Corticosteroid-binding globulin deficiency

Corticosteroid-binding globulin (CBG) deficiency is a rare endocrine disorder caused by mutations in the SERPINA6 gene, which encodes corticosteroid-binding globulin (also known as transcortin). CBG is the primary transport protein for cortisol in the bloodstream, carrying approximately 80-90% of circulating cortisol. When CBG is deficient or functionally impaired, total serum cortisol levels are low, although free (unbound) cortisol levels may be normal or near-normal. This distinction is clinically important because standard cortisol assays measure total cortisol, which can lead to a misleading impression of adrenal insufficiency. Affected individuals may experience chronic fatigue, hypotension, and excess fatigue particularly during periods of physiological stress such as illness, surgery, or pregnancy. Some patients report chronic pain and weakness. However, many individuals with CBG deficiency may be relatively asymptomatic under normal conditions because their free cortisol levels remain adequate. The condition primarily affects the hypothalamic-pituitary-adrenal (HPA) axis regulation and cortisol bioavailability. During periods of stress, the reduced cortisol-buffering capacity provided by CBG may result in inadequate cortisol delivery to tissues, leading to symptoms resembling relative adrenal insufficiency. Diagnosis is established by measuring CBG levels in the blood and confirmed through genetic testing of the SERPINA6 gene. Treatment is generally supportive. Some patients may benefit from stress-dose glucocorticoid supplementation during periods of physiological stress, similar to management strategies used in mild adrenal insufficiency. Routine glucocorticoid replacement is typically not required in asymptomatic individuals. Awareness of this condition is important to avoid unnecessary treatment for presumed adrenal insufficiency based solely on low total cortisol measurements.

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