What is the evaluation and management approach for a patient with primary macronodular adrenal hyperplasia, presenting with hypertension and hypokalemia?

Primary Macronodular Adrenal Hyperplasia: Evaluation and Management

Initial Diagnostic Evaluation

For a patient presenting with hypertension and hypokalemia with suspected primary macronodular adrenal hyperplasia (PMAH), immediately screen for primary aldosteronism using the aldosterone-to-renin ratio (ARR), followed by evaluation for autonomous cortisol secretion, as this presentation suggests either concurrent aldosterone excess or cortisol-mediated hypertension with secondary hypokalemia. 1

Hormonal Assessment

• Screen for primary aldosteronism by measuring plasma aldosterone concentration and plasma renin activity simultaneously in the morning, with the patient seated for 5-15 minutes after being out of bed for at least 2 hours 1
• A positive ARR requires both ARR ≥30 (when aldosterone is in ng/dL and renin activity in ng/mL/h) AND plasma aldosterone concentration ≥10-15 ng/dL 1
• Ensure the patient is potassium-replete before testing, as hypokalemia suppresses aldosterone production and causes false-negative results 1
• Evaluate for autonomous cortisol secretion using the 1 mg overnight dexamethasone suppression test, as PMAH frequently presents with subclinical or mild cortisol excess rather than overt Cushing's syndrome 2, 3
• Measure midnight salivary cortisol or 24-hour urinary free cortisol to establish the degree of cortisol excess 2
• Measure ACTH levels to confirm ACTH-independent cortisol production, which should be low or suppressed in PMAH 2, 4
• Rule out pheochromocytoma by measuring fractionated plasma-free metanephrines before proceeding with any intervention 5

Imaging Characterization

• Obtain adrenal protocol CT scan or MRI to characterize bilateral macronodular enlargement, evaluating each lesion separately for size, heterogeneity, lipid content, and margin characteristics 5, 2
• PMAH typically presents with bilateral adrenal macronodules (>1 cm), though the degree of enlargement varies from subtle to massive 2, 3
• Imaging alone cannot distinguish PMAH from bilateral hyperplasia in primary aldosteronism, necessitating adrenal venous sampling if aldosterone excess is confirmed 5, 1

Subtype Determination for Aldosterone Excess

If primary aldosteronism is confirmed biochemically, adrenal venous sampling (AVS) is mandatory before offering adrenalectomy to distinguish unilateral from bilateral aldosterone production, as up to 25% of patients would undergo unnecessary adrenalectomy based on CT findings alone. 1

• AVS can be omitted only in patients <40 years when imaging shows a single affected gland, as bilateral hyperplasia is rare in this population 1
• Cortisol measurement in catheterization samples confirms proper catheter placement 5
• Unilateral aldosterone production warrants laparoscopic unilateral adrenalectomy, which improves blood pressure in virtually 100% of patients and cures hypertension in approximately 50% 1
• Bilateral aldosterone production requires lifelong medical management with mineralocorticoid receptor antagonists (spironolactone 50-100 mg daily, titrated up to 300-400 mg daily if necessary) 1

Management Based on Cortisol Excess Severity

Overt Cushing's Syndrome

Bilateral adrenalectomy is reserved only for patients with severe, symptomatic Cushing's syndrome causing significant morbidity, as it results in lifetime steroid dependency and requires lifelong glucocorticoid and mineralocorticoid replacement. 2, 3

• Severe presentations include profound muscle weakness, severe osteoporosis with fractures, uncontrolled diabetes, severe psychiatric manifestations, or life-threatening complications 2
• Laparoscopic bilateral adrenalectomy is the preferred surgical approach when indicated 5, 4

Mild to Moderate Cortisol Excess

Unilateral adrenalectomy should be considered in selected patients with asymmetric disease or when one gland is predominantly responsible for cortisol production, as this approach may achieve biochemical control while preserving some adrenal function. 2, 3

• This approach requires careful preoperative assessment to identify lateralization of cortisol production 2
• Post-operative monitoring is essential, as residual disease may progress over time 3

Medical Management Options

• Cortisol synthesis inhibitors (metopirone, ketoconazole) can be used when surgery is contraindicated or refused, though long-term efficacy data are limited 2, 3
• Specific GPCR antagonists may have potential in cases where aberrant G-protein-coupled receptors regulate cortisol secretion (e.g., GIP-dependent PMAH), though this remains largely investigational 2, 3
• Medical therapy is particularly relevant for patients with mild autonomous cortisol secretion who do not meet criteria for surgical intervention 2

Genetic Evaluation

• Test for germline ARMC5 mutations in all patients with PMAH, as these are identified in 20-25% of apparently sporadic cases and more frequently in familial cases 2, 3
• ARMC5 mutations can be associated with meningiomas, requiring additional screening 3
• Consider KDM1A genetic testing specifically in patients with GIP-dependent PMAH, as combined germline and somatic KDM1A inactivation leads to GIPR overexpression 3
• Genetic testing allows early detection and surveillance of at-risk family members 3

Conservative Management for Subclinical Disease

For patients with bilateral adrenal incidentalomas showing PMAH morphology but only mild autonomous cortisol secretion without overt Cushing's syndrome, conservative management with surveillance may be appropriate, treating associated comorbidities (hypertension, diabetes, osteoporosis) medically. 2, 3

• Repeat imaging in 6-12 months to assess for growth, with consideration for adrenalectomy if enlarging >1 cm in 1 year 5
• Annual hormonal reassessment to monitor for progression of cortisol excess 2
• Aggressive management of cardiovascular risk factors, as even mild cortisol excess increases cardiovascular morbidity 3

Critical Pitfalls to Avoid

• Never rely on hypokalemia alone to screen for primary aldosteronism, as it is absent in approximately 50% of cases 1
• 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
• Do not assume ACTH-independence without measuring ACTH levels, as recent evidence shows ectopic adrenocortical ACTH production in PMAH tissues 6
• Avoid bilateral adrenalectomy in patients with mild or subclinical disease, as the morbidity of lifelong adrenal insufficiency outweighs benefits in these cases 2, 3