Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle

Abstract

The first adult case of 11β-hydroxysteroid dehydrogenase (11β-OHSD) deficiency is described. The impaired conversion of cortisol to cortisone (indicated by urinary cortisol and cortisone metabolites and failure to metabolize 11α-[3H]cortisol to [3H]H2O, was associated with hypertension, hypokalemia, and suppression of the renin-angiotensin-aldosterone system. When established on a fixed Na+/K+ intake, dexamethasone, given orally, produced a natriuresis and potassium retention. Plasma renin activity became detectable. When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis (urinary Na+/K+ falling from 1.2 to 0.15), with suppression of plasma renin activity and an increase in blood pressure. These changes were also seen with the subject on no treatment. Conversion of cortisone to cortisol was not affected. These results suggest that cortisol acts as a potent mineralocorticoid in 11β-OHSD deficiency. The major site for the oxidation of cortisol to cortisone is the kidney. In this patient congenital deficiency of 11β-OHSD results in high intrarenal cortisol levels which then act on renal type I mineralocorticoid receptors. This condition can be treated with dexamethasone, which suppresses cortisol secretion and binds to the type II glucocorticoid receptor. We suggest that 11β-OHSD exerts a critical paracrine role in determining the specificity of the type I receptor. In the normal state cortisol is converted by 11β-OHSD to cortisone which thus allows aldosterone to bind preferentially to the type I receptors in the kidney and gut. In this patient deficiency of 11β-OHSD results in high intrarenal cortisol concentrations that then bind to the type I receptor.