What is the next step in managing a patient with hypercortisolism and an adrenocorticotropic hormone (ACTH) level of 16 that is not suppressed?

Management of Hypercortisolism with Non-Suppressed ACTH Level of 16

For a patient with confirmed hypercortisolism and a non-suppressed ACTH level of 16, the next step should be bilateral inferior petrosal sinus sampling (BIPSS) to differentiate between pituitary Cushing's disease and ectopic ACTH syndrome. 1

Diagnostic Algorithm for ACTH-Dependent Hypercortisolism

Interpretation of ACTH Level

• An ACTH level of 16 confirms ACTH-dependent Cushing's syndrome, as ACTH is detectable (>5 ng/l or >1.1 pmol/l) 1
• In ACTH-independent Cushing's syndrome (adrenal causes), ACTH would be low or undetectable due to negative feedback inhibition 2
• A detectable ACTH level indicates either pituitary Cushing's disease or ectopic ACTH production 1

Imaging Studies

• Pituitary MRI should be performed to look for adenoma 1
• However, approximately one-third of pituitary MRI scans in Cushing's disease patients remain negative despite the presence of disease 1
• If MRI shows a definite pituitary adenoma that is unlikely to be an incidentaloma, this may be sufficient for diagnosis 1

Confirmatory Testing

• BIPSS is the gold standard for differentiating between pituitary and ectopic sources of ACTH 1
• BIPSS should be performed especially when:
  • MRI findings are negative or equivocal 1
  • Clinical, biochemical, or radiological studies are discordant 3
  • There is suspicion of ectopic ACTH syndrome despite normal imaging 4

BIPSS Procedure and Interpretation

• BIPSS should only be performed at specialized centers with experienced interventional radiologists 1
• During BIPSS, a pituitary source of ACTH is confirmed by:
  • ≥2:1 ratio of central-to-peripheral ACTH before CRH or desmopressin stimulation 1
  • ≥3:1 ratio after CRH or desmopressin stimulation 1
• 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
• Hypercortisolemia should be confirmed immediately prior to BIPSS to ensure active disease phase, especially in cyclical Cushing's disease 1

Important Considerations

• Medical therapy for hypercortisolism (steroidogenesis inhibitors) must be stopped before BIPSS to ensure accurate interpretation 1
• If BIPSS confirms Cushing's disease, surgical resection of the pituitary adenoma is the optimal treatment 5
• If BIPSS suggests ectopic ACTH syndrome, additional imaging (CT chest/abdomen) should be performed to locate the source 6, 7
• Untreated hypercortisolism can lead to significant morbidity and mortality, including severe infections, clotting disorders, and metabolic complications 1

Treatment Considerations

• Surgical resection of the tumor (pituitary or ectopic source) is the optimal treatment for all forms of Cushing's syndrome 5
• If surgery is not immediately possible or effective, medical therapy with steroidogenesis inhibitors like ketoconazole may be considered 2, 5
• Pasireotide may be considered for Cushing's disease patients, with monitoring for hyperglycemia and QT prolongation 8
• Bilateral adrenalectomy may be necessary in cases where the source cannot be identified or controlled 4

BIPSS is crucial for accurate diagnosis and appropriate management of ACTH-dependent Cushing's syndrome, as it will guide the surgical approach and overall treatment strategy, ultimately improving morbidity, mortality, and quality of life outcomes.