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The role of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in the assessment of fibrosis in children with chronic hepatitis C


Subject’s characteristics

The baseline characteristics of children with chronic hepatitis C and control children are shown in Table 1. Circulating platelet counts were significantly lower in the HCV group than in the control group, as were the FIB-4 index scores. Both serum AST and ALT levels were significantly higher in the HCV group than in the control group, as were the APRI index scores and M2BPGi levels.

Table 1 Baseline characteristics of HCV patients and control children.

Thirty-three children with chronic hepatitis C underwent a liver biopsy in this study. No active necroinflammation was observed in three (9%) patients, while mild (A1) and moderate activities (A2) were observed in 27 (82%) and three (9%) patients, respectively. No severe activity (A3) was observed. In terms of liver fibrosis, F0 was noted in nine (27%) patients, and mild (F1) and moderate degrees of liver fibrosis (F2) were observed in 22 (67%) and two (6%) patients, respectively. Advanced liver fibrosis (F3 or F4) was not found among the present children (Table 1).

Reference values in control children

M2BPGi levels from 100 of the 104 control children were below 1.0. The remaining four children showed a level greater than 1.0 at the first examination. Repeated assays performed a few months later (3–4 months) showed a level less than 1.0 in all four subjects. After excluding those four children, the median value of M2BPGi with 95% confidence interval (95%CI) for 100 control children was 0.56 (0.28–0.91) (Fig. 1A). The median values with 95%CI for APRI and FIB-4 were 0.28 (0.21–0.47) (Fig. 1B) and 0.25 (0.12–0.39) (Fig. 1C), respectively.

Figure 1
figure 1

M2BPGi, APRI and FIB-4 levels were expressed by using box-and-whisker plots for control children and for two groups of patients with chronic hepatitis C (F0 and F1). Median value with 95% confidence interval were described for the control, F0 and F1 groups.

Reproducibility

The levels of M2BPGi in the first and second assays were 0.42 ± 0.15 and 0.47 ± 0.15, respectively. Differences between the two assays were 0.13 ± 0.08 in 26 children whose underlying liver diseases were clinically cured or stable in remission (Supplementary Fig. 1). Accordingly, a change in M2BPGi of greater than 0.30 COI was arbitrarily regarded as significant in this study because the average plus 2.0 × SD; 0.13 + (0.08 × 2.0) = 0.29.

Baseline levels of serum M2BPGi in children with chronic hepatitis C

There was a marginal but significant correlation between M2BPGi and APRI (r = 0.332, P = 0.007, n = 46) but not between M2BPGi and FIB-4 index (r = 0.143, P = 0.262, n = 46) (data not shown). The baseline levels of serum M2BPGi in HCV-infected children were greater than those in control subjects (0.95 ± 0.55 vs. 0.57 ± 0.19, P < 0.001) (Table 1).

There was a slight but significant difference in the levels of M2BPGi between the control group and the HCV F0 group (P = 0.002, Fig. 1A). The levels of M2BPGi in the HCV F1 group were also significantly higher than those in the control group (P < 0.001) but not those in the HCV F0 group (P = 0.186, Fig. 1). Because only two patients showed F2 fibrosis, their data were not suitable for this analysis and excluded from Fig. 1A–C.

ROC analysis

ROC analyses showed that to discriminate stage F1 fibrosis from F0, the cut-off value was 0.95 for M2BPGi, with a sensitivity of 52%, specificity of 90%, and area under the curve (AUROC) of 0.687 (Fig. 2A). The cut-off value was 0.37 for APRI, with a sensitivity of 73%, specificity of 70%, and AUROC of 0.639 (Fig. 2B). The cut-off value was 0.22 for FIB-4 with a sensitivity of 78%, specificity of 60%, and AUROC of 0.680 (Fig. 2C).

Figure 2
figure 2

ROC curve analysis of M2BPGI (A), APRI (B) and FIB-4 (C) to discriminate stage F1 fibrosis from F0.

Changes in serum M2BPGi levels in children with chronic hepatitis C during the natural course of disease

Changes in M2BPGi levels during the natural course of disease were evaluated in l3 children with chronic hepatitis C. The median duration from the first assay to the second assay was four years (range 3–6) (Supplementary Fig. 2A). There was no significant change in M2BPGi levels from 0.66 ± 0.33 at the first assay to 0.89 ± 0.42 at the second assay (P = 0.149, Supplementary Fig. 2B). Baseline data of these 13 patients were shown in Supplementary Table 1. The 13 patients were divided into two group by a median value of change in M2BPGi, 0.07 COI:group A with an increase in M2BPGi with a median of 0.79 (range 0.26–0.79), and group B with no apparent increase in M2BPGi with a median of 0.04 (range − 0.33–0.07) (Supplementary Table 2). Group A were all female (P = 0.021) and younger than those in group B (P = 0.127). There were no significant changes regarding other baseline factors including M2BPGi, APRI and FIB-4.

Changes in serum M2BPGi levels in children with chronic hepatitis C during treatment

Changes in M2BPGi levels during treatment were evaluated in 27 patients, all of whom showed an SVR to treatment. The median duration of the follow-up after the end of treatment was 4 years (range 2–9) (Fig. 3A). There was a substantial decrease in M2BPGi levels from 0.89 ± 0.57 pretreatment to 0.43 ± 0.16 posttreatment (P < 0.001, Fig. 3B). Seventeen of the 27 showed a significant change of greater than 0.3 The COI decreased from 1.09 ± 0.61 pretreatment to 0.42 ± 0.16 posttreatment (P < 0.001, data not shown). Regarding APRI there was a significant decrease in APRI scores from 0.46 ± 0.31 to 0.30 ± 0.10 (P = 0.021, Fig. 3C,D). Regarding FIB-4 there was a significant increase in FIB-4 indices from 0.21 ± 0.10 to 0.31 ± 0.12 (P = 0.001, Fig. 3E,F). The changes between pretreatment and post-treatment levels were apparently larger in M2BPGi (P < 0.001) than in APRI and in FIB-4 (P = 0.007 and P = 0.003), respectively (Fig. 3B,D,F).

Figure 3
figure 3

Change in M2BPGi, APRI and FIB-4 levels by treatment. In A,C,E dots indicating M2BPGi levels were plotted at age in years when measurement of M2BPGi was done. M2BPGi dots at pretreatment and at posttreatment are connected for each child in all six Figures.



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