What is the approach to screening and treatment for primary aldosteroneism?

Primary Aldosteronism Screening and Treatment

Who to Screen

Screen all patients with resistant hypertension (BP uncontrolled on 3 medications including a diuretic), spontaneous or significant diuretic-induced hypokalemia, incidentally discovered adrenal mass, family history of early-onset hypertension, or stroke before age 40. 1

Additional high-risk populations warranting screening include: 1, 2

• Patients with severe hypertension (BP >180/110 mmHg)
• Patients with well-controlled hypertension who have a first-degree relative with primary aldosteronism
• Patients with atrial fibrillation or obstructive sleep apnea

Primary aldosteronism affects up to 20% of patients with resistant hypertension, yet only 2-4% of eligible patients actually get screened—a critical missed opportunity. 2, 3

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

Use the plasma aldosterone-to-renin ratio as the initial screening test, with a positive result defined as ARR ≥30 (when aldosterone is in ng/dL and renin activity in ng/mL/h) AND plasma aldosterone concentration ≥10 ng/dL. 1, 2

Patient Preparation for ARR Testing

• Correct hypokalemia before testing, as low potassium suppresses aldosterone production and causes false-negative results 2
• Ideally discontinue interfering medications when clinically safe: 2
  • Stop mineralocorticoid receptor antagonists (spironolactone, eplerenone) at least 4 weeks before testing
  • Stop beta-blockers, centrally acting drugs, and diuretics when feasible
  • Use long-acting calcium channel blockers and alpha-receptor antagonists as alternatives, as they minimally interfere with ARR
• If medications cannot be stopped, interpret results in the context of the specific medications the patient is taking 2
• Ensure unrestricted salt intake before testing 1, 2

Blood Collection Technique

• Draw blood in the morning (ideally 0800-1000h) with the patient seated 2, 4
• Patient should be out of bed for 2 hours prior to collection 2
• Patient should be seated for 5-15 minutes immediately before blood draw 2

ARR Interpretation Nuances

The specificity improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations to avoid false positives from very low renin levels. 2 An ARR >20 ng/dL per ng/mL/hr has excellent sensitivity and specificity (>90%) for confirming hyperaldosteronism. 2

Critical pitfall: Do not rely on hypokalemia as a screening criterion—it is absent in the majority of primary aldosteronism cases and has low negative predictive value. 1, 5

Confirmatory Testing

A positive ARR screening test requires confirmatory testing to demonstrate autonomous aldosterone secretion that cannot be suppressed. 1, 2

Confirmatory test options include: 1, 2, 3

• Intravenous saline suppression test: Infuse 2L of 0.9% saline over 4 hours; failure to suppress plasma aldosterone below 5-10 ng/dL confirms diagnosis
• Oral sodium loading test: Administer high sodium diet (>200 mEq/day) for 3 days with measurement of 24-hour urine aldosterone; urinary aldosterone >12-14 mcg/24h confirms diagnosis
• Captopril challenge test: Administer captopril 25-50mg; failure to suppress aldosterone confirms diagnosis
• Fludrocortisone suppression test: 4-day protocol with fludrocortisone and sodium loading 2

All confirmatory testing should be performed with unrestricted salt intake and normal serum potassium levels. 1, 2

Subtype Determination: Unilateral vs Bilateral Disease

After biochemical confirmation, determining whether aldosterone excess is unilateral or bilateral is critical for treatment decisions. 2, 5

Initial Imaging

• Obtain non-contrast CT scan of the adrenal glands as the first imaging study 2
• CT findings alone are insufficient for treatment decisions, as adenomas on imaging can represent non-functioning nodules, and bilateral hyperplasia can appear as unilateral adenoma 2

Adrenal Venous Sampling (AVS)

Perform adrenal venous sampling before offering adrenalectomy to distinguish unilateral from bilateral disease, as up to 25% of patients might undergo unnecessary adrenalectomy based on CT findings alone. 2, 5

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

AVS should be performed at specialized centers with expertise in this technically demanding procedure. 5

Referral

Refer all patients with a positive screening test to a hypertension specialist or endocrinologist for confirmatory testing, subtype determination, and treatment planning. 1, 2

Treatment Algorithm

Unilateral Disease (Aldosterone-Producing Adenoma or Unilateral Hyperplasia)

Laparoscopic unilateral adrenalectomy is the treatment of choice for unilateral disease, improving blood pressure in virtually 100% of patients and curing hypertension in approximately 30-60%. 5, 6, 4

For patients who are not surgical candidates, treat medically with mineralocorticoid receptor antagonists. 5, 7

Bilateral Disease (Idiopathic Hyperaldosteronism)

Medical therapy with mineralocorticoid receptor antagonists is the cornerstone of treatment for bilateral disease. 5, 4

First-Line Medical Therapy

• Spironolactone 100-400 mg daily is the first-line treatment for primary aldosteronism 7

  • Start at 100 mg daily and titrate based on blood pressure and potassium response
  • Can be used as long-term maintenance therapy at the lowest effective dose
  • Monitor for anti-androgenic side effects (gynecomastia, decreased libido, menstrual irregularities)

• Eplerenone 50-100 mg daily in 1-2 divided doses is an alternative with fewer sexual side effects 5

  • Preferred in patients who cannot tolerate spironolactone's anti-androgenic effects
  • Less potent than spironolactone, may require higher doses

Critical Safety Considerations for MRA Therapy

• Monitor serum potassium closely—avoid combining MRAs with other potassium-sparing medications or potassium supplements due to hyperkalemia risk 5
• Use MRAs with caution in patients with eGFR <45 mL/min/1.73m² 5
• Do not combine MRAs with ACE inhibitors or ARBs without careful potassium monitoring 5
• In heart failure patients with eGFR 30-50 mL/min/1.73m², consider initiating spironolactone at 25 mg every other day 7

Special Subtype: Familial Hyperaldosteronism Type 1

For glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type 1), treat with low-dose dexamethasone rather than surgery or MRAs. 5 This rare subtype should be suspected in patients with family history of early-onset hypertension or stroke at young age. 1

Common Pitfalls to Avoid

• Delayed diagnosis leads to irreversible cardiovascular and renal damage—aldosterone excess causes target organ damage beyond simple blood pressure elevation 5, 6
• Not screening high-risk patients remains the most common error in clinical practice 2
• Relying on CT imaging alone for subtype determination without AVS leads to inappropriate surgical decisions in up to 25% of cases 2
• Testing patients while hypokalemic causes false-negative results 2
• Failing to withdraw mineralocorticoid receptor antagonists for at least 4 weeks before testing invalidates results 1, 2