What is the workup for bilateral adrenal hyperplasia?

Workup for Bilateral Adrenal Hyperplasia

The workup for bilateral adrenal hyperplasia requires simultaneous hormonal screening for cortisol, aldosterone, and catecholamine excess combined with dedicated adrenal imaging, followed by adrenal vein sampling when surgical intervention is being considered to distinguish unilateral from bilateral hormone production. 1, 2

Initial Hormonal Evaluation

Cortisol Excess Assessment

• Perform 1 mg overnight dexamethasone suppression test as the primary screening tool for autonomous cortisol secretion in all patients with bilateral adrenal masses. 1, 3
• If serum cortisol remains ≥50 nmol/L (≥1.8 μg/dL) after dexamethasone, proceed with confirmatory testing including 24-hour urinary free cortisol (three separate collections) and midnight serum cortisol or late-night salivary cortisol. 1, 3
• Measure plasma ACTH levels to establish ACTH-independency—normal or suppressed ACTH with elevated cortisol confirms primary adrenal pathology rather than pituitary or ectopic sources. 1, 3

Aldosterone Excess Screening

• Measure plasma aldosterone concentration and plasma renin activity in all patients, particularly those with hypertension or hypokalemia. 1, 2
• Calculate the aldosterone-to-renin ratio; a ratio >30 (when aldosterone is in ng/dL and renin activity in ng/mL/h) with aldosterone ≥10 ng/dL suggests primary aldosteronism. 1, 2
• Perform confirmatory testing with saline suppression test or oral salt loading test, as both false-positives and false-negatives can occur with screening ratios alone. 1
• Check serum potassium and sodium, as excessive aldosterone causes sodium retention and potassium excretion. 1

Catecholamine Excess Evaluation

• Skip pheochromocytoma screening if unenhanced CT shows Hounsfield units <10 in both adrenal masses and the patient has no symptoms of adrenergic excess (hypertensive paroxysms, headaches, palpitations, diaphoresis). 1
• If either mass shows >10 HU on non-contrast CT or symptoms are present, measure plasma-free metanephrines and normetanephrines or 24-hour urinary fractionated metanephrines. 1

Androgen and Steroid Precursor Assessment

• Measure serum DHEA-S, 17-hydroxyprogesterone, androstenedione, and testosterone when virilization is present or when imaging suggests possible adrenocortical carcinoma. 1, 4
• 17-hydroxyprogesterone >200 ng/dL suggests congenital adrenal hyperplasia, which fundamentally changes management from acquired forms. 4
• Consider 24-hour urine steroid metabolite profiling, which can distinguish adrenocortical carcinoma from adenomas based on patterns of immature, early-stage steroidogenesis. 1

Imaging Characterization

First-Line Imaging

• Obtain non-contrast CT of the abdomen as the initial imaging modality to assess each adrenal mass separately for size, morphology, and attenuation values. 1, 5
• Measure Hounsfield units on unenhanced CT: values <10 HU indicate benign lipid-rich adenomas, while values >10 HU require further evaluation. 1
• Assess each lesion individually for size, margins (smooth vs irregular), homogeneity, and presence of calcifications—irregular morphology, heterogeneity, or size >4-5 cm raises concern for malignancy. 1

Second-Line Imaging for Indeterminate Masses

• If non-contrast CT shows >10 HU, perform contrast-enhanced CT with 15-minute delayed washout imaging or chemical-shift MRI. 1
• Enhancement washout >60% at 15 minutes on CT suggests benign adenoma, while <60% washout requires consideration of malignancy or pheochromocytoma. 1
• Chemical-shift MRI demonstrating signal dropout on opposed-phase images compared to in-phase images confirms lipid-rich adenoma. 1

Imaging for Metastatic Disease

• If the patient has a known extra-adrenal malignancy, obtain CT chest/abdomen/pelvis to evaluate for metastatic disease, as bilateral adrenal metastases fundamentally alter management. 1, 4

Adrenal Vein Sampling (AVS)

Indications for AVS

• Perform AVS in all surgical candidates with confirmed primary aldosteronism to distinguish unilateral adenoma from bilateral hyperplasia, as CT imaging alone leads to unnecessary adrenalectomy in approximately 25% of cases. 1, 2
• AVS is also indicated for bilateral adrenal masses with ACTH-independent Cushing's syndrome when imaging shows asymmetric nodules to determine if cortisol production is unilateral or bilateral. 1
• Consider omitting AVS only in patients <40 years with a single unilateral mass >1 cm and completely normal contralateral gland on imaging, as bilateral hyperplasia is rare in this population. 1

AVS Preparation and Technique

• Discontinue mineralocorticoid receptor antagonists (spironolactone, eplerenone) at least 4 weeks before AVS to avoid pharmacologic interference with lateralization. 2
• Normalize serum potassium and permit unrestricted dietary salt intake prior to the procedure. 2
• Measure both aldosterone and cortisol in bilateral adrenal vein samples and peripheral vein samples simultaneously; cortisol confirms correct catheter placement (adrenal vein cortisol significantly higher than peripheral). 2

AVS Interpretation

• For aldosterone excess: central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH or desmopressin stimulation confirms pituitary source; inter-petrosal sinus gradient ≥1.4 suggests lateralization. 1, 2
• For cortisol excess: asymmetric cortisol production between the two adrenal veins indicates unilateral disease amenable to unilateral adrenalectomy; symmetric production mandates medical management. 1

Critical Diagnostic Pitfalls

• Never rely on CT imaging alone to distinguish unilateral from bilateral disease in primary aldosteronism—non-functioning adenomas and nodular hyperplasia are common, producing false-positive results in 25% of cases. 1, 2
• Do not assume all bilateral adrenal hyperplasia has the same etiology—failure to screen for congenital adrenal hyperplasia with 17-hydroxyprogesterone leads to inappropriate treatment. 4
• Recognize that adrenal biopsy should not be performed routinely for workup of bilateral adrenal masses, as it cannot distinguish adenoma from carcinoma and risks seeding if malignancy is present. 1
• Always exclude pheochromocytoma before any adrenal biopsy or surgery to prevent hypertensive crisis; this is the only absolute indication for catecholamine screening regardless of imaging characteristics. 1

Genetic and Familial Considerations

• Screen for germline ARMC5 mutations in patients with bilateral macronodular hyperplasia and evidence of hypercortisolism, as these account for 20-25% of sporadic cases and are more frequent in familial cases. 6, 7
• Consider genetic testing for KDM1A mutations in patients with GIP-dependent PBMAH, as combined germline and somatic KDM1A inactivation leads to GIPR overexpression. 7
• Evaluate for hereditary syndromes including Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, MEN1, and familial polyposis coli when bilateral adrenal masses are identified, particularly in younger patients. 1