What is the initial step in the workup of a patient with suspected Cushing's syndrome?

Initial Workup for Suspected Cushing's Syndrome

The initial step in the workup of a patient with suspected Cushing's syndrome should be one of three first-line screening tests: 24-hour urinary free cortisol measurement, late-night salivary cortisol testing, or the 1mg overnight dexamethasone suppression test. 1

Clinical Suspicion: When to Test

Before ordering any tests, ensure the patient has clinical features suggestive of Cushing's syndrome:

• High-specificity features:

  • Facial plethora
  • Proximal myopathy
  • Wide (>1cm) purple striae
  • Easy bruising
  • Unexplained osteoporosis
  • Unusual fat distribution (face, neck, trunk)

• Common but less specific features:

  • Hypertension
  • Weight gain
  • Diabetes mellitus
  • Menstrual irregularities

First-Line Screening Tests

According to the Endocrine Society guidelines, any of these three tests can be used as initial screening 2, 1:

1. 24-hour Urinary Free Cortisol (UFC)

   • Collect at least 2-3 samples
   • Patient should avoid strenuous physical activity 24-48 hours before and during collection
   • Note: UFC is usually the last test to become abnormal in recurrent disease

2. Late-Night Salivary Cortisol (LNSC)

   • Multiple collections (≥2) on consecutive days
   • High sensitivity (>90%) and specificity (100%)
   • Particularly useful for detecting subtle hypercortisolism

3. 1mg Overnight Dexamethasone Suppression Test (DST)

   • Administer 1mg dexamethasone at midnight
   • Measure serum cortisol between 7:30-8:00 AM the following morning
   • Failure to suppress cortisol suggests Cushing's syndrome

Important Considerations

• Rule out exogenous glucocorticoid use before biochemical testing 2
• Multiple tests may be needed - two abnormal results from different tests strongly suggest Cushing's syndrome
• Medications can affect results - consider using LC-MS/MS instead of immunoassays if patient is taking medications that might interfere with cortisol measurement 1
• Physiologic hypercortisolism ("pseudo-Cushing's") can occur in:
  • Depression
  • Alcoholism
  • Obesity
  • Uncontrolled diabetes
  • Pregnancy

Next Steps After Positive Screening

If initial screening tests are positive:

1. Measure plasma ACTH levels to differentiate ACTH-dependent from ACTH-independent Cushing's syndrome 1, 3
2. Refer to endocrinology for further evaluation and management 2

Pitfalls to Avoid

• Don't test patients with low pre-test probability - biochemical screening should only be performed if clinical suspicion is reasonably high 4
• Avoid testing during acute illness - can lead to false positive results
• Don't rely on a single test - CS diagnosis typically requires multiple abnormal test results
• Be aware of cyclic Cushing's syndrome - may require repeated testing during symptomatic periods

Remember that Cushing's syndrome is rare (1-3 cases per million per year) but associated with significant morbidity and mortality if left untreated 4. Early diagnosis is crucial for improving outcomes, but testing should be reserved for patients with a reasonable clinical suspicion to avoid unnecessary workup.