Why is adrenal venous sampling (AVS) not necessary in bilateral macronodular adrenal hyperplasia (BMAH)?

Why Adrenal Venous Sampling is Not Needed in Bilateral Macronodular Adrenal Hyperplasia

Adrenal venous sampling (AVS) is unnecessary in bilateral macronodular adrenal hyperplasia (BMAH) because the diagnosis is already established by imaging showing bilateral disease, and the treatment decision—whether unilateral or bilateral adrenalectomy versus medical management—is determined by clinical factors (degree of hypercortisolism, surgical candidacy, adrenal size asymmetry) rather than by lateralization of hormone production.

The Fundamental Difference: BMAH vs. Primary Aldosteronism

The key distinction lies in understanding what AVS actually accomplishes and when it changes management:

AVS is Essential for Primary Aldosteronism

• AVS serves to distinguish unilateral adenoma from bilateral hyperplasia in primary aldosteronism, fundamentally altering treatment from surgical (unilateral adrenalectomy) to medical (mineralocorticoid antagonists) 1, 2
• The AACE/AAES guidelines emphasize that AVS lateralizes aldosterone production and is recommended in the majority of primary aldosteronism patients, even with masses well-visualized on imaging 1
• CT imaging alone is unreliable, with 25% of patients potentially receiving unnecessary adrenalectomy based on CT findings alone, and AVS results alter management in 35.7% of cases 2

AVS Provides Limited Value in BMAH

• In BMAH, bilateral disease is already evident on imaging, so the question is not "unilateral vs. bilateral" but rather "which side to remove first" or "remove both sides" 3, 4
• Research demonstrates that AVS was technically successful in documenting bilateral cortisol hypersecretion in all patients with BMAH, but this finding merely confirmed what imaging already showed 4
• The combined volume of adrenals correlates positively with urinary free cortisol, suggesting that adrenal size is the dominant determinant of cortisol secretion rather than functional lateralization 3

Clinical Decision-Making in BMAH Without AVS

When Adrenal Asymmetry is Present

• Surgical decision-making is guided by adrenal mass size rather than AVS results 4
• In patients with marked adrenal asymmetry, unilateral adrenalectomy of the larger gland is performed without AVS, as the gain of information through AVS is limited 3
• Among patients who underwent surgery, 3 had unilateral adrenalectomy of the larger mass based on size alone 4

When Bilateral Disease is Symmetric

• Bilateral adrenalectomy is considered for severe, refractory Cushing's disease or when both adrenals are significantly enlarged (>4 cm) 5, 4
• Medical management with adrenostatic agents (ketoconazole 400-1200 mg/day, mitotane) is an alternative to surgery 2
• The decision is based on severity of hypercortisolism, comorbidities (hypertension, diabetes, osteoporosis), and surgical candidacy—not on AVS lateralization 2, 6

Evidence from AVS Studies in BMAH

Recent research specifically examining AVS in BMAH reveals its limitations:

Limited Lateralization Despite Technical Success

• In a 2022 study of 16 PBMAH patients, AVS showed lateralization in only 8 of 16 patients, and in 3 of those 8, lateralization occurred in bilaterally identical adrenals—making the information clinically meaningless 3
• Even when lateralization was present toward morphologically larger adrenals (5 of 8 cases), this merely confirmed what imaging already demonstrated 3

AVS Confirms Bilateral Disease But Doesn't Change Management

• A 2019 study found that all 8 successful AVS procedures indicated bilateral cortisol hypersecretion, yet surgical decisions were still based primarily on adrenal size 4
• Final pathology revealed macronodular adrenal hyperplasia in all surgical cases, confirming the bilateral nature of the disease 4

High Specificity for Distinguishing Unilateral from Bilateral Disease

• A 2023 study demonstrated that AVS can distinguish unilateral from bilateral disease with 95-100% specificity using specific cutoffs (AV/IVC cortisol ratio >9 for one side, <2.0 for the opposite side, and CLR >2.3) 7
• However, this distinction is already apparent on imaging in BMAH, where bilateral macronodules are visible 7

The Practical Algorithm for BMAH Management

Step 1: Confirm BMAH Diagnosis

• Bilateral adrenal masses >1 cm on CT or MRI with macronodular appearance 3, 6
• ACTH-independent Cushing's syndrome: suppressed ACTH (<10 pg/mL), elevated cortisol after 1 mg dexamethasone suppression test (>138 nmol/L or >5.0 μg/dL), elevated 24-hour urinary free cortisol 2, 6

Step 2: Assess Severity and Surgical Candidacy

• Evaluate for overt Cushing's syndrome vs. mild autonomous cortisol excess (MACE) 6
• Screen for cortisol-induced comorbidities: hypertension (present in 87.8%), diabetes (53.7%), obesity (56%), osteoporosis (7.3%) 6
• Determine surgical candidacy based on age, comorbidities, and anesthetic risk 5

Step 3: Choose Treatment Based on Clinical Factors

For marked adrenal asymmetry:

• Unilateral adrenalectomy of the larger gland (laparoscopic preferred) 3, 4
• No AVS needed as size correlates with cortisol production 3

For bilateral symmetric disease with severe hypercortisolism:

• Bilateral adrenalectomy if both glands >4 cm or life-threatening Cushing's 5, 4
• Lifelong glucocorticoid (hydrocortisone 15-25 mg daily) and mineralocorticoid (fludrocortisone 50-200 μg daily) replacement required 2, 5

For MACE or poor surgical candidates:

• Medical management with ketoconazole (400-1200 mg/day) or mitotane 2
• Treat comorbidities: antihypertensives, diabetes management, bone protection 2, 6

Common Pitfalls to Avoid

Pitfall 1: Ordering AVS "Just to Be Sure"

• AVS in BMAH wastes time and resources while exposing patients to procedural risks (adrenal hemorrhage, venous thrombosis, adrenal infarction) without changing management 3, 4
• The procedure is technically demanding with success rates of 81% even in experienced centers 3

Pitfall 2: Assuming All Bilateral Disease Requires Bilateral Surgery

• Unilateral adrenalectomy can be effective in BMAH with marked asymmetry, avoiding lifelong steroid dependence 3, 4
• However, patients must be counseled about potential recurrence from the contralateral gland 4

Pitfall 3: Forgetting Postoperative Hormone Replacement

• After unilateral adrenalectomy, postoperative corticosteroid supplementation is required until recovery of the hypothalamus-pituitary-adrenal axis 2
• After bilateral adrenalectomy, lifelong replacement is mandatory with medical alert identification and steroid emergency cards 2, 5

Pitfall 4: Not Screening for Congenital Adrenal Hyperplasia

• Measure 17-hydroxyprogesterone levels in all patients with bilateral adrenal masses to rule out congenital adrenal hyperplasia, which requires entirely different management 5