What are the guidelines for the work-up of hyperaldosteronism?

Work-up for Hyperaldosteronism

Screen all patients with resistant hypertension (BP uncontrolled on 3 medications including a diuretic), severe hypertension (BP >180/110 mmHg), hypokalemia, adrenal incidentaloma, family history of early-onset hypertension, or stroke at age <40 years using the aldosterone-to-renin ratio (ARR), followed by confirmatory testing if positive, then adrenal venous sampling to determine laterality before proceeding to treatment. 1, 2

Patient Preparation Before Screening

Medication Management

• Withdraw mineralocorticoid receptor antagonists at least 4 weeks before testing as they significantly interfere with ARR interpretation 2, 3
• Stop beta-blockers, centrally acting drugs (clonidine, methyldopa), and diuretics when clinically feasible, as these cause false-positive results by suppressing renin 1, 2
• Switch to long-acting calcium channel blockers (dihydropyridines) or alpha-receptor antagonists, which minimally interfere with ARR 2
• If medications cannot be stopped, proceed with testing but interpret results in the context of the specific medications being used 2—ACE inhibitors and ARBs cause false-negative results by raising renin, while beta-blockers and NSAIDs cause false-positive results by suppressing renin 1

Electrolyte Correction

• Ensure potassium repletion before testing as hypokalemia suppresses aldosterone production and causes false-negative results 2, 4
• Maintain unrestricted salt intake (normal sodium diet) before testing 2, 3

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

Collection Protocol

• Draw blood in the morning after the patient has been out of bed for 2 hours 2
• Patient should be seated for 5-15 minutes immediately before blood draw 2
• Blood must be drawn with patient in seated position 2

Interpretation Criteria

• ARR ≥30 (when aldosterone measured in ng/dL and plasma renin activity in ng/mL/h) is considered positive 2, 4
• Plasma aldosterone concentration must be ≥10-15 ng/dL in addition to the elevated ratio to interpret as positive 2, 4
• Using a minimum plasma renin activity of 0.5 ng/mL/h in calculations improves specificity 2

Common Pitfall

• Do not rely on hypokalemia as a screening trigger—it is absent in approximately 50% of primary aldosteronism cases 2, 3, 5
• The ARR can be performed while patients continue antihypertensive therapy, though results must be interpreted accordingly 6

Confirmatory Testing

All positive ARR screening tests require confirmatory testing to demonstrate autonomous aldosterone secretion that cannot be suppressed with sodium loading. 2, 4

Test Options

• Intravenous saline suppression test: Infuse 2L of normal saline over 4 hours; failure to suppress plasma aldosterone below 5 ng/dL confirms diagnosis 2, 4
• Oral sodium loading test: Administer high-salt diet (>200 mEq/day) for 3 days with measurement of 24-hour urine aldosterone; elevated urinary aldosterone despite sodium loading confirms diagnosis 2
• Fludrocortisone suppression test: Failure to reduce plasma aldosterone below threshold after fludrocortisone administration confirms diagnosis 2

Testing Conditions

• Perform with unrestricted salt intake and normal serum potassium levels 2, 3
• Mineralocorticoid receptor antagonists must be withdrawn at least 4 weeks before confirmatory testing 2

Subtype Determination

Initial Imaging

• Obtain non-contrast CT scan of adrenal glands after biochemical confirmation 2
• CT findings alone are insufficient for treatment decisions, as adenomas on imaging can represent hyperplasia and false positives are common due to nodular hyperplasia 2

Adrenal Venous Sampling (AVS)

• AVS is mandatory before offering adrenalectomy to distinguish unilateral from bilateral disease 2, 3
• Exception: Patients <40 years with a single affected gland on imaging may proceed without AVS, as bilateral hyperplasia is rare in this population 2
• Do not proceed to surgery based on CT findings alone—up to 25% of patients might undergo unnecessary adrenalectomy without AVS 2
• AVS should be performed in specialized centers with expertise 3

Referral Recommendations

• Refer all patients with confirmed primary aldosteronism to a hypertension specialist or endocrinologist for subtype determination and treatment planning 2, 3
• Refer patients with resistant hypertension to clinical centers with expertise in hypertension management 2

Treatment Algorithm 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, 4, 3
• Surgery normalizes hypokalemia, lowers blood pressure, reduces antihypertensive medication requirements, and improves cardiac and kidney function parameters 2

Bilateral Disease (Idiopathic Hyperaldosteronism)

• Medical therapy with mineralocorticoid receptor antagonists (MRAs) is the cornerstone of treatment 2, 3
• Spironolactone is first-line treatment: Start at 12.5-25 mg daily, titrate up to 100 mg daily as needed 3, 7, 8
• Eplerenone is an alternative (50-100 mg daily) with fewer anti-androgenic side effects for patients who develop gynecomastia, breast tenderness, or sexual dysfunction on spironolactone 3

Safety Monitoring for MRA Therapy

• Verify serum potassium ≤5.0 mEq/L and serum creatinine <2.0-2.5 mg/dL or eGFR >30 mL/min before initiating 3
• Discontinue potassium supplements before starting MRAs 3
• Check potassium and creatinine at 3 days, 1 week, then monthly for first 3 months, then every 3 months if stable 3
• Avoid combining MRAs with potassium supplements, potassium-sparing diuretics, ACE inhibitors/ARBs (without close monitoring), or NSAIDs due to hyperkalemia risk 3
• Use MRAs with caution in patients with eGFR <45 mL/min 3

Critical Clinical Considerations

• Primary aldosteronism is present in up to 20% of individuals with resistant hypertension 2, 4
• Patients with primary aldosteronism have a 12-fold increased risk of target organ damage including kidney injury compared to primary hypertension 4
• Delayed diagnosis and treatment may lead to irreversible vascular remodeling and target organ damage, resulting in residual hypertension even after appropriate treatment 3
• The toxic tissue effects of aldosterone produce widespread tissue fibrosis and increased kidney damage through mechanisms independent of blood pressure elevation 4
• These deleterious effects are often reversible with unilateral laparoscopic adrenalectomy or treatment with MRAs 4