What is the appropriate workup for Cushing's (Cushing's syndrome) syndrome?

Workup for Cushing's Syndrome

The appropriate workup for Cushing's syndrome involves first confirming hypercortisolism through 2-3 first-line screening tests (late-night salivary cortisol, 24-hour urinary free cortisol, and overnight dexamethasone suppression test), followed by measuring ACTH levels to determine if the condition is ACTH-dependent or independent, with subsequent imaging and specialized testing to localize the source. 1, 2

Initial Screening Tests

• Perform late-night salivary cortisol (LNSC) measurements, collecting at least 2-3 samples on consecutive days (sensitivity 95%, specificity 100%) 1
• Measure 24-hour urinary free cortisol (UFC) with at least 2-3 samples to account for variability (sensitivity 89%, specificity 100%) 1
• Conduct overnight dexamethasone suppression test (DST) with 1mg dexamethasone at midnight and measuring serum cortisol at 8 AM (normal response: cortisol <1.8 μg/dL or 50 nmol/L) 1
• Rule out exogenous glucocorticoid use (oral, injections, inhalers, topical) before proceeding with testing 3

Determining Etiology

• Measure morning plasma ACTH levels to differentiate ACTH-dependent from ACTH-independent causes 2

  • ACTH-dependent: Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L)
  • ACTH-independent: Low/undetectable ACTH

• For ACTH-dependent Cushing's syndrome (normal/elevated ACTH): 4

  • Perform pituitary MRI to identify potential adenoma
  • Consider CRH stimulation test (≥20% increase in cortisol from baseline supports pituitary origin)
  • For lesions <6 mm or equivocal MRI findings, proceed with bilateral inferior petrosal sinus sampling (BIPSS)
  • BIPSS results: central-to-peripheral ACTH ratio ≥2:1 before CRH and ≥3:1 after CRH confirms pituitary source

• For ACTH-independent Cushing's syndrome (low/undetectable ACTH): 2

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

Special Considerations

• Be aware of pseudo-Cushing's states that can cause false-positive results: 1, 2

  • Severe obesity
  • Uncontrolled diabetes
  • Depression
  • Alcoholism

• Consider cyclic Cushing's syndrome in cases with inconsistent results, requiring periodic re-evaluation 2

• For pituitary lesions on MRI: 3

  • Lesions <6 mm: BIPSS recommended
  • Lesions ≥10 mm with dynamic testing consistent with Cushing's disease: BIPSS not necessary
  • Lesions 6-9 mm: Expert opinions differ, but majority recommend BIPSS

• Measure dexamethasone levels along with cortisol during DST to improve test interpretability 2

Diagnostic Algorithm

1. Rule out exogenous glucocorticoid use 3
2. Perform 2-3 first-line screening tests based on clinical suspicion 1
3. If screening tests are abnormal, measure plasma ACTH 2
4. For normal/high ACTH (ACTH-dependent):
   • Perform pituitary MRI 3
   • Consider CRH stimulation test 4
   • Perform BIPSS if MRI is negative or shows lesion <6 mm 3
5. For low ACTH (ACTH-independent):
   • Perform adrenal imaging (CT or MRI) 3

Common Pitfalls

• Relying on a single screening test can lead to misdiagnosis due to variability in cortisol secretion 1
• Not measuring ACTH levels can lead to inappropriate management strategies 2
• Failing to consider cyclic Cushing's syndrome when test results are inconsistent 2
• Not accounting for medications that can affect dexamethasone metabolism (e.g., estrogen-containing oral contraceptives) 1
• Overlooking pseudo-Cushing's states that can mimic true Cushing's syndrome 1, 2