S5541 Checkpoint Inhibitor Hepatotoxicity Unresponsive to Steroids: A Case for Ursodiol

Introduction: Drug-induced liver injury (DILI) is a leading cause of acute liver failure and is often a diagnosis of exclusion. It may present as hepatocellular, cholestatic, or mixed injury, with variable symptoms ranging from asymptomatic transaminitis to fulminant hepatic failure. Immune checkpoint inhibitors (ICIs), such as pembrolizumab (Keytruda), are increasingly associated with hepatotoxicity. While corticosteroids remain the first-line treatment for immune-mediated DILI, alternative therapies may be required in steroid-refractory cases. Ursodiol, a bile acid commonly used in primary biliary cholangitis, is not a standard DILI treatment but may be beneficial in select cases. Case Description/Methods: A 74-year-old woman with a history of endometrial cancer completed 3 cycles of carboplatin, paclitaxel, and pembrolizumab. She was asymptomatic but found to have elevated liver function tests (LFTs) during routine follow-up. Labs showed a cholestatic pattern with elevated alkaline phosphatase and alanine aminotransferase. A liver biopsy revealed bile duct injury, inflammation, and fibrosis consistent with mixed-pattern DILI. Extensive infectious, autoimmune, and imaging workup was negative. The suspected culprit was pembrolizumab, known to cause immune-mediated hepatotoxicity. The patient was treated with intravenous methylprednisolone over 6 months without improvement in LFTs. After discontinuation of steroids, she was started on ursodiol 300 mg twice daily, leading to gradual normalization of her liver enzymes. Discussion: This case illustrates a steroid-refractory presentation of ICI-induced DILI successfully managed with ursodiol. Ursodiol, though not routinely used in DILI, promotes bile flow and reduces bile acid–mediated hepatocellular damage. The response suggests bile acid retention may contribute to ICI-related DILI, and targeting this mechanism can be therapeutic. Recognition of atypical treatment responses is critical, especially as ICI use expands in oncology. Liver biopsy played a key role in identifying the pattern of injury and guiding management.