Management of Ectopic ACTH Syndrome with Liver Metastases – A Case Series

Introduction:
Ectopic ACTH syndrome (EAS) causes 5-10% of all Cushing’s syndromes (CS). The hypercortisolism may present as a challenging endocrinologic emergency with life-threatening hypokalemia and infections. In patients with liver metastases from neuroendocrine tumors (NETs), medical management and trans-arterial embolization (TAE) of liver metastases can help reduce tumor burden and control hypercortisolism.

Case Description:
We present a case series of 3 female patients of ages 69 (patient A), 71 (patient B), and 84 (patient C) who presented with severe CS from EAS, were found to have NETs with unknown primary, and were managed with medications and TAE of liver metastases.

All 3 patients presented to the hospital with significant weakness developing over a few months. They were all found to be significantly hypertensive and hypokalemic on admission. None of them had any Cushingoid features. Morning cortisol ranged from 64.5 to 241.1 (4.8-19.5) ug/dL and ACTH 193.2 to 504.9 (7.2 - 63.3) pg/mL. The cortisol did not suppress with 1-mg or 8-mg dexamethasone. An MRI pituitary showed normal pituitary gland. A PET scan (⁶⁴Cu-DOTATATE in patient A, F18-FDG in patient B, and ⁶⁸Ga DOTATATE in patient C) revealed hepatic metastases in all patients. Patient A was started on levoketoconazole and metyrapone, underwent trans-arterial radio-embolization (TARE) of the liver metastases, after which levoketoconazole was stopped. Patient B was started on ketoconazole, intravenous etomidate infusion and underwent bland TAE of liver metastases. She eventually pursued hospice care and passed away from complications of pneumonia. Patient C underwent bland TAE of the liver metastases and did not require any medications. All patients had improvement of cortisol, electrolytes, blood pressure, and blood glucose after these interventions.

Discussion:
Cushing’s syndrome due to EAS is usually associated with intense hypercortisolism, hypertension, hypokalemia, hyperglycemia, infections and thromboembolism. Cushingoid features are typically absent due to acuity of hypercortisolism. While surgical excision of the primary tumor is curative, patients might present with symptomatic hypercortisolism and unknown primary tumor or metastatic disease. Utilizing steroidogenic inhibitors to alleviate hypercortisolism and using TAE/TARE for patients with liver metastases to reduce disease burden, when appropriate, will improve quality of life and preserve adrenal function as compared to bilateral adrenalectomy.