What is the diagnosis and treatment approach for bilateral adrenal hyperplasia?

Bilateral Adrenal Hyperplasia: Diagnosis and Treatment

Diagnostic Approach

The first step in evaluating bilateral adrenal hyperplasia is to determine whether it is ACTH-dependent or ACTH-independent by measuring plasma ACTH levels, followed by hormonal workup to assess for autonomous cortisol or aldosterone secretion. 1

Initial Biochemical Evaluation

• Measure plasma ACTH levels to distinguish ACTH-dependent from ACTH-independent causes, as low ACTH with elevated cortisol indicates primary adrenal disease 2
• Perform 1 mg dexamethasone suppression test with serum cortisol measured the following morning: values >50 nmol/L (>1.8 μg/dL) indicate autonomous cortisol secretion 3, 1
• Obtain 24-hour urinary free cortisol and 17-hydroxycorticosteroids to assess for hypercortisolism 2
• Measure plasma aldosterone-to-renin ratio if hypertension or hypokalemia is present, with ratio >30 suggesting primary hyperaldosteronism 1

Etiologic Workup

• Measure 17-hydroxyprogesterone levels to rule out congenital adrenal hyperplasia (CAH), particularly 21-hydroxylase deficiency 4
• Test for 21-hydroxylase autoantibodies (21OH-Ab) as the first-line test to identify autoimmune causes, which account for approximately 85% of primary adrenal insufficiency cases in Western Europe 4
• Exclude pheochromocytoma with plasma or 24-hour urinary metanephrines before any invasive procedures 3

Imaging Studies

• CT imaging is the primary modality for adult adrenal evaluation, showing either diffuse enlargement, micronodular (nodules <1 cm), or macronodular (nodules >1 cm) patterns 5, 6
• MRI and ultrasound are preferred in pediatric cases to evaluate congenital adrenal hyperplasia and avoid radiation exposure 5
• Adrenal vein sampling (AVS) is the gold standard for distinguishing unilateral adenoma from bilateral hyperplasia in primary aldosteronism when surgery is being considered 1

Critical pitfall: CT imaging alone misidentifies lateralization in 25% of primary aldosteronism cases, making AVS essential before surgical decisions 1

Treatment Approach

For Primary Aldosteronism with Bilateral Hyperplasia

Medical management with mineralocorticoid receptor antagonists is the treatment of choice for bilateral adrenal hyperplasia causing primary aldosteronism, as bilateral adrenalectomy would cause permanent adrenal insufficiency. 1, 7

• Spironolactone 50-200 mg daily or eplerenone as first-line therapy to control hypertension and hypokalemia 1, 7
• Normalize serum potassium and ensure unrestricted salt intake during diagnostic workup 1
• Spironolactone is specifically FDA-approved for long-term maintenance therapy in patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism) 7

For Cushing's Syndrome with Bilateral Hyperplasia

The treatment approach depends on the specific subtype and severity of hypercortisolism, with bilateral adrenalectomy reserved for severe, medically refractory cases. 1, 2, 6

Medical Management Options:

• Ketoconazole 400-1200 mg/day as first-line adrenostatic agent for hypercortisolism 3, 1
• Mitotane as alternative steroidogenesis inhibitor 3, 1
• Octreotide can be considered if ectopic ACTH syndrome is Octreoscan-positive 1

Surgical Management:

• Bilateral adrenalectomy is definitive treatment for ACTH-independent bilateral macronodular adrenal hyperplasia (PBMAH) with severe Cushing's syndrome 2, 6
• Laparoscopic approach is preferred for smaller glands (typically <30 grams), while anterior approach is needed for massively enlarged glands (>30 grams) 2
• Unilateral adrenalectomy is emerging as an option in select PBMAH cases to avoid permanent adrenal insufficiency, though data are limited 6

Critical consideration: Primary pigmented micronodular adrenocortical disease (PPNAD) typically presents with small adrenal glands (2.5-13.4 grams) and can be approached posteriorly, while PBMAH presents with massively enlarged glands (32-81 grams) often requiring anterior approach 2

For Congenital Adrenal Hyperplasia

Medical management with glucocorticoid replacement is standard therapy, but bilateral adrenalectomy may be considered in severe cases with persistent hyperandrogenism despite maximal medical therapy. 8

• Hydrocortisone 15-25 mg daily in split doses is the glucocorticoid of choice for adults 1
• Fludrocortisone 50-200 μg daily for mineralocorticoid replacement in salt-losing forms 1
• Bilateral adrenalectomy should be considered when medical management fails to control hyperandrogenism, particularly in females with virilization, irregular menses, or decreased fertility 8

Post-Treatment Management

After Bilateral Adrenalectomy

All patients require lifelong glucocorticoid and mineralocorticoid replacement with immediate IV hydrocortisone 100 mg for any acute illness or stress. 1

• Hydrocortisone 15-25 mg daily in 2-3 divided doses for glucocorticoid replacement 1
• Fludrocortisone 50-200 μg daily for mineralocorticoid replacement 1
• Immediate treatment of adrenal crisis: IV or IM hydrocortisone 100 mg, then 100 mg every 6-8 hours, plus 0.9% saline at 1 L/hour initially 1
• All patients must wear medical alert identification and carry a steroid alert card 1

After Unilateral Adrenalectomy

Postoperative corticosteroid supplementation is required until recovery of the hypothalamus-pituitary-adrenal axis, which may take months. 1

Long-Term Monitoring

• Annual review at minimum assessing health status, weight, blood pressure, and serum electrolytes 1
• Screen for new autoimmune disorders, particularly hypothyroidism with TSH and TPO antibodies 4, 1
• Monitor bone mineral density every 3-5 years to assess for glucocorticoid-induced osteoporosis 4, 1
• Assess for complications of glucocorticoid therapy including weight gain, glucose intolerance, and cardiovascular risk factors 1

Key Clinical Pitfalls

• Never delay treatment for diagnostic testing if adrenal crisis is suspected; secure blood samples for cortisol and ACTH before giving hydrocortisone if possible, but treatment takes priority 4
• A phenotypic male newborn with bilateral nonpalpable testes may be a 46 XX female with severe CAH and can present with life-threatening salt-wasting crisis 4
• Avoid bilateral adrenalectomy for asymptomatic cortisol-secreting adenomas due to the burden of lifelong adrenal insufficiency 4
• Withdraw spironolactone for at least 4 weeks before AVS to ensure accurate results in primary aldosteronism workup 1