MD University of Iowa hospital and clinics, United States
Introduction: Pembrolizumab (PBZ) is a humanized monoclonal antibody to programmed cell death receptor-1 (PD-1), which acts as a checkpoint inhibitor. It has rarely been associated with delayed check point inhibitor immune induced liver toxicity. We present a case of Check point inhibitor induced delayed immune mediated hepatotoxicity, 16 months after initiation of and 3 months after stopping PBZ.
Description: 72 y/o female with no significant history of alcohol use, history of NASH, DLBCL s/p autologous stem cell transplant, nodular malignant melanoma, diagnosed in March 2022, s/p PBZ, last dose 3 months prior to admission, total duration 1 year, in remission, presented with fatigue and painless jaundice. Labs revealed AST 343(5x ULN), ALT 346(5x ULN), ALP 947(10x ULN), GGT 348, Lipase 144, Bilirubin 9.1, direct bilirubin 8.1. Patient had stable normal LFTs prior to presentation. Acetaminophen levels, Ceruloplasmin was unremarkable. HIV, Hepatitis A, B, C, E, EBV, CMV serologies were negative. Anti-smooth muscle, LKM serologies were negative. US abdomen revealed stable mild bile duct dilation secondary to prior cholecystectomy, no focal lesions in liver. MRCP abdomen revealed mildly enlarged ampulla, no pancreatic duct dilation, mild biliary duct dilation, mild hepatomegaly. ERCP to assess enlarged ampulla and pancreas was unsuccesfull (due to Roux en Y bypass). Liver biopsy suggested pauci-immune inflammatory focal granulomatous biliary injury favoring PBZ hepatitis (when cholestatic, referred to as checkpoint inhibitor cholangiopathy). Patient was started on Budesonide with improvement in LFTs including AST, ALT, ALP, Total Bilirubin. Patient was discharged with outpatient follow up with hepatology.
Discussion: Most cases of PBZ induced immune related hepatotoxicity occur within 1-2 months after initiation of the medication. While mild to moderate ALT/AST elevation is common (20-30%), elevation exceeding 5 times ULN is seen in 1-4%. Clinically significant liver injury is rarer with 1-2% incidence. Mechanism likely involves PBZ mediated immune-mediated T cell activation targeting hepatocellular or cholangiocyte antigens. Monitoring liver enzymes (3x ULN) is advised; PBZ discontinuation at 5-10x ULN. Steroid therapy may be warranted for high or persistent ALT elevations and symptomatic jaundice.
