What is the diagnostic and treatment approach for Cushing's syndrome, including the use of the low dose dexamethasone (DEX) suppression test?

Low Dose Dexamethasone Suppression Test (LDDST) for Cushing's Syndrome Diagnosis

The overnight 1-mg dexamethasone suppression test (DST) is recommended as a first-line screening test for Cushing's syndrome due to its high sensitivity and ability to effectively rule out the condition when negative, with a normal response defined as cortisol suppression below 1.8 μg/dL (50 nmol/L). 1

Initial Screening for Cushing's Syndrome

• When clinical suspicion for Cushing's syndrome arises, first determine if the patient is taking exogenous glucocorticoids (oral, injections, inhalers, topical) which should be stopped if possible 2
• For low clinical suspicion, start with late night salivary cortisol (LNSC) testing (≥2 tests) 2
• For intermediate or high clinical suspicion, perform 2-3 screening tests including 24-hour urinary free cortisol (UFC) (≥2 tests), LNSC, and/or overnight 1-mg DST 2
• Normal results indicate Cushing's syndrome is unlikely; abnormal results require repeat testing to confirm 2

Overnight 1-mg Dexamethasone Suppression Test Protocol

• Administer 1 mg of dexamethasone orally at 11:00 PM 1
• Measure serum cortisol between 8:00-9:00 AM the following morning 1, 3
• Normal response: cortisol <1.8 μg/dL (50 nmol/L) strongly predicts absence of Cushing's syndrome 1
• Measuring dexamethasone levels concomitantly with cortisol improves test accuracy, with a lower limit of normal dexamethasone concentration of 1.8 ng/mL (4.6 nmol/L) 1, 4

2-Day Low-Dose Dexamethasone Suppression Test Protocol

• Administer 0.5 mg dexamethasone every 6 hours (09:00,15:00,21:00,03:00) for 48 hours 5
• Measure cortisol at 0,24, and 48 hours 5
• Normal response: cortisol suppression below 50 nmol/L (1.8 μg/dL) 5
• Sensitivity of 95% and specificity of 80% for diagnosing Cushing's syndrome 1, 5

Interpretation of Results

• If cortisol suppresses to <1.8 μg/dL (50 nmol/L), Cushing's syndrome is unlikely 1, 5
• If cortisol fails to suppress, proceed to measure ACTH levels to determine if Cushing's syndrome is ACTH-dependent or ACTH-independent 6
• ACTH-dependent (normal or high ACTH): proceed with pituitary MRI 2, 6
• ACTH-independent (low ACTH): proceed with adrenal CT or MRI 2, 6

Further Diagnostic Steps Based on ACTH Results

• For ACTH-dependent Cushing's syndrome with pituitary MRI findings:
  • Adenoma <6 mm: perform inferior petrosal sinus sampling (IPSS) 2
  • Adenoma 6-9 mm: consider CRH and DDAVP test; IPSS may be needed 2
  • Adenoma ≥10 mm: presumed Cushing's disease 2
• For ACTH-independent Cushing's syndrome: adrenal imaging to identify lesion(s) 2, 6

Potential Pitfalls and Considerations

• False positives (failure to suppress despite no Cushing's) can occur with:
  • Medications affecting dexamethasone metabolism (CYP3A4 inducers like phenobarbital, carbamazepine) 5
  • Estrogen-containing oral contraceptives (avoid DST in women on these medications) 2
  • Severe obesity, uncontrolled diabetes, depression, alcoholism 2, 6
• False negatives (suppression despite Cushing's) can occur with:
  • Medications inhibiting dexamethasone metabolism (fluoxetine, cimetidine) 5
  • Cyclic Cushing's syndrome (requires periodic re-evaluation) 2
• Up to 18% of patients with Cushing's disease may suppress cortisol to <5 μg/dL on the overnight 1-mg test, and 8% may suppress to <2 μg/dL 7

Special Considerations

• For suspected pseudo-Cushing's states (depression, alcoholism), the combined dexamethasone-CRH test may help distinguish from true Cushing's syndrome 8
• For adrenal incidentalomas, DST is particularly useful as a first-line test, with cortisol values >5 μg/dL generally identifying patients with dysregulated cortisol secretion 1
• DST may be preferred for shift workers and patients with disrupted circadian rhythm 1
• Measuring dexamethasone levels can reduce false-positive results, as approximately 6% of patients may not achieve adequate dexamethasone levels 4