Abstract
Hepatitis B (HBV)-related fibrosis can be reversed after effective antiviral therapy. However, detailed changes of collagen characteristics during fibrosis regression remain unclear. Paired biopsy samples obtained from chronic hepatitis B patients were imaged with second harmonic generation/two photon excitation fluorescence (SHG/TPEF)-based microscopy to identify and quantify collagen features in portal, septal, and fibrillar areas. According to the changes of Ishak stage and qFibrosis score, a total of 117 patients with paired liver biopsy appeared to have four different outcomes after 78-week antiviral therapy: fast reverse (9%), reverse (63%), stable (15%), or progress (13%) on fibrosis. Among 71 collagen features identified by SHG/TPEF analysis, the most prominent fibrosis reversion occurred in the “septal” area, followed by the “fibrillar” area, but not in the “portal” area (P < 0.001). Further analysis of 1060 individual septa identified four parameters that correlated with fibrosis reversion: average width, maximum width, number of fibers, and number of cross-link fibers (P < 0.001). Average septal width was independently associated with regressive septa (odds ratio (OR) = 5.22, 95% confidence interval (CI): 4.17–6.53; P < 0.001), with an AUROC of 0.96 (95% CI: 0.95–0.97). The threshold used to discriminate reversal of fibrosis was 30 μm. In conclusion, septal collagen was determined to be the most useful histological feature for evaluation of dynamic changes in liver fibrosis. Septal width was the most predictive indicator of prognosis in liver fibrosis.
Highlights
Liver fibrosis is a dynamic process resulting from the wound-healing response to liver injury of any etiologies [1]
Treatment-naive patients were eligible for recruitment if they aged at 18–65 years, had been tested positive for hepatitis B surface antigen (HBsAg) > 6 months, positive for HBeAg with Hepatitis B virus (HBV)DNA levels higher than 20,000 IU/mL or negative for HBeAg with HBV-DNA levels higher than 2000 IU/mL, had a liver biopsy showing an Ishak fibrosis score ≥ 3 at baseline or week 78 after treatment with qualified biopsy
Because reversal rate was found to differ significantly among groups, this classification scheme was used to categorize histological features related to fibrosis reversion
Summary
Liver fibrosis is a dynamic process resulting from the wound-healing response to liver injury of any etiologies [1]. Chronic hepatitis B is a major cause of liver fibrosis and cirrhosis. Liver fibrosis and early cirrhosis can be reversed. Liver biopsy has traditionally been regarded as the gold standard for evaluation of fibrosis reversion. It was defined as at least one-point decrease after antiviral therapy based on semi-quantitative scoring systems in most clinical trials [4, 6]. These semi-quantitative scores could partly reflect the architectural distortion. There is a need for further refinements in the histological assessment of liver fibrosis reversion
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