Robert J Fontana, Yi-Ju Li, Vincent Chen, David Kleiner, Andrew Stolz, Joe Odin, Raj Vuppalanchi, Jiezhun Gu, Lily Dara, Huiman Barnhart
{"title":"与检查点抑制剂免疫介导的肝损伤相关的基因变异。","authors":"Robert J Fontana, Yi-Ju Li, Vincent Chen, David Kleiner, Andrew Stolz, Joe Odin, Raj Vuppalanchi, Jiezhun Gu, Lily Dara, Huiman Barnhart","doi":"10.1097/HC9.0000000000000518","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The clinical features, liver histology, and genetic variants in 57 patients with moderate to severe immune-mediated liver injury from checkpoint inhibitors (ILICI) are presented.</p><p><strong>Methods: </strong>Between 2010 and 2022, 57 high-causality ILICI cases were enrolled in the Drug-Induced Liver Injury Network. HLA and selected candidate gene variants were tested for association with ILICI risk compared to the general population and other DILI controls.</p><p><strong>Results: </strong>The 57 high-causality cases were attributed to pembrolizumab (16), ipilimumab (15), ipilimumab and nivolumab (13), and other immune checkpoint inhibitors (13) and occurred at a median of 72 days after the first infusion. Median age was 57.8 years, 66% male, and 89% were non-Hispanic Whites. At DILI onset, 53% had hepatocellular, 35% mixed, and 15% cholestatic, with younger patients more likely to have hepatocellular injury. The incidence of ANA, smooth muscle antibody, and elevated IgG levels was low (17%, 23%, and 0%), but corticosteroids were given to 86%. Microgranulomas and hepatic steatosis were seen in 54% and 46% of the 26 liver biopsies, respectively. The HLA alleles associated with autoimmune hepatitis were not over-represented, but 2 host immune response genes (EDIL3 and SAMA5A) and 3 other genes (GABRP, SMAD3, and SLCO1B1) were associated with ILICI (OR: 2.08-2.4, p<0.01).</p><p><strong>Conclusions: </strong>ILICI typically arises within 12 weeks of initiating immunotherapy and is self-limited in most cases. Genetic variants involved in host T-cell regulation and drug disposition were identified, implicating these pathways in the pathogenesis of ILICI. If validated, these findings could lead to improved diagnostic instruments and possible treatments for ILICI.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 9","pages":""},"PeriodicalIF":5.6000,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11357698/pdf/","citationCount":"0","resultStr":"{\"title\":\"Genetic variants associated with immune-mediated liver injury from checkpoint inhibitors.\",\"authors\":\"Robert J Fontana, Yi-Ju Li, Vincent Chen, David Kleiner, Andrew Stolz, Joe Odin, Raj Vuppalanchi, Jiezhun Gu, Lily Dara, Huiman Barnhart\",\"doi\":\"10.1097/HC9.0000000000000518\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The clinical features, liver histology, and genetic variants in 57 patients with moderate to severe immune-mediated liver injury from checkpoint inhibitors (ILICI) are presented.</p><p><strong>Methods: </strong>Between 2010 and 2022, 57 high-causality ILICI cases were enrolled in the Drug-Induced Liver Injury Network. HLA and selected candidate gene variants were tested for association with ILICI risk compared to the general population and other DILI controls.</p><p><strong>Results: </strong>The 57 high-causality cases were attributed to pembrolizumab (16), ipilimumab (15), ipilimumab and nivolumab (13), and other immune checkpoint inhibitors (13) and occurred at a median of 72 days after the first infusion. Median age was 57.8 years, 66% male, and 89% were non-Hispanic Whites. At DILI onset, 53% had hepatocellular, 35% mixed, and 15% cholestatic, with younger patients more likely to have hepatocellular injury. The incidence of ANA, smooth muscle antibody, and elevated IgG levels was low (17%, 23%, and 0%), but corticosteroids were given to 86%. Microgranulomas and hepatic steatosis were seen in 54% and 46% of the 26 liver biopsies, respectively. The HLA alleles associated with autoimmune hepatitis were not over-represented, but 2 host immune response genes (EDIL3 and SAMA5A) and 3 other genes (GABRP, SMAD3, and SLCO1B1) were associated with ILICI (OR: 2.08-2.4, p<0.01).</p><p><strong>Conclusions: </strong>ILICI typically arises within 12 weeks of initiating immunotherapy and is self-limited in most cases. Genetic variants involved in host T-cell regulation and drug disposition were identified, implicating these pathways in the pathogenesis of ILICI. If validated, these findings could lead to improved diagnostic instruments and possible treatments for ILICI.</p>\",\"PeriodicalId\":12978,\"journal\":{\"name\":\"Hepatology Communications\",\"volume\":\"8 9\",\"pages\":\"\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-08-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11357698/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Hepatology Communications\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/HC9.0000000000000518\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hepatology Communications","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/HC9.0000000000000518","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Genetic variants associated with immune-mediated liver injury from checkpoint inhibitors.
Background: The clinical features, liver histology, and genetic variants in 57 patients with moderate to severe immune-mediated liver injury from checkpoint inhibitors (ILICI) are presented.
Methods: Between 2010 and 2022, 57 high-causality ILICI cases were enrolled in the Drug-Induced Liver Injury Network. HLA and selected candidate gene variants were tested for association with ILICI risk compared to the general population and other DILI controls.
Results: The 57 high-causality cases were attributed to pembrolizumab (16), ipilimumab (15), ipilimumab and nivolumab (13), and other immune checkpoint inhibitors (13) and occurred at a median of 72 days after the first infusion. Median age was 57.8 years, 66% male, and 89% were non-Hispanic Whites. At DILI onset, 53% had hepatocellular, 35% mixed, and 15% cholestatic, with younger patients more likely to have hepatocellular injury. The incidence of ANA, smooth muscle antibody, and elevated IgG levels was low (17%, 23%, and 0%), but corticosteroids were given to 86%. Microgranulomas and hepatic steatosis were seen in 54% and 46% of the 26 liver biopsies, respectively. The HLA alleles associated with autoimmune hepatitis were not over-represented, but 2 host immune response genes (EDIL3 and SAMA5A) and 3 other genes (GABRP, SMAD3, and SLCO1B1) were associated with ILICI (OR: 2.08-2.4, p<0.01).
Conclusions: ILICI typically arises within 12 weeks of initiating immunotherapy and is self-limited in most cases. Genetic variants involved in host T-cell regulation and drug disposition were identified, implicating these pathways in the pathogenesis of ILICI. If validated, these findings could lead to improved diagnostic instruments and possible treatments for ILICI.
期刊介绍:
Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction.