Work-up for Hyperaldosteronism
Who Should Be Screened
Screen all patients with resistant hypertension (BP uncontrolled on ≥3 medications including a diuretic), as primary aldosteronism affects up to 20% of this population and carries dramatically higher cardiovascular risk than essential hypertension. 1
Additional high-risk populations requiring screening include:
- Severe hypertension (BP >180/110 mmHg) 1
- Spontaneous or diuretic-induced hypokalemia – though critically, hypokalemia is absent in approximately 50% of primary aldosteronism cases, so normal potassium does not exclude the diagnosis 1, 2
- Adrenal incidentaloma discovered on imaging 1, 2
- Family history of early-onset hypertension or stroke before age 40 1, 2
- Young-onset hypertension in patients <30-40 years without traditional risk factors 1
Patient Preparation Before Testing
Medication Management
Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) for at least 4 weeks before any testing, as they directly interfere with results. 1, 2
When clinically feasible, discontinue interfering medications:
- Beta-blockers – suppress renin, causing false-positive ARR; stop 2-5 days before testing 1
- Diuretics – increase renin, causing false-negative ARR; discontinue when possible 1
- ACE inhibitors/ARBs – increase renin, causing false-negative ARR; withdraw at least 2 weeks before testing 1
Use long-acting calcium channel blockers (verapamil slow-release) and alpha-receptor antagonists (prazosin, doxazosin, hydralazine) as safe alternatives during washout, as they minimally interfere with ARR. 1
If medications cannot be stopped due to severe hypertension, proceed with testing but interpret results in the context of known drug effects. 1
Metabolic Preparation
Ensure potassium repletion before testing, targeting serum potassium 4.0-5.0 mEq/L, as hypokalemia suppresses aldosterone production and causes false-negative results. 1, 2
- Encourage unrestricted (liberal) salt intake before testing 1
- Ensure adequate hydration, especially if diuretics were recently used 1
Initial Screening Test: Aldosterone-to-Renin Ratio (ARR)
Blood Collection Protocol
Collect blood in the morning (ideally 0800-1000 hours), with the patient out of bed for at least 2 hours and seated for 5-15 minutes immediately before blood draw. 1, 2
Interpretation Criteria
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
Common Pitfalls to Avoid
- Never rely on hypokalemia alone – it is absent in 50% of cases 1, 2
- Do not skip screening in normokalemic patients with resistant hypertension 3, 4
- Recognize that normal aldosterone levels in basal conditions do not exclude hyperaldosteronism – dynamic testing is required 3
- Consider repeat screening in patients with persistent resistant hypertension despite initial negative testing, as false-negatives occur 5
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
Intravenous saline suppression test:
- Infuse 2L of normal saline over 4 hours
- Failure to suppress plasma aldosterone below 5 ng/dL confirms the diagnosis 1
Oral sodium loading test:
- Measure 24-hour urine aldosterone with unrestricted salt intake
- Elevated urinary aldosterone (>14 μg/24 hours) confirms autonomous secretion 1, 6
Fludrocortisone suppression test:
- Failure to reduce plasma aldosterone below threshold confirms diagnosis 1
Perform confirmatory testing with unrestricted salt intake and normal serum potassium levels. 1, 2
Subtype Determination
After biochemical confirmation, determine if the disease is unilateral or bilateral, as this dictates treatment – surgery for unilateral disease versus lifelong medical therapy for bilateral disease. 1, 2
Initial Imaging
Obtain non-contrast CT scan of the adrenal glands to identify potential adenomas and exclude adrenocortical carcinoma. 2
Adrenal Venous Sampling (AVS)
AVS is mandatory before offering adrenalectomy to distinguish unilateral from bilateral disease, as up to 25% of patients might undergo unnecessary adrenalectomy based on CT findings alone. 1, 2
Exception: In patients <40 years with imaging showing a single affected gland, AVS may be omitted, as bilateral hyperplasia is rare in this population. 1
AVS should be performed by an experienced radiologist, as it has 95% sensitivity and 100% specificity for lateralization. 1
Referral
Refer all patients with confirmed primary aldosteronism to a hypertension specialist or endocrinologist for subtype determination and treatment planning. 1, 2
Treatment 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 curing hypertension in approximately 50%. 1, 2
- Adrenalectomy normalizes hypokalemia, lowers blood pressure, reduces antihypertensive medication requirements, and improves cardiac and kidney function 1
- The rate of cure is higher when diagnosis is made early in the disease course 1
- Even after successful surgery, some patients have residual hypertension due to vascular remodeling from delayed diagnosis 1
Bilateral Disease (Bilateral Adrenal Hyperplasia)
Medical therapy with mineralocorticoid receptor antagonists (MRAs) is the cornerstone of lifelong treatment. 1, 2
Spironolactone is first-line therapy:
- Start 50-100 mg once daily, titrate up to 300-400 mg once daily if necessary 1
- Provides significant BP reduction of 25/12 mmHg when added to multidrug regimens 1
- Low doses (25-50 mg daily) are effective and minimize adverse effects 1
Eplerenone is an alternative:
- Less potent than spironolactone, requires twice-daily administration 1
- Fewer anti-androgenic side effects 1
Monitoring During MRA Therapy
Monitor serum potassium within 1 week of MRA initiation and regularly thereafter. 1
- Risk of hyperkalemia is increased in older patients, those with diabetes, CKD (especially eGFR <45 mL/min), or concomitant use of ACE inhibitors/ARBs/NSAIDs 1, 2
- Avoid combining MRAs with other potassium-sparing medications or potassium supplements 2
- Use MRAs with caution in patients with significant renal dysfunction 2
Special Consideration: Empiric Spironolactone in Resistant Hypertension
In patients with resistant hypertension and positive ARR screening (ARR ≥30 with aldosterone ≥10 ng/dL), add spironolactone 25-50 mg daily immediately while awaiting confirmatory testing, as this provides significant blood pressure reduction regardless of whether primary aldosteronism is ultimately confirmed. 1
This approach is justified because spironolactone provides benefit in both true primary aldosteronism and aldosterone-sensitive hypertension. 1
Clinical Impact of Early Diagnosis
Primary aldosteronism causes dramatically worse cardiovascular outcomes than essential hypertension at equivalent blood pressure levels: 1
- 3.7-fold increase in heart failure
- 4.2-fold increase in stroke
- 6.5-fold increase in myocardial infarction
- 12.1-fold increase in atrial fibrillation
Prompt identification and targeted treatment—either unilateral adrenalectomy or MRA therapy—can reverse aldosterone-mediated target-organ damage and mitigate this excess cardiovascular risk. 1