Pediatric Hypothyroidism

The fetal hypothalamic-pituitary-thyroid system develops independently of the mother's pituitary-thyroid axis. During embryogenesis, primordial thyroid cells arise from epithelial cells on the pharyngeal floor; they then migrate caudally to fuse with the ventral aspect of the fourth pharyngeal pouch by 4 weeks' gestation. The thyroid continues to develop anteriorly to the third tracheal cartilage. Thyroglobulin is produced by 8 weeks' gestation. Trapping of iodine occurs by 10-12 weeks' gestation, followed by the synthesis of iodothyronines. Colloid formation and pituitary secretion of thyrotropin, also termed thyroid-stimulating hormone (TSH), occur by the 12 weeks' gestation.

Normal physiology

The primary function of the thyroid gland is synthesis of thyroxine (T4) and triiodothyronine (T3). Pituitary thyrotropin regulates thyroid hormone production. TSH synthesis and secretion are stimulated by thyrotropin-releasing hormone (TRH), which is synthesized by the hypothalamus and is secreted into the hypophyseal portal vasculature for transport to the anterior pituitary gland. Serum T4 concentration modulates secretion of both TRH and TSH by means of a classic negative feedback loop.

Circulating T4 is predominantly bound to T4-binding globulin (TBG). T4 is deiodinated in peripheral tissue to T3, the more bioactive thyroid hormone. T3 carries 3-4 times the metabolic potency of T4, freely enters cells, and binds to receptors of the hormone into the cell nucleus. Thyroid hormone exerts profound effects on the regulation of gene transcription. Some major clinical phenomena of thyroid hormone action include differentiation of the CNS and maintenance of muscle mass. Thyroid hormone also controls skeletal growth and differentiation and metabolism of carbohydrates, lipids, and vitamins.

Thyroid hormone synthesis absolutely requires iodine. Dietary iodine deficiency is endemic in several areas of the world, particularly high mountain plateaus. In the United States, supplementation of salt with iodine has nearly eliminated dietary deficiency of this essential element. The recommended dietary allowance of iodine is 40-50 mcg daily in infants, 70-120 mcg daily for children, and 150 mcg daily for adolescents and adults. The daily intake in North America varies from 240 mcg to more than 700 mcg.

In the thyroid gland, iodide is trapped, transported, and concentrated in the follicular lumen for thyroid hormone synthesis. Before trapped iodide can react with tyrosine residues, it must be oxidized by thyroidal peroxidase. Iodination of tyrosine forms mono-iodotyrosine and di-iodotyrosine. Two molecules of di-iodotyrosine combine to form T4, and one molecule of mono-iodotyrosine combines with one molecule of di-iodotyrosine to form T3. Formed thyroid hormones are stored within thyroglobulin in the lumen of the thyroid follicle until release. TSH stimulates uptake and organification of iodide as well as liberation of T4 and T3 from thyroglobulin.

Congenital hypothyroidism

Approximately 75% of infants with congenital hypothyroidism have defects in thyroid gland development, 10% have hereditary defects in thyroid hormone synthesis or uptake, 5% have secondary (pituitary) or tertiary (hypothalamus) hypothyroidism, and 10% have transient hypothyroidism.

• Thyroid dysgenesis: Defective thyroid gland development accounts for most instances of congenital hypothyroidism. Thyroid dysgenesis occurs sporadically in most cases but is occasionally familial because of mutations or deletions of genes (TSHR, PAX8, NKX2-1, FOXE1, and NKX2-5) that are involved in fetal thyroid formation. Thyroid dysgenesis ranges in severity from thyroid aplasia or hypoplasia to functional ectopic thyroid tissue. Approximately 40-60% of infants with thyroid gland dysgenesis have some functioning tissue. Laboratory and imaging studies facilitate the determination of the degree of dysgenesis. Thyroid agenesis is suggested by a low serum T4 level with an elevated serum TSH level and undetectable serum thyroglobulin. Newborns with ectopic or hypoplastic thyroid glands manifest low serum T4, elevated serum TSH, and measurable levels of circulating thyroglobulin. Imaging aids in confirming the diagnosis of aplastic, hypoplastic, or ectopic thyroid.

• Familial thyroid dyshormonogenesis: Rare autosomal recessive inborn errors of thyroid hormone synthesis, secretion, or uptake also cause congenital hypothyroidism. The following 8 inborn errors have been identified:

  • Failure to respond to TSH secondary to defective activation of the thyroid receptor and related cyclic adenosine monophosphate (cAMP) signal transduction pathway

  • Defect in trapping of iodide secondary to sodium-iodide symporter failure

  • Defective oxidation of iodide to iodine secondary to thyroid peroxidase deficiency

  • Defective coupling of iodotyrosines

  • Deiodination defects

  • Defective thyroglobulin synthesis

  • Defective proteolysis of thyroglobulin

  • Release of T3 and T4 into the circulation

• Partial peripheral resistance to thyroid hormones (autosomal dominant defect): Patients relate a family history of goiter with euthyroidism or hypothyroidism in the face of elevated serum levels of T4 or T3 but nonsuppressed serum TSH concentrations.

• Hypopituitarism

• Transplacental passage of maternal TSH-binding inhibitory antibodies: This can cause transient neonatal hypothyroidism. In mothers with autoimmune thyroiditis, immunoglobulin G (IgG) antithyroid antibodies can be transmitted across the placenta. These antibodies block binding of TSH to its receptor on the fetal thyroid. The half-life of these antibodies is approximately 1 week, and this form of congenital hypothyroidism usually resolves within 2-3 months of life. Although these infants are asymptomatic, they require thyroid hormone replacement until the pituitary-thyroid axis recovers. Monitoring the infant's serum titer of maternal antibodies is unnecessary, although monitoring serum TSH values is essential for guiding therapy.

• Maternal exposure to radioiodine: The fetal thyroid is able to trap iodide by 70-75 days' gestation. Hypothyroidism can develop if the mother is exposed to radioiodine to treat Graves disease or thyroid carcinoma.

• Goitrogens: These include iodides found in certain asthma medications, amiodarone, neonatal exposure to iodine-containing antiseptics, propylthiouracil, or methimazole.

Acquired hypothyroidism

CLT (ie, autoimmune thyroiditis, Hashimoto thyroiditis) is the most common cause of acquired hypothyroidism and goiter in children living in iodine-sufficient areas. An increased frequency of CLT occurs in children with trisomy 21 syndrome, Ulrich-Turner syndrome, Klinefelter syndrome, or other autoimmune diseases, including type 1 diabetes mellitus. CLT appears to require both an environmental trigger and a genetically determined defect in immune surveillance.

Evidence suggests that the disease develops secondary to a defect in cell-mediated immunity whereby suppressor T lymphocytes fail to destroy forbidden clones of thyroid-directed T lymphocytes, which form as part of random immunologic differentiation. The attack on the thyroid involves natural killer cells and the complement cascade. Various thyroid autoantibodies (antithyroglobulin antibody, antithyroid peroxidase antibody) are demonstrable in the serum but are not believed to play a role in the pathogenesis of CLT.

Clinical manifestations of CLT vary depending on the type and predominance of thyroid antibodies produced. Most children present with an asymptomatic goiter and may be biochemically euthyroid, although compensated hypothyroidism and symptomatic hypothyroidism are more common presentations. Rarely, the child with CLT may be symptomatic with a small atrophied gland. A small percentage of children with CLT initially present with transient symptoms of hyperthyroidism. This short-lived thyrotoxic phase may be secondary to autonomous release of stored T4 and T3 (with progressive inflammatory lymphocytic infiltration of the thyroid) or secondary to an initial predominance of TSH-receptor stimulating immunoglobulins (termed hashitoxicosis).

Subacute thyroiditis is a rare disorder in children. Typically, a painful thyroid gland is accompanied by signs and symptoms of hyperthyroidism, with elevated serum T4 and suppressed serum TSH. Patients with this condition may present later manifesting a hypothyroid phase with goiter. The clinical hallmarks are painful swelling of the thyroid, usually after a viral infection, with lymphocytosis and elevated sedimentation rate. The inflammation results in autonomous release of thyroid hormone and a thyrotoxic phase, followed by a euthyroid phase and then a hypothyroid phase. Each phase lasts at least 1 week and is commonly followed by a return to an euthyroid state, depending on the degree of tissue damage. Treatment of the thyroid disorder is usually unnecessary.

Drug-induced hypothyroidism can result from use of thioamides, lithium, amiodarone, and excess dietary iodine. Exposure to these substances most often results in biochemical evidence of hypothyroidism in the absence of clinical symptoms.

Endemic goiter results from nutritional iodine deficiency with or without environmental goitrogen exposure. Endemic regions include high mountain plateaus and other areas that do not have ready access to salt water or seafood.

Euthyroid sick syndrome involves the following:

• T4 is converted in peripheral tissues to bioactive T3 by thyroxine-5'-deiodinase enzyme. This enzyme is also responsible for clearing small amounts of reverse T3 (rT3), which are the by-products of T4 metabolism. Many nonthyroidal illnesses are associated with inhibition of 5'-deiodinase activity in peripheral tissues, resulting in a decrease of circulating bioactive T3 and an increase in reverse T3 (rT3).

• Examples include acute or chronic severe illness, surgery, trauma, fasting, malnutrition, and use of certain drugs. TSH secretion is also decreased and does not appropriately respond to falling serum levels of T4. The classic findings include low or normal TSH, low T4 and free T4, low T3 and free T3, and elevated rT3 levels in serum. Thyroid hormone replacement is not needed because the disorder resolves with improvement of the underlying disease.

Childhood onset of congenital hypothyroidism secondary to hypoplastic or ectopic gland, which becomes unable to meet the demands of the growing child. Radioiodine uptake imaging assists in making the diagnosis.

Irradiation of the thyroid gland may be a cause. For example, the Chernobyl disaster of 1987 released massive quantities of radioactive iodine and cesium into the environment, leading to an increase in the subsequent incidence of both hypothyroidism and thyroid malignancy.

Infiltrative and storage disorders of the thyroid gland, including histiocytosis X and cystinosis, may be associated with hypothyroidism. In these instances, the primary disease is usually evident prior to the development of hypothyroidism.

Surgical excision may be associated with hypothyroidism.

United States statistics

Congenital hypothyroidism has a frequency of 1 case per 1500-3000 live births. ^[3]

International statistics

Hypothyroidism can be congenital. Thyroid dysgenesis affects 1 per 4000 newborns worldwide. Hypothalamic or pituitary insufficiency, which results in secondary or tertiary hypothyroidism, respectively, affects 1 per 60,000-140,000 newborns worldwide.

Hypothyroidism can be acquired. Depending on the criteria used for diagnosis, as many as 10% of young females are estimated to have some signs of autoimmune thyroid disease, usually chronic lymphocytic thyroiditis (CLT). Not all cases progress to frank hypothyroidism; however, these patients remain at an increased risk compared with the general population.

Race-, sex-, and age-related demographics

In descending order, thyroid dysgenesis occurs more frequently in Hispanics than in whites, followed by blacks.

Thyroid dysgenesis occurs more frequently in females than in males, with a female-to-male ratio of 2:1. CLT also has a 4:1 female-to-male preponderance in childhood.

Congenital hypothyroidism can present with goiter at birth or with the gradual development of symptoms over the first several months of life. ^[4] The age of symptom onset is unpredictable in a child who has thyroid dysgenesis with a hypoplastic and/or ectopic thyroid gland because initial increases in TSH may be able to initially overcome the relative insufficiency of the thyroid gland. CLT typically presents during adolescence; however, it may present any time in life.

The prognosis for patients with congenital hypothyroidism that is appropriately treated within 6 weeks of birth is excellent.

Children with acquired hypothyroidism who receive adequate treatment at least 5 years before the onset of puberty typically achieve a final adult height consistent with their genetic potential. Overtreating with thyroid hormone does not enhance catch-up growth and may compromise final adult height by advancing osseous maturation.

Morbidity/mortality

Untreated congenital hypothyroidism in early infancy results in profound growth failure and disrupted development of the CNS, leading to developmental cognitive delay (cretinism). Untreated hypothyroidism in older children leads to growth failure as well as slowed metabolism and impaired memory.

Complications

The etiology of adverse clinical outcomes is multifactorial. Even with optimal therapy, some children with congenital hypothyroidism display intelligence quotient values lower than would be expected on the basis of genetic potential. Factors associated with this adverse outcome include a markedly low T4 value at birth, a markedly delayed bone age at diagnosis, delay in treatment, and low serum T4 levels during the first year of therapy.