Primary Bilateral Macronodular Adrenal Hyperplasia

Primary bilateral macronodular adrenal hyperplasia is a cause of ACTH-independent hypercortisolism, with bilateral adrenal nodules over 10 mm. Cortisol excess is usually mild or subclinical and develops over many years.

It is rare, accounts for under 2% of Cushing syndrome, and presents at 50 to 60 years. It is increasingly found as bilateral incidentalomas.

Germline ARMC5 variants (autosomal dominant, about 25% of cases) are the commonest cause, and meningioma is associated. KDM1A variants cause food dependent disease. Other links are MEN1, APC (familial adenomatous polyposis) and fumarate hydratase variants.

Pathophysiology.

Adrenal cells express aberrant receptors (for gastric inhibitory polypeptide, vasopressin, beta adrenergic agonists, luteinising hormone, serotonin) that drive cortisol secretion in response to meals, posture or hormones. Raised cortisol suppresses ACTH.

Cortisol production for each cell is low, so large adrenal mass is needed for clinical disease.

• Weight gain, hypertension, glucose intolerance, osteoporosis, fatigue, bruising and mood change. Overt Cushing syndrome develops late.
• Symptoms may fluctuate with meals (food dependent disease).
• Bilateral abdominal masses on imaging, often incidentally.

Red flags.

• Overt Cushing features with hypokalaemia, infection or thromboembolism.
• Suspicion of phaeochromocytoma or malignancy in a large nodule.

• Confirm hypercortisolism: 1 mg overnight dexamethasone suppression (cortisol over 50 nmol/L, 1.8 micrograms/dL), late night salivary cortisol and urinary free cortisol. ACTH low (under 10 ng/L, 2 pmol/L) and low dehydroepiandrosterone sulphate.
• CT: bilateral enlarged glands with multiple nodules over 10 mm. Metanephrines to exclude phaeochromocytoma, and aldosterone to renin ratio.
• ARMC5 sequencing and family screening of first degree relatives with dexamethasone testing and imaging. Consider meningioma imaging in ARMC5 carriers.
• Test for aberrant receptors: cortisol response to posture, a mixed meal (gastric inhibitory polypeptide), vasopressin, metoclopramide and gonadotrophin releasing hormone.

Differential diagnosis.

• ACTH-dependent Cushing syndrome (Cushing disease, ectopic ACTH) with adrenal hyperplasia.
• Primary pigmented nodular adrenocortical disease and McCune-Albright syndrome.
• Bilateral adenomas, adrenal metastasis, lymphoma and congenital adrenal hyperplasia.

• Overt Cushing syndrome: bilateral adrenalectomy with lifelong hydrocortisone 15 to 25 mg daily in two or three divided doses and fludrocortisone 0.05 to 0.2 mg daily. Unilateral adrenalectomy of the larger gland is an option for mild disease, accepting relapse.
• Medical treatment: ketoconazole 200 mg twice daily up to 1200 mg daily, or metyrapone 250 mg three times daily up to 6 g daily, or osilodrostat 2 mg twice daily up to 30 mg twice daily.
• Aberrant receptor targeted treatment: propranolol for beta adrenergic response, and long acting somatostatin analogues for gastric inhibitory polypeptide dependent disease, with limited and inconsistent benefit.
• Treat hypertension, diabetes and osteoporosis.
• After adrenalectomy give sick day rules: double the dose in illness and give 100 mg intramuscularly or intravenously for vomiting or collapse.

Special groups. Family members: test first degree relatives of ARMC5 carriers regularly from adulthood.

Monitoring. Cortisol tests every 6 to 12 months, imaging yearly while nodules grow, and comorbidity review.

Referral and escalation. Endocrinology with adrenal surgery; clinical genetics for family screening.