What are the causes of hyperaldosteronism?

Causes of Hyperaldosteronism

Hyperaldosteronism is caused by either autonomous aldosterone production from the adrenal glands (primary aldosteronism) or excessive renin-angiotensin system activation (secondary aldosteronism), with primary aldosteronism accounting for 5-10% of all hypertensive patients and representing the most common endocrine cause of hypertension. 1

Primary Aldosteronism (Autonomous Production)

Primary aldosteronism results from aldosterone production that is independent of the renin-angiotensin system and cannot be suppressed with sodium loading. 2

Unilateral Causes (50% of cases)

• Aldosterone-producing adenoma (APA) is the most frequent unilateral cause, typically presenting as a solitary benign tumor that autonomously secretes aldosterone. 1, 2
• Somatic mutations drive autonomous aldosterone production in most adenomas, including mutations in KCNJ5 (potassium channel), CACNA1D (calcium channel), ATP1A1 and ATP2B3 (ATPases), and CTNNB1 (β-catenin). 3, 4
• Unilateral adrenal hyperplasia is a rare cause of unilateral disease. 2
• Adrenocortical carcinoma represents a rare malignant cause. 4

Bilateral Causes (50% of cases)

• Bilateral adrenal hyperplasia (idiopathic hyperaldosteronism) accounts for the remaining 50% of primary aldosteronism cases. 2
• Aldosterone-producing cell clusters accumulate beneath the adrenal capsule with age, are more frequent in idiopathic hyperaldosteronism, and harbor the same somatic mutations found in adenomas, suggesting they may be precursors to adenomas. 4

Familial Forms (Rare)

• Familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism) should be suspected in patients with early-onset hypertension or cerebrovascular accident at young age (<40 years). 5, 1
• Familial hyperaldosteronism types 2,3, and 4 are caused by rare germline variants in genes including CYP11B2, CLCN2, KCNJ5, CACNA1H, and CACNA1D. 4

Secondary Hyperaldosteronism (Reactive Production)

Secondary hyperaldosteronism occurs when aldosterone production is appropriately elevated in response to activation of the renin-angiotensin system. 5

Common Causes

• Renovascular hypertension from renal artery stenosis (atherosclerosis in patients >60 years, fibromuscular dysplasia in patients <40 years) stimulates renin release. 5
• Renal parenchymal disease with decreased renal perfusion activates the renin-angiotensin system. 5
• Heart failure with reduced cardiac output triggers compensatory renin-angiotensin-aldosterone activation. 5
• Cirrhosis with ascites causes effective arterial underfilling and secondary hyperaldosteronism. 5
• Sodium restriction physiologically increases both renin and aldosterone levels. 5

Medication-Induced Changes

• Diuretics (both potassium-wasting and potassium-sparing) increase renin and aldosterone levels. 5
• ACE inhibitors and ARBs increase renin while decreasing aldosterone, lowering the aldosterone-to-renin ratio. 5
• Beta-blockers decrease both renin and aldosterone, potentially causing false-positive screening results. 5

Critical Diagnostic Distinction

The key to differentiating primary from secondary hyperaldosteronism is measuring both aldosterone and renin: primary aldosteronism shows elevated aldosterone with suppressed renin (high aldosterone-to-renin ratio >30), while secondary hyperaldosteronism shows elevated aldosterone with appropriately elevated renin (normal or low ratio). 6, 2

Important Exception

• In patients with severe hypertension and hypertensive kidney damage, renin can escape suppression despite primary aldosteronism, though the aldosterone-to-renin ratio remains elevated due to disproportionately high aldosterone levels. 7
• These patients may have high-normal or slightly elevated serum creatinine and can develop severe hyperkalemia when treated with mineralocorticoid receptor antagonists due to decreased filtered sodium load. 7

Clinical Implications

• Primary aldosteronism causes 3.7-fold increased heart failure, 4.2-fold increased stroke, 6.5-fold increased MI, and 12.1-fold increased atrial fibrillation compared to primary hypertension matched for blood pressure, emphasizing the importance of identifying the underlying cause. 5, 1
• Do not rely on hypokalemia to suspect hyperaldosteronism—it is absent in 50% of primary aldosteronism cases. 6, 1