What are the initial tests for diagnosing Cushing's syndrome?

Initial Tests for Diagnosing Cushing's Syndrome

The recommended initial screening tests for diagnosing Cushing's syndrome include late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), and overnight dexamethasone suppression test (DST), with at least 2-3 of these tests recommended based on clinical suspicion.

First-Line Screening Tests

Late-Night Salivary Cortisol (LNSC)

• LNSC is highly sensitive (95%) and specific (100%) for diagnosing Cushing's syndrome 1
• At least 2-3 samples should be collected on consecutive days to account for variability 1, 2
• LNSC is a simple, non-invasive test that measures free cortisol and reflects the loss of circadian rhythm 2
• Multiple LNSC collections may be easier for patient compliance compared to 24-hour urine collection 3

24-Hour Urinary Free Cortisol (UFC)

• UFC measures overall cortisol production with high sensitivity (89%) and specificity (100%) 1, 4
• At least 2-3 samples should be collected to account for variability 1, 5
• UFC may be less sensitive in mild cases of Cushing's syndrome, with some patients showing normal or only mildly elevated levels 5, 4
• UFC is particularly useful when combined with other screening tests, as the combination of elevated UFC and/or elevated LNSC has been shown to identify 100% of patients with Cushing's syndrome 2

Overnight Dexamethasone Suppression Test (DST)

• DST measures the inability to suppress cortisol with dexamethasone 1
• A serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after 1 mg dexamethasone at midnight indicates a normal response 1
• DST has a sensitivity of 95% but lower specificity (80%) compared to other tests 6
• DST may be less useful in women taking estrogen-containing oral contraceptives 3
• Measuring dexamethasone levels along with cortisol improves test interpretability 3, 7

Diagnostic Algorithm

Step 1: Initial Screening Based on Clinical Suspicion

• For high clinical suspicion: Perform multiple tests (LNSC, UFC, DST) 1, 3
• For low clinical suspicion: Start with LNSC as the simplest screening test 1
• In children and adolescents, consider screening only if weight gain is inexplicable and combined with either decreased height standard deviation score or height velocity 3

Step 2: Interpretation of Results

• If any test is abnormal, repeat 1-2 screening tests to confirm 3
• If all tests are normal, Cushing's syndrome is unlikely 3
• If results are equivocal, consider periodic re-evaluation or specialized testing (Dex-CRH, midnight serum cortisol) 3

Step 3: Determining Etiology (After Confirming Hypercortisolism)

• Measure plasma ACTH levels to differentiate ACTH-dependent from ACTH-independent causes 1, 6
• Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L) suggests ACTH-dependent Cushing's syndrome 1, 7
• Low/undetectable ACTH indicates ACTH-independent Cushing's syndrome 7

Special Considerations

Potential False Positives

• Rule out exogenous glucocorticoid use before biochemical testing 1, 6
• Pseudo-Cushing's states can cause false-positive results, including 1, 7:
  • Severe obesity
  • Uncontrolled diabetes
  • Depression
  • Alcoholism

Challenging Cases

• Multiple samples (urine/saliva) may be needed to diagnose mild Cushing's syndrome 5
• Neither a normal UFC nor a normal LNSC excludes mild Cushing's syndrome 5, 8
• Consider cyclic Cushing's syndrome in cases with inconsistent results 3, 7
• In patients with repeatedly equivocal results, reevaluate after several months or consider CRH stimulation test following low-dose dexamethasone suppression 9

Conclusion

For diagnosing Cushing's syndrome, a comprehensive approach using multiple screening tests is recommended, with LNSC, UFC, and DST being the first-line options. At least 2-3 tests should be performed, especially in cases with high clinical suspicion. After confirming hypercortisolism, ACTH measurement is essential to determine the etiology and guide further diagnostic workup.