巨细胞病毒和（或）EB病毒再活化对肝衰竭预后的影响

发布时间：2018-05-12 17:09

本文选题：肝衰竭 + 巨细胞病毒　；参考：《重庆医科大学》2017年硕士论文

【摘要】：背景肝衰竭是多种因素导致的肝功能严重障碍,其临床表现通常包括肝功能异常、肝脏生化指标异常、凝血功能障碍,部分可进展为肝性脑病、多器官功能衰竭和发生死亡。肝衰竭可并发多种严重的并发症,预后极差,在病程中可出现类似脓毒血症的炎症因子风暴及免疫麻痹等免疫紊乱现象,容易继续各种感染(包括病毒、细菌及真菌)。巨细胞病毒(Cytomegalovirus,CMV)与EB病毒(Epstein-Barr virus,EBV)均属于疱疹病科中的DNA病毒,均具有潜伏-活化的病毒学特点,人体感染上两种病毒后,病毒不能完全从体内清除,由于其特殊的病毒学特性可逃过宿主的免疫监视从而长期潜伏在机体内,但均具有潜在的再活化的风险。在人体免疫力低下时上述两种病毒可出现再活化,比如获得性免疫缺陷的患者、长期服用免疫抑制剂的患者、及某些肿瘤患者等。我们前期工作中已证明男同性恋的群体体内CMV及EBV的再活化率较正常人高。研究发现脓毒血症患者体内CMV的再活化较多,且CMV活化感染可增加脓毒血症患者的死亡率。亦有报道在慢性乙型病毒性肝炎患者、及肝衰竭患者体内CMV再活化率明显高于正常人,但对肝衰竭患者体内EBV的活化研究甚少。巨细胞病毒及EB病毒再活化是否导致病情加重目前尚无报道。因此本研究拟对肝衰竭患者住院治疗期间CMV、EBV感染状态进行监测,观察了解肝衰竭患者体内CMV和(或)EBV的再活化是否加重病情,影响患者的预后。同时对肝衰竭患者的部分炎症因子进行检测,了解在肝衰竭患者体内的免疫状态以及与这两种病毒再激活的相关性。目的肝衰竭患者体内巨细胞病毒(Cytomegalovirus,CMV)和(或)EB病毒(Epstein-Barr virus,EBV)的再活化是否加重病情,影响患者的预后。方法1.收集2015年9月-2016年9月在我院诊断为肝衰竭患者35例,诊断标准参照2012年《肝衰竭诊治指南》。在患者入院时及入院治疗2周收集患者的外周静脉血离心后取上层血清备用,同时在患者入院治疗2周统计患者肝功及凝血象;同时收集我院25例健康体检者的血清作为对照组。对各组的血清进行病毒定量及病毒相关抗体的检测,凡是能检测到CMV和(或)EBV定量扩增阳性或Ig M抗体阳性均考虑为病毒活化感染。将35例肝衰竭患者按有无病毒活化分为病毒活化组及无病毒活化组。将在住院期间死亡的与病情危重自动放弃治疗均视为死亡。2.采用ELISA法检测各分组中血清样本的CMV-Ig G、CMV-Ig M抗体及EBV-VCA-Ig M、EBV-VCA-Ig G抗体;采用荧光实时定量法测定血清中巨细胞病毒及EB病毒的扩增量;采用ELISA法测定入院治疗2周肝衰竭血清及健康对照组中4种细胞因子的浓度,分别为IL-4,IL-10,IL-17及IFN-r。3.采用统计学分析软件SPSS 23.0进行数据分析,不符合正态分布的数据均用中位数(M)及四分位数间距(Q)表示。秩和检验用于各组之间的比较,当P0.05时差异具有统计学意义。各组间率之间的比较采用四格表的行×列卡方检验,当n≤40或最小理论频数T1时采用Fisher确切概率法检验;当n40且最小理论频数1≤T5时采用连续性校正卡方检验,以P0.05表示差异具有统计学意义。结果1、肝衰竭组共35例,存在CMV和(或)EBV病毒再活化的肝衰竭患者共7例,无病毒活化的共28例,肝衰竭组中病毒活化率为20%,健康对照组病毒活化率为0,肝衰竭组患者体内CMV和(或)EBV再活化率较健康对照组显著升高(P0.05)。2、有CMV和(或)EBV病毒活化的肝衰竭组病死率为71.4%,无病毒活化的肝衰竭组病死率为17.85%,存在病毒活化的肝衰竭组的病死率显著升高,差异具有统计学意义(P0.05)。3、有CMV和(或)EBV病毒活化的肝衰竭组患者的ALT、TB、INR均较无病毒活化的肝衰竭组明显升高(P0.05),有病毒活化的肝衰竭组患者的PTA、白蛋白较无病毒活化的肝衰竭组显著降低(P0.05),有病毒活化的肝衰竭组与无病毒活化的肝衰竭组比较AST差异无统计学意义(P0.05)。4、有CMV和(或)EBV病毒活化的肝衰竭组患者血清中IL-4、IL-10、IL-17三种细胞因子的浓度比健康对照组显著增高(P0.05);无病毒活化的肝衰竭组患者血清中的IL-10、IL-17的浓度较健康对照组显著增高(P0.05);有病毒活化的肝衰竭组患者血清中的IL-4、IL-10浓度比无病毒活化的肝衰竭组显著增高(P0.05);有病毒活化的肝衰竭组患者血清中IL-17细胞因子的浓度与无病毒活化的肝衰竭组之间对比无差异无统计学意义(P0.05);有病毒活化的肝衰竭组、无病毒活化的肝衰竭与健康对照组体内IFN-r浓度三者无明显差异(p0.05)。结论1、35例肝衰竭患者CMV-Ig G抗体及EBV-VCA-Ig G抗体均阳性,说明体内均有潜伏的CMV及EBV,且肝衰竭患者容易继发CMV和(或)EBV的再活化。2、CMV和(或)EBV的再活化可能会加重肝衰竭患者的病情,并与患者的病死率密切相关。3、再次证实了在肝衰竭患者体内存在促炎症反应及抗炎症反应的相互作用,同时IL-4与IL-10的升高可能与CMV和(或)EBV活化感染密切相关。
[Abstract]:Background liver failure is a serious obstacle to liver function caused by a variety of factors. Its clinical manifestations usually include abnormal liver function, abnormal biochemical indexes of the liver, coagulation dysfunction, partial progression to hepatic encephalopathy, multiple organ failure and death. Liver failure can be complicated with many severe complications, and the prognosis is extremely poor and similar in the course of the disease. The inflammatory factors such as the inflammatory factor storm and immune paralysis of sepsis are easy to continue various infections (including viruses, bacteria and fungi). Cytomegalovirus (CMV) and EB virus (Epstein-Barr virus, EBV) all belong to the DNA virus in the herpes department, which have latent and activated virological characteristics and two diseases of human infection. After the virus, the virus can not be completely removed from the body. Because of its special virological characteristics, the virus can escape from the host's immune surveillance and lurk in the body for a long time, but it has a potential reactivation risk. The above two viruses can be reactivated when the human immunity is low, such as those who have acquired immune deficiency, for long-term use of immunosuppression. We have shown that the reactivation rate of CMV and EBV in the male homosexual population is higher in our earlier work. The study found that the reactivation of CMV in the patients with sepsis is more, and the CMV activation infection can increase the death rate of the patients with sepsis. The reactivation rate of CMV in patients with liver failure is significantly higher than that of normal people, but the activation of EBV in patients with liver failure is rarely studied. It is not reported that the reactivation of cytomegalovirus and EB virus has not been reported. Therefore, this study is to monitor the status of CMV and EBV infection during the hospitalization of patients with liver failure and observe the liver failure. Whether the reactivation of CMV and / or EBV in the exhaustive patients will aggravate the condition and affect the prognosis of the patients. At the same time, the partial inflammatory factors of the patients with liver failure are detected, the immune state in the patients with liver failure and the correlation with the reactivation of these two viruses. And (Cytomegalovirus, CMV) in the patients with liver failure (CMV) and ( Whether or not the reactivation of the EB virus (Epstein-Barr virus, EBV) aggravates the condition and affects the patient's prognosis. Method 1. collect 35 cases of liver failure diagnosed in our hospital in September -2016 September 2015. The diagnostic criteria refer to the guidelines for the diagnosis and treatment of liver failure in 2012. At the same time, the liver function and Hemogram of the patients were counted for 2 weeks, and the serum of 25 healthy persons in our hospital was collected as the control group. The serum of each group was detected by virus quantitative and virus related antibodies, and all the CMV and / or EBV quantitative positive or Ig M antibody positive were considered for the virus activation Infection. 35 patients with liver failure were divided into virus activation group and non viral activation group according to the activation of virus without virus. The death of the patients during hospitalization and the critical automatic abandonment treatment were all considered as death.2., and the serum samples of CMV-Ig G, CMV-Ig M, EBV-VCA-Ig M, EBV-VCA-Ig G antibody were detected by ELISA. The amplification of cytomegalovirus and EB virus in serum was measured by quantitative method, and the concentration of 4 cytokines in the 2 weeks liver failure serum and the healthy control group were measured by ELISA. The statistical analysis software SPSS 23 was used to analyze the data of IL-4, IL-10, IL-17 and IFN-r.3., and the median (M) did not conform to the normal distribution. And the four quantile spacing (Q). The rank sum test is used for the comparison between each group. The difference between P0.05 is statistically significant. The comparison between the rates of each group uses a row x column test of the four lattice, when the N < 40 or the minimum theoretical frequency T1 is tested by the exact probability method of Fisher; and the continuity correction is adopted when N40 and the minimum theoretical frequency 1 are less than T5. A total of 35 cases of liver failure in the liver failure group, 7 cases of liver failure with CMV and / or EBV reactivation, 28 cases of no virus activation, 20% in the liver failure group, 0 in the healthy control group and 0 in the healthy control group, and the reactivation rate of CMV and / or EBV in the liver failure group were 1. The fatality rate of the liver failure group with CMV and (or) EBV virus activation was 71.4%, the fatality rate of the liver failure group without virus activation was 17.85%, the mortality rate of the virus activated liver failure group was 17.85%, the mortality rate of the virus activated liver failure group was significantly higher, the difference was statistically significant (P0.05).3, with CMV and (or) EBV virus activated liver failure group patients with CMV and / or EBV virus activated liver failure group. ALT, TB and INR were significantly higher than those in the non viral activated liver failure group (P0.05). The PTA of the patients with viral activated liver failure was significantly lower than that of the non viral activated liver failure group (P0.05). There was no significant difference between the virus activated liver failure group and the non viral activated liver failure group than the AST (P0.05).4, CMV and / or EBV disease (P0.05). The concentration of three cytokines in serum IL-4, IL-10 and IL-17 in the patients with toxic activated liver failure was significantly higher than that in the healthy control group (P0.05). The concentration of IL-10 and IL-17 in the serum of the patients with no virus activated liver failure was significantly higher than that in the healthy control group (P0.05), and the concentration of IL-10 in the serum of the patients with virus activated liver failure group was less than that of the disease. There was no significant difference between the concentration of IL-17 cytokine in the serum of the patients with virus activated liver failure and the non virus activated liver failure group (P0.05), and there was no virus activated liver failure group, no virus activated liver failure and the IFN-r concentration of three in the healthy control group of three patients with virus activated liver failure. Significant differences (P0.05). Conclusion the CMV-Ig G antibody and EBV-VCA-Ig G antibody in patients with 1,35 liver failure are both positive, indicating that there are latent CMV and EBV in the body, and that the patients with liver failure are prone to secondary reactivation of CMV and / or EBV, and the reactivation of CMV and / or reactivation may aggravate the condition of the patients with liver failure and be closely related to the mortality of the patients. The interaction of proinflammatory and anti inflammatory reactions in patients with liver failure is confirmed, and the increase of IL-4 and IL-10 may be closely related to the activation of CMV and / or EBV.

【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R575.3

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