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- Adrenal steroid biosynthesis
- Approach to the patient with hypertension and hypokalemia
- Chapter 6C: Aldosterone
- Clinical features of primary aldosteronism
- Extrarenal manifestations of autosomal dominant polycystic kidney disease
- Genetic disorders of the collecting tubule sodium channel: Liddle's syndrome and pseudohypoaldosteronism type 1
Glucocorticoid-remediable aldosteronism
| AuthorsWilliam F Young, Jr, MD, MScNorman M Kaplan, MD | Section EditorsRichard H Sterns, MDAndre Lacroix, MD | Deputy EditorKathryn A Martin, MD |
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Glucocorticoid-remediable aldosteronism (GRA) is a rare form of hyperaldosteronism in which the hypersecretion of aldosterone can be reversed with physiologic doses of glucocorticoid [1,2]. GRA is familial and usually associated with bilateral adrenal hyperplasia; it is also known as familial hyperaldosteronism type I [3].
Normal subjects synthesize aldosterone in the zona glomerulosa (which lacks the 17-hydroxylase required for cortisol synthesis), but not in the ACTH-sensitive zona fasciculata (which lacks the enzymes required to add the necessary aldehyde to corticosterone at the 18-carbon position). (See "Adrenal steroid biosynthesis".)
Patients with GRA, on the other hand, have ACTH-sensitive aldosterone production occurring in the zona fasciculata. Two isozymes of 11-beta-hydroxylase encoded by two genes on chromosome 8 are responsible for the biosynthesis of aldosterone and cortisol (algorithm 1):
- The isozyme in the zona glomerulosa (CYP11B2, aldosterone synthase, P450as) catalyzes the conversion of deoxycorticosterone to corticosterone and of 18-hydroxycorticosterone to aldosterone.
- The isozyme in the zona fasciculata (CYP11B1, P450c11) catalyzes the conversion of 11-deoxycortisol to cortisol and does not contribute to aldosterone synthesis.
The mutation in patients with GRA is fusion of the promoter region of the gene for CYP11B1 and the coding sequences of CYP11B2, resulting in ACTH-dependent activation of the aldosterone synthase effect on cortisol, corticosterone, and cortisol precursors [4,5]. As a result, these patients are biochemically unique in having markedly increased levels of 18-oxocortisol and 18-hydroxycortisol [1,4,5].
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