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

Workup for Cushing's Syndrome

Begin the diagnostic workup by first excluding exogenous glucocorticoid use (oral, inhaled, topical, or injections), then proceed with 2-3 screening tests based on clinical suspicion level, followed by ACTH measurement to determine etiology. 1

Initial Assessment

Rule Out Exogenous Glucocorticoids

• Stop all exogenous glucocorticoid sources if possible before proceeding with diagnostic testing, as this is the most common cause of Cushing's syndrome 1, 2
• Review medications including oral steroids, inhalers, topical preparations, and injections 1

Clinical Features to Assess

Look specifically for these high-specificity findings 3, 4:

• Abnormal fat distribution: supraclavicular and temporal fossae fat pads, truncal obesity 3, 4
• Skin changes: wide purple striae (>1 cm), facial plethora, easy bruising 2, 3
• Proximal muscle weakness 3
• In children: decreased linear growth with continued weight gain 1, 3
• Additional features: buffalo hump, moon facies, hypertension, abdominal striae, centripetal fat distribution 1

Screening Tests (Step 1: Confirm Hypercortisolism)

Test Selection Based on Clinical Suspicion

For LOW clinical suspicion: 1

• Perform late-night salivary cortisol (≥2 tests on consecutive days) 1

For INTERMEDIATE or HIGH clinical suspicion: 1

• Perform 2-3 screening tests from the following options 1, 2:
  • 24-hour urinary free cortisol (UFC): average 2-3 collections 1, 4
  • Late-night salivary cortisol (LNSC): ≥2 tests on consecutive days 1
  • Overnight 1 mg dexamethasone suppression test (DST): measure cortisol the morning after evening dexamethasone dose 1, 2

Test-Specific Considerations

• Measuring dexamethasone level along with morning cortisol after 1 mg DST improves test interpretability 1
• DST is particularly useful in shift workers but should not be used in women taking estrogen-containing oral contraceptives 1
• Multiple LNSC collections may be easier for patient compliance 1
• If initial tests are abnormal, repeat 1-2 screening tests to confirm 1

Exclude Pseudo-Cushing States

If screening tests are abnormal, consider and exclude 1:

• Severe obesity
• Pregnancy
• Polycystic ovary syndrome (PCOS)
• Uncontrolled diabetes mellitus
• Anorexia/malnutrition
• Acute illness or recent surgery
• Excessive exercise

Consider additional tests like Dex-CRH test, DDAVP stimulation, or midnight serum cortisol if results are equivocal 1

Differential Diagnosis (Step 2: Determine Etiology)

Measure Plasma ACTH Level

Once hypercortisolism is confirmed, measure ACTH to distinguish between causes 1, 2:

LOW or SUPPRESSED ACTH = ACTH-independent Cushing's syndrome 1, 2

• Proceed to adrenal CT or MRI 1
• Indicates adrenal tumor or bilateral adrenal disease 2, 5

NORMAL or HIGH ACTH = ACTH-dependent Cushing's syndrome 1, 2

• Proceed to pituitary MRI 1
• Indicates Cushing's disease (pituitary adenoma) or ectopic ACTH secretion 2, 5

Further Localization for ACTH-Dependent Disease

Pituitary MRI Findings Guide Next Steps 1

Adenoma ≥10 mm: 1

• Presumed Cushing's disease—no IPSS needed (consensus) 1

Adenoma 6-9 mm: 1

• Gray zone—expert opinions differ; consider CRH and DDAVP testing or proceed to IPSS 1

Adenoma <6 mm or no adenoma/equivocal: 1

• Perform bilateral inferior petrosal sinus sampling (IPSS) with CRH or DDAVP stimulation 1, 3
• IPSS is the most accurate test to distinguish pituitary from ectopic ACTH secretion 3
• If ectopic source suspected, perform whole-body CT to locate ectopic ACTH-secreting tumor 1

Additional Screening Tests for Secondary Hypertension Workup

If evaluating Cushing's as part of secondary hypertension workup 1:

• 24-hour urinary cortisol or overnight dexamethasone suppression test 1
• Clinical clues: truncal obesity, glucose intolerance, purple striae, sudden onset or resistant hypertension 1

Pediatric Considerations

In children over age 6: 1

• Cushing's disease is the most common cause 1
• Use same screening tests: 24-hour UFC, LNSC, or overnight 1 mg DST 1
• Dex-CRH test is NOT useful in children 1
• IPSS role is more limited compared to adults 1

In children under age 6: 1

• Adrenal causes are more common than pituitary 1

Common Pitfalls

• Do not use DST in women on estrogen-containing contraceptives—falsely elevated cortisol-binding globulin affects results 1
• Avoid proton pump inhibitors (PPIs) when using ketoconazole for treatment—needs gastric acid for absorption 1
• Consider cyclic Cushing's—if initial tests normal but clinical suspicion high, periodically re-evaluate with repeat testing 1
• LNSC has lower specificity in patients with adrenal tumors 1
• Always measure dexamethasone levels with DST when possible to confirm adequate absorption 1