Pathogenesis of the type 2 variant of the syndrome of apparent mineralocorticoid excess.

The syndrome of apparent mineralocorticoid excess, which is not a primary disorder of the adrenal cortex, describes the association of an unexplained hypermineralocorticoid state with a decreased rate of peripheral 11 beta-hydroxydehydrogenation of cortisol to cortisone. Studies in this syndrome have led to the hypothesis that peripheral cortisol inactivation is the normal mechanism permitting specific mineralocorticoid recognition. This view reconciled developing evidence that the mineralocorticoid receptor itself could not distinguish between mineralocorticoids and glucocorticoids. The syndrome occurs in two forms. In both forms there is decreased turnover of a normal level of plasma cortisol, consistent with the view that delayed removal of the glucocorticoid from strategic receptor sites unmasks its potential mineralocorticoid agonism. In the type 1 variant, impaired 11 beta-hydroxydehydrogenation is reflected by an elevated cortisol/cortisone metabolite ratio. In three patients with the type 2 variant, this ratio was normal, suggesting that the rate of 11 beta-hydroxydehydrogenation was unimpaired. The hypertension and hypokalemic alkalosis of both forms are improved by spironolactone, but patients with the type 2 variant have responded somewhat better to the suppression of cortisol by dexamethasone.