What is the next step in management for a patient with elevated late night salivary cortisol (cortisol) levels suggestive of Cushing's syndrome?

Management of Elevated Late Night Salivary Cortisol Suggestive of Cushing's Syndrome

For a patient with elevated late night salivary cortisol (LNSC) levels suggestive of Cushing's syndrome, the next step in management is to confirm the diagnosis with additional testing, including a 24-hour urinary free cortisol (UFC) test and an overnight 1-mg dexamethasone suppression test (DST), before proceeding to determine the cause of Cushing's syndrome. 1, 2

Confirming the Diagnosis of Cushing's Syndrome

• Perform at least one additional test to confirm hypercortisolism, as no single test has 100% diagnostic accuracy 1
• Collect 24-hour urinary free cortisol (UFC) for at least two measurements, which has >90% sensitivity but somewhat lower specificity than LNSC 1, 2
• Perform overnight 1-mg dexamethasone suppression test (DST), with cortisol <1.8 μg/dL (50 nmol/L) considered normal response 1
• Consider measuring dexamethasone levels concomitantly with cortisol during DST to reduce risk of false-positive results 1
• For patients with suspected cyclic Cushing's syndrome, periodic repeated testing may be necessary as cortisol levels can fluctuate 1, 3

Determining the Cause of Cushing's Syndrome

Once Cushing's syndrome is confirmed, determine whether it is ACTH-dependent or ACTH-independent:

• Measure morning plasma ACTH levels 1, 2
  • ACTH-dependent (normal or elevated ACTH): Suggests pituitary adenoma (Cushing's disease) or ectopic ACTH source
  • ACTH-independent (low or undetectable ACTH): Suggests adrenal source

For ACTH-Dependent Cushing's Syndrome:

• Perform pituitary MRI 1, 2
• If MRI is negative or inconclusive, consider:
  • CRH stimulation test 2, 4
  • Bilateral inferior petrosal sinus sampling (BIPSS) - gold standard for differentiating between pituitary and ectopic sources 1, 4

For ACTH-Independent Cushing's Syndrome:

• Perform adrenal CT or MRI to identify adrenal lesion(s) 1, 2

Treatment Options Based on Etiology

For Cushing's Disease (Pituitary Source):

• First-line: Transsphenoidal surgery to remove the ACTH-secreting tumor 1, 5
• For patients who are not surgical candidates or with persistent disease after surgery:
  • Medical therapy with pasireotide LAR (starting dose 10 mg every 28 days, can be increased to maximum 40 mg) 6
  • Other medical options include adrenal steroidogenesis inhibitors (ketoconazole, metyrapone) 1, 2
  • Radiation therapy for cases refractory to surgery and medical therapy 1

For Adrenal Causes:

• Adrenal adenoma: Laparoscopic adrenalectomy 2, 5
• Adrenal carcinoma: Open adrenalectomy with possible adjuvant therapy 2
• Bilateral adrenal hyperplasia: Medical management or unilateral adrenalectomy 2

For Ectopic ACTH Syndrome:

• Surgical removal of the ectopic tumor when possible 4
• If unresectable: Medical therapy or bilateral adrenalectomy 4

Important Considerations and Pitfalls

• False positive LNSC results can occur with severe obesity, alcoholism, depression, and disrupted sleep-wake cycles 2, 7
• LNSC should not be performed in patients with disruption of normal day/night cycle, such as night-shift workers 1
• In children and adolescents, Cushing's syndrome typically presents with weight gain combined with growth failure, which distinguishes it from simple obesity 1, 2
• Untreated Cushing's syndrome leads to significant morbidity and mortality, including cardiovascular disease, diabetes, osteoporosis, and immunologic disorders 2, 5
• For patients with suspected cyclic Cushing's syndrome, multiple, periodic, sequential LNSC measurements are particularly useful 1, 3
• Mass spectrometry for LNSC has better sensitivity but reduced specificity compared to immunoassay 1, 7