Non-Classical Apparent Mineralocorticoid Excess Syndrome: Current Evidence and Future Challenges

Hypertension affects over 1.3 billion people worldwide and is the leading modifiable cause of cardiovascular morbidity and mortality. Approximately one-third of individuals with hypertension exhibit a low-renin phenotype, a clinically heterogeneous subgroup in whom the underlying etiology remains uncharacterized in most cases. Among its mechanistic contributors, non-classical apparent mineralocorticoid excess (NC-AME), defined by partial insufficiency of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), represents a prevalent and underrecognized cause of cortisol-mediated mineralocorticoid receptor overactivation that has, to date, lacked a formal clinical definition, standardized diagnostic criteria, or evidence-based therapeutic framework. This Scientific Statement addresses that gap. The panel formally defines NC-AME as a syndrome of partial 11β-HSD2 insufficiency occurring in the absence of biallelic HSD11B2 variants, biochemically characterized by an elevated cortisol-to-cortisone (F/E) ratio and low cortisone concentration, and typically associated with low plasma renin, normal-to-low aldosterone, and elevated blood pressure. The Statement consolidates evidence across three mechanistic domains, genetic and epigenetic dysregulation of HSD11B2, endogenous and exogenous enzyme inhibition, and patient-specific alterations (i.e. age, sex, renal function), and proposes both a structured, an LC-MS/MS-based diagnostic algorithm, and a resource-adapted diagnostic approach. Mineralocorticoid receptor antagonists are endorsed as mechanism-directed first-line therapy, with blood pressure and renin normalization as co-primary treatment targets. Acquired and reversible causes are classified separately to guide clinical management. A research agenda is advanced to drive threshold standardization, multicenter validation, and integration of NC-AME into hypertension guidelines across endocrinology, cardiology, and nephrology.