Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure

Annarein Kerbert ,Ida Lønsmann,Vicente Arroyo,Dave Yeung,Eman Alabsawy,Richard Moreau,Saurabh Gupta,Stewart Macdonald,Rajiv Jalan,Paolo Angeli,Fausto Andreola,Iwona Dobler,Andrew Hall,Signe Holm Nielsen,Jane Macnaughtan,William R Treem ,R Mookerjee ,Morten Karsdal ,Diana Julie Leeming ,Àlex Amorós ,Henning Grønbæk ,Mette Juul Nielsen

doi:10.1016/j.jhepr.2021.100355

Abstract

Background & AimsAcute-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.MethodsWe 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.ResultsPRO-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.ConclusionsThis 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 summaryThis 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.

Highlights

Liver fibrosis is a consequence of chronic hepatocyte injury and is characterised by excessive deposition of extracellular matrix (ECM) consisting of different collagen types that are produced by hepatic myofibroblasts derived from activated hepatic stellate cells (HSCs).[1,2,3]
When comparing the subpopulation with Acute-on-chronic liver failure (ACLF) of study cohort A with the validation cohort, we found that the latter had a higher proportion of patients with ACLF grade III (32% vs. 11.4%), which was reflected by significantly higher CLIF-C CLIF Consortium Organ Failure (OF) scores (11 [10–13] vs. 10 [9–11], p
This study describes for the first time that ACLF is associated with marked increases in plasma levels of biomarkers of interstitial ECM formation (PRO-C3 and PRO-C6) but unchanged levels of markers of ECM breakdown (C4M and C6M)

Summary

Introduction

Liver fibrosis is a consequence of chronic hepatocyte injury and is characterised by excessive deposition of extracellular matrix (ECM) consisting of different collagen types that are produced by hepatic myofibroblasts derived from activated hepatic stellate cells (HSCs).[1,2,3] Fibrosis progression is a dynamic process that involves both formation and degradation of the ECM and that becomes unbalanced during liver disease. The sites of degradation by specific MMPs are distinct, and the fragments, known as neo-epitopes, serve as markers of tissue degradation quantified by collagen degradation.[4] the pro-peptides that are released during the maturation of the collagen molecule can serve as markers of fibrogenesis; ECM formation exemplified by collagen formation These markers of collagen turnover (especially collagen types III, IV, and VI) have been studied in different contexts of chronic liver disease and have been found to be useful as biomarkers of fibrotic processes and the degree of fibrosis in different aetiologies.[5]. 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.

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