What is the initial test for diagnosing Cushing syndrome?

Initial Testing for Cushing Syndrome

The overnight 1-mg Dexamethasone Suppression Test (DST) is recommended as the initial screening test for diagnosing Cushing syndrome, according to the Endocrine Society guidelines. 1

First-Line Diagnostic Tests

The Endocrine Society recommends the following initial tests for screening patients with suspected Cushing syndrome:

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

   • Procedure: 1 mg dexamethasone administered at 11 PM, with cortisol measured at 8 AM the next day
   • Interpretation: Failure to suppress morning cortisol suggests Cushing syndrome
   • Best used for: Initial screening, evaluation of adrenal incidentalomas, and patients with disrupted circadian rhythms 1

2. Late-Night Salivary Cortisol (LNSC)

   • Sensitivity: >90%, Specificity: 100%
   • Particularly useful for: Initial screening and longitudinal surveillance of cyclic Cushing syndrome 1

3. 24-hour Urinary Free Cortisol (UFC)

   • Used to support diagnosis and reflect overall cortisol production 1

Test Selection Algorithm

1. Start with overnight 1-mg DST as the initial screening test
2. Consider adding LNSC if there is suspicion of cyclic Cushing syndrome
3. Use 24-hour UFC as a supporting diagnostic test
4. Measure plasma ACTH to differentiate between ACTH-dependent and ACTH-independent causes once hypercortisolism is confirmed 1

Important Considerations and Pitfalls

• Test Limitations: The standard 1-mg overnight DST may have reduced sensitivity in patients with mild and/or episodic hypercortisolism. Studies have shown that many patients with mild Cushing syndrome can suppress to overnight dexamethasone, potentially leading to false negatives 2

• Improved Specificity: Measuring serum dexamethasone levels simultaneously with cortisol can improve test specificity. The lower limit of normal for dexamethasone is 1.8 ng/mL 1

• Alternative Approaches: Some research suggests that a lower dose (0.5 mg) DST may provide better sensitivity and specificity (99.1% and 98.4% respectively) with a cortisol cut-off of 3.05 μg/dL 3

• Medication Interference: Women on estrogen-containing oral contraceptives may have false positive results when undergoing the 1-mg DST due to estrogen's effect on dexamethasone metabolism 1

• Pediatric Considerations: In children, Cushing's disease accounts for 75-80% of cases in those over age 6, while adrenal causes are more common in younger children. Unexplained weight gain combined with growth failure is a key indicator 1

Next Steps After Initial Testing

If the initial screening test is positive:

1. Confirm hypercortisolism with additional tests (LNSC or 24-hour UFC)
2. Measure plasma ACTH to differentiate between ACTH-dependent and ACTH-independent causes
3. Proceed with appropriate imaging studies based on ACTH status
4. Consider bilateral inferior petrosal sinus sampling (IPSS) for ACTH-dependent cases with equivocal results 1

Remember that no single test is perfect for diagnosing Cushing syndrome, especially in mild or cyclic cases. The overnight 1-mg DST remains the recommended initial test, but clinicians should maintain a high index of suspicion and follow up with additional testing when clinical features strongly suggest Cushing syndrome despite a negative initial test.