Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure
Annarein J.C. Kerbert,
Saurabh Gupta,
Eman Alabsawy,
Iwona Dobler,
Ida Lønsmann,
Andrew Hall,
Signe Holm Nielsen,
Mette J. Nielsen,
Henning Gronbaek,
Àlex Amoros,
Dave Yeung,
Jane Macnaughtan,
Rajeshwar P. Mookerjee,
Stewart Macdonald,
Fausto Andreola,
Richard Moreau,
Vicente Arroyo,
Paolo Angeli,
Diana J. Leeming,
William Treem,
Morten A. Karsdal,
Rajiv Jalan
Affiliations
Annarein J.C. Kerbert
Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
Saurabh Gupta
Translational and Biomarker Research, GI-DDU, Takeda Pharmaceuticals International Co., Cambridge, MA, USA
Eman Alabsawy
Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK; Faculty of Medicine, Alexandria University, Alexandria, Egypt
Iwona Dobler
Statistical and Quantitative Sciences, Takeda Pharmaceuticals International Co., Cambridge, MA, USA
Ida Lønsmann
Biomarkers and Research, Nordic Bioscience, Herlev, Denmark
Andrew Hall
Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
Signe Holm Nielsen
Biomarkers and Research, Nordic Bioscience, Herlev, Denmark; Department of Biomedicine and Biotechnology, Technical University of Denmark, Lyngby, Denmark
Mette J. Nielsen
Biomarkers and Research, Nordic Bioscience, Herlev, Denmark
Henning Gronbaek
Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
Àlex Amoros
European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
Dave Yeung
Translational and Biomarker Research, GI-DDU, Takeda Pharmaceuticals International Co., Cambridge, MA, USA
Jane Macnaughtan
Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
Rajeshwar P. Mookerjee
Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK; Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
Stewart Macdonald
Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
Fausto Andreola
Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
Richard Moreau
European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Inserm and Université de Paris, Centre de Recherche sur l’Inflammation (CRI), Paris, France; Service d’Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
Vicente Arroyo
European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
Paolo Angeli
Unit of Internal Medicine and Hepatology, Department of Medicine, DIMED, University of Padova, Padua, Italy
Diana J. Leeming
Biomarkers and Research, Nordic Bioscience, Herlev, Denmark
William Treem
Clinical Science, GI-TAU, Takeda Pharmaceuticals International Co., Cambridge, MA, USA
Morten A. Karsdal
Biomarkers and Research, Nordic Bioscience, Herlev, Denmark
Rajiv Jalan
Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK; Corresponding author. Address: Institute for Liver and Digestive Health, University College London, Royal Free Campus, Rowland Hill Street, NW3 2PF, London, UK. Tel.: +44-207-4332845.
Background & Aims: Acute-on-chronic liver failure (ACLF) is characterised by organ failure(s), high short-term mortality, and, pathophysiologically, deranged inflammatory responses. The extracellular matrix (ECM) is critically involved in regulating the inflammatory response. This study aimed to determine alterations in biomarkers of ECM turnover in ACLF and their association with inflammation, organ failures, and mortality. Methods: We studied 283 patients with cirrhosis admitted for acute decompensation (AD) with or without ACLF, 64 patients with stable cirrhosis, and 30 healthy controls. A validation cohort (25 ACLF, 9 healthy controls) was included. Plasma PRO-C3, PRO-C4, PRO-C5, PRO-C6, and PRO-C8 (i.e. collagen type III–VI and VIII formation) and C4M and C6M (i.e. collagen type IV and VI degradation) were measured. Immunohistochemistry of PRO-C6 was performed on liver biopsies (AD [n = 7], ACLF [n = 5]). A competing-risk regression analysis was performed to explore the prognostic value of biomarkers of ECM turnover with 28- and 90-day mortality. Results: PRO-C3 and PRO-C6 were increased in ACLF compared to AD (p = 0.089 and p <0.001, respectively), whereas collagen degradation markers C4M and C6M were similar. Both PRO-C3 and PRO-C6 were strongly associated with liver function and inflammatory markers. Only PRO-C6 was associated with extrahepatic organ failures and 28- and 90-day mortality (hazard ratio [HR; on log-scale] 6.168, 95% CI 2.366–16.080, p <0.001, and 3.495, 95% CI 1.509–8.093, p = 0.003, respectively). These findings were consistent in the validation cohort. High PRO-C6 expression was observed in liver biopsies of patients with ACLF. Conclusions: This study shows, for the first time, evidence of severe net interstitial collagen deposition in ACLF and makes the novel observation of the association between PRO-C6 and (extrahepatic) organ failures and mortality. Further studies are needed to define the pathogenic significance of these observations. Lay summary: This study describes a disrupted turnover of collagen type III and VI in Acute-on-chronic liver failure (ACLF). Plasma biomarkers of these collagens (PRO-C3 and PRO-C6) are associated with the severity of liver dysfunction and inflammation. PRO-C6, also known as the hormone endotrophin, has also been found to be associated with multi-organ failure and prognosis in acute decompensation and ACLF.
