Elevated soluble 4-1BB is associated with serum markers of hepatitis B virus in patients with chronic hepatitis B

BACKGROUND Previous studies have suggested that the costimulatory molecule 4-1BB plays pivotal roles in regulating immunity during chronic viral infection.However,up to now,there are few studies about 4-1BB in chronic hepatitis B(CHB).AIM To clarify this issue,we report our comprehensive study results on the expression levels of 4-1BB in patients with CHB.METHODS From September 2018 to June 2019,a total of 64 patients with CHB were recruited from the Department of Hepatology,The First Hospital of Jilin University.Peripheral blood samples were collected from 52 treatment-naïve and 12 entecavir-treated patients with CHB as well as 37 healthy donors(including 24 healthy adults and 13 healthy children).The levels of soluble 4-1BB(s4-1BB)in plasma were measured by ELISA.4-1BB mRNA expression in peripheral blood mononuclear cells was detected by real-time quantitative PCR.RESULTS The s4-1BB levels in the plasma of patients with CHB were significantly higher than those in healthy adults(94.390±7.393 ng/mL vs 8.875±0.914 ng/mL,P<0.001).In addition,the s4-1BB level in plasma was significantly increased in patients with a higher viral load and a disease flare up.However,there were no significant differences between treatment-naïve and entecavir-treated patients.Interestingly,among treatment-naïve patients with CHB,the levels of s4-1BB in plasma had a significant positive correlation with hepatitis B surface antigen,hepatitis B virus DNA,hepatitis B e antigen,and triglyceride levels(r=0.748,P<0.001;r=0.406,P=0.004;r=0.356,P=0.019 and r=-0.469,P=0.007,respectively).The 4-1BB mRNA expression was higher in the peripheral blood mononuclear cells of patients with CHB than in the peripheral blood mononuclear cells of healthy adults,but the difference was not statistically significant.CONCLUSION These results suggest that the levels of s4-1BB may be associated with pathogenesis of hepatitis B virus and therefore may be a promising biomarker for disease progression.

sFRP-4, a potential novel serum marker for chronic hepatitis B-related hepatocellular carcinoma

BACKGROUND：The current methods used for diagnosing hepatocellular carcinoma（HCC）are unsatisfactory.Here,we assessed the serum levels of secreted frizzled related protein 4（s FRP-4）for diagnosing HCC in patients infected with chronic hepatitis B（CHB）.METHODS：In 272 patients with CHB enrolled,142 were pa tients with HCC.Thirty-three healthy subjects were recruited as healthy controls.The CHB patients were assigned to a test group or a validation group based on the time of enrollment. Human antibody arrays were used to screen 15 patients （8 CHB-related HCC patients, 7 CHB patients） for serum mark- ers. Four markers and one candidate marker were assessed in the test group and validation group, respectively. RESULTS： Human antibody assays indicated that the serum levels of sFRP-4 in HCC patients were significantly higher than those in CHB patients （P〈0,05）. Additionally, serum sFRP-4 levels were significantly higher in the HCC patients than those in the non-HCC patients in both test group （79.7 vs 41.3 ng/mL; P〈0.001） and validation group （89.0 vs 39.0 ng/mL; P〈0.001）. Areas under the Receiver Operating Charac- teristic curves （AUCs） for alpha-fetoprotein （AFP） and sFRP-4 were similar in both test group and validation group. In the test group, the combination of sFRP-4 （a sensitivity of 94.4%, a specificity of 60.5% at 46.4 ng/mL） and AFP （a sensitivity of 75.0%, a specificity of 87.2% at 11.3 ng/mL） showed better performance for diagnosing HCC （a sensitivity of 79.2% and a specificity of 95.3%）. The AUC for combined sFRP-4 and AFP increased to 0.941 （95% CI： 0.908-0.975）, and similar results were seen in the validation group. CONCLUSION： sFRP-4 is a candidate serum marker for diagnosing HCC in CHB patients, and the combination of sFRP-4 with AFP may improve the diagnostic accuracy of HCC.