How do you diagnose and rule out primary aldosteronism in an adult patient with hypertension, potential hypokalemia, and a family history of the condition?

Primary Aldosteronism: Definition and Diagnostic Approach

Primary aldosteronism is a group of disorders characterized by inappropriately high aldosterone production that is relatively autonomous of its major regulators (angiotensin II and potassium) and cannot be suppressed with sodium loading, causing hypertension, cardiovascular damage, and potentially hypokalemia—though hypokalemia is absent in approximately 50% of cases. 1

What Exactly Is Primary Aldosteronism?

Primary aldosteronism represents excessive aldosterone secretion independent of the renin-angiotensin system, distinguishing it from physiologic aldosterone production. 2 This autonomous production leads to:

• Hypertension through sodium retention and volume expansion 1, 3
• Suppressed plasma renin activity due to volume expansion 1, 2
• Increased potassium excretion which may cause hypokalemia if prolonged and severe, though this occurs in only ~50% of patients 1
• Dramatically increased cardiovascular risk compared to essential hypertension at equivalent blood pressure levels, including 3.7-fold increase in heart failure, 4.2-fold increase in stroke, 6.5-fold increase in MI, and 12.1-fold increase in atrial fibrillation 1, 2

Subtypes

Approximately 50% of cases result from unilateral aldosterone production (usually aldosterone-producing adenoma or rarely unilateral adrenal hyperplasia), while the remaining 50% have bilateral adrenal hyperplasia (idiopathic hyperaldosteronism). 1, 3

Who Should Be Screened?

Screen all patients with the following high-risk features: 1, 2

• Resistant hypertension (BP not controlled on 3 medications including a diuretic)—prevalence up to 20% 1, 2
• Severe hypertension (BP >180/110 mmHg)—prevalence up to 12% 2
• Spontaneous or diuretic-induced hypokalemia (though normal potassium does NOT exclude the diagnosis) 1
• Incidentally discovered adrenal mass on CT or MRI 1
• Family history of early-onset hypertension or stroke at young age (<40 years) 1
• Young-onset hypertension (<30-40 years) without traditional risk factors 2

Diagnostic Algorithm

Step 1: Initial Screening Test - Aldosterone-to-Renin Ratio (ARR)

Order simultaneous plasma aldosterone concentration and plasma renin activity to calculate the ARR. 2 This is the most accurate and reliable screening method. 1

Patient Preparation for ARR Testing:

• Correct hypokalemia before testing—hypokalemia suppresses aldosterone production and causes false-negative results 2, 4
• Collect blood in the morning (ideally 0800-1000 hours) with patient out of bed for 2 hours prior and seated for 5-15 minutes immediately before collection 2
• Encourage unrestricted (liberal) salt intake before testing 2

Medication Management:

• Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) for at least 4 weeks before testing 2, 4
• Discontinue when clinically feasible: beta-blockers, centrally acting drugs, and diuretics (these suppress renin and cause false-positives) 2
• Safe alternatives to use: long-acting calcium channel blockers (verapamil slow-release) and alpha-receptor antagonists (prazosin, doxazosin, hydralazine) minimally interfere with ARR 2
• If medications cannot be stopped: interpret results in context of known drug effects 2

Positive Screening Criteria:

A positive ARR requires BOTH: 1, 2

• ARR ≥20-30 (when aldosterone measured in ng/dL and renin activity in ng/mL/hr)
• Plasma aldosterone concentration ≥10-15 ng/dL

The specificity improves if minimum plasma renin activity of 0.5 ng/mL/h is used in calculations. 1, 2

Step 2: Confirmatory Testing

All positive ARR screening tests require confirmatory testing to demonstrate autonomous aldosterone secretion that cannot be suppressed with sodium loading. 1, 2 The ARR alone has low specificity due to common low-renin states. 2

Confirmatory Test Options:

Perform ONE of the following: 1, 2

1. Intravenous saline suppression test: Infuse 2L normal saline over 4 hours; failure to suppress plasma aldosterone below 5 ng/dL confirms diagnosis 2

2. Oral sodium loading test: Administer high-salt diet (>200 mEq/day) for 3 days with 24-hour urine aldosterone measurement on day 3; aldosterone >12 mcg/24h confirms diagnosis 1, 2

3. Fludrocortisone suppression test: Failure to reduce plasma aldosterone below threshold confirms diagnosis 2

Critical requirements for confirmatory testing: 2

• Unrestricted salt intake
• Normal serum potassium levels
• Mineralocorticoid receptor antagonists withdrawn ≥4 weeks

Step 3: Subtype Determination

Once primary aldosteronism is biochemically confirmed, distinguish unilateral from bilateral disease to guide treatment. 2

Initial Imaging:

Order non-contrast CT scan of adrenal glands as initial imaging to identify potential unilateral adenoma versus bilateral hyperplasia. 2

Adrenal Venous Sampling (AVS):

AVS is mandatory before offering adrenalectomy to definitively distinguish unilateral from bilateral disease—CT findings alone are insufficient, as up to 25% of patients might undergo unnecessary adrenalectomy based on CT alone. 2 AVS has 95% sensitivity and 100% specificity. 2

Exception: AVS may be omitted in patients <40 years when imaging shows a single affected gland, as bilateral hyperplasia is rare in this population. 2

Step 4: Referral

Refer all patients with confirmed primary aldosteronism to a hypertension specialist or endocrinologist for subtype determination and treatment planning. 1, 2

Treatment Based on Subtype

Unilateral Disease (Aldosterone-Producing Adenoma):

Laparoscopic unilateral adrenalectomy is the treatment of choice, improving blood pressure in virtually 100% of patients and achieving complete cure of hypertension in approximately 50%. 2, 3, 4 Surgery also normalizes hypokalemia, reduces antihypertensive medication requirements, and improves cardiac and kidney function. 2

Bilateral Disease (Idiopathic Hyperaldosteronism):

Medical therapy with mineralocorticoid receptor antagonists is the cornerstone of lifelong treatment. 2, 3, 4

• Spironolactone 50-100 mg once daily, titrating up to 300-400 mg once daily if necessary 2, 4
• Eplerenone 50-100 mg daily (alternative with fewer anti-androgenic side effects), titrating up to 200-300 mg daily 5
• Amiloride 5-10 mg once or twice daily if both spironolactone and eplerenone are not tolerated 5

Monitor serum potassium and creatinine within 2-3 days of initiation or dose increases, then at 7 days, with continued monthly monitoring for first 3 months. 5 Risk of hyperkalemia increases substantially when combining with ACE inhibitors or ARBs. 5, 4

Common Diagnostic Pitfalls to Avoid

• Do not rely on presence or absence of hypokalemia—it is absent in 50% of primary aldosteronism cases 1, 2
• Do not proceed to surgery based on CT findings alone—always perform AVS to avoid unnecessary adrenalectomy 2
• Do not test patients on mineralocorticoid receptor antagonists—these must be withdrawn ≥4 weeks before any testing 2
• Do not forget to correct hypokalemia before testing—this causes false-negative results 2
• Do not skip confirmatory testing—positive ARR alone has insufficient specificity 2