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

Abstract

Summary 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.

Binge drinking induces an acute burst of markers of hepatic fibrogenesis (PRO‐C3)

“…Our analyses of the net deposition ratio of PRO‐C3 and C3M in the hepatic blood showed that the ratio between the two also increased with the liver fibrosis stage at baseline. This confirms another recent study by our group where turnover, in general, was found to be increased in patients with ALD 26 …”

“…PRO‐C3 displays high diagnostic accuracy of advanced fibrosis and predicts fibrosis progression and outcomes in several liver disease etiologies 15,22‐26 . In our study, PRO‐C3 increased in all three study groups within 24 hours, and when liver‐diseased patients were divided according to the aetiological background.…”

“…and predicts fibrosis progression and outcomes in several liver disease etiologies. 15,[22][23][24][25][26] In our study, PRO-C3 increased in all three study groups within 24 hours, and when liver-diseased patients were divided according to the aetiological background. This indicates that binge drinking induces a fibrogenic response independent of disease Data are presented as n (%).…”

“…This confirms another recent study by our group where turnover, in general, was found to be increased in patients with ALD. 26 Markers of hepatic collagen formation and degradation have been studied and measured for several years in different aetiologies and stages of disease. Comparing our results to that of other cohorts, we find similar levels according to the fibrosis stage for the markers why we believe this enhances the external validity of the findings.…”

Diagnostic challenges in patients with alcohol-related liver disease

“…Assessment of liver fibrosis -Fibrosis is not a disease but rather an outcome of the tissue repair response that becomes dysregulated following many types of chronic liver injury and results in accumulation of extracellular matrix proteins, primarily collagen and fibronectin, the structural component of fibrosis and cirrhosis [36,37,38]. Liver fibrosis represents the early pre-cirrhotic stages of chronic liver disease, which in general is asymptomatic and characterized by slow progression through years to decades [6].…”