S3125 Overlapping Hepatotoxicity and Colitis Associated With Immune Checkpoint Inhibitors

Abstract

Introduction: Immunotherapy with immune checkpoint inhibitors (ICIs) has become the standard of care for many solid-organ and hematologic malignancies. Gastrointestinal toxicities are common side effects that typically occur 6 weeks after starting ICI therapy. Overlapping hepatotoxicity and colitis associated with ICIs is rare and may be overlooked, resulting in high mortality. Case Description/Methods: A 73-year-old man with metastatic squamous cell carcinoma (SCC) of the head and neck presented with intermittent, diffuse abdominal discomfort, bloating and painless non-bloody diarrhea (up to 6 episodes daily) triggered by meals. Symptom onset was 6 weeks after starting pembrolizumab for head and neck SCC. Pembrolizumab therapy was held, and supportive therapy with proton pump inhibitors, antacids and antidiarrheals provided partial symptom relief. Laboratory work up showed elevated AST 132 U/L, ALT 220 U/L, ALP 851 U/L and normal total bilirubin. ANA was elevated with titer 1:80, with normal total IgG (699.5 mg/dL) and negative serologies for anti-smooth muscle antibody, CMV, EBV, and HSV. Abdominal CT with contrast showed a dilated common bile duct (CBD) of 11 mm and a new curvilinear filling defect in the distal CBD, without choledocholithiasis. MRCP revealed mildly dilated intrahepatic biliary ducts, CBD dilation (13 mm), and an ovoid 8mm soft tissue nodule in the periampullary duodenum. Upper endoscopy was nondiagnostic. At this time, the patient’s symptoms improved, but there was high suspicion of grade-2 ICI-associated hepatitis (ICIH). Percutaneous liver biopsy showed interlobular bile duct injury with intraepithelial lymphocytes and neutrophils and a neutrophilic ductular reaction consistent with ICIH. Serial lab work demonstrated improvement of liver enzymes, with AST 77 U/L, ALT 69 U/L and ALP 667 U/L at 60 days after initial labs. Diarrhea resumed, up to 6 episodes per day, consistent with the Common Terminology Criteria for Adverse Events diagnosis of ICI-related colitis (ICIC). Initial supportive therapy failed to improve diarrhea; thus, a prednisone taper was started, resolving the colitis. He declined the option to resume immunotherapy and transitioned to comfort care (Figure 1). Discussion: Overlapping ICIH and ICIC is rare and may have discordance between symptomatology and lab findings. Early recognition of overlapping ICIH and ICIC, supportive treatment, permanent cessation of the inciting ICI and switching it with alternative immunosuppressive therapy may improve patient outcomes and quality of life.Figure 1.: Panel A - CT chest/abdomen with contrast (coronal view) showing common bile duct dilation of 1.2 cm (yellow calipers) status post cholecystectomy. Panel B. Upper endoscopy showing prominent ampulla with free-flowing bile. Panel C. Histology of percutaneous, ultrasound-guided liver biopsy with H&E staining (10×) shows preserved lobular hepatic architecture with mixed inflammatory infiltrate including lymphocytes, histiocytes, and scattered eosinophils expanding the portal tracts. Table 1. - Immune Checkpoint Inhibitor Associated Hepatitis Grades, adapted from the American Society of Clinical Oncology, 2021 Grade Criteria 1 Asymptomatic (AST or ALT > ULN to 3.0 X ULN and/or total bilirubin > ULN to 1.5 X ULN) 2 Asymptomatic (AST or ALT > 3.0 to ≤ 5 X ULN and/or total bilirubin > 1.5 to ≤ 3 X ULN) 3 AST or ALT 5-20 X ULN and/or total bilirubin 3-10 X ULN, OR symptomatic liver dysfunction; fibrosis by biopsy; compensated cirrhosis; and reactivation of chronic hepatitis 4 AST or ALT > 20 X ULN and/or total bilirubin > 10 X ULN OR decompensated liver function (e.g., ascites, coagulopathy, encephalopathy, and coma) Abbreviations: AST, aspartate transferase; ALT, alanine transaminase; ULN, upper limit of normal.