Primary Aldosteronism: Screening, Confirmation, Subtyping, and Management
Who to Screen
Screen this patient immediately with a plasma aldosterone-to-renin ratio (ARR), as they meet three high-risk criteria: resistant hypertension, hypokalemia, and an adrenal incidentaloma. 1
The ACC/AHA guidelines provide Class I recommendations (highest level) for screening in the presence of any of the following 1:
- Resistant hypertension (BP uncontrolled on ≥3 drugs including a diuretic, or controlled on ≥4 drugs) 1
- Hypokalemia (spontaneous or substantial if diuretic-induced) 1
- Incidentally discovered adrenal mass 1
- Family history of early-onset hypertension or stroke at age <40 years 1
Primary aldosteronism affects 5-10% of all hypertensive patients and up to 20% of those with resistant hypertension, making it the most common cause of secondary hypertension 2. Importantly, hypokalemia is absent in approximately 50% of cases, so normal potassium does not exclude the diagnosis 1.
Screening Test: Aldosterone-to-Renin Ratio (ARR)
Patient Preparation
Correct hypokalemia before testing (target 4.0-5.0 mEq/L), as hypokalemia suppresses aldosterone production and causes false-negative results 2.
Medication adjustments (when clinically feasible) 2:
- Stop for 2-5 days: Beta-blockers (suppress renin → false-positive ARR) 2
- Stop for ≥2 weeks: ACE inhibitors and ARBs (increase renin → false-negative ARR) 2
- Stop for ≥4 weeks: Mineralocorticoid receptor antagonists (spironolactone, eplerenone) 2
- Stop when possible: Diuretics (increase renin → false-negative ARR) 2
- Safe alternatives: Long-acting calcium channel blockers and alpha-receptor antagonists minimally interfere with ARR 2
If medications cannot be stopped, test on current medications and interpret results in context 1.
Blood Collection Technique
- Morning collection (ideally 0800-1000 hours) 2
- Patient out of bed for ≥2 hours before collection 2
- Seated for 5-15 minutes immediately before blood draw 2
- Unrestricted salt intake before testing 2
Interpretation
A positive screening test requires BOTH 1, 2:
- ARR ≥20-30 (when aldosterone in ng/dL and renin activity in ng/mL/hr)
- Plasma aldosterone concentration ≥10-15 ng/dL
The specificity improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations 2.
Confirmatory Testing
A positive ARR is only a screening test—confirmatory testing is mandatory to demonstrate autonomous aldosterone secretion that cannot be suppressed with sodium loading 1, 2.
Confirmatory Test Options
Oral sodium loading test 1:
- Administer oral sodium chloride (6 g/day for 3 days) with unrestricted salt intake
- Measure 24-hour urine aldosterone on day 3
- Positive if urinary aldosterone >12-14 mcg/24 hours with adequate sodium excretion (>200 mEq/24 hours)
- Supplement potassium to maintain normal levels during testing
Intravenous saline suppression test 1:
- Infuse 2 liters of 0.9% saline over 4 hours
- Measure plasma aldosterone at 4 hours
- Positive if plasma aldosterone >5-10 ng/dL after saline loading
Fludrocortisone suppression test 2:
- Less commonly used but can confirm diagnosis when other tests are equivocal
Critical preparation: Ensure normal serum potassium and unrestricted salt intake before all confirmatory tests 1, 2. Mineralocorticoid receptor antagonists must be withdrawn ≥4 weeks before testing 2.
Subtype Determination: Unilateral vs. Bilateral Disease
This distinction is mandatory because it determines treatment: unilateral disease is treated surgically, bilateral disease is treated medically 2.
Step 1: Adrenal CT Scan (Non-Contrast)
Order a non-contrast CT scan of the adrenal glands as initial imaging 1, 2.
Critical caveat: CT findings alone are insufficient for treatment decisions. Up to 25% of patients would undergo unnecessary adrenalectomy based on CT alone, as adenomas on imaging can represent bilateral hyperplasia and false positives are common due to nodular hyperplasia 2.
Step 2: Adrenal Venous Sampling (AVS)
AVS is mandatory before offering adrenalectomy to definitively distinguish unilateral from bilateral aldosterone hypersecretion 2, 3.
Exception: AVS may be omitted in patients <40 years old** with a **solitary unilateral macroadenoma (>1 cm) and normal contralateral adrenal on CT, as bilateral hyperplasia is rare in this population 3.
AVS has 95% sensitivity and 100% specificity for lateralization 2.
Management
Unilateral Disease (Aldosterone-Producing Adenoma or Unilateral Hyperplasia)
Laparoscopic unilateral adrenalectomy is the treatment of choice 1, 4:
- Improves blood pressure in virtually 100% of patients 4
- Achieves complete cure of hypertension in approximately 50% 4
- Normalizes hypokalemia in 100% 2
- Improves cardiac and kidney function parameters 4
The rate of cure is higher when diagnosis is made early, before irreversible vascular remodeling occurs 2.
Bilateral Disease (Bilateral Adrenal Hyperplasia/Idiopathic Hyperaldosteronism)
Medical therapy with mineralocorticoid receptor antagonists (MRAs) is the cornerstone of lifelong treatment 2, 4:
First-line: Spironolactone 2:
- Start 25-50 mg once daily
- Titrate up to 300-400 mg once daily if necessary
- Monitor serum potassium within 1 week of initiation and regularly thereafter
- Risk of hyperkalemia is increased in older patients, those with diabetes, CKD, or concomitant use of ACE inhibitors/ARBs/NSAIDs 2
- Anti-androgenic side effects (gynecomastia, erectile dysfunction, menstrual irregularities) may limit use
Alternative: Eplerenone 2:
- Fewer anti-androgenic side effects than spironolactone
- Less potent than spironolactone
- Requires twice-daily administration
Referral
Refer all patients with a positive screening test to a hypertension specialist or endocrinologist for confirmatory testing, subtype determination, and treatment planning 1. The diagnostic workup requires specialized technical expertise and experience in data interpretation 1.
Clinical Impact and Urgency
Patients with primary aldosteronism experience dramatically worse cardiovascular outcomes than those with essential hypertension at equivalent blood pressure levels 2:
| Cardiovascular Outcome | Relative Risk Increase |
|---|---|
| Heart failure | 3.7-fold |
| Stroke | 4.2-fold |
| Myocardial infarction | 6.5-fold |
| Atrial fibrillation | 12.1-fold |
Excess aldosterone causes direct toxic effects on cardiovascular and renal tissue through mechanisms independent of blood pressure elevation, producing widespread tissue fibrosis and target organ damage 4, 5. These deleterious effects are often reversible with appropriate treatment (adrenalectomy or MRAs), reducing adverse cardiovascular events 4, 5.
Common Pitfalls to Avoid
- Do not rely on hypokalemia as a screening trigger—it is absent in 50% of cases 1
- Do not proceed to surgery based on CT findings alone—AVS is mandatory except in young patients (<40 years) with clear unilateral adenoma 2, 3
- Do not test patients on mineralocorticoid receptor antagonists—withdraw for ≥4 weeks before testing 2
- Do not forget to correct hypokalemia before testing—it suppresses aldosterone and causes false-negatives 2
- Do not skip confirmatory testing—a positive ARR alone is not diagnostic 1, 2