An Evaluation of the Collagen Fragments Related to Fibrogenesis and Fibrolysis in Nonalcoholic Steatohepatitis

Abstract

Fibrosis, resulted from the imbalance of fibrogenesis and fibrolysis, is a key readout of disease progression in nonalcoholic steatohepatitis (NASH) and reflects mortality risk. Non-invasive biomarkers capable of diagnosing fibrosis stages and monitoring fibrosis changes in NASH patients are urgently needed. This study is to evaluate collagen formation and degradation biomarkers, reflective of fibrogenesis or fibrolysis, in patients with biopsy proven NASH. Collagen formation biomarker PRO-C3 and PRO-C6 levels were significantly higher in patients with advanced fibrosis stage 3-4 than those with fibrosis stage 0-2. Elevated PRO-C3 levels were also associated with severe lobular inflammation and ballooning, but not with steatosis. Multivariate logistic regression analysis identified PRO-C3 and PRO-C6 to be independently related to fibrosis stage. PRO-C3 showed similar performance to identify patients with advanced fibrosis in discovery and validation cohorts. Furthermore, in a longitudinal study cohort with paired biopsies, mean PRO-C3 increased with worsening of fibrosis and decreased with fibrosis improvement. The results suggest that PRO-C3 may be a potentially useful biomarker in identifying patients with advanced fibrosis and active fibrogenesis, as well as in assessing changes in fibrosis over time. It is worthy of further evaluation to confirm its diagnostic value and clinical utility.

Figure 1

Association of PRO-C3 and PRO-C6 with histological scores. (a) Serum PRO-C3 levels were significantly higher in patients with advanced fibrosis (F3–4). ^###p < 0.002 compared to F3 or F4; ^##p < 0.006 compared to F3 or F4; ^#p < 0.008 compared F3 or F4. (b) Elevation of PRO-C3 in patients with severe lobular inflammation and hepatocellular ballooning grade. ^#p < 0.02 compared to Grade 2. (c) Serum PRO-C3 levels do not correlate with steatosis grade. (d) Serum PRO-C6 levels were significantly higher in patients with advanced fibrosis. ^##p < 0.004 compared to F3 or F4. Means with standard error were displayed. Non-parametric Wilcoxon analysis were performed to compare each group.

Figure 2

Association of PRO-C3 change from baseline with fibrosis stage changes. (a) Patients with fibrosis improvement during follow up had significant decrease of PRO-C3 from baseline compared to those with worsening or stable fibrosis. Mean percent changes from baseline with standard error were shown. Non-parametric Wilcoxon analysis were performed to compare each group. (b) PRO-C3 changes from baseline at follow up for individual patients. BL: baseline; FU: follow up.