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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) affects over a quarter of adults in North America[1]
The current study represents the first to assess the diagnostic performance of circulating collagen fragments reflective of fibrogenesis or fibrolysis to determine the fibrosis stage in patients with NAFLD
Higher PRO-C3 levels were associated with higher grade of lobular inflammation and ballooning, suggesting that PRO-C3 levels may be reflective of active disease
Summary
Nonalcoholic fatty liver disease (NAFLD) affects over a quarter of adults in North America[1]. PRO-C3, PRO-C5 and C4M have been correlated with hepatic venous pressure gradient which is an invasive diagnostic and prognostic marker in cirrhosis for portal hypertension[21,22] These collagen fragments have not been evaluated in patients with NASH. The current study represents an initial assessment of a panel of collagen neo-epitope biomarkers (PRO-C3, P4NP7S, PRO-C5, PRO-C6, C3M, and C4M) to determine their relationship to fibrosis stage in a population of subjects with NAFLD and the full spectrum of fibrosis. The study included both a cross-sectional cohort and a longitudinal cohort with blood samples obtained at the time of liver biopsy
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