What is the initial workup for a patient with suspected Cushing's syndrome and a history of gouty arthritis?

Workup for Cushing's Syndrome

Begin by excluding exogenous glucocorticoid use through a thorough medication review, then perform 2-3 first-line screening tests (24-hour urinary free cortisol, late-night salivary cortisol, and/or overnight 1-mg dexamethasone suppression test) to confirm hypercortisolism, followed by morning plasma ACTH measurement to determine ACTH-dependency. 1, 2

Step 1: Exclude Exogenous Glucocorticoid Use

• Review all potential sources of exogenous steroids including oral medications, inhaled corticosteroids, topical preparations, injectable steroids, and over-the-counter supplements that may contain steroids 1, 3
• This is the most common cause of iatrogenic Cushing's syndrome and must be ruled out before proceeding with biochemical testing 1

Step 2: Confirm Hypercortisolism with First-Line Screening Tests

Perform at least 2 of the following 3 tests to establish the diagnosis of endogenous Cushing's syndrome 1:

• 24-hour urinary free cortisol: Sensitivity 89%, specificity 100% 1
• Late-night salivary cortisol: Sensitivity 95%, specificity 100% 1
• Overnight 1-mg dexamethasone suppression test: Sensitivity 95%, specificity 80%; normal suppression is cortisol <1.8 μg/dL 1, 2

Important Caveats for Screening Tests

• False positives can occur with severe obesity, uncontrolled diabetes, alcoholism, depression, rapid dexamethasone absorption/malabsorption, CYP3A4 inducers, oral estrogens, or pregnancy 2, 4
• None of these tests reach 100% specificity, and results may be discordant in up to one-third of patients 1, 2
• Consider measuring dexamethasone levels during suppression testing to confirm adequate absorption and rule out false-positive results 2

Step 3: Determine ACTH-Dependency

Measure morning (08:00-09:00h) plasma ACTH to differentiate ACTH-dependent from ACTH-independent Cushing's syndrome 1, 2:

• ACTH >5 ng/L: Indicates ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 1, 2
• ACTH >29 ng/L: 70% sensitivity and 100% specificity for Cushing's disease 2
• Low or undetectable ACTH: Indicates ACTH-independent Cushing's syndrome (adrenal source) 2

Step 4A: ACTH-Independent Cushing's Syndrome (Low ACTH)

Perform adrenal CT or MRI to identify adrenal lesion(s) 2:

• Unilateral adrenal adenoma: Most common finding 2
• Adrenal carcinoma: Consider if large mass with concerning features 2
• Bilateral adrenal hyperplasia: Less common 2

Step 4B: ACTH-Dependent Cushing's Syndrome (Elevated ACTH)

Initial Imaging

Obtain high-quality pituitary MRI with gadolinium enhancement using thin slices (3T MRI preferred over 1.5T) 1, 2:

• Pituitary adenoma ≥10 mm: Strongly suggests Cushing's disease; proceed to surgery 2
• Pituitary adenoma 6-9 mm: Consider CRH stimulation test or bilateral inferior petrosal sinus sampling (BIPSS) 2
• No adenoma or lesion <6 mm: Proceed to BIPSS 2

Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the gold standard for differentiating pituitary from ectopic ACTH sources when MRI is inconclusive 2, 5:

• Diagnostic criteria: Central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin stimulation and ≥3:1 after stimulation 2
• Must be performed in a specialized center by an experienced interventional radiologist 2
• Medical therapy for Cushing's disease must be stopped before BIPSS 2
• For cyclical Cushing's, confirm active hypercortisolism immediately prior to the procedure 2

Additional Testing for Ectopic ACTH Syndrome

If ectopic ACTH syndrome is suspected (very high urinary free cortisol, profound hypokalemia, or BIPSS suggests ectopic source) 2:

• Neck-to-pelvis thin-slice CT scan to identify neuroendocrine tumors 2
• 68Ga-DOTATATE PET imaging for localizing occult neuroendocrine tumors not visible on conventional imaging 2
• Bronchoscopy if bronchopulmonary NET suspected 6

Special Considerations

Bronchopulmonary and Thymic NETs

• Workup for Cushing's syndrome is indicated if signs and symptoms of hypercortisolemia are present in patients with bronchopulmonary or thymic neuroendocrine tumors 6
• Evaluate with 24-hour urine collection for 5-HIAA if carcinoid syndrome suspected 6

Cyclical Cushing's Syndrome

• Can produce inconsistent results requiring periodic re-evaluation 2
• Confirm active hypercortisolism immediately before performing diagnostic procedures like BIPSS 2

Pseudo-Cushing's States

• Depression, alcoholism, severe obesity, and PCOS can cause false-positive screening results 2, 5
• Dex-CRH test (sensitivity 90%, specificity 95%) can help distinguish true Cushing's from pseudo-Cushing's states 2