What is the diagnostic and treatment approach for primary hyperaldosteronism (PHA) with an elevated aldosterone-to-renin ratio (ARR)?

Diagnostic Algorithm for Primary Hyperaldosteronism with Elevated Aldosterone-Renin Ratio

The diagnostic approach for primary hyperaldosteronism (PHA) with elevated aldosterone-to-renin ratio (ARR) should follow a stepwise algorithm of confirmatory testing, imaging, and adrenal vein sampling to determine appropriate treatment based on disease subtype.

Initial Screening and Confirmatory Testing

When to Screen

• Patients with resistant hypertension
• Hypertension with spontaneous or diuretic-induced hypokalemia
• Hypertension with adrenal incidentaloma
• Early-onset hypertension or family history of early-onset hypertension 1

ARR Testing Considerations

• Medication management before testing:
  • Ideally, discontinue interfering medications when feasible:
    • Beta-blockers, centrally acting drugs (clonidine, alpha-methyldopa), diuretics, and mineralocorticoid receptor antagonists 2
  • Medications with minimal interference that can be continued:
    • Long-acting calcium channel blockers (dihydropyridine or non-dihydropyridine)
    • Alpha-receptor antagonists 2, 1
  • If medications cannot be stopped for safety reasons (severe hypokalemia or hypertension), proceed with testing as accuracy is only marginally impacted 2

Confirmatory Testing

After positive ARR (≥30 when plasma aldosterone in ng/dL and plasma renin activity in ng/mL/h), one of these confirmatory tests must be performed 1:

• Oral sodium loading test with 24-h urine aldosterone measurement
• IV saline infusion test with plasma aldosterone measurement
• Fludrocortisone suppression test

Subtype Determination

Imaging

• Non-contrast CT scan of adrenal glands (or MRI if CT contraindicated) after biochemical confirmation 1

Adrenal Vein Sampling (AVS)

• Gold standard for distinguishing unilateral from bilateral aldosterone production
• Indications for AVS:
  • Age >40 years
  • Normal-appearing adrenal glands on imaging
  • Discordance between biochemical and imaging results 1

Treatment Algorithm Based on Subtype

Unilateral Disease (Aldosterone-Producing Adenoma)

• First-line treatment: Laparoscopic adrenalectomy
  • Improves blood pressure in virtually 100% of patients
  • Achieves complete cure of hypertension in approximately 50% 1
  • Better outcomes in younger patients 1

Bilateral Disease (Idiopathic Hyperaldosteronism)

• First-line treatment: Medical therapy with mineralocorticoid receptor antagonists
  • Spironolactone: Initial dose 25-100 mg daily, may require up to 400 mg daily 1, 3
  • Eplerenone: Alternative option with fewer anti-androgenic side effects
  • Monitor for hyperkalemia, especially in patients with reduced renal function 1

Primary Hyperaldosteronism in Special Situations

• Preoperative management: Spironolactone 100-400 mg daily 3
• Long-term maintenance for inoperable cases: Lowest effective dose of spironolactone 3

Clinical Pearls and Pitfalls

Important Considerations

• Normal potassium levels do not rule out PHA (61% of patients have normal potassium) 1
• Assess 24-hour urinary sodium or sodium-to-creatinine ratio when interpreting ARR 2
• Consider menstrual cycle timing in females when interpreting ARR 2
• Screening rates for PHA are extremely low (1.6%), leading to underdiagnosis 1

Monitoring After Treatment

• Regular monitoring of:
  • Blood pressure
  • Serum potassium levels
  • Renal function
  • Signs of cardiovascular damage 1

Potential Complications

• With spironolactone treatment: Hyperkalemia, especially at initiation and with dose increases
• After adrenalectomy: Monitor for resolution of hypertension and normalization of potassium levels

Outcomes

With appropriate treatment, primary hyperaldosteronism has excellent outcomes, including reduction in blood pressure, normalization of potassium levels, reversal of left ventricular hypertrophy, and reduction in cardiovascular and renal complications 1.