Cushing's%20syndrome Diagnosis

Lab tests and radiological findings confirm diagnosis and determine the actual cause of Cushing’s syndrome

• A thorough drug history must be obtained to exclude exogenous glucocorticoid use before biochemical testing
• Recommended initial biochemical tests for Cushing's syndrome may be one of the following:
  • 24-hour urinary free cortisol (UFC) (≥2 measurements)
  • Late-night salivary cortisol (2 measurements)
  • 1-mg overnight Dexamethasone suppression test (DST)
  • Longer low-dose DST (2mg/day for 48 hours)
• In patients with low index of suspicion, one of the above tests may be done while in patients with high index of suspicion two first-line tests are recommended
• Once the diagnosis of Cushing's syndrome is confirmed, the next step is determining whether the cause is ACTH-dependent or ACTH-independent
  

• Once the diagnosis of Cushing’s syndrome is confirmed, the next step is determining whether the cause is adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent

Tests to Screen for Hypercortical State

• 24-Hour Urinary Free Cortisol (UFC) Excretion
  
  • Mainstay diagnostic test for endogenous adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome
  • Gives direct and reliable practical index of cortisol excretion
  • Normal range: Urinary cortisol <250 nmol/24 hours (90 mcg/24 hours)
  • Diagnostic range: Urinary cortisol >830 nmol/24 hours (300 mcg/24 hours)
  • 2-3 consecutive measurements required to confirm diagnosis

• Low-Dose Dexamethasone Suppression Test (DST)
  • Standard screening test to differentiate patients without Cushing’s syndrome and those with Cushing’s syndrome of any cause
  • 1 mg Overnight Dexamethasone Suppression Test
    • 1 mg Dexamethasone PO at 11 pm or midnight, determine plasma cortisol at 8 am the next day
    • Diagnostic range: Plasma cortisol >50 nmol/L (1.8 mcg/dL)
  • 48-hours Low-Dose Dexamethasone Suppression Test with CRH Stimulation Test
    • 0.5 mg Dexamethasone per orem (PO) 6 hourly x 8 doses, 1 mcg/kg corticotropin-releasing hormone (CRH) IV 2 hours after last dose of Dexamethasone, determine plasma cortisol levels 15 minutes after CRH administration
    • Diagnostic range: Plasma cortisol 6 hours after last Dexamethasone dose >50 nmol/L (1.8 mcg/dL) or urinary cortisol >27 nmol/24 hours (10 mcg/24 hours)

• Late-Night Salivary Cortisol with Low-Dose Dexamethasone Suppression Test
  
  • Obtain sample of salivary cortisol at 11 pm on at least 2 separate nights
  • Measurement is done in the evening due to the fact that normal evening nadir in serum cortisol is preserved in obese and depressed patients but not in patients with Cushing’s syndrome
  • Noninvasive valid alternative to urinary free cortisol test for Cushing’s syndrome diagnosis
  • Accurately reflects concentrations of plasma free cortisol concentrations irrespective of the saliva production rate and corticosteroid-binding globulin variability
  • Diagnostic range: >3.6 nmol/L (0.13 mcg/dL) cortisol levels have sensitivity and specificity of approximately 95% for diagnosis of Cushing’s syndrome

• Late-Night Serum Cortisol
  • Obtain sample by inserting a heparin-lock earlier in the day to prevent stress-induced cortisol release then ask the patient to return between 11 PM and midnight for blood drawing on at least 2 separate nights
  • Measurement is done in the late evening, same as late-night salivary cortisol, due to the fact that normal evening nadir in serum cortisol is preserved in obese and depressed patients but not in patients with Cushing’s syndrome
  • Diagnostic range: 207 nmol/L (>7.5 mcg/dL)

Localize Cushing’s Syndrome

• High-Dose Dexamethasone Suppression Test
  
  • This test is most useful in distinguishing pituitary from ectopic corticotropin-dependent Cushing’s syndrome
  • 2 mg PO 6 hourly x 8 doses in 48 hours, or 8 mg PO overnight, or 4-7 mg IV test
  • Plasma and/or urinary cortisol is measured before, during and/or after intake of Dexamethasone

• Late Afternoon Adrenocorticotropic Hormone (ACTH) Test
  
  • Adrenocorticotropic hormone measurement at 4 pm or later when adrenocorticotropic hormone levels are normally low
  • ACTH-dependent, diagnostic range: ACTH >3.3 pmol/L (15 pg/mL)
  • ACTH-independent, diagnostic range: ACTH <1 pmol/L (5 pg/mL)
  • Intermediate adrenocorticotropic hormone values require further study with corticotropin-releasing hormone stimulation test

• Corticotropin-Releasing Hormone (CRH) Stimulation Test
  
  • This test helps differentiate patients with pituitary adenomas from those with ectopic adrenocorticotropic hormone syndrome or cortisol-secreting adrenal tumors
  • Administer 1 mcg/kg corticotropin-releasing hormone IV, measure adrenocorticotropic hormone and cortisol values before injection and at 15, 30, 45, 60, 90 and 120 minutes after injection
  • ACTH-dependent, diagnostic range: ACTH ≥50% above basal or cortisol ≥20% above basal

• Bilateral Inferior Petrosal Sinus Sampling (BIPSS)
  
  • Recommended in patients with ACTH-dependent Cushing’s syndrome whose lab tests and radiological findings produce equivocal results
  • Administer 1 mcg/kg CRH IV, obtain blood samples after 3, 5 and 10 minutes from inferior petrosal sinus (IPS) and peripheral vein
  • Diagnostic range: ≥2 IPS to peripheral vein ratio before CRH or ≥3 after CRH
    
    

• Performed after biochemical confirmation to identify exact cause 
• Pituitary MRI is the preferred imaging modality in diagnosing ACTH-dependent hypercortisolemic states (Cushing's disease)
• Necessary for localization of pituitary or ectopic corticotropin-producing tumors and adrenal masses