What is the initial workup for a patient suspected of having Cushing's (Cushing's syndrome)?

Workup for Cushing's Syndrome

Initial Step: Rule Out Exogenous Glucocorticoids

Before any biochemical testing, exclude iatrogenic Cushing's syndrome by thoroughly reviewing all glucocorticoid use including oral, inhaled, topical, and injected formulations. 1, 2, 3

• This is a strong recommendation based on high-quality evidence that failure to exclude exogenous glucocorticoid use leads to unnecessary testing without patient benefit. 1

First-Line Screening Tests

For patients with intermediate to high clinical suspicion, perform 2-3 of the following first-line screening tests: 1, 2, 3

Late-Night Salivary Cortisol (LNSC)

• Collect at least 2-3 samples on consecutive days for optimal sensitivity (95%) and specificity (100%). 3, 4
• This test is preferred for low clinical suspicion cases due to easier patient compliance compared to 24-hour urine collection. 2, 3
• Multiple LNSC collections are more convenient than urine collections. 3

24-Hour Urinary Free Cortisol (UFC)

• Collect 2-3 samples to account for day-to-day variability, with diagnostic cutoff >193 nmol/24h (>70 μg/m²). 3, 4
• Sensitivity is 89% and specificity is 100%. 4

Overnight 1 mg Dexamethasone Suppression Test (DST)

• Administer 1 mg dexamethasone at midnight and measure serum cortisol at 8 AM; normal response is cortisol <1.8 μg/dL (50 nmol/L). 3, 4
• Sensitivity is 95% and specificity is 80%. 4
• Measuring dexamethasone levels along with cortisol improves test interpretability. 1, 3
• Less useful in women taking estrogen-containing oral contraceptives. 3

Interpretation of Screening Results

• If any test is abnormal, repeat 1-2 screening tests to confirm the diagnosis. 2, 3
• If all tests are normal and clinical suspicion is low to moderate, Cushing's syndrome is unlikely. 1, 3
• If tests are normal but clinical suspicion remains high, refer to an endocrinologist for further evaluation. 1

Important Caveats for False Positives

Consider pseudo-Cushing's states that can cause false-positive results: 2, 3

• Severe obesity 3
• Uncontrolled diabetes 2, 3
• Depression 2, 3
• Alcoholism 2, 3
• Pregnancy 2

In cases with inconsistent results, consider cyclic Cushing's syndrome. 3

Determining the Etiology

Step 1: Measure Morning Plasma ACTH

Once Cushing's syndrome is confirmed, measure morning plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes: 2, 3, 4

• Normal or elevated ACTH (>5 ng/L or >1.1 pmol/L) indicates ACTH-dependent Cushing's syndrome (pituitary or ectopic source). 3, 4
• Low or undetectable ACTH indicates ACTH-independent Cushing's syndrome (adrenal source). 3

Step 2A: For ACTH-Dependent Cases

Perform pituitary MRI to detect pituitary adenoma: 2, 4

• Sensitivity is 63% and specificity is 92%. 2, 4
• For lesions ≥10 mm, Cushing's disease is presumed. 1

If pituitary MRI is negative or equivocal, proceed with bilateral inferior petrosal sinus sampling (BIPSS): 1, 2

• Diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after CRH stimulation. 1
• Sensitivity is 100%. 1

CRH stimulation test can support pituitary origin if ≥20% increase in cortisol from baseline occurs. 3, 4

Step 2B: For ACTH-Independent Cases

Proceed with adrenal imaging (CT or MRI) to identify adrenal adenoma or carcinoma. 3

Special Populations

Children and Adolescents

• Screen only if weight gain is inexplicable and combined with either decreased height standard deviation score or decreased height velocity. 3, 4
• Lack of height gain with concurrent weight gain is the most common presentation. 2
• Growth failure sensitively discriminates simple obesity from Cushing's syndrome in prepubertal children but is unreliable in post-pubertal children. 4

Paraneoplastic Cushing's Syndrome in Lung Cancer

• Suspect in patients with lung cancer presenting with moon facies, acne, purple striae, proximal muscle weakness, peripheral edema, hypertension, and metabolic alkalosis with hypokalemia. 1
• Skin hyperpigmentation is usually more prominent with ectopic ACTH. 1
• Weight loss occurs in about 10% of cases associated with small cell lung cancer. 1

Common Pitfalls

• Neither a normal UFC nor a normal LNSC excludes mild Cushing's syndrome—multiple samples and DST are needed for diagnosis. 5
• Do not perform biochemical screening unless pre-test probability is reasonably high, as common symptoms like hypertension, weight gain, or diabetes occur frequently in the general population and do not justify testing alone. 6
• Be aware that severe obesity can cause false-positive results on all screening tests. 3