Evidence for persistent dysfunction of wild-type aldosterone synthase gene in glucocorticoid-treated familial hyperaldosteronism type I

BACKGROUNDIn familial hyperaldosteronism type I (FH-I), glucocorticoid treatment suppresses adrenocorticotrophic hormone-regulated hybrid gene expression and corrects hyperaldosteronism. OBJECTIVETo determine whether the wild-type aldosterone synthase genes, thereby released from chronic suppression, are capable of functioning normally. METHODSWe compared mid-morning levels of plasma potassium, plasma aldosterone, plasma renin activity (PRA) and aldosteronePRA ratios, measured with patients in an upright position, and responsiveness of aldosterone levels to infusion of angiotensin II (AII), for 11 patients with FH-I before and during long-term (0.8–14.3 years) treatment with 0.25–0.75 mg/day dexamethasone or 2.5–10 mg/day prednisolone. RESULTSDuring glucocorticoid treatment, hypertension was corrected in all. Potassium levels, which had been low (< 3.5 mmol/l) in two patients before treatment, were normal in all during treatment (mean 4.0 ± 0.1 mmol/l, range 3.5–4.6). Aldosterone levels during treatment [13.2 ± 2.1 ng/100 ml (mean ± SEM)] were lower than those before treatment (20.1 ± 2.5 ng/100 ml, P < 0.05). PRA levels, which had been suppressed before treatment (0.5 ± 0.2 ng/ml per h), were unsuppressed during treatment (5.1 ± 1.5 ng/ml per h, P < 0.01) and elevated (> 4 ng/ml per h) in six patients. AldosteronePRA ratios, which had been elevated (> 30) before treatment (101.1 ± 25.9), were much lower during treatment (4.1 ± 1.0, P < 0.005) and below normal (< 5) in eight patients. Surprisingly, aldosterone level, which had not been responsive (< 50% rise) to infusion of AII for all 11 patients before treatment, remained unresponsive for 10 during treatment. CONCLUSIONSApparently regardless of duration of glucocorticoid treatment in FH-I, aldosterone level remains poorly responsive to AII, with a higher than normal PRA and a low aldosteronePRA ratio. This is consistent with there being a persistent defect in functioning of wild-type aldosterone synthase gene.