Is a failed Low-Dose Dexamethasone Suppression Test (LDDST) with two random elevated cortisol levels and normal Adrenocorticotropic Hormone (ACTH) levels sufficient to establish Adrenocorticotropic Hormone (ACTH) dependence?

Diagnosing ACTH Dependency in Cushing's Syndrome

Two random elevated cortisol levels with normal ACTH and a failed low-dose dexamethasone suppression test (LDDST) with less than 50% suppression are not sufficient to establish ACTH dependence; in fact, these findings suggest ACTH-independent Cushing's syndrome.

Diagnostic Criteria for ACTH Dependency

• ACTH levels are the definitive factor in distinguishing between ACTH-dependent and ACTH-independent Cushing's syndrome 1
• Any ACTH level >5 ng/L is detectable and suggests an ACTH-dependent form of Cushing's syndrome 1
• Normal or elevated ACTH levels indicate ACTH-dependent Cushing's syndrome, while low or undetectable ACTH levels indicate ACTH-independent Cushing's syndrome 1
• An ACTH level >29 ng/L has 70% sensitivity and 100% specificity for diagnosing Cushing's disease (pituitary-dependent Cushing's syndrome) 1

Interpretation of Your Case Findings

• Normal ACTH levels with elevated cortisol levels and failed LDDST could represent either:

  • Early ACTH-independent Cushing's syndrome (adrenal source) 2
  • Possible pseudo-Cushing's states that need to be excluded 2

• Failed LDDST with <50% suppression suggests autonomous cortisol production, which is characteristic of adrenal adenomas rather than ACTH-dependent causes 3

Proper Diagnostic Algorithm

1. Confirm Hypercortisolism first with at least two first-line tests:

   • Late-night salivary cortisol (LNSC)
   • 24-hour urinary free cortisol (UFC)
   • Low-dose dexamethasone suppression test (LDDST) 4

2. Determine ACTH Dependency:

   • Measure morning plasma ACTH levels 4
   • ACTH levels >5 ng/L indicate ACTH-dependent Cushing's 4
   • ACTH levels <5 ng/L indicate ACTH-independent Cushing's 1

3. For ACTH-Dependent Cushing's:

   • Perform pituitary MRI 2, 4
   • Consider CRH stimulation test (≥20% increase in cortisol supports pituitary origin) 4
   • If inconclusive, proceed to bilateral inferior petrosal sinus sampling (BIPSS) 2, 4

4. For ACTH-Independent Cushing's:

   • Perform adrenal CT or MRI to identify adrenal lesion(s) 2, 1

Common Pitfalls and Caveats

• Relying solely on LDDST without measuring ACTH levels can lead to misdiagnosis 2

• Normal ACTH levels must be interpreted in context - they could represent early adrenal disease with incomplete suppression of pituitary ACTH 3

• Cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation 2

• Certain conditions can cause false positive results in screening tests:

  • Severe obesity
  • Uncontrolled diabetes
  • Depression
  • Alcoholism 2, 4

• ACTH assays have variable sensitivity and specificity across laboratories, so values must be interpreted according to local reference ranges 4

Conclusion

The combination of elevated cortisol, normal ACTH, and failed LDDST suggests ACTH-independent Cushing's syndrome rather than ACTH-dependent disease. Further evaluation with adrenal imaging would be the appropriate next step to identify a potential adrenal source 2, 1.