What are the recommended initial laboratory tests for Cushing's syndrome?

Initial Laboratory Tests for Cushing's Syndrome

The recommended initial screening tests for Cushing's syndrome are late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), and/or the overnight 1-mg dexamethasone suppression test (DST). 1, 2

First-Line Screening Tests

Late-Night Salivary Cortisol (LNSC)

• High sensitivity (>90%) and specificity (89-100%) 3, 4
• Advantages:
  • Non-invasive collection at home
  • Reflects free (active) cortisol
  • Multiple samples can be easily collected
  • Particularly useful for detecting mild or cyclic Cushing's syndrome
  • Measurement of both LNSC and late-night salivary cortisone can improve diagnostic accuracy 4

24-Hour Urinary Free Cortisol (UFC)

• High sensitivity (97%) and specificity (91%) when measured by liquid chromatography-tandem mass spectrometry 3
• Reflects overall cortisol production
• Collect 2-3 specimens for optimal accuracy 1

Overnight 1-mg Dexamethasone Suppression Test (DST)

• Useful initial test, especially when LNSC is not feasible 1
• At cutoff of 138 nmol/L: high specificity (97%)
• At cutoff of 50 nmol/L: high sensitivity (100%) 3
• Measuring dexamethasone levels along with cortisol improves test interpretability 1

Test Selection Based on Clinical Scenario

For General Screening:

• Start with either UFC and/or LNSC; DST is an alternative if LNSC not feasible 1
• Multiple LNSC collections may be easier for patient compliance 1

For Suspected Adrenal Tumor:

• Start with DST 1
• Note that LNSC has lower specificity in these patients 1

For Patients with High Clinical Suspicion:

• Use 2-3 screening tests for optimal diagnostic accuracy 2
• An elevated 2300-h salivary cortisol and/or an elevated UFC identified 100% of patients with Cushing's syndrome in one study 5

Important Considerations and Potential Pitfalls

False Positives

Be aware of conditions that can cause false positive results:

• Severe obesity
• Pregnancy
• Polycystic ovary syndrome (PCOS)
• Uncontrolled diabetes mellitus
• Anorexia/malnutrition
• Acute illness/surgery
• Excessive exercise
• Depression
• Alcoholism 2

Medication Interference

Certain medications can alter cortisol metabolism or interfere with measurements:

• Oral estrogens (affects DST)
• Anticonvulsants
• Antitubercular drugs
• CYP3A4 inducers/inhibitors 2

Pseudo-Cushing's States

Conditions like depression, alcoholism, and poorly controlled diabetes can cause hypercortisolism that resolves when the underlying condition is treated 2

After Initial Screening

If screening tests suggest Cushing's syndrome:

1. Determine if ACTH-dependent or independent
   • Measure plasma ACTH levels
2. Localize the source:
   • ACTH-independent: Adrenal CT or MRI
   • ACTH-dependent: Pituitary MRI and potentially inferior petrosal sinus sampling (IPSS) 2

Key Points to Remember

• No single test has 100% diagnostic accuracy for mild Cushing's syndrome
• Multiple samples and multiple testing modalities may be necessary 6
• UFC measured by liquid chromatography tandem-mass spectrometry achieves excellent accuracy 3
• Combined measurement of LNSC and LNS cortisone may improve diagnostic accuracy 4

Remember that Cushing's syndrome is rare but associated with significant morbidity and mortality, making accurate diagnosis crucial 7.