What are the clinical features of bilateral adrenal hyperplasia?

Clinical Features of Bilateral Adrenal Hyperplasia

Bilateral adrenal hyperplasia presents primarily with hypertension, hypokalemia, and muscle weakness when caused by primary aldosteronism, or with features of Cushing syndrome (weight gain, proximal muscle weakness, centripetal obesity, purple striae) when ACTH-dependent. 1, 2

Primary Aldosteronism Presentation (Most Common)

When bilateral adrenal hyperplasia causes primary aldosteronism, patients present with:

• Hypertension that is often resistant to standard antihypertensive therapy 1, 3
• Hypokalemia due to excessive aldosterone-driven potassium excretion 1, 2
• Muscle weakness secondary to hypokalemia and electrolyte disturbances 1, 3
• Sodium retention with normal or mildly elevated serum sodium 1
• Plasma aldosterone-to-renin ratio typically >30 (with aldosterone in ng/dL and renin activity in ng/mL/h) 1, 2
• Elevated plasma aldosterone levels (≥10 ng/dL) with suppressed renin activity 4, 2

Critical diagnostic pitfall: CT imaging alone misidentifies the etiology in approximately 25% of cases, leading to unnecessary adrenalectomy when bilateral hyperplasia is actually present. 4 Adrenal vein sampling is the gold standard to distinguish bilateral hyperplasia from unilateral adenoma in surgical candidates. 1, 4

ACTH-Dependent Cushing Syndrome Presentation

When bilateral adrenal hyperplasia results from pituitary or ectopic ACTH oversecretion, patients exhibit:

• Weight gain with centripetal obesity pattern 1
• Proximal muscle weakness affecting hip and shoulder girdles 1
• Purple striae (>1 cm wide) on abdomen, thighs, or breasts 1
• Buffalo hump and supraclavicular fat pad enlargement 1
• Hypertension and hyperglycemia 1
• Psychiatric disturbances including depression and anxiety 1
• Hirsutism in women 1
• Elevated 24-hour urinary free cortisol 1
• Elevated plasma ACTH levels (distinguishing this from primary adrenal tumors) 1, 5

The elevated ACTH indicates the excessive cortisol is not originating from autonomous adrenal production but rather from pituitary adenoma (Cushing's disease) or ectopic ACTH-producing tumors in lung, thyroid, pancreas, or bowel. 1, 5

Congenital Adrenal Hyperplasia Presentation

Bilateral adrenal hyperplasia from enzyme deficiencies (most commonly 21-hydroxylase deficiency) presents with:

• Elevated 17-hydroxyprogesterone levels (diagnostic hallmark) 1, 2, 5
• Virilization in females: hirsutism, deepening voice, oligomenorrhea or amenorrhea 1
• Salt-wasting crisis in severe cases with hyponatremia and hyperkalemia 2
• Hyperpigmentation from elevated ACTH 3

Essential screening: Measure 17-hydroxyprogesterone in all patients with bilateral adrenal masses to avoid missing this diagnosis. 1, 2, 5

Rare Presentations

• Bilateral macronodular adrenal hyperplasia (BMAH) may present with subclinical or overt Cushing syndrome, often discovered incidentally on imaging 6, 7
• Primary pigmented micronodular adrenal dysplasia (PPNAD) typically diagnosed during systematic screening in patients with Carney complex 7
• Bilateral virilizing tumors (extremely rare) present with hyperandrogenism and may co-secrete cortisol 8

Key Diagnostic Algorithm

1. Measure plasma aldosterone and renin activity if hypertension or hypokalemia present; ratio >30 suggests primary aldosteronism 1, 2
2. Perform 1 mg dexamethasone suppression test if Cushing features present; serum cortisol >50 nmol/L (>1.8 μg/dL) indicates autonomous secretion 1, 2
3. Measure plasma ACTH to distinguish ACTH-dependent (elevated) from ACTH-independent (suppressed) causes 2, 5
4. Check 17-hydroxyprogesterone to exclude congenital adrenal hyperplasia 1, 2, 5
5. Obtain adrenal vein sampling in surgical candidates with confirmed primary aldosteronism to distinguish bilateral hyperplasia from unilateral adenoma 1, 4

Common pitfall to avoid: Do not rely on CT imaging characteristics alone to determine lateralization, as this leads to inappropriate surgical management in one-quarter of cases. 4 Adrenal vein sampling should be performed in the majority of patients, even those with masses well visualized on imaging. 1