Glucocorticoid remediable aldosteronism | |
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Other names | GRA |
Specialty | Endocrinology |
Glucocorticoid remediable aldosteronism also describable as aldosterone synthase hyperactivity, is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient.
It is a cause of primary hyperaldosteronism. [1]
Patients with GRA may be asymptomatic, but the following symptoms can be present:[ citation needed]
Aldosterone synthase is a steroid hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone. It is localized to the mitochondrial inner membrane. The enzyme has steroid 18-hydroxylase activity to synthesize aldosterone and other steroids. Aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex. Aldosterone synthase normally is not ACTH sensitive, and is only activated by angiotensin II.[ citation needed]
Aldosterone causes the tubules of the kidneys to retain sodium and water. This increases the volume of fluid in the body and drives up blood pressure.[ citation needed]
Steroid hormones are synthesized from cholesterol within the adrenal cortex. Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is either mediated by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone).[ citation needed]
The genes encoding aldosterone synthase and 11β-hydroxylase are 95% identical and are close together on chromosome 8. In individuals with GRA, there is unequal crossing over so that the 5' regulatory region of the 11-hydroxylase gene is fused to the coding region of the aldosterone synthase.[ citation needed]
The product of this hybrid gene is aldosterone synthase that is ACTH-sensitive [2] in the zona fasciculata of the adrenal gland. [3]
Although in normal subjects, ACTH accelerates the first step of aldosterone synthesis, ACTH normally has no effect on the activity of aldosterone synthase. However, in subjects with glucocorticoid-remediable aldosteronism, ACTH increases the activity of existing aldosterone synthase, resulting in an abnormally high rate of aldosterone synthesis and hyperaldosteronism. [4]
Genetic testing is done to ascertain that the individual in question does indeed have the condition [5]
In GRA, the hypersecretion of aldosterone and the accompanying hypertension are remedied when ACTH secretion is suppressed by administering glucocorticoids. [6] Dexamethasone, spironolactone and eplerenone have been used in treatment. [7]