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

Maja Thiele, Stine Johansen, Natasja S Gudmann, Bjørn Madsen, Maria Kjaergaard, Mette Juul Nielsen, Diana J Leeming, Suganya Jacobsen, Flemming Bendtsen, Søren Møller, Sönke Detlefsen, Morten Karsdal, Aleksander Krag, Galaxy Consortium, Jonel Trebicka (Medlem af forfattergruppering)

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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.

TidsskriftAlimentary Pharmacology & Therapeutics
Udgave nummer8
Sider (fra-til)1070-1080
StatusUdgivet - okt. 2021

Bibliografisk note

Funding information: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 668031, Innovation Fund Denmark, Odense University Hospital's research funds, University of Southern Denmark's PhD funds and Region of Southern Denmark's postdoc funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


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