The study led by researchers at the European Foundation for the Study of Chronic Liver Failure (EF CLIF), Spain, in collaboration with the University of Münster, Germany, and the PREDICT and ACLARA study groups, analyzed blood samples from 700 hospitalized patients with acutely decompensated cirrhosis identifying 28 immune cell-related genes that best distinguished severe from less severe cases, including acute-on-chronic liver failure (ACLF), regardless of etiology of liver disease, ancestry or precipitating event.

“Traditional biomarkers have limitations due to their overlap and lack of sensitivity across patient groups. With the CLIF-SIG score, we now have a gene-based tool that captures the complexity of systemic inflammation more precisely,” said senior co-author Joan Clària, Director of the Grifols Chair and Head of Translational Operations at EF CLIF, and Group Leader of the Inflammation and Liver Disease group at Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic of Barcelona and CIBEREHD, Spain. 

The CLIF-SIG score was significantly more effective than standard biomarkers in predicting severity induced by systemic inflammation with an area under the curve – a measure of test accuracy – of 0.803 compared to 0.658 for traditional methods as estimated by the Chronic liver failure-Standard biomarkers composite (CLIF-SBC) score. Notably, 80% of patients with a CLIF-SIG score above 0.386 at admission went on to develop ACLF during hospitalization. Sequential measurements also showed that most patients were admitted to hospital at the peak or descending phase of an inflammation wave, suggesting that tracking CLIF-SIG scores over time could aid clinical decision-making.

“Our analysis shows that the CLIF-SIG score not only identifies patients at risk but also provides insights into the inflammatory trajectory of their disease”, said co-first author Jonel Trebicka, principal investigator and Deputy Director at EF CLIF, and Head of Department of Internal Medicine B at University of Münster. 

“The CLIF-SIG score may help clinicians to assess and manage systemic inflammation in acutely decompensated cirrhosis”, added Trebicka.

Beyond its predictive power, the CLIF-SIG score could serve as a valuable tool in clinical trials, helping stratify patients based on their inflammatory profile and assess responses to new treatments targeting systemic inflammation.

“One of the major challenges in chronic liver disease research is identifying reliable biomarkers for systemic inflammation that could predict patient’s outcome. Our work provides a strong foundation for future studies and potential applications in clinical practice”, added Clària.

This study marks an important step towards precision medicine in cirrhosis care, offering a novel way to improve risk assessment and personalize treatment strategies. “We are already working on implementing the gene score across various platforms. This will enable bedside computation of the score, making inflammation assessment more accessible and practical”, explained co-first author Ferran Aguilar, bioinformatician at EF CLIF. As research continues, the CLIF-SIG score could become an essential tool for guiding clinical decisions and improving patient outcomes in acutely decompensated cirrhosis.

Other authors in the study Alberto Queiroz Farias, Juan-José Lozano, Cristina Sánchez-Garrido, Eva Usón-Raposo, Carlos de la Peña-Ramirez, Julia Sidorova, Anna Curto-Vilalta, Patricia Sierra-Casas, Patricia Momoyo Zitelli, Maria Papp, Gustavo Pereira, Paolo Caraceni, Luciana L Goncalves, Carlo Alessandria, Aldo Torre, Wim Laleman, Adrián Gadano, Salvatore Piano, Angelo Z Mattos, Wenyi Gu, Maximilian Joseph Brol, Robert Schierwagen, Frank Erhard Uschner, Julia Fischer, Liliana S C Mendes, Victor Vargas, Mario R Alvares-da-Silva, Raj Mookerjee, Paolo L Bittencourt, Carlos Benitez, Agustín Albillos, Cláudia Couto, Manuel Mendizabal, Rafael Bañares, Claudio L Toledo, Daniel F Mazo, Martin Janicko, Mauricio Castillo-Barradas, Pedro Martin Padilla Machaca, Pietro Gatti, Adelina Zarela-Lozano Miranda, René Malé-Velázquez, Alexander Zipprich, André Castro-Lyra, Thierry Gustot, William Bernal, Alexander L Gerbes, Rajiv Jalan, Javier Fernández, Paolo Angeli, Flair Jose Carrilho, Richard Moreau, and Vicente Arroyo.

This study was sponsored by the European Foundation for the Study of Chronic Failure (EF CLIF). Joan Clària is supported by the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Spain.