How does dexamethasone (corticosteroid) diagnose Cushing's disease?

How Dexamethasone Diagnoses Cushing's Disease

Dexamethasone is used in suppression tests to diagnose Cushing's disease by evaluating the abnormal feedback mechanism in the hypothalamic-pituitary-adrenal axis, with failure to suppress cortisol production after dexamethasone administration being diagnostic of pathological hypercortisolism. 1

Diagnostic Approach Using Dexamethasone

Initial Screening with Dexamethasone Suppression Test (DST)

• Overnight 1-mg DST:

  • Administration: 1 mg dexamethasone given orally between 11:00 PM and midnight
  • Measurement: Serum cortisol at 8:00 AM the following morning
  • Interpretation: Normal response is cortisol <1.8 μg/dL (50 nmol/L)
  • Sensitivity: >90% (highest among screening tests) 1
  • A negative result strongly predicts absence of Cushing's syndrome 1

• Measuring dexamethasone levels simultaneously with cortisol improves test interpretability and reduces false-positive results 1, 2

  • Threshold of 4.5 nmol/L for dexamethasone has been validated to ensure adequate drug exposure 2

Differential Diagnosis Using High-Dose DST

After confirming hypercortisolism, dexamethasone helps differentiate between causes:

• High-dose DST (8 mg overnight or 2 mg q6h for 2 days):

  • In Cushing's disease (pituitary adenoma): Cortisol typically suppresses by ≥50%
  • In ectopic ACTH or adrenal causes: Minimal or no suppression occurs 1, 3

• Very high-dose DST (32 mg) may be used in cases where 8 mg fails to suppress cortisol

  • Particularly useful in patients with pituitary macroadenomas who may be resistant to standard doses 3

Pitfalls and Considerations

False Positive Results (Failure to Suppress Despite No Cushing's)

• Rapid dexamethasone metabolism (increased CYP3A4 activity)
• Medications: phenobarbital, carbamazepine, St. John's wort
• Increased cortisol-binding globulin: oral estrogens, pregnancy
• Chronic active hepatitis 1
• About 6% of non-Cushing's patients fail to achieve adequate dexamethasone levels 2

False Negative Results (Inappropriate Suppression Despite Cushing's)

• Inhibition of dexamethasone metabolism: fluoxetine, cimetidine, diltiazem
• Decreased binding proteins (nephrotic syndrome) 1

Special Populations

• Shift workers: DST may be preferred over late-night salivary cortisol 1
• Women on estrogen-containing contraceptives: Avoid DST due to altered binding proteins 1
• Children and adolescents:
  • For overnight test: 25 μg/kg at 11:00 PM (maximum 1 mg)
  • For low-dose test: 30 μg/kg/day for patients <40 kg 1

Diagnostic Algorithm

1. Initial screening: Overnight 1-mg DST, with simultaneous measurement of dexamethasone level

   • If cortisol <1.8 μg/dL: Cushing's syndrome unlikely
   • If cortisol >1.8 μg/dL but <5 μg/dL: Possible Cushing's syndrome
   • If cortisol >5 μg/dL: Highly suspicious for Cushing's syndrome 1

2. Confirmation: Repeat testing or additional tests (UFC, LNSC)

   • Multiple tests increase diagnostic certainty 1

3. Differential diagnosis: Measure ACTH levels

   • If ACTH is detectable/elevated: ACTH-dependent Cushing's (pituitary or ectopic)
   • If ACTH is suppressed: ACTH-independent Cushing's (adrenal) 1

4. For ACTH-dependent cases: High-dose DST (8 mg)

   • 50% suppression suggests Cushing's disease

   • <50% suppression suggests ectopic ACTH or resistant Cushing's disease 1, 4

5. For resistant cases: Consider very high-dose DST (32 mg) or CRH stimulation test 3

The dexamethasone suppression test remains a cornerstone in diagnosing Cushing's disease, but interpretation must consider factors affecting dexamethasone metabolism and cortisol binding to avoid misdiagnosis.