Can Cushing's disease cause adrenal hyperplasia if left untreated?

Cushing's Disease Can Lead to Adrenal Hyperplasia if Left Untreated

Yes, untreated Cushing's disease can cause adrenal hyperplasia due to chronic ACTH hypersecretion from the pituitary adenoma, leading to bilateral adrenal enlargement over time. 1

Pathophysiology of Adrenal Changes in Cushing's Disease

• Cushing's disease is characterized by a pituitary adenoma (usually benign) that secretes excessive ACTH, which stimulates the adrenal glands to produce cortisol 2
• Chronic ACTH hypersecretion from the pituitary leads to diffuse adrenal hyperplasia in approximately 57% of patients with ACTH-dependent Cushing's syndrome 1
• The width of adrenal glands measured on CT correlates positively with circulating plasma ACTH levels, cortisol levels, and urinary free cortisol (UFC) levels 1
• Duration of disease also correlates positively with adrenal size - the longer Cushing's disease remains untreated, the more pronounced the adrenal hyperplasia becomes 1

Types of Adrenal Hyperplasia in Cushing's Disease

• Diffuse bilateral adrenal hyperplasia is the most common adrenal finding in untreated Cushing's disease 2, 1
• Nodular hyperplasia can also develop in some cases, with both micronodular and macronodular patterns possible 3, 4
• In rare cases, focal adrenal nodules may develop within the hypertrophied adrenal glands 1

Diagnostic Considerations

• Elevated ACTH levels indicate that excessive cortisol secretion is not coming from the adrenal gland itself but from pituitary or ectopic sources 2
• Adrenal imaging (CT or MRI) can demonstrate the presence of adrenal hyperplasia in patients with untreated Cushing's disease 1
• Bilateral adrenal vein sampling may be needed in cases where imaging is inconclusive or to differentiate between various causes of adrenal hyperplasia 2
• Petrosal sinus sampling helps distinguish between pituitary and ectopic sources of ACTH when the diagnosis is unclear 5

Clinical Implications of Adrenal Hyperplasia

• Adrenal hyperplasia in Cushing's disease contributes to the clinical manifestations of hypercortisolism, including hypertension, hyperglycemia, hypokalemia, and muscle atrophy 2
• If Cushing's disease remains untreated, progressive adrenal hyperplasia can lead to worsening of clinical symptoms and increased morbidity 4
• After successful treatment of the pituitary source of ACTH (through surgery or radiation), the hyperplastic adrenal glands typically regress in size over time 6

Treatment Considerations

• The primary treatment for Cushing's disease is removal of the pituitary adenoma, which addresses the root cause of the adrenal hyperplasia 2
• If the pituitary tumor is unresectable, medical management with adrenostatic agents (ketoconazole, mitotane) or bilateral adrenalectomy may be necessary 2
• In cases of severe, refractory Cushing's disease, bilateral adrenalectomy may be required to control hypercortisolism, despite the presence of adrenal hyperplasia rather than primary adrenal disease 2
• Following successful treatment of Cushing's disease, patients should be monitored for recovery of the hypothalamic-pituitary-adrenal axis, as temporary corticosteroid supplementation is typically required 2

Potential Complications

• Untreated adrenal hyperplasia due to Cushing's disease can lead to progressive metabolic complications, cardiovascular disease, and decreased quality of life 4
• Bilateral adrenalectomy for persistent Cushing's disease carries a risk of Nelson's syndrome (continued growth of the pituitary tumor after adrenal removal) 6
• Long-term follow-up is essential for patients with Cushing's disease, even after successful treatment, to monitor for recurrence and manage any residual adrenal dysfunction 6