What is the appropriate workup for Cushing's disease (Cushing's syndrome caused by a pituitary adenoma)?

Workup for Cushing's Disease

The diagnostic workup for Cushing's disease requires a two-step approach: first confirming hypercortisolism (Cushing's syndrome), then determining its pituitary origin through specific testing including plasma ACTH measurement, CRH stimulation testing, pituitary MRI, and bilateral inferior petrosal sinus sampling. 1

Step 1: Confirming Hypercortisolism (Cushing's Syndrome)

Initial screening should be performed in patients with suspicious clinical features, particularly:

• Unexplained weight gain combined with growth rate deceleration or decreasing height percentile (high sensitivity and specificity in children/adolescents) 1
• Characteristic physical findings: facial plethora, purple striae, proximal muscle weakness, and abnormal fat distribution 2

Recommended first-line tests (at least two positive tests recommended):

1. 24-hour urinary free cortisol (UFC)

   • Collect for 3 consecutive days
   • Diagnostic cutoff: >193 nmol/24h (>70 μg/m²)
   • Sensitivity: 89%, Specificity: 100% 1

2. Late-night salivary cortisol

   • Based on local assay cutoff
   • Sensitivity: 95%, Specificity: 100% 1

3. Serum cortisol circadian rhythm study

   • Measure at 09:00h, 18:00h, and midnight (while sleeping)
   • Midnight cortisol ≥50 nmol/l (≥1.8 μg/dl) is diagnostic
   • Sensitivity: 100%, Specificity: 60% 1

4. Low-dose dexamethasone suppression test (LDDST)

   • 0.5 mg every 6 hours (09:00h, 15:00h, 21:00h, 03:00h) for 48 hours
   • For patients <40kg: 30 μg/kg/day
   • Measure serum cortisol at 0,24, and 48 hours
   • Failure to suppress to <50 nmol/l (<1.8 μg/dl) is diagnostic
   • Sensitivity: 95%, Specificity: 80% 1

Step 2: Determining Pituitary Origin (Cushing's Disease)

Once hypercortisolism is confirmed, determine if it is ACTH-dependent:

1. Morning plasma ACTH measurement (09:00h)

   • ACTH >1.1 pmol/l (>5 ng/l) indicates ACTH-dependency
   • Using cutoff of 29 ng/l (6.4 pmol/l): 70% sensitivity, 100% specificity for Cushing's disease 1
   • Detectable ACTH in all Cushing's disease patients 1

2. Corticotropin-releasing hormone (CRH) stimulation test

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

3. Pituitary MRI with contrast

   • To identify pituitary adenoma
   • Sensitivity: 63%, Specificity: 92% 1
   • Note: Microadenomas account for 98% of cases in children/adolescents, often ≤2mm in diameter 1

4. Bilateral inferior petrosal sinus sampling (BIPSS)

   • Strong recommendation for patients with ACTH-dependent Cushing's syndrome and no identified adenoma on MRI 1
   • Must be performed at specialized centers by experienced interventional radiologists 1
   • Confirm hypercortisolemia immediately before procedure 1
   • Diagnostic criteria:
     • Central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin
     • Central-to-peripheral ACTH ratio ≥3:1 after CRH/desmopressin
     • Sensitivity: 100% 1
   • May provide tumor lateralization if inter-petrosal sinus ACTH gradient ≥1.4 between sides 1

Important Clinical Considerations

• Distinguish from pseudo-Cushing's syndrome using dexamethasone-CRH test 3
• Exclude exogenous steroid use before testing 2, 4
• Growth failure sensitively discriminates simple obesity from Cushing's syndrome in prepubertal children but is unreliable in post-pubertal adolescents 1
• Male predominance exists in pediatric Cushing's disease (63%), unlike adult cases 1
• Boys tend to have more aggressive disease with higher BMI, shorter height, and higher plasma ACTH levels 1

Diagnostic Algorithm

1. Screen patients with suspicious clinical features
2. Confirm hypercortisolism using at least two first-line tests
3. Determine ACTH-dependence with morning plasma ACTH
4. Confirm pituitary source with CRH test and pituitary MRI
5. Perform BIPSS if MRI is negative or inconclusive
6. Monitor for recurrence after treatment with 6-monthly clinical examination, 24h UFC, electrolytes, and morning serum cortisol for at least 2 years 1

Early diagnosis and treatment are critical as Cushing's disease is associated with significant morbidity including psychiatric and neurocognitive effects, which may not fully resolve even after successful treatment 1.