What is the diagnosis and treatment for a patient with elevated cortisol levels and non-suppressed Adrenocorticotropic Hormone (ACTH) levels?

Diagnosis and Treatment for Elevated Cortisol with Non-Suppressed ACTH

Yes, ACTH is indeed the key diagnostic factor here, as elevated cortisol with non-suppressed ACTH levels indicates ACTH-dependent Cushing syndrome, most commonly caused by a pituitary adenoma (Cushing disease) or ectopic ACTH production.

Diagnostic Approach

• Elevated cortisol with detectable or elevated ACTH levels indicates ACTH-dependent Cushing syndrome, with the most likely sources being pituitary tumors (usually benign) or ectopic tumors in the lung, thyroid, pancreas, or bowel 1
• Normal or elevated ACTH levels rule out primary adrenal causes of hypercortisolism, as adrenal adenomas or carcinomas would suppress ACTH production 1
• A 24-hour urinary free cortisol test should be performed to confirm hypercortisolism 1

Differentiating Between Pituitary and Ectopic Sources

• Perform a CRH stimulation test - a >20% increase in cortisol from baseline suggests pituitary origin 1
• High-dose dexamethasone suppression test may help distinguish between sources - pituitary tumors often show some suppression while ectopic sources typically don't 1
• Pituitary MRI should be performed to identify potential adenomas, though it's important to note that adenomas are detected in only about 63% of cases 1
• If MRI is negative or equivocal, bilateral inferior petrosal sinus sampling (BSIPSS) is the gold standard to confirm a pituitary source 1
  • A central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin and ≥3:1 after stimulation confirms a pituitary source 1

Treatment Approach

For Pituitary (Cushing Disease)

• First-line treatment is transsphenoidal surgical resection of the pituitary adenoma when identified 1
• Postoperative corticosteroid supplementation is required until recovery of the hypothalamus-pituitary-adrenal (HPA) axis 1
• For patients with persistent disease after surgery or those who are not surgical candidates, medical management options include:
  • Ketoconazole (400-1200 mg/day) - most commonly used due to relatively tolerable side effect profile 1
  • Mitotane - alternative adrenostatic agent 1
  • Pasireotide - particularly for patients with visible tumors that are Octreoscan-positive 2
  • Metyrapone - blocks cortisol synthesis 3

For Ectopic ACTH Production

• Surgical removal of the ectopic tumor if possible 1
• If the primary tumor is unresectable, options include:
  • Bilateral laparoscopic adrenalectomy 1
  • Medical management with adrenostatic agents (ketoconazole, mitotane) 1
  • Octreotide for Octreoscan-positive tumors, though it may be less effective for ectopic ACTH control than in other contexts 1

Monitoring and Follow-up

• Monitor for symptoms of hypercortisolism: hypertension, hyperglycemia, hypokalemia, and muscle atrophy 1
• For patients on medical therapy, monitor for hypocortisolism (weakness, fatigue, anorexia, nausea, vomiting, hypotension) 2
• Regular glucose monitoring is essential, especially in the first 2-3 months of treatment 2
• Follow-up imaging and biomarkers should be performed every 3-6 months 1

Common Pitfalls and Caveats

• Suppressed ACTH doesn't always indicate autonomous cortisol secretion - a significant percentage of patients with adrenal incidentalomas may have suppressed ACTH without evidence of autonomous cortisol secretion 4
• Longstanding ACTH stimulation from a pituitary adenoma can induce adrenal hyperplasia that may eventually develop autonomous cortisol production 5
• Cyclic Cushing syndrome is a rare variant with periodic cortisol excess that can be triggered by exogenous glucocorticoids 6
• Patients may rarely have multiple sources of hormone excess, such as concurrent ACTH-producing and aldosterone-producing tumors 7