What are the steps to diagnose Cushing's syndrome?

Diagnosing Cushing's Syndrome: A Systematic Approach

The diagnosis of Cushing's syndrome requires a stepwise approach beginning with screening tests to confirm hypercortisolism, followed by tests to determine the etiology, with at least two first-line tests recommended for initial screening. 1, 2

Initial Assessment for Cushing's Syndrome

Step 1: Rule Out Exogenous Glucocorticoid Use

• First determine if the patient is taking exogenous glucocorticoids (oral, injections, inhalers, topical) as these must be discontinued if possible before testing 2
• Document clinical features suggesting Cushing's syndrome, including unexplained weight gain with height velocity deceleration (particularly important in children) 2

Step 2: First-Line Screening Tests

• Late-night salivary cortisol (LNSC): Collect at least 2-3 samples on consecutive days; sensitivity 95%, specificity 100% 1, 3
• 24-hour urinary free cortisol (UFC): Collect 2-3 samples; sensitivity 89%, specificity 100% 2, 1
• Overnight 1-mg dexamethasone suppression test (DST): Normal response is serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after 1 mg dexamethasone at midnight; sensitivity 95%, specificity 80% 1, 4

Step 3: Interpretation of Screening Results

• Normal results in all tests suggest Cushing's syndrome is unlikely 2, 1
• Abnormal results require repeat testing to confirm 2
• Consider cyclical Cushing's syndrome if results are inconsistent 2, 5
• Be aware of potential false positives in pseudo-Cushing's states (severe obesity, uncontrolled diabetes, depression, alcoholism) 1, 6

Determining the Etiology of Cushing's Syndrome

Step 4: ACTH Measurement

• If screening tests confirm hypercortisolism, measure morning plasma ACTH level 2, 7
• ACTH-dependent Cushing's syndrome: Normal or elevated ACTH (>5 ng/L or >1.1 pmol/L) 1, 7
• ACTH-independent Cushing's syndrome: Low or undetectable ACTH 1, 7

Step 5: Further Testing Based on ACTH Status

For ACTH-Dependent Cushing's Syndrome:

• Perform pituitary MRI (sensitivity 63%, specificity 92%) 7, 2
• If pituitary adenoma ≥10 mm is identified, presume Cushing's disease 2
• If pituitary MRI is negative or shows lesion <6 mm, proceed with bilateral inferior petrosal sinus sampling (BIPSS) 2
• For lesions 6-9 mm, consider CRH stimulation test (≥20% increase in cortisol supports pituitary origin) 2, 7

For ACTH-Independent Cushing's Syndrome:

• Perform adrenal CT or MRI to identify adrenal adenoma or other pathology 2

Step 6: Specialized Testing

• Bilateral inferior petrosal sinus sampling (BIPSS): Central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after CRH stimulation confirms pituitary source; sensitivity 100% 7, 2
• CRH stimulation test: ≥20% increase in cortisol from baseline supports pituitary origin 7, 2

Special Considerations

• Measuring dexamethasone levels during DST improves test interpretability (lower limit of normal: 1.8 ng/mL) 4, 2
• Multiple samples are needed for mild Cushing's syndrome as a single normal test does not exclude the diagnosis 5, 6
• Certain medications can affect test results (e.g., CYP3A4 inducers can cause false positives in DST) 4, 6
• For suspected pseudo-Cushing's states, the combined LDDT-CRH test may help distinguish from true Cushing's syndrome 4, 8

Common Pitfalls to Avoid

• Relying on a single test for diagnosis, especially in mild cases 5, 6
• Not accounting for cyclical Cushing's syndrome, which may require repeated testing over time 2, 5
• Failing to measure ACTH levels to determine the source of hypercortisolism 1, 7
• Not confirming hypercortisolemia immediately prior to BIPSS to ensure active disease phase 7
• Overlooking potential drug interactions or conditions that may affect test results 4, 6