What is the recommended approach for screening for Cushing's syndrome?

Screening for Cushing's Syndrome

The recommended approach for screening Cushing's syndrome includes three first-line tests: 1 mg overnight dexamethasone suppression test (DST), late-night salivary cortisol (LNSC), and 24-hour urinary free cortisol (UFC), with LNSC being the most useful initial screening test due to its high sensitivity and specificity. 1

When to Consider Screening

Consider screening for Cushing's syndrome in patients with:

• Multiple and progressive features suggestive of Cushing's syndrome
• Unusual features for age (e.g., osteoporosis, hypertension in young patients)
• Classic signs: facial plethora, proximal myopathy, wide purple striae, supraclavicular fat pads
• Common signs: weight gain, hypertension, glucose abnormalities, menstrual irregularities
• Children with decreased linear growth and continued weight gain 1, 2

First-Line Screening Tests

1. Late-Night Salivary Cortisol (LNSC)

• Preferred initial test with >90% sensitivity and 100% specificity 1
• Advantages:
  • Non-invasive, convenient collection
  • Reflects free (active) cortisol
  • Particularly useful for:
    • Initial screening
    • Longitudinal surveillance of cyclic Cushing's syndrome
    • Patients with renal impairment (preferred over UFC)
    • Patients with disrupted circadian rhythms 1, 3

2. 1 mg Overnight Dexamethasone Suppression Test (DST)

• Patient takes 1 mg dexamethasone at 11 PM, cortisol measured at 8 AM next day
• Values over 5 μg/dL generally identify patients with dysregulated cortisol secretion
• Cortisol result of ≤2.2 μg/dL indicates adequate suppression (rules out Cushing's) 1
• Particularly useful for:
  • Initial screening
  • Adrenal incidentalomas
  • Shift workers or those with disrupted circadian rhythms 1

3. 24-hour Urinary Free Cortisol (UFC)

• Reflects overall cortisol production
• Useful as supporting diagnostic evidence
• At least 2-3 collections recommended for confirmation 1

Potential False Results and Considerations

False Positives

• Pseudo-Cushing's states: psychiatric disorders, alcohol use disorder, polycystic ovary syndrome, obesity
• Medications affecting dexamethasone metabolism (CYP3A4 inducers): phenobarbital, carbamazepine, St. John's wort
• Increased CBG levels: oral estrogens, pregnancy, chronic active hepatitis 1

False Negatives

• CYP3A4 inhibitors: fluoxetine, cimetidine, diltiazem
• Decreased CBG/albumin levels (e.g., nephrotic syndrome)
• Absorption issues: rapid absorption/malabsorption of dexamethasone 1

Confirmatory Testing

If initial screening is positive or clinical suspicion remains high despite normal results:

1. Measure dexamethasone levels concomitantly with cortisol to confirm adequate absorption
2. Perform additional confirmatory tests (e.g., additional UFC measurements)
3. Measure plasma ACTH to differentiate ACTH-dependent from ACTH-independent Cushing's syndrome:
   • Elevated ACTH: suggests pituitary Cushing's disease or ectopic ACTH syndrome
   • Low/suppressed ACTH: suggests adrenal source 1

Special Considerations

• For women on estrogen-containing oral contraceptives: Consider potential false positives with DST
• For patients on medications affecting dexamethasone metabolism: Consider using 2 mg DST instead of 1 mg DST
• For shift workers: DST may be preferred over tests requiring specific timing
• For patients with renal impairment: LNSC preferred over UFC 1

Key Pitfalls to Avoid

1. Relying on random cortisol measurements (unreliable for screening) 2
2. Failing to recognize mild or cyclical hypercortisolism 4
3. Not considering medication interactions that may affect test results 1
4. Overlooking Cushing's syndrome in patients with common conditions like hypertension, obesity, and diabetes 5
5. Not collecting adequate samples for UFC (at least 2-3 collections recommended) 1

Although Cushing's syndrome is relatively uncommon, early diagnosis is crucial to mitigate associated morbidity and mortality. Using the recommended screening tests appropriately and understanding their limitations will help identify patients who require further evaluation.