What are the diagnostic criteria for Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome?

Diagnostic Criteria for ACTH-Dependent Cushing's Syndrome

ACTH-dependent Cushing's syndrome is diagnosed through a two-step process: first confirming hypercortisolism (Cushing's syndrome), then establishing ACTH dependency with normal or elevated plasma ACTH levels (>5 ng/L or >1.1 pmol/L) and additional confirmatory testing. 1, 2

Step 1: Confirming Cushing's Syndrome

Initial screening requires at least two of the following first-line tests:

• Late-night salivary cortisol (LNSC): Collect 2-3 samples on different days

  • Sensitivity: 95%, Specificity: 100%
  • Based on local assay cut-off values 1, 2

• 24-hour urinary free cortisol (UFC): Collect 3 samples

  • Sensitivity: 89%, Specificity: 100%
  • Diagnostic cut-off: >193 nmol/24h (>70 μg/m²) 1, 2

• Low-dose dexamethasone suppression test (LDDST):

  • 0.5 mg dexamethasone every 6 hours for 48 hours (30 μg/kg/day for patients <40 kg)
  • Serum cortisol measured at 0,24, and 48 hours
  • Diagnostic cut-off: ≥50 nmol/L (≥1.8 μg/dL)
  • Sensitivity: 95%, Specificity: 80% 1, 2

• Overnight dexamethasone suppression test:

  • 25 μg/kg at 23:00h (maximum 1 mg)
  • Serum cortisol measured at 09:00h
  • Diagnostic cut-off: ≥50 nmol/L (≥1.8 μg/dL) 1

• Serum cortisol circadian rhythm study:

  • Measurements at 09:00h, 18:00h, and midnight (sleeping)
  • Midnight diagnostic cut-off: ≥50 nmol/L (≥1.8 μg/dL)
  • Sensitivity: 100%, Specificity: 60% 1

Step 2: Confirming ACTH Dependency

Once Cushing's syndrome is confirmed, determine ACTH dependency:

• Morning plasma ACTH (08:00-09:00h):

  • Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L) indicates ACTH-dependent Cushing's
  • Low/undetectable ACTH indicates ACTH-independent Cushing's
  • Using cut-off value of 29 ng/L (6.4 pmol/L): Sensitivity 70%, Specificity 100% 1, 2

• CRH stimulation test:

  • 1.0 μg/kg CRH intravenously
  • ≥20% increase in cortisol from baseline supports pituitary origin
  • Sensitivity: 74-100% 1, 2

• Pituitary MRI:

  • Adenoma detection: Sensitivity 63%, Specificity 92% 1

• Bilateral inferior petrosal sinus sampling (BSIPSS):

  • Indicated when ACTH-dependent Cushing's is confirmed but no adenoma is visible on MRI
  • Performed with CRH or desmopressin stimulation
  • Diagnostic criteria:
    • Central-to-peripheral ACTH ratio ≥2:1 before stimulation
    • Central-to-peripheral ACTH ratio ≥3:1 after stimulation
    • Sensitivity: 100% 1, 2
  • Inter-petrosal sinus ACTH gradient ≥1.4 between sides may provide tumor lateralization information 1

Clinical Considerations

• Patient selection: Screen for Cushing's syndrome in patients with unexplained weight gain combined with either decreased height SDS or height velocity 1

• Potential pitfalls:

  • Pseudo-Cushing's states (severe obesity, uncontrolled diabetes, depression, alcoholism) can cause false-positive results 2, 3
  • Mild Cushing's syndrome may present with normal or only mildly elevated UFC 4
  • Cyclical Cushing's syndrome requires multiple samples over time 1, 3

• Special considerations:

  • Confirm hypercortisolemia immediately prior to BSIPSS to ensure active disease phase 1
  • BSIPSS should only be performed in specialized centers by experienced interventional radiologists 1
  • Rule out exogenous glucocorticoid use before biochemical testing 1, 2

Diagnostic Algorithm

1. Screen with at least two first-line tests (LNSC, UFC, DST) 2
2. If positive, measure morning plasma ACTH 1, 2
3. If ACTH is normal/elevated, proceed with pituitary MRI 2
4. If MRI shows adenoma, diagnose ACTH-dependent Cushing's disease 1
5. If MRI is negative/equivocal, perform BSIPSS to confirm pituitary source 1, 2
6. If BSIPSS is negative for central source, investigate for ectopic ACTH syndrome 2, 3