What is the diagnostic test to confirm Cushing's disease (Hyperadrenocorticism)?

Diagnostic Tests to Confirm Cushing's Disease

Bilateral inferior petrosal sinus sampling (IPSS) is the gold standard diagnostic test to confirm Cushing's disease when MRI findings are negative or equivocal. 1

Initial Screening and Confirmation of Cushing's Syndrome

Before confirming the specific etiology (Cushing's disease), first establish the presence of hypercortisolism:

• Use one or more of these first-line tests to confirm hypercortisolism 2, 3:

  • Overnight 1mg dexamethasone suppression test (DST) - serum cortisol >1.8 μg/dL suggests Cushing's syndrome
  • Late-night salivary cortisol (LNSC) - collect at least 2-3 samples
  • 24-hour urinary free cortisol (UFC) - collect 2-3 samples to evaluate variability

• For patients with mild or fluctuating hypercortisolism, additional testing may be needed 1:

  • Dexamethasone-CRH test
  • Desmopressin test (less complex and expensive than Dex-CRH)

Determining ACTH Dependency

Once Cushing's syndrome is confirmed, determine if it's ACTH-dependent:

• Measure plasma ACTH levels 2, 3:
  • ACTH levels >5 ng/L suggest ACTH-dependent Cushing's syndrome (pituitary or ectopic)
  • Low or undetectable ACTH suggests ACTH-independent Cushing's syndrome (adrenal source)

Confirming Cushing's Disease (Pituitary Source)

For ACTH-dependent Cushing's syndrome, follow this algorithm:

1. Pituitary MRI with contrast 1, 2:

   • If tumor ≥10 mm is detected and dynamic testing is consistent with Cushing's disease, IPSS is not necessary
   • For lesions <6 mm, IPSS is recommended
   • For lesions 6-9 mm, expert opinions differ, but majority recommend IPSS

2. Dynamic hormone testing 1:

   • CRH stimulation test - increased ACTH and cortisol response suggests pituitary source
   • Desmopressin stimulation test - positive response suggests pituitary source
   • Using both tests may improve diagnostic accuracy

3. Bilateral inferior petrosal sinus sampling (IPSS) 1:

   • Gold standard for differentiating pituitary from ectopic ACTH source
   • Central-to-peripheral ACTH gradient ≥2 before or ≥3 after CRH stimulation confirms pituitary source
   • Measuring prolactin can improve diagnostic accuracy
   • Should be performed when patient is hypercortisolemic
   • Not reliable for tumor lateralization within the pituitary gland

Alternative Non-invasive Approach

In specialized centers, a non-invasive approach may be used 1:

• Combination of CRH and desmopressin stimulation tests
• Pituitary MRI
• Followed by whole-body CT if diagnosis is equivocal
• This approach correctly diagnosed CD in approximately half of patients in one series

Important Pitfalls to Avoid

• Relying on a single test for diagnosis can lead to false results 2
• IPSS should not be used to diagnose hypercortisolism itself, only to determine the source 1
• Ensure the patient is hypercortisolemic at the time of IPSS to avoid false negatives 1
• Consider that a pituitary lesion seen on MRI could be an incidental non-functioning adenoma 1
• For patients with cyclic Cushing's disease, confirm active hypercortisolism before performing dynamic tests 1

Special Considerations

• No single laboratory test or combination of tests can absolutely differentiate between pituitary and ectopic ACTH-secreting tumors with 100% accuracy 1
• Clinical context and test results should be used together to guide management 1
• IPSS should preferably be performed in specialized centers due to potential patient risks 1