What is Conn syndrome (primary hyperaldosteronism)?

What is Conn Syndrome (Primary Hyperaldosteronism)?

Conn syndrome, or primary hyperaldosteronism, is the most common form of secondary hypertension—affecting 5-10% of all hypertensive patients and up to 20% of those with resistant hypertension—characterized by excessive, autonomous aldosterone production by the adrenal glands that is independent of the renin-angiotensin system. 1, 2

Pathophysiology

Primary aldosteronism results from unregulated aldosterone secretion that cannot be suppressed by sodium loading, distinguishing it from normal physiologic aldosterone production. 2 The excessive aldosterone drives several key pathologic processes:

• Sodium retention and volume expansion occur through aldosterone's action on the distal renal tubule, leading to hypertension and suppression of plasma renin activity. 3

• Potassium wasting results from increased renal excretion, though hypokalemia is present in only approximately 50% of cases—making it an unreliable screening marker. 1, 2

• Direct tissue toxicity causes cardiovascular and renal damage through mechanisms independent of blood pressure elevation, producing widespread fibrosis and inflammation. 3

Disease Subtypes

The condition divides into two main categories with critical treatment implications:

• Unilateral disease (≈50% of cases) typically results from an aldosterone-producing adenoma (the classic "Conn adenoma") or rarely unilateral adrenal hyperplasia, and is potentially curable with surgery. 3, 4

• Bilateral adrenal hyperplasia (≈50% of cases), also called idiopathic hyperaldosteronism, requires lifelong medical therapy with mineralocorticoid receptor antagonists. 3, 4

• Familial forms are much less common and include familial hyperaldosteronism types 1-4, with type 1 (glucocorticoid-remediable) uniquely treatable with low-dose dexamethasone. 1, 4

Clinical Presentation

The syndrome presents with hypertension that is often severe or resistant to standard therapy, but lacks specific identifying features that make it easily recognizable:

• Hypertension is universal, frequently severe (>180/110 mmHg) or resistant to three or more medications including a diuretic. 1, 2

• Hypokalemia occurs in only 50% of patients, so normal potassium levels do not exclude the diagnosis. 2, 5

• Muscle weakness and cramps may occur when hypokalemia is present. 6

• Most patients are normokalaemic and clinically indistinguishable from essential hypertension, contributing to massive underdiagnosis. 7, 8

Cardiovascular Risk Profile

Primary aldosteronism carries dramatically higher cardiovascular risk than essential hypertension at equivalent blood pressure levels, making early diagnosis critical:

• 12.1-fold increased risk of atrial fibrillation 2
• 6.5-fold increased risk of myocardial infarction 2
• 4.2-fold increased risk of stroke 2
• 3.7-fold increased risk of heart failure 2

These excess risks result from aldosterone-mediated target organ damage that occurs independently of blood pressure elevation. 2, 3

Diagnostic Approach

The diagnosis follows a structured three-step process:

Step 1: Screening with aldosterone-to-renin ratio (ARR)

• Performed in morning with patient seated for 5-15 minutes after being upright for 2 hours 2
• Positive screen requires both ARR ≥20-30 and plasma aldosterone ≥10-15 ng/dL 2, 5
• Patient must be potassium-replete, as hypokalemia suppresses aldosterone and causes false-negatives 2

Step 2: Confirmatory testing

• Required for all positive screens to demonstrate autonomous aldosterone secretion 2, 4
• Options include intravenous saline suppression test or oral sodium loading with 24-hour urine aldosterone 1, 2
• Mineralocorticoid receptor antagonists must be withdrawn ≥4 weeks before testing 2, 5

Step 3: Subtype determination

• Non-contrast CT of adrenal glands as initial imaging 2
• Adrenal venous sampling is mandatory before offering surgery, as CT alone leads to unnecessary adrenalectomy in up to 25% of patients 2, 4

Treatment

Management depends entirely on whether disease is unilateral or bilateral:

For unilateral disease:

• Laparoscopic unilateral adrenalectomy is the treatment of choice, improving blood pressure in virtually 100% of patients and achieving complete cure in approximately 50%. 1, 3, 5
• Surgery normalizes hypokalemia, reduces medication requirements, and improves cardiac and kidney function. 2

For bilateral disease:

• Spironolactone 50-100 mg once daily is first-line medical therapy, titrated up to 300-400 mg daily if needed. 1, 5
• Eplerenone is an alternative with fewer anti-androgenic side effects (less gynecomastia and erectile dysfunction), though less potent and requiring twice-daily dosing. 1, 5
• Lifelong treatment with mineralocorticoid receptor antagonists is required. 7, 9

For familial hyperaldosteronism type 1:

• Low-dose dexamethasone corrects the condition without glucocorticoid side effects and is safe during pregnancy. 1, 5

Critical Clinical Pitfalls

• Do not rely on hypokalemia to trigger screening—it is absent in 50% of cases yet the disease still causes severe cardiovascular damage. 2, 5

• Do not proceed to surgery based on CT findings alone—adrenal venous sampling is essential to prevent unnecessary adrenalectomy. 2, 4

• Delayed diagnosis leads to irreversible vascular remodeling, resulting in persistent hypertension even after appropriate treatment; early diagnosis dramatically improves cure rates. 1, 5

• The condition is massively underdiagnosed—only 2-4% of eligible patients are screened despite affecting up to 20% of resistant hypertension. 2

• Testing on interfering medications (beta-blockers, diuretics, ACE inhibitors/ARBs) causes false results; ideally substitute with calcium channel blockers or alpha-blockers during workup. 2