Journal article
Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure
University College London1
University of Padua2
Takeda Pharmaceutical Company Limited3
Nordic Bioscience AS4
Royal Free London NHS Foundation Trust5
Department of Biotechnology and Biomedicine, Technical University of Denmark6
Section for Protein Science and Biotherapeutics, Department of Biotechnology and Biomedicine, Technical University of Denmark7
Protease Network Degradomics, Section for Protein Science and Biotherapeutics, Department of Biotechnology and Biomedicine, Technical University of Denmark8
Aarhus University Hospital9
European Foundation for the Study of Chronic Liver Failure10
...and 0 moreBackground & 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.
| Language: | English |
|---|---|
| Publisher: | Elsevier |
| Year: | 2021 |
| Pages: | 100355 |
| ISSN: | 25895559 |
| Types: | Journal article |
| DOI: | 10.1016/j.jhepr.2021.100355 |
| ORCIDs: | 0000-0001-8998-7910 , 0000-0001-9845-2176 , 0000-0001-5911-852X , 0000-0003-1211-9298 , 0000-0002-6275-9384 , 0000-0003-0862-403X , 0000-0001-7507-8062 , 0000-0001-5026-8740 and 0000-0002-7747-4015 |
ACLF, acute-on-chronic liver failure AD, acute decompensation CLIF-C ACLF, CLIF Consortium Acute-on-Chronic Liver CLIF-C AD, CLIF Consortium Acute Decompensation CLIF-C OF, CLIF Consortium Organ Failure CPE, concordance probability estimate DAMP, danger-associated molecular pattern Diseases of the digestive system. Gastroenterology ECM, extracellular matrix HC, healthy control HR, hazard ratio HSC, hepatic stellate cell IHC, immunohistochemistry INR, international normalised ratio K18, keratin 18 MELD, model for end-stage liver disease MMP, matrix metalloproteinase NGAL, neutrophil gelatinase-associated lipocalin NIS, noninterventional Study PAMP, pathogen-associated molecular pattern RC799-869 ROC, receiver operating characteristic SC, stable cirrhosis TLR, toll-like receptor UCL, University College London UCLH, University College London Hospitals WCC, white cell count cK18, caspase-cleaved keratin 18 α-SMA, alpha-smooth muscle actin
