S5703 When Is a Liver Biopsy Warranted? A Case of Immune Checkpoint Inhibitor Hepatitis With Diagnostic Uncertainty

Introduction: Immune checkpoint inhibitors (ICIs) have become a cornerstone of cancer therapy across a range of malignancies. However, they are increasingly associated with immune-related adverse events including hepatotoxicity. While ICI-induced hepatitis is frequently diagnosed based on clinical and laboratory findings, the role of liver biopsy remains important in cases complicated by recent exposure to other potentially hepatotoxic agents. As ICI use expands, diagnostic uncertainty in liver injury is increasingly common. However, clear criteria for when to pursue liver biopsy are lacking. Determining when to biopsy is critical, as premature or unnecessary immunosuppression may obscure alternative diagnoses or disrupt effective oncologic treatment. Case Description/Methods: A 68-year-old man with metastatic renal cell carcinoma (RCC) on pembrolizumab (ICI) and lenvatinib (kinase inhibitor) presented after routine oncology labs revealed a significant new elevation in liver enzymes including aspartate aminotransferase 3,885 U/L and alanine aminotransferase >3,300 U/L, total bilirubin 7.1 mg/dL, and international normalized ratio 2.13. He was asymptomatic aside from scleral icterus. Notably, he had recently completed a 7-day course of cephalexin for an arm wound infection, also raising concern for drug-induced liver injury (DILI) from antibiotics. Due to diagnostic uncertainty, both cancer therapies were held. Abdominal imaging showed hepatic cysts without biliary obstruction or metastases. Comprehensive evaluation for infectious, autoimmune, and metabolic liver disease was unrevealing. A percutaneous liver biopsy was performed and histopathology revealed zone 3 confluent and bridging necrosis with parenchymal collapse and lobular and portal inflammation—findings consistent with ICI-induced hepatitis. High-dose corticosteroids were initiated, with rapid improvement of liver enzymes. Discussion: This case illustrates the diagnostic utility of a liver biopsy in evaluating acute liver injury in patients receiving ICIs, especially when other hepatotoxic exposures confound the clinical picture. In this case, ICI use was critical for treatment of RCC, and confirmation of the cause of hepatitis was essential to avoid unnecessary discontinuation of ICI therapy. Histologic confirmation excluded alternative causes and enabled more informed decisions regarding future cancer treatment including risk stratification for ICI rechallenge. As ICIs are increasingly used in complex clinical settings, biopsy should be considered when diagnostic uncertainty may affect management.