Lukas Otero Sanchez, Joan Clària, Clélia Galvanin, Ferran Aguilar, Richard Layese, Matteo Serra, Laura Jiménez-Gracia, Paula Nieto, Darko Castven, Sona Frankova, Milan Jirsa, David Tornai, Anna Curto-Vilalta, Alberto Queiroz Farias, Maria Papp, Patricia Momoyo Zitelli, Paolo Caraceni, Giacomo Zaccherini, Luciana L Goncalves, Carlo Alessandria, Gustavo Pereira, Wim Laleman, Adrian C Gadano, Salvatore Piano, Angelo Z Mattos, Desislava Germanova, Valério Lucidi, Daphnée Soret, Line Carolle Ntandja Wandji, Frank Erhard Uschner, Aldo Torre, Victor Vargas, Liliana S C Mendes, Rajeshwar P Mookerjee, Carlos Benitez, Mario R Alvares-da-Silva, Myriam Remmelink, Paulo L Bittencourt, Agustin Albillos, Claudia Alves Couto, Rafael Bañares, Manuel Mendizabal, Delphine Degré, Claudio L Toledo, Martin Janicko, Daniel F Mazo, Mauricio Castillo Barradas, William Bernal, Adelina Zarela Lozano Miranda, P Martín Padilla-Machaca, Alexander Zipprich, René Malé-Velázquez, Christophe Moreno, André Castro Lyra, Flair Carrilho, Javier Fernandez, Jonel Trebicka, Rajiv Jalan, Paolo Angeli, Horia Stefanescu, Pierre-Emmanuel Rautou, Stephan Buch, Alexandre Louvet, Jens U Marquardt, Thierry Gustot, Holger Heyn, Juan C Nieto, Vicente Arroyo, Nathalie Ganne-Carrié, Jan Sperl, Richard Moreau, Philippe Mathurin, Pierre Nahon, Eric Trépo
{"title":"Genetic variants and the risk of renal impairment in decompensated cirrhosis: a multi-ancestry genome-wide association study.","authors":"Lukas Otero Sanchez, Joan Clària, Clélia Galvanin, Ferran Aguilar, Richard Layese, Matteo Serra, Laura Jiménez-Gracia, Paula Nieto, Darko Castven, Sona Frankova, Milan Jirsa, David Tornai, Anna Curto-Vilalta, Alberto Queiroz Farias, Maria Papp, Patricia Momoyo Zitelli, Paolo Caraceni, Giacomo Zaccherini, Luciana L Goncalves, Carlo Alessandria, Gustavo Pereira, Wim Laleman, Adrian C Gadano, Salvatore Piano, Angelo Z Mattos, Desislava Germanova, Valério Lucidi, Daphnée Soret, Line Carolle Ntandja Wandji, Frank Erhard Uschner, Aldo Torre, Victor Vargas, Liliana S C Mendes, Rajeshwar P Mookerjee, Carlos Benitez, Mario R Alvares-da-Silva, Myriam Remmelink, Paulo L Bittencourt, Agustin Albillos, Claudia Alves Couto, Rafael Bañares, Manuel Mendizabal, Delphine Degré, Claudio L Toledo, Martin Janicko, Daniel F Mazo, Mauricio Castillo Barradas, William Bernal, Adelina Zarela Lozano Miranda, P Martín Padilla-Machaca, Alexander Zipprich, René Malé-Velázquez, Christophe Moreno, André Castro Lyra, Flair Carrilho, Javier Fernandez, Jonel Trebicka, Rajiv Jalan, Paolo Angeli, Horia Stefanescu, Pierre-Emmanuel Rautou, Stephan Buch, Alexandre Louvet, Jens U Marquardt, Thierry Gustot, Holger Heyn, Juan C Nieto, Vicente Arroyo, Nathalie Ganne-Carrié, Jan Sperl, Richard Moreau, Philippe Mathurin, Pierre Nahon, Eric Trépo","doi":"10.1016/S2468-1253(26)00217-7","DOIUrl":"https://doi.org/10.1016/S2468-1253(26)00217-7","url":null,"abstract":"<p><strong>Background: </strong>Renal impairment is a major complication of decompensated cirrhosis and a key driver of mortality. Despite its clinical significance, the genetic architecture of susceptibility to renal impairment in this context remains largely unexplored. We conducted a multi-ancestry genome-wide association study (GWAS) to identify genetic loci associated with renal impairment in decompensated cirrhosis.</p><p><strong>Methods: </strong>We performed a GWAS for serum creatinine levels in 3220 patients with decompensated cirrhosis across five cohorts (CANONIC [n=707], PREDICT [n=825], ACLARA [n=671], Bologna [n=272], and Brussels [n=745]); with 83% of patients having European and 17% having admixed American genetic ancestry. Findings were replicated in 1728 European patients with decompensated cirrhosis across four independent cohorts (Czech-Romanian [n=988], CirVir-CIRRAL [n=139], French-Belgian [n=294], and German [n=307]). Associations were evaluated in 3139 patients with compensated cirrhosis (EuroLiver [n=851], CirVir-CIRRAL [n=1142], and the UK Biobank [n=1146]) and 402 683 individuals from the UK Biobank with no history of cirrhosis, who served as a general population comparator. Single-cell and spatial transcriptomics mapped GWAS associations to cell types in the liver, blood, and kidney.</p><p><strong>Findings: </strong>We identified a genome-wide significant association at the SUSD1 locus (lead variant rs2099161[C→T]; trans-ancestry-discovery β=0·16 [95% CI 0·11 to 0·21], p=4·32 × 10<sup>-10</sup>; independent replication β=0·09 [0·03 to 0·16], p=5·34 × 10<sup>-3</sup>; combined meta-analysis β=0·13 [0·09 to 0·17], p=8·31 × 10<sup>-11</sup>; I<sup>2</sup>=0%). The effect was specific to decompensated cirrhosis, with no association in compensated cirrhosis (β= -0·0003 [-0·0460 to 0·0454], p=0·99) or the general population (β= -0·005 [-0·009 to -0·002], p=3·78 × 10<sup>-3</sup>). Each additional copy of the rs2099161(C) risk allele was associated with a higher risk of kidney failure at inclusion in the ACLARA, CANONIC, PREDICT, Bologna, Brussels, Czech-Romanian, and French-Belgian cohorts (n=4390, p=6·34 × 10<sup>-4</sup>). The risk was highest in CC homozygotes compared with patients with the TT genotype (odds ratio 1·60 [95% CI 1·21 to 2·11]). A similar pattern was observed for incident kidney failure at 1 week (CANONIC cohort n=638, p=0·035, CC vs TT genotypes 2·00 [1·10 to 3·65]), and terlipressin requirement (PREDICT, ACLARA, and Brussels cohorts, n=2161, p=0·027, CC vs TT genotypes 2·06 [1·08 to 3·93]). Transcriptomic analyses identified plasmacytoid dendritic cells as the primary SUSD1-expressing cell-type with elevated expression in patients with renal impairment across compartments. Patients with renal impairment showed increased abundance of plasmacytoid dendritic cells and type-I-interferon signalling in liver and kidney tissues.</p><p><strong>Interpretation: </strong>SUSD1 is a risk locus for renal impairment in","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":" ","pages":""},"PeriodicalIF":39.1,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lessons from the European LiverScreen and Chinese LiverHealth projects","authors":"Laurens A van Kleef,Willem Pieter Brouwer","doi":"10.1016/s2468-1253(26)00269-4","DOIUrl":"https://doi.org/10.1016/s2468-1253(26)00269-4","url":null,"abstract":"","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":"103 1","pages":""},"PeriodicalIF":35.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shinji Okabayashi, Lindsay Hracs, Joseph W Windsor, Julia Gorospe, Stephanie Coward, Raja Affendi Raja Ali, Ida Hilmi, Tadakazu Hisamatsu, Joyce W Y Mak, Ren Mao, Katsuyoshi Matsuoka, Yoshitaka Murakami, Siew C Ng, Sang Hyoung Park, Zhihua Ran, Jeongkuk Seo, Suk-Kyun Yang, Gilaad G Kaplan
{"title":"The trajectory of inflammatory bowel disease in east and southeast Asia: transitioning from acceleration in incidence to compounding prevalence","authors":"Shinji Okabayashi, Lindsay Hracs, Joseph W Windsor, Julia Gorospe, Stephanie Coward, Raja Affendi Raja Ali, Ida Hilmi, Tadakazu Hisamatsu, Joyce W Y Mak, Ren Mao, Katsuyoshi Matsuoka, Yoshitaka Murakami, Siew C Ng, Sang Hyoung Park, Zhihua Ran, Jeongkuk Seo, Suk-Kyun Yang, Gilaad G Kaplan","doi":"10.1016/s2468-1253(26)00162-7","DOIUrl":"https://doi.org/10.1016/s2468-1253(26)00162-7","url":null,"abstract":"","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":"4 1","pages":""},"PeriodicalIF":35.7,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148715539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The spectrum of steatotic liver disease in the USA.","authors":"Hans Scherübl","doi":"10.1016/s2468-1253(26)00129-9","DOIUrl":"https://doi.org/10.1016/s2468-1253(26)00129-9","url":null,"abstract":"","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":"27 1","pages":"654-655"},"PeriodicalIF":35.7,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Virginia Solitano, Vipul Jairath, Fernando Magro, Alessandro Armuzzi, Laurent Peyrin-Biroulet, Silvio Danese
{"title":"Breaking the therapeutic ceiling in inflammatory bowel disease: myth or reality?","authors":"Virginia Solitano, Vipul Jairath, Fernando Magro, Alessandro Armuzzi, Laurent Peyrin-Biroulet, Silvio Danese","doi":"10.1016/S2468-1253(26)00085-3","DOIUrl":"10.1016/S2468-1253(26)00085-3","url":null,"abstract":"<p><p>Despite an expanding therapeutic armamentarium, remission rates in inflammatory bowel disease (IBD) appear to plateau at 30-50% after 1 year of treatment, leading to the concept of a therapeutic ceiling with single agents. This Viewpoint challenges the notion that this ceiling represents a biological limit and instead interprets it as the consequence of current therapeutic and methodological constraints, including late intervention, reliance on monotherapy, trial designs that fail to capture disease complexity, and stringent clinical trial endpoints. We outline a conceptual and strategic framework to overcome these limitations through prevention, early interception, and sustainable innovation. Advances in biomarker discovery, multiomic profiling, and integrated risk modelling might enable identification of at-risk individuals long before diagnosis, whereas population-level measures, such as healthy diet, smoking cessation, and reduced antibiotic exposure, could substantially lower IBD incidence. Methodological innovation, including adaptive designs, Bayesian trials, and platform trials, is essential to evaluate multiple therapies efficiently and account for disease heterogeneity. From a therapeutic standpoint, rational advanced combination treatment targeting complementary pathways can extend efficacy, whereas emerging cell-based and immune-engineered interventions could ultimately redefine remission. Precision medicine should integrate clinical durability, economic and environmental responsibility, and equitable global access. We critically appraise recent evidence and argue that harmonisation, standardisation, and a decisive shift from empiricism to mechanism-based precision medicine can raise, or even break, the therapeutic ceiling.</p>","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":" ","pages":"713-719"},"PeriodicalIF":39.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147943685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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