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.
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.
Table 4-3.Signs and Symptoms of Hypothyroidism ||Download (.pdf) Table 4-3. Signs and Symptoms of Hypothyroidism
Delayed skeletal maturation
Abnormal pubertal development (delay or pseudoprecocity)
Bradycardia (decreased cardiac output)
Fluid retention and weight gain (impaired renal free water clearance)
Dry, sallow skin
Delayed deep tendon reflexes
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.
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.
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.
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 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.
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.
Thyroid gland enlargement in a 10-year-old girl with documented autoimmune (Hashimoto) thyroiditis and hypothyroidism. Her initial serum TSH was greater than 1000 mU/L.
(A) A 14-year-old juvenile-appearing boy with long-standing autoimmune hypothyroidism. He was as tall as the average 8.5-year-old and had a skeletal maturation of 7.5 years. (B) The boy’s general physically immature appearance. The 5th percentile of height for age is shown as the black line above his head. (C) The boy’s appearance after 3.5 years of replacement thyroid hormone treatment. The stadiometer is set at the 5th percentile of height for age. Note that before leuprolide treatment was available, many children with long-standing hypothyroidism would undergo rapid pubertal development and skeletal maturation once started on treatment and would fail to reach “expected” adult height, as was the case in this child.
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.
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 European22-24 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.
A 17-year-old girl with untreated congenital hypothyroidism. The patient is the average height of a 3-year-old and her estimated bone age is 9 months. (Reproduced with permission from Brent G, Davies T, Larsen P. Hypothyroidism and thyroiditis. In: Kronenberg HM, Melmed S, Larsen PR, Polonsky KS, eds. Williams Textbook of Endocrinology, 12th ed. Philadelphia, PA: Saunders/Elsevier; 2011.)
A 1-year-old child with undiagnosed/untreated congenital hypothyroidism who was born before national screening programs for this condition. She was treated with replacement thyroid hormone, and 6 months later she had a more normal facial appearance but significant developmental delays due to delay in diagnosis and treatment.
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.
An 8-year-old hypothyroid girl with a sublingual thyroid outlined.
A 9-year-old hypothyroid girl with a lingual thyroid, visible as a “goiter” at the base of the tongue.
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 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 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.
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
Table 4-4.Recommended Doses of Levothyroxine, Based on Body Weight ||Download (.pdf) Table 4-4. Recommended Doses of Levothyroxine, Based on Body Weight
|Recommended L-T4 Treatment Doses |
|Age ||L-T4 Dose (μg/kg) |
|0-3 mo ||10-15 |
|3-6 mo ||8-10 |
|6-12 mo ||6-8 |
|1-3 y ||4-6 |
|3-10 y ||3-4 |
|10-15 y ||2-4 |
|> 15 y ||2-3 |
|Adult ||1.6 |
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
Box 4-1. When to Refer
Because thyroid hormone is critical for pediatric growth and development, referral to an endocrine specialist is appropriate when hypothyroidism is diagnosed in a child.
In infancy, inadequately treated hypothyroidism causes permanent neurologic injury, so referral and the initiation of treatment are urgent.
Once linear growth is complete, levothyroxine requirements are usually stable and treatment can be transferred from the endocrinologist to the patient’s primary care provider.