What is the next step in evaluating a patient with elevated morning adrenocorticotropic hormone (ACTH) level, previously showing elevated fasting morning cortisol and 24-hour urinary cortisol, and failed dexamethasone suppression testing?

Diagnostic Approach for ACTH-Dependent Cushing's Syndrome

The next step in evaluation for this patient with elevated morning cortisol, 24-hour urinary cortisol, failed dexamethasone suppression, and ACTH level of 22.6 pg/mL should be pituitary MRI to identify a potential pituitary adenoma. 1, 2

Interpretation of Current Findings

• The patient's laboratory profile with elevated fasting AM cortisol, elevated 24-hour urinary cortisol, failed dexamethasone suppression testing, and detectable ACTH level of 22.6 pg/mL is diagnostic of ACTH-dependent Cushing's syndrome 2, 3
• ACTH levels >5 pg/mL are considered detectable and suggest ACTH-dependent Cushing's syndrome with high certainty 2, 3
• ACTH levels >29 pg/mL have 70% sensitivity and 100% specificity for diagnosing Cushing's disease (pituitary source), but levels between 5-29 pg/mL still strongly suggest ACTH-dependent disease requiring further evaluation 2, 3

Diagnostic Algorithm

• For confirmed ACTH-dependent Cushing's syndrome, pituitary MRI is the recommended next step to identify a potential pituitary adenoma 1, 2
• High-quality MRI with thin slices (3T MRI preferred over 1.5T where available) should be performed to maximize detection of small pituitary adenomas 1
• If a pituitary adenoma ≥10 mm is detected on MRI, this strongly suggests Cushing's disease (pituitary source) 1, 2
• If a pituitary adenoma 6-9 mm is found on MRI, CRH stimulation testing should be considered to confirm the diagnosis 2

Further Testing if MRI is Inconclusive

• If no adenoma or a lesion <6 mm is found on MRI, bilateral inferior petrosal sinus sampling (BIPSS) should be performed to definitively distinguish between pituitary and ectopic sources of ACTH 1, 2
• BIPSS is considered the gold standard for differentiating between pituitary and ectopic ACTH-secreting tumors, with diagnostic criteria of central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after stimulation 1, 3
• Prolactin measurement during BIPSS can improve diagnostic accuracy 1
• It is essential that the patient is hypercortisolemic at the time of BIPSS to ensure accurate results 1, 2

Additional Testing Considerations

• If suspicion for ectopic ACTH syndrome is high (such as in males with very high UFC and/or profound hypokalemia), a neck-to-pelvis thin-slice CT scan should be performed 1
• CRH and desmopressin stimulation testing can be useful in distinguishing between pituitary and ectopic tumors, with increased plasma ACTH and cortisol following administration usually indicating Cushing's disease 1
• A non-invasive approach using a combination of CRH and desmopressin stimulation plus MRI, followed by whole-body CT if diagnosis is equivocal, may be considered in some cases 1
• For suspected ectopic ACTH-secreting tumors, 68Ga-DOTATATE PET imaging can be useful in localizing neuroendocrine tumors not seen on conventional imaging 1

Important Clinical Considerations

• BIPSS should preferably be performed in a specialized center due to potential patient risk 1
• None of the diagnostic tests reach 100% specificity, and results may be discordant in up to one-third of patients 1
• The clinical context and test results should be used together to guide management 1
• Certain medications can affect test results, so drugs affecting pituitary or adrenocortical function should be stopped before diagnostic testing 4