What is the appropriate workup for a patient with suspected Cushing's (Cushing's) syndrome?

Workup for Suspected Cushing's Syndrome

The appropriate workup for suspected Cushing's syndrome should include screening tests to confirm hypercortisolism, followed by tests to determine the cause, with 1 mg overnight dexamethasone suppression test being the preferred initial screening method. 1

Initial Evaluation

Clinical Assessment

• Look specifically for:
  • Characteristic physical features: facial plethora, purple striae, easy bruising, proximal muscle weakness, dorsal/supraclavicular fat pad ("buffalo hump"), central obesity
  • Metabolic abnormalities: hypertension, hyperglycemia, hypokalemia
  • Neuropsychiatric symptoms: mood disorders, cognitive changes
  • Menstrual irregularities in women
  • Exclude exogenous glucocorticoid use (oral, injections, topical, inhaled)

First-Line Screening Tests

1. 1 mg overnight dexamethasone suppression test (preferred initial test)

   • Patient takes 1 mg dexamethasone at 11 PM
   • Measure serum cortisol at 8 AM the next morning
   • Failure to suppress cortisol suggests Cushing's syndrome

2. Late-night salivary cortisol (collect at least 2 samples)

   • Elevated levels suggest loss of normal diurnal cortisol rhythm

3. 24-hour urinary free cortisol (collect 2-3 samples)

   • Elevated levels indicate increased cortisol production

Confirming the Diagnosis

• Perform at least two different screening tests
• Repeat abnormal tests to confirm results
• Consider measuring dexamethasone levels along with cortisol to ensure proper absorption and metabolism 1

Determining the Cause

Step 1: Measure Plasma ACTH

• Low ACTH: ACTH-independent Cushing's (adrenal source)
• Normal or elevated ACTH: ACTH-dependent Cushing's (pituitary or ectopic source)

Step 2: Based on ACTH Results

For ACTH-Independent Cushing's:

• Adrenal CT or MRI to identify adrenal adenoma, carcinoma, or hyperplasia

For ACTH-Dependent Cushing's:

1. Pituitary MRI with contrast

   • If adenoma ≥10 mm: Likely Cushing's disease
   • If adenoma <6 mm or no visible tumor: Proceed to IPSS
   • For adenomas 6-9 mm: Consider IPSS based on clinical judgment 1

2. Bilateral inferior petrosal sinus sampling (IPSS)

   • Gold standard for differentiating pituitary from ectopic ACTH source
   • ACTH gradient between petrosal sinus and peripheral blood confirms pituitary source

3. CRH stimulation test or high-dose dexamethasone suppression test

   • Can help differentiate pituitary from ectopic sources
   • Pituitary tumors typically respond to CRH with increased ACTH and suppress with high-dose dexamethasone

4. Whole-body imaging

   • CT chest/abdomen/pelvis to locate potential ectopic ACTH-secreting tumors (lung, thymus, pancreas, etc.)

Special Considerations

• Cyclic Cushing's: Consider repeated testing if initial results are equivocal but clinical suspicion remains high
• Pseudo-Cushing's states: Conditions that can mimic Cushing's include severe obesity, uncontrolled diabetes, depression, alcoholism, and polycystic ovary syndrome 1
• Adrenal incidentalomas: All patients with adrenal incidentalomas should be screened for autonomous cortisol secretion 1

Common Pitfalls to Avoid

• Failing to exclude exogenous glucocorticoid use before extensive workup
• Relying on a single screening test (false positives/negatives are common)
• Not considering cyclical Cushing's when results are inconsistent
• Performing imaging before biochemical confirmation of hypercortisolism
• Interpreting mildly abnormal results in patients with conditions that can cause pseudo-Cushing's

By following this systematic approach, clinicians can effectively diagnose Cushing's syndrome and determine its etiology, leading to appropriate treatment decisions that will improve morbidity, mortality, and quality of life outcomes.