Diagnosing Cushing Syndrome
To diagnose Cushing syndrome, perform 2-3 first-line screening tests (late-night salivary cortisol, 24-hour urinary free cortisol, and overnight dexamethasone suppression test) to confirm hypercortisolism, then measure morning plasma ACTH to determine whether the cause is ACTH-dependent or ACTH-independent. 1, 2
Initial Screening for Hypercortisolism
Before any testing, rule out exogenous glucocorticoid use, which is the most common cause of Cushing syndrome. 2
For patients with intermediate to high clinical suspicion, perform multiple screening tests: 1, 2
Late-night salivary cortisol (LNSC): Collect at least 2-3 samples on consecutive days. This test has 95% sensitivity and 100% specificity. 1 For low clinical suspicion, start with this test as it's easiest for patient compliance. 2
24-hour urinary free cortisol (UFC): Collect at least 2-3 samples to account for variability. This test has 89% sensitivity and 100% specificity. 1
Overnight 1 mg dexamethasone suppression test (DST): Give 1 mg dexamethasone at midnight, measure serum cortisol at 8 AM. Normal response is cortisol <1.8 μg/dL (50 nmol/L). This test has 95% sensitivity and 80% specificity. 1, 3 Note that measuring dexamethasone levels alongside cortisol improves test interpretability. 1
If any test is abnormal, repeat 1-2 screening tests to confirm the diagnosis. 1, 2 If all tests are normal, Cushing syndrome is unlikely. 1
Important Pitfalls to Avoid
Pseudo-Cushing's states can cause false-positive results: 1, 2
- Severe obesity
- Uncontrolled diabetes
- Depression
- Alcoholism
- Pregnancy
The DST may be less reliable in women taking estrogen-containing oral contraceptives. 1
Consider cyclic Cushing syndrome if results are inconsistent across multiple testing occasions. 1
Determining the Etiology
Once hypercortisolism is confirmed, measure morning plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes: 1, 2, 3
Normal or elevated ACTH (>5 ng/L or >1.1 pmol/L): Indicates ACTH-dependent Cushing syndrome (pituitary adenoma or ectopic ACTH secretion). 1
Low or undetectable ACTH: Indicates ACTH-independent Cushing syndrome (adrenal tumor). 1
For ACTH-Dependent Cases
Perform pituitary MRI with gadolinium enhancement (sensitivity 63%, specificity 92%). 2, 3 If a lesion ≥10 mm is found, Cushing disease (pituitary adenoma) is presumed. 2, 3
If pituitary imaging is negative or equivocal, proceed with bilateral inferior petrosal sinus sampling (BIPSS): 1, 2
- Diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after stimulation
- This test has 100% sensitivity for distinguishing pituitary from ectopic ACTH sources 2
CRH stimulation test can also support pituitary origin if there is ≥20% increase in cortisol from baseline. 1
For ACTH-Independent Cases
Proceed with adrenal CT or MRI imaging to identify adrenal adenoma, carcinoma, or bilateral hyperplasia. 2
Special Considerations for Children and Adolescents
Screen children for Cushing syndrome only if weight gain is inexplicable AND combined with either: 4, 1
- Decreased height standard deviation score (SDS), OR
- Decreased height velocity
This combination has high sensitivity and specificity for Cushing syndrome in prepubertal children. Growth failure sensitively discriminates simple obesity from Cushing syndrome in prepubertal children but is unreliable in post-pubertal adolescents, who should be assessed using adult guidelines. 4
In children with confirmed Cushing syndrome, use the following diagnostic cut-offs: 4
- UFC: >193 nmol/24 h (>70 μg/m²) with 89% sensitivity and 100% specificity
- Sleeping midnight serum cortisol: ≥50 nmol/L (≥1.8 μg/dL) with 100% sensitivity
- Low-dose dexamethasone suppression test (0.5 mg every 6 hours for 48 hours, or 30 μg/kg/day for patients <40 kg): cortisol ≥50 nmol/L (≥1.8 μg/dL) at 48 hours indicates Cushing syndrome with 95% sensitivity
Children with confirmed Cushing syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise. 2, 3