Is two serum elevated cortisol levels with Adrenocorticotropic hormone (ACTH) >15 pg/mL and a failed Low-Dose Dexamethasone Suppression Test (LDDST) with a greater than 50% drop sufficient to proceed to Bilateral Inferior Petrosal Sinus Sampling (BIPSS) if Magnetic Resonance Imaging (MRI) is inconclusive?

Diagnostic Criteria for Proceeding to BIPSS in ACTH-Dependent Cushing's Syndrome

Yes, two serum elevated cortisol levels with ACTH >15 pg/mL and a failed Low-Dose Dexamethasone Suppression Test (LDDST) with less than 50% cortisol suppression is sufficient to proceed to Bilateral Inferior Petrosal Sinus Sampling (BIPSS) if MRI is inconclusive. 1, 2

Diagnostic Algorithm for ACTH-Dependent Cushing's Syndrome

• Confirmation of ACTH-dependent Cushing's syndrome requires:

  • Biochemical evidence of hypercortisolism (elevated serum cortisol) 1, 3
  • ACTH levels >5 ng/L (>1.1 pmol/L), with levels >15 pg/mL clearly indicating ACTH-dependency 3
  • Failed LDDST (cortisol not suppressed by at least 50%) 1

• After confirming ACTH-dependent Cushing's syndrome, the next step is pituitary MRI 1, 3

• BIPSS is indicated when:

  • Pituitary MRI is negative or inconclusive (no adenoma identified) 1, 2
  • There is discordance between biochemical testing and imaging findings 1, 2

BIPSS Procedure and Interpretation

• BIPSS should only be performed:

  • In specialized centers with expertise in the procedure 1
  • By experienced interventional radiologists who regularly perform this procedure 1
  • After confirming hypercortisolemia immediately prior to the procedure to ensure active disease phase (especially important for cyclical Cushing's disease) 1, 2
  • After discontinuing any medical therapy for Cushing's disease 2

• Diagnostic criteria for confirming pituitary source of ACTH excess:

  • Central-to-peripheral ACTH ratio ≥2:1 before CRH or desmopressin stimulation 1, 2
  • Central-to-peripheral ACTH ratio ≥3:1 after CRH or desmopressin stimulation 1, 2

• BIPSS may also provide information on tumor lateralization if the inter-petrosal sinus ACTH gradient after stimulation is ≥1.4 between the two sides 1, 2

Important Considerations

• BIPSS has superior diagnostic accuracy compared to high-dose dexamethasone suppression testing (HDDST), which has limited value in clinical practice with sensitivity of 81% and specificity of only 66.7% for diagnosing pituitary-dependent Cushing's syndrome 4

• Recent research suggests that urinary free cortisol (UFC) levels can help predict the likelihood of ectopic ACTH syndrome (EAS) vs. Cushing's disease and guide diagnostic approaches:

  • UFC <3× upper limit of normal: very low probability of EAS (0%)
  • UFC 3-10× upper limit of normal: low probability of EAS (6.1%)
  • UFC >10× upper limit of normal: high probability of EAS (66.7%) 5

• Some centers are exploring non-invasive alternatives combining HDDST with high-resolution contrast-enhanced MRI (hrMRI), which may achieve diagnostic performance comparable to BIPSS with better tumor lateralization accuracy 6

Pitfalls and Caveats

• Ensure that the patient is not taking exogenous glucocorticoids before testing 1

• Confirm active hypercortisolism immediately before BIPSS, especially in cases of cyclical Cushing's disease 1, 2

• Be aware that certain conditions (severe obesity, alcoholism, uncontrolled diabetes) can cause false positive results in screening tests 3

• BIPSS should not be used as a first-line test but reserved for cases where MRI does not show a clear pituitary adenoma 2

• False lateralization can occur during BIPSS due to altered pituitary blood flow 2