BackgroundPatients with Cushing's syndrome exhibit a bimodal distribution of maximal rates of the erythrocyte amiloride-sensitive Na+/H+exchange (NHE). Enhanced erythrocyte NHE has recently been found in patients with primary aldosteronism.ObjectiveTo test the hypothesis that occult hypermineralocorticoidism in a subset of patients with Cushing's syndrome is responsible for the greater than normal NHE.MethodsNHE was measured as maximal initial rate (Vmax) of amiloride-inhibited efflux of H+into an alkaline Na+-containing medium, for 47 patients with hypercortisolism (20 with pituitary adenomas, 18 with adrenal adenomas, and nine with ectopic production of adrenocorticotropin). Clinical appearance, blood pressure levels, plasma aldosterone and deoxycorticosterone levels, serum electrolytes, and urine (tetrahydrocortisol plus 5-α-tetrahydrocortisol): tetrahydrocortisone ratios were assessed for all patients. Twenty patients (10 with greater than normal NHE and 10 with low-to-normal NHE) were randomly selected from 47 patients with hypercortisolism, and treated with 200 mg/day spironolactone for 7 days. NHE in these patients was assessed before starting the treatment and 2 days after its cessation.ResultsGreater than normal NHE (Vmax) was associated with peripheral edema, high diastolic blood pressure, hypokalemia, and high urine (tetrahydrocortisol plus 5-α-tetrahydrocortisol): tetrahydrocortisone ratios. The enhanced NHE was rapidly normalized by treatment with spironolactone.ConclusionErythrocyte NHE in patients with hyper-cortisolism and functional hypermineralocorticoidism is greater than normal due to incomplete peripheral conversion of cortisol (which binds to mineralocorticoid receptors) into metabolically inactive cortisone.