Enhanced HBsAg synthesis correlates with increased severity of fibrosis in chronic hepatitis B patients

Abstract

Background and aims: Little is known about whether low serum HBsAg levels result from impaired HBsAg synthesis or a reduced number of hepatocytes caused by advanced liver fibrosis. Therefore, we investigated the capacity for HBsAg synthesis in a cross-sectional cohort of treatment-naïve chronic hepatitis B patients.

Methods: Chronic hepatitis B patients (n = 362) were enrolled; liver biopsies were performed and liver histology was scored, and serum HBsAg and HBV DNA levels were investigated. In the enrolled patients, 183 out of 362 have quantitative serum HBsAg levels. Tissue HBsAg was determined by immunohistochemistry.

Results: A positive correlation between serum HBsAg and HBV DNA levels was revealed in HBeAg(+) patients (r = 0.2613, p = 0.0050). In HBeAg(+) patients, serum HBsAg and severity of fibrosis were inversely correlated (p = 0.0094), whereas tissue HBsAg levels correlated positively with the stage of fibrosis (p = 0.0280). After applying the mean aminopyrine breath test as a correction factor, adjusted serum HBsAg showed a strong positive correlation with fibrosis severity in HBeAg(+) patients (r = 0.5655, p<0.0001). The adjusted serum HBsAg values predicted 'moderate to severe' fibrosis with nearly perfect performance in both HBeAg(+) patients (area under the curve: 0.994, 95% CI: 0.983-1.000) and HBeAg(-) patients (area under the curve: 1.000, 95% CI: 1.000-1.000).

Conclusions: Although serum HBsAg levels were negatively correlated with fibrosis severity in HBeAg(+) patients, aminopyrine breath test-adjusted serum HBsAg and tissue HBsAg, two indices that are unaffected by the number of residual hepatocytes, were positively correlated with fibrosis severity. Furthermore, adjusted serum HBsAg has an accurate prediction capability.

Figure 1. Patients’ characteristics stratified according to HBeAg status.

(A) grade of inflammatory activity; (B) stage of fibrosis; (C) immunohistochemistry grade of tissue HBsAg; (D) HBV DNA (log10 IU/ml); (E) serum HBsAg (log10 IU/ml).

Figure 2. Correlation between serum HBsAg and HBV DNA and stage of fibrosis in treatment-naïve CHB patients.

(A–C) correlation between serum HBsAg (log10 IU/ml) and HBV DNA (log10 IU/ml) in 183 patients with quantified serum HBsAg values, HBeAg(+) patients, and HBeAg(−) patients, respectively. (D–F) correlation between serum HBsAg (log10 IU/ml) and stage of fibrosis in 183 patients with quantified serum HBsAg values, HBeAg(+) patients, and HBeAg(−) patients, respectively.

Figure 3. Correlation between aminopyrine breath test (ABT)-adjusted serum HBsAg and fibrosis severity.

(A–C) correlation between ABT-adjusted serum HBsAg (log10 IU/ml) and fibrosis severity in 183 patients with quantified serum HBsAg values, HBeAg(+) patients and HBeAg(−) patients, respectively. Stage of fibrosis was determined according to the Scheuer scoring system. (D–F) diagnostic performance (AUC) of aminopyrine breath test -adjusted serum HBsAg in recognizing moderate to severe fibrosis (S3 and S4) in all of 183 patients, HBeAg(+) patients, and HBeAg(−) patients, respectively.

Figure 4. Expression of tissue HBsAg in patients with different stages of fibrosis.

(A–C) grade of tissue HBsAg in CHB patients stratified according to the stage of fibrosis in all enrolled patients, HBeAg(+) patients, and HBeAg(−) patients, respectively. Stage of fibrosis was determined according to the Scheuer scoring system.