Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
® pediatric endocrinology Board Review Manual Statement of Editorial Purpose The Hospital Physician Pediatric Endocrinology Board Review Manual is a study guide for fel lows and practicing physicians preparing for board examinations in pediatric endocrinology. Each manual reviews a topic essential to the current practice of pediatric endocrinology. PUBLISHING STAFF PRESIDENT, Group PUBLISHER Bruce M. White editorial director Debra Dreger Associate EDITOR Tricia Faggioli EDITORial assistant Congenital and Acquired Hypothyroidism Editor: Jill D. Jacobson, MD Professor of Pediatrics, Section of Endocrinology and Diabetes, Children’s Mercy Hospital and Clinics, University of Missouri–Kansas City School of Medicine, Kansas City, MO Contributor: John S. Fuqua, MD Associate Professor of Clinical Pediatrics, Section of Pediatric Endocrinology and Diabetology, Indiana University School of Medicine, Indianapolis, IN Farrawh Charles executive vice president Barbara T. White executive director of operations Jean M. Gaul PRODUCTION Director Suzanne S. Banish PRODUCTION associate Kathryn K. Johnson ADVERTISING/PROJECT manager Patricia Payne Castle sales & marketing manager Deborah D. Chavis Table of Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Thyroid Development and Physiology. . . . . . . . . . . . . 2 NOTE FROM THE PUBLISHER: This publication has been developed with out involvement of or review by the Amer ican Board of Pediatrics. Endorsed by the Association for Hospital Medical Education Congenital Hypothyroidism. . . . . . . . . . . . . . . . . . . . . 3 Acquired Hypothyroidism. . . . . . . . . . . . . . . . . . . . . . . 8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Cover Illustration by May S. Cheney Copyright 2007, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of appropriate topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. www.turner-white.com Pediatric Endocrinology Volume 1, Part 2 Pediatric Endocrinology Board Review Manual Congenital and Acquired Hypothyroidism John S. Fuqua, MD INTRODUCTION Hypothyroidism refers to a state of decreased production and release of thyroid hormone from the thyroid gland. It is one of the most common endocrine abnormalities seen by primary care physicians and pediatric endocrinologists alike. Hypothyroidism in childhood may be congenital (present at birth) or acquired. Both forms of hypothyroidism can be further categorized as primary or central. This manual reviews clinical knowledge that is essential when caring for patients who present with laboratory or clinical evidence of hypothyroidism. The manual begins with an overview of thyroid development and physiology and then follows a case-based approach to review the causes, approach to evaluation, and treatment of congenital and acquired hypothyroidism. THYROID DEVELOPMENT AND PHYSIOLOGY EMBRYOLOGY AND FETAL THYROID FUNCTION Thyroid gland organogenesis begins at 26 days gestation, with the evagination of the medial thyroid bud from the floor of the developing pharynx. By 7 weeks, the developing gland lies in the thyroid bed. Function of the gland is first detected at 10 weeks, when the thyroid becomes able to trap iodide and synthesize thyroid hormone precursors. Thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) are secreted between 15 and 18 weeks, and by 18 to 20 weeks, the thyroid gland is able to release thyroid hormone in significant amounts in response to stimulation.1,2 The fetus has relatively low circulating levels of triiodothyronine (T3) and high levels of reverse T3 (rT3). Although maternal thyroxine (T4) and T3 can cross the placenta, only a small amount enters the fetal circulation, because the placental type 3 deiodinase (D3) avidly converts maternal T4 and T3 to inactive metabolites, limiting passage to the fetus. During the first half of gestation, the fetus relies on maternal thyroid hormone to support normal development of the central nervous system (CNS). In the hypothyroid fetus, the fetal brain Hospital Physician Board Review Manual www.turner-white.com is partially protected against low circulating levels of thyroid hormone by upregulation of type 2 deiodinase (D2) activity, which serves to increase the levels of T3 in the CNS.3 Nevertheless, otherwise healthy infants born to mothers with inadequately treated hypothyroidism have lower developmental scores, underscoring the importance of early fetal euthyroidism.4,5 After 30 weeks gestation, the level of fetal T3 gradually increases, the level of rT3 decreases, and fetal production of T4 and TSH increases. Most circulating thyroid hormones at this point are derived from the fetal thyroid. The ratio of TSH to T4 decreases, indicating the development and maturation of the fetal hypothalamic-pituitary-thyroid axis.2,3 Hence, in mid gestation, levels of both T4 and T3 are low compared to a term infant, and TSH secretion is relatively high as a result of the immaturity of the negative feedback system. NEONATAL THYROID FUNCTION At delivery, exposure to the cold extrauterine environment causes a surge in TSH secretion, with the concentration peaking at 70 mIU/mL by 30 minutes after birth. This TSH surge stimulates T4 secretion. The T3 level also increases, partly as a result of direct secretion from the thyroid gland and partly as a result of increases in tissue type 1 deiodinase (D1) and the absence of the deactivating placental D3. TSH gradually declines over the first 3 to 5 days of life to levels at or below 10 mIU/mL, while the increased T4 and T3 levels persist for weeks to months. THYROID HORMONE PHYSIOLOGY Synthesis of Thyroid Hormones Dietary iodide is actively taken up by the sodiumiodide symporter located on the basement membrane of the thyrocyte (Figure 1). The iodide is oxidized to iodine by thyroid peroxidase (TPO) and is incorporated into tyrosine residues on the thyroglobulin molecule. This process is termed organification. During organification, the iodinated tyrosine residues are also cross-linked to form the precursors of T3 and T4. The iodinated thyroglobulin is then stored in the colloid of the thyroid follicles. During secretion of thyroid www.turner-white.com Pediatric Endocrinology Volume 1, Part 3 Congenital and Acquired Hypothyroidism hormone, thyroglobulin is taken up from the colloid by endocytosis, and T3 and T4 are hydrolyzed from the thyroglobulin protein. Binding and Transport Approximately 99% of circulating thyroid hormones are bound to carrier proteins. Thyroxine-binding globulin (TBG) avidly binds both T4 and T3 and carries 70% of thyroid hormones. Two other proteins, transthyretin (formerly known as thyroxine-binding prealbumin) and albumin, have lower affinity but carry 10% and 15% to 20% of circulating thyroid hormones, respectively. Protein binding influences laboratory measurements of T4 and T3. Assays of total T4 levels do not measure the more physiologically relevant free fraction of T4. Direct (nonequilibrium dialysis) assays of free T4 are used frequently and are less influenced by abnormalities of binding proteins, such as TBG deficiency or excess. Equilibrium dialysis assays are more accurate but are not as readily available and are more time-consuming and expensive. Metabolism All circulating T4 is derived from the thyroid gland. Only 20% of T3 is secreted from the thyroid; the remaining 80% is produced from peripheral metabolism of T4. Both T4 and T3 are metabolized through the action of several deiodinases (Figure 2). D1, an activating enzyme that converts T4 to T3, is present in a variety of tissues and is responsible for the extrathyroidal production of T3. D1 is inhibited by propylthiouracil. D2 is confined to the brain, pituitary, placenta, and brown adipose tissue and is involved in the negative feedback regulation of the thyroid. D3, an inactivating enzyme, is located in the brain, placenta, and skin. Eighty percent of T4 is metabolized by deiodinases, and the other 20% is conjugated and excreted by the liver. ROLE OF THYROID HORMONE Thyroid hormones cross the plasma membrane through both passive diffusion and active transport. In the nucleus, T3 binds to thyroid hormone receptors. The hormone-receptor complex dimerizes and causes the activation or repression of the expression of numerous genes controlling many physiologic and developmental processes, including mitochondrial-based cellular respiration, which regulates energy economy and thermogenesis. Thyroid hormone also has important effects on lipid metabolism. In children, thyroid hormone has important developmental effects in the CNS, bone, heart, lung, skin, and gastrointestinal system. In the developing brain, thyroid hormone is critical for normal neuronal differentiation, myelinization, Hospital Physician Board Review Manual MIT T4 Thyroglobulin molecule T3 Thyroid colloid stores Peroxidase enzyme complex DIT IThyroglobulin MIT DIT Sodiumiodide symporter I- I- RNA DNA T T 4 3 TSH receptor T4 T3 TSH Blood vessel Figure 1. Synthesis and processing of thyroid hormones. Under thyroid-stimulating hormone (TSH) stimulation, iodide is actively taken up by the sodium-iodide symporter and thyroglobulin is syn thesized. Iodide is incorporated into thyroglobulin by the thyroid peroxidase complex. TSH also stimulates the uptake of iodinated thyroglobulin by endocytosis. The iodothyronines are cleaved off, and thyroxine (T4) and triiodothyronine (T3) are released, while the iodine from monoiodotyrosine (MIT) and diiodotyrosine (DIT) is recycled. (Adapted from Fisher DA. Thyroid disorders in childhood and adolescence. In: Sperling, MA, editor. Pediatric endocrinology. 2nd ed. Philadelphia: Saunders; 2002:190. Copyright 2002, with permission from Elsevier.) dendritic arborization, and synapse formation. Its effect on growth is well known and is mediated in part by its influence on growth hormone (GH) secretion. CONGENITAL HYPOTHYROIDISM CASE 1 PRESENTATION An 8-day-old female infant is referred to a pediatric endocrinologist after laboratory tests conducted as part of newborn screening revealed a TSH level of 374 mIU/mL and a total T4 level of 3.7 mg/dL. The mother states that the baby is breast-feeding well and has 6 to 8 wet diapers and 3 to 4 stools per day. She sleeps for several hours at a time but wakes regularly to nurse. On examination, the baby has regained her birth weight (3.2 kg) and appears healthy. www.turner-white.com Congenital and Acquired Hypothyroidism Thyroxine (T4) I H H I HO O I Type 1 and type 2 deiodinases I Triiodothyronine (T3) I H H HO O I C I C C H NH2 Type 3 deiodinase C C C H NH2 O OH Type 3 deiodinase Reverse triiodothyronine (rT3) I H H O HO OH O I I H H O I C I C H NH2 C H NH2 Type 1 and type 2 deiodinases Diiodothyronine (T2) HO C C C O OH Figure 2. Metabolism of the thyroid hor mones occurs via the action of 3 isoen zymes that catalyze deiodination. Type 1 deiodinase (D1) removes an iodine atom from the outer ring of thyroxine (T4) to form triiodothyronine (T3). Type 2 deio dinase (D2) also removes an iodine from the outer ring, converting T4 to T3. Type 3 deiodinase (D3) removes an iodine from the inner ring of T4 and T3, resulting in reverse T3 (rT3) and diiodothyronine (T2), both of which are physiologically inactive. O OH • What are the signs and symptoms of congenital hypothyroidism? the most common cause of congenital hypothyroidism and preventable mental retardation worldwide. CLINICAL FEATURES Dysgenesis of the Thyroid Gland Patients with thyroid dysgenesis most often have an ectopically located gland as a result of partial failure of both development and migration of the thyroid into the inferior neck. There is no goiter, although a small mass of thyroid tissue may rarely be seen on the posterior tongue near the foramen cecum, the embryonic origin of the thyroid bud. Some patients may also have residual thyroid tissue located in the superior neck in the midline, along the path of the thyroglossal duct. Thyroid gland ectopy must be distinguished from agenesis of the thyroid gland, or athyreosis. Athyreosis accounts for approximately 20% to 30% of cases of thyroid dysgenesis.7 Typically, athyreotic patients exhibit very high TSH and low T4 levels. Finally, some dysgenetic thyroid glands may be normally placed in the thyroid bed but are hypoplastic, with decreased function. Most infants presenting for evaluation of an abnormal newborn screening result will appear healthy and have few or no specific signs or symptoms that lead the physician to suspect a thyroid disorder. However, a thorough history and physical examination should be performed to identify factors that may affect the patient’s treatment or outcome. A careful family history might reveal affected relatives. A baby with severe congenital hypothyroidism lasting more than 4 to 6 weeks may present with poor feeding, constipation, lethargy or excessive sleeping, and hoarse cry. The physical examination may reveal failure to thrive, large anterior and posterior fontanelles, dry skin, jaundice, mottling, abdominal protuberance, an umbilical hernia, or coarsening of the facies. A goiter may be present. • What are potential causes of hypothyroidism? ETIOLOGIES The causes of congenital hypothyroidism can be roughly categorized into 4 groups: (1) dysgenesis of the thyroid gland, accounting for approximately 80% of cases; (2) inborn errors of thyroid hormone biosynthesis (collectively termed dyshormonogenesis), which cause approximately 10% to 15% of cases; (3) central hypothyroidism, accounting for less than 5% of cases; and (4) transient hypothyroidism, which occurs in approximately 5% of patients (Table 1).6 Although it is uncommon in the United States, iodine deficiency is www.turner-white.com Dyshormonogenesis Dyshormonogenesis refers to a group of genetic defects that may affect any step in the biosynthetic process; the most common defect is TPO deficiency. Most dyshormonogenesis defects are inherited in an autosomal recessive fashion, although TSH receptor (TSHR) defects may be autosomal dominant.8 Hence, most causes of dyshormonogenesis have a recurrence risk in subsequent pregnancies of 25%. Thyroid abnormalities are variable. Typically, the hypothyroidism is milder than that in patients with athyreosis. TPO deficiency. TPO oxidizes intracellular iodide, Pediatric Endocrinology Volume 1, Part 2 Congenital and Acquired Hypothyroidism Table 1. Etiologies of Congenital Hypothyroidism Etiology TSH T4 Goiter Scan Results Ultrasound Results Athyreosis Increased Decreased No No uptake No gland Ectopic thyroid Increased Decreased No Positive uptake at base of tongue No gland Eutopic thyroid Increased Decreased No Positive uptake Small gland TSH receptor defect Increased Decreased No No uptake Normal to small gland Na-I symporter defect Increased Decreased Yes No uptake Enlarged gland Organification defect Increased Decreased Yes Positive uptake Enlarged gland Thyroglobulin synthesis defect Increased Decreased Yes Positive uptake Enlarged gland Deiodination defect Increased Decreased Yes Positive uptake Enlarged gland Central hypothyroidism Low to normal Decreased No Positive uptake Normal to small gland Transient hypothyroidism Increased Thyroid dysgenesis Dyshormonogenesis Decreased If iodine-deficient or Positive uptake or normal exposed to goitrogen Normal gland Na-I symporter = sodium-iodide symporter.; T4 = thyroxine; TSH = thyroid-stimulating hormone. (Adapted from Fuqua J. Genetics, clinical manage ment and natural history of congenital hypothyroidism. Expert Rev Endocrinol Metab 2006;1:270, with permission of Future Drugs Ltd.) covalently binds the resulting intermediate to tyrosine residues on the thyroglobulin backbone, and couples monoiodotyrosines and diiodotyrosines to form the precursors of T3 and T4. In a recent study, mutations of the TPO gene were found in 24% of patients with congenital hypothyroidism and eutopic glands.9 TSHR defects. The TSHR is a 7 transmembrane domain, G protein–coupled receptor. Mutations of the TSHR gene are thought to be a rare cause of congenital hypothyroidism. Similar biochemical findings may be seen in patients with pseudohypoparathyroidism with the Albright’s hereditary osteodystrophy phenotype, which results from mutations in the GNAS gene.2 Pendred's syndrome. This uncommon cause of congenital hypothyroidism is the result of mutations in the gene coding for pendrin, a chloride-iodide transporter located at the apical membrane of the thyrocyte. Pendrin is involved in the presentation of iodide to TPO for organification. Affected patients present with an associated sensorineural hearing loss. Although thyroid function often is normal, some patients may present with elevated TSH and low T4. Goiter is a common feature but usually is not noted until childhood. Central Congenital Hypothyroidism Deficiencies of TRH or TSH are uncommon causes of congenital hypothyroidism. Patients present with either low or inappropriately normal or near-normal TSH and low T4. There is no goiter. Abnormalities of other hypothalamic-pituitary hormone systems are common. Midline CNS defects are often present. Some affected Hospital Physician Board Review Manual individuals with combined deficiencies of TSH, GH, and prolactin have defects in one of the pituitary transcription factors, such as PROP1 or PIT1. Transient Congenital Hypothyroidism The causes of transient congenital hypothyroidism vary. Maternal factors include transplacental passage of TSH-blocking antibodies, maternal iodine deficiency, or transplacental passage of medications taken by mothers with Graves' disease (propylthiouracil, methimazole).2 These medications may also be passed through breast milk and lead to thyroid suppression in neonates. Infant factors leading to transient hypothyroidism include neonatal exposure to iodine contained in surgical scrubs and intravenous contrast agents.10 Infants with transient congenital hypothyroidism usually present with mildly elevated TSH, although some patients with transient dysfunction may be more severely affected. A goiter may be present in cases of iodine deficiency. It is often difficult to distinguish infants with transient congenital hypothyroidism from those with permanent congenital hypothyroidism and eutopic, normally sized thyroid glands. Maternally derived TSH-blocking antibodies may persist in the infant’s circulation for several months before being cleared. • What is the next step in evaluating this baby? EVALUATION All infants with abnormal newborn screens should have venous blood samples measured for TSH and www.turner-white.com Congenital and Acquired Hypothyroidism total or free T4 concentrations, and treatment with l-thyroxine should be started. If the venous sample confirms congenital hypothyroidism, treatment may be continued; if the tests are normal, treatment may be stopped and the infant monitored. It is common to obtain imaging studies to identify the cause of congenital hypothyroidism.2 Classically, this has included technetium 99m (99mTc) scanning to identify the location of any residual functioning thyroid tissue. 99mTc scanning is cheaper, quicker, and more readily available than iodine 123 (123I) scanning. Many physicians have begun using ultrasonography to separate infants with a eutopic thyroid gland from those with thyroid ectopy and athyreosis. Patients with transient congenital hypothyroidism usually have a normal-appearing thyroid gland on ultrasonography and 99mTc scanning, although in the presence of TSHblocking antibodies, decreased tracer uptake may be noted. Patients with dyshormonogenesis or subtle dysgenesis may have mild hyperthyrotropinemia and a normal-appearing thyroid gland. If an organification defect is suspected, a perchlorate discharge test may aid in the diagnosis. Perchlorate will displace iodide from the thyroid that is not yet bound to thyroglobulin. In the presence of an organification defect, an abnormally large percentage of administered 123 I will be displaced upon administration of perchlorate, typically more than 10%.11 The test may be done at the time of diagnosis of congenital hypothyroidism or may be deferred until later in childhood. • How should this baby be treated? TREATMENT The goal of treatment is to establish normal thyroid function as quickly as possible. Normal thyroid function is indicated by a TSH in the normal range for age (ie, usually < 10 mIU/mL after 2 weeks of age). The American Academy of Pediatrics recommends a starting dose of lthyroxine of 10 to 15 mg/kg/day, with consideration of a higher dose in infants who are more severely affected and who have a T4 less than 5 mg/dL.12 l-Thyroxine should be prescribed as tablets, which may be crushed and mixed with a small amount of water. Premade solutions of lthyroxine should not be used because of the potential loss of stability. The family should be advised that soybased infant formulas can affect l-thyroxine absorption from the gut.13 Patients with central congenital hypothyroidism often require lower replacement doses of thyroid hormone than those with primary congenital hypothyroidism,14 and the TSH level often declines to near zero after treatment has begun.15 www.turner-white.com Patients should be closely monitored, with regular assessment of thyroid function. The first assessment should occur 2 weeks after initiation of therapy to avoid oversuppression of TSH, particularly if a high dose is used.16 Long-term oversuppression of TSH may lead to craniosynostosis and advancement of the bone age. TSH and T4 levels should be measured every 4 to 6 weeks during the first year and every 2 to 3 months during the second and third years. After the third birthday, levels should be checked every 6 to 12 months. To avoid the chance that the patient will outgrow his or her dose, the TSH level should be maintained in the mid to lower portion of the normal range and the T4 level kept in the upper half of the normal range. Following dose changes, the TSH and T4 levels should be measured after 4 to 6 weeks to ensure that the new dose is appropriate. As the child’s age advances, the dose of l-thyroxine per kg of body weight gradually declines. If diagnostic imaging showed a normally placed gland or if no imaging studies were obtained, the possibility exists that the patient may have had transient congenital hypothyroidism. In this case, it is advisable to temporarily stop l-thyroxine treatment after the child is 3 years old to confirm persistent hypothyroidism. One month later, if the TSH is elevated, treatment may resume.12 If the TSH is normal, the patient should have further observation off therapy and periodic monitoring of thyroid function.12 CASE 1 CONCLUSION The baby is started on l-thyroxine at a dose of 50 mg/day (15.6 mg/kg/day). Repeat thyroid function studies from a venous sample obtained prior to treat ment show that the baby’s TSH is 384 mIU/mL and free T4 is 0.27 ng/dL. A 99mTc scan shows no tracer uptake, consistent with athyreosis. Two weeks later, a repeat TSH measurement is 7.7 mIU/mL. Thyroid function studies are monitored every 4 to 6 weeks, during which time the infant appears to grow and develop normally. CASE 2 PRESENTATION A 3-month-old male infant is urgently referred for evaluation of abnormal thyroid function. The baby was previously thought to be well until his 2-month checkup, at which time his pediatrician noted poor weight gain and poor linear growth, constipation, cool dry skin, and a high-pitched cry. Thyroid function studies showed a TSH of 89 mIU/mL and a total T4 of 3.6 mg/dL, prompting the referral. • Why was this infant’s hypothyroidism missed on newborn screening? Pediatric Endocrinology Volume 1, Part 2 Congenital and Acquired Hypothyroidism NEWBORN SCREENING FOR HYPOTHYROIDISM Two major newborn screening strategies exist. The goal of both is to identify infants with abnormal values and to notify the appropriate physicians, ideally within the first 7 to 10 days of life. The first strategy, employed by most states in the United States, is primary measurement of T4. With this approach, all infants undergo measurement of the T4 level in a filter paper blood spot taken at approximately 48 hours of age, and those with a T4 level below a preset limit undergo a TSH measurement performed on the same blood spot. Many states also include a second round of newborn screening at 2 weeks of age. The second strategy, used in some states, involves TSH measurements in all infants, with repeat testing including T4 concentrations in those with TSH levels above the preset cutoff. Each screening strategy has its advantages. Primary T4 measurement allows detection of central hypothyroidism, in which TSH is not typically elevated. This strategy also allows detection of cases of congenital hypothyroidism in which T4 is low and there is a delayed rise in TSH. It may also be a more reliable tool for detecting neonatal hyperthyroidism.12 Primary TSH measurement has the advantage of detecting “compensated hypothyroidism,” in which T4 is normal but TSH is elevated. TSH-based screening also offers the advantage of nonisotopic assay techniques. Primary TSH measurement does not detect cases of TBG deficiency, a common nonpathologic cause of abnormal thyroid function tests. Unfortunately, screening programs do not detect every infant with congenital hypothyroidism. The infant in this case was screened in a primary T4 program. Although his T4 was above the cutoff on initial screening, he clearly developed primary hypothyroidism by age 3 months. This infant probably has a form of thyroid dysgenesis or dyshormonogenesis that was not severe enough at birth to be detected. Primary care providers must maintain a high index of suspicion for missed congenital hypothyroidism and consider the diagnosis when signs and symptoms consistent with congenital hypothyroidism are noted. or near-normal with early initiation of treatment and rapid normalization of the TSH level, studies consistently show that delays in initiating l-thyroxine replacement are associated with worse motor development and IQ.18 There does not appear to be a safe minimum age for initiation of treatment that guarantees a normal developmental outcome. Developmental outcomes are also related to the degree of severity of congenital hypothyroidism. Children with athyreosis tend to have lower scores on developmental testing than those with mild dysgenesis or dyshormonogenesis, reflecting the degree of in utero deprivation of thyroid hormone.19 If there is simultaneous maternal and fetal hypothyroidism, the infant with congenital hypothyroidism is at very high risk for a poor developmental outcome. The osseous maturation of the skeleton is sometimes used as a marker of severity. Infants with severe congenital hypothyroidism do not have any ossification centers in the knee, as opposed to normal neonates or those with mild congenital hypothyroidism. Studies evaluating outcomes following different doses of l-thyroxine demonstrate the superiority of doses in the 10 to 15 mg/kg/day range over lower doses.20 Infants with the most severe degree of congenital hypothyroidism may benefit from doses in the range of 12 to 17 mg/kg/day.21 Hence, the child in this case is at high risk for developmental problems. Treatment should be initiated immediately, and the child should be referred for developmental therapies and early intervention programs. • What is this infant’s developmental prognosis? CASE 3 PRESENTATION A pediatric endocrinologist is called by the neonatal intensive care unit (NICU) to see an 8-day-old female infant who was born at 27 weeks gestation. She is intubated and conventionally ventilated and receiving trophic feedings via a nasogastric tube. She is completing a course of antibiotics for suspected sepsis, although all cultures thus far have been negative. Cardiac function has been normal, and screening ultrasonography of the head was normal. Newborn screening was remarkable OUTCOME OF CONGENITAL HYPOTHYROIDISM Long-term studies of growth and physical and mental development of children with congenital hypothyroidism have shown that, with proper treatment, outcomes are good.17 Appropriately treated patients experience normal pubertal development and achieve normal adult height. Although motor and cognitive outcomes are normal Hospital Physician Board Review Manual CASE 2 CONCLUSION l-Thyroxine treatment is started at a dose of 50 mg/day. Follow-up thyroid function studies after 2 weeks show normalization of the TSH level. T4 and TSH levels are measured monthly, and the patient is enrolled in an early intervention program for infants at risk for developmental delay. His thyroid function remains normal, and at age 12 months, he is pulling up to a stand but not cruising. He says “mama” and “dada” nonspecifically, consistent with possible mild developmental delay. www.turner-white.com Congenital and Acquired Hypothyroidism for a low T4 of 6.2 mg/dL. The NICU staff obtained a venous sample on day 6 of life, which showed a TSH of 6.4 mIU/mL, a total T4 of 5.9 mg/dL, and a free T4 of 0.81 ng/dL. • Does this baby have congenital hypothyroidism? THYROID FUNCTION IN THE PREMATURE INFANT In preterm infants, particularly those less than 30 weeks gestation or with a birth weight less than 1500 g, the normal surge in TSH following delivery is blunted, and the increases in T4 and T3 are not as great as in term infants. The lower T4 and T3 levels are thought to be related to the immaturity of the hypothalamicpituitary-thyroid axis. In addition, very premature infants may exhibit a variety of illnesses, including pulmonary disease, intracranial hemorrhage, inadequate nutritional status, and hemodynamic instability requiring dopamine infusion, all of which have been associated with decreased thyroid hormones.22 Nevertheless, TSH levels usually are in the normal range during this time, and in the face of primary thyroid dysfunction, most infants, even if premature, are able to mount a TSH response, although the increase in TSH may be delayed.23,24 The low levels of T4 and T3 associated with normal TSH levels is known as hypothyroxinemia of prematurity. Decreased T4 levels have been associated with a variety of adverse outcomes in premature infants, including increased mortality, cerebral palsy, and low scores on developmental testing.25 However, causality has not been firmly established because of the association of increased severity of illness with low thyroid hormone concentrations. Treatment of low T4 levels in premature infants remains controversial. CASE 3 CONCLUSION A second set of thyroid function studies is ordered. At 12 days of age, the baby’s TSH is 5.15 mIU/mL and free T4 is 0.95 ng/dL. These results are interpreted as being normal for an ill premature infant. Prior to discharge 8 weeks later, the NICU obtains additional thyroid studies, and the child’s TSH is 2.05 mIU/mL and free T4 is 1.49 ng/dL, clearly within normal limits. However, since age 5, height velocity has dramatically slowed. Recent measurements show that her height is now 3 standard deviations below the mean. During this same interval, she has continued to gain weight, and her current weight is in the 10th percentile. The child was recently seen by a new pediatrician, who obtained a TSH level, which was greater than 500 mIU/mL. • What are the signs and symptoms of acquired hypothyroidism? CLINICAL FEATURES Typical signs and symptoms of hypothyroidism are listed in Table 2. Symptoms often develop gradually, however, and the patient or parent may not be aware that problems exist. In patients who abruptly discontinue thyroid hormone replacement, symptoms are usually more apparent. Rarely, patients with primary hypothyroidism may have evidence of precocious puberty, including breast development in girls and testicular enlargement in boys, usually without significant pubic hair growth.26 The bone age in these children is delayed. This phenomenon is sometimes called the Van Wyk-Grumbach syndrome. The cause is unclear but appears to involve stimulation of gonadotropin secretion or “cross talk” between gonadotropin-releasing hormone and TRH. CASE 4 CONTINUED Upon further questioning, the parents think that the child may have been less active than other children her age. She has had occasional complaints of constipation but has not required regular treatment for this problem. She has never had any neck complaints. She has had no skin rashes or complaints of bone pain. There is a family history of hypothyroidism in a maternal aunt. On physical examination, the patient is a small, slightly chubby, quiet-appearing girl without much spontaneous movement. Her dental development is delayed; she has all of her primary dentition. She has no palpable goiter and no neck tenderness. She is prepubertal. Her skin and hair are somewhat dryer than average. Her reflexes are 1+, and there is a delay in their relaxation. • What are the causes of acquired hypothyroidism? ACQUIRED HYPOTHYROIDISM CASE 4 PRESENTATION An 8-year-old girl is referred for short stature. The child’s growth records show that she had been growing along the 25th percentile between ages 2 and 5 years. www.turner-white.com ETIOLOGIES The causes of acquired hypothyroidism (Table 3) may be divided into primary diseases of the thyroid gland and central causes, including diseases of the pituitary and hypothalamus. Autoimmune thyroid disease is by far the most common cause of acquired Pediatric Endocrinology Volume 1, Part 2 Congenital and Acquired Hypothyroidism Table 2. Symptoms and Signs of Hypothyroidism Table 3. Etiologies of Acquired Hypothyroidism Symptoms Signs Primary Central Fatigue Poor growth Mild obesity Autoimmune thyroid disease (chronic lymphocytic thyroiditis) CNS tumor Increased sleep Dry skin Mental slowness Iodine deficiency Chemotherapy Hair loss Dry skin Medications Head trauma CNS irradiation Constipation Thin, coarse hair Lithium Cold intolerance Cool skin Amiodarone Anorexia nervosa Depression Sallow complexion Iodinated radiographic contrast Meningitis Menstrual disturbances Nonpitting edema Iodine-containing surgical scrubs Congenial malformation Neck enlargement/compression Voice changes Radioactive iodine Dysphagia Bradycardia Propylthiouracil Delayed puberty Hyporeflexia Methimazole Galactorrhea Delayed relaxation of deep tendon reflexes Subacute thyroiditis Decreased pulse pressure Histiocytosis Goiter (depending on etiology) Hemochromatosis Delayed tooth eruption Birth asphyxia Septo-optic dysplasia Other Histiocytosis Granulomatous diseases External radiation Cystinosis hypothyroidism in the United States, although the most common cause worldwide is iodine deficiency. Hashimoto’s thyroiditis is the term used to describe goitrous autoimmune thyroid disease, which is clinically distinguished from atrophic autoimmune thyroid disease by the presence or absence of a goiter. The prevalence of thyroid autoimmunity is quite high, with positive antibodies found in as many as 18% of the general population.27 Autoimmune thyroiditis is more common in females and can occur in young children, although it is rare in infancy. In the pediatric population, there is a clear increase in frequency in peripubertal and pubertal girls. A family history is often present. Physical examination often reveals a goiter, which is typically described as exhibiting a “pebbly” texture. In the atrophic form of autoimmune thyroiditis, a goiter is not palpable. Histologic evaluation of the thyroid tissue reveals a lymphocytic infiltrate, and germinal centers are sometimes present. The majority of individuals with autoimmune thyroiditis are biochemically euthyroid. Progression to hypothyroidism usually occurs slowly, and many individuals remain euthyroid.28 Patients with iodine deficiency present with identical clinical symptoms and signs, including the presence of a goiter of varying size. Patients with central hypothyroidism may present with signs and symptoms that are identical to those of patients with primary hypothyroidism, although a goiter is not present. In addition, there may be evidence of other pituitary hormone deficiencies. Patients with GH deficiency may occasionally develop central hypothyroidism after institution of GH therapy, possibly related to increases in somatostatin levels.29 10 Hospital Physician Board Review Manual CNS = central nervous system. The case patient is known to have an abnormal TSH. Hence, she clearly has primary hypothyroidism but no goiter. She has no known history of exposure to agents that cause hypothyroidism, and does not have symptoms of other conditions that may cause primary dysfunction of the thyroid, such as subacute thyroiditis or histiocytosis. It is most likely that she has atrophic autoimmune thyroiditis. • What studies should be obtained in this case? EVALUATION Few laboratory studies are required for the typical patient presenting with concerns about thyroid function. TSH measurement is needed, as is measurement of the T4 level (free or total). Many clinicians prefer to measure free T4, as this avoids errors related to abnormalities of binding proteins. In this particular patient, either test is adequate, as both are likely to be low. For the patient who is not known to have a TSH elevation, a free T4 level will help to avoid confusion in cases of a protein-losing disease, genetic deficiency of TBG, or TBG excess related to oral contraceptive use. Measurement of T3 or free T3 is of little clinical use in this setting. The autoimmune nature of the thyroid disease can be assessed through the measurement of antibodies to TPO and thyroglobulin antibodies. Further diagnostic studies in a patient such as this are probably not necessary. In patients with an www.turner-white.com Congenital and Acquired Hypothyroidism asymmetrically enlarged gland or a palpable nodule, imaging studies may prove useful. Ultrasonography in patients with autoimmune thyroiditis shows a hetero geneous echogenicity, often with the presence of numerous small cysts or nodules; a dominant or large nodule is not usually present. Iodine deficiency is best assessed by measuring urinary excretion of iodine. Central hypothyroidism manifests as low levels of T4 without an appropriate elevation in the TSH concentration. In patients with central hypothyroidism resulting from hypothalamic disease, the TSH may be slightly above the upper limit of normal but is typically not as elevated as would be expected in cases of primary hypothyroidism. If a destructive lesion of the pituitary gland is present, both T4 and TSH levels will be low. Other measures of pituitary function may also be abnormal. Although it is not currently available in the United States, TRH has been used to assess for central hypothyroidism. Pituitary disease is indicated by the absence of a response of TSH to administration of TRH. Hypothalamic disease is indicated by a late and prolonged rise of TSH in response to TRH. Primary hypothyroidism is indicated by an exaggerated TSH response to TRH.30 CASE 4 CONTINUED Thyroid testing reveals the following: free T4, 0.4 ng/dL (normal, 0.8–2.1 ng/dL); TSH, 653 µIU/mL (normal, 0.5–4.5 µIU/mL); TPO antibodies, 2599 IU/mL (normal, 0–20 IU/mL); and thyroglobulin antibodies, 1953 IU/mL (normal, 0–100 IU/mL). On the basis of the history, physical examination, and laboratory studies, a diagnosis of atrophic auto immune thyroiditis is made. • How should this patient be treated? TREATMENT Hypothyroidism is treated with thyroid replacement. The l-thyroxine dose varies with age. The dose for an individual patient is not entirely predictable based on age and body weight alone, and monitoring of thyroid function is essential. Treatment with other forms of thyroid hormone, such as T3 or combined T4 and T3 therapy, is not recommended. The goal of hormone replacement is to achieve a TSH in the normal range. Thyroid function studies, typically including a TSH and either a total or free T4, are obtained 4 to 6 weeks following initiation of treatment. Because the half-life of l-thyroxine is approximately 1 week, measurement of levels before this length of time does not allow for a steady-state l-thyroxine level www.turner-white.com to be reached and for the pituitary secretion of TSH to stabilize. Following any dose change, repeat thyroid studies should be obtained after a similar interval. In patients with long-standing hypothyroxinemia, it is often recommended to begin replacement therapy with a low dose and then gradually advance to full replacement doses over a period of several months. This is thought to minimize the risk of benign intracranial hypertension (pseudotumor cerebri) and to delay the rapid advancement in bone age that is usually seen in treatment of severe, long-standing hypothyroidism.14 In cases of central hypothyroidism, TSH measurements are not helpful, and they often decline to near zero with treatment. Measurement of total or free T4 is sufficient in such cases, and the goal should be to obtain levels in the mid to upper range of normal for age, without the induction of signs or symptoms of hyperthyroidism. Patients with central hypothyroidism often require doses that are lower than those used in patients with primary hypothyroidism.15 A variety of medications may alter thyroid hormone homeostasis (Table 4), and this may be reflected in thyroid function tests. Exposure to iodine-containing compounds may acutely decrease the iodination of thyroid hormones and lower their serum levels, a phenomenon known as the Wolff-Chaikoff effect. This is temporary and resolves over several days as the intrathyroidal concentration of iodide is down-regulated. CASE 4 CONCLUSION Treatment with l-thyroxine is initiated at a dose of 37.5 mg/day. Several weeks after beginning treatment, the patient’s mother calls to report that her daughter is sleeping less than before and seems much brighter. Her energy level is clearly increased, but she seems very “hyper” and is having behavior problems in school. Thyroid function studies obtained 6 weeks after initiating l-thyroxine therapy show that the patient's TSH has declined to 9.5 mIU/mL and free T4 is 1.4 ng/dL. • What is this child’s prognosis? LONG-TERM EFFECTS OF HYPOTHYROIDISM Deterioration of school performance is a common complaint in cases of newly treated long-standing hypothyroidism. It is helpful to inform families that this may occur, so they can discuss this problem with teachers and school administrators. Decreased school performance is usually temporary and typically resolves over several months. Gradual escalation of l-thyroxine doses may help reduce the severity. Linear growth is often impaired in children with Pediatric Endocrinology Volume 1, Part 2 11 Congenital and Acquired Hypothyroidism Table 4. Drugs That Alter Thyroid Hormone Concentrations Mechanism Dopamine Reduce TSH secretion Somatostatin analogs Reduce TSH secretion Glucocorticoids Reduce TSH secretion Reduce TRH secretion Decrease T4 to T3 conversion Decrease TBG concentration Furosemide Decrease T4 and T3 binding to TBG Salicylates Decrease T4 and T3 binding to TBG Methimazole Decrease thyroid hormone biosynthesis Propylthiouracil Decrease thyroid hormone biosynthesis Decrease T4 to T3 conversion Propranolol Decrease T4 to T3 conversion Iodine excess (including iodinated patients) Decrease thyroid hormone synthesis and secretion (may cause thyrotoxicosis in iodine-deficient contrast agents) Lithium Decrease thyroid hormone biosynthesis Amiodarone Decrease T4 to T3 conversion Induction of thyroid autoimmunity Interferon-α Induction of thyroid autoimmunity Phenytoin Increase nondeiodinative metabolism of T4 and T3 in liver Carbamazepine Increase nondeiodinative metabolism of T4 and T3 in liver Rifampin Increase nondeiodinative metabolism of T4 and T3 in liver Phenobarbitol Increase nondeiodinative metabolism of T4 and T3 in liver T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globu lin; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone. Serum hormone concentration Medication rT3 TSH Normal range FT4 T4 T3 Mild Moderate Severe Recovery Figure 3. Effect of critical illness on thyroid function. Levels of triiodothyronine (T3) are typically low, while reverse T3 (rT3) levels are elevated. Thyroxine (T4) may be suppressed, but free T4 (FT4) levels are usually normal except in severely ill patients. Thyroidstimulating hormone (TSH) concentrations are usually normal, although they may rise transiently during the recovery phase. (Adapted with permission from Brent GA, Hershman JM. Effects of nonthyroidal illness on thyroid function tests. In: Van Mid dlesworth L, editor. The thyroid gland: a practical clinical treatise. Chicago: Year Book Medical Publishers; 1986:83–110.) it is important to obtain a baseline bone age around the time of the initial diagnosis. It is also important to monitor closely for the possibilities of GH deficiency, precocious puberty, rapid progression of puberty, and other endocrine problems that may further compromise adult height. CASE 5 PRESENTATION A pediatric endocrinologist is asked to see an 11-year-old boy who has been in the pediatric intensive care unit (PICU) with meningococcal septic shock without meningitis for 1 week. The patient is intubated and mechanically ventilated for acute respiratory distress syndrome. He is receiving dopamine for blood pressure support. Thyroid function studies ordered by the PICU staff revealed a low total T4 of 4.1 mg/dL and a TSH of 0.95 mIU/mL. long-standing hypothyroidism, as in this case patient. The short stature is usually associated with a major delay in bone age, initially suggesting that the child’s future growth potential is good.31 Typically, a very rapid catchup growth is seen following institution of l-thyroxine treatment. However, the rate of skeletal maturation is often excessive, and long-term height gain may be limited. Although it is thought that gradual institution of treatment may slow the bone age advancement, there is little evidence to support this. Ultimately, early diagnosis is the best way to ensure that adult height will not be impaired. Excessively high doses of thyroid hormone can also cause rapid advancement in skeletal maturation. Although height velocity may also be increased, the unduly rapid bone age advancement may limit final adult height. Because of the potential for compromised adult height in patients with acquired hypothyroidism, NONTHYROIDAL ILLNESS SYNDROME Nonthyroidal illness syndrome, also known as sick euthyroid syndrome, is a poorly understood response to severe illness. It is manifested biochemically by a suppression of total and free T4 and total T3 levels without an increase in TSH levels (Figure 3). The pathogenesis of sick euthroid syndrome is marked by an alteration of the activity of D1, leading to lower rates of synthesis of T3 and decreases in 12 Hospital Physician Board Review Manual www.turner-white.com • Does this boy have central hypothyroidism? Congenital and Acquired Hypothyroidism degradation of rT3, leading to elevated concentrations of rT3. In severely ill individuals, the changes may occur within a day. With recovery, there may be a transient increase in the TSH until the T4 and T3 levels return to normal. In critically ill patients, the use of dopamine or high doses of glucocorticoids often causes suppression of TSH levels that may lead to further reductions in T4 and T3. Although there is a clear relationship between the severity of sick euthyroid syndrome and outcome measures such as mortality, a causal link between the two has not been established. The question of whether sick euthyroid syndrome is an adaptive response or one that is at least partly maladaptive remains unanswered. Treatment with thyroid hormone has not proved beneficial in studies of critically ill adults and is not recommended. CASE 5 CONCLUSION The specialist informs the PICU team that the patient probably has sick euthyroid syndrome. The physician requests a total T3 and rT3 and recommends that the clinical team monitor the boy’s thyroid function tests. His total T3 is 85 ng/dL (normal, 119–218 ng/dL), and his rT3 is 262 ng/dL (normal, 10–50 ng/dL). He begins to make a gradual recovery and is successfully weaned off pressors and the ventilator. Ten days after the initial consult, the patient’s TSH is slightly elevated at 8.2 mIU/mL, and his total T4 is up to 7.8 mg/dL. His free T4 is normal at 0.9 ng/dL, and his total T3 is 140 ng/dL. One week later, his TSH, total T4, and free T4 are all normal. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. REFERENCES 24. 1. Trueba SS, Auge J, Mattei G, et al. PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations. J Clin Endocrinol Metab 2005;90:455–62. 2. MacGillivray M. Congenital hypothyroidism. In: Pescovitz OH, Eugster EA, editors. Pediatric endocrinology: mechanisms and management. Philadelphia: Lippincott Williams & Wilkins; 2004:490–507. 3. Fisher D. Fetal-perinatal thyroid physiology. In: Eugster EA, Pescovitz OH, editors. Developmental endocrinology: from research to clinical practice. Totowa (NJ): Humana Press, Inc.; 2002:135–49. 4. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549–55. 5. Pop VJ, Brouwers EP, Vader HL, et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 2003;59:282–8. 6. Fuqua J. Genetics, clinical management and natural history of congenital hypothyroidism. Expert Rev Endocrinol Metab 2006;1:265–79. 7. Bubuteishvili L, Garel C, Czernichow P, Leger J.Thyroid abnormalities by ultrasonography in neonates with congenital hypothyroidism. J Pediatr 2003;143:759–64. 8. Alberti L, Proverbio MC, Costagliola R, et al. Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism. J Clin Endocrinol Metab 2002;87:2549–55. 9. Rodrigues C, Jorge P, Soares JP, et al. Mutation screening of the thyroid peroxidase gene in a cohort of 55 Portuguese patients with congenital 25. 26. 27. 28. 29. 30. 31. hypothyroidism. Eur J Endocrinol 2005;152:193–8. Linder N, Sela B, German B, et al. Iodine and hypothyroidism in neonates with congenital heart disease. Arch Dis Child Fetal Neonatal Ed 1997;77: F239–40. Meller J, Zappel H, Conrad M, et al. Diagnostic value of 123iodine scintigraphy and perchlorate discharge test in the diagnosis of congenital hypothyroidism. Exp Clin Endocrinol Diabetes 1997;105 Suppl 4:24–7. Rose SR, Brown RS, Foley T, et al. Update of newborn screening and therapy for congenital hypothyroidism. American Academy of Pediatrics; Section on Endocrinology and Committee on Genetics, American Thyroid Association; Public Health Committee, Lawson Wilkins Pediatric Endocrine Society. Pediatrics 2006;117:2290–303. Conrad SC, Chiu H, Silverman BL. Soy formula complicates management of congenital hypothyroidism. Arch Dis Child 2004;89:37–40. Rivkees S. Hypothyroidism and hyperthyroidism in children. In: Pescovitz OH, Eugster EA, editors. Pediatric endocrinology: mechanisms and management. Philadelphia: Lippincott Williams & Wilkins; 2004:508–21. Carrozza V, Csako G, Yanovski JA, et al. Levothyroxine replacement therapy in central hypothyroidism: a practice report. Pharmacotherapy 1999;19:349–55. Australasian Paediatric Endocrine Group. Guidelines for diagnosis, management & follow-up of children with congenital primary hypothyroidism. Available at www.racp.edu.au/apeg/cph.htm. Accessed 22 Mar 2007. Bongers-Schokking JJ, Koot HM, Wiersma D, et al. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000;136:292–7. Kooistra L, Laane C, Vulsma T, et al. Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment. J Pediatr 1994;124:903–9. Rovet JF. Children with congenital hypothyroidism and their siblings: do they really differ? Pediatrics 2005;115:e52–7. Salerno M, Militerni R, Bravaccio C, et al. Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism. Thyroid 2002;12:45–52. Selva KA, Harper A, Downs A, et al. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr 2005;147:775–80. Filippi L, Cecchi A, Tronchin M, et al. Dopamine infusion and hypothyroxinaemia in very low birth weight preterm infants. Eur J Pediatr 2004;163:7– 13. Larson C, Hermos R, Delaney A, et al. Risk factors associated with delayed thyrotropin elevations in congenital hypothyroidism. J Pediatr 2003; 143:587–91. Gruneiro-Papendieck L, Chiesa A, Mendez V, et al. Efficacy of congenital hypothyroidism neonatal screening in preterms less than 32 weeks of gestational age: more evidence. J Pediatr Endocrinol Metab 2005;18:373–7. Rapaport R, Rose SR, Freemark M. Hypothyroxinemia in the preterm infant: the benefits and risks of thyroxine treatment. J Pediatr 2001;139:182– 8. Niedziela M, Korman E. Severe hypothyroidism due to autoimmune atrophic thyroiditis––predicted target height and a plausible mechanism for sexual precocity. J Pediatr Endocrinol Metab 2001;14:901–7. 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;87:489–99. Radetti G, Gottardi E, Bona G, et al. The natural history of euthyroid Hashimoto's thyroiditis in children. Study Group for Thyroid Diseases of the Italian Society for Pediatric Endocrinology and Diabetes (SIEDP/ISPED). J Pediatr 2006;149:827–32. Giavoli C, Porretti S, Ferrante E, et al. Recombinant hGH replacement therapy and the hypothalamus-pituitary-thyroid axis in children with GH deficiency: when should we be concerned about the occurrence of central hypothyroidism? Clin Endocrinol 2003;59:806–10. Evliyaoglu O, Berberoglu M, Ocal G, et al. Exaggerated TSH responses to TRH in patients with goiter and 'normal' basal TSH levels. Horm Res 2005;64:299–302. Chiesa A, Gruneiro de Papendieck L, Keselman A, et al. Final height in long-term primary hypothyroid children. J Pediatr Endocrinol Metab 1998;11:51–8. Copyright 2007 by Turner White Communications Inc., Wayne, PA. All rights reserved. www.turner-white.com Pediatric Endocrinology Volume 1, Part 2 13