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

The Role of High-Dose Dexamethasone Suppression Test in Diagnosing Cushing's Syndrome

The high-dose dexamethasone suppression test is primarily used to differentiate between ACTH-dependent causes of Cushing's syndrome, particularly to distinguish pituitary Cushing's disease from ectopic ACTH syndrome, after the diagnosis of Cushing's syndrome has been established. 1, 2

Diagnostic Algorithm for Cushing's Syndrome

First-Line Screening Tests

• Initial diagnosis of Cushing's syndrome should begin with first-line screening tests: late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), or overnight 1-mg dexamethasone suppression test (DST) 1, 2
• Multiple tests are recommended for intermediate or high clinical suspicion (at least 2-3 tests) 1, 2
• LNSC has high sensitivity (95%) and specificity (100%), with at least 2-3 samples collected on consecutive days 2
• 24-hour UFC has high sensitivity (89%) and specificity (100%), with 2-3 collections recommended to account for variability 2
• Overnight 1-mg DST with cortisol <1.8 μg/dL (50 nmol/L) at 8 AM indicates normal response 2, 3

Determining ACTH Dependency

• After confirming hypercortisolism, measure morning plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes 1, 2
• Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L) suggests ACTH-dependent Cushing's syndrome 1, 2
• Low/undetectable ACTH indicates ACTH-independent Cushing's syndrome 2

High-Dose Dexamethasone Suppression Test

Purpose and Protocol

• The high-dose dexamethasone test is used specifically to differentiate between pituitary Cushing's disease and ectopic ACTH syndrome in ACTH-dependent cases 1, 4
• Two common protocols:
  • Overnight 8-mg DST: 8 mg dexamethasone given at midnight, with cortisol measured at 8 AM 4, 5
  • 2-day 2-mg DST every 6 hours (total 16 mg over 48 hours) with measurement of serum cortisol or UFC 4

Interpretation

• In pituitary Cushing's disease, cortisol typically suppresses by >50% with high-dose dexamethasone 4, 5
• In ectopic ACTH syndrome, cortisol typically does not suppress significantly 4, 5
• The overnight 8-mg DST has shown 95% sensitivity using >50% suppression criterion, but only 62% sensitivity using >80% suppression criterion 4
• The 2-day 2-mg DST with >90% suppression of UFC has shown 64% sensitivity 4

Limitations

• The high-dose DST has limited precision and may not be reliable in all cases 4, 6
• Some patients with pituitary Cushing's disease may not show adequate suppression with standard doses 7
• Some cases of ectopic ACTH syndrome may show suppression, leading to misdiagnosis 6
• Test results should be interpreted in conjunction with other clinical and biochemical data 6

Alternative and Confirmatory Tests

CRH Stimulation Test

• The CRH stimulation test has shown better diagnostic accuracy than high-dose DST 7
• A ≥20% increase in cortisol from baseline during CRH testing supports pituitary origin 1, 2

Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

• BIPSS is the gold standard for differentiating pituitary from ectopic sources of ACTH 1, 2
• Recommended for ACTH-dependent cases with equivocal findings 2
• Should not be used to diagnose hypercortisolism itself 1

Special Considerations

Factors Affecting Test Interpretation

• Measuring dexamethasone levels along with cortisol improves test interpretability 1, 3
• DST may not be reliable in women taking oral estrogen 1, 3
• DST is preferred for shift workers and patients with disrupted circadian rhythm 1, 3
• Pseudo-Cushing's states (obesity, depression, alcoholism) can cause false-positive results 2

Pediatric Considerations

• In children, screening should focus on those with unexplained weight gain combined with growth rate deceleration 1
• Diagnostic protocols for children follow similar principles as adults but with age-appropriate cutoffs 1

Conclusion

• The high-dose dexamethasone suppression test has value in the differential diagnosis of ACTH-dependent Cushing's syndrome but should not be used in isolation 4, 6
• Modern diagnostic algorithms increasingly rely on a combination of tests, with BIPSS being the gold standard for differentiating pituitary from ectopic sources 1, 2
• The overnight 8-mg DST offers better sensitivity than the 2-day protocol and is more convenient for patients 4, 5