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Thyroid disorders present with overt symptoms or insidiously with few signs of disease. Here’s how pediatricians can identify and effectively treat children with thyroid disease or refer patients for further evaluation.
Thyroid hormones play an essential role in growth, development, and physiology. Abnormal thyroid function can have profound deleterious effects in the pediatric population.
Thyroid disorders can present with or without thyromegaly (goiter), with overt symptoms, or insidiously with few symptoms or signs of thyroid disease. Whereas the evaluation and management of pediatric thyroid disorders typically involves a pediatric endocrinologist, the primary care provider plays a critical role in identifying children with thyroid disease or those who need referral. This article provides an overview on the manifestations, evaluation, and management of the most common thyroid disorders seen in the pediatric population.
Evaluation of the thyroid
ASSESSMENT OF THYROID STRUCTURE/ANATOMY
Examination of the thyroid gland for symmetry, consistency, and size should be part of the complete physical examination performed in children. The examination consists of both visual inspection and palpation (see Figure; also go to https://www.youtube.com/watch?v=Z9norsLPKfU).1 The visual inspection portion is as important as palpation.
Until the end of puberty, the thyroid gland size (in grams) is approximately equal to the patient’s age in years multiplied by 0.5 to 0.7. For example, normal total gland weight in a 10-year-old child would be 5 g to 7 g, and the size of each lobe would be approximately equivalent to a one-half teaspoon.
If thyroid asymmetry is noted or if the gland is believed to be enlarged, further evaluation is needed. This evaluation may include assessment of thyroid hormone concentrations, a thyroid ultrasound (see “Thyroid ultrasound”), and/or referral to a pediatric endocrinologist.
THYROID PHYSIOLOGY AND BIOCHEMICAL ASSESSMENT
Laboratory findings for select thyroid disorders are outlined in the Table.
Tetraiodothyronine (T4; also known as thyroxine) and triiodothyronine (T3) are the major thyroid hormones, and their production is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH; also known as thyrotropin-releasing factor) produced by the hypothalamus stimulates anterior pituitary production of thyroxine stimulating hormone (TSH; also known as thyrotropin). Thyrotropin then binds to TSH receptors on thyroid follicular cells, causing the production and release of T3 and T4. T4 represents the majority of thyroid hormone released by the thyroid gland, but it is T3 that principally binds to thyroid hormone receptors. Most T3 in the circulation is derived from peripheral deiodination of T4. In the circulation, both T4 and T3 are mostly bound to proteins (thyroxine-binding globulin [TBG], prealbumin, and albumin). Concentrations of the thyroid-binding proteins are affected by genetic conditions, decreased by androgens, and increased by estrogens (eg, with use of oral contraceptives). Only free (unbound) T3 and T4 are biologically active.
The euthyroid state is maintained by a feedback loop in which TRH production is suppressed by increasing circulating T3/T4 concentrations and increased when T3/T4 concentrations decline. Thyroid hormone production also can be affected by antibodies that stimulate or block TSH action. For example, in Graves’ disease (GD), which is the most common form of hyperthyroidism in children, thyroid-stimulating immunoglobulins [TSI; also known as thyroid receptor antibodies [TRAb]) bind to and activate TSH receptors in the thyroid. TSH receptor-blocking immunoglobulins (TBI) that antagonize TSH action are a rare cause of hypothyroidism.
Laboratory testing of thyroid function includes assessments of total T4 and total T3; T3 resin uptake, which is an index reflecting thyroid hormone-binding proteins; free T4 (FT4), representing the unbound hormone; and TSH. Assays for T3 are usually not necessary for diagnosing hypothyroidism. Because TBG is elevated in infants, estimated FT4 values may not be accurate; equilibrium dialysis assay or measurement by tandem mass spectrometry (MS) will provide a more accurate measurement of FT4.
Thyroid stimulating hormone (TSH) is the most sensitive marker for evaluating thyroid gland function, and assessment of TSH with ultrasensitive assays has greatly improved the evaluation of thyroid status. Critical in the interpretation of TSH values in children is recognition that the normative range differs from that of adults-the upper normal limit of TSH is 5.6 Î¼IU/mL in healthy children and adolescents without thyroid disease versus 4 Î¼IU/mL in adults.2,3 However, one should always compare the measured value with the reference range for each specific assay used. Application of the adult reference range to children risks erroneous diagnosis of subclinical hypothyroidism and unnecessary referral for subspecialty care. It is also important to obtain a repeat determination before referral if the TSH is only slightly elevated, as concentrations will normalize in the vast majority of children.2 In addition, overweight and obese children also often have a mildly elevated TSH without this being caused by thyroid disease.4
Among the 2 functional disorders, hypothyroidism is more common in children than hyperthyroidism. Hypothyroidism can occur as a congenital or acquired condition and is also categorized based on whether it is due to disease of the thyroid gland itself (primary) or a defect at the level of the pituitary gland (secondary) or hypothalamus (tertiary). Hypothyroidism related to a pituitary or hypothalamic disorder is also referred to as central hypothyroidism and is much less common than primary hypothyroidism.
Congenital hypothyroidism (CH) is the most common preventable form of mental retardation. It occurs in about 1 in 3000 to 4000 newborns and is more common in Asian, Native American, and Hispanic infants than in Caucasians and African Americans. Among infants born in developed countries, CH is most often due to thyroid dysgenesis (about 90%) in which there is complete or partial failure of gland development or failure of normal migration to a eutopic position. Approximately two-thirds of all thyroid dysgenesis is due to ectopic glands. Thyroid dyshormonogenesis, defined by defects in thyroid hormone biosynthesis or secretion, accounts for most of the remaining cases (about 10%), and central hypothyroidism is even less common. Congenital hypothyroidism also can occur as a transient condition secondary to maternal transfer of TSH receptor-blocking antibodies or medications that interfere with fetal thyroid function.
The majority of cases of CH occur sporadically, so it is not possible to predict which infants are likely to be affected. Rare familial as well as sporadic cases of thyroid dysgenesis are due to mutations in certain transcription factors (PAX-8, TTF-1, and TTF-2) involved in thyroid morphogenesis and differentiation. Thyroid dyshormonogenesis, on the other hand, is typically transmitted in an autosomal recessive pattern.
DETECTION When the mother has normal thyroid status, the fetus is at least partially protected from effects of hypothyroidism in utero. Children with CH are typically asymptomatic at birth. Newborn screening tests using blood from a heel stick have therefore been instrumental for allowing timely diagnosis and initiation of thyroid replacement treatment critical for normal neurocognitive development. A low T4 and/or high TSH represents a positive result and indicates a need for confirmatory testing with blood obtained by venipuncture to measure TSH and free T4. However, practitioners need to be aware that the screening test will not detect all cases of CH. A low TSH will not be detected by some screening tests, thus CH due to pituitary or hypothalamic defects may be missed. In addition, newborn screening within the first 24 hours after birth can result in false-positive results because of the surge in TSH that occurs immediately after birth.
Interpretation of screening test results is different in premature infants and acutely ill term babies, who initially often have a low TSH and low total T4. This is attributed to immaturity of the hypothalamic-pituitary-thyroid axis. These infants should be followed with serial testing. Data show no benefit of initiating thyroid hormone replacement therapy for infants with isolated low FT4 levels. Babies with a low T4 with an elevated TSH may require treatment.
MANAGEMENT Treatment for CH with levothyroxine (LT4) should be started within the first 2 weeks of life with a goal of normalizing T4 within 1 to 2 weeks and TSH by 4 weeks. The recommended dose is 10-15 Î¼g/day with 25-37.5 Î¼g/day being the average dose for a healthy term infant (or 100 Î¼g/m2/day). Overtreatment with LT4 should be avoided because it may be as detrimental to neurocognitive development as undertreatment.
Levothyroxine is available only as tablets that will need to be crushed, and parents should be instructed to avoid co-administration with calcium, iron, antacids (aluminum), simethicone, and soy because these interfere with LT4 absorption. Generic forms of medication are indeed acceptable for treating children with thyroid disorders.
When children are treated for CH, it is recommended that thyroid hormone concentrations be assessed monthly for the first 6 months, then every 2 months from 6 to 12 months, every 3 months from 12 to 24 months, and every 4 months from 24 to 36 months. Thereafter, testing can take place every 6 months. At age 3 years, a child who had an initial TSH of <10-15 Î¼IU/mL in the newborn period, and who remained on a stable LT4 dose that did not require repeated dose increases, and who showed normal growth and development, can be given a trial off LT4 with serial laboratory testing to determine current thyroid function and to rule out a transient form of neonatal hypothyroidism. A thyroid ultrasound may be done before stopping the LT4 to check for normal thyroid gland development and position. Thyroid scintigraphy (technetium scan) is the best radiologic study to detect ectopic thyroid gland position.
Delayed treatment of hypothyroidism in children aged up to 3 years can result in permanent decrements in neurocognitive function. Children who develop hypothyroidism after age 3 years may develop reversible behavior changes and growth issues but are not at risk for having permanent neurocognitive development deficits.
The most common clinical features of acquired hypothyroidism are tiredness and fatigue, cold intolerance, constipation, dry skin, and menstrual irregularities. Because these signs and symptoms are nonspecific and can overlap with common complaints of daily life, diagnosis based on symptoms alone may result in overdiagnosis. Thyroid gland enlargement is also a common feature of hypothyroidism but is also a sign of hyperthyroidism. Hypothyroidism does not cause obesity, but TSH may be slightly increased in obese patients, which can lead to a misdiagnosis of hypothyroidism.
Autoimmune thyroid it is, or Hashimoto thyroiditis, is the most common cause of acquired hypothyroidism among children and adolescents. It occurs more often in females than males, and affected children often have a family history of autoimmune thyroid disease.
Autoimmune thyroiditis is associated with antibodies against thyroglobulin (Tg) and/or thyroperoxidase (TPO). Lymphocytic infiltration of the thyroid gland results in thyromegaly, and thyroid damage occurs by both antibody- and cell-mediated pathways. The thyroid gland has a pebbly surface (“cobblestone effect”) on palpation.
Laboratory testing in patients with Hashimoto thyroiditis shows low T4 and/or free T4, elevated TSH, and measurable titers of antithyroid antibodies (anti-Tg and/or anti-TPO). However, only approximately 20% of children with antithyroid antibodies develop hypothyroidism needing therapy, and often these children have very high antithyroid antibody titers.5 At present, there is not a defined threshold titer above which treatment is recommended.
Children with lower antithyroid antibody values can be followed up with thyroid indices every 6 to 12 months and started on therapy only if TSH rises above the upper limit of normal using the pediatric reference standard. When T4 concentrations are modestly depressed (<5 ug/dL) or normal, LT4 can be initiated with a dose of 1 to 2 Î¼g/kg/day to prevent frank hypothyroidism and progressive gland enlargement. Laboratory testing should be repeated every 6 months with a goal of maintaining a TSH concentration of 0.5-5 Î¼IU/mL.
Subclinical hypothyroidism refers to a condition in which circulating T4 and T3 concentrations are normal, but TSH is elevated.
Only a minority of children with mild TSH elevations (5-10 Î¼IU/mL) progress to develop TSH elevations greater than 10 Î¼IU/mL, and available evidence indicates that children with TSH just slightly above 5 Î¼IU/mL do not exhibit somatic or other benefits when treated with levothyroxine.6,7
Central hypothyroidism should be considered in children with a history of head trauma, brain tumors, meningitis, central nervous system irradiation, or congenital nervous system malformations. In contrast to primary hypothyroidism, the diagnosis of hypothyroidism related to hypothalamic or pituitary dysfunction may be difficult to establish. Often, circulating T4 is in the low-normal range, and TSH may be low, normal, or elevated. FT4 values, however, are usually low.
When central hypothyroidism is suspected, central nervous system imaging should also be performed to look for congenital malformations or hypothalamic-pituitary lesions. Care should be taken to search for other pituitary hormone deficiencies, especially abnormalities of the hypothalamic-pituitary adrenal and growth hormone axes.
Hyperthyroidism has profound influences on the fetus, neonate, growing child, and adolescent, including physical and behavioral effects, but it is often present for extended periods before recognition, contributing to significant health problems. Hyperthyroidism typically presents with specific symptoms that include decreased attention and school performance, anxiety, increased heart rate, weight loss, fatigue, tremor, and thyroid enlargement (goiter), although onset may also be indolent. Hyperthyroidism is unlikely in the absence of tachycardia, which is one of its universal features. Characteristic eye findings of hyperthyroidism-prominent stare and proptosis-develop less often in children than in adults.
A number of conditions result in hyperthyroidism in childhood, but GD is the most common cause.8 Graves’ disease is more common in girls than in boys, has a peak age of onset between 10 and 15 years, may coexist with Hashimoto thyroiditis, and may be associated with other autoimmune diseases in the patient or the patient’s family. Laboratory testing will show elevated T3 and T4, often (but not always) an increased T3:T4 ratio, suppression of TSH, and elevated TSI or TSH-receptor antibody concentrations. Elevation in T3 can occur prior to an increase in T4.
TREATMENT Methimazole (MMI) is the antithyroid drug (ATD) of choice for treating hyperthyroidism in children. Propylthiouracil is not used anymore because of its association with severe and even fatal liver injury. In contrast, the risk of liver injury in children treated with MMI is rare, but MMI is not free from serious adverse effects. Agranulocytosis can occur, and MMI should be stopped immediately and a complete blood cell count obtained if a patient feels ill, becomes febrile, or develops pharyngitis (this could lead to the development of a retropharyngeal abscess). The risk of agranulocytosis is greatest in the first 100 days of therapy and is dose related. Thus, it is best to begin with relatively low doses. Time to resolution of hyperthyroidism is comparable using low- or high-dose MMI.
Dosing of MMI may be determined by patient age that generally corresponds to 0.1-0.3 mg/kg/day: infants, 1.25 mg/day; age 1 to 5 years, 2.5 to 5.0 mg/day; age 5 to 10 years, 5 to 10 mg/day; and age 10 to 18 years, 10 to 20 mg/day. The MMI dose may also be weight-based (0.2 to 1 mg/kg/day). The MMI tablets (5 mg and 10 mg) are small and difficult to cut, thus one-quarter or one-half fraction of tablets can be used, avoiding the need for compounding. Because it takes 1 or 2 months for biochemical hyperthyroidism to resolve, treatment with a beta-blocker (propranolol, atenolol, or metoprolol) can be used in the interim to control hyperthyroidism symptoms.9
Even after several years of ATD therapy, however, the majority of pediatric patients with GD will not achieve remission after MMI is discontinued. Thus, most pediatric patients will require definitive therapy with either radioactive iodine (131I) or surgery.
The goal for 131I therapy for GD is to induce permanent hypothyroidism. Antithyroid drug therapy should be stopped 3 to 5 days prior to treatment with 131I, and children should be placed on a beta-blocker until T4 and/or FT4 levels normalize post 131I therapy. There are rare reports of children with severe hyperthyroidism developing thyroid storm after receiving 131I.10 Thus, children should be treated with MMI until T4 and/or FT4 levels normalize (T4 ≤20 Î¼g/dL; FT4 <5 ng/dL) before proceeding with 131I therapy.11 Because of concern about total-body radiation exposure, it is prudent to avoid 131I therapy in children aged younger than 5 years and, if possible, to avoid >10 mCi in children aged younger than 10 years.
Surgery is an effective form of therapy for GD and is preferred over 131I in children aged younger than 5 years when definitive therapy is needed, and the procedure can be performed by a skilled pediatric thyroid surgeon. Surgery is also recommended for patients who have a large thyroid gland (>80 g) because they have a poor response to 131I.12 When surgery is performed, near-total or total-thyroidectomy is indicated, as subtotal thyroidectomy is associated with a higher relapse rate.13 Hypothyroidism is nearly universal after total thyroidectomy.
Thyroid nodules and thyroid cancer
Thyroid nodules and masses occur in children much less often than functional thyroid disorders but can portend the presence of thyroid cancer. In children, about 20% of thyroid nodules larger than 1 cm in diameter are malignant.14 Differentiated thyroid cancer (DTC), which includes papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most common form of thyroid cancer in children. With rare exception, medullary thyroid cancer (MTC) in children and adolescents is associated with multiple endocrine neoplasia type 2 (MEN2).
The workup for a child with a thyroid nodule should include serum TSH, T4 or FT4, ultrasound (US) of the thyroid and neck, and serum calcitonin if MTC is suspected. If the TSH is low and T3 and/or T4 levels are high-normal or elevated, a radionuclide scan may be performed to identify a hyperfunctioning nodule, which carries a lower risk for malignancy.15 A thyroid US should be considered in all patients with persistent, cervical lymphadenopathy prior to excisional biopsy to determine if the adenopathy is secondary to thyroid cancer metastasis. Ultrasound of the thyroid is the most efficient and accurate method for determining if a thyroid nodule may be surveilled or should undergo further evaluation with fine needle aspiration (FNA). Although certain features on US indicate a higher likelihood of malignancy, for many nodules the US appearance cannot reliably distinguish whether the lesion is benign or malignant; thus, FNA is the most accurate method to determine if a thyroid nodule is malignant. Ultrasound assessment of the lateral neck should be performed on all patients with an indeterminate or suspicious thyroid nodule to determine if there is lymphadenopathy, which raises concern for thyroid cancer metastasis. Recently detailed guidelines have been published to aid in the evaluation and management of thyroid nodules in children and adolescents.16,17
Thyroid cancer is most frequently diagnosed after the incidental discovery of a thyroid nodule on radiologic or physical examination. The majority of patients with thyroid cancer are asymptomatic at the time of diagnosis and have normal thyroid function. Exposure to radiation and a familial thyroid cancer predisposition are the only known risk factors for developing DTC. However, in most patients there will be no identifiable explanation for why the cancer developed.
Compared with adults, children with DTC present with more extensive disease at the time of diagnosis. Fortunately, even in the presence of metastatic disease, long-term follow-up data show 30-year survival rates of 90% to 99% for children with DTC.18-20 Even with distant metastases, mortality rates are more favorable in children than adults, and pulmonary metastases can remain stable over years to decades of time.21,22
Total thyroidectomy with prophylactic central compartment lymph node dissection is usually recommended as treatment for DTC because of the increased incidence of bilateral/multifocal disease and regional lymph node metastasis in pediatric patients.23 Adjunctive treatment with radioactive iodine is recommended for patients categorized as being at intermediate or high risk of persistent postoperative disease. Referral to a center with expertise in thyroid cancer is critical to optimize the outcome and reduce complications of therapy.
Because TSH suppression reduces the DTC recurrence rate, patients are placed on supraphysiologic doses of LT4 after surgery.24,25 The TSH goals proposed in the American Thyroid Association pediatric guidelines recommend maintaining TSH levels in the low normal range (0.5-1.0 Î¼IU/mL) for low-risk patients, between 0.1-0.5 Î¼IU/mL for intermediate-risk patients, and <0.1 Î¼IU/mL for high-risk patients.16 Once a patient enters remission, TSH suppression may be relaxed into the low-risk range (0.5-1.0 Î¼IU/mL). Follow-up care of the child with DTC involves regular assessment of circulating thyroid hormone levels, measurement of Tg and anti-Tg, and radiologic imaging. The Tg concentrations must be interpreted in relation to simultaneous TSH, and every effort must be made to use the same lab and assay method in order to accurately determine the trend in the Tg level.26
Thyroid disorders are among the most common endocrine conditions that pediatricians will encounter in their patient population. Examination of the thyroid gland should be incorporated into all regular physical examinations and trigger further evaluation if thyroid asymmetry, enlargement, or nodularity is found.
Functional problems, which include hypothyroidism and hyperthyroidism, can present with few symptoms. Thus, thyroid function tests should be obtained in children with nonspecific symptoms of not feeling well or poor growth without other detectable causes.
The care of children with CH and GD should involve the expertise of pediatric endocrinologists. Pediatricians have the necessary expertise to manage care for their patients with Hashimoto thyroiditis or subclinical hypothyroidism.
Fortunately, irrespective of the diagnosis, the majority of pediatric patients with thyroid disease can be effectively treated with minimal disruption to daily activities, go on to achieve their goals, and experience a healthy and productive life.
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24. Cooper DS, Specker B, Ho M, et al. Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry. Thyroid. 1998;8(9):737-744.
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