What is the diagnostic approach for Cushing's syndrome?

Diagnostic Approach for Cushing's Syndrome

The diagnosis of Cushing's syndrome requires a three-step approach: first confirm hypercortisolism using 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), or overnight 1 mg dexamethasone suppression test (DST); then determine if it's ACTH-dependent or independent by measuring plasma ACTH; finally identify the source through appropriate imaging and dynamic testing. 1, 2

Step 1: Confirming Hypercortisolism

First-line screening tests (perform at least two):

• Late-night salivary cortisol (LNSC): >90% sensitivity, 100% specificity

  • Particularly useful for initial screening and monitoring cyclic Cushing's syndrome
  • Reflects disrupted circadian rhythm of cortisol secretion

• 24-hour urinary free cortisol (UFC):

  • Reflects overall cortisol production
  • Collect at least two samples

• Overnight 1 mg dexamethasone suppression test (DST):

  • Normal response: morning cortisol <1.8 μg/dL
  • Useful for adrenal incidentalomas and patients with disrupted circadian rhythms

Important considerations:

• False positives can occur in:

  • Severe obesity
  • Uncontrolled diabetes
  • Pregnancy
  • Polycystic ovary syndrome
  • Psychiatric disorders
  • Alcohol use disorder 2

• False negatives can occur in:

  • Cyclic Cushing's syndrome
  • Mild Cushing's syndrome 2

• Women taking estrogen-containing oral contraceptives may have false positive DST results 2

• Avoid medications that interfere with dexamethasone metabolism (particularly CYP3A4 inducers) 2

Step 2: Determining the Source of Hypercortisolism

Measure plasma ACTH:

• Low ACTH (<5 pg/mL): ACTH-independent (adrenal source)

  • Proceed to adrenal imaging (CT or MRI)

• Normal or high ACTH (≥5 pg/mL): ACTH-dependent

  • Proceed to pituitary MRI and further testing 1, 2

Step 3: Localizing the Source in ACTH-Dependent Cushing's Syndrome

For ACTH-dependent cases:

1. Pituitary MRI with contrast:

   • High-resolution pituitary protocols have 80.2% sensitivity and 83.3% specificity 2
   • Interpretation based on adenoma size:
     • ≥10 mm: IPSS generally not needed if clinical and biochemical features consistent with Cushing's disease
     • <6 mm: IPSS recommended
     • 6-9 mm: Expert opinions differ on need for IPSS 1

2. Dynamic testing:

   • High-dose dexamethasone suppression test
   • CRH stimulation test
   • Both tests help differentiate pituitary from ectopic sources 2

3. Inferior Petrosal Sinus Sampling (IPSS):

   • Gold standard for establishing ACTH source
   • Recommended when clinical, biochemical, or radiological studies are discordant or equivocal
   • Central-to-peripheral ACTH gradient >2 at baseline or >3 after CRH stimulation indicates pituitary source 1, 2

Special Considerations

Pediatric Cushing's Syndrome:

• Growth failure with weight gain is the key distinguishing feature
• Cushing's disease accounts for 75-80% of pediatric cases in children over age 6
• Adrenal causes more common in younger children
• IPSS has more limited role compared to adults 1, 2

Diagnostic Algorithm:

1. Rule out exogenous glucocorticoid use
2. Assess clinical likelihood of endogenous Cushing's syndrome
3. Perform 2-3 screening tests (LNSC, 24h UFC, overnight 1 mg DST)
4. If abnormal, repeat testing to confirm
5. Measure ACTH to determine source
6. Proceed with appropriate imaging and dynamic testing based on ACTH status 1

Common Pitfalls:

• Failing to exclude exogenous glucocorticoid use
• Not repeating abnormal screening tests for confirmation
• Misinterpreting results in conditions that can cause false positives
• Not considering cyclic Cushing's syndrome when results are inconsistent
• Relying solely on imaging without biochemical confirmation 1, 2, 3

By following this systematic approach, clinicians can accurately diagnose Cushing's syndrome and determine its etiology, which is crucial for appropriate treatment planning and improved patient outcomes.