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 serving as a recommended first-line screening test due to its high sensitivity and ability to effectively rule out the condition when negative. 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 next morning 1

  • Normal response: cortisol <1.8 μg/dL (50 nmol/L), which strongly predicts absence of Cushing's syndrome 1
  • Particularly useful for ruling out dysregulated cortisol production from adrenal incidentalomas 1

• 2-day Low-Dose DST (LDDST): Dexamethasone 0.5 mg every 6 hours (09:00,15:00,21:00,03:00) for 48 hours, with cortisol measurements at 0,24, and 48 hours 3

  • Normal response: cortisol suppression below 50 nmol/L (1.8 μg/dL) 3
  • Sensitivity of 95% and specificity of 80% for diagnosing Cushing's syndrome 3

• High-Dose DST: Used for differential diagnosis of ACTH-dependent Cushing's syndrome 4, 5

  • Helps distinguish pituitary (Cushing's disease) from ectopic ACTH sources 4
  • Overnight 8-mg test has 95% sensitivity using >50% suppression criterion 5

Diagnostic Algorithm for Cushing's Syndrome

1. Initial screening based on clinical suspicion 1, 2:

   • Low suspicion: Start with late-night salivary cortisol (LNSC)
   • Intermediate/high suspicion: Perform 2-3 screening tests (LNSC, 24h UFC, overnight DST)

2. Interpretation of screening results 1:

   • Normal results: Cushing's syndrome unlikely
   • Abnormal results: Repeat 1-2 screening tests
   • Persistently abnormal: Proceed to ACTH measurement

3. Differential diagnosis based on ACTH levels 1, 2:

   • Low ACTH: ACTH-independent CS (adrenal imaging)
   • Normal/high ACTH: ACTH-dependent CS (pituitary MRI)

Improving DST Accuracy

• Measure dexamethasone levels concomitantly with cortisol to reduce false-positive results 1, 6

  • Lower limit of normal dexamethasone concentration: 1.8 ng/mL (4.6 nmol/L) 6
  • This approach can increase clinical specificity from 67.5% to 92.4% while maintaining 100% sensitivity 6

• Consider factors that may affect test interpretation 1:

  • False positives: Rapid dexamethasone absorption/malabsorption, CYP3A4 inducers (phenobarbital, carbamazepine), increased CBG levels (oral estrogens, pregnancy) 1
  • False negatives: Inhibition of dexamethasone metabolism (fluoxetine, cimetidine, diltiazem), decreased CBG levels (nephrotic syndrome) 1

Limitations and Pitfalls

• The overnight DST has reduced sensitivity in patients with mild and/or episodic hypercortisolism 7

  • In one study, using a cortisol cutoff of >5 μg/dL showed only 18% sensitivity in mild/periodic cases 7
  • Even with a stringent cutoff of >1.8 μg/dL, sensitivity was only 41% 7

• DST should not be used in shift workers or those with disrupted day/night cycles 1

• Multiple tests may be needed for accurate diagnosis, especially in cases of cyclic Cushing's syndrome 1, 2

Special Considerations

• For adrenal incidentalomas, DST is particularly useful as a first-line test 1

  • Cortisol values >5 μg/dL generally identify patients with dysregulated cortisol secretion from an incidentaloma 1

• In cases of suspected pseudo-Cushing's states (psychiatric disorders, alcohol use disorder, obesity), additional testing may be required as DST can yield false positives 1, 2

  • Combined LDDT-CRH (Dex-CRH) test may help distinguish between ACTH-dependent CS and pseudo-CS 1