What is the next step in the workup for Cushing's syndrome when morning (AM) cortisol is elevated, 24-hour urinary cortisol is elevated, and the dexamethasone suppression test is abnormal?

Next Steps in Workup for Cushing's Syndrome After Positive Initial Tests

When morning cortisol is elevated, 24-hour urinary cortisol is elevated, and dexamethasone suppression test is abnormal, the next step in workup for Cushing's syndrome is to measure plasma ACTH levels to determine if the syndrome is ACTH-dependent or ACTH-independent. 1, 2

Diagnostic Algorithm

• Measure plasma ACTH levels to differentiate between ACTH-dependent and ACTH-independent causes of Cushing's syndrome 1, 3
  • ACTH levels >5 pg/mL indicate ACTH-dependent Cushing's syndrome 1, 2
  • ACTH levels <5 pg/mL suggest ACTH-independent (adrenal) Cushing's syndrome 1, 2

For ACTH-Dependent Cushing's Syndrome (elevated ACTH):

• Perform pituitary MRI to identify potential pituitary adenoma 1, 4
• If pituitary MRI is inconclusive or negative:
  • Perform bilateral inferior petrosal sinus sampling (BIPSS) with CRH stimulation 1, 5
  • A central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after stimulation confirms pituitary source 2
• If BIPSS suggests ectopic source, perform chest and abdominal imaging to locate ectopic ACTH-producing tumor 6, 4

For ACTH-Independent Cushing's Syndrome (suppressed ACTH):

• Perform adrenal CT or MRI to identify adrenal lesion(s) 1, 7
• Unilateral lesions suggest adrenal adenoma or carcinoma 1
• Bilateral lesions may indicate nodular adrenal hyperplasia 1

Important Clinical Considerations

• The combination of elevated morning cortisol, elevated 24-hour urinary cortisol, and failed dexamethasone suppression test already confirms hypercortisolism, making ACTH measurement the critical next step 1, 8
• Normal cortisol suppression on dexamethasone suppression test would be <1.8 μg/dL (50 nmol/L); values above this threshold indicate abnormal feedback inhibition 7, 3
• False positive results in screening tests may occur with:
  • Rapid absorption/malabsorption of dexamethasone 7
  • Concomitant treatment with CYP3A4 inducers (e.g., phenobarbital, carbamazepine) 7
  • Increased corticosteroid binding globulin levels from oral estrogens or pregnancy 7
  • Severe obesity or uncontrolled diabetes 1, 3

Potential Pitfalls

• Cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation 1
• Subclinical Cushing's syndrome (abnormal dexamethasone suppression without overt signs of cortisol excess) may require additional testing and careful clinical correlation 7
• Pseudo-Cushing's states (e.g., depression, alcoholism, obesity) can cause false positive screening results 7, 1
• Measuring dexamethasone levels along with cortisol during testing can improve test interpretability and rule out abnormal dexamethasone metabolism 7, 1

Treatment Implications

• Accurate classification based on ACTH levels is essential for proper treatment planning 1
• For ACTH-dependent Cushing's disease (pituitary source), transsphenoidal surgery is typically the first-line treatment 6
• For ACTH-independent Cushing's syndrome from adrenal adenoma, laparoscopic adrenalectomy is recommended 7, 1
• For adrenocortical carcinoma, open adrenalectomy with possible adjuvant therapy is recommended 1
• For ectopic ACTH syndrome, surgical removal of the ectopic tumor when possible, or medical management if unresectable 1