Is elevated cortisol with adrenocorticotropic hormone (ACTH) levels greater than 15 and a failed low-dose dexamethasone suppression test (LDDST) with a greater than 50% drop sufficient to diagnose adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome?

Diagnosing ACTH-Dependent Cushing's Syndrome

Elevated cortisol with ACTH levels >15 pg/mL and a failed low-dose dexamethasone suppression test (LDDST) with >50% drop is sufficient to diagnose ACTH-dependent Cushing's syndrome. 1, 2

Diagnostic Criteria for ACTH-Dependency

• ACTH levels >5 pg/mL are detectable and suggest ACTH-dependent Cushing's syndrome with high certainty 1
• ACTH levels >29 pg/mL have 70% sensitivity and 100% specificity for diagnosing Cushing's disease (pituitary source of ACTH) 1, 2
• Morning plasma ACTH levels combined with elevated cortisol and failed LDDST establish the diagnosis of ACTH-dependent Cushing's syndrome 2

Diagnostic Algorithm

1. First step: Confirm hypercortisolism using at least two first-line tests:

   • 24-hour urinary free cortisol (UFC)
   • Late-night salivary cortisol (LNSC)
   • Low-dose dexamethasone suppression test (LDDST) 2

2. Second step: Determine ACTH-dependency:

   • ACTH levels >5 pg/mL indicate ACTH-dependent Cushing's syndrome 1, 2
   • ACTH levels <5 pg/mL suggest ACTH-independent (adrenal) Cushing's syndrome 1

3. Third step: For confirmed ACTH-dependent Cushing's syndrome, determine the source:

   • Pituitary MRI to identify adenoma (sensitivity 63%, specificity 92%) 2
   • CRH stimulation test (≥20% increase in cortisol supports pituitary origin) 2
   • Bilateral inferior petrosal sinus sampling (BIPSS) if needed 1, 2

Important Clinical Considerations

• ACTH-dependent Cushing's syndrome accounts for 75-80% of pediatric cases and is most commonly caused by pituitary adenomas 3
• In adults with Cushing's syndrome, ACTH-dependent forms are also predominant 1
• The combination of elevated cortisol, ACTH >15 pg/mL, and failed LDDST with >50% drop strongly supports ACTH-dependent Cushing's syndrome 1, 2

Common Pitfalls and Caveats

• Cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation 1
• Pseudo-Cushing's states (severe obesity, alcoholism, depression) can cause false positive results in screening tests and must be excluded 1
• Exogenous glucocorticoid use must be ruled out before biochemical testing 2
• In pediatric patients, growth failure combined with weight gain has high sensitivity and specificity for Cushing's syndrome 3

Further Diagnostic Steps

• For confirmed ACTH-dependent Cushing's syndrome, pituitary MRI is recommended as the next step 1, 2
• If pituitary imaging is negative or equivocal, BIPSS should be performed to differentiate between pituitary and ectopic sources of ACTH 2, 4
• BIPSS has diagnostic criteria of central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after stimulation, with sensitivity of 100% 2

The diagnostic approach should be systematic, and while the combination of elevated cortisol, ACTH >15 pg/mL, and failed LDDST with >50% drop is highly suggestive of ACTH-dependent Cushing's syndrome, additional testing is typically required to confirm the source of ACTH excess for definitive treatment planning 1, 2, 4.