Can a simple cortisol test be used as the first screening test for suspected Cushing's syndrome, and what are its sensitivity and specificity compared to the 24-hour urine free cortisol (UFC) test, late-night salivary cortisol test, and overnight dexamethasone suppression test?

First-Line Screening Tests for Suspected Cushing's Syndrome

For suspected Cushing's syndrome, a simple cortisol test alone is not recommended as the first screening test; instead, use one of the three recommended tests: 24-hour urinary free cortisol (UFC), overnight 1-mg dexamethasone suppression test (DST), or late-night salivary cortisol (LNSC). 1

Recommended First-Line Screening Tests and Their Performance

Late-Night Salivary Cortisol (LNSC)

• Sensitivity: >90%
• Specificity: 100% 1
• Advantages:
  • Easy to collect
  • Stable at room temperature
  • Particularly useful for longitudinal surveillance of cyclic Cushing's syndrome 2
  • Preferred for patients with renal impairment 1
• Limitations:
  • Should not be performed in patients with disrupted day/night cycles (e.g., shift workers) 2
  • False results may occur due to inadequate sample collection 3

Overnight 1-mg Dexamethasone Suppression Test (DST)

• Cutoff value: <1.8 μg/dL (50 nmol/L) to exclude Cushing's syndrome
• Specificity: 97% at cutoff of 138 nmol/L 1, 4
• Advantages:
  • Strong negative predictive value (a negative result strongly predicts absence of CS) 2
  • Preferred for shift workers and patients with disrupted circadian rhythm 1
• Limitations:
  • False positives may occur with rapid absorption/malabsorption of dexamethasone, CYP3A4 inducers, or increased corticosteroid binding globulin levels 2
  • False negatives may result from inhibition of dexamethasone metabolism by medications 2

24-hour Urinary Free Cortisol (UFC)

• Sensitivity: 97%
• Specificity: 91% (when measured by liquid chromatography-tandem mass spectrometry) 4
• Advantages:
  • Independent of CBG changes
  • Reflects integrated tissue exposure to free cortisol over 24 hours 3
  • Recent research suggests UFC measured by LC-MS/MS may have the best overall diagnostic accuracy 4
• Limitations:
  • Requires accurate 24-hour collection by patient
  • Influenced by BMI, age, urinary volume, and sodium intake
  • Not recommended for patients with renal impairment or significant polyuria 2
  • Random variability can be as high as 50% 2

Test Selection Algorithm

1. For most patients with suspected Cushing's syndrome:

   • Any of the three first-line tests can be used based on availability and patient factors

2. For specific patient populations:

   • Shift workers or disrupted circadian rhythm: Use DST 1
   • Renal impairment: Use LNSC 1
   • Suspected cyclic Cushing's syndrome: Use LNSC 2
   • Adrenal incidentaloma evaluation: Start with DST 1

3. Based on clinical suspicion:

   • Low clinical suspicion: Single screening test may be sufficient
   • Intermediate to high clinical suspicion: Use 2-3 screening tests 1

Important Clinical Considerations

• Morning serum cortisol alone is not recommended as a screening test due to significant overlap between Cushing's syndrome patients and normal subjects 5

• False positive results can occur in pseudo-Cushing's states (psychiatric disorders, alcohol use disorder, polycystic ovary syndrome, and obesity) 2

• Multiple collections are recommended for UFC (at least 2-3) to account for intra-patient variability 2

• Measuring dexamethasone concomitantly with cortisol during DST can reduce the risk for false-positive results 2

• For children and adolescents, growth failure combined with weight gain is a key indicator for testing 1

• The most recent evidence suggests that UFC measured by liquid chromatography-tandem mass spectrometry may achieve the best accuracy in diagnosing Cushing's syndrome among the three first-line tests 4

Common Pitfalls to Avoid

• Relying on a single random cortisol measurement, which has poor diagnostic value
• Failing to account for medications that can interfere with test results
• Not ensuring complete 24-hour urine collection for UFC
• Using inappropriate cutoff values for interpretation
• Not considering pseudo-Cushing's states in the differential diagnosis
• Not repeating abnormal tests to confirm results, especially given the variability in cortisol secretion

Remember that no single test has 100% diagnostic accuracy, and combining tests may be necessary in cases with equivocal results or high clinical suspicion.