyroid hormone therapy and, 184 Hair loss/disorders AITD and, 126–127 cicatricial alopecias lichen planopilaris, 133, 134 lupus erythematosus, 133–134 morphea, 134–135 congenital syndromes and CH, 135–136 congenital atrichia, 135

GD and, 128 HT and, 127–128 hyperthyroidism and, 125–126 hypothyroidism and, 125 thyroid disease and alopecia areata, 131–132 androgenetic alopecia, 129–130 DS, 132–133 madarosis, 129 metabolic syndrome/PCOS, 130 seborrheic dermatitis, 130–131 telogen effluvium, 128–129 thyroid diseases and, 122 thyroid screening for, 123 Hashimoto thyroiditis (HT). See Chronic autoimmune thyroiditis hCG. See Human chorionic gonadotropin Hirsutism, 136 HT. See Hashimoto thyroiditis Human chorionic gonadotropin (hCG), 9 Hyaluronidase, 81, 113 Hydrocortisone, 136 Hydroquinone, 167 Hyperthyroidism clinical manifestations of, 18 common signs/symptoms of, 18 conclusion on, 83 cutaneous diseases associated with, 82, 83 cutaneous manifestations of, 75 dermatologic signs of, 74–77 epidermis/sweat/sebaceous glands, 75–76 hair/nails/dermis, 76–77 palmar erythema, 75 diagnosis of, 79–80 etiology of, 74 increased iodine uptake, 17–18 low iodine uptake, 17 hair loss and, 125–126 introduction to, 73–74 onycholysis and, 76 overt primary, 16 pregnancy/congenital, 78–79 skeletal system and, 78 skin manifestations of, new insights/reports on, 82–83 subclinical primary, 16

190 Hyperthyroidism (Cont’d) suspicion of, 31 systemic manifestations, 79 thyroid ophthalmopathy and, 77–78 treatment of, 80–82 vascular changes and, 77 Hypertrichosis, 136–137 Hypothalamic-pituitary problem, suspicion of, 32 Hypothyroidism. See Congenital hypothyroidism causes of, 90 clinical manifestations of, common signs/symptoms of, 16 cutaneous diseases associated with, 96–97 cutaneous manifestations of, 91, 96 dermatologic signs of, 90–94 epidermis, 90–92 hair, 92–93 sweat glands, 90–92 diagnosis of, 95 etiology of, 89–90 central hypothyroidism, 15–16 drug-induced, 15 external neck irradiation, 15 HT, 14 industrial/environmental agents, 15 radioiodine therapy, 15 thyroidectomy, 14 hair loss and, 125 introduction to, 89 nerves/eyes and, 94 overt primary, 14 PPK and, 92 skin manifestations of, new insights/reports into, 97–98 subclinical primary, 14 suspicion of, 30–31 treatment for, 95–96 vascular changes and, 94 xerosis and, 90–91 Ichthyosis, 172, 173 IDL. See Intermediate-density lipoprotein IGF-1. See Insulin-like growth factor 1 IIF. See Indirect immunofluorescence

Index Imaging studies, for thyroid disease FDG/PET, 33 isotope scan, 33 MRI/CT, 33 PET, 33 sonography, 32 Immune thrombocytopenia (ITP), 158 Indirect immunofluorescence (IIF), 163 Infliximab, 82 Insulin-like growth factor 1 (IGF-1), 11 Interferon alpha, 15 Interleukin 2, 15 Intermediate-density lipoprotein (IDL), 11 Intravenous immunoglobulin (IVIG), 146 Iodide, 7, 82 Iodine uptake, increased, hyperthyroidism and Graves disease, 17 toxic multinodular thyroid/toxic adenoma, 17 TSH-secreting pituitary adenoma, 17–18 Iodine uptake, low, hyperthyroidism and amiodarone, 17 exogenous thyroid hormone, 17 iodine-induced hypothyroidism, 17 thyroiditis, 17 Iopanoic acid, 82 Ipodate, 82 IR-TSH. See Isolated raised thyroid-stimulating hormone Isolated raised thyroid-stimulating hormone (IR-TSH), 60 Isotope scan, 33 ITP. See Immune thrombocytopenia IVIG. See Intravenous immunoglobulin JDM. See Juvenile dermatomyositis Juvenile dermatomyositis (JDM), 161 KI. See Potassium iodide Lactic dehydrogenase (LDH), 161 LAMB syndrome. See Carney complex

LDH. See Lactic dehydrogenase LDL. See Low-density lipoproteins Levothyroxine, 137, 153 LH. See Luteinizing hormone LHRH. See Luteinizing hormone-releasing hormone Lichen planopilaris, 133 Lichen sclerosis et atrophicus (LSA), 172–173 characteristics of, 173 Lingual thyroid, 4 location of, 5 Liothyronine, 137 Lipid/cholesterol metabolism, thyroid hormone action and, 11 Lithium, 80, 139 Low-density lipoproteins (LDL), 11 LSA. See Lichen sclerosis et atrophicus L-thyroxine, 95, 152, 154 Lugol’s iodine solution, 80, 82 Lupus erythematosus, 133–134 Luteinizing hormone (LH), 58 Luteinizing hormone-releasing hormone (LHRH), 58 Macroglossia, DS and, 56 Madarosis, 129 Magnetic resonance imaging (MRI), 33 MAS. See McCune-Albright syndrome McCune-Albright syndrome (MAS), 57–59 polyostotic fibrous dysplasia/ CAL and, 58 MCTD. See Mixed connective tissue disease Medications amiodarone, 168–169 bexarotene, 169–170 DHS/hypothyroidism, 170 influencing thyroid function, 138 influencing thyroid gland/ hormones, 138–139 KI, 168 Medullary thyroid carcinomas (MTCs), 6 Melasma, 166–167 MEN 2A. See Multiple endocrine neoplasia type 2 MEN 2B. See Multiple endocrine neoplasia type 2

Index Metastatic papillary thyroid carcinoma, histology of, 45 Methimazole, 18, 59, 77, 80, 82, 138 Methotrexate, 82, 159, 161, 162 Metoprolol, 80 Minoxidil, 136 MIT. See Monoiodotyrosine Mixed connective tissue disease (MCTD), 161–162 MNG. See Multinodular goiter Monoiodotyrosine (MIT), 8 Morphea, 134–135 MRI. See Magnetic resonance imaging MTCs. See Medullary thyroid carcinomas Multinodular goiter (MNG), 31 Multiple endocrine neoplasia type 2 (MEN 2A/MEN 2B), thyroid cancer and, 48 Multiple hamartoma syndrome. See Cowden syndrome Nadolol, 80 Nails changes of, 171 hyperthyroidism and, 76–77 hypothyroidism and, 93 NAME syndrome. See Carney complex National Health and Nutrition Examination Survey (NHANES), 13 Nephrogenic systemic fibrosis (NSF), 174 Nerves, hypothyroidism and, 94 Neuromuscular system, thyroid hormone action and, 10–11 NHANES. See National Health and Nutrition Examination Survey Nicotinamide, 82 NSF. See Nephrogenic systemic fibrosis Octreotide acetate, 81, 112 Octreotide therapy, 113 Onycholysis, hyperthyroidism and, 76 Palmar erythema, hyperthyroidism and, 75

191 Palmoplantar keratoderma (PPK) characteristics of, 172 hypothyroidism and, 92 Palmoplantar pustulosis (PPP), 171 Particular postpartum thyroiditis (PPT), 150 PCOS. See Polycystic ovarian syndrome Pemphigoid gestationis (PG), 163, 164 Pemphigus foliaceus (PF), 163, 164–165 Pemphigus vulgaris (PV), 163, 164–165 Pendred syndrome, 59 Pentoxifylline, 81, 82 PET. See Positron emission tomography PF. See Pemphigus foliaceus PG. See Pemphigoid gestationis Phenytoin, 136 Phospholamban, 10 PHP. See Pseudohypoparathyroidism Pigmentation disorders melasma, 166–167 vitiligo, 167–168 PM. See Polymyositis Polycystic ovarian syndrome (PCOS), 130 Polymyositis (PM), 160–161 Polyostotic fibrous dysplasia, 58 Positron emission tomography (PET), 33 Potassium iodide (KI), 168 Potassium perchlorate, 80 PPK. See Palmoplantar keratoderma PPNAD. See Primary pigmented nodular adrenocortical disease PPP. See Palmoplantar pustulosis PPT. See Particular postpartum thyroiditis Prader Willi syndrome (PWS), 63 Prednisone, 82 Pregnancy hyperthyroidism and, 78–79 suspicion of, 32 Pretibial myxedema. See also Thyroid dermopathy GD and, 75 Primary pigmented nodular adrenocortical disease (PPNAD), 59

Propranolol, 80, 82, 139 Propylthiouracil (PTU), 18, 59, 77, 80, 82, 124, 138, 184 Pseudohypoparathyroidism (PHP), 59 PTU. See Propylthiouracil PV. See Pemphigus vulgaris PWS. See Prader Willi syndrome Pyramidal lobe, of thyroid gland, 2 RA. See Rheumatoid arthritis Radioactive iodine (RAI), 77, 81 RAI. See Radioactive iodine RANTES. See Regulated Activation Normal T cell Expressed and Secreted Regulated Activation Normal T cell Expressed and Secreted (RANTES), 150 Retinoid X receptor (RXR), 169 Retrosternal thyroid, 2 RF. See Rheumatoid factor Rheumatoid arthritis (RA), 160, 162–163 subcutaneous nodules of, 162 Rheumatoid factor (RF), 159 Rifampin, 98 Rituximab, 82 RXR. See Retinoid X receptor Saturated solution of potassium iodide (SSKI), 80, 82 Scleroderma, 159–160 Scleromyxedema, 173–174 Sebaceous glands hyperthyroidism and, 75–76 thyroid gland and, 124 Seborrheic dermatitis, 130–131 SEER. See Surveillance, Epidemiology, and End Results program Sjögren syndrome (SS), 160 dry lips/oral mucosa due to, 160 Skeletal system hyperthyroidism and, 78 thyroid hormone action and, 11 SLE. See Systemic lupus erythematosus Sonography, 32 SS. See Sjögren syndrome SSc. See Systemic sclerosis SSKI. See Saturated solution of potassium iodide Surgery, for TGDC, 39, 40

192 Surveillance, Epidemiology, and End Results (SEER) program, 18 Sweat glands. See Epidermis/sweat glands Systemic immunomodulation, 113 Systemic lupus erythematosus (SLE), 133, 158–159 Systemic sclerosis (SSc), 158 T3. See Triiodothyronine T4. See Thyroxine TA. See Thyroid autoimmunity TBG. See Thyroid hormone-binding globulin Telogen effluvium, 128–129 Tetraiodothyronine (Thyroxine), 7 Tg. See Thyroglobulin TG3. See Transglutaminase 3 TGDC. See Thyroglossal duct cysts Thalidomide, 174 Thermogenesis/energy metabolism, thyroid hormone action and, 11 Thiocyanate, 137 Thyroglobulin (Tg), biochemical test of, 27–28 Thyroglossal duct, 3–4 location of, 5 Thyroglossal duct cysts (TGDC) diagnosis of, 37–38 embryology of, 37 introduction to, 37 presentation of, 37, 38 radiology of, 38–39 CT scan, 38, 39 treatment of anesthesia for, 39 complications of, 40 history of, 39 postoperative care for, 40 preoperative preparation for, 39 recurrence and, 40 special considerations for, 40 surgical procedure of, 39, 40 Thyroid acropachy, clinical symptoms/signs of, 106–107 Thyroid autoimmunity (TA), 149 Thyroid-binding protein, hair follicle and, 124 Thyroid cancer classification/prognosis of, 44–45 clinical staging of, 46 common types of, 44

Index conclusion of, 50 cutaneous metastases from, 45–47 etiology of, 44 FNAB dissemination and, 47–48 genetic syndromes associated with Carney complex, 48–49 characteristics of, 50 Cowden syndrome, 49 MEN 2A/MEN 2B, 48 immunohistochemical stains for, 47 introduction to, 43–44 Thyroid dermopathy, 103–114 clinical symptoms/signs of, 104–106 distinct forms of, 105, 106 conclusion on, 114 diagnosis of, 111 differential diagnosis of, 111 histopathology of, 108–109 photomicrographs, 108 introduction to, 103–104 pathogenesis of cellular process, 109–110 immunologic process, 109 mechanical contribution, 110 thyroid function and, 104 treatment for associated ophthalmopathy management, 112 CDP, 113 compressive therapy, 113 local corticosteroid therapy, 112–113 long-term outcome of, 113, 114 octreotide therapy, 113 risk factor management, 111 surgical lesion excision, 113 systemic immunomodulation, 113 thyroid disfunction management, 111–112 Thyroid disease CIU and, 151–154 practical considerations for, 153–154 proposed mechanism of, 152–153 classification/epidemiology of hyperthyroidism, 16–18 hypothyroidism, 14–16

introduction to, 13–14 thyroid nodules, 18–19 drug therapy for hyperthyroidism, 137 hypothyroidism, 137 hair loss/disorders and, 122 alopecia areata, 131–132 androgenetic alopecia, 129–130 DS, 132–133 madarosis, 129 metabolic syndrome/PCOS, 130 seborrheic dermatitis, 130–131 telogen effluvium, 128–129 laboratory diagnosis of biochemical tests, 24–28 conclusion of, 33 imaging studies, 32–33 introduction to, 23–24 thyroid function tests, 28–32 screening for, 19, 122 Thyroid diverticulum, 3 Thyroidectomy, 14 Thyroid follicles schematic of, 8 thyroid gland and, 2–3 Thyroid function medications influencing, 138 regulation of, 9 tests for in different conditions, 29 screening, 28, 30–32 suggested initial tests, 30 thyroid dermopathy and, 104 Thyroid gland anatomy of pyramidal lobe, 1, 2 retrosternal thyroid, 2 thyroid follicles, 2–3 ectopic tissue location and, 5 embryology of, 3–6 C cells of, 5 foramen cecum, 3 lingual thyroid and, 4, 5 thyroglossal duct, 3–4, 5 thyroid diverticulum, 3 hair follicle and, 123–124 histology of, 3 hormonal products of, 8 introduction to, 1 medication influencing, 138–139 sebaceous gland and, 124

Index Thyroid hormone(s) action of cardiovascular system, 10 lipid/cholesterol metabolism, 11 neuromuscular system, 10–11 skeletal system/growth, 11 thermogenesis/energy metabolism, 11 biochemical test of, 26 medications influencing, 138–139 metabolism of, 10 physiology of, 7–11 function regulation of, 9 introduction to, 7–9 therapeutic uses of background on, 182 conclusion on, 184 deiodination pathways, 182 hair growth and, 184 introduction to, 181 wound healing and, 183 xerosis and, 184 transport/tissue delivery of, 9 Thyroid hormone-binding globulin (TBG), 9 Thyroid hormone receptors (TRs), 10 Thyroid nodules, 18–19 Thyroid ophthalmopathy, hyperthyroidism and, 77–78 Thyroid peroxidase (TPO), 8 Thyroid response elements (TREs), hair follicle and, 123, 124 Thyroid-stimulating hormone (TSH), 3 biochemical tests of, 24–25 appropriate serum use, 25 negative-feedback pathway, 25

193 Thyroid-stimulating hormone receptor autoantibodies (TRAbs), biochemical tests of, 28 Thyroid-stimulating immunoglobulin (TSI), 79 Thyroperoxidase antibodies (TPO-A), biochemical test of, 28 Thyrotoxicosis. See Hyperthyroidism Thyroxine (T4), 7, 124 biochemical test of, 25–26 TI-5′D. See Type I 5′-deiodinase TII-5′D. See Type II 5′-deiodinase TNM. See Tumor, node, metastasis method TPO. See Thyroid peroxidase TPO-Ab. See Thyroperoxidase antibodies TRAbs. See Thyroid-stimulating hormone receptor autoantibodies Transglutaminase 3 (TG3), 165 Transthyretin, 9 TREs. See Thyroid response elements TRH. See TSH-releasing hormone Triiodothyronine (T3), 7 biochemical test of resin uptake, 26–27 reverse, 27 wound healing accelerated by, 183 TRs. See Thyroid hormone receptors TS. See Turner syndrome TSH. See Thyroid-stimulating hormone

TSH-releasing hormone (TRH), 9 TSH-secreting pituitary adenoma, 17–18 TSI. See Thyroid-stimulating immunoglobulin Tumor, node, metastasis (TNM) method, definition of, 45 Turner syndrome (TS) characteristics of, 62 congenital lymphedema and, 62 Type I 5′-deiodinase (TI-5′D), 10 Type II 5′-deiodinase (TII-5′D), 10 Vascular changes. See Cardiovascular system Velocardiofacial syndrome. See 22q11.2 Deletion syndrome Vitiligo, 167–168 WCE. See Wolff-Chaikoff effect WHO. See World Health Organization Williams-Beuren Syndrome (WS), 63–64 Wolff-Chaikoff effect (WCE), 168 World Health Organization (WHO), 7 Wound healing, T3 acceleration of, 183 WS. See Williams-Beuren Syndrome Xerosis hypothyroidism and, 90–91 thyroid hormone therapy and, 184