What Causes Hyperaldosteronism
Hyperaldosteronism occurs through two distinct mechanisms: primary aldosteronism (autonomous, renin-independent aldosterone production from the adrenal glands) and secondary aldosteronism (renin-dependent aldosterone excess driven by activation of the renin-angiotensin system). 1
Primary Aldosteronism (Renin-Independent)
Primary aldosteronism represents autonomous aldosterone production that cannot be suppressed with sodium loading, distinguishing it from physiologic secretion. 2 This is the most common endocrine cause of hypertension and accounts for 5-10% of all hypertensive patients, rising to 20% in those with resistant hypertension. 3
Unilateral Disease (~50% of cases)
- Aldosterone-producing adenoma is the most frequent unilateral cause, typically a solitary benign tumor that autonomously secretes aldosterone. 1, 4
- Unilateral adrenal hyperplasia is a rare unilateral form. 4
- Aldosterone-producing carcinoma is an extremely rare malignant cause. 4
- Somatic mutations in ion channels or transporters (identified in the past decade) drive autonomous aldosterone production in most adenomas and aldosterone-producing cell clusters. 4, 5
Bilateral Disease (~50% of cases)
- Bilateral adrenal hyperplasia (also called idiopathic hyperaldosteronism) accounts for the remaining half of primary aldosteronism cases. 1, 4
- Aldosterone-producing cell clusters may represent precursors of adenomas and correlates of bilateral hyperplasia, containing the same somatic mutations found in adenomas. 4, 5
Familial Forms (Rare)
- Familial hyperaldosteronism types 1-4 are caused by germline mutations in overlapping genes with somatic mutations. 4, 5
- Glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type-1) should be suspected in patients with early-onset hypertension or cerebrovascular accident at young age. 3
Secondary Aldosteronism (Renin-Dependent)
Secondary aldosteronism results from appropriate physiologic stimulation of aldosterone production through activation of the renin-angiotensin system. 4
Common Causes
- Diuretic therapy stimulates renin release and subsequent aldosterone production in hypertensive patients. 4
- Renal artery stenosis causes decreased renal perfusion, triggering renin-angiotensin-aldosterone system activation. 4
- Volume depletion states from any cause activate compensatory aldosterone secretion. 4
Pathophysiologic Consequences
Regardless of etiology, excessive aldosterone induces hypertension through sodium retention and suppression of plasma renin activity, with increased potassium excretion causing hypokalemia if prolonged and severe (though only 50% of patients present with hypokalemia). 1, 3 The toxic tissue effects of aldosterone cause greater target organ damage than primary hypertension alone, including 3.7-fold increased heart failure, 4.2-fold increased stroke, 6.5-fold increased MI, and 12.1-fold increased atrial fibrillation. 3
Clinical Pitfall
Do not rely on hypokalemia as a screening marker—it is absent in the majority of primary aldosteronism cases. 2 The traditional view that hypokalemia is required for diagnosis has led to massive underdiagnosis of this treatable condition. 3, 5