What is the role of a dexamethasone (dex) suppression test in the workup for Cushing's syndrome?

Role of Dexamethasone Suppression Test in Cushing's Syndrome Workup

The dexamethasone suppression test (DST) is a cornerstone first-line screening test for Cushing's syndrome, with the overnight 1-mg DST being the preferred initial screening method due to its practicality and reliability in detecting hypercortisolism. 1

Types of Dexamethasone Suppression Tests

• Overnight 1-mg DST:

  • First-line screening test
  • Procedure: 1 mg dexamethasone given at midnight, plasma cortisol measured at 8:00 AM the following morning
  • Interpretation: Cortisol >2.4 μg/dL (66 nmol/L) suggests Cushing's syndrome 2

• Low-dose DST (LDST):

  • Used to confirm hypercortisolism
  • Can help distinguish between Cushing's syndrome and pseudo-Cushing's states

• High-dose DST (HDST):

  • Used for differential diagnosis between different causes of Cushing's syndrome
  • Suppression of plasma cortisol levels to <50% of baseline suggests Cushing's disease (pituitary origin) 3

Diagnostic Algorithm

1. Initial Screening:

   • Use any of these tests based on clinical suspicion and availability:
     • Overnight 1-mg DST
     • Late-night salivary cortisol (LNSC)
     • 24-hour urinary free cortisol (UFC)

2. Confirmatory Testing:

   • If initial screening is positive, confirm with a different test
   • For patients with mild or fluctuating hypercortisolism, multiple tests may be needed

3. Differential Diagnosis:

   • Measure plasma ACTH to determine if Cushing's is ACTH-dependent or independent
   • Use high-dose DST to differentiate pituitary from ectopic sources in ACTH-dependent cases

Clinical Considerations

• Test Selection Based on Patient Factors:

  • DST is preferred for shift workers and patients with disrupted circadian rhythm 4
  • LNSC may be better for patients with normal sleep patterns
  • Women on estrogen-containing oral contraceptives may have false-positive results on DST 1, 5

• Improving Test Accuracy:

  • Consider measuring dexamethasone levels to verify adequate drug exposure and improve specificity 2
  • Method-specific cortisol cutoffs can increase diagnostic accuracy

• Limitations:

  • False-negative results can occur in mild or episodic Cushing's syndrome 6
  • False-positive results can occur with certain medications, obesity, depression, alcoholism (pseudo-Cushing's)
  • The sensitivity of overnight DST in mild/periodic Cushing's syndrome can be as low as 18-41% 6

Special Considerations

• Subclinical Cushing's Syndrome/Mild Autonomous Cortisol Secretion (MACS):

  • Most common hormonal dysfunction in adrenal incidentalomas 4, 1
  • Defined by abnormal DST results without overt signs/symptoms of cortisol excess
  • Present in up to 30% of adrenal incidentalomas 1
  • Management decisions should consider patient preference and severity of comorbidities 4

• Pseudo-Cushing's States:

  • Can cause mildly elevated cortisol levels (UFC usually <3-fold of normal)
  • Combined LDDT-CRH test or desmopressin test may help distinguish from true Cushing's syndrome 4
  • Consider monitoring for 3-6 months to see if symptoms resolve with treatment of underlying condition 4

Pitfalls to Avoid

• Don't rely solely on a single test - no single test has 100% sensitivity and specificity
• Don't exclude Cushing's syndrome based only on a negative DST - especially in mild or cyclic cases 7
• Don't forget to consider medication interference - phenytoin, phenobarbital, ephedrine, and rifampin can enhance dexamethasone clearance, leading to false positives 5
• Don't interpret DST results in isolation - clinical presentation and other biochemical tests should be considered together

The dexamethasone suppression test remains a valuable tool in the diagnostic workup for Cushing's syndrome, but must be interpreted in the context of the clinical picture and other biochemical tests to ensure accurate diagnosis.