What is the next step if a morning cortisol test is highly suggestive of Cushing's (Cushing's syndrome)?

Next Steps After Morning Cortisol Test Suggestive of Cushing's Syndrome

The next step after a morning cortisol test suggestive of Cushing's syndrome is to confirm hypercortisolism with additional screening tests, specifically 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and low-dose dexamethasone suppression test (LDDST), followed by determination of ACTH status. 1

Confirming Hypercortisolism

A single morning cortisol test alone is insufficient for diagnosis. You must first confirm the presence of hypercortisolism using established algorithms:

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
   • Ensure complete collections with appropriate total volumes

2. Late-Night Salivary Cortisol (LNSC):

   • Collect at bedtime
   • Based on local assay cutoff
   • Sensitivity: 95%, Specificity: 100% 1
   • Particularly useful for detecting cyclic Cushing's syndrome 1, 2

3. Low-Dose Dexamethasone Suppression Test (LDDST):

   • 0.5 mg every 6 hours for 48 hours (or overnight 1-mg test)
   • Diagnostic cutoff: ≥50 nmol/l (≥1.8 μg/dl)
   • Sensitivity: 95%, Specificity: 80% 1
   • Consider measuring dexamethasone levels to ensure adequate absorption 1

Determining ACTH Status

After confirming hypercortisolism, determine if it's ACTH-dependent or independent:

• Measure morning plasma ACTH (09:00h):
  • ACTH detectable (>5 ng/l or >1.1 pmol/l): ACTH-dependent Cushing's syndrome
  • ACTH low or undetectable: ACTH-independent Cushing's syndrome 1

Further Evaluation Based on ACTH Status

If ACTH-Dependent:

1. Pituitary MRI with contrast:

   • Sensitivity for adenoma detection: 63%, Specificity: 92% 1

2. CRH Stimulation Test:

   • 1.0 μg/kg CRH intravenously
   • Diagnostic cutoff: ≥20% increase in cortisol
   • Sensitivity: 74-100% 1

3. If MRI negative or equivocal:

   • Bilateral inferior petrosal sinus sampling (BSIPSS) with CRH or desmopressin
   • Central-to-peripheral ACTH ratio ≥3 confirms pituitary source
   • Must be performed at specialized centers by experienced interventional radiologists 1

If ACTH-Independent:

• Adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral hyperplasia 1

Important Considerations

• False positives/negatives: Be aware of factors that can interfere with test results:

  • Medications affecting CYP3A4 (phenobarbital, carbamazepine, fluoxetine)
  • Altered corticosteroid binding globulin levels (oral estrogens, pregnancy)
  • Renal impairment (affects UFC) 1

• Cyclic Cushing's syndrome: Consider multiple, sequential measurements if cortisol production fluctuates 2

• Children vs. adults: In prepubertal children, growth failure combined with weight gain is highly specific for Cushing's syndrome. Post-pubertal adolescents should be evaluated using adult criteria 1, 2

• Test quality: Mass spectrometry methods are preferred over immunoassays for better sensitivity in cortisol measurements 2

Remember that early diagnosis and treatment are crucial for reducing morbidity and mortality associated with Cushing's syndrome, including cardiovascular complications, infections, and neuropsychiatric disorders 3.