BIOMARKERS OF EXTRACELLULAR MATRIX FORMATION ARE ASSOCIATED WITH ACUTE-ON-CHRONIC LIVER FAILURE

Abstract Background & Aims Acute-on-chronic liver failure (ACLF) is characterized by organ failure(s), high short-term mortality and pathophysiologically by 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 cirrhosis patients 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, 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 Conclusion 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, (extra-hepatic) 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 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 AD and ACLF.