What are the next steps for a patient with elevated cortisol and ACTH levels?

Management of Elevated Cortisol (33) with ACTH of 15

For a patient with elevated cortisol of 33 and ACTH of 15, a 24-hour urinary free cortisol test should be performed to confirm Cushing syndrome, followed by imaging studies to identify the likely adrenal source of cortisol excess. 1

Diagnostic Interpretation

• The combination of elevated cortisol with a normal/non-elevated ACTH level (15) suggests ACTH-independent Cushing syndrome, most likely caused by an adrenal source 1
• This pattern indicates that excessive cortisol secretion is coming from the adrenal gland itself rather than being driven by excessive ACTH from the pituitary or an ectopic source 1
• When ACTH is not elevated in the presence of hypercortisolism, the most common causes are adrenal adenoma, adrenal carcinoma, or bilateral adrenal hyperplasia 1

Recommended Diagnostic Algorithm

1. Confirm hypercortisolism: Perform a 24-hour urinary free cortisol test to confirm the diagnosis of Cushing syndrome 1
2. Adrenal imaging: Obtain CT scan or MRI of the adrenal glands with adrenal protocol to determine:
   • Size of adrenal mass(es)
   • Presence of unilateral vs. bilateral abnormalities
   • Features suggesting malignancy (size >4-5 cm, irregular margins, heterogeneity) 1
3. Assess for malignancy: If tumor is >5 cm, has irregular margins, or shows heterogeneous appearance, consider adrenal carcinoma and obtain chest/abdomen/pelvis imaging to evaluate for metastases 1

Treatment Approach Based on Findings

For Adrenal Adenoma (Most Likely)

• Laparoscopic adrenalectomy is the treatment of choice for benign adrenal tumors 1
• Postoperative corticosteroid supplementation will be required until recovery of the hypothalamus-pituitary-adrenal (HPA) axis 1

For Bilateral Adrenal Hyperplasia

• If imaging shows bilateral abnormalities, adrenal vein sampling of cortisol production should be performed to determine treatment 1
• If cortisol production is asymmetric, laparoscopic unilateral adrenalectomy of the most active side is recommended 1
• If cortisol production is symmetric, medical management is indicated 1

For Adrenal Carcinoma (If Suspected)

• Open adrenalectomy with removal of adjacent lymph nodes is recommended 1
• May require removal of adjacent structures for complete resection 1
• Consider adjuvant radiation therapy if there is concern about tumor spillage or close margins 1

Medical Management (When Surgery Not Possible)

• Adrenostatic agents can be used for medical management of hypercortisolism 1:
  • Ketoconazole (400-1200 mg/day) is most commonly used due to availability and relatively tolerable toxicity profile 1
  • Mitotane is another option 1
  • Metyrapone can be used for diagnostic testing and management 2

Follow-up and Monitoring

• Monitor for symptoms of adrenal insufficiency post-surgery 1
• For patients with adrenal carcinoma, follow-up imaging and biomarkers should be performed every 3-6 months 1
• Patients should be monitored for improvement of Cushing syndrome manifestations including hypertension, hyperglycemia, hypokalemia, and muscle atrophy 1

Common Pitfalls to Avoid

• Don't delay treatment if adrenal insufficiency is suspected during workup 1
• Don't miss bilateral disease: Even when imaging shows only one affected gland, bilateral disease may be present, especially in older patients 1
• Don't forget post-surgical corticosteroid supplementation: This is essential after adrenalectomy until HPA axis recovery 1
• Don't overlook malignancy: Adrenal carcinoma should be suspected in tumors >4-5 cm with irregular margins or heterogeneous appearance 1