How is Cushing's disease diagnosed?

Diagnosing Cushing's Disease

The diagnosis of Cushing's disease requires a systematic three-step approach: first confirming hypercortisolism through screening tests, then determining ACTH dependency, and finally localizing the source through appropriate imaging and dynamic testing. 1

Step 1: Confirming Hypercortisolism

Initial screening should include 2-3 of these first-line tests:

• Late-night salivary cortisol (LNSC): >90% sensitivity, 100% specificity; particularly useful for initial screening and monitoring cyclic Cushing's syndrome 1
• 24-hour urinary free cortisol (UFC): Reflects overall cortisol production 1
• Overnight 1 mg dexamethasone suppression test (DST): Recommended for initial screening, especially in cases with disrupted circadian rhythms 1

Important considerations:

• Two normal test results usually exclude Cushing's syndrome 2
• Multiple samples may be needed for mild cases, as neither a normal UFC nor a normal NSC alone can exclude mild Cushing's syndrome 3
• False positives can occur in patients with severe obesity, uncontrolled diabetes, pregnancy, PCOS, psychiatric disorders, and alcohol use disorder 1
• Women on estrogen-containing oral contraceptives may have false positive DST results 1

Step 2: Determining ACTH Dependency

Once hypercortisolism is confirmed, measure plasma ACTH levels:

• ACTH <5 pg/mL: Indicates ACTH-independent (adrenal source) 1
• ACTH ≥5 pg/mL: Indicates ACTH-dependent (pituitary or ectopic source) 1

Step 3: Localizing the Source

For ACTH-dependent Cushing's syndrome:

1. Pituitary MRI with contrast: 80.2% sensitivity and 83.3% specificity 1
2. Dynamic testing:
   • High-dose dexamethasone suppression test
   • CRH stimulation test
3. Inferior Petrosal Sinus Sampling (IPSS): Gold standard for establishing ACTH source 1
   • Required when clinical, biochemical, or radiological studies are discordant or equivocal
   • Not necessary when pituitary tumor ≥10 mm is detected on MRI and dynamic testing results are consistent with Cushing's disease
   • Generally recommended for lesions <6 mm to confirm the diagnosis 1

For ACTH-independent Cushing's syndrome:

• Adrenal imaging (CT or MRI): To identify adrenal tumors 1

Special Considerations

Pediatric Patients

• Cushing's disease accounts for 75-80% of cases in children over age 6 1
• Adrenal causes are more common in younger children 1
• Key indicator: Unexplained weight gain combined with growth failure 1

Mild Cushing's Syndrome

• May present with normal or mildly elevated UFC 3
• Multiple samples and tests are essential for diagnosis 3
• DST may be more sensitive than UFC in mild cases 3

Common Pitfalls to Avoid

1. False negatives in:

   • Cyclic Cushing's syndrome (periodic hypercortisolism)
   • Mild Cushing's syndrome 1

2. Diagnostic delay: Average time to diagnosis is 3 years 2

3. Over-testing patients with common symptoms like hypertension, weight gain, or diabetes without other specific features of Cushing's syndrome 2

4. Under-recognition of the characteristic phenotype: unusual fat distribution (face, neck, trunk), skin changes (plethora, acne, hirsutism, livid striae, easy bruising), and signs of protein catabolism (thinned skin, osteoporotic fractures, proximal myopathy) 2

5. Discordant test results: When clinical, biochemical, or radiological findings are inconsistent, IPSS should be performed 4