What is the next step in managing a patient with elevated morning (AM) cortisol and high 24-hour urinary cortisol?

Next Steps for a Patient with Elevated AM Cortisol and High 24-Hour Urinary Cortisol

The next step for a patient with elevated morning cortisol and high 24-hour urinary cortisol should be to perform additional confirmatory tests to establish a diagnosis of Cushing's syndrome, followed by determining the source of hypercortisolism through ACTH level measurement. 1, 2

Diagnostic Confirmation of Cushing's Syndrome

• Perform late-night salivary cortisol test as an additional screening test to confirm the diagnosis, as the combination of elevated 24-hour urinary free cortisol and abnormal diurnal cortisol rhythm strongly suggests Cushing's syndrome 1
• Conduct a low-dose dexamethasone suppression test (1 mg overnight) to further confirm hypercortisolism before proceeding with source identification 1, 3
• Ensure multiple tests are performed, as relying on a single cortisol measurement is insufficient for diagnosis of Cushing's syndrome 2, 4

Determining the Source of Hypercortisolism

• Measure plasma ACTH levels to differentiate between ACTH-dependent and ACTH-independent causes of Cushing's syndrome 1, 3
  • ACTH >5 ng/L suggests ACTH-dependent Cushing's syndrome (pituitary or ectopic source)
  • ACTH ≤5 ng/L suggests ACTH-independent Cushing's syndrome (adrenal source)

Further Localization Based on ACTH Status

For ACTH-Dependent Cushing's Syndrome:

• Perform pituitary MRI to identify potential pituitary adenoma 1, 5
• Consider bilateral inferior petrosal sinus sampling (BIPSS) to confirm pituitary source, especially if MRI is negative or inconclusive 1, 6
• Perform CRH stimulation test to help differentiate between pituitary and ectopic sources of ACTH 1, 7
• Conduct chest and abdominal CT scans to look for potential ectopic ACTH-secreting tumors 1, 6

For ACTH-Independent Cushing's Syndrome:

• Perform adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral adrenal hyperplasia 1, 4

Important Clinical Considerations

• Be aware of potential false positives in cortisol testing that can occur with severe obesity, alcoholism, depression, and disrupted sleep-wake cycles 1, 2
• Monitor for clinical features suggestive of Cushing's syndrome, including central obesity, facial plethora, proximal muscle weakness, easy bruising, and wide purple striae 1, 4
• Recognize that untreated Cushing's syndrome leads to significant morbidity and mortality, with complications including cardiovascular disease, diabetes, osteoporosis, and immunologic disorders 1

Treatment Planning

• Treatment will depend on the identified cause:
  • For Cushing's disease (pituitary source): transsphenoidal surgery is first-line treatment 1, 5
  • For adrenal adenoma: laparoscopic adrenalectomy 1
  • For adrenal carcinoma: open adrenalectomy with possible adjuvant therapy 1
  • For ectopic ACTH syndrome: surgical removal of the source tumor 4
• Medical therapy with steroidogenesis inhibitors like metyrapone may be considered when surgery is contraindicated or unsuccessful 1, 8

Pitfalls to Avoid

• Relying solely on a single cortisol measurement for diagnosis 2
• Failing to consider the time of day when interpreting cortisol levels 2
• Overlooking the need for multidisciplinary review when evaluating potential adrenal disorders 2
• Starting other hormone replacements before addressing cortisol excess, as other hormones can accelerate cortisol clearance 9