Clinical syndromes of glucocorticoid resistance and hypersensitivity

Purpose of reviewThis review focuses on clinical syndromes of glucocorticoid resistance and hypersensitivity in humans. Recent findingsGlucocorticoid resistance and hypersensitivity syndromes can be categorized by mechanism into syndromes caused by glucocorticoid receptor (GR) gene mutations or polymorphisms, and syndromes caused by abnormal glucocorticoid metabolism. GR mutations cause generalized glucocorticoid resistance. More common GR polymorphisms are associated with phenotypic characteristics suggesting either mild resistance or hypersensitivity to glucocorticoid. Pharmaceutical inhibitors of the cytochrome P450 3A4 system such as ritonavir and itraconazole cause hypersensitivity to inhaled glucocorticoids. Enzymes controlling cortisol and cortisone interconversion are tissue specific. A deficiency of cortisone reductase (decreased conversion of cortisone to cortisol) in adipose tissue causes a glucocorticoid resistance syndrome, with the absence of Cushingoid features in a patient with Cushing's syndrome. A renal tubule deficiency in 11β-hydroxysteroid dehydrogenase type 2 (decreased conversion of cortisol to cortisone) causes hypertension and hypokalemia due to an apparent hypersensitivity to cortisol. SummaryGR and glucocorticoid metabolism abnormalities cause glucocorticoid resistance and hypersensitivity with diverse clinical presentations. Therapies are targeted to the specific mechanistic abnormalities.