How to manage a patient with primary macronodular adrenal hyperplasia, presenting with hypertension and hypokalemia, and abnormal activated renin concentration and plasma renin activity (PRA) levels?

Management of Primary Macronodular Adrenal Hyperplasia with Hypertension and Hypokalemia

Initial Diagnostic Workup

Screen immediately for primary aldosteronism using the aldosterone-to-renin ratio (ARR), as this presentation of hypertension with hypokalemia in the setting of bilateral adrenal enlargement strongly suggests autonomous aldosterone production. 1, 2

Patient Preparation Before Testing

• Ensure the patient is potassium-replete before testing, as hypokalemia suppresses aldosterone production and causes false-negative results 1, 2
• Discontinue interfering medications when clinically feasible: beta-blockers, centrally acting drugs, and diuretics should be stopped as they suppress renin and cause false-positive ARR results 2
• Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) at least 4 weeks before testing 2
• Use long-acting calcium channel blockers (verapamil) or alpha-receptor antagonists (doxazosin, prazosin) as alternative antihypertensives during the workup, as these minimally interfere with ARR 2

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
• Measure simultaneous plasma aldosterone concentration (PAC) and plasma renin activity (PRA) 1, 2

Interpretation of Screening Results

• A positive screening test requires both an ARR ≥20-30 ng/dL per ng/mL/hr and a plasma aldosterone concentration ≥10-15 ng/dL 2
• The specificity improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations 2

Confirmatory Testing

All positive ARR screening tests require confirmatory testing to demonstrate autonomous aldosterone secretion that cannot be suppressed with sodium loading. 1, 2

• Perform either intravenous saline suppression test (2L normal saline over 4 hours, with failure to suppress plasma aldosterone below 5 ng/dL confirming diagnosis) or oral sodium loading with 24-hour urine aldosterone measurement 2, 3, 4
• Testing should be performed with unrestricted salt intake and normal serum potassium levels 1, 2

Rule Out Pheochromocytoma

• Measure fractionated plasma-free metanephrines before proceeding with any intervention, as this is mandatory to exclude pheochromocytoma 1

Imaging Characterization

• Obtain adrenal protocol CT scan or MRI to characterize the bilateral macronodular enlargement, evaluating each lesion separately for size, heterogeneity, lipid content, and margin characteristics 1

Critical Step: Adrenal Venous Sampling (AVS)

Adrenal venous sampling is mandatory before offering adrenalectomy to distinguish unilateral from bilateral aldosterone production, as imaging alone cannot reliably distinguish these entities. 1, 2

• Up to 25% of patients would undergo unnecessary adrenalectomy based on CT findings alone 1
• Cortisol measurement in catheterization samples confirms proper catheter placement during AVS 1
• The only exception to mandatory AVS is in patients <40 years when imaging shows a single affected gland, as bilateral hyperplasia is rare in this population 2

Treatment Based on Lateralization

For Unilateral Aldosterone Production

• Laparoscopic unilateral adrenalectomy is the treatment of choice, which improves blood pressure in virtually 100% of patients and cures hypertension in approximately 50% 1, 2, 4
• Normalization of hypokalemia occurs in all patients post-operatively 4

For Bilateral Aldosterone Production

• Lifelong medical management with mineralocorticoid receptor antagonists is the cornerstone of treatment 1, 2
• Start spironolactone 50-100 mg daily, titrated up to 300-400 mg daily if necessary 1, 5
• Eplerenone is an alternative with fewer anti-androgenic side effects but is less potent and requires twice-daily dosing 2
• Monitor serum potassium within 1 week of initiation and regularly thereafter, as the risk of hyperkalemia is increased in older patients, those with diabetes, chronic kidney disease, or concomitant use of ACE inhibitors/ARBs/NSAIDs 2

Evaluation for Autonomous Cortisol Secretion

• Rule out autonomous cortisol secretion in addition to aldosterone excess, as primary macronodular adrenal hyperplasia can produce both 1
• If severe, symptomatic Cushing's syndrome is present causing significant morbidity, laparoscopic bilateral adrenalectomy may be the preferred surgical approach 1

Critical Pitfalls to Avoid

• Never rely on hypokalemia alone to screen for primary aldosteronism, as it is absent in approximately 50% of cases 1, 2
• Never proceed to surgery based on CT findings alone without adrenal venous sampling when primary aldosteronism is confirmed, as imaging cannot reliably distinguish unilateral from bilateral disease 1, 2
• Do not assume normal adrenal appearance on CT excludes primary aldosteronism—functional testing and AVS are essential 3, 6

Referral and Follow-Up

• Refer all patients with confirmed primary aldosteronism to a hypertension specialist or endocrinologist for subtype determination and treatment planning 2
• Even after successful adrenalectomy, some patients have residual hypertension due to vascular remodeling from delayed diagnosis, so continued blood pressure monitoring is essential 2