How should I screen, confirm, localize, and treat a typical adult with resistant hypertension, hypokalemia, or an incidental adrenal mass suspected of primary hyperaldosteronism?

Screening, Confirmation, Localization, and Treatment of Primary Aldosteronism

Who to Screen

Screen all adults with resistant hypertension (BP uncontrolled on ≥3 medications including a diuretic), spontaneous or substantial diuretic-induced hypokalemia, incidentally discovered adrenal mass, family history of early-onset hypertension or stroke at age <40 years, or severe hypertension (BP >180/110 mmHg). 1, 2

• Primary aldosteronism affects 5-10% of all hypertensive patients and up to 20% of those with resistant hypertension 2
• Do not rely on the presence of hypokalemia to trigger screening—it is absent in approximately 50% of confirmed cases 1, 2
• Patients with primary aldosteronism have dramatically higher cardiovascular risk than essential hypertension at equivalent BP levels: 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 2

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

Order simultaneous plasma aldosterone concentration and plasma renin activity to calculate the ARR as your initial screening test. 1, 2

Patient Preparation Before Testing

• Correct hypokalemia first—target serum potassium 4.0-5.0 mEq/L, as hypokalemia suppresses aldosterone production and causes false-negative results 1, 2
• Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) for at least 4 weeks before testing 1, 2
• Stop beta-blockers, centrally acting drugs, and diuretics when clinically feasible—these suppress renin and cause false-positive results 1, 2
• Use long-acting calcium channel blockers (verapamil slow-release) and alpha-receptor antagonists (prazosin, doxazosin) as safe alternatives during washout—they minimally interfere with ARR 1, 2
• If medications cannot be stopped, test on current medications and interpret results in context of known drug effects 1, 2

Blood Collection Technique

• Collect blood in the morning (ideally 0800-1000 hours) with the patient out of bed for at least 2 hours prior 1, 2
• Patient should be seated for 5-15 minutes immediately before blood draw 1, 2
• Ensure unrestricted (liberal) salt intake before testing 1, 2

Interpreting the ARR

A positive screening test requires BOTH:

• ARR ≥20-30 (when aldosterone is in ng/dL and renin activity in ng/mL/h) 1, 2

• Plasma aldosterone concentration ≥10-15 ng/dL 1, 2

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

• An ARR >30 with aldosterone ≥10 ng/dL has excellent sensitivity and specificity (>90%) 2

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Confirmatory Testing

All positive ARR screening tests require confirmatory testing to demonstrate autonomous aldosterone secretion that cannot be suppressed with sodium loading. 1, 2

Confirmatory Test Options

Choose one of the following:

1. Intravenous saline suppression test (most commonly used):

   • Infuse 2L of normal saline over 4 hours 1, 2
   • Failure to suppress plasma aldosterone below 5 ng/dL after saline loading confirms the diagnosis 2

2. Oral sodium loading test:

   • High-salt diet (>200 mEq sodium/day) for 3 days 1, 2
   • Measure 24-hour urine aldosterone on day 3 1, 2
   • Elevated urinary aldosterone (>12-14 mcg/24h) with urinary sodium >200 mEq/24h confirms diagnosis 2

3. Fludrocortisone suppression test (most sensitive but rarely used due to complexity):

   • Failure to reduce plasma aldosterone below threshold confirms diagnosis 2

Critical Requirements for Confirmatory Testing

• Perform with unrestricted salt intake and normal serum potassium levels 1, 2
• Mineralocorticoid receptor antagonists must be withdrawn for at least 4 weeks 1, 2
• Ensure adequate potassium supplementation during testing to maintain K+ 4.0-5.0 mEq/L 2

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Subtype Determination: Unilateral vs. Bilateral Disease

After biochemical confirmation, determine whether the disease is unilateral or bilateral—this distinction is mandatory because it determines surgical candidacy versus lifelong medical therapy. 1, 2, 3

Initial Imaging

• Obtain non-contrast CT scan of the adrenal glands as initial imaging 2, 3
• CT findings alone are insufficient for treatment decisions—adenomas on imaging can represent hyperplasia, and false positives are common 2

Adrenal Venous Sampling (AVS)

Adrenal venous sampling is mandatory before offering adrenalectomy to distinguish unilateral from bilateral disease. 2, 3

• AVS is the gold standard with 95% sensitivity and 100% specificity 2
• Exception: AVS may be omitted in patients <40 years when imaging shows a single unilateral adenoma, as bilateral hyperplasia is rare in this population 2
• Up to 25% of patients would undergo unnecessary adrenalectomy based on CT findings alone without AVS 2
• Lateralization is confirmed when the aldosterone-to-cortisol ratio is >4 times higher on the affected side compared to the contralateral side 4

Referral for Subtype Determination

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

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Treatment Based on Subtype

Unilateral Disease (Aldosterone-Producing Adenoma or Unilateral Hyperplasia)

Laparoscopic unilateral adrenalectomy is the treatment of choice for unilateral disease. 1, 3, 5

• Improves blood pressure in virtually 100% of patients 3, 5
• Achieves complete cure of hypertension in approximately 50% of cases 3, 5
• Normalizes hypokalemia, lowers BP, reduces antihypertensive medication requirements, and improves cardiac and kidney function 2, 3
• Even after successful adrenalectomy, some patients have residual hypertension due to vascular remodeling from delayed diagnosis—the cure rate is higher when diagnosis is made early 2

Bilateral Disease (Idiopathic Hyperaldosteronism)

Medical therapy with mineralocorticoid receptor antagonists (MRAs) is the cornerstone of lifelong treatment for bilateral disease. 3, 5

First-Line: Spironolactone

• Start spironolactone 25-50 mg once daily 2, 5
• Titrate up to 100-400 mg once daily if necessary for BP control 2, 5
• Provides significant additional BP reduction of 25/12 mmHg when added to multidrug regimens in resistant hypertension 2
• Low doses (25-50 mg daily) are effective and minimize adverse effects 2

Alternative: Eplerenone

• Use eplerenone 50-100 mg daily (in 1-2 divided doses) for patients who develop gynecomastia, breast tenderness, or sexual dysfunction on spironolactone 5
• Eplerenone has fewer anti-androgenic side effects but is less potent than spironolactone 2, 5

Safety Monitoring for MRAs

Before initiating any MRA:

• Verify serum potassium ≤5.0 mEq/L 5
• Confirm serum creatinine <2.0-2.5 mg/dL or eGFR >30 mL/min 5
• Discontinue potassium supplements 5

Monitoring schedule:

• Check potassium and creatinine at 3 days, 1 week, then monthly for the first 3 months 5
• Subsequently monitor every 3 months if stable 5

Critical drug interactions to avoid:

• Do not combine MRAs with potassium supplements or potassium-sparing diuretics 5
• Do not combine with ACE inhibitors or ARBs without close monitoring—markedly increased hyperkalemia risk 5
• Avoid NSAIDs or COX-2 inhibitors—increased risk of hyperkalemia and renal dysfunction 5
• Use MRAs with caution in patients with eGFR <45 mL/min 5

Additional Antihypertensive Therapy if Needed

• If BP is not normalized by MRA monotherapy, add potassium-sparing diuretics (amiloride or triamterene) or calcium channel antagonists 6

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Common Pitfalls to Avoid

• Never rely on the presence or absence of hypokalemia alone to screen for primary aldosteronism—50% of cases have normal potassium 1, 2
• Never proceed to surgery based on CT findings alone—AVS is mandatory to prevent unnecessary adrenalectomy 2
• Never perform confirmatory testing or AVS while the patient is taking mineralocorticoid receptor antagonists—withdraw for at least 4 weeks 1, 2
• Never test patients with uncorrected hypokalemia—it suppresses aldosterone production and causes false-negative results 1, 2
• Never ignore suppressed renin in patients on multiple antihypertensive drugs—if renin remains suppressed despite ACE inhibitors or ARBs, this may be the only clue to a curable adenoma 4, 7
• In patients with severe hypertension and renal damage, renin may escape suppression despite primary aldosteronism—an elevated aldosterone/renin ratio is still useful for screening 7
• Delayed diagnosis leads to irreversible target organ damage, including cardiovascular and renal complications 3, 5