What is the appropriate workup for Cushing's (Cushing's syndrome) syndrome?

Appropriate Workup for Cushing's Syndrome

The appropriate workup for Cushing's syndrome should begin with screening tests to confirm hypercortisolism, followed by tests to determine the cause, with measurement of plasma ACTH being the critical test to differentiate ACTH-dependent from ACTH-independent causes. 1, 2

Initial Screening Tests

For patients with clinical features suggestive of Cushing's syndrome, the following screening tests should be performed:

1. First-line screening tests (at least 2 tests for intermediate to high clinical suspicion):

   • 24-hour urinary free cortisol (UFC) measurement (2-3 collections)
   • Late night salivary cortisol (LNSC) (at least 2-3 samples)
   • Overnight 1-mg dexamethasone suppression test (DST)

2. Test selection considerations:

   • For shift workers or those with disrupted circadian rhythm: DST is preferred
   • For monitoring cyclic Cushing's syndrome: LNSC is preferred
   • For patients taking oral estrogens: Avoid DST (may give false positives)

Confirming Diagnosis and Determining Etiology

If initial screening tests are abnormal:

1. Repeat testing to confirm hypercortisolism

2. Measure plasma ACTH to differentiate:

   • Low ACTH: ACTH-independent Cushing's (adrenal causes)
   • Normal or high ACTH: ACTH-dependent Cushing's (pituitary or ectopic sources)

3. For ACTH-independent Cushing's:

   • Adrenal CT or MRI to identify adrenal tumors

4. For ACTH-dependent Cushing's:

   • Pituitary MRI to identify pituitary adenomas
   • For adenomas <6mm or no visible adenoma: Bilateral inferior petrosal sinus sampling (IPSS)
   • For adenomas ≥10mm: No IPSS needed
   • For adenomas 6-9mm: Expert opinions differ on need for IPSS 1

5. Additional tests for ACTH-dependent cases:

   • CRH stimulation test
   • High-dose dexamethasone suppression test
   • Whole-body CT if ectopic source suspected

Special Considerations

• Rule out exogenous glucocorticoid use before proceeding with workup 3

• Exclude non-neoplastic hypercortisolism caused by:

  • Severe obesity
  • Pregnancy
  • Polycystic ovary syndrome
  • Uncontrolled diabetes mellitus
  • Anorexia/malnutrition
  • Acute illness/surgery
  • Excessive exercise
  • Depression
  • Alcoholism 2

• Medication interferences:

  • Anticonvulsants, barbiturates, antitubercular drugs can alter cortisol metabolism
  • Oral estrogens, CYP3A4 inhibitors/inducers can interfere with cortisol measurement 2

Pitfalls to Avoid

1. Don't use IPSS to diagnose hypercortisolism - it should only be used to differentiate between pituitary and ectopic sources of ACTH 1

2. Don't rely on a single test - false positives and negatives are common, especially in mild cases 2

3. Don't forget to measure dexamethasone levels when performing DST if false-positive results are suspected 1

4. Don't perform dynamic testing in cyclic Cushing's syndrome without first confirming the patient is in an active phase 1

5. Don't delay diagnosis - early detection and treatment are critical to reduce morbidity and mortality associated with prolonged hypercortisolism 2, 3

The diagnostic approach to Cushing's syndrome requires careful attention to detail and proper test selection based on clinical presentation. Following this systematic approach will help ensure accurate diagnosis and appropriate treatment planning for patients with suspected Cushing's syndrome.