Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure
© 2021 The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:3 |
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| Enthalten in: |
JHEP reports : innovation in hepatology - 3(2021), 6 vom: 19. Dez., Seite 100355 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kerbert, Annarein J C [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 28.04.2022 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.jhepr.2021.100355 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM333431480 |
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| 100 | 1 | |a Kerbert, Annarein J C |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Revised 28.04.2022 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2021 The Author(s). | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ACLF, acute-on-chronic liver failure | |
| 650 | 4 | |a AD, acute decompensation | |
| 650 | 4 | |a CLIF-C ACLF, CLIF Consortium Acute-on-Chronic Liver | |
| 650 | 4 | |a CLIF-C AD, CLIF Consortium Acute Decompensation | |
| 650 | 4 | |a CLIF-C OF, CLIF Consortium Organ Failure | |
| 650 | 4 | |a CPE, concordance probability estimate | |
| 650 | 4 | |a Collagen | |
| 650 | 4 | |a DAMP, danger-associated molecular pattern | |
| 650 | 4 | |a ECM, extracellular matrix | |
| 650 | 4 | |a HC, healthy control | |
| 650 | 4 | |a HR, hazard ratio | |
| 650 | 4 | |a HSC, hepatic stellate cell | |
| 650 | 4 | |a IHC, immunohistochemistry | |
| 650 | 4 | |a INR, international normalised ratio | |
| 650 | 4 | |a K18, keratin 18 | |
| 650 | 4 | |a Liver cirrhosis | |
| 650 | 4 | |a MELD, model for end-stage liver disease | |
| 650 | 4 | |a MMP, matrix metalloproteinase | |
| 650 | 4 | |a Multi-organ failure | |
| 650 | 4 | |a NGAL, neutrophil gelatinase-associated lipocalin | |
| 650 | 4 | |a NIS, noninterventional Study | |
| 650 | 4 | |a PAMP, pathogen-associated molecular pattern | |
| 650 | 4 | |a Prognosis | |
| 650 | 4 | |a ROC, receiver operating characteristic | |
| 650 | 4 | |a SC, stable cirrhosis | |
| 650 | 4 | |a TLR, toll-like receptor | |
| 650 | 4 | |a UCL, University College London | |
| 650 | 4 | |a UCLH, University College London Hospitals | |
| 650 | 4 | |a WCC, white cell count | |
| 650 | 4 | |a cK18, caspase-cleaved keratin 18 | |
| 650 | 4 | |a α-SMA, alpha-smooth muscle actin | |
| 700 | 1 | |a Gupta, Saurabh |e verfasserin |4 aut | |
| 700 | 1 | |a Alabsawy, Eman |e verfasserin |4 aut | |
| 700 | 1 | |a Dobler, Iwona |e verfasserin |4 aut | |
| 700 | 1 | |a Lønsmann, Ida |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Nielsen, Signe Holm |e verfasserin |4 aut | |
| 700 | 1 | |a Nielsen, Mette J |e verfasserin |4 aut | |
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| 700 | 1 | |a Amoros, Àlex |e verfasserin |4 aut | |
| 700 | 1 | |a Yeung, Dave |e verfasserin |4 aut | |
| 700 | 1 | |a Macnaughtan, Jane |e verfasserin |4 aut | |
| 700 | 1 | |a Mookerjee, Rajeshwar P |e verfasserin |4 aut | |
| 700 | 1 | |a Macdonald, Stewart |e verfasserin |4 aut | |
| 700 | 1 | |a Andreola, Fausto |e verfasserin |4 aut | |
| 700 | 1 | |a Moreau, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Arroyo, Vicente |e verfasserin |4 aut | |
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| 700 | 1 | |a Treem, William |e verfasserin |4 aut | |
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