What is the first test to check for Cushing's (Cushing's syndrome)?

First Test for Cushing's Syndrome Screening

The Endocrine Society recommends performing three first-line screening tests—late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), and 1 mg overnight dexamethasone suppression test (DST)—rather than relying on a single test, as no single test can reliably exclude Cushing's syndrome in all cases. 1, 2

Recommended Screening Approach

All Three Tests Should Be Performed Initially

• For patients with intermediate to high clinical suspicion, perform 2-3 first-line screening tests simultaneously to maximize diagnostic accuracy, as a single normal test does not exclude Cushing's syndrome, especially in mild or cyclic cases 1, 2

• The three recommended first-line tests are:

  • Late-night salivary cortisol (LNSC): 95% sensitivity and 100% specificity when 2-3 samples collected on separate days 1
  • 24-hour urinary free cortisol (UFC): 89% sensitivity and 100% specificity with 2-3 collections 1
  • 1 mg overnight dexamethasone suppression test (DST): Failure to suppress cortisol to <50 nmol/L (<1.8 μg/dL) at 8 AM suggests hypercortisolism 1

If Forced to Choose One Test

Late-night salivary cortisol (LNSC) appears to be the most useful single screening test based on its superior specificity (93-100%, the highest among all first-line tests) and ease of collection 2, 3

• LNSC detects the loss of normal circadian nadir of cortisol secretion that occurs in Cushing's syndrome 2
• Collect at least 2-3 samples at the patient's usual bedtime (typically 11 PM-midnight) on consecutive days 1, 2
• Critical contraindication: Do NOT use LNSC in night-shift workers or anyone with disrupted day/night cycles 2

Practical Algorithm for Test Selection

High Clinical Suspicion (Multiple Specific Features Present)

• Perform all three tests (LNSC, UFC, DST) simultaneously 2
• Specific features include: supraclavicular/temporal fat pads, proximal muscle weakness, wide purple striae, or decreased linear growth with weight gain in children 3

Moderate Clinical Suspicion

• Start with LNSC (2-3 samples) as the primary screening test 2, 3
• Add UFC or DST if LNSC results are equivocal or if cyclic Cushing's is suspected 1

Special Patient Populations

Renal impairment (CrCl <60 mL/min) or significant polyuria:

• Prefer LNSC over UFC, as renal dysfunction affects UFC accuracy 1, 4

Women on oral estrogen therapy:

• DST may be less reliable; consider measuring dexamethasone levels along with cortisol to improve interpretability 2
• LNSC or UFC may be preferred in this population 2

Suspected cyclic Cushing's syndrome:

• Multiple sequential LNSC measurements over weeks to months are particularly useful 2
• UFC variability can reach 50%, requiring 2-3 collections 4

Critical Pitfalls to Avoid

• Never rely on a single test result: A single normal test does not exclude Cushing's syndrome 1, 5
• Always exclude exogenous glucocorticoid use first: Review all glucocorticoid medications (including topical, inhaled, and injected forms) before any biochemical testing 2
• Beware of pseudo-Cushing states: Severe obesity, uncontrolled diabetes, depression, and alcoholism can cause false-positive results with mildly elevated cortisol (typically <3 times upper limit of normal) 1, 2
• Avoid topical steroid contamination: Topical hydrocortisone can contaminate salivary samples, particularly with mass spectrometry assays 2

Interpretation of Abnormal Results

• If any screening test is abnormal: Repeat 1-2 screening tests to confirm the diagnosis 2
• If confirmed abnormal: Measure morning plasma ACTH to differentiate ACTH-dependent (normal/elevated ACTH >5 ng/L) from ACTH-independent (low/undetectable ACTH) causes 1, 2
• If all tests normal with low-moderate suspicion: Cushing's syndrome is unlikely 2
• If all tests normal but high clinical suspicion persists: Refer to endocrinologist for further evaluation and consider cyclic Cushing's syndrome 2