What is the single best test to diagnose Cushing syndrome?

Best Test for Diagnosing Cushing Syndrome

The 24-hour urinary free cortisol (UFC) measurement is the single best test for diagnosing Cushing syndrome. 1

Diagnostic Approach to Cushing Syndrome

The Endocrine Society recommends confirming hypercortisolism using a combination of tests, with 24-hour urinary free cortisol measurement being a cornerstone diagnostic test. This test directly reflects overall cortisol production and provides the most reliable assessment of cortisol status 1.

Comparison of Diagnostic Tests:

1. 24-hour Urinary Free Cortisol (Option D)

   • Directly measures cortisol excretion over a full day
   • Captures overall cortisol production
   • Recommended by the Endocrine Society for definitive diagnosis
   • Multiple collections (at least 2-3 samples) are recommended to confirm diagnosis 1
   • Highest specificity when properly collected

2. Overnight Dexamethasone Suppression Test (Option A)

   • Excellent screening tool but not the best definitive diagnostic test
   • Has limitations in patients with mild or episodic hypercortisolism 2
   • Sensitivity can be as low as 18-41% in patients with mild/periodic Cushing syndrome 2
   • Better suited for initial screening rather than definitive diagnosis

3. Plasma Cortisol (Option B)

   • Single measurements have poor diagnostic value
   • Subject to diurnal variation
   • Cannot differentiate Cushing syndrome from normal physiological stress responses
   • Not recommended as a standalone diagnostic test

4. Plasma ACTH Level (Option C)

   • Used to determine ACTH status and differentiate between ACTH-dependent and ACTH-independent Cushing syndrome 1
   • Helps in determining the source of excess cortisol (pituitary, ectopic, or adrenal)
   • Not used for initial diagnosis but rather for classification after Cushing syndrome is confirmed

Diagnostic Algorithm

1. Initial clinical suspicion based on symptoms (unexplained weight gain, hypertension, glucose intolerance)
2. First-line diagnostic testing with 24-hour UFC measurements (collect multiple samples)
3. Confirmatory testing with late-night salivary cortisol and 1mg overnight dexamethasone suppression test
4. Determine ACTH status using plasma ACTH measurements to classify the type of Cushing syndrome
5. Localization studies (imaging) based on ACTH status

Important Considerations

• False positives can occur with 24-hour UFC in patients with high fluid intake, so proper collection technique is essential
• At least 2-3 24-hour urine samples should be collected for UFC measurement to confirm diagnosis 1
• The overnight dexamethasone suppression test, while convenient, may miss cases of mild or episodic Cushing syndrome 2
• No single test has 100% diagnostic accuracy, which is why multiple tests are often used in clinical practice

Common Pitfalls

• Relying solely on a single test for diagnosis
• Inadequate urine collection technique for 24-hour UFC
• Failing to recognize that certain medications can interfere with test results
• Not accounting for conditions that can cause false positive results (severe obesity, depression, alcoholism)
• Using plasma ACTH levels for initial diagnosis rather than for determining the etiology after diagnosis is confirmed

While the overnight dexamethasone suppression test is an excellent screening tool with historical support 3, 4, the 24-hour urinary free cortisol measurement provides the most reliable assessment for definitive diagnosis of Cushing syndrome according to current guidelines 1.