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Original research
Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis
  1. Adrià Juanola1,2,3,
  2. Ann Thu Ma4,
  3. Koos de Wit5,
  4. Kohilan Gananandan6,
  5. Olivier Roux7,
  6. Giacomo Zaccherini8,9,
  7. César Jiménez10,
  8. Marta Tonon11,
  9. Cristina Solé12,
  10. Clara Villaseca13,
  11. Frank E Uschner14,
  12. Isabel Graupera1,2,3,
  13. Elisa Pose1,2,3,
  14. Maria José Moreta1,2,
  15. Daniela Campion15,
  16. Ulrich Beuers16,
  17. Rajeshawar P Mookerjee17,
  18. Claire Francoz7,
  19. Francois Durand18,19,
  20. Victor Vargas10,
  21. Salvatore Piano11,
  22. Sonia Alonso13,
  23. Jonel Trebicka14,20,
  24. Wim Laleman21,
  25. Sumeet K Asrani22,
  26. German Soriano23,
  27. Carlo Alessandria15,
  28. Miquel Serra-Burriel24,
  29. Manuel Morales-Ruiz25,
  30. Ferran Torres26,27,
  31. Andrew S Allegretti28,
  32. Aleksander Krag29,
  33. Paolo Caraceni8,
  34. Hugh Watson30,
  35. Juan G Abraldes31,
  36. Elsa Solà32,
  37. Patrick S Kamath33,
  38. Ruben Hernaez34,35,
  39. Pere Ginès1,2,3,36
  40. On behalf of LiverHope Investigators
    1. 1 Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
    2. 2 Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
    3. 3 Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
    4. 4 Toronto Centre for Liver Disease Francis Family Liver Clinic, Toronto General Hospital, Toronto, Ontario, Canada
    5. 5 Gastroenterology and Hepatology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
    6. 6 Institute for Liver and Digestive Health, University College London, London, UK
    7. 7 Department of Hepatology, Beaujon Hospital, Clichy, France
    8. 8 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
    9. 9 Unit of Semeiotics, Liver and Alcohol-related Diseases, University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic, Bologna, Italy
    10. 10 Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain
    11. 11 Department of Medicine (DIMED), University of Padova, Padova, Italy
    12. 12 Department of Gastroenterology and Hepatology, Consorci Corporació Sanitària Parc Taulí, Sabadell, Spain
    13. 13 Digestive Disease Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
    14. 14 Department of Internal Medicine B, University of Münster, Munster, Germany
    15. 15 Division of Gastroenterology and Hepatology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
    16. 16 Gastroenterology & Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
    17. 17 Institute of Liver and Digestive Health, University College London Medical School, London, UK
    18. 18 DHU Unity, Pôle des Maladies de l’Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France
    19. 19 Université Denis Diderot-Paris 7, Paris, France
    20. 20 European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
    21. 21 Division of Liver and Biliopanreatic Disorders, KU Leuven, University of Leuven, Leuven, Belgium
    22. 22 Division of Hepatology, Department of Medicine, Baylor University Medical Center at Dallas, Dallas, Texas, USA
    23. 23 Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
    24. 24 University of Zurich Institute of Epidemiology Biostatistics and Prevention, Zurich, Switzerland
    25. 25 Biochemistry and Molecular Genetics Department-CDB, Hospital Clinic de Barcelona, Barcelona, Spain
    26. 26 Biostatistics and Data Management Core Facility, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain
    27. 27 Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
    28. 28 Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
    29. 29 Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
    30. 30 Evotec ID (Lyon) SAS, Lyon, France
    31. 31 Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada
    32. 32 Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, California, USA
    33. 33 Gastroenterology and Hepatology, Mayo Medical School, Rochester, Minnesota, USA
    34. 34 Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
    35. 35 Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
    36. 36 Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
    1. Correspondence to Dr Pere Ginès, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain; PGINES{at}


    Background Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications.

    Methods We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not.

    Results Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46).

    Conclusion Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.

    • liver cirrhosis

    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information. The data that support the findings of this study are available from the corresponding author, (PG), on reasonable request.

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information. The data that support the findings of this study are available from the corresponding author, (PG), on reasonable request.

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    • AJ and ATM are joint first authors.

    • Twitter @Zac_MD

    • Collaborators M Aban, R Andrade, P Angeli, S K Asrani, E Avitabile, O Bassegoda, M Bernardi, M Carol, M Cervera, MT Chiappa, V Esnault, N Fabrellas, J Farrés, P Ferstl, J Gratacós-Ginès, P Ginès, M Joyera, M Korenjak, S Martínez, S Montagnese, L Napoleone, G Nicolao, E Palacio, M Pavesi, M Pérez- Guasch, A B Rubio, M Schulz, M Simon-Talero, A Vives.

    • Contributors All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. AJ designed the study, acquired data, developed the database, undertook statistical analyses and interpretation, and drafted and revised the manuscript. ATM designed the study, acquired data, developed the database, interpreted the data, and drafted and revised the manuscript. KdW, KG and OR acquired and interpreted data, contributed to manuscript drafting and revision. GZ, CJ, MT, CS, CV, FEU, IG, EP and MJM acquired data and revised the manuscript. ES designed the study, acquired and interpreted data, and revised the manuscript. RH designed the study, acquired data, developed the database, interpreted the data, and drafted and revised the manuscript. DC, UB, RM, CF, FD, VV, SP, SAsrani, JT, WL, SAsrani, GS, CA, MS-B, MM, FT, AA, AK, PC, HW, JGA, PSK and PG revised the manuscript. RH and PG Shared co-principal investigator. AJ, ATM, RH and PG accept full responsibility for the work and/or the conduct of the study, had access to the data and controlled the decision to publish.

    • Funding This work has been supported by the European Commission Horizon 2020 (LIVERHOPE project number 731875), ISCIII‐Subdirección General de Evaluación and European Regional Development Fund for the Plan Nacional I+D+I (grant number PI20/00579 to PG and PI18/00727 to ES), and the Agency for Administration of University and Research (grant number 2017SGR‐01281 to PG, ES, EP). ATM received funding from the Canadian Association for the Study of Liver and the Canadian Liver Foundation. JT was supported by the German Research Foundation (DFG) project ID 403224013—SFB 1382 (A09), by the German Federal Ministry of Education and Research (BMBF) for the DEEP-HCC project and by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) for the ENABLE and ACLF-I cluster projects. The MICROB-PREDICT (project ID 825694), DECISION (project ID 847949), GALAXY (project ID 668031) and IHMCSA (project ID A) projects have received funding from the European Union’s Horizon 2020 research and innovation programme.

    • Disclaimer The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the U.S. Department of Veterans Affairs or the United States government.

    • Competing interests FD consults for Biotest. VV consults for Promethera and is on the speakers bureau for Intercept. SP advises Mallinckrodt. HW is employed by Evotec and owns stock in Sanofi. PG consults for and received grants from Gilead, Grifols and Mallinckrodt, and consults for Novartis, Martin and Ferring. JT has received speaking and/or consulting fees from Versantis, Gore, Boehringer-Ingelheim, Falk, Grifols, Genfit and CSL Behring. RH is part of the Editorial Board of the Gut journal.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.