Treatment of Familial Hyperaldosteronism Type I: Only Partial Suppression of Adrenocorticotropin Required to Correct Hypertension

Abstract

In familial hyperaldosteronism type I, inheritance of a hybrid 11␤-hydroxylase/aldosterone synthase gene leads to ACTH-regulated overproduction of aldosterone (causing hypertension) and of "hybrid" steroids, 18-hydroxy-and 18-oxo-cortisol. To determine whether complete suppression of the hybrid gene is necessary to normalize blood pressure, we sought evidence of persisting expression in eight patients who were rendered normotensive for 1.3-4.5 yr by glucocorticoid treatment. At the time of the study, six patients were receiving dexamethasone (0.125-0.25 mg/day) and two patients were taking prednisolone (2.5 or 5 mg/day). Urinary 18-oxo-cortisol levels during treatment demonstrated close correlation with mean "day curve" (blood collected every 2 h for 24 h) cortisol (r ϭ 0.74), consistent with regulation by ACTH. Although urinary 18-oxo-cortisol levels were lower during than before treatment (mean 12.6 Ϯ 2.4 SEM vs. 35.0 Ϯ 5.6 nmol/mmol creatinine; P Ͻ 0.01), they remained above normal (0.8 -5.2 nmol/mmol creatinine) in all eight patients. Although mean upright plasma potassium levels during treatment were higher, aldosterone levels lower, PRA levels higher, and aldosterone to PRA ratios lower than before treatment, PRA levels were uncorrected (Ͻ13 pmol/L⅐min) and aldosterone to PRA ratios were uncorrected (Ͼ65) during treatment in four patients. For each of the eight patients, day curve aldosterone levels during treatment correlated more tightly with cortisol (mean r for the eight patients, 0.87 Ϯ 0.05 SEM) than with PRA (mean r ϭ 0.36 Ϯ 0.10 SEM). Hence, control of hypertension by glucocorticoid treatment was associated, in all patients, with only partial suppression of ACTH-regulated hybrid steroid and aldosterone production. Normalization of urinary hybrid steroid levels and abolition of ACTH-regulated aldosterone production is not a requisite for hypertension control and, if used as a treatment goal, may unnecessarily increase the risk of Cushingoid side effects. (J Clin Endocrinol Metab 85: 3313-3318, 2000)

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

“…In contrast, the lower doses that we have used in our center are associated with only partial suppression of cortisol, consistent with a lower total glucocorticoid level and therefore a lower risk of side effects. As expected, hybrid gene expression is not completely suppressed at these doses, as evidenced by suppressed PRA, elevated ARR, and elevated urinary 18-oxo-cortisol levels and tight correlation of circadian aldosterone with cortisol (rather than PRA) levels (485). It therefore appears that hypertension control can be achieved without having to normalize urinary 18-oxo-cortisol levels and completely abolish ACTH-regulated aldosterone overproduction.…”

“…In our experience, most patients are able to maintain control of hypertension on doses of dexamethasone as low as 0.125-0.25 mg/day (485). Previously recommended higher daily doses (0.5-2.0 mg; Refs.…”

“…No matter how severe the hypertension, however, control can be readily achieved by the administration of glucocorticoids in small, well-tolerated doses (485,512). Such dramatic disease-specific treatment responses make accurate diagnosis of affected family members paramount.…”

Heritable forms of hypertension

“…A number of patients have been first diagnosed with hypertension in adolescence [35]. Phenotype severity may vary within the same family.…”

Pathophysiology, Diagnosis, and Treatment of Mineralocorticoid Disorders

“…Additionally, hypokalemia is not commonly a feature of the syndrome. Patients with FH-I respond to treatment with dexamethasone (0.125-0.25 mg/day) with a significant decrease in aldosterone secretion (349). Mineralocorticoid blockers are an alternative treatment (135).…”