What is the first non-invasive test to screen for suspected Cushing's syndrome?

First-Line Non-Invasive Screening Test for Suspected Cushing's Syndrome

For suspected Cushing's syndrome, any of the following three tests can be used as first-line non-invasive screening: 24-hour urinary free cortisol (UFC), overnight 1-mg dexamethasone suppression test (DST), or late-night salivary cortisol (LNSC), with the choice depending on specific patient factors and local availability. 1, 2

Recommended Screening Tests

1. 24-Hour Urinary Free Cortisol (UFC)

• Measures overall cortisol production
• Independent of CBG changes
• Collect 2-3 specimens to account for intra-patient variability (up to 50%)
• Sensitivity: 97%, Specificity: 91% when measured by liquid chromatography-tandem mass spectrometry 3
• Limitations:
  • Requires accurate 24-hour collection by patient
  • Influenced by body mass index, age, urinary volume, and sodium intake
  • Not preferred for patients with renal impairment (CrCl <60mL/min) or significant polyuria (>5 L/24h) 1

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

• Serum cortisol cutoff <50 nmol/L to exclude Cushing's syndrome
• High specificity (97%) at cutoff of 138 nmol/L 2
• Preferred for shift workers and patients with disrupted circadian rhythm
• Limitations:
  • May not be reliable in women taking oral estrogen
  • False positives from medications that inhibit dexamethasone metabolism (fluoxetine, cimetidine, diltiazem)
  • Requires patient compliance with dexamethasone administration 1

3. Late-Night Salivary Cortisol (LNSC)

• Measures cortisol at expected nadir (typically collected at 11 PM)
• Sensitivity: >90%, Specificity: 100% 2
• Easy collection method for patients
• Particularly useful for longitudinal surveillance of cyclic Cushing's syndrome
• Limitations:
  • May be affected by oral/gingival conditions
  • Not recommended if cortisone levels cannot be reported when adrenal tumor is suspected 1

Patient-Specific Considerations for Test Selection

1. For patients with suspected adrenal tumor: Start with DST; use LNSC only if cortisone levels can also be reported 1

2. For shift workers or patients with disrupted circadian rhythm: DST is preferred 1

3. For patients with renal impairment: LNSC is preferred over UFC 1

4. For monitoring cyclic Cushing's syndrome: LNSC is particularly useful 2

5. For children and adolescents: Consider growth failure combined with weight gain as key indicators for testing 1, 2

Diagnostic Approach

• For low clinical suspicion: A single screening test may be sufficient
• For intermediate to high clinical suspicion: Perform 2-3 screening tests 2
• Abnormal results should be repeated to confirm diagnosis
• Consider cyclic Cushing's syndrome if initial tests are normal but clinical suspicion remains high 2

Common Pitfalls and Caveats

• False positives can occur in pseudo-Cushing's states (psychiatric disorders, alcohol use disorder, polycystic ovary syndrome, obesity)
• Abnormal results in pseudo-Cushing's tend to be mildly elevated (UFC usually within 3-fold of normal) 1
• Exogenous glucocorticoid use must be ruled out before testing 2
• Random variability in UFC can be as high as 50%, necessitating multiple collections 1
• Medications can interfere with test results (oral estrogens, anticonvulsants) 2

Remember that no single test has 100% diagnostic accuracy. The combination of an elevated late-night salivary cortisol and/or an elevated UFC can identify most patients with Cushing's syndrome 2, 3. When multiple tests are performed, they should be interpreted in the context of the clinical presentation.