Richard Moreau1, Joan Clària2, Ferran Aguilar3, François Fenaille4, Juan José Lozano5, Christophe Junot4, Benoit Colsch4, Paolo Caraceni6, Jonel Trebicka7, Marco Pavesi3, Carlo Alessandria8, Frederik Nevens9, Faouzi Saliba10, Tania M Welzel11, Agustin Albillos12, Thierry Gustot13, Javier Fernández2, Christophe Moreno13, Maurizio Baldassarre6, Giacomo Zaccherini6, Salvatore Piano14, Sara Montagnese14, Victor Vargas15, Joan Genescà15, Elsa Solà16, William Bernal17, Noémie Butin4, Thaïs Hautbergue4, Sophie Cholet4, Florence Castelli4, Christian Jansen18, Christian Steib19, Daniela Campion8, Raj Mookerjee20, Miguel Rodríguez-Gandía12, German Soriano21, François Durand22, Daniel Benten23, Rafael Bañares24, Rudolf E Stauber25, Henning Gronbaek26, Minneke J Coenraad27, Pere Ginès16, Alexander Gerbes19, Rajiv Jalan28, Mauro Bernardi6, Vicente Arroyo3, Paolo Angeli29. 1. EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain; Inserm, U1149, Centre de Recherche sur l'Inflammation (CRI) UMRS1149, Université de Paris, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France. Electronic address: richard.moreau@inserm.fr. 2. EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain; Hospital Clínic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain; CIBERehd, Barcelona, Spain. 3. EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain. 4. Service de Pharmacologie et Immuno-Analyse (SPI), Laboratoire d'Etude du Métabolisme des Médicaments, CEA, INRA, Université Paris Saclay, MetaboHUB, F-91191 Gif-sur-Yvette, France. 5. CIBERehd, Barcelona, Spain. 6. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. 7. EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain; J.W. Goethe University Hospital, Frankfurt, Germany. 8. Division of Gastroenterology and Hepatology, San Giovanni Battista Hospital, Torino, Italy. 9. University Hospital Gasthuisberg, KU Leuven, Belgium. 10. Hôpital Paul Brousse, Université Paris-Sud, Villejuif, France. 11. J.W. Goethe University Hospital, Frankfurt, Germany. 12. Department of Gastroenterology, Hospital Universitario Ramón y Cajal, IRYCIS, University of Alcalá, CIBEREHD, Madrid, Spain. 13. CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 14. Unit of Internal Medicine and Hepatology, Dept. of Medicine, DIMED, University of Padova, Italy. 15. Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. 16. Hospital Clínic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain; CIBERehd, Barcelona, Spain. 17. Liver Intensive Therapy Unit, Institute of Liver Studies, Division of Inflammation Biology, King's College London, London, UK. 18. Department of Internal Medicine I, University of Bonn, Germany. 19. Department of Medicine II, Liver Center Munich, University Hospital LMU Munich, Munich, Germany. 20. Liver Failure Group, Institute for Liver Disease Health, University College London, Royal Free Hospital, London, UK. 21. Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 22. Inserm, U1149, Centre de Recherche sur l'Inflammation (CRI) UMRS1149, Université de Paris, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France. 23. University Hospital Hamburg-Eppendorf, Germany. 24. Digestive Diseases Department, Hospital General Universitario Gregorio Marañón; Instituto de Investigación Sanitaria Gregorio Marañón; Facultad de Medicina, Universidad Complutense, Madrid; and CIBERehd. 25. Medical University of Graz, Graz, Austria. 26. Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. 27. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands. 28. EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain; Liver Failure Group, Institute for Liver Disease Health, University College London, Royal Free Hospital, London, UK. 29. EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain; Unit of Internal Medicine and Hepatology, Dept. of Medicine, DIMED, University of Padova, Italy.
Abstract
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF. METHODS: We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals. RESULTS: Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins. CONCLUSIONS: In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures. LAY SUMMARY: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF. METHODS: We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals. RESULTS: Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins. CONCLUSIONS: In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures. LAY SUMMARY: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.
Authors: Jasmohan S Bajaj; Guadalupe Garcia-Tsao; K Rajender Reddy; Jacqueline G O'Leary; Hugo E Vargas; Jennifer C Lai; Patrick S Kamath; Puneeta Tandon; Ram M Subramanian; Paul Thuluvath; Andrew Fagan; Tejasav Sehrawat; Randolph de la Rosa Rodriguez; Leroy R Thacker; Florence Wong Journal: Hepatology Date: 2021-07-08 Impact factor: 17.298