What is the next step in evaluating a patient with elevated morning cortisol and high 24-hour urinary cortisol, suggestive of hypercortisolism?

Next Steps in Evaluation of Suspected Cushing's Syndrome

The next step in evaluation of a 24-year-old woman with elevated AM cortisol of 28.48 and high 24-hour urinary cortisol of 48 should be a low-dose dexamethasone suppression test (LDDST) to confirm the diagnosis of Cushing's syndrome, followed by measurement of plasma ACTH levels to determine if the condition is ACTH-dependent or ACTH-independent. 1, 2

Confirming the Diagnosis

• Initial screening tests showing elevated morning cortisol and high 24-hour urinary cortisol are suggestive of hypercortisolism, but confirmation requires additional testing 1, 2
• The Endocrine Society recommends using multiple tests to confirm Cushing's syndrome, as no single test is perfect 1
• Low-dose dexamethasone suppression test (1 mg overnight or 2 mg/day for 2 days) is recommended as the next step to confirm the diagnosis 1
• Multiple late-night salivary cortisol measurements can also be used as an alternative or additional confirmatory test 1
• It's important to exclude iatrogenic Cushing's syndrome (from exogenous glucocorticoid use) before proceeding with biochemical testing 1

Determining the Etiology

After confirming the diagnosis, the next step is to determine the cause:

• Measure plasma ACTH levels to differentiate between ACTH-dependent and ACTH-independent Cushing's syndrome 2, 3
• ACTH levels >5 ng/L suggest ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 3
• Low or undetectable ACTH levels suggest ACTH-independent Cushing's syndrome (adrenal source) 3
• For ACTH-dependent disease, pituitary MRI is recommended to look for adenoma 1, 3
• For ACTH-independent disease, adrenal CT or MRI is indicated to identify adrenal lesion(s) 1, 3

Additional Testing Based on ACTH Results

If ACTH-Dependent:

• Pituitary MRI with contrast to look for adenoma 1
• CRH stimulation test may help differentiate pituitary from ectopic sources 1, 3
• Bilateral inferior petrosal sinus sampling (BIPSS) if MRI is negative or inconclusive 1

If ACTH-Independent:

• Adrenal CT or MRI to identify adrenal adenoma, carcinoma, or hyperplasia 2, 3

Special Considerations

• False positive results can occur with severe obesity, alcoholism, depression, and disrupted sleep-wake cycles 2, 3
• Measuring dexamethasone levels during the suppression test can improve interpretation and rule out abnormal dexamethasone metabolism 1, 3
• Cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation 2, 3
• In a young female patient, the most common cause would be Cushing's disease (pituitary adenoma), but all possibilities must be systematically evaluated 4, 5

Pitfalls to Avoid

• Relying on a single test for diagnosis can lead to false positives or negatives 1
• Failing to exclude exogenous glucocorticoid use before testing 1
• Not considering pseudo-Cushing's states (depression, alcoholism, obesity) that can cause mild hypercortisolism 2, 3
• Proceeding directly to imaging without biochemical confirmation and ACTH determination can lead to incidental findings and misdiagnosis 1
• Not considering cyclic Cushing's syndrome when test results are inconsistent 2, 3

Following this systematic approach will help determine the cause of hypercortisolism and guide appropriate treatment decisions to reduce morbidity and mortality associated with Cushing's syndrome 4, 6.