Initial Workup for Suspected Cushing's Syndrome
The initial workup for suspected Cushing's syndrome should include three key screening tests: 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and overnight 1-mg dexamethasone suppression test (DST). 1
Clinical Suspicion: When to Screen
Before proceeding with biochemical testing, it's important to identify patients with appropriate clinical features:
- For adults: Look for central obesity, facial plethora, purple striae, proximal muscle weakness, easy bruising, and metabolic abnormalities (hypertension, hyperglycemia)
- For children/adolescents: Screen only if weight gain is inexplicable AND combined with either:
- Decreasing height standard deviation score (SDS)
- Decreasing height velocity 1
Common Pitfall #1: Exogenous Glucocorticoid Use
Always first rule out exogenous glucocorticoid exposure from any source:
- Oral medications
- Injections
- Inhalers
- Topical preparations 1
Step 1: Initial Screening Tests
Perform at least two of the following tests:
24-hour Urinary Free Cortisol (UFC)
- Collect 2-3 samples
- Sensitivity: 89%, Specificity: 100% (when properly collected)
- Diagnostic cutoff: >193 nmol/24h (>70 μg/m²) 1
Late-Night Salivary Cortisol (LNSC)
- Collect ≥2 samples on consecutive days
- Sensitivity: 95%, Specificity: 100%
- Based on local assay cutoff values
- Easier for patient collection than UFC 1
Overnight 1-mg Dexamethasone Suppression Test (DST)
- Administer 1mg dexamethasone at 11 PM-midnight
- Measure serum cortisol at 8-9 AM next morning
- Diagnostic cutoff: ≥50 nmol/L (≥1.8 μg/dL)
- Sensitivity: 95%, Specificity: 80% 1
- Consider measuring dexamethasone levels alongside cortisol to improve test interpretability
Common Pitfall #2: Test Selection Based on Clinical Context
- For shift workers: DST is preferred over LNSC
- For women on estrogen-containing contraceptives: Avoid DST (false positives)
- For patients with renal impairment: Avoid UFC
- For suspected adrenal tumor: Start with DST 1
Common Pitfall #3: False Positives
Be aware of conditions that can cause false positive results:
- Severe obesity
- Uncontrolled diabetes mellitus
- Pregnancy
- Polycystic ovary syndrome
- Anorexia/malnutrition
- Acute illness/surgery
- Excessive exercise 1
Step 2: Confirming Cushing's Syndrome
If initial screening tests are abnormal:
- Repeat 1-2 screening tests to confirm
- Consider additional tests for equivocal cases:
- Dexamethasone-CRH test
- DDAVP test
- Midnight serum cortisol (≥50 nmol/L is diagnostic) 1
Step 3: Determining Etiology
Once Cushing's syndrome is confirmed, determine the cause:
Measure plasma ACTH levels:
- Low ACTH: ACTH-independent (adrenal source)
- Normal/high ACTH: ACTH-dependent (pituitary or ectopic source) 1
For ACTH-independent CS:
- Proceed to adrenal CT or MRI
For ACTH-dependent CS:
- Pituitary MRI
- For lesions <6mm or no visible lesion: Bilateral inferior petrosal sinus sampling (IPSS)
- For lesions ≥10mm: No IPSS needed
- For lesions 6-9mm: Consider CRH and DDAVP tests; IPSS may be needed 1
Common Pitfall #4: Cyclic Cushing's Syndrome
In cases of suspected cyclic Cushing's syndrome, multiple periodic sequential LNSC measurements are particularly useful for longitudinal surveillance, as these patients may have weeks to months of normal cortisol secretion interspersed with episodes of cortisol excess 1.
Special Considerations for Children and Adolescents
- Growth failure (subnormal growth velocity) with weight gain is a key distinguishing feature from simple obesity in prepubertal children
- Post-pubertal adolescents should be assessed according to adult guidelines 1
- Microadenomas account for 98% of Cushing's disease cases in children/adolescents, with adenoma diameter frequently ≤2mm 1
By following this systematic approach to the workup of suspected Cushing's syndrome, clinicians can efficiently diagnose this condition and proceed with appropriate treatment to reduce the significant morbidity and mortality associated with prolonged hypercortisolism.