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Chapter 376: Hypothyroidism

J. Larry Jameson; Susan J. Mandel; Anthony P. Weetman

HYPOTHYROIDISM

Iodine deficiency remains a common cause of hypothyroidism worldwide. In areas of iodine sufficiency, autoimmune disease (Hashimoto’s thyroiditis) and iatrogenic causes (treatment of hyperthyroidism) are most common (Table 376-1).

TABLE 376-1Causes of Hypothyroidism
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TABLE 376-1 Causes of Hypothyroidism
Primary
Autoimmune hypothyroidism: Hashimoto’s thyroiditis, atrophic thyroiditis
Iatrogenic: 131I treatment, subtotal or total thyroidectomy, external irradiation of neck for lymphoma or cancer
Drugs: iodine excess (including iodine-containing contrast media and amiodarone), lithium, antithyroid drugs, p-aminosalicylic acid, interferon α and other cytokines, aminoglutethimide, tyrosine kinase inhibitors (e.g., sunitinib)
Congenital hypothyroidism: absent or ectopic thyroid gland, dyshormonogenesis, TSH-R mutation
Iodine deficiency
Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, scleroderma, cystinosis, Riedel’s thyroiditis
Overexpression of type 3 deiodinase in infantile hemangioma and other tumors
Transient
Silent thyroiditis, including postpartum thyroiditis
Subacute thyroiditis
Withdrawal of supraphysiologic thyroxine treatment in individuals with an intact thyroid
After 131I treatment or subtotal thyroidectomy for Graves’ disease
Secondary
Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders, Sheehan’s syndrome, trauma, genetic forms of combined pituitary hormone deficiencies
Isolated TSH deficiency or inactivity
Bexarotene treatment
Hypothalamic disease: tumors, trauma, infiltrative disorders, idiopathic

Abbreviations: TSH, thyroid-stimulating hormone; TSH-R, TSH receptor.

CONGENITAL HYPOTHYROIDISM

Prevalence

Hypothyroidism occurs in about 1 in 4000 newborns and neonatal screening is performed in most industrialized countries. It may be transient, especially if the mother has TSH-R blocking antibodies or has received antithyroid drugs, but permanent hypothyroidism occurs in the majority. Neonatal hypothyroidism is due to thyroid gland dysgenesis in 80–85%, to inborn errors of thyroid hormone synthesis in 10–15%, and is TSH-R antibody-mediated in 5% of affected newborns. The developmental abnormalities are twice as common in girls. Mutations that cause congenital hypothyroidism are being increasingly identified, but most remain idiopathic (Table 376-2). Transplacental passage of maternal thyroid hormone occurs before the fetal thyroid gland begins to function and provides partial hormone support to a fetus with congenital hypothyroidism.

TABLE 376-2Genetic Causes of Congenital Hypothyroidism
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TABLE 376-2 Genetic Causes of Congenital Hypothyroidism
DEFECTIVE GENE PROTEIN INHERITANCE CONSEQUENCES
PROP-1 Autosomal recessive Combined pituitary hormone deficiencies with preservation of adrenocorticotropic hormone
PIT-1

Autosomal recessive

Autosomal dominant

 Combined deficiencies of growth hormone, prolactin, thyroid-stimulating hormone (TSH)
TSHβ Autosomal recessive TSH deficiency
TTF-1 (TITF-1) Autosomal dominant Variable thyroid hypoplasia, choreoathetosis, pulmonary problems
TTF-2 (FOXE-1) Autosomal recessive Thyroid agenesis, choanal atresia, spiky hair
PAX-8 Autosomal dominant Thyroid dysgenesis, kidney abnormalities
NKX2-1 Autosomal dominant Thyroid dysgenesis, brain, lung abnormalities
NKX2-5 Autosomal dominant Thyroid dysgenesis, heart abnormalities
TSH-receptor Autosomal recessive Resistance to TSH
GSα (Albright hereditary osteodystrophy) Autosomal dominant Resistance to TSH
Na+/I– symporter (SLC5A5) Autosomal recessive Inability to transport iodide
DUOX2 (THOX2) Autosomal dominant Organification defect
DUOXA2 Autosomal recessive Organification defect
Thyroid peroxidase Autosomal recessive Defective organification of iodide
Thyroglobulin Autosomal ...

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