Chapter 4: Thyroid

Thyroid hormone is a potent regulator of metabolic rate and is essential to the function of most organ systems. In addition, the maintenance of normal thyroid status through childhood is necessary for normal growth and neurodevelopment. Best outcome in pediatric thyroid disease requires early detection as well as appropriate therapy with careful monitoring. These tasks are generally accomplished through successful collaboration between primary care providers and endocrine specialists. With an appropriate index of suspicion, pediatric thyroid disease can be detected in early stages and outcome is usually excellent. This chapter begins with a review of thyroid physiology and clinical testing. We then present diagnostic approaches to common pediatric thyroid disorders, grouped into the categories of hypothyroidism, thyrotoxicosis, and nodular thyroid disease.

Embryonic Development

The fetal thyroid begins as a thickening of the pharyngeal floor which forms a diverticulum that descends caudally into the resting position of the mature thyroid gland. During this migration, a track called the thyroglossal duct is formed that connects the pharyngeal floor to the thyroid bed. This thyroglossal duct normally involutes and, by embryonic day 50, the thyroid primordium has fused with the ventral aspect of the fourth pharyngeal pouch to form a bilobed structure. The cells of this primordium differentiate into thyroid follicular cells that synthesize thyroid hormone. Thyroid C cells, which produce calcitonin, have a distinct embryologic origin and are derived from the ultimobranchial glands.

By 11 to 12 weeks of gestation, the fetal thyroid is capable of concentrating iodine and synthesizing thyroxine (T₄). Prior to this point, the human fetus is dependent on maternal thyroid hormone. Even in later pregnancy, transplacental passage remains an important source of fetal thyroid hormone, as evidenced by the fact that T₄ is detectable in the serum of infants born with complete thyroid agenesis.

Analyses of serum obtained through cordocentesis indicate that the fetal relationship of thyrotropin (also called thyroid-stimulating hormone [TSH]) to T₄ matures throughout gestation. Compared to maternal serum, fetal serum has low concentrations of both thyroxine (T₄) and triiodothyronine (T₃). Birth is associated with a robust but transient peak in both serum TSH and T₄ (referred to as the neonatal surge), followed by rapid changes in the metabolism of thyroid hormone in peripheral tissues. This normal neonatal thyroid surge typically lasts 1 to2 days, which is the rationale for delaying newborn screening until 2 days after birth.

From a clinical standpoint, deviation from the normal anatomic development of the thyroid (termed thyroid dysgenesis) is the most common cause of congenital hypothyroidism. As described in the following text, the study of patients with thyroid dysgenesis has provided valuable insight into the molecular biology of normal thyroid development.

Thyroid Hormone Synthesis

The sole physiologic function of the thyroid gland is to synthesize T₄ and T₃. Dietary iodine is a critical nutritional requirement for the formation of both these thyroid hormones. Endemic cretinism is a term that describes the clinical consequence of dietary iodine deficiency, which is characterized by thyroid enlargement and neurodevelopmental retardation from thyroid hormone insufficiency. The pathophysiology of endemic cretinism is fully prevented by supplementation of dietary iodine.

Iodine is absorbed from the small intestine via a TSH-independent mechanism. Once in the circulation, iodine is transported into thyroid follicular cells via the sodium-iodine symporter, oxidized, and organified onto tyrosyl residues of thyroglobulin, a large glycoprotein that resides in thyroid colloid (Figure 4-1). These iodinated tyrosyl residues are coupled to form T₄ and T₃, which are eventually released into the circulation after proteolysis of thyroglobulin. Each step in the synthesis of thyroid hormone is catalyzed by enzymes that, when deficient, may lead to goiter and/or hypothyroidism. Autosomal recessive mutations in genes that encode these enzymes or their cofactors have been shown to cause dyshormonogenic congenital hypothyroidism.

Regulation of the Hypothalamic Pituitary Axis

The hypothalamus produces thyrotropin-releasing hormone (TRH), which stimulates pituitary thyrotrophs to secrete TSH, which in turn stimulates the thyroid to secrete thyroid hormone. Both thyroid hormones, T₄ and T₃, exert negative feedback on the hypothalamus and pituitary (Figure 4-2). Because the inverse relationship between free T₄ and TSH is log-linear, small changes in serum T₄ produce large compensatory changes in serum TSH (Figure 4-3). For this reason, serum TSH is the most sensitive test for the diagnosis of primary thyroid dysfunction. Laboratory results that consistently document deviation from the normal free T₄ to TSH relationship warrant an investigation for central thyroid disease due to an abnormality of the hypothalamus and/or pituitary (Table 4-1).

Thyroid Hormone Action

The effects of thyroid hormone are mediated by the binding of T₄ and T₃ to thyroid hormone receptors (TRs) in the nuclei of target cells (Figure 4-4). TRs are encoded by two distinct genes, THRA and THRB, which encode several distinct receptors via alternative splicing. Three of these TR isoforms are functional (TRα1, TRβ1, and TRβ2), and each has a unique tissue distribution. Binding of T₄ or T₃ to a functional TR leads to the formation of a transcriptional complex that stimulates or represses the expression of target genes.

Though both T₄ and T₃ can bind TRs and signal thyroid hormone action, T₃ is more potent because it binds TRs with 15-fold greater affinity than T₄. Most thyroid hormone is secreted from the thyroid gland in the form of T₄, which is subsequently converted into the more active T₃ by enzymatic outer-ring deiodination in peripheral tissues (Figure 4-5). Because of this peripheral activation, T₄ is often referred to as a prohormone.

Thyroid Hormone Metabolism

The main pathway of thyroid hormone metabolism is sequential deiodination, which is catalyzed by a family of enzymes called the deiodinases. The three members of this family include designated type 1 (D1), type 2 (D2), and type 3 (D3) deiodinase. Each deiodinase is encoded by a distinct gene and has unique enzyme kinetics and tissue distribution. D1 and D2 remove a single iodine from the outer ring of T₄, converting it to the more active T₃. Together, D1 and D2 activity produce 80% of circulating T₃, which explains why hypothyroid patients treated with T₄ alone have normal serum levels of T₃. Conversely, inner-ring deiodination of either T₄ or T₃ produces the inactive metabolites reverse T₃ (rT₃) and T₂, respectively. D3 is the major inactivating enzyme for both T₄ and T₃ (see Figure 4-5).

Free Hormone Hypothesis

The vast majority of thyroid hormone in the circulation is bound to serum proteins, including thyroxine-binding globulin (TBG), transthyretin, and albumin. In euthyroid individuals, only 0.02% of T₄ and 0.3% of T₃ is unbound or “free” and immediately available to enter cells and mediate thyroid hormone signaling. An understanding of this is helpful in the interpretation of serum thyroid function tests because individuals with normal thyroid status (and normal free thyroid hormone concentrations) but abnormal binding proteins can have deranged serum measurements of total T₄ and/or total T₃. Recognizing this is important to avoid the false diagnosis of thyroid disease in such individuals (see Table 4-1).

Whereas many tests are available to evaluate thyroid disorders, most patients can be accurately diagnosed by a focused history and physical examination, combined with standard serum thyroid tests (see Table 4-1). In a minority of thyrotoxic patients, quantification of thyroid radioiodine uptake (RAIU) can be useful to distinguish transient thyroiditis from early Graves hyperthyroidism. Anatomic imaging (such as sonography) can generally be reserved for patients with thyroid nodules.

Physical Examination

The normal thyroid is located in the midline of the neck, between the thyroid cartilage and the suprasternal notch. Physical examination should begin with visual inspection of the neck for gross thyroid enlargement or asymmetry, followed by palpation of the gland. The examiner may palpate the thyroid with the fingertips while standing behind the patient, or may face the patient and palpate the thyroid with his or her thumbs (Figure 4-6A and B). In the authors’ opinion, the latter approach is more sensitive for detecting small nodules and offers the benefit of visual correlation during palpation. Because it is encased by pretracheal fascia, the thyroid moves with swallowing, a feature that is critical in distinguishing the gland from adjacent structures. Accordingly, the patient should be provided a cup of water and asked to sip intermittently while the examiner palpates the gland, beginning in the midline and moving laterally to define the lateral borders of the gland. Infants too small to stand or sit may be examined in the supine position. One hand should be placed under the infant’s shoulders and slowly raised until the neck falls gently into mild hyperextension. The anterior neck can then be palpated with the opposite hand (Figure 4-6A).

Thyroid size and the presence of any nodules should be noted. If a thyroid nodule is present, the cervical lymph node chains should be carefully palpated to assess the possibility of local metastasis from thyroid cancer. The normal thyroid grows during childhood and a helpful “rule of thumb” is to remember that each thyroid lobe should be about the size of the distal segment of the patient’s thumb. With practice, one should be able to palpate the normal thyroid gland of nearly all patients of school age or older.

Serum Thyroid Tests

Clinical testing to accurately measure serum TSH, T₄, and T₃ is widely available. Because variations in thyroid hormone–binding proteins can occur, when measuring total thyroid hormone concentrations it is important to include an index of hormone binding, such as thyroid hormone–binding ratio (also called T₃ resin uptake). These values can then be used to calculate a free T₄ index. Alternatively, free T₄ and free T₃ concentrations may be assayed directly. In general, the highly sensitive methods required to measure accurately the picomolar concentrations of free thyroid hormone exist only in reference laboratories. The less expensive free T₄ assays used in most clinical laboratories indirectly estimate free T₄ concentrations without physically separating free from bound hormone. These estimates are useful in many routine settings but may be inaccurate in patients with binding abnormalities or intercurrent nonthyroidal illness. Thus, if an initial free T₄ measurement deviates from the clinical impression or indicates a very rare disorder such as central thyroid dysfunction, measuring free T₄ by a gold standard method (direct dialysis or ultrafiltration) is justified to avoid extensive evaluations for potentially artifactual abnormalities. These issues are discussed in detail in consensus guidelines.¹

As noted previously, serum TSH is the most sensitive single test to screen for primary thyroid disease (see Figure 4-3). If central thyroid disease is being considered, or if the index of suspicion for thyroid dysfunction is high, serum-free T₄ (or free T₄ index) should be added. Though adjunctive tests may be helpful after thyroid dysfunction is diagnosed, the combination of serum TSH and free T₄ is a sufficient initial screen, as the combination of normal TSH and normal free T₄ effectively rules out treatable forms of thyroid dysfunction. Of note, though Table 4-1 represents the vast majority of patients with thyroid dysfunction, two rare additions should be noted. Though patients with mutations in THRB show the classic pattern of resistance to thyroid hormone (RTH) (hyperthyroxinemia and hypertriiodothyronemia), rare patients with mutations in THRA display a different pattern of thyroid function tests characterized by high-normal T₃, low-normal T₄, and low-normal TSH.^{2, 3, and 4} This same pattern is seen in Allan-Herndon-Dudley syndrome, a rare X-linked disorder caused by loss-of-function mutations in SLC16A2, which encodes the neuronal T₃ transporter MCT8. In clinical practice, both THRA and SLC16A2 mutations are associated with severe extrathyroidal dysmorphology (growth retardation, skeletal dysplasia, and constipation with THRA mutation; congenital hypotonia, intellectual disability, and limited motor and language skills with SLC16A2 mutation) so thyroid dysfunction is almost never the presenting feature of these conditions. However, awareness of these thyroid function patterns avoids the risk of misdiagnosingcentral thyroid disease in such individuals and risksof inappropriate treatment with thyroid hormone or antithyroid medications.

When interpreting thyroid tests, it is important to apply age-specific normal ranges (Table 4-2)⁵ and to be aware that certain medications, including amiodarone and common anticonvulsants (such as phenytoin and carbamazepine), can also confound the interpretation of serum thyroid tests by altering the normal serum T₄:T₃ ratio. During some stages of childhood the normal limits of free T₄ extend outside the standard adult reference range. Failure to consider this can lead to incorrect diagnosis of central thyroid disease. Clinicians must also take into account preanalytic factors that may alter serum thyroid tests in the absence of true thyroid pathology. The most common of these is nonthyroidal illness, a term used to describe the pattern of transient derangement of serum thyroid function tests found in up to 75% of hospitalized patients in the absence of true thyroid disease. Though varies from one patient to another, this pattern is generally characterized by a fall in serum T₃, followed by a fall in serum T₄ and then serum TSH as the severity of illness progresses. As patients recover from their illness, serum TSH can transiently rebound above the normal reference range. Thus, many critically ill patients display abnormal serum thyroid function. As there is no available clinical test to reliably distinguish nonthyroidal illness from true thyroid disease, it is generally recommended that thyroid function tests be avoided in critically ill patients unless there is a specific suspicion for thyroid dysfunction. In addition, if mild thyroid function abnormalities are observed during illness, it is appropriate to defer treatment and monitor closely for resolution as recovery proceeds.

Thyroid Radioiodine Uptake

This test permits a direct assessment of thyroid function by quantifying the ability of an individual’s thyroid gland to concentrate iodine. Thyroid radioiodine uptake (RAIU) is calculated by measuring thyroidal radioactivity 4 or 24 hours after oral administration of radioactive iodine. Though both ¹³¹I and ¹²³I can be used, ¹²³I is preferred in children because it provides much lower radiation exposure. Because RAIU depends on dietary iodine intake, normal ranges vary among geographic regions. High RAIU values are characteristic of all hyperthyroid conditions, and this feature distinguishes hyperthyroid patients from those with thyrotoxicosis due to exogenous thyroid hormone or transient thyroiditis, in whom RAIU is low. Though RAIU can be low in certain forms of hypothyroidism, its measurement is not useful to diagnose hypothyroidism in iodine-sufficient populations (such as North America) because in this setting even euthyroid individuals can have RAIU values as low as 4%.

Thyroid Scintigraphy

Images may be obtained with a pinhole gamma camera after oral ¹²³I administration to define the location of functional thyroid tissue. This can identify sites of ectopic thyroid tissue or determine the functional status of thyroid nodules (Figure 4-7). Thyroid scintigraphy can also be used to detect iodine-avid metastases in patients with differentiated thyroid cancers of follicular cell origin (Figure 4-8). Like RAIU testing, thyroid scintigraphy is affected by dietary iodine intake, and high pharmacologic doses of iodine (from sources such as iodinated computed tomography [CT] contrast) can compromise ¹²³I imaging.

Thyroid Sonography

Sonography of the thyroid is a noninvasive tool that can accurately quantify thyroid size. In the hands of an experienced user, it is also an ideal modality to confirm the presence of thyroid nodules and, when appropriate, to monitor the size of thyroid nodules over time. When fine-needle aspiration of the thyroid is performed, sonographic guidance is critical to optimizing both diagnostic accuracy and patient safety.

Definitions and Epidemiology

Hypothyroidism is defined as inadequate action of thyroid hormone at the tissue level. Hypothyroidism is the most common thyroid disorder, with an estimated population prevalence in childhood of 0.14% and a female to male ratio of 3:1.⁶ Autoimmune thyroiditis is the most common etiology.

Pathogenesis

Hypothyroidism can arise from secretory defects at any level of the hypothalamic-pituitary-thyroid axis (central or primary hypothyroidism), from decreased tissue responsiveness (RTH), or from accelerated degradation of circulating thyroid hormone at a rate that exceeds the synthetic capacity of the normal thyroid gland (consumptive hypothyroidism).

Clinical Presentation and Diagnosis

Common signs and symptoms of hypothyroidism are listed in Table 4-3. Of note, none is completely sensitive or specific for hypothyroidism, and symptom severity can vary greatly between patients with similar degrees of biochemical derangement. The clinician’s history should include inquiry into energy level, sleep pattern, cold intolerance, and weight gain. In addition to thyroid palpation, the physical examination should include an assessment of fluid status, muscle strength, heart rate, and deep tendon reflexes. Because autoimmune hypothyroidism can be the first presentation of an autoimmune polyglandular syndrome (see Chapter 5), signs and symptoms of possible coexisting autoimmune disorders such as diabetes mellitus and Addison disease should be sought.

Long-standing hypothyroidism causes growth retardation that disproportionately impairs linear growth more than weight gain. Prolonged elevation of TSH from untreated primary hypothyroidism can also cause pseudopubertal changes such as testicular enlargement, premature breast development, or premature menarche due to cross-reactivity of TSH with the follicle-stimulating hormone (FSH) receptor. These changes can be distinguished from true puberty by the absence of growth acceleration and by the fact that hypothyroidism causes delay rather than advancement in skeletal maturation.

Algorithm

Serum thyroid tests are sensitive for diagnosing hypothyroidism and sufficient for identifying the common subtypes (see Table 4-1). Growth data and the review of systems can provide insight into the duration of thyroid insufficiency.

Diagnostic Tests

Serum TSH and free T₄ should be measured when hypothyroidism is suspected (see Table 4-1). Serum TSH is elevated in all patients with primary hypothyroidism; in more severe cases, serum-free T₄ is low. If serum-free T₄ is low with an inappropriately normal or low serum TSH, central hypothyroidism should be considered. Conversely, if serum-free T₄ and/or free T₃ are persistently high with an inappropriately normal or high TSH, the diagnosis of thyroid hormone resistance should be investigated. Measurement of serum T₃ is not useful in the diagnosis of hypothyroidism because compensatory increases in thyroidal T₃ secretion and peripheral T₄-to-T₃ conversion maintain normal serum T₃ levels in many hypothyroid patients.

Differential Diagnosis

This section reviews the major causes of hypothyroidism in children. Though identifying the specific cause of a child’s hypothyroidism rarely changes initial therapy, this information is useful to predict the patient’s long-term course and to counsel parents appropriately.

Primary Hypothyroidism

Primary hypothyroidism refers to disorders of the thyroid gland itself that reduce its production of T₄ and T₃. As serum T₄ and T₃ fall, even within the normal range, loss of inhibitory feedback results in TSH hypersecretion. Elevation of serum TSH is the first abnormality detected in primary hypothyroidism. As the severity of primary hypothyroidism increases, serum T₄ and then serum T₃ fall below normal. Common causes of primary hypothyroidism are discussed in the following sections.

Autoimmune hypothyroidism

Autoimmunity is the most common cause of acquired hypothyroidism in both children and adults (Figures 4-9 and 4-10). Persistent hypothyroidism may be caused by two forms of chronic autoimmune thyroiditis: type 2A (goitrous, classic Hashimoto disease) and type 2B (nongoitrous, atrophic thyroiditis). Both are characterized by lymphocytic infiltration of the thyroid parenchyma, destruction of follicular thyroid cells, and high serum concentrations of thyroid autoantibodies. Documenting high serum titers of either thyroperoxidase antibodies or thyroglobulin antibodies is sufficient for diagnosing chronic autoimmune thyroiditis as the cause of a patient’s hypothyroidism. Thyroperoxidase antibodies are more sensitive and should be measured first, but thyroglobulin antibodies may be added if thyroperoxidase antibodies are not elevated. Approximately 95% of patients with autoimmune thyroiditis are positive for at least one of these antibodies.

The prevalence of autoimmune hypothyroidism increases with age, with a 3:1 female to male ratio.⁶ Presentation under 3 years of age is rare, but cases have been described even in infancy. Though the pathophysiology of thyroid autoimmunity is incompletely understood, there is a strong familial component. Individuals with Down syndrome, Klinefelter syndrome, and Turner syndrome are at increased risk.⁷

Upon diagnosis, families should be counseled that autoimmune hypothyroidism is usually lifelong, but that replacement therapy is effective. Children on levothyroxine treatment should be followed carefully to ensure consistent euthyroidism. Because autoimmune thyroiditis may be the initial presentation of an autoimmune polyglandular syndrome (see Chapter 5), the review of systems should include direct inquiry into symptoms concerning for other autoimmune endocrinopathies such as type 1 diabetes and Addison disease.

Congenital hypothyroidism

Etiologies of congenital hypothyroidism.

Approximately one in 3000 children is born with permanent hypothyroidism. Eighty-five percent of these cases are due to thyroid dysgenesis, defined as defective anatomic development of the gland with resultant agenesis, hypoplasia, or ectopy. Though mutations in transcription factors such as TITF1/NKX2-1 (formerly called TTF-1), FOXE1 (formerly called TTF-2), and PAX-8 that are required for normal thyroid development can cause thyroid dysgenesis in humans, such patients are extremely rare (representing only 2% of children with thyroid dysgenesis) and their congenital hypothyroidism typically arises in the context of broader phenotypic syndromes. For instance, mutations in TITF1/NKX2-1 cause choreoathetosis, respiratory distress, and variabledegrees of thyroid deficiency, whereas mutations in FOXE1 cause Bamfort-Lazarus syndrome, characterized by cleft palate, choanal atresia, spiky hair, and athyreosis.⁸ In contrast, the vast majority of children with thyroid dysgenesis have hypothyroidism as their only congenital defect and 98% of these cases are sporadic.⁹

Ten to 15% of congenital hypothyroidism cases are due to dyshormonogenesis, or inborn defects in thyroid hormone synthesis, that are often inherited in an autosomal recessive fashion. Mutations in several of the genes important in thyroid hormone synthesis (including those encoding thyroperoxidase, thyroglobulin, thyroid dual oxidase 2 and 2A, iodotyrosine deiodinase, the sodium-iodine symporter, and the TSH receptor) have been found to cause congenital hypothyroidism in humans (see Figure 4-1).¹⁰ Because such kindreds represent a small minority of patients with congenital hypothyroidism, the relevance of these findings to genetic testing and counseling is limited, but these cases have provided important insight into the mechanisms of thyroid hormone synthesis. Interestingly, mild mutations in several of these genes resulting in less severe enzymatic deficiency may present not as congenital hypothyroidism but rather as acquired hypothyroidism or euthyroid goiter in later childhood or adolescence. Recent research has shown that the presentation of human dyshormonogenesis can vary even within the newborn period, presenting as permanent primary hypothyroidism, transient hypothyroidism (reported in infants with monoallelic mutations in DUOX2, which encodes thyroid dual oxidase 2),¹¹ or as delayed TSH rise (due to mutations in DEHAL1, which encodes iodotyrosine deiodinase).¹²

Radiographic studies such as neck sonography and radionuclide scintigraphy may be performed to characterize the subtype of a child’s congenital hypothyroidism, but, because these findings rarely alter acute management, they should be considered optional. When testing to diagnose etiology is desired, most clinicians obtain a thyroid ultrasound and measure serum thyroglobulin. Visualization of a eutopic thyroid gland indicates dyshormonogenesis or hypoplasia. The absence of a eutopic thyroid gland indicates agenesis if serum thyroglobulin is undetectable or ectopy if serum thyroglobulin is present/elevated. For the latter, if ultrasonography shows no glandular tissue superior to the thyroid bed, ¹²³I scintigraphy may be considered to identify the location of ectopic thyroid tissue. These tests must be interpreted in the context of the patient’s prenatal history, as exposure to maternal antithyroid drugs or the transplacental passage of maternal TSH receptor-blocking autoantibodies can compromise the sensitivity and specificity of imaging. For instance, infants with transient hypothyroidism from maternal TSH receptor-blocking antibodies can have reductions in RAIU and serum thyroglobulin that are diagnostically indistinguishable from thyroid hypoplasia or agenesis.

A small percentage of congenital hypothyroidism is central in origin due to pituitary or hypothalamic defects. Congenital central hypothyroidism is usually accompanied by deficiencies in other pituitary hormones,¹³ so a full evaluation of pituitary function must be performed whenever secondary hypothyroidism is diagnosed. Germline mutations in genes that regulate pituitary gland formation, including POU1F1, PROP1, HESX1, LHX3, and LHX4 have been documented as causes of familial hypopituitarism in humans.

Transient hypothyroidism can occur in the newborn period secondary to the transplacental passage of maternal medications or thyroid autoantibodies or in infants born to mothers who ingest excessive amounts of iodine (due to transfer through the placental circulation or the breast milk).¹⁴ A careful medical and prenatal history will reveal these risk factors.

Newborn screening for congenital hypothyroidism.

Clinical signs and symptoms of congenital hypothyroidism can be difficult to detect in the newborn period and, as the majority of cases are sporadic, it not possible to predict which infants will be affected. Accordingly, newborn screening for congenital hypothyroidism is universally recommended and available in most developed countries. Affected neonates who are diagnosed by screening and begin treatment within the first weeks of life can have normal intelligence. Though this is a great triumph of newborn screening, it is important to remember that up to 75% of the world’s population is born in countries without newborn screening. Thus, from a global health perspective, congenital hypothyroidism remains one of the most common preventable causes of mental retardation.

In the United States, screening is performed on dried heel-stick blood and the testing strategy varies between regions.¹⁵ There are three common screening strategies: (1) initial T₄ test with “reflex” TSH measurement in the subset of samples with the lowest T₄ levels; (2) initial TSH test; and (3) combined initial T₄ and TSH test.¹⁶ Strategies that measure TSH have the potential advantage of detecting isolated hyperthyrotropinemia or mild/subclinical hypothyroidism. In contrast, strategies that measure T₄ have the ability to diagnose central hypothyroidism. Screening samples should be obtained between 2 and 5 days of age, and some programs also routinely obtain a second specimen between 2 and 6 weeks of age to capture infants with delayed TSH rise. This phenomenon of delayed TSH rise occurs in about 1:30,000 term newborns but is much more common in low-birth-weight infants (1:95).¹⁷ Delayed TSH rise is commonly attributed to mild forms of primary hypothyroidism or to the presence of confounding factors such as prematurity or critical illness that blunt the normal hyperthyrotropinemic response to hypothyroidism.^15,18

Newborn screening is not sufficient for diagnosing congenital hypothyroidism, so abnormal results must be immediately confirmed by the formal measurement of serum TSH and free T₄. As detailed earlier in section Thyroid Testing, in-house free T₄ assays that do notseparate free from bound hormone can be unreliable in the presence of serum-binding protein abnormalities or critical illness, so serum-free T₄ should be measured by direct dialysis if initial tests suggest central hypothyroidism. Factors such as prematurity, neonatal illness, and the transplacental transfer of maternal TSH receptor-blocking autoantibodies can delay TSH elevation. Thus, serum thyroid tests should be obtained in children who develop clinical symptoms of hypothyroidism later in infancy, even if their newborn screening results were normal.

Evidence of an increasing incidence of congential hypothyroidism.

A number of groups have reported an increasing incidence of congenital hypothyroidism diagnosed by newborn screening since the 1970s.¹⁹ This has been described in American,²⁰ Australian,²¹ and European^22-24 populations. In some regions, an increase can be partially explained by a growing representation of Hispanic and Asian families as these groups have intrinsically higher rates of congenital hypothyroidism.^19,25 The growing numbers of low-birth-weight infants may also increase the overall rate of abnormal newborn screens, as such neonates are commonly hypothyroxinemic (see the following section).²⁶ Interestingly, some recent research provides strong evidence that the increased incidence of congenital hypothyroidism in many populations is simply due to the implementation of more sensitive TSH and T₄ screening cutoffs.^26,27 While this reveals important detection bias, it is noteworthy that the majority of additional cases detected by these more sensitive cutoffs appear to have permanent (albeit mild) hypothyroidism. Further research is necessary to define the benefits of early levothyroxine treatment in this subpopulation, but, in the interim, we recommend that even mild hypothyroidism be treated if persistent.

Treatment of congenital hypothyroidism.

Optimal levels of thyroid hormone are required for normal neurodevelopment, and the brain is especially vulnerable to hypothyroidism in the first year of life. Untreated congenital hypothyroidism can produce profound somatic and neurologic injury (Figures 4-11 and 4-12) and, as mentioned earlier, delay in treating congenital hypothyroidism remains one of the most common preventable causes of mental retardation in the world. Outcome is excellent, however, when adequate replacement is initiated early in the newborn period, ideally within the first 2 weeks of life. Normal development, including cognitive outcome, is observed even in children with complete thyroid agenesis, illustrating the protective effects of maternal thyroid hormone to the fetus in utero.

Consensus guidelines for the therapy of congenital hypothyroidism are maintained by the American Academy of Pediatrics²⁸ and the European Society of Pediatric Endocrinology.²⁹ Goals of therapy include the rapid restoration and maintenance of euthyroidism, as both are required for optimal neurodevelopment. In newborns confirmed to have hypothyroidism, treatment with high-dose levothyroxine (10-15 μg/day) should be initiated immediately.

As neurodevelopment remains dependent on thyroid hormone throughout infancy, serum thyroid tests should be measured frequently and levothyroxine therapy titrated to maintain serum T₄ concentrations in the upper half normal range and serum TSH less than 5 μU/mL (ideally between 0.5 and 2.0 μU/mL).¹⁶ It is generally recommended that TSH be measured 2 to 4 weeks after treatment is begun, every 1 to 2 months in the first 6 months of life, every 2 to 3 months between 6 months and 3 years of age, every 6 to 12 months thereafter, and 4 weeks after any dose adjustment.^16,28 However, the frequency of laboratory monitoring should be increased as needed to achieve therapeutic targets, and this is commonly required in children with severe hypothyroidism,³⁰ prior laboratory abnormalities, or intermittent medication noncompliance.

Parents should be counseled that neurologic outcome will be normal with early and consistent treatment. A trial-off levothyroxine therapy may be offered after 3 years of age to assess the possibility that congenital hypothyroidism was transient.

Hypothyroxinemia of prematurity

Transient hypothyroxinemia of prematurity refers to a pattern of low serum-free T₄ with an inappropriately normal serum TSH concentration. Its occurrence increases with the degree of prematurity, so it is present in more than half of extremely low gestational age neonates born at less than or equal to 28 weeks’ gestation. Although hypothyroxinemia in preterm infants has been associated with diminished neurologic outcome,³¹ trials of thyroid hormone therapy have yet to demonstrate a definitive benefit.^32,33 Improvements in neonatology have increased the survival of even extremely premature neonates between 24 and 28 weeks’ gestation to 80%, and it is estimated that more than 25,000 such neonates are born annually in the United States.³¹ Thus, there is great need for further research to investigate the potential benefits and risks of treatment in hypothyroxinemia of prematurity.

Other forms of acquired primary hypothyroidism

Incomplete descent of the thyroid gland (sublingual thyroid—Figure 4-13) or complete lack of descent of the gland (lingual thyroid—Figure 4-14) may lead to hypothyroidism in the first decade of life, owing in part to anatomical “entrapment” of the gland that makes it unable to keep up with the need for thyroid hormone as the child grows.

Primary hypothyroidism can develop after exposure to environmental goitrogens such as resorcinol, or to medications with antithyroid effect such as lithium, iodine, amiodarone, and the thionamide derivatives (eg, methimazole, propylthiouracil [PTU]) used to treat hyperthyroidism. Interferon therapy is associated with an increased risk of autoimmune thyroid disease, including primary hypothyroidism. Over the past decade, the increasing use of tyrosine kinase inhibitors for various cancers has revealed that up to one-half of treated patients develop thyroid dysfunction, most commonly hypothyroidism. The etiology of tyrosine kinase inhibitor-associated hypothyroidism is incompletely understood, but it appears to be multifactorial, with evidence that thyroiditis, decreased vascularity of the gland, and decreased iodine uptake and organification are all contributing mechanisms.³⁴ As symptoms of hypothyroidism are variable and can be masked by the patient’s primary disease, monitoring of TSH is recommended for all individuals receiving interferon or tyrosine kinase inhibitors.

Hypothyroidism can also occur as a consequence of thyroid surgery or thyroid irradiation, including both ¹³¹I radioiodine ablation and the external-beam radiation used to treat Hodgkin lymphoma and other pediatric cancers.

Hypothyroidism may also develop in some patients after painful subacute thyroiditis or painless sporadic thyroiditis (see Transient Thyroiditis). This possibility should be considered in hypothyroid patients with normal serum antithyroid autoantibody titers, especially if there are recent symptoms of thyroid pain or transient thyrotoxicosis. Though hypothyroidism is usually transient in these cases, levothyroxine may be offered if symptoms are significant, with a trial-off levothyroxine performed later.³⁵

In both adults and children, obesity is associated with higher serum concentrations of TSH. While this association was first investigated to explore the hypothesis that hyperthyrotropinemia causes obesity, recent studies have shown that obesity-associated hyperthyrotropinemia normalizes with weight loss alone, indicatingthat transient subclinical hypothyroidism is a consequence rather than a cause of obesity.^36,37

Central Hypothyroidism

Central hypothyroidism refers to disorders that decrease the production or biological activity of TRH or TSH. In these diseases, serum-free T₄ is low and serum TSH is usually inappropriately normal or low (see Table 4-1). While provocative testing with TRH was previously used as a diagnostic tool, unstimulated serum thyroid tests are now considered sufficient to diagnose central hypothyroidism. However, it is important to recognize that the pattern of serum tests seen in central hypothyroidism may also be present transiently in preterm infants and in older children during nonthyroidal illness, so thyroid tests must be interpreted with caution in these settings. Because central hypothyroidism is usually accompanied by other pituitary endocrinopathies, its diagnosis warrants pituitary imaging and biochemical assessment for other pituitary hormone deficiencies.

Central hypothyroidism occurs congenitally in about 1 in 20,000 to 50,000 newborns. Congenital central hypothyroidism can occasionally occur in isolation due to mutations in the gene for the TRH receptor (TRHR), TSH β-subunit (TSHB), or IGSF1 (IGSF1), but much more commonly it occurs in combination with other pituitary hormone deficiencies.¹³ The presence of hypoglycemia, microphallus, polyuria, eye or ear abnormalities, or midline anatomic abnormalities in a newborn should raise suspicion for combined pituitary hormone deficiency.²⁸

More often, central hypothyroidism is acquired. The most common causes are pituitary adenomas or craniopharyngiomas (as well as the surgery and radiation therapy used in their treatment), but central hypothyroidism can occur in association with other brain tumors and in infiltrative diseases such as Langerhans cell histiocytosis and sarcoidosis.³⁵

Resistance to Thyroid Hormone

Resistance to thyroid hormone (RTH) is a syndrome of tissue-specific decrease in thyroid hormone responsiveness due to genetic defects in the thyroid hormone receptor TRβ. Over 1000 cases have been reported and the vast majority are due to autosomal dominant mutations in the THRB gene.³⁸ Affected individuals have high serum concentrations of T₄ and T₃ with inappropriately normal or high serum TSH concentrations (see Table 4-1). This pattern indicates defective feedback inhibition of the hypothalamic-pituitary-thyroid axis and is presumably due to impaired pituitary responsiveness to thyroid hormone. Despite high circulating levels of thyroid hormone, tissues that express the mutant TRβ (such as pituitary and liver) are functionally hypothyroid; in contrast, tissues expressing primarily TRα (such as heart) may be functionally thyrotoxic. Interestingly, because different TR isoforms are expressed in a tissue-specific manner, individuals with RTH simultaneously can manifest signs and symptoms of hypothyroidism in tissues expressing the mutant TRβ (such as growth delay and hearing impairment) and hyperthyroidism in tissues expressing primarily the normal TRα (such as tachycardia and anxiety).

For reasons that are not understood, thyroid status and symptoms vary greatly among affected individuals, even among those who carry the same TRb mutation. Patients may appear clinically hypothyroid, euthyroid, or hyperthyroid. Symptoms often change with time and may improve spontaneously with age. Therapies directed to the symptoms of RTH (such as β-blockers for palpitations and anxiolytics for nervousness) can be helpful, but treatments to directly alter thyroid status are generally avoided. The high levels of circulating thyroid hormone in patients with RTH are considered to be an adaptive response to their tissue resistance, so antithyroid medications are contraindicated. Treatment with exogenous thyroid hormone may be considered in young children with RTH for the relative indications of seizure; developmental delay; extremely elevated TSH; failure to thrive that cannot be explained on the basis of another illness or defect; and a history of growth or mental retardation in affected siblings.³⁹ For such patients, levothyroxine is typically used and the dose titrated to normalize serum TSH. The benefit of this intervention is unclear.

When considering the diagnosis of RTH, one must recognize that the typical pattern of serum thyroid tests (simultaneously high serum-free T₄ and TSH) may be found in a number of other conditions. This pattern, often referred to as inappropriate TSH secretion, is also characteristic of TSH-secreting pituitary adenomas (see Table 4-1), and it can also be observed transiently in patients without thyroid disease during nonthyroidal illness or while taking certain medications such as amiodarone. Finally, laboratory artifact is a common cause of this pattern of test results. Because both RTH and TSH-secreting pituitary adenomas are extremely rare, the discovery of suggestive thyroid function tests should be addressed first by a complete medication history and by repeating thyroid tests 1 to 2 weeks later. If the pattern resolves, it was most likely due to nonthyroidal illness. If the pattern persists, an aliquot of the same serum should be assessed for possible artifact by repeating the thyroid tests on an alternative assay platform (eg, from another institution) and by performing serial dilutions to confirm linearity. These simple maneuvers are important to avoid inappropriate testing and treatment.

Once the serum pattern of inappropriate TSH secretion is confirmed and shown to be persistent, the diagnostic evaluation should focus on distinguishing RTH from a TSH-secreting pituitary adenoma. This is critical because therapy for these conditions differs dramatically. Obtaining thyroid function tests in the patient’s first-degree relatives is useful because documentation of the same pattern strongly supports the diagnosis of RTH. Though a number of specialized biochemical tests such as TRH stimulation testing and measurement of the TSH α-subunit can be helpful to distinguish RTH from TSH-secreting adenomas, pituitary imaging with magnetic resonance imaging (MRI) is usually required and is a reasonable first-line test.

Until recently, all reported cases of human RTH were attributed to THRB mutation. However, rare patients with dominant negative mutations in the THRA gene have now been identified. Remarkably, their phenotype differs dramatically from individuals with THRB mutation, and is characterized by severe growth and developmental retardation (resembling untreated hypothyroidism) with minimal derangement of serum thyroid function tests (low-normal TSH, low-normal T₄, and high-normal T₃ levels).²

Consumptive Hypothyroidism

Consumptive hypothyroidism is a rare condition caused by the accelerated degradation of circulating thyroid hormones. Several tumors, including infantile hemangiomas, express high levels of the thyroid hormone-inactivating enzyme D3. In individuals with both high specific D3 activity and large tumor burden, systemic hypothyroidism can develop due to the rapid degradation of circulating T₄ and T₃ at rates that exceed the synthetic capacity of the normal thyroid. Unlike other forms of hypothyroidism, thyroid gland function is normal to increased. The most common cause of consumptive hypothyroidism in children is a massive hepatic hemangioma, but other D3-expressing tumor types including hemangioendotheliomas and malignant fibrous tumors can also cause hypothyroidism. Because hemangiomas proliferate during the first year of life, when the brain is critically dependent on thyroid hormone, infants with large hemangiomas should be screened for thyroid dysfunction with monthly serum TSH measurements until 1 year of age. Aside from infantile hemangiomas, acquired hypothyroidism in a patient with a large tumor should also raise suspicion for consumptive hypothyroidism.

In consumptive hypothyroidism, thyroid function tests are identical to those seen in patients with primary hypothyroidism (see Table 4-1), but evidence is also present of increased thyroid hormone inactivation (elevated serum rT₃, supernormal requirement for thyroid hormone replacement), and increased thyroid hormone production (goiter, high RAIU, elevated serum thyroglobulin). The severity of hypothyroidism is variable, with some patients responding adequately to conventional doses of levothyroxine and others requiring massive doses. Because of the shortened half-life of circulating thyroid hormone, frequent monitoring is required and daily doses may be divided bid or tid to minimize excursions in serum T₄. In some patients, the reduction of serum T₃ is disproportionately greater than the fall in serum T₄, presumably because of the difference in affinity of D3 for different substrates. In such cases, if serum TSH remains elevated despite a high-normal serum T₄, liothyronine (T₃) can be administered in combination with levothyroxine therapy. Communication between caregivers is critical as thyroid hormone therapy must be adjusted in response to changes in tumor mass. Tumor proliferation warrants more frequent monitoring for the possibility of increased requirements. Conversely, clinicians must be prepared to taper or discontinue thyroid hormone therapy upon tumor involution or resection to avoid iatrogenic thyrotoxicosis.

Treatment

Levothyroxine is the ideal therapy for hypothyroidism. While reactions to manufacturer-specific tablet binders or dyes may occur, the medication itself is universally tolerated and its long serum half-life of 5 to 7 days permits once-daily dosing. While pseudotumor cerebri has been reported in a small number of school-age children upon initiation of levothyroxine therapy, this complication is very rare and resolves with temporary dose reduction.

Age-specific guidelines exist for the initiation of levothyroxine in children (Table 4-4).⁴⁰ While on therapy, serum thyroid tests should be obtained every 3 to6 months in growing children and 4 to 8 weeks after any dose adjustment. Because thyroid hormone is critically important to infant neurodevelopment, more frequent monitoring is recommended in the first year of life.²⁸ In patients with primary hypothyroidism, therapy should be adjusted to achieve a serum TSH in the normal range. However, more precise TSH targets are recommended for certain populations, including congenitally hypothyroid infants (see above section), pregnant women (generally up to 2.5 μU/mL in the first trimester, up to 3.0 μU/mL in the second trimester, and up to 3.5 μU/mLin the third trimester), and patients with significant thyroid cancers (see following section on TSH Suppression).⁴¹ Patients with central hypothyroidism should be dosed to achieve a serum-free T₄ concentration within the upper half of the normal range.⁴²

To maximize intestinal absorption, it is generally recommended that levothyroxine be administered 30 to 60 minutes prior to food or other medications; however, from a practical standpoint it is more important that the dose be given the same way every day. As the bioequivalence of levothyroxine preparations varies between manufacturers, prescriptions should specify that the manufacture remain constant when refills are dispensed.⁴³ Parents should be counseled that consistent medication compliance is important, but, should a dose be inadvertently missed, they should double the dose the following day to compensate.

In infants, the daily levothyroxine dose can be crushed and mixed with a small volume of formula, expressed breast milk, or water. This suspension should be immediately administered via syringe (squirted into the cheek pad) or an open nipple. We recommend against the use of thyroid hormone suspensions prepared by compounding pharmacies as they are unnecessary and run the risk of instability and inconsistent dosing. In hospitalized patients of any age who are temporarily unable to take levothyroxine enterally, levothyroxine can be given at 70% of their usual oral dose⁴¹ and thyroid function closely monitored. If the interruption of oral levothyroxine is anticipated to be brief, it may simply be held for 1 to 2 days and the missed tablets administered when the medication is restarted.

As described in section Thyroid Hormone Metabolism, the normal thyroid primarily secretes T₄ and the vast majority of circulating T₃ (80%) is derived from the peripheral conversion of T₄ into T₃ by outer-ring deiodination (see Figure 4-5). This explains why serum T₃ is normal with adequate levothyroxine monotherapy for primary or central hypothyroidism.⁴² While one recent study of hypothyroid adults reported improved mood and cognitive function with a combined levothyroxine/liothyronine regimen compared to levothyroxine alone, subsequent studies failed to confirm this finding or to convincingly show other benefit. Therefore, levothyroxinemonotherapy remains the preferred treatment for children with primary or central hypothyroidism. Combined therapy with supernormal doses of both levothyroxine and liothyronine has been used to treat infants with severe consumptive hypothyroidism, in whom peripheral metabolism of thyroid hormone is by definition deranged.

Several common conditions can alter a patient’s levothyroxine requirements. Oral iron supplements, calcium carbonate, sucralfate, or soy-based infant formula can bind intestinal levothyroxine and reduce its absorption. Other drugs such as phenytoin, carbamazepine, and rifampin can increase levothyroxine requirements by enhancing its hepatic metabolism. Of note, normal pregnancy increases thyroid hormone requirements by an average of 47%.⁴⁴ Because this increase typically occurs in early pregnancy, adequately treated hypothyroid females can be counseled to increase their prepregnancy levothyroxine dose by 29% (by taking two extra daily doses each week) if pregnancy is discovered and access to full serum testing will not be immediate.⁴⁵ Thyroid function tests should be monitored every 4 weeks in the first half of pregnancy and at least once between 26 and 32 weeks’ gestation.⁴⁶

Definition and Epidemiology

The yearly incidence of childhood hyperthyroidism is cited at 1 to 8 per 100,000 children. In adolescence, there is a high female to male ratio (6:1), and Graves disease is the most common etiology.⁴⁷ Though the terms of thyrotoxicosis and hyperthyroidism are often used interchangeably, they are not synonyms. Thyrotoxicosis refers generally to any condition of elevated circulating thyroid hormones, whereas hyperthyroidism refers only to the subset of thyrotoxic disorders that are due to increased function of the thyroid gland itself. This distinction is clinically important because the antithyroid therapies used to treat hyperthyroidism have no role in the management of thyrotoxicosis without hyperthyroidism.

Pathogenesis

Etiologies of thyrotoxicosis can be divided into those that are caused by hyperthyroidism (thyroid gland hyperfunction) and those that are not (Table 4-5). Hyperthyroidism can result from the excessive stimulation of normal thyroid tissue (Graves disease, TSH-secreting pituitary adenomas) or from the presence of abnormal thyroid tissue that is intrinsically hyperfunctioning or “autonomous” (toxic thyroid nodules). In addition, thyrotoxicosis without hyperthyroidism can result from glandular injuries that release large amounts of preformed thyroid hormone (transient thyroiditis) or from excess administration of exogenous thyroid hormone (thyrotoxicosis factitia).

Clinical Presentation and Diagnosis

Common signs and symptoms of thyrotoxicosis are described in Table 4-6. The clinical history should include inquiry into energy level, sleep pattern, heat intolerance, weight loss, decreased school performance, skin changes, visual complaints, and acceleration of linear growth. In addition to thyroid palpation, the physical examination should include a careful assessment of heart rate, extraocular movements, skin, and whether a tremor is present. Because autoimmune hyperthyroidism can be the presenting component of an autoimmune polyglandular syndrome (see Chapter 5), symptoms of potential coexisting autoimmune disorders such as diabetes mellitus or Addison disease should be elicited.

Serum thyroid function tests are a sensitive screen for the presence of thyrotoxicosis (see Table 4-1). A focused history and physical examination will usually identify the cause, but adjunctive testing with ¹²³I scintigraphy can be helpful in selected cases.

Algorithm

Serum TSH and free T₄ should be measured if thyrotoxicosis is suspected. In patients with normal hypothalamic-pituitary feedback, serum TSH will suppress to less than 0.1 μU/mL during thyrotoxicosis. If serum TSH is less than 0.1 μU/mL and serum-free T₄ is high, significant thyrotoxicosis is present and subsequent evaluation should focus on determining the cause. Because the normal thyroid gland contains a finite amount of preformed hormone (about a 30- to 60-day supply), thyrotoxicosis from transient thyroiditis is relatively short-lived; therefore, the duration of thyrotoxicosis is an important clue to its cause (Figure 4-15).

If signs and symptoms of thyrotoxicosis have been present for more than 8 weeks, hyperthyroidism is likely. If a diffuse goiter is noted with orbitopathy or dermopathy, Graves disease can be diagnosed clinically and no further tests are required. If instead the examiner palpates a large thyroid nodule, the possibility of a toxic adenoma should be considered and ¹²³I thyroid scintigraphy should be performed (see Figure 4-7).

If sign and symptoms of thyrotoxicosis have been present for less than 8 weeks, the possibility of transient thyroiditis should be addressed before offering antithyroid therapy, especially if thyromegaly is subtle. In patients with minimal symptoms, serum thyroid tests may be followed monthly without therapy, and thyrotoxicosis that resolves spontaneously over the subsequent 2 months can be attributed to transient thyroiditis. In patients with more significant biochemical derangement or more pronounced clinical symptoms, thyroid RAIU should be measured. An elevated RAIU is consistent with hyperthyroidism and antithyroid therapy should be offered, whereas a low RAIU indicates thyrotoxicosis without hyperthyroidism (see Figure 4-15).

Rarely, serum thyroid tests reveal the unusual pattern of high free T₄ with a simultaneously normal or high TSH (see Table 4-1). When this pattern of inappropriate TSH secretion is persistent, the rare disorders of TSH-secreting pituitary adenoma and RTH should be considered. As described in section Resistance to Thyroid Hormone, preanalytic factors and laboratory artifact must be ruled out to avoid unnecessary tests and the risk of inappropriate therapy.

Diagnostic Tests

Measuring serum TSH and free T₄ is adequate for the evaluation of thyrotoxicosis. Serum-free T₃ (or a free T₃ index) should be added only if serum TSH is low and free T₄ is normal. Thyroid palpation should focus on thyroid size and whether a discrete nodule is present.

While a focused history and physical examination will accurately diagnose the cause of thyrotoxicosis in most patients, measuring thyroid RAIU can be helpful to distinguish early Graves disease from painless sporadic thyroiditis in those rare patients who present without prolonged symptoms or obvious thyromegaly. Documenting elevated serum titers of TSH receptor autoantibodies can also support the diagnosis of Graves disease, but this is rarely necessary in clinical care. In patients with thyrotoxicosis not due to hyperthyroidism, the level of serum thyroglobulin may distinguish thyroiditis from ingestion of exogenous thyroid hormone.

Differential Diagnosis

This section reviews the major causes of thyrotoxicosis in children. Unlike hypothyroidism, in which knowledge of the specific cause rarely affects treatment, optimal management of thyrotoxicosis requires the accurate diagnosis of its etiology.

Graves disease

Graves disease is a form of autoimmune thyroiditis caused by the production of autoantibodies that bind and stimulate the TSH receptor, leading to thyroid gland hyperfunction (Figure 4-16). Like other forms of autoimmune thyroiditis, lymphocytes infiltrate the thyroid parenchyma, and circulating autoantibodies against thyroperoxidase, thyroglobulin, and the TSH receptor are often detectable. In addition to hyperthyroidism, the classic clinical triad of Graves disease also includes orbitopathy and dermopathy. However, these extrathyroidal manifestations—which are caused by lymphocytic infiltration and accumulation of glycosaminoglycans in the periorbital tissues and skin, respectively—are less common in children than in adults.

Controversy exists regarding the optimal therapy for childhood Graves disease.^48,49 As in adults, a significant minority of affected children (~20%-30%) experience remission of their hyperthyroidism after several years of treatment with antithyroid medication. Though several studies have associated young age and more severe hyperthyroidism with lower rates of remission, it is not possible to reliably predict the likelihood of remission in individual patients.⁵⁰ Because of this unpredictability and concerns about the risks of definitive therapy in children, most pediatric centers offer antithyroid medication as first-line therapy for Graves disease.

Of note, all standard treatments for Graves hyperthyroidism (see section Definitive Therapy) are directed against the thyroid gland, not against the autoimmune cause of Graves disease itself. Accordingly, extrathyroidal features such as orbitopathy and dermopathy may persist or even progress despite the successful treatment of hyperthyroidism.

Rarely, Graves hyperthyroidism can occur in the fetal or neonatal period due to transplacental passage of maternal stimulating TSH receptor autoantibodies (Figure 4-17). Women with a history of Graves hyperthyroidism who have undergone definitive therapy, or who have had a prior affected offspring, should have their titers of TSH receptor autoantibody measured at 20 to24 weeks’ gestation.⁴⁶ If these are elevated, an endocrinologist should be consulted to collaborate with the obstetrician and monitor thyroid status through gestation. In high-risk mothers, fetal growth and thyroid size should be monitored by ultrasound, and serum thyroid tests should be performed on cord blood at birth and then measured monthly in the baby until 3 months of age. If the mother received antithyroid medications during the third trimester of pregnancy, an extra set of thyroid function tests should be done on the baby at 7 days of life to detect delayed hyperthyroidism masked by the effect of maternal thionamides.

Toxic thyroid nodules

A small minority of thyroid nodules (< 5%-10%) are “autonomous,” producing thyroid hormone even in the absence of TSH. Such nodules are as a rule benign, but treatment may be required if they grow large enough to cause hyperthyroidism. In this setting, autonomous nodules are also referred to as hyperfunctioning, toxic, or “hot.” The presence of a thyroid nodule in a hyperthyroid patient should raise suspicion for a toxic nodule. The diagnosis of autonomy is made by thyroid scintigraphy performed when serum TSH is low (< 0.1 μU/mL) by documenting ¹²³I uptake into the nodule (see Figure 4-7) despite the absence of serum TSH. Autonomous nodules must be large (2-3 cm in diameter) to cause hyperthyroidism, so scintigraphy should be reserved for patients with palpable abnormalities.

Because hyperthyroidism from toxic nodules rarely remits, definitive therapy with either ¹³¹I radioiodine ablation or surgical lobectomy is the standard initial treatment in adults. However, ¹³¹I therapy for toxic nodules should not be used in children because it delivers a subcytotoxic dose of radiation to the rim of normal thyroid parenchyma around the nodule, increasing the risk of thyroid cancer in the very young. Surgical resection may be considered instead, or antithyroid medications may be used until the patient reaches adulthood and ¹³¹I therapy can be offered safely.

Transient thyroiditis

Various forms of thyroiditis can cause transient thyrotoxicosis due to the release of preformed hormone from the gland. As discussed earlier, because the normal thyroid contains a finite amount of preformed hormone, these forms of thyrotoxicosis are self-limited and generally last less than 8 weeks. Both painless sporadic thyroiditis and painful subacute thyroiditis can cause transient thyrotoxicosis. These types of thyroiditis should be distinguished from acute suppurative thyroiditis, a bacterial infection that typically presents with symptoms of inflammation and a painful thyroid mass rather than with thyroid dysfunction.⁵¹

Mild thyromegaly is present in about one-half of patients with painless sporadic thyroiditis, and care must be taken to avoid misdiagnosing Graves disease. Measurement of thyroid RAIU can be helpful, as it is low in painless sporadic thyroiditis and high in Graves hyperthyroidism (see Table 4-5).

No therapy is required for thyrotoxicosis due to transient thyroiditis other than reassurance and the potential treatment of symptoms such as tachycardia and thyroid pain with β-blockers and nonsteroidal anti-inflammatory drugs, respectively. Some patients develop hypothyroidism after the thyrotoxic phase of transient thyroiditis. This hypothyroidism is generally transient, but a short course of levothyroxine replacement can be offered if symptoms are significant.

It is worth noting that multiple classification schemes with variable terminology are used to refer to thyroiditis, which can be a source of confusion. Silent sporadic thyroiditis and subacute lymphocytic thyroiditis are synonyms for painless sporadic thyroiditis. The terms de Quervain thyroiditis, de Quervain disease, subacute thyroiditis, subacute nonsuppurative thyroiditis, giant cell thyroiditis, subacute granulomatous thyroiditis, pseudogranulomatous thyroiditis, and struma granulomatosa are all variably used as synonyms for painful subacute thyroiditis. The term hashitoxicosis generally refers to painless sporadic thyroiditis associated with elevated serum antithyroid antibodies. However, other authors apply this term to any hyperthyroid patient who has negative TSH receptor autoantibodies or to patients with persistent autoimmune hypothyroidism who develop hypothyrotropinemia on small levothyroxine doses due to coexisting thyroid-stimulating antibodies.

Thyrotoxicosis factitia

Thyrotoxicosis can occur in patients who take large doses of exogenous thyroid hormone, either intentionally or by accident. A careful history is usually sufficient to diagnose this. On physical examination, the thyroid will be normal or decreased in size. Because endogenous thyroid function is suppressed, thyroid RAIU will be low. In addition, serum levels of thyroglobulin will be low, rather than high as in patients with thyroiditis (see Table 4-5).

TSH-secreting pituitary adenoma

TSH-secreting pituitary adenomas are an extremely rare cause of hyperthyroidism. The characteristic pattern of serum thyroid tests is high free T₄ with inappropriately normal or high TSH (see Table 4-1). As discussed in section Resistance to Thyroid Hormone, it is important to rule out medication use and laboratory artifact as the explanation for this pattern. Pituitary imaging is helpful to distinguish TSH-secreting pituitary adenomas from RTH. The therapy of patients with TSH-secreting pituitary adenomas is directed at decreasing TSH secretion, either by surgical removal of the adenoma or by suppression of TSH secretion with dopaminergic agonists or somatostatin analogs.

Subclinical hyperthyroidism

A subset of hyperthyroid patients presents with mildly suppressed TSH and normal serum concentrations of free T₄ and free T₃. When persistent, this pattern reflects a state of mild thyroid hormone excess and is termed “subclinical hyperthyroidism.” Patients are generally asymptomatic. While subclinical hyperthyroidism in the elderly is associated with increased risk of atrial fibrillation and low postmenopausal bone mineral density, similar risks have not been identified in children.⁵² Accordingly, it is reasonable to monitor children with subclinical hyperthyroidism without therapy, thereby avoiding the risks of antithyroid medication. In the absence of symptoms, serum thyroid tests may be obtained every 3 to 6 months, monitoring both for progression to overt hyperthyroidism (when therapy can be initiated) and for the possibility of spontaneous remission.

Treatment

As discussed previously, the first step in managing the thyrotoxic patients is to determine whether hyperthyroidism is present, as antithyroid therapies have no benefit in its absence. Graves disease is the most common cause of hyperthyroidism and is therefore the focus of this section. Treatments for hyperthyroidism can be divided into antithyroid medication and definitive therapy. Debate exists regarding the optimal treatment for childhood Graves disease.⁴⁸ Because all standard therapies are directed at hyperthyroidism and not at the autoimmune cause of Graves disease itself, physicians must be aware that extrathyroidal manifestations such as orbitopathy and dermopathy can persist or progress even after successful antithyroid treatment.

Antithyroid medications

The thionamide derivatives methimazole and PTU decrease thyroid hormone synthesis and are the mainstays of medical therapy for hyperthyroidism. When given at high doses (over 400 mg/day), PTU has the additional benefit of decreasing T₄ to T₃ conversion. However, methimazole is generally favored over PTU because the longer half-life of methimazole usually permits once-daily maintenance dosing. In addition, PTU carries a higher risk of life-threatening liver failure than methimazole,⁵³ and this risk is disproportionately greater in children.⁵⁴ Based on these data, PTU is no longer recommended as first-line treatment for hyperthyroid children. The single setting in which PTU is preferred to methimazole is during early pregnancy, because in utero methimazole exposure has been associated with a rare congenital defect, aplasia cutis.

Rare but potentially serious adverse reactions, including neutropenia, can occur with either thionamide derivative. These risks must be explained to parents and to referring physicians before starting antithyroid medications. Families should be provided written instructions to immediately discontinue antithyroid medication and page the treating physician if they develop signs or symptoms of neutropenia (fever > 101°F, sore throat, mouth lesions, other concerning symptoms of infection) or hepatitis (right upper quadrant pain, jaundice). A complete blood count with differential or liver function tests should be obtained urgently in such cases to assess for a potentially life-threatening reaction. Thus, patient education and physician communication are especially important in pediatrics, where febrile illness is common and, because of the relative rarity of hyperthyroidism, primary care pediatricians are often unfamiliar with the risks of thionamide administration.

Despite the risks noted above, antithyroid medications are well tolerated in most children and serve as first-line therapy in most pediatric centers. Weight-based guidelines have been recommended for the initiation of methimazole in children (0.5-1.0 mg/kg/day). However, it is logical to consider the severity of hyperthyroidism and the authors recommend the rule of thumb shown in Table 4-7 for starting methimazole in adolescents and young adults. Graves hyperthyroidism alone can cause mild pancytopenia, so a baseline white blood cell count should be obtained prior to starting antithyroid medications.

In patients with severe hyperthyroidism, inorganic iodine can accelerate the decline in serum thyroid hormones and is a helpful adjunct to thionamides. Saturated solution of potassium iodide (SSKI), administered as three drops by mouth three times daily, has a potent and rapid antithyroid effect. Clinicians must remember that patients can escape from the antithyroid effect of SSKI after about 2 weeks, so it cannot be relied on as chronic monotherapy. Furthermore, SSKI is contraindicated if radioiodine ablation is desired in the near future, as even brief administration will compromise thyroidal uptake of radioiodine for months.

Because the serum half-life of T₄ is long (5-7 days), biochemical correction takes time and patients should be counseled that symptoms generally take 3 to 4 weeks to improve. While on antithyroid medication, serum thyroid tests should be obtained every 3 months and 3 weeks after any dose adjustment. After prolonged hyperthyroidism, serum TSH may remain suppressed for many months, and serum-free T₄ is the best initial test to guide therapy during this period. Once serum-free T₄ falls into the upper half of normal range, the starting dose of methimazole should be reduced by one-half to one-third to avoid iatrogenic hypothyroidism. After TSH secretion recovers, normalization of serum TSH is the best index to guide maintenance therapy.

Some experts advocate a “block-and-replace” approach that consists of high doses of antithyroid medication to block endogenous secretion combined with a full replacement dose of levothyroxine. While one study reported higher remission rates with this strategy, subsequent attempts to reproduce this finding have failed.⁵⁵ For simplicity, the authors favor monotherapy, titrated to the lowest methimazole dose required to maintain euthyroidism. If euthyroidism is maintained for 6 to 12 months on a very low methimazole dose (2.5 or 5 mg/day), a trial-off medication can be offered. Serum TSH should be measured every 3 to 4 weeks after the thionamide is discontinued. If TSH remains normal, the patient is in remission. If TSH falls below normal range, methimazole should be restarted or, if appropriate, definitive therapy offered. In the authors’ opinion, because the risks of definitive therapy in the pediatric population are incompletely defined, it is appropriate to offer prolonged courses of methimazole to children until they become adults.

Definitive therapy

In children, definitive therapy is typically used after an adverse reaction to antithyroid medication has occurred or when thionamide therapy has failed to achieve consistent euthyroidism. Two options are available: thyroidectomy and radioiodine ablation. Both definitive therapies are administered with the goal of ablating as much thyroid tissue as possible, and parents should be counseled that the desired outcome of either treatment is lifelong hypothyroidism. Both definitive therapies carry a risk of failure or later relapse. Like antithyroid medication, definitive therapy is directed only against the thyroid and not the underlying autoimmunity that causes Graves disease, so extrathyroidal manifestation such as orbitopathy and dermopathy may progress even after successful definitive therapy.

Surgery.

Surgery was the first definitive therapy used to treat hyperthyroidism. Today, its use in adults is generally reserved for rare patients who have massive goiters (more than eight times normal size) or coexisting cytologically abnormal thyroid nodules. Outcome studies are limited in children, but subtotal thyroidectomy is cited to achieve lasting hypothyroidism in 84% to 99% of pediatric cases.⁴⁹ If thyroidectomy is considered, parents should be fully informed of the risks of both surgery (including vocal cord paralysis and permanent hypoparathyroidism) and anesthesia. The risk of serious operative complications is greatly reduced by referral to a surgeon with extensive experience in subtotal thyroidectomy; in such hands, complication rates may be as low as 2%.⁴⁹

Radioiodine ablation.

Radioiodine ablation with ¹³¹I is the most common definitive therapy in adults with hyperthyroidism. Unlike older dosing guidelines that were intended to leave behind a functional thyroid remnant, full ablative doses are now recommended with the intent of minimizing the risks of both treatment failure and secondary thyroid cancer. Therapeutic ¹³¹I doses are generally adjusted on the basis of estimated thyroid size and RAIU to deliver greater than or equal to 150 μCi/g of thyroid tissue.^56,57 While recent reports of pediatric high-dose ¹³¹I regimens have been reassuring, the absorbed radiation dose to the bone marrow and other normal tissues is inversely proportional to body size. Based on this concept and theoretical modeling of radiation exposures, current consensus guidelinesrecommend that ¹³¹I therapy be avoided in children younger than 5 years and that administered doses be less than 10 mCi in children between 5 and 10 years of age.^56,57

Antithyroid medications should be discontinued 3 to 5 days before radioiodine administration, to optimize RAIU. Thyroid RAIU should be measured in advance with ¹²³I to facilitate determination of the proper ablative dose of ¹³¹I. Thionamide derivatives can be restarted7 days after ¹³¹I administration and thyroid function tests measured monthly thereafter to monitor for response. Parents should be counseled that the response to ¹³¹I is delayed and that an interval of 6 months should pass before considering a second ¹³¹I dose.

Definitions and Epidemiology

A thyroid nodule is a discrete mass within the thyroid gland that is distinct from the surrounding parenchyma. The frequency of thyroid nodules increases with age, with an estimated prevalence of 0.05% to 1.8% in children^58,59 but up to 19% to 67% of randomly selected adults.⁶⁰ Whereas early pediatric series cited very high rates of cancer in thyroid nodules, recent studies of children estimate a much lower cancer prevalence of 5% to 33%, similar to the rates observed in adults. Like thyroid nodules, thyroid cancers are relatively rare in childhood, with a reported frequency of 0.2 to 5 cases per million children per year.⁶¹ The vast majority of differentiated thyroid cancers are of follicular cell origin, with papillary thyroid cancer being the most common subtype.

Pathogenesis

Childhood neck irradiation increases the risk of thyroid neoplasia, and the risk is inversely proportional to the child’s age at the time of exposure. Though neck irradiation is no longer performed for benign conditions, this risk remains relevant for young children who receive radiation therapy for lymphoma and other malignancies. Certain familial disorders also predispose to the development of thyroid neoplasia. However, it is important to note that the vast majority of children who present with thyroid neoplasia have no history of either neck irradiation or familial thyroid cancer.

Clinical Presentation and Diagnosis

Thyroid nodules may present as a neck mass noted by the patient or may be discovered by a clinician’s physical examination. Nodules may also be discovered as incidental findings on radiographic studies performed for unrelated reasons. Regardless of how it is detected, any thyroid nodule of significant size should be evaluated for thyroid cancer.

Algorithm for the Evaluationof Thyroid Nodules

As with most solid cancers, the prognosis of thyroid carcinoma depends in part on tumor size. Accordingly, the primary goal in evaluating nodular thyroid disease is timely identification of the minority of patients with malignant nodules, so that therapy can begin promptly. The following is a suggested approach to the evaluation of thyroid nodules.

When a thyroid nodule is detected, serum thyroid tests should be obtained. If serum TSH is low, ¹²³I thyroid scintigraphy should be performed to determine whether the nodule is autonomous, or “toxic.” As described in section Thyrotoxicosis, such nodules are as a rule benign and do not require further evaluation for malignancy. If serum TSH is normal or high, the patient should be referred to sonography. Any nodule 1 cm or more in diameter should be evaluated by fine-needle aspiration performed under ultrasound guidance (Figure 4-18).

Diagnostic Tests

Thyroid scintigraphy can diagnose toxic thyroid nodules, but clinicians should recognize that such nodules are extremely rare and that autonomy can be confirmed only if scintigraphy is performed while the serum TSH is suppressed. For these reasons, serum TSH should be measured in all patients upon discovery of a thyroid nodule, and scintigraphy reserved only for children whose serum TSH is low. For the majority of patients who present with a normal or high serum TSH, thyroid ultrasound is the optimal modality to confirm or refute the presence of a thyroid nodule.

If a thyroid nodule 1 cm or more in diameter is documented by sonography in a child with a normal or high serum TSH concentration, the nodule should be biopsied. Ultrasound-guided fine-needle aspiration is the preferred technique because it is minimally invasive and easily detects the nuclear changes that are pathognomonic of papillary thyroid cancer.⁶⁰ When reviewed by an experienced cytopathologist, benign cytology is highly accurate and surgery can usually be deferred. Cytology that is positive for papillary thyroid cancer is also highly predictive (> 98% accuracy in our center), so near-total thyroidectomy is the recommended treatment in this setting. For patients with unilateral nodules and intermediate cytologic abnormalities that predict a less than 50% likelihood of cancer, thyroid lobectomy (removal of the ipsilateral lobe and isthmus) is recommended. Completion thyroidectomy (removal of the contralateral lobe) should then be performed as a second operation in patients who are confirmed to have cancer by lobectomy.

Differential Diagnosis

This section reviews the common types of benign and malignant thyroid nodules.

Benign thyroid nodules

The majority of thyroid nodules are benign and, in the absence of associated hyperthyroidism or compressive symptoms, no therapy is required. As described previously, benign cytology has high negative predictive value and usually permits the deferral of surgery. Such patients should be carefully monitored by annual sonography to address the small possibility of a false-negative cytologic result. If a nodule is over 4 cm in size, the authors recommend thyroid lobectomy even with benign cytology due to potentially reduced sensitivity of needle biopsy with very large nodules.

Approximately 5% to 10% of thyroid nodules are autonomous and, if they reach significant size and/or number, can cause hyperthyroidism. Though rare exceptions have been reported, autonomous nodules are as a rule benign. Therefore, if ¹²³I scintigraphy performed during TSH suppression documents focal uptake in the nodule (see Figure 4-7), biopsy can be deferred. Although their cancer risk is extremely low, autonomous nodules may warrant treatment for hyperthyroidism or local compressive symptoms (see Thyrotoxicosis).

Thyroid cancers of follicular cell origin

Over 95% of childhood thyroid cancers are of follicular thyroid cell origin.⁶² Of the two subtypes, papillary and follicular carcinoma, papillary is more common. Compared to adult disease, childhood thyroid cancer is characterized by high rates of regional and distant metastases and high rates of recurrence. Despite this, the outcome of pediatric thyroid cancer is generally favorable. Estimates of cause-specific mortality in children with thyroid cancer vary widely from 0% to 18%.⁶³ Though these estimates approximate the statistics for adults with thyroid cancer, direct comparison of pediatric and adult outcome studies is problematic because pediatric series generally have much shorter follow-up periods.

Most thyroid cancers are characterized by slow growth relative to other common solid tumors. This slow progression contributes to the favorable short-term outcome observed in most patients but may also be responsible for the late recurrences that can occur 20 years or more after initial treatment. Thyroid cancers are refractory to conventional chemotherapy. However, adjunctive therapies such as TSH suppression and radioiodine treatment which exploit similarities between malignant and benign thyroid tissue have been shown to improve outcome. For this reason, specially trained endocrinologists, rather than oncologists, typically serve as the continuity physicians for thyroid cancer.

Though thyroid cancer usually occurs sporadically, several familial syndromes are known to be associated with an increased risk of thyroid neoplasia. These include the PTEN hamartoma tumor syndromes, which are caused by mutations in the PTEN gene and include Cowden syndrome (mucocutaneous lesions, macrocephaly, breast and endometrial carcinoma) and Bannayan-Riley-Ruvalcaba syndrome (macrocephaly, cutaneous lipomas, hemangiomas, and penile freckling in males). There is an increased risk of thyroid cancer in familial adenomatous polyposis (characterized by the progressive development of numerous adenomatous colonic polyps). Germline mutations in DICER-1 have also been recently identified as a risk factor for thyroid neoplasia. In addition, there are families with nonsyndromic thyroid cancer inherited in an apparently autosomal dominant pattern. Accordingly, the evaluation of a new thyroid nodule should include a complete family history and direct assessment for signs or symptoms of the syndromes described here.

Medullary thyroid cancer and multiple endocrine neoplasia type 2

Medullary thyroid cancer is a rare form of thyroid cancer. In contrast to papillary and follicular carcinomas, which arise from the thyroid follicular cells, medullary thyroid cancer arises from the parafollicular C cells that produce calcitonin. For this reason, the adjunctive therapies of TSH suppression and radioiodine are of no benefit in medullary thyroid cancer and treatment is primarily surgical.

Medullary thyroid cancer can occur sporadically or in the context of a familial syndrome. The autosomal dominant disorders familial medullary thyroid cancer (FMTC) and multiple endocrine neoplasia type 2A (MEN2A) and type 2B (MEN2B) are all associated with germline mutations in the RET proto-oncogene. The component endocrine neoplasias of MEN2A are medullary thyroid cancer, hyperparathyroidism, and pheochromocytoma. MEN2B is characterized by medullary thyroid cancer, pheochromocytoma, and the development of mucosal neuromas. All of these disorders must be distinguished from multiple endocrine neoplasia type 1 (MEN1), which is not associated with thyroid cancer but rather with neoplasia of the parathyroids, pituitary, pancreatic islets, and other neuroendocrine cells (eg, gastrinoma).

Medullary thyroid cancer is highly penetrant in all forms of MEN2 and carries a significant risk of mortality, so prophylactic thyroidectomy is recommended. Careful study of families with FMTC and MEN2 has allowed risk stratification for medullary thyroid cancer in patients with the most common RET mutations, so that knowledge of an individual child’s specific RET mutation often allows prediction of thyroid cancer aggressiveness. Consensus guidelines categorize germline RET mutations into risk categories that correspond to specific recommendations for the timing of prophylactic thyroidectomy: before 12 months of life for category D (highest risk); before 5 years of age for category C (high risk); and before 5 to 10 years of age for category A or B (least high risk).⁶⁴ The potential role of surveillance imaging (typically with neck ultrasonography) and serial serum calcitonin measurements to further individualize the timing of thyroidectomy in children with lower-risk RET mutations is an active area of research. In addition to prophylactic thyroidectomy, individuals with MEN2A and MEN2B should have regular biochemical surveillance for pheochromocytoma with plasma metanephrines and, in MEN2A, for hyperparathyroidism by measuring serum calcium. Finally, the discovery of a germline RET mutation in a patient should prompt genetic testing of all relatives for this mutation.

Treatment

This section discusses general concepts in the treatment of thyroid cancer, focusing on cancers of follicular cell origin (papillary carcinoma and follicular carcinoma), which represent over 95% of childhood thyroid cancers.⁶² Medullary thyroid cancer, which arises from parafollicular C cells, is typically treated with surgery alone. While a detailed discussion of the management of thyroid cancer is beyond the scope of this chapter, consensus guidelines from organizations such as the American Thyroid Association are regularly updated and accessible on the internet (http://thyroidguidelines.net).^60,64

Surgery

Surgery is the initial therapy for all primary thyroid cancers. The optimal operation is near-total thyroidectomy, which removes possible occult microscopic disease in the contralateral lobe, lowers recurrence risk in patients with advanced disease, and increases the sensitivity of the tests used to monitor for disease progression. Though lobectomy may be appropriate for certain individuals with unifocal microcarcinomas, such patients are rare in pediatrics and, in practice, near-total thyroidectomy is the most common operation performed.

In addition to the general risks of surgery and anesthesia, thyroid surgery is associated with the specific risks of vocal cord paralysis (due to injury to the recurrent laryngeal nerve) and permanent hypoparathyroidism (due to inadvertent injury to or removal of the parathyroid glands). These risks are greatly reduced by referral to a surgeon with extensive experience in thyroid surgery. As described in section Diagnostic Tests, we recommend a staged approach using nodule cytology to triage patients to initial lobectomy versus near-total thyroidectomy. Because most nodules are benign, this staged approach avoids the risks of bilateral surgery in the majority of children who present with nodules. Hypothyroidism is the expected consequence of near-total thyroidectomy and, as it is readily treated, it should not affect decisions regarding operative strategy.

About one-third of children treated successfully for thyroid cancer experience disease recurrence that is most often local. If recurrent regional lymph node metastasis is macroscopic (palpable or easily visualized by sonography), surgical neck dissection should be considered. As with thyroid nodules, neck sonography and ultrasound-guided fine-needle aspiration should be performed preoperatively to confirm the presence of metastatic disease and to plan the surgical approach.

Radioiodine therapy

Even after near-total thyroidectomy, RAIU usually persists in the thyroid bed due to a microscopic residuum of normal thyroid tissue. In patients with more advanced disease and higher risk of disease progression, postoperative radioiodine ablation of this remnant with ¹³¹I has been shown to lower recurrence rates (presumably due to the destruction of malignant thyroid cells within the remnant) and to improve the sensitivity of the surveillance tests used to monitor for disease progression. Apart from remnant ablation, higher ¹³¹I doses may be used to treat foci of thyroid cancer that are not amenable to surgical resection, including distant metastases.^65,66

¹³¹I doses are calculated to deliver therapeutic radioactivity without exceeding safe radiation exposures to normal tissues such as bone marrow and gonads. Pediatricians must be aware that the absorbed radiation dose to normal tissues is higher in children due to their smaller organ volumes and increased cross radiation, so administered doses must be reduced accordingly. An interval of 12 months between ¹³¹I treatments is generally recommended to minimize the risk of radiation-induced leukemia.

To optimize RAIU into thyroid cells, patients should be prepared with a low-iodine diet, and hyperthyrotropinemia (TSH > 25 μU/mL) should be induced by levothyroxine withdrawal. Children may become nauseous after ¹³¹I administration, so antiemetics such as ondansetron or lorazepam should be used as needed (or given prophylactically to children who have vomited with prior ¹³¹I doses). Oral hydration, frequent urination, and regular stooling should be encouraged for 2 to 3 days after ¹³¹I administration to minimize radiation exposure to the intestinal tract, bladder, and gonads. The authors also recommend using sialogogues beginning 1 day after ¹³¹I administration to minimize radiation to the salivary glands. Levothyroxine therapy and a normal diet can be reinstituted 2 days after ¹³¹I administration, and a posttherapy whole-body scan should be performed 4 to 7 days after treatment.

TSH suppression

TSH stimulates thyroid follicular cell growth, so suppression of serum TSH is recommended in children with papillary or follicular thyroid cancers. When used to an adjunct to surgery, TSH suppression reduces recurrence risk and can improve survival in patients with advanced disease. Levothyroxine should be titrated to a goal serum TSH of 0.1 μU/mL or lower. This can usually be achieved without hyperthyroxinemia or thyrotoxic symptoms. The parents of children with thyroid cancer should be counseled that consistent compliance with levothyroxine administration is critical not only for hormone replacement after thyroidectomy but also as a means of suppressing cancer progression.

Monitoring for disease progression

Pediatric thyroid cancer can recur 30 years or more after initial surgery, and all children with thyroid cancer warrant lifelong surveillance. The timely detection of cancer recurrence provides the greatest opportunity to eradicate disease in its early stages.

Serum thyroglobulin is produced exclusively by thyroid follicular cells and is therefore used as a tumor marker. Because thyroglobulin is produced by both thyroid cancer and normal thyroid tissue, its greatest utility as a tumor marker is realized only after surgical thyroidectomy and radioiodine ablation of the thyroid remnant. Surveillance should also include serial neck imaging. In the hands of an experienced operator, thyroid sonography is an extremely sensitive and, when coupled with ultrasound-guided fine-needle aspiration, highly specific modality to screen for local recurrence. Institutions with less experience in neck sonography may consider MRI or CT instead. Stimulated surveillance studies with ¹²³I diagnostic whole-body scans should be performed in children at risk of distant metastasis.