慢性乙型肝炎病毒感染者恩替卡韦抗病毒治疗前后血清高尔基体蛋白GP73的变化

目的观察慢性乙型肝炎病毒感染患者恩替卡韦（ETV）抗病毒治疗前后血清GP73浓度的变化，探讨血清GP73水平对CHB病情进展和疾病转归的影响。 方法2012年1月至2014年10月于解放军第一八〇医院就诊的慢性乙型肝炎病毒（HBV）感染者1 150例，其中慢性HBV携带者（HBV-C）100例，CHB 550例，HBV相关肝硬化（LC）250例、原发性肝细胞癌（HCC）250例。选择同期50名健康体检者作为对照。采用ELISA法检测血清GP73浓度。入组患者中在知情同意基础上行肝组织活检的30例CHB患者肝组织标本进行免疫组织化学染色检查，探讨血清GP73浓度与肝组织GP73表达的相关性。550例CHB患者中共200例接受ETV抗病毒治疗1年以上，观察治疗前及治疗后1个月、3个月、6个月、9个月和12个月血清GP73浓度的变化。 结果慢性HBV感染者血清GP73水平显著高于对照组（F =191.60、P = 0.000），且随着病情的进展，血清GP73浓度在HBV-C [（47.21 ± 17.69）ng/ml]、CHB [（101.56 ± 67.18）ng/ml]、HCC [（195.01 ± 104.22）ng/ml]和LC [（225.71 ± 99.37）ng/ml]中持续升高，各组间，差异均具有统计学意义（q_{HBV-C vs CHB} = 7.82，P = 0.000；q_{CHB vs HCC} = 15.85，P = 0.000；q_{HCC vs LC} = 2.63，P = 0.009）。经过相关性分析，血清GP73含量与慢性HBV感染者病情严重程度呈正相关（r = 0.576、P = 0.000）。30例CHB肝组织标本中，肝组织GP73表达呈弱阳性、中度阳性和强阳性的分别为6例（20.00%）、16例（53.33%）和8例（26.67%）。随着肝组织GP73表达程度的加重，其血清GP73浓度亦同步升高（F = 7.285、P = 0.003）。经过相关性分析，血清GP73浓度与肝组织GP73表达程度呈正相关（r = 0.592、P = 0.001）。200例CHB患者已接受ETV抗病毒治疗1年以上，随着病情的恢复，血清GP73浓度在ETV抗病毒治疗1、3、6、9和12个月后逐渐下降，分别为（97.26 ± 42.52）ng/ml、（68.21 ± 33.65）ng/ml、（58.57 ± 29.52）ng/ml、（51.76 ± 25.39）ng/ml和（53.37 ± 21.62）ng/ml，与治疗前血清GP73浓度[（113.09 ± 48.91）ng/ml]比较，差异均具有统计学意义（t_{1月后vs治疗前} = 3.45，P = 0.001；t_{3月后vs治疗前} = 10.69，P = 0.000；t_{6月后vs治疗前} = 13.50，P = 0.000；t_{9月后vs治疗前} = 15.74，P = 0.000；t_{12月后vs治疗前} = 15.79，P = 0.000）。血清GP73浓度在ETV抗病毒治疗3个月内下降幅度最大，与病情缓解及丙氨酸氨基转移酶复常相符合。 结论血清GP73水平与慢性HBV感染者疾病进展密切相关。接受ETV抗病毒治疗后血清GP73浓度的下降，提示肝脏炎症损伤的缓解。血清GP73可用于慢性肝病的预后监测指标。

Changes of serum GP73 before and after entecavir antiviral treatment in patients with chronic hepatitis B

ObjectiveTo investigate the changes of serum GP73 before and after entecavir (ETV) antiviral treatment in patients with chronic hepatitis B virus infection, and to explore the influence of serum GP73 level on diseases progression and prognosis in CHB. MethodsA total of 1 150 patients with chronic hepatitisB virus (HBV) infection admitted to The 180th Hospital of PLA during January 2012 to October 2014 were selected, including 100 cases with HBV carriers (HBV-C), 550 cases with CHB, 250 cases with HBV related primary hepatocellular carcinoma (HCC) and 250 cases with hepatitis B liver cirrhosis (LC). While 50 healthy controls were collected during the same period. The serum GP73 concentrations were detected by ELISA. The 30 cases of CHB liver tissue samples who took liver biopsy performed on the basis of informed consent were stained by immunohistochemistry, and the correlation of serum GP73 concentration and GP73 expression of liver tissues were discussed, respectively. The 200 patients among the 500 cases with CHB received ETV antiviral treatment for over one year, the condition changes were monitored, and the serum of GP73 were detected before and after 1 month, 3 months, 6 months, 9 months and 12 months treatment, respectively. ResultsThe serum levels of GP73 were significantly higher in patients with chronic HBV infections than those in healthy controls (F = 191.60, P = 0.000). With the development of chronic HBV infections, the serum GP73 showed a continuous increase among patients with HBV-C [(47.21 ± 17.69) ng/ml], CHB [(101.56 ± 67.18) ng/ml], HCC [(195.01 ± 104.22) ng/ml] and LC [(225.71 ± 99.37) ng/ml], and there were significant differences in all the groups (q_{HBV-C vs CHB} = 7.82, P = 0.000; q_{CHB vs HCC} = 15.85, P = 0.000; q_{HCC vs LC} = 2.63, P = 0.009). The serum GP73 concentration was positively correlated with the severity in patients with chronic HBV infections (r = 0.576, P = 0.000). The expression of GP73 protein in liver tissues of 30 CHB patients were weakly positive (6 cases, 20.00%), moderately positive (16 cases, 53.33%) and strongly positive (8 cases, 26.67%). With the increase of GP73 expression in liver tissues, the serum GP73 concentrations were synchronous elevated (F = 7.285, P = 0.003). The serum GP73 concentration was positively correlated with the expression of GP73 in liver tissues (r = 0.592, P = 0.001). After ETV antiviral treatment, with the recovery of the diseases, the serum GP73 concentration decreased significantly after the treatment for 1 month [(97.26 ± 42.52) ng/ml], 3 months [(68.21 ± 33.65) ng/ml], 6 months [(58.57 ± 29.52) ng/ml], 9 months [(51.76 ± 25.39) ng/ml] and 12 months [(53.37 ± 21.62) ng/ml], and there were significant differences compared with the levels of serum GP73 before [(113.09 ± 48.91) ng/ml] and after the treatment (t_{after 1 month vs. before} = 3.45, P = 0.001; t_{after 3 mo vs before} = 10.69, P = 0.000; t_{after 6 month vs before} = 13.50, P = 0.000; t_{after 9 month vs. before} = 15.74, P = 0.000; t_{after 12 mo vs before} = 15.79, P = 0.000). The largest serum GP73 concentration decrease occurred after 3 months of treatment, coinciding with the alanine aminotransferase normalization. ConclusionsSerum GP73 levels are correlated with diseases progression in patients with chronic HBV infection. In patients treated with ETV, GP73 serum levels were reduced in response to the mitigation of liver injury. Serum GP73 could be a prognostic marker for chronic liver diseases.