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Progressive alcohol-related liver fibrosis is characterised by imbalanced collagen formation and degradation

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@article{fb3c0e8f71e74a36a012fa1818abcc02,
title = "Progressive alcohol-related liver fibrosis is characterised by imbalanced collagen formation and degradation",
abstract = "BACKGROUND: Liver fibrosis accumulation is considered a turnover disease, with formation exceeding degradation, although this hypothesis has never been tested in humans.AIMS: To investigate extracellular matrix (ECM) remodelling in a biopsy-controlled study of alcohol-related liver disease (ALD) patients.METHODS: We evaluated the relationship between formation and degradation of four collagens as a function of histological fibrosis, inflammation and steatosis in 281 patients with ALD and 50 matched healthy controls. Post hoc, we tested the findings in a cohort of patients with alcohol-related cirrhosis and assessed the collagens' prognostic accuracy. We assessed the fibrillar collagens type III (PRO-C3/C3M) and V (PRO-C5/C5M), the basement membrane collagen IV (PRO-C4/C4M), and the microfilament interface collagen VI (PRO-C6/C6M).RESULTS: Mean age was 54 ± 6 years, 74% male, fibrosis stage F0/1/2/3/4 = 33/98/84/18/48. Compared to controls, patients with ALD had higher levels of type III collagen formation and degradation, with the highest concentrations in those with cirrhosis (PRO-C3 = 8.2 ± 1.7 ng/mL in controls, 14.6 ± 13.5 in ALD, 34.8 ± 23.1 in cirrhosis; C3M 7.4 ± 1.9 in controls, 9.3 ± 4.4 in ALD, 14.0 ± 5 in cirrhosis). ECM remodelling became increasingly imbalanced in higher stages of liver fibrosis, with formation progressively superseding degradation. This was particularly pronounced for type III collagen. We observed similar imbalance for inflammatory severity, but not steatosis.CONCLUSIONS: ALD is characterised by both elevated collagen formation and degradation, which becomes increasingly imbalanced with more severe disease. Net increase in fibrillar collagens contributes to fibrosis progression. This has important implications for monitoring and very early identification of patients at highest risk of progressing to cirrhosis.",
author = "Maja Thiele and Stine Johansen and Gudmann, {Natasja S} and Bj{\o}rn Madsen and Maria Kjaergaard and Nielsen, {Mette Juul} and Leeming, {Diana J} and Suganya Jacobsen and Flemming Bendtsen and S{\o}ren M{\o}ller and S{\"o}nke Detlefsen and Morten Karsdal and Aleksander Krag and {GALAXY Consortium}",
note = "{\textcopyright} 2021 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.",
year = "2021",
month = oct,
doi = "10.1111/apt.16567",
language = "English",
volume = "54",
pages = "1070--1080",
journal = "Alimentary Pharmacology and Therapeutics",
issn = "0269-2813",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "8",

}

RIS

TY - JOUR

T1 - Progressive alcohol-related liver fibrosis is characterised by imbalanced collagen formation and degradation

AU - Thiele, Maja

AU - Johansen, Stine

AU - Gudmann, Natasja S

AU - Madsen, Bjørn

AU - Kjaergaard, Maria

AU - Nielsen, Mette Juul

AU - Leeming, Diana J

AU - Jacobsen, Suganya

AU - Bendtsen, Flemming

AU - Møller, Søren

AU - Detlefsen, Sönke

AU - Karsdal, Morten

AU - Krag, Aleksander

AU - GALAXY Consortium

N1 - © 2021 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

PY - 2021/10

Y1 - 2021/10

N2 - BACKGROUND: Liver fibrosis accumulation is considered a turnover disease, with formation exceeding degradation, although this hypothesis has never been tested in humans.AIMS: To investigate extracellular matrix (ECM) remodelling in a biopsy-controlled study of alcohol-related liver disease (ALD) patients.METHODS: We evaluated the relationship between formation and degradation of four collagens as a function of histological fibrosis, inflammation and steatosis in 281 patients with ALD and 50 matched healthy controls. Post hoc, we tested the findings in a cohort of patients with alcohol-related cirrhosis and assessed the collagens' prognostic accuracy. We assessed the fibrillar collagens type III (PRO-C3/C3M) and V (PRO-C5/C5M), the basement membrane collagen IV (PRO-C4/C4M), and the microfilament interface collagen VI (PRO-C6/C6M).RESULTS: Mean age was 54 ± 6 years, 74% male, fibrosis stage F0/1/2/3/4 = 33/98/84/18/48. Compared to controls, patients with ALD had higher levels of type III collagen formation and degradation, with the highest concentrations in those with cirrhosis (PRO-C3 = 8.2 ± 1.7 ng/mL in controls, 14.6 ± 13.5 in ALD, 34.8 ± 23.1 in cirrhosis; C3M 7.4 ± 1.9 in controls, 9.3 ± 4.4 in ALD, 14.0 ± 5 in cirrhosis). ECM remodelling became increasingly imbalanced in higher stages of liver fibrosis, with formation progressively superseding degradation. This was particularly pronounced for type III collagen. We observed similar imbalance for inflammatory severity, but not steatosis.CONCLUSIONS: ALD is characterised by both elevated collagen formation and degradation, which becomes increasingly imbalanced with more severe disease. Net increase in fibrillar collagens contributes to fibrosis progression. This has important implications for monitoring and very early identification of patients at highest risk of progressing to cirrhosis.

AB - BACKGROUND: Liver fibrosis accumulation is considered a turnover disease, with formation exceeding degradation, although this hypothesis has never been tested in humans.AIMS: To investigate extracellular matrix (ECM) remodelling in a biopsy-controlled study of alcohol-related liver disease (ALD) patients.METHODS: We evaluated the relationship between formation and degradation of four collagens as a function of histological fibrosis, inflammation and steatosis in 281 patients with ALD and 50 matched healthy controls. Post hoc, we tested the findings in a cohort of patients with alcohol-related cirrhosis and assessed the collagens' prognostic accuracy. We assessed the fibrillar collagens type III (PRO-C3/C3M) and V (PRO-C5/C5M), the basement membrane collagen IV (PRO-C4/C4M), and the microfilament interface collagen VI (PRO-C6/C6M).RESULTS: Mean age was 54 ± 6 years, 74% male, fibrosis stage F0/1/2/3/4 = 33/98/84/18/48. Compared to controls, patients with ALD had higher levels of type III collagen formation and degradation, with the highest concentrations in those with cirrhosis (PRO-C3 = 8.2 ± 1.7 ng/mL in controls, 14.6 ± 13.5 in ALD, 34.8 ± 23.1 in cirrhosis; C3M 7.4 ± 1.9 in controls, 9.3 ± 4.4 in ALD, 14.0 ± 5 in cirrhosis). ECM remodelling became increasingly imbalanced in higher stages of liver fibrosis, with formation progressively superseding degradation. This was particularly pronounced for type III collagen. We observed similar imbalance for inflammatory severity, but not steatosis.CONCLUSIONS: ALD is characterised by both elevated collagen formation and degradation, which becomes increasingly imbalanced with more severe disease. Net increase in fibrillar collagens contributes to fibrosis progression. This has important implications for monitoring and very early identification of patients at highest risk of progressing to cirrhosis.

UR - http://www.scopus.com/inward/record.url?scp=85113342185&partnerID=8YFLogxK

U2 - 10.1111/apt.16567

DO - 10.1111/apt.16567

M3 - Journal article

C2 - 34428307

VL - 54

SP - 1070

EP - 1080

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

SN - 0269-2813

IS - 8

ER -

ID: 67247731