The Role And Clinical Significance Of Serum IL-21 In Patients With Chronic Hepatitis B, Cirrhosis And Liver Failure

Objective: The infection of Hepatitis B virus is one of the big challenges.There were 6 billion populations all the world, and about 2 billion peoples were infected with HBV, of which 350 million peoples were infected chronicly with HBV. According to national epidemiological investigation of hepatitis B in the 2006, there were 93 million peoples of chronic HBV infection in our country, including about 20 million patients with chronic hepatitis B. So the HBV prevention has become a primary problem in Chinese health and the control of infectious disease. The pathogenesis of chronic hepatitis B is very complicated, it is generally believed that the immune response after HBV infection is mediated mainly through CD4+T and CD8+T cell, which are participated in liver injury caused by HBV infection, play an important role in the disease progression, and have important influence on the prognosis of the disease. IL-21 is a cytokine which secreted by a variety of activated CD4+T cells(mainly produced by Th17 cells and Follicular Helper T cells(Follicular Helper T cells, Tfh), etc.), NK cells. IL-21 could regulate differentiation of cytotoxic T lymphocyte by enhancing the activation, proliferation and effect functional of CD8+T cell. Current studies suggested that IL-21 plays an important role in the onset and outcome of hepatitis B. In this study, we detected the change of serum IL-21 in chronic hepatitis B, cirrhosis, acute-on-chronic liver failure in order to investigate the role and clinical significance of serum IL-21 in chronic hepatitis B, cirrhosis and liver failure.Methods:There was a total of 176 cases, that come from outpatient and inpatient of The third hospital of hebei medical university and Baoding infectious diseases hospital from December 2013 to December 2014, including 89 cases of patients with CHB(mild 31 cases, moderate 51 cases, severe 7 cases), 36 cases of ACLF, 29 cases of LC-d, 12 cases of LC-c. Among the 176 cases,90 cases were HBe Ag positive,86 cases were HBe Ag negative,meanwhile we choose 10 healthy volunteers as the healthy control group. All the cases were conventionally detected blood and urine routine, liver function indicators, and clotting function, HBV-DNA loads, five items of hepatitis B, abdominal ultrasound, or CT, etc., and 57 cases detected by liver tissue pathological examination. ELASA method was used to detect the contents of serum IL-21, IFN-γ to comparing the difference of the serum IL-21 level in each group. The research made correlation analysis of the serum IL-21 level with liver function, HBe Ag, HBV-DNA loads, liver tissue pathological changes and the model for end-stage liver disease(model of end-stage liver diseases, MELD) score and prognosis.Results:1 Serum levels of IL-21, IFN-γ in patients with different clinical classification analysis Compared with healthy controls, the level of serum IL-21 and IFN-γ in the groups of CHB(CHB-l,CHB-m)LC-c,LC-d and ACLF increased significantly, the difference was statistically significant(P < 0.05); Compared with CHB(CHB-l,CHB-m),the serum IL-21 and IFN-γ levels in the groups of CHB-s, ACLF, LC-c,LC-d increased significantly, the difference was statistically significant(P < 0.05); There was no statistically significant difference during the groups of decompensation period,compensatory period of cirrhosis and CHB-s(P > 0.05); and, there was no statistical significance between the group of CHB-l and that of CHB-m(P > 0.05). 2 The correlation between the serum IL-21 and liver inflammation 2.1 The correlation between Serum IL-21 and ALT The level of IL-21 in the group of ALT > 5 ULN, was significantly higher than the group of ALT < 5 ULN, the difference was statistically significant(P < 0.05). The level of IL-21 in the group of ULN < ALT < 5 was a bit higher than that in the group of ALT < ULN, but there was no statistical significance.(Table 3) 2.2 The correlation between serum IL-21 and inflammation hierarchical of liver tissue By analysing liver tissue pathology results of 57 patients with chronic hepatitis B, it showed that the IL-21 level did not increase with the increase of liver inflammation grades, there was no statistical significance difference in all kind of groups(P > 0.05). 3 The correlation between serum IL-21 and liver fibrosis 56 cases appeared different degree of liver fibrosis in 57 cases patients with liver biopsy. As the results shown, the level of IL-21 had nothing to do with the liver fibrosis stage(P > 0.05).( Table 5) 4 The correlation between Serum IL- 21 and severe chronic hepatitis b(CHB) 4.1the correlation between serum IL-21 and TBIL, PTA, ALB, ALT The results of linear correlation analysis had shown that there was correlation between the level of IL-21 and TBIL, PTA, ALB, ALT, and the correlation coefficients(r) were 0.631(P < 0.05), 0.591( P < 0.05), 0.743,(P < 0.05) and 0.276( P < 0.05) respectively.( table 6) 4.2The correlation between serum IL-21 and the prognosis of patients with acute-on-chronic liver failure. In 36 cases of patients with acute on chronic liver failure, there were 11 patients lived and 25 patients died. The level of IL-21 in patients with liver failure died was higher than that in liver failure lived, but there was no statistically significant difference(P > 0.05)( table 7). 4.3The correlation between serum IL-21 and MELD score The level of IL-21 in the group of MELD>40 was higher than the groups of MELD≤40,and there was statistically significant difference(P < 0.05); compared with the group of 20 < MELD≤30,it was no statistical significance difference in the group of 30 < MELD < 40 groups(P > 0.05);and so, there was no statistical significance between the group of 40 < MELD ≤ 50 and the group of 50 <MELD ≤60(P > 0.05).( Table 8) 5 The correlation between serum IL-21 and HBV replication According to different HBV-DNA loads, there could be divided into 3 groups, that the group of HBV-DNA < 5 log10copies/ml were 60 cases, the group of,5≤HBV-DNA≤7log10copies/ml were 69 cases, the group of HBV-DNA > 7 log10copies/ml were 47 cases. The results of statistical analysis showed that there were no statistically significant difference in the serum level of IL-21 by the two-two compared for the three groups(P > 0.05). 6 The correlation between Serum IL-21 and HBe Ag In the all patients,the cases with HBe Ag(+) were 90, and the cases with HBe Ag(-) were 86. The results of statistical analysis showed that there were no statistically significant difference in the serum level of IL-21 between the group with HBe Ag(+) and the group with HBe Ag(+)(P > 0.05). 7 The correlation between serum IL-21 and IFN-γ The results of linear correlation analysis had shown that there was certain correlation between the level of serum IL-21 and IFN-γ, and the correlation coefficient was 0.874(P < 0.05).( Table 10)Conclusions:1 IL-21 played a role in HBV caused hepatitis, to a certain degree, it reflected the degrees of liver damages. It indicates that IL-21 is possibly involved in the pathogenesis of liver damages. 2 The level of serum IL-21 in the group of MELD>40 group was obviously higher than that of MELD≤40 groups, and it was significantly negative correlation with PTA, which indicated that IL-21 May be associated with the aggravating of chronic hepatitis B, and it maybe is one of the reference indexes to predict prognosis. 3 Neither the expression of HBe Ag positive expression nor the load of HBV-DNA correlated with the level of serum IL-21, which indicatd IL-21 itself may be no obvious effect on HBV replication.