Monogenic Forms of Low-Renin Hypertension

Vesna D Garovic; Anthony A Hilliard; Stephen T Turner


Nat Clin Pract Nephrol. 2006;2(11):624-630. 

In This Article

Familial Hyperaldosteronism Type I

Primary hyperaldosteronism, commonly due to either an aldosterone-producing adrenal adenoma or bilateral adrenal hyperplasia, is one of the most common causes of secondary hypertension. One report estimates that primary aldosteronism affects 8% and 13% of individuals with hypertension grades 2 and 3, respectively.[3] Familial forms are much less common, with literature reports limited to several pedigrees, small series, and isolated case reports.

The recommended screening test for both familial and non-familial forms of primary hyperaldosteronism is the ratio of plasma aldosterone concentration to plasma renin activity.[4] A ratio higher than 30, together with a plasma aldosterone concentration of at least 0.42 nmol/l (15 ng/dl), is widely accepted as a positive screening-test result. The diagnostic accuracy of this approach is only fair, with reported sensitivities of 73-78% and specificities of 74-83%.[5,6] Confirmation of the diagnosis is dependent upon measurement of urinary aldosterone in a 24 h urine collection. Aldosterone values greater than 14 ng/day in the setting of a high sodium diet (indicated by urine sodium excretion exceeding 200 mEq/day and plasma renin activity <1.0 ng/dl/h) is a positive confirmatory-test result for primary hyperaldosteronism.

Familial hyperaldosteronism type I (FH-I)—also known as glucocorticoid-remediable aldosteronism—was the first form of monogenic hypertension to be recognized as a single-gene hypertensive disorder. The genetic defect is characterized by the presence of a hybrid or chimeric gene on chromosome 8q (Figure 1) consisting of the regulatory region of the 11β-hydroxylase gene, CYP11B1, coupled with the structural region of the aldosterone synthase gene, CYP11B2.[7] Its mode of inheritance is autosomal dominant with complete penetrance.

Figure 1.

Familial hyperaldosteronism type I (also known as glucocorticoid-remediable aldosteronism). The genetic defect that causes this disorder is characterized by the presence of a hybrid or chimeric gene on chromosome 8q consisting of the regulatory region of the 11β-hydroxylase gene coupled to the coding sequence of the aldosterone synthase gene. Abbreviations: ACTH = adrenocorticotropic hormone; Ang II = angiotensin II.

Normally, aldosterone is produced by the zona glomerulosa via angiotensin-II-mediated stimulation of CYP11B2, and cortisol is produced by the zona fasciculata via adrenocorticotropic hormone (ACTH)-mediated stimulation of CYP11B1. In FH-I, ectopic secretion of aldosterone and 18-OH corticosterone metabolites in the zona fasciculata is positively regulated by ACTH and is not affected by angiotensin II and potassium. Plasma renin activity is typically suppressed while aldosterone levels are increased, although normokalemia is present in nearly half of all FH-I cases. Patients with this genetic defect typically present with a family history of severe hypertension with moderate to severe hypertension usually occurring before the age of 21 years, and are at particularly high risk for hemorrhagic strokes due to ruptured aneurysms.[8] Therefore, all patients with genetically proven FH-I should undergo a cerebral MR angiogram at puberty, and subsequently every 5 years. Preferred treatment is low-dose glucocorticoids, amiloride, and spironolactone, which blocks binding of aldosterone to the mineralocorticoid receptor (MCR). Thiazide diuretics are not the recommended first-line treatment, but might improve control of blood pressure when used concurrently with spironolactone. Thiazide diuretics can cause marked hypokalemia secondary to increased sodium delivery to the cortical collecting duct.[9]


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