Defects of Thyroxine-Binding Globulin

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Chapter 558 Defects of Thyroxine-Binding Globulin

Stephen LaFranchi

Abnormalities in levels of thyroxine-binding globulin (TBG) are not associated with clinical disease and do not require treatment. They are usually uncovered by a chance finding of abnormally low or high levels of thyroxine (T₄) and may be a source of confusion in the diagnosis of hypothyroidism or hyperthyroidism.

TBG deficiency occurs as an X-linked dominant disorder. Congenital TBG deficiency is most often discovered through screening programs for neonatal hypothyroidism that use levels of T₄ as the primary screen. Affected patients have low levels of T₄ and elevated resin triiodothyronine uptake (RT₃U), but levels of free T₄ and thyroid-stimulating hormone (TSH) are normal. The diagnosis is confirmed by the finding of absent or low levels of TBG. TBG deficiency occurs in 1 in 2,400 male newborns, 36% of whom have TBG levels <1 mg/dL. Milder forms of TBG deficiency occur in approximately 1/42,000 heterozygous female newborns. Complete TBG deficiency (<5 µg/dL) occurs much less often. To date, 26 different mutations have been reported in the TBG gene, resulting in either decreased TBG levels or reduced affinity of TBG for T₄. Acquired TBG deficiency occurs with androgen or other anabolic steroids, glucocorticoid, and L-asparaginase treatment, hepatic insufficiency (not hepatitis), renal disease and proteinuria, and protein-losing enteropathies.

TBG excess also is a harmless X-linked dominant anomaly, occurring in about 1/25,000 persons. It has been recognized primarily in adults, but neonatal screening programs uncover the condition in the neonate. The level of T₄ is elevated, T₃ is variably elevated, TSH and free T₄ are normal, and RT₃U is decreased. The elevated levels of TBG confirm the diagnosis. In neonates, levels of T₄ as high as 95 µg/dL have been found, which decrease to 20-30 µg/dL after 2-3 wk. Such high levels of T₄ may be related in part to the normally elevated levels of TBG in neonates during the 1st mo of life, presumably as an effect of maternal estrogens. Affected patients are euthyroid. Family studies may be indicated to alert other affected family members. Acquired elevations of TBG occur with pregnancy, estrogen treatment, hepatitis, and certain drugs (clofibrate, methadone, perphenazine).

Familial dysalbuminemic hyperthyroxinemia is an autosomal dominant disorder that may be confused with hyperthyroidism. Markedly increased binding of T₄ to an abnormal albumin variant leads to increased serum concentrations of T₄. However, the levels of free T₄, free T₃, and TSH are normal. Levels of T₃ are normal or only slightly elevated. Affected patients are euthyroid.

Benvenga S. Thyroid hormone transport proteins and the physiology of hormone binding. In: Braverman LE, Utiger RD, editors. Werner & Ingbar’s the thyroid: a fundamental and clinical text. ed 9. Philadelphia: Lippincott Williams & Wilkins; 2005:97-108.

LaFranchi SH, Snyder DB, Sesser DE, et al. Follow-up of newborns with elevated screening T₄ concentrations. J Pediatr. 2003;143:296-301.

Mandel SH, Hanna CE, Boston BA, et al. Thyroxine binding globulin deficiency detected by newborn screening. J Pediatr. 1993;122:227-230.

Mannavola D, Vannucchi G, Fugazzola L, et al. TBG deficiency: description of two novel mutations associated with complete TBG deficiency and review of the literature. J Mol Med. 2006;84:864-871.

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