What is the role of the dexamethasone (DXM) suppression test in diagnosing Cushing's syndrome?

Role of Dexamethasone Suppression Test in Diagnosing Cushing's Syndrome

The dexamethasone suppression test (DST) is a cornerstone diagnostic tool for Cushing's syndrome, with the overnight 1-mg DST recommended as one of the first-line screening tests due to its high sensitivity and convenience compared to other testing methods. 1, 2

Types of Dexamethasone Suppression Tests

• Overnight 1-mg DST: Patient takes 1 mg dexamethasone between 11 PM and midnight, with serum cortisol measured at 8 AM the following morning; cortisol <1.8 μg/dL (50 nmol/L) is considered normal and rules out Cushing's syndrome 1
• 2-day Low-Dose DST (LDDST): Dexamethasone 0.5 mg every 6 hours for 48 hours with cortisol measurements at 0,24, and 48 hours; suppression to <1.8 μg/dL (50 nmol/L) is considered normal 3
• High-Dose DST: Used for differential diagnosis of ACTH-dependent Cushing's syndrome (not for initial screening) 4

Diagnostic Algorithm for Cushing's Syndrome

1. Initial Clinical Assessment

   • Rule out exogenous glucocorticoid use (oral, injections, inhalers, topical) 1
   • Assess clinical likelihood of endogenous Cushing's syndrome 1

2. First-line Screening Tests (perform 1-3 based on clinical suspicion):

   • Late-night salivary cortisol (LNSC) - at least 2 tests 1, 2
   • 24-hour urinary free cortisol (UFC) - at least 2-3 collections 1, 2
   • Overnight 1-mg DST 1

3. Interpretation of DST Results:

   • Normal response: Cortisol <1.8 μg/dL (50 nmol/L) - rules out Cushing's syndrome 1, 3
   • Abnormal response: Cortisol ≥1.8 μg/dL (50 nmol/L) - suggests Cushing's syndrome 1, 3

4. If screening tests are abnormal:

   • Measure plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes 1, 2
   • Proceed with appropriate imaging based on ACTH results 1

Advantages of DST

• High sensitivity for excluding Cushing's syndrome when negative 1, 2
• Particularly useful for evaluating adrenal incidentalomas (cortisol values <1.8 μg/dL excludes dysregulated cortisol production) 1
• Can be performed on an outpatient basis 5

Limitations and Pitfalls

• False positive results (failure to suppress despite no Cushing's) can occur with:

  • Medications affecting dexamethasone metabolism (CYP3A4 inducers like phenobarbital, carbamazepine) 1, 3
  • Increased corticosteroid binding globulin (CBG) levels from oral estrogens or pregnancy 1
  • Rapid absorption/malabsorption of dexamethasone 1
  • Obesity, depression, alcoholism, and uncontrolled diabetes (pseudo-Cushing's states) 1, 2

• False negative results (suppression despite Cushing's) can occur with:

  • Medications inhibiting dexamethasone metabolism (fluoxetine, cimetidine, diltiazem) 1, 3
  • Decreased CBG and albumin levels 1
  • Mild and/or episodic hypercortisolism (sensitivity as low as 18-41% in these cases) 6

Improving Test Accuracy

• Measuring dexamethasone level along with cortisol improves test interpretability 1, 7
• Using method-specific cortisol cutoffs can increase clinical specificity from 67.5% to 92.4% while maintaining 100% sensitivity 7
• Consider the lower limit of normal for dexamethasone (1.8 ng/mL) to identify non-compliance or altered metabolism 7

Special Considerations

• Not recommended in shift workers due to disruption of normal day/night cycle 1
• Use caution in patients taking estrogen-containing oral contraceptives 1
• May be less reliable in patients with mild or cyclic Cushing's syndrome 6
• For patients with suspected adrenal tumor, DST is the preferred initial test 1