Fibrosis Staging Using Direct Serum Biomarkers is Influenced by Hepatitis Activity Grading in Hepatitis C Virus Infection

Abstract

Background: Chronic liver diseases (CLDs) generally progress from inflammation to fibrosis and finally to carcinogenesis. Staging of liver fibrosis progression is inevitable for the management of CLD patients. The purpose of this study was to compare the diagnostic abilities of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA-M2BP), Enhanced liver fibrosis (ELF) score, Fibrosis-4 index, and AST to platelet ratio index (APRI) based on histopathological analysis of liver biopsy samples, from patients with positive Hepatitis C Virus (HCV) infection.

Methods: Japanese patients with HCV infection who underwent liver biopsy examinations were enrolled in this study. WFA-M2BP levels and ELF scores were calculated using preserved serum samples. The fibrosis staging and activity grading were assessed using a modified METAVIR score.

Results: A total of 122 patients were enrolled; the cohort included 27 patients with stage 1, 66 with stage 2, 20 with stage 3, and nine with stage 4 fibrosis. All four biomarkers distinguished stage 3 and stage 2 fibrosis. ROC curves revealed that all four fibrosis biomarkers presented AUC values greater than 0.8. Each of the four biomarkers in stage 2 was significantly different between the activity grade 1 and 2 groups.

Conclusion: Fib-4 index and APRI were comparable with WFA-M2BP and ELF score in the diagnosis of advanced liver fibrosis in Japanese patients with HCV infection. All four biomarkers of liver fibrosis were influenced by histopathological activity grading, which implies that liver biopsy should be the gold standard to evaluate liver fibrosis staging even though several noninvasive biomarkers have been investigated well.

Keywords: biomarkers; biopsy; chronic; hepatitis C; interferons; liver cirrhosis; needle.

Figure 1

Difference in the median values for each fibrosis biomarker between two fibrosis stages. The four biomarkers distinguished stage 3 from stage 2 (p < 0.05); (A) ELF score, (B) WFA-M2BP, (C) Fib-4 index and (D) APRI. The median values of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA-M2BP), Enhanced liver fibrosis (ELF) score, and Fibrosis-4 (Fib-4) index for stage 3 were also significantly different from those for stage 4. Data were analyzed using Mann–Whitney U test. p values less than 0.05 were considered statistically significant.

Figure 2

ROC analysis to assess the ability of the four fibrosis biomarkers to diagnose advanced liver fibrosis (stages 3 and 4) and distinguish these stages from nonadvanced stages 1 and 2; (A) ELF score, (B) WFA-M2BP, (C) Fib-4 index and (D) APRI. ROC curves revealed that all four fibrosis biomarkers presented AUC values greater than 0.8; the value for Fib-4 index was the highest among them (0.9020).

Figure 3

Prediction of sustained viral response after interferon therapy. (A–D) The median values of AST to platelet ratio index (APRI) alone were significantly different between the sustained viral response (SVR) group and the non-SVR group. (E) Histological staging of fibrosis was not significantly different between these two groups. (F) The results indicated that APRI was directly influenced by Plt in its equation and that the Plt of the SVR group was significantly greater than that of the non-SVR group. Data were analyzed using Mann–Whitney U test. p values less than 0.05 were considered statistically significant.