What's the next step in diagnosis for a patient with Cushing's disease suspected after a Low-Dose Dexamethasone Suppression Test (LDDST) showing more than 50% suppression of cortisol to a level of 6 ug/dL and an inconclusive MRI?

Next Diagnostic Step for Cushing's Disease with Inconclusive MRI and >50% Cortisol Suppression to 6 μg/dL on LDDST

For a patient with suspected Cushing's disease showing >50% suppression of cortisol to 6 μg/dL on LDDST and an inconclusive MRI, the next appropriate diagnostic step is bilateral inferior petrosal sinus sampling (BIPSS).

Understanding the Current Diagnostic Picture

• The patient's LDDST shows >50% suppression of cortisol but only to 6 μg/dL, which is still above the normal cutoff of 1.8 μg/dL, suggesting Cushing's syndrome is still likely present 1
• Normal cortisol suppression on LDDST would be to <1.8 μg/dL (50 nmol/L), and values above this threshold indicate abnormal feedback inhibition consistent with Cushing's syndrome 1
• The >50% suppression pattern is suggestive of Cushing's disease (pituitary source) rather than ectopic ACTH or adrenal causes 1
• With an inconclusive MRI and suggestive but not definitive LDDST results, further testing is needed to confirm the diagnosis and localize the source 1, 2

Diagnostic Algorithm for This Scenario

1. Confirm ACTH dependency:

   • Measure plasma ACTH levels to confirm ACTH-dependent Cushing's syndrome 2, 3
   • ACTH levels >5 pg/mL indicate ACTH-dependent disease 3
   • ACTH levels >29 pg/mL have 70% sensitivity and 100% specificity for pituitary Cushing's disease 4

2. Proceed to BIPSS:

   • With inconclusive MRI findings, BIPSS is indicated to differentiate between pituitary and ectopic sources 1, 2
   • BIPSS has diagnostic criteria of central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after stimulation 4
   • BIPSS has a sensitivity of 100% for diagnosing Cushing's disease 4

Why BIPSS is the Appropriate Next Step

• According to the 2021 consensus guidelines, patients with lesions <6mm or inconclusive MRI findings should undergo BIPSS to confirm the diagnosis 1
• The >50% suppression on LDDST suggests pituitary source, but this needs confirmation, especially with inconclusive imaging 1, 2
• BIPSS is considered the gold standard test for differentiating between pituitary and ectopic sources of ACTH-dependent Cushing's syndrome 1, 4

Alternative Diagnostic Considerations

• CRH stimulation test could be considered as an alternative, with a ≥20% increase in cortisol from baseline supporting pituitary origin (sensitivity 74-100%) 4
• High-dose dexamethasone suppression test (8 mg) has lower sensitivity (71.85%) compared to BIPSS and is not recommended as the next step 5
• The combined low-dose dexamethasone suppression-CRH test has been studied but does not add significant diagnostic value over BIPSS in this scenario 6, 7

Important Clinical Considerations

• Ensure hypercortisolism is still active at the time of BIPSS to avoid false negative results 4
• Measure dexamethasone levels along with cortisol during LDDST to improve test interpretability and rule out abnormal dexamethasone metabolism 1
• Be aware that cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation 2

Following this diagnostic algorithm will provide the most definitive diagnosis for a patient with suspected Cushing's disease, inconclusive MRI, and partial suppression on LDDST.