What are the recommended tests for diagnosing Cushing's (Cushing's) syndrome?

Recommended Tests for Diagnosing Cushing's Syndrome

The recommended first-line screening tests for Cushing's syndrome include the overnight 1-mg dexamethasone suppression test (DST), late-night salivary cortisol (LNSC), and 24-hour urinary free cortisol (UFC) measurements, with multiple tests often needed for accurate diagnosis in mild cases. 1

First-Line Screening Tests

The Endocrine Society recommends using one of these three tests with high diagnostic accuracy for initial screening:

1. Overnight 1-mg Dexamethasone Suppression Test (DST)

   • Procedure: 1 mg dexamethasone administered at 11 PM, cortisol measured at 8 AM next day
   • Interpretation: Failure to suppress morning cortisol suggests Cushing's syndrome
   • Cutoff values:
     • <50 nmol/L generally excludes Cushing's syndrome 2
     • 138 nmol/L cutoff offers best specificity (97%) 3
   • Pitfalls: Can be affected by medications, stress, and sleep disturbances 1

2. Late-Night Salivary Cortisol (LNSC)

   • Rationale: Normal circadian rhythm is disrupted in Cushing's syndrome
   • Advantages: High sensitivity (>90%), excellent specificity (100%), easy collection 1
   • Particularly useful for: Initial screening and longitudinal surveillance of cyclic Cushing's syndrome 1
   • Pitfalls: False results possible with inadequate sample collection 2

3. 24-hour Urinary Free Cortisol (UFC)

   • Reflects integrated tissue exposure to free cortisol over 24 hours 2
   • When measured by liquid chromatography tandem-mass spectrometry (LC-MS/MS), shows excellent sensitivity (97%) and specificity (91%) 3
   • Particularly useful for: Supporting diagnosis and reflecting overall cortisol production 1
   • Pitfalls: Requires complete 24-hour collection; may be normal in mild cases 4

Additional Diagnostic Tests

• Plasma ACTH Levels

  • Used to determine ACTH status and differentiate between ACTH-dependent and independent cortisol excess 1
  • Helps distinguish pituitary from ectopic or adrenal causes

• Imaging Studies (after biochemical confirmation)

  • MRI of pituitary for suspected Cushing's disease
  • CT scan of abdomen for suspected adrenal causes
  • Additional imaging based on suspected ectopic sources

Diagnostic Algorithm

1. Initial Screening: Perform at least one of the three first-line tests (DST, LNSC, or UFC)
2. Confirmatory Testing: If first test is positive, perform a second different test
3. Multiple Sampling: For suspected mild or cyclic Cushing's syndrome, collect multiple samples over time
4. ACTH Assessment: Once hypercortisolism is confirmed, measure ACTH to determine the source
5. Localization: Perform appropriate imaging based on biochemical profile

Important Considerations

• No single test is perfect: In mild Cushing's syndrome, UFC may be normal or only mildly elevated 4
• Multiple samples are crucial: Research shows that neither normal UFC nor normal NSC alone can exclude mild Cushing's syndrome 4
• Test combinations improve accuracy: Using both DST and UFC together can increase diagnostic certainty 3
• Laboratory methods matter: LC-MS/MS measurement of UFC achieves better accuracy than immunoassays 3

Common Pitfalls to Avoid

• Relying on a single negative test: Especially in mild or cyclic cases, multiple tests over time are necessary 4
• Ignoring medication effects: Estrogen-containing oral contraceptives can cause false positive DST results 1
• Incomplete urine collections: Ensure proper 24-hour collection with appropriate total volumes 2
• Overlooking cyclic Cushing's: Consider repeated testing when clinical suspicion remains high despite normal results 1

By following this systematic approach with multiple testing modalities, the diagnosis of Cushing's syndrome can be established accurately, even in mild or atypical presentations.