Association between serum S100A9 levels and liver necroinflammation in chronic hepatitis B

Rui Wu, Yuhong Zhang, Yu Xiang, Yishu Tang, Fang Cui, Ju Cao, Lan Zhou, Yan You, Liang Duan

S100A9 protein, which is recently classified as a novel damage associated molecular pattern, is released from stressed cells undergoing necrosis or secreted by living cells undergoing a stress that act as endogenous danger signal associated with infection, tissue damage and cancer. Here, we evaluated the relationship of serum S100A9 with viral replication and liver necroinflammation in patients with chronic hepatitis B (CHB) infection. A total of one hundred and eighty-three recruited patients with CHB infection underwent liver biopsy for grading of necroinflammation (G) and staging of fibrosis (S). Forty-nine healthy individuals were included as healthy controls (HCs). Serum S100A9 levels were determined by enzyme-linked immunosorbent assay. Correlations of serum S100A9 with viral replication and liver necroinflammation were analyzed. The receiver operating characteristic curve was used to assess the discriminating power of serum S100A9 to grade liver necroinflammation (G). Liver normal L02 cells were transfected with a HBV plasmid, and S100A9 levels were determined. Serum S100A9 levels were increased in CHB patients compared to HCs. Intrahepatic immunoreactivity for S100A9 was enhanced in liver sample from CHB patients. Infection of HBV also resulted in an elevated S100A9 expression in L02 cells. Serum S100A9 was correlated with the serum HBV DNA levels. CHB patients with moderate-to-severe liver necroinflammation (G ≥ 2) showed significantly higher serum S100A9 levels than those without or with mild necroinflammation (G < 2). In patients with normal ALT levels, the area under the curve (AUC) of S100A9 for discriminating patients with moderate-to-severe necroinflammation (G ≥ 2) was 0.791 [95% confidence interval (CI), 0.670-0.913] with 91.7% sensitivity, 65.0% specificity and 78.3% accuracy. In patients with an alanine aminotransferase (ALT) < 2 upper limit of normal, the AUC of S100A9 for discriminating patients with moderate-to-severe necroinflammation (G ≥ 2) was 0.826 (95% CI, 0.729-0.923) with 87.9% sensitivity, 72.5% specificity and 80.2% accuracy. HBV infection may enhance S100A9 expression. Serum S100A9 levels are correlated with viral load. Serum S100A9 has potential to discriminate the grades of liver necroinflammation, particularly in CHB patients with normal or mildly increased ALT levels.