What is the appropriate workup for a patient suspected of having Cushing syndrome?

Cushing Syndrome Workup

Initial Critical Step: Exclude Exogenous Glucocorticoids

Before any diagnostic testing, you must stop all exogenous glucocorticoid sources, as this is the most common cause of Cushing syndrome. 1

• Review all medications including oral steroids, inhalers, topical preparations, and injections to rule out exogenous use 1
• This step is non-negotiable and must precede all biochemical testing 2, 3

Step 1: Screening Tests to Confirm Hypercortisolism

Use one or more of the following first-line screening tests, which have sensitivities of 89-95%: 1

• 24-hour urinary free cortisol (UFC) 1, 2, 3
• Late-night salivary cortisol 1, 2, 3
• 1 mg overnight dexamethasone suppression test (DST) - cortisol should suppress to <1.8 μg/dL; failure to suppress indicates Cushing syndrome 1, 4

Important caveats for screening tests:

• Women on estrogen-containing contraceptives should not undergo dexamethasone suppression testing, as estrogen falsely elevates cortisol-binding globulin 1
• Severe obesity, uncontrolled diabetes, alcoholism, and depression can cause false positives (pseudo-Cushing's states) 4, 5
• CYP3A4 inducers can cause rapid dexamethasone metabolism and false positives 4
• Consider measuring dexamethasone levels during DST to confirm adequate absorption 4

Step 2: Measure Plasma ACTH to Determine Etiology

Once hypercortisolism is confirmed, measure morning (08:00-09:00h) plasma ACTH to distinguish ACTH-dependent from ACTH-independent disease. 1, 4, 2

ACTH Interpretation:

• ACTH >5 ng/L (detectable): Indicates ACTH-dependent Cushing syndrome 4
• ACTH >29 ng/L: 70% sensitivity and 100% specificity for Cushing disease (pituitary source) 4
• ACTH low or undetectable (<5 ng/L): Indicates ACTH-independent Cushing syndrome (adrenal source) 4

Technical considerations:

• ACTH must be collected in the morning (08:00-09:00h) when levels are highest 4
• Fasting is not required for ACTH measurement 4
• Patient must not be on exogenous steroids, which suppress ACTH 4

Step 3A: ACTH-Independent Cushing Syndrome (Low ACTH)

Proceed directly to adrenal imaging with CT or MRI to identify adrenal lesion(s). 1, 4

Imaging findings guide management:

• Benign adrenal adenoma: Unilateral cortisol-secreting tumor; treat with laparoscopic adrenalectomy 6, 4
• Adrenal carcinoma suspected when: Tumor >5 cm, irregular margins, inhomogeneity, or local invasion; requires open adrenalectomy with possible adjuvant therapy 6, 4
• Bilateral hyperplasia: Consider medical management or unilateral adrenalectomy 4

Step 3B: ACTH-Dependent Cushing Syndrome (Elevated ACTH)

Perform high-quality pituitary MRI with thin slices (3T preferred over 1.5T) to identify pituitary adenoma. 1, 4

MRI-based algorithm:

If pituitary adenoma ≥10 mm detected:

• Presume Cushing disease (pituitary source) and proceed to surgery 1, 4
• No further localization testing needed 4

If pituitary adenoma 6-9 mm detected:

• Consider CRH stimulation test for additional confirmation 1, 4
• May proceed to bilateral inferior petrosal sinus sampling (BIPSS) if equivocal 1

If no adenoma or lesion <6 mm:

• Proceed to BIPSS, which is the gold standard for distinguishing pituitary from ectopic ACTH sources 1, 4, 5
• MRI has only 63% sensitivity for ACTH-secreting microadenomas, which are often ≤2 mm 4

Step 4: Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the definitive test when pituitary MRI is normal or shows only small lesions (<6 mm), with 96-100% sensitivity and near 100% specificity. 4

BIPSS diagnostic criteria:

• Central-to-peripheral ACTH ratio ≥2:1 at baseline OR ≥3:1 after CRH or desmopressin stimulation confirms pituitary source 1, 4
• Measure prolactin simultaneously from petrosal sinuses to confirm adequate venous sampling 4
• Inter-petrosal sinus ACTH gradient ≥1.4 after stimulation may indicate tumor lateralization 4

Critical technical requirements:

• Must be performed at a specialized center by experienced interventional radiologist 1, 4
• Bilateral cannulation success rate should exceed 85% 4
• For cyclic Cushing disease, confirm active hypercortisolism immediately before BIPSS 4
• Stop medical therapy for Cushing disease before BIPSS to enable accurate interpretation 4

Step 5: If Ectopic ACTH Suspected

If BIPSS indicates ectopic source or clinical features suggest ectopic ACTH (very high UFC, profound hypokalemia):

• Perform whole-body CT (neck to pelvis, thin-slice) to locate ectopic ACTH-secreting tumor 1, 4
• Consider 68Ga-DOTATATE PET imaging for neuroendocrine tumors not visible on conventional imaging 4
• Thymic sources account for up to 2% of ectopic ACTH cases 6

Special Populations

Children over 6 years:

• Use same screening tests as adults (24-hour UFC, late-night salivary cortisol, or overnight 1 mg DST) 1

Children under 6 years:

• Adrenal causes more common than pituitary causes 1
• Dex-CRH test not useful; IPSS role more limited 1

Key Clinical Features to Support Diagnosis

Most specific features for Cushing syndrome include: 1, 6

• Buffalo hump, moon facies, supraclavicular and temporal fat pads 1, 7
• Purple abdominal striae (wide, >1 cm) 7
• Proximal muscle weakness 7
• Fragile skin with easy bruising 6
• Hypertension (70-90% of patients) 6
• Glucose abnormalities (>80% of patients) 6
• Centripetal fat distribution 1

Critical Pitfalls to Avoid

• Never proceed with diagnostic testing without first excluding exogenous glucocorticoid use 1, 2
• Do not perform DST in women on oral contraceptives - falsely elevated results 1
• Recognize pseudo-Cushing's states (obesity, depression, alcoholism) that mimic biochemical findings 4, 5
• Do not rely on MRI alone for ACTH-dependent disease - proceed to BIPSS when MRI is negative or shows only small lesions 4
• Ensure morning ACTH collection - afternoon levels are unreliable and don't correspond to diagnostic thresholds 4
• Average diagnostic delay is 3 years - maintain high clinical suspicion to reduce morbidity and mortality from cardiovascular events 1