How should I diagnose Cushing syndrome?

Diagnosing Cushing Syndrome

Start by excluding exogenous glucocorticoid use, then perform 2-3 first-line screening tests (late-night salivary cortisol, 24-hour urinary free cortisol, or overnight 1 mg dexamethasone suppression test) to confirm hypercortisolism, followed by morning plasma ACTH measurement to determine ACTH-dependent versus ACTH-independent etiology. 1, 2

Step 1: Exclude Exogenous Glucocorticoids

• Review all glucocorticoid exposure including oral, inhaled, topical, intra-articular, and epidural corticosteroids before any biochemical testing, as iatrogenic Cushing syndrome is the most common cause and failure to exclude it leads to unnecessary testing. 1, 2, 3

Step 2: Initial Screening Tests for Hypercortisolism

Perform at least 2-3 of the following first-line tests based on clinical suspicion and local availability: 4, 1, 2

Late-Night Salivary Cortisol (LNSC)

• Collect 2-3 samples at the patient's usual bedtime (typically 11 PM-midnight) on consecutive days to detect loss of normal circadian rhythm. 4, 1
• Sensitivity 95%, specificity 93-100%—the highest among screening tests. 1
• Contraindicated in night-shift workers or anyone with disrupted sleep-wake cycles. 4, 1
• Avoid topical hydrocortisone contamination, which can cause false positives. 1
• Preferred test for patient compliance as multiple collections are easier than 24-hour urine. 4, 1, 2

24-Hour Urinary Free Cortisol (UFC)

• Collect 2-3 samples to account for day-to-day variability. 4, 1
• Sensitivity 89%, specificity 100%. 1
• Measures overall cortisol production. 1

Overnight 1 mg Dexamethasone Suppression Test (DST)

• Administer 1 mg dexamethasone at 11 PM, measure serum cortisol at 8 AM. 1
• Normal suppression is cortisol <1.8 μg/dL (50 nmol/L); values above indicate abnormal feedback inhibition. 1, 5
• Preferred for shift workers and patients with irregular sleep schedules. 4
• Less reliable in women taking oral estrogen (increases cortisol-binding globulin). 4, 5
• Measure dexamethasone level simultaneously to confirm adequate absorption and rule out false positives from rapid metabolism or CYP3A4 inducers. 4, 1, 2

Interpretation of Screening Results

• If any test is abnormal, repeat 1-2 screening tests to confirm hypercortisolism before proceeding. 1, 2
• If all tests are normal, Cushing syndrome is unlikely unless clinical suspicion remains very high. 1
• Consider false positives in severe obesity, uncontrolled diabetes, major depression, chronic alcoholism, and pregnancy (pseudo-Cushing states). 4, 1, 2

Step 3: Rule Out Pseudo-Cushing States

• Pseudo-Cushing states (depression, alcoholism, severe obesity, uncontrolled diabetes) can mimic mild hypercortisolism. 4, 1
• Most specific physical signs for true Cushing syndrome versus pseudo-Cushing: supraclavicular fat pads, proximal myopathy, thin skin with easy bruising, and wide (>1 cm) purple striae. 6, 7
• Monitor for 3-6 months if mild hypercortisolism is present; treat underlying condition (e.g., depression) and repeat testing. 4
• Dexamethasone-CRH test can help distinguish true Cushing from pseudo-Cushing: cortisol rise >38 nmol/L at 15 minutes post-CRH indicates true Cushing disease. 5

Step 4: Determine Etiology with Morning Plasma ACTH

Once hypercortisolism is confirmed, measure morning (8-9 AM) plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes: 1, 5, 2

ACTH-Independent Cushing Syndrome (Low/Undetectable ACTH)

• ACTH <5 ng/L (<1.1 pmol/L) indicates adrenal source. 1, 5
• Next step: Adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral hyperplasia. 1, 5, 2

ACTH-Dependent Cushing Syndrome (Normal/Elevated ACTH)

• Any ACTH >5 ng/L suggests ACTH-dependent disease (pituitary or ectopic source). 1, 5
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing disease (pituitary adenoma). 1, 5
• Next step: Pituitary MRI with thin slices (3T preferred over 1.5T) to detect pituitary adenoma. 1, 5, 2

Step 5: Localize ACTH-Dependent Source

If Pituitary Adenoma ≥10 mm on MRI

• Presume Cushing disease and proceed to transsphenoidal surgery. 1, 5, 2

If Pituitary Adenoma 6-9 mm on MRI

• Consider CRH stimulation test or proceed to bilateral inferior petrosal sinus sampling (BIPSS) for confirmation. 1, 5

If No Adenoma or Lesion <6 mm on MRI

• Perform BIPSS to definitively distinguish pituitary from ectopic ACTH source, as MRI has only 63% sensitivity for microadenomas. 1, 5, 2
• BIPSS diagnostic criteria: Central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH/desmopressin stimulation confirms pituitary source. 1, 5, 2
• BIPSS must be performed at specialized centers by experienced interventional radiologists. 5, 2
• Measure prolactin simultaneously from petrosal sinuses to confirm adequate venous sampling. 5

If Ectopic ACTH Suspected

• High suspicion indicators: Very high urinary free cortisol, profound hypokalemia, rapid onset of symptoms. 5
• Perform neck-to-pelvis thin-slice CT to locate ectopic ACTH-secreting tumor (often neuroendocrine). 5
• Consider 68Ga-DOTATATE PET imaging if conventional imaging is negative. 5

Critical Pitfalls to Avoid

• Never use BIPSS to diagnose hypercortisolism—it is only for localizing the ACTH source after hypercortisolism is confirmed. 4
• In cyclic Cushing syndrome, confirm active hypercortisolism with LNSC, DST, or UFC immediately before BIPSS or other dynamic testing. 4, 5
• Stop steroidogenesis inhibitors before BIPSS to allow accurate interpretation. 5
• Do not rely on single abnormal test—repeat testing is essential to avoid false positives. 4, 1, 2
• ACTH measurement does not require fasting and must be done in the morning (8-9 AM) for accurate interpretation against established diagnostic thresholds. 5