解毒凉血法治疗乙型肝炎慢加急性肝衰竭的疗效评价及机制研究
|
摘要
肝衰竭是多种因素引起的严重肝脏损害,导致其合成、解毒、排泄和生物转化等功能发生严重障碍或失代偿,出现以凝血机制障碍和黄疸、肝性脑病、腹水等为主要表现的一组临床症候群,乙型肝炎慢加急性肝衰竭(Hepatitis B vir us related acute-on-chronic liver failure, HBV-ACLF)是在HBV导致的慢性肝病基础上出现的急性肝功能失代偿。本病进展迅速、病情凶险、并发症多、病死率高,对我国HBV-ACLF患者的发病诱因、临床特点和预后做出较为详细的描述和结局分析,疾病早期准确、客观地判断患者预后,积极探索、寻求有效的治疗措施成为HBV-ACLF研究的重要课题。
[目的]
1.系统了解乙型肝炎慢加急性肝衰竭的发病诱因、临床特点、总体病死率及不同分期患者的病死率、生存时间的分布特点及对预后判断有价值的临床指标。
2.通过随机对照临床研究对基于解毒凉血法的中西医结合方案治疗乙型肝炎慢加急性肝衰竭的疗效和安全性进行评价。
3.基于差异蛋白质组学的研究方法,初步探索乙型肝炎慢加急性肝衰竭发病过程中、不同预后及中西医治疗后患者间差异蛋白质的表达,为揭示HBV-ACLF的发病机制、寻找判断疾病预后的生物标志物以及为进一步研究解毒凉血方治疗HBV-ACLF的作用途径和机制奠定基础。
[方法]
1.收集首都医科大学附属北京地坛医院2008年9月-2012年12月间确诊为乙型肝炎慢加急性肝衰竭住院患者的临床资料,建立Epidata数据库,将患者的发病年龄、性别、发病诱因、基础疾病、疾病分期、不同预后患者的各项实验室检查等进行描述性分析；将各项指标进行单因素和多因素分析,筛选出与HBV-ACLF患者预后相关的指标,并以前瞻性队列验证和评估该指标的准确性及应用价值。
2.采用开放式随机对照试验的方法,按照2：1的比例将受试者随机分配到中西医结合组和西医治疗组,西医治疗组予西医内科综合治疗,中西医结合组在西医治疗的基础上予解毒凉血方加减,治疗8周,随访40周,评估患者治疗后和随访至48周时的临床疗效和用药安全性。
3.采用蛋白质组学的研究方法检测慢性乙型肝炎、乙型肝炎慢加急性肝衰竭、HBV-ACLF死亡者和生存者以及中西医结合治疗和单纯西医治疗后患者血清差异蛋白质的表达,运用凝胶电泳法分离、去除高丰度的白蛋白和免疫球蛋白,用ITRAQ试剂标记各组肽段后进行质谱检测,Q-EXACTIVE质谱仪检测肽段信号,Protein Discovery软件分析质谱数据对蛋白质进行定性和定量,通过生物信息库检索和分析这些差异蛋白质的具体生物学功能。
[结果]
1.共纳入316例HBV-ACLF患者,男女比例为5.58：1,未进行抗病毒治疗及抗病毒药物的不正确使用是诱发HBV-ACLF的主要原因,乙肝肝硬化继发ACLF的患者病死率高达64.12%。
2.316例患者中死亡131例,发病两个月时总体病死率为41.5%,疾病早期184例,病死率为27.17%；疾病中期76例,病死率为55.26%；疾病晚期56例,病死率为69.64%。
3.接受抗病毒治疗者269例,未进行抗病毒治疗的患者47例;抗病毒组病死率为39.03%,未进行抗病毒治疗的患者病死率为53.19%,两组比较具有统计学差异(P=0.007)。
4.单因素分析显示,基线TBIL、PTA、NC、LC、NLR和MELD评分在生存组和死亡组间存在显著差异(P<0.01),多因素分析显示年龄、TBIL、NLR和MELD评分对患者预后有重要影响。年龄、TBIL、NLR和MELD评分的曲线下面积(AUC)分别为0.615、0.691、0.781和0.744,NLR和MELD评分AUC比较无统计学差异,P=0.945。
5.回顾性队列基线NLR≤2.36为阴性临界值,NLR>6.12为阳性界值,特异度为90.1%,敏感度为91.6%；57例基线NLR≤2.36的HBV-ACLF患者中,第8周时生存率为86.0%(49/57例),61例NLR>6.12的患者生存率为19.7%(12/61例)。NLR比值介于2.36-6.12的患者生存率为61.22%(60/98例)。Log-rank检验显示三组间的生存率有显著差异(P=0.004)。
6.随机对照临床研究共纳入患者105例HBV-ACLF患者,中西医结合组64例,西医治疗组41例,治疗第48周两组总体病死率分别为21.88%和39.02%,P=0.026,基于解毒凉血法的中西医结合方案能够显著降低HBV-ACLF中期患者的病死率(中西医结合组vs西医治疗组：25%vs64.7%, x2=8.749,P=0.003)。
7.治疗第8周时,中西医结合组与西医治疗组总胆红素比较(中西医结合组：64.54±79.76vs西医治疗组：168.44±114.80,P=0.04)有统计学差异；治疗第4周和第6周,中西医结合组与西医治疗组比较凝血酶原活动度差异有统计学意义,P<0.05。
8. MELD评分低于22.6患者中西医结合组病死率为15.0%(6/40),西医治疗组病死率15.8%(3/19),两组比较无统计学差异(P=0.851); MELD评分介于22.6-29.9患者,中西医结合组和西医治疗组病死率为23.81%和58.82%,(P<0.05)。
9.慢性乙型肝炎组和乙型肝炎慢加急性肝衰竭组比较,共鉴定出40个下调蛋白和10个上调的蛋白；HBV-ACLF死亡组和生存组比较,鉴定出24个上调蛋白和24个下调蛋白,这些差异表达的蛋白质涉及能量代谢、细胞骨架、氧化应激、转化调控等方面。中西医结合组与西医治疗组比较,治疗后出现上调的蛋白质有4种,下调的蛋白质2种,表达消失的蛋白质3种。
[结论]
1.核苷(酸)类抗病毒药物能够降低HBV-ACLF患者病死率,积极抗病毒治疗具有重要的治疗价值。
2.基线NLR是一个简便的预测HBV-ACLF患者短期预后的指标,其cut-off值分别为2.36和6.12。
3.基于解毒凉血法的中西医结合方案能够显著降低HBV-ACLF患者的病死率。特别是对于病情中期或MELD评分介于22.6-29.9之间或NLR≤6的患者,中医药应及早介入。
4.在HBV-ACLF发生、发展过程中,上调或下调蛋白质涉及能量代谢、细胞骨架、氧化应激、转化调控等方面,其中：a) α1-酸性糖蛋白可作为肝硬化患者肝脏储备功能及预后判断的标志。b)角蛋白可能参与了肝衰竭时肝细胞凋亡的信号转导。c)硫酸化糖蛋白在死亡组患者中显著下调,可能具有抑制肝细胞的凋亡的作用。
5.中西医结合治疗组患者血清中α2-巨球蛋白高表达,提示解毒凉血方可能具有促进肝细胞再生的作用。
Acute-on-chronic liver failure (ACLF) is a severe life-threatening clinical syndrome. It has been defined as "an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within4weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease". Hepatitis B virus (HBV) infection is a leading cause of ACLF in Asia, and HBV associate acute-on-chronic liver failure (HBV-ACLF) account for more than70%. Acute hepatic deterioration often results in multiple complications (bacterial infection, hepatorenal syndrome, hepatic encephalopathy and so on) and multisystem organ failure, and short-term mortality is up to50-90%in ACLF patients. ACLF is charactered by rapid progress, dangerous disease, severe complications and high mortality of patients. It is important to understand its clinical features and make a more detailed description on prognosis and outcome of ACLF. Thus, accurately and objectively determine the prognosis of ACLF patients and explore effective therapy in early stage become an important research topic in HBV-ACLF.
[objective]
1. Systematically understanding predisposing factors, clinical features, overall mortality and mortality in different stages of patients with HBV-ACLF.
2. Evaluating efficacy and safety of integrative medicine measure basing on the method of detoxification and cooling blood for HBV-ACLF by randomized controlled clinical study.3. Exploring expression differential proteomics in HBV-ACLF, HBV-ACLF patients with different prognosis and integrative medicine treatment, in order to reveal the pathogenesis of HBV-ACLF, find biomarkers of disease prognostic as well as further study pathways and mechanisms of the cooling blood detoxification treating HBV-ACLF.
[Methods]
1. Collecting patients admitted with HBV-associated ACLF at the Capital Medical University, Beijing Ditan Hospital were entered in this study. All patients with available clinical information and baseline laboratory parameters were enrolled from from September2008to December2012. Establishing Epidata database and descriptively analysing age, sex, predisposing factors, stage of disease and laboratory examination in patients with different prognosis. Single factors and multivariate analysis were performed to screen prognostic indicators associated with HBV-ACLF, and assessing accuracy and value of the marker by prospective validation cohort.
2. Evaluating efficacy and safety of integrative medicine measure basing on the method of detoxification and cooling blood for HBV-ACLF by randomized controlled clinical study. All patients were randomly assigned to the Integrative Medicine group and Western medicine group. Western medicine group was treated by the comprehensive treatment of Western medicine, and Integrative Medicine group was given Western medicine treatment and jiedu liangxue prescriptions. All patients was treated8weeks and followed up40weeks.
3. basing on theITRAQ techniques in proteomics, we Explored expression of differential proteomics in HBV-ACLF, IIBV-ACLF patients with different prognosis and integrative medicine treatment, Using gel electrophores to separate and remove the high abundance of albumin and immunoglobulin, marking each group by ITRAQ reagents and detectoring peptide signal by Q-EXACTIVE mass spectrometer. Protein Discovery software was used to analyes mass spectrometry data qualitatively and quantitatively, and the biological information database was used to retrieve specific biological function of Protein.
[Results]
1. A total of316patients with HBV-ACLF were enrolled in the second part of the study. The ratio was5.58:lmale to female. Incorrect use of the antiviral drugs is a main cause to induce HBV-ACLF, and the fatality rate was up to68.27%in HBV-ACLF patients with decomponsated cirrhosis.
2.131cases of316were dead, and overall mortality in two months was41.5%.184cases in the early stage died and the fatality rate was27.17%; the fatality rate was55.26%in the mid-stage;56patients died of advanced disease and the mortality was69.64%.
3. Single factor analysis showed that baseline TBTL, PTA, NC, LC, NLR and MELD score exist differences between the survival group and death group (P<0.01). Multi-factor analysis show age, TBIL NLR and MELD score of patients affect the prognosis of HBV-ACLF patients. Area under the curve (AUC) of Age, TBIL, NLR and MELD score was0.615,0.691,0.781and0.744, respectively. There was no significant difference between NLR and MELD score (P=0.945).
4. Baseline NLR≤2.36was the negative threshold and NLR>6.12was positive threshold for retrospective cohort with a90.1%specificity and91.6%sensitivity; the survival rate was86.0%(49/57cases) in57HBV-ACLF patients with baseline NLR≤2.36at the end of8weeks, and the survival rate was19.7%(12/61cases) in61cases with NLR>6.12; the survival rate was61.22%(60/98cases) in HBV-ACLF patients with NLR ratio ranged from2.36to6.12. Log-rank test showed that the survival rate among the three groups were significantly different (P=0.004).
5. A total of105patients with HBV-ACLF were enrolled in our randomized controlled clinical study. Integrative Medicine group consisted of64cases, and Western medicine group consisted of41patients. After48Weeks, the overall fatality rate of two groups were21.88%and-39.02%, respectively(P=0.026). Integrative measure basing on the cooling blood and detoxification can significantly reduce the mortality in medium-term patients with HBV-ACLF (25%vs.64.7%, χ2=8.749, P=0.003).
6. There was statistical difference in total bilirubin (at8th week) and PTA (at4th week and6th week) between Integrative Medicine group and Western medicine group.(Total bilirubin:Integrative group:64.54±79.76vs Western medicine group:168.44±114.80, P=0.04).
7. About40down-regulated proteins and10up-regulated proteins were identified between Chronic hepatitis B and HBV-ACLF groups; comparing to HBV-ACLF survival group, the death group had24up-regulated proteins and24down-regulated proteins, which involved in energy metabolism, cytoskeleton, oxidative stress and transforming regulation. Integrative Medicine group comparing with Western medicine group, there are four kinds of proteins up-regulated and2proteins down-regulated after treatment in Integrative Medicine group, and three kinds of proteins disappeared.
[Conclusion]
1. Baseline NLR may be a potential marker to predict the short-term prognosis of patients with HBV-ACLF, which is as accuracy as the MELD score.
2. The overall mortality was41.5%of patients with HBV-ACLF in two months, and the case fatality rate in terminal patients was significantly greater than patients in the early and middle stages. Thus, early diagnosis and reasonable treatment is the key to reducing mortality of HBV-ACLF patients.
3."Cooling blood, detoxification, fu-unblocking therapy and invigorating spleen to re solve dampness" is the important rule for the treatment of HBV-ACLF, which can significantly reduce the mortality of patients, improve the synthetic function of the liver and reduce the level of total bilirubin.
4. The α1-acid glycoprotein was significantly lowered in patients of the death group, which can be as a sign for liver reserve function and prognosis in patients with liver failure; sulfated glycoproteins significantly down-regulated in the death group patients may inhibit apoptosis of liver cells; the a2-macroglobul in expression was raised in Integrative group, suggesting method of detoxification and cooling blood may have a role to promote regeneration for liver cell.
[目的]
1.系统了解乙型肝炎慢加急性肝衰竭的发病诱因、临床特点、总体病死率及不同分期患者的病死率、生存时间的分布特点及对预后判断有价值的临床指标。
2.通过随机对照临床研究对基于解毒凉血法的中西医结合方案治疗乙型肝炎慢加急性肝衰竭的疗效和安全性进行评价。
3.基于差异蛋白质组学的研究方法,初步探索乙型肝炎慢加急性肝衰竭发病过程中、不同预后及中西医治疗后患者间差异蛋白质的表达,为揭示HBV-ACLF的发病机制、寻找判断疾病预后的生物标志物以及为进一步研究解毒凉血方治疗HBV-ACLF的作用途径和机制奠定基础。
[方法]
1.收集首都医科大学附属北京地坛医院2008年9月-2012年12月间确诊为乙型肝炎慢加急性肝衰竭住院患者的临床资料,建立Epidata数据库,将患者的发病年龄、性别、发病诱因、基础疾病、疾病分期、不同预后患者的各项实验室检查等进行描述性分析；将各项指标进行单因素和多因素分析,筛选出与HBV-ACLF患者预后相关的指标,并以前瞻性队列验证和评估该指标的准确性及应用价值。
2.采用开放式随机对照试验的方法,按照2：1的比例将受试者随机分配到中西医结合组和西医治疗组,西医治疗组予西医内科综合治疗,中西医结合组在西医治疗的基础上予解毒凉血方加减,治疗8周,随访40周,评估患者治疗后和随访至48周时的临床疗效和用药安全性。
3.采用蛋白质组学的研究方法检测慢性乙型肝炎、乙型肝炎慢加急性肝衰竭、HBV-ACLF死亡者和生存者以及中西医结合治疗和单纯西医治疗后患者血清差异蛋白质的表达,运用凝胶电泳法分离、去除高丰度的白蛋白和免疫球蛋白,用ITRAQ试剂标记各组肽段后进行质谱检测,Q-EXACTIVE质谱仪检测肽段信号,Protein Discovery软件分析质谱数据对蛋白质进行定性和定量,通过生物信息库检索和分析这些差异蛋白质的具体生物学功能。
[结果]
1.共纳入316例HBV-ACLF患者,男女比例为5.58：1,未进行抗病毒治疗及抗病毒药物的不正确使用是诱发HBV-ACLF的主要原因,乙肝肝硬化继发ACLF的患者病死率高达64.12%。
2.316例患者中死亡131例,发病两个月时总体病死率为41.5%,疾病早期184例,病死率为27.17%；疾病中期76例,病死率为55.26%；疾病晚期56例,病死率为69.64%。
3.接受抗病毒治疗者269例,未进行抗病毒治疗的患者47例;抗病毒组病死率为39.03%,未进行抗病毒治疗的患者病死率为53.19%,两组比较具有统计学差异(P=0.007)。
4.单因素分析显示,基线TBIL、PTA、NC、LC、NLR和MELD评分在生存组和死亡组间存在显著差异(P<0.01),多因素分析显示年龄、TBIL、NLR和MELD评分对患者预后有重要影响。年龄、TBIL、NLR和MELD评分的曲线下面积(AUC)分别为0.615、0.691、0.781和0.744,NLR和MELD评分AUC比较无统计学差异,P=0.945。
5.回顾性队列基线NLR≤2.36为阴性临界值,NLR>6.12为阳性界值,特异度为90.1%,敏感度为91.6%；57例基线NLR≤2.36的HBV-ACLF患者中,第8周时生存率为86.0%(49/57例),61例NLR>6.12的患者生存率为19.7%(12/61例)。NLR比值介于2.36-6.12的患者生存率为61.22%(60/98例)。Log-rank检验显示三组间的生存率有显著差异(P=0.004)。
6.随机对照临床研究共纳入患者105例HBV-ACLF患者,中西医结合组64例,西医治疗组41例,治疗第48周两组总体病死率分别为21.88%和39.02%,P=0.026,基于解毒凉血法的中西医结合方案能够显著降低HBV-ACLF中期患者的病死率(中西医结合组vs西医治疗组：25%vs64.7%, x2=8.749,P=0.003)。
7.治疗第8周时,中西医结合组与西医治疗组总胆红素比较(中西医结合组：64.54±79.76vs西医治疗组：168.44±114.80,P=0.04)有统计学差异；治疗第4周和第6周,中西医结合组与西医治疗组比较凝血酶原活动度差异有统计学意义,P<0.05。
8. MELD评分低于22.6患者中西医结合组病死率为15.0%(6/40),西医治疗组病死率15.8%(3/19),两组比较无统计学差异(P=0.851); MELD评分介于22.6-29.9患者,中西医结合组和西医治疗组病死率为23.81%和58.82%,(P<0.05)。
9.慢性乙型肝炎组和乙型肝炎慢加急性肝衰竭组比较,共鉴定出40个下调蛋白和10个上调的蛋白；HBV-ACLF死亡组和生存组比较,鉴定出24个上调蛋白和24个下调蛋白,这些差异表达的蛋白质涉及能量代谢、细胞骨架、氧化应激、转化调控等方面。中西医结合组与西医治疗组比较,治疗后出现上调的蛋白质有4种,下调的蛋白质2种,表达消失的蛋白质3种。
[结论]
1.核苷(酸)类抗病毒药物能够降低HBV-ACLF患者病死率,积极抗病毒治疗具有重要的治疗价值。
2.基线NLR是一个简便的预测HBV-ACLF患者短期预后的指标,其cut-off值分别为2.36和6.12。
3.基于解毒凉血法的中西医结合方案能够显著降低HBV-ACLF患者的病死率。特别是对于病情中期或MELD评分介于22.6-29.9之间或NLR≤6的患者,中医药应及早介入。
4.在HBV-ACLF发生、发展过程中,上调或下调蛋白质涉及能量代谢、细胞骨架、氧化应激、转化调控等方面,其中：a) α1-酸性糖蛋白可作为肝硬化患者肝脏储备功能及预后判断的标志。b)角蛋白可能参与了肝衰竭时肝细胞凋亡的信号转导。c)硫酸化糖蛋白在死亡组患者中显著下调,可能具有抑制肝细胞的凋亡的作用。
5.中西医结合治疗组患者血清中α2-巨球蛋白高表达,提示解毒凉血方可能具有促进肝细胞再生的作用。
Acute-on-chronic liver failure (ACLF) is a severe life-threatening clinical syndrome. It has been defined as "an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within4weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease". Hepatitis B virus (HBV) infection is a leading cause of ACLF in Asia, and HBV associate acute-on-chronic liver failure (HBV-ACLF) account for more than70%. Acute hepatic deterioration often results in multiple complications (bacterial infection, hepatorenal syndrome, hepatic encephalopathy and so on) and multisystem organ failure, and short-term mortality is up to50-90%in ACLF patients. ACLF is charactered by rapid progress, dangerous disease, severe complications and high mortality of patients. It is important to understand its clinical features and make a more detailed description on prognosis and outcome of ACLF. Thus, accurately and objectively determine the prognosis of ACLF patients and explore effective therapy in early stage become an important research topic in HBV-ACLF.
[objective]
1. Systematically understanding predisposing factors, clinical features, overall mortality and mortality in different stages of patients with HBV-ACLF.
2. Evaluating efficacy and safety of integrative medicine measure basing on the method of detoxification and cooling blood for HBV-ACLF by randomized controlled clinical study.3. Exploring expression differential proteomics in HBV-ACLF, HBV-ACLF patients with different prognosis and integrative medicine treatment, in order to reveal the pathogenesis of HBV-ACLF, find biomarkers of disease prognostic as well as further study pathways and mechanisms of the cooling blood detoxification treating HBV-ACLF.
[Methods]
1. Collecting patients admitted with HBV-associated ACLF at the Capital Medical University, Beijing Ditan Hospital were entered in this study. All patients with available clinical information and baseline laboratory parameters were enrolled from from September2008to December2012. Establishing Epidata database and descriptively analysing age, sex, predisposing factors, stage of disease and laboratory examination in patients with different prognosis. Single factors and multivariate analysis were performed to screen prognostic indicators associated with HBV-ACLF, and assessing accuracy and value of the marker by prospective validation cohort.
2. Evaluating efficacy and safety of integrative medicine measure basing on the method of detoxification and cooling blood for HBV-ACLF by randomized controlled clinical study. All patients were randomly assigned to the Integrative Medicine group and Western medicine group. Western medicine group was treated by the comprehensive treatment of Western medicine, and Integrative Medicine group was given Western medicine treatment and jiedu liangxue prescriptions. All patients was treated8weeks and followed up40weeks.
3. basing on theITRAQ techniques in proteomics, we Explored expression of differential proteomics in HBV-ACLF, IIBV-ACLF patients with different prognosis and integrative medicine treatment, Using gel electrophores to separate and remove the high abundance of albumin and immunoglobulin, marking each group by ITRAQ reagents and detectoring peptide signal by Q-EXACTIVE mass spectrometer. Protein Discovery software was used to analyes mass spectrometry data qualitatively and quantitatively, and the biological information database was used to retrieve specific biological function of Protein.
[Results]
1. A total of316patients with HBV-ACLF were enrolled in the second part of the study. The ratio was5.58:lmale to female. Incorrect use of the antiviral drugs is a main cause to induce HBV-ACLF, and the fatality rate was up to68.27%in HBV-ACLF patients with decomponsated cirrhosis.
2.131cases of316were dead, and overall mortality in two months was41.5%.184cases in the early stage died and the fatality rate was27.17%; the fatality rate was55.26%in the mid-stage;56patients died of advanced disease and the mortality was69.64%.
3. Single factor analysis showed that baseline TBTL, PTA, NC, LC, NLR and MELD score exist differences between the survival group and death group (P<0.01). Multi-factor analysis show age, TBIL NLR and MELD score of patients affect the prognosis of HBV-ACLF patients. Area under the curve (AUC) of Age, TBIL, NLR and MELD score was0.615,0.691,0.781and0.744, respectively. There was no significant difference between NLR and MELD score (P=0.945).
4. Baseline NLR≤2.36was the negative threshold and NLR>6.12was positive threshold for retrospective cohort with a90.1%specificity and91.6%sensitivity; the survival rate was86.0%(49/57cases) in57HBV-ACLF patients with baseline NLR≤2.36at the end of8weeks, and the survival rate was19.7%(12/61cases) in61cases with NLR>6.12; the survival rate was61.22%(60/98cases) in HBV-ACLF patients with NLR ratio ranged from2.36to6.12. Log-rank test showed that the survival rate among the three groups were significantly different (P=0.004).
5. A total of105patients with HBV-ACLF were enrolled in our randomized controlled clinical study. Integrative Medicine group consisted of64cases, and Western medicine group consisted of41patients. After48Weeks, the overall fatality rate of two groups were21.88%and-39.02%, respectively(P=0.026). Integrative measure basing on the cooling blood and detoxification can significantly reduce the mortality in medium-term patients with HBV-ACLF (25%vs.64.7%, χ2=8.749, P=0.003).
6. There was statistical difference in total bilirubin (at8th week) and PTA (at4th week and6th week) between Integrative Medicine group and Western medicine group.(Total bilirubin:Integrative group:64.54±79.76vs Western medicine group:168.44±114.80, P=0.04).
7. About40down-regulated proteins and10up-regulated proteins were identified between Chronic hepatitis B and HBV-ACLF groups; comparing to HBV-ACLF survival group, the death group had24up-regulated proteins and24down-regulated proteins, which involved in energy metabolism, cytoskeleton, oxidative stress and transforming regulation. Integrative Medicine group comparing with Western medicine group, there are four kinds of proteins up-regulated and2proteins down-regulated after treatment in Integrative Medicine group, and three kinds of proteins disappeared.
[Conclusion]
1. Baseline NLR may be a potential marker to predict the short-term prognosis of patients with HBV-ACLF, which is as accuracy as the MELD score.
2. The overall mortality was41.5%of patients with HBV-ACLF in two months, and the case fatality rate in terminal patients was significantly greater than patients in the early and middle stages. Thus, early diagnosis and reasonable treatment is the key to reducing mortality of HBV-ACLF patients.
3."Cooling blood, detoxification, fu-unblocking therapy and invigorating spleen to re solve dampness" is the important rule for the treatment of HBV-ACLF, which can significantly reduce the mortality of patients, improve the synthetic function of the liver and reduce the level of total bilirubin.
4. The α1-acid glycoprotein was significantly lowered in patients of the death group, which can be as a sign for liver reserve function and prognosis in patients with liver failure; sulfated glycoproteins significantly down-regulated in the death group patients may inhibit apoptosis of liver cells; the a2-macroglobul in expression was raised in Integrative group, suggesting method of detoxification and cooling blood may have a role to promote regeneration for liver cell.
引文
1 Lu FM, Zhuang H. Management of hepatitis B in China. Chin Med J.2009; 122(1):1-2.
2 石清兰,毛德文.浅述肝衰竭的病因病机.实用中医药杂志.2009；25(11)：764-765.
3 韩德伍.肝功能衰竭的发病机制的研究———肠源性内毒素血症假说. 中华肝脏病杂志.1995；3(3)：134-136.
4 陈海龙,吴威中,关凤林,等.中医通里攻下法以多器官功能不全综合征时肠屏障功能保护作用的实验研究. 中国中西医结合杂志,2000;20(2)：120-122.
5 Higgins JPT, Green S, the Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions. Version 5.0.2. http://www. cochrane-handbook.org,2009.
6 谷灿立,付月箫,尚现伟,谢大亮,张沛.中西医结合治疗慢性重型病毒性肝炎临床研究.中医药学刊.2006；24(2)：377-378.
7 邱华,毛德文,黄彬,龙富立,陈月桥,王丽,武建华.解毒化瘀颗粒对慢性重型肝炎患者预后的影响. 中西医结合肝病杂志.2007;17(5)：259-260.
8 王建萍.内服退黄清肝汤在慢性重型肝炎治疗中应用分析.中国实用医药.2009；4(32)：111-112.
9 李筠,王立福,李丰衣,等.慢性重型肝炎中西医结合治疗方案研究.2011年第二十次全国中西医结合肝病学术会议论文汇编.
10高建蓉.中西医结合治疗慢性重型肝炎并腹膜炎26例.中西医结合肝杂志.1999；9(4)：4-5.
11李晶滢,过建春,姚鹏,田一梅,勾春燕,张佳莹,李秀惠.益气养阴方法治疗慢性乙型重型肝炎临床分析.中华中医药杂志.2011；26(6)：1300-1302.
12扈晓宇,吴疆,李运东,钟森,刘光伟.清肝解毒法对慢性重型肝炎病情及MELD预后的改善作用.中华中医药学会第十三届内科肝胆病学术会议论文汇编.2008.
13李召忠.三君退黄汤治疗慢性重型肝炎的研究.中国病原生物学杂志.2009；4(10)：779-781.
14李芹,李丹,张良宏.重肝合剂对慢性重型肝炎肝功能指标的改善作用.中医药临床杂志.2008；18(4)：387-388.
15邓欣,杨大国,吴其恺,陶艳艳,聂广.赤芍承气汤治疗慢性重型肝炎近期疗效观察.中西医结合肝病杂志.2004；14(2)：67-69.
16朱清静,梁红梅.丹黄方与综合疗法联用治疗慢性重型乙型肝炎的临床研究.中西医结合肝病杂志.2009；19(5)：263-265.
17安铁军.芍丹承气汤治疗慢性重症肝炎合并肠源性内毒素血症疗效观察.延边大学医学学报.2005；28(2)：129-130.
18黄加权,黄铁军,张建军,等.抗肝衰复方联合西药治疗重型肝炎临床疗效观察.中西医结合肝病杂志.2006；16(6)：331-333.
19马瑞红.中医辨证配合新鲜血浆治疗慢性重型肝炎20例疗效观察.中医临床研究.2010；2(2)：49-51.
20宋爱军,于培龙. 中西医结合治疗慢性重型肝炎疗效观察. 中华中医药学刊.2010;28(12)：2608-2610.
21傅海龙,裴蕾,魏品康. 中西医结合治疗慢性重型肝炎恢复期的临床观察.现代中西医结合杂.2004；13(5)：567.
22罗欣拉. 中西医结合治疗慢性重型肝炎湿热内蕴型35例. 中西医结合肝病杂志.2001；11(3)：178-179.
23李芳,尹盛强,邓文钦.中药治疗慢性重型肝炎疗效观察.辽宁中医杂志.2006；33(7)：845-846.
24曾德欣,张小玲.生大黄联合凯时注射液治疗早期慢性重型肝炎32例疗效观察.湖南中医药导报.2004；10(10)：11-12.
25张薇薇,秦明华.岩黄连联合灯盏花素注射液治疗慢性重型肝炎43例.新中医.2006；27(1)：21-23.
26孙克伟,陈斌,黄裕红,等.凉血解毒、清热化湿和凉血解毒、健脾温阳法治疗慢性重型肝炎的临床观察.中国中西医结合杂志.2006； 26(11)：981-983.
27许勤英,张世彬.中药保留灌肠用于慢性重型肝炎的临床观察.中国当代医药.2011；18(7)：105-106.
28那健松.中药保留灌肠治疗慢性重型肝炎疗效观察.辽宁中医杂志.2006；33(10)：1284-1286.
29过建春,施军平,陈群伟,等.中药结肠透析治疗慢性重型肝炎的临床研究.中医药学刊.2006;24(7)：1254-1255.
30李文勇,钱宜丹,邱绍勤,王淑平,彭秋萍,张振纲,田德英.结肠灌洗后中药保留灌肠治疗慢性重型肝炎内毒素血症的临床评价.实用肝脏病杂志.2009;12(2)：133-134.
31石伟珍,王宇芳,过建春,等.结肠灌洗联合中药结肠透析治疗慢性重型肝炎对患者血清内毒素与肿瘤坏死因子α等的影响.医药导报.2008,27(8)：935-937.
32吴其恺,徐晓婧,郑燕群,王平,刘晓晖.结肠透析联合中药灌肠治疗慢性重型乙型肝炎的临床观察.中西医结合肝病杂志.2009；19(5)：269-271.
33积明,王邦茂.序贯结肠透析联合人工肝治疗慢性重型肝炎25例.世界华人消化杂志,2009,17(35)：3657-3660.
34王利东.大黄水煎液灌肠治疗慢性重型肝炎65例临床观察.中国中医药信息杂志,2000,7(10)：46-47.
35肠透析配合中药灌肠治疗慢性重型肝炎疗效观察.现代中西医结合杂志.2011,20(34)：4333-4334.
36张囡囡,汪静,刘鹏,张志霞. 中医药多途径联合治疗慢性乙型重型肝炎的临床研究.辽宁中医药杂志.2009；36(7)：1137-1138.
37刘鹏,张囡囡,杨华秀,魏嵋.中药凉血解毒化瘀多渠道给药治疗慢性重型 肝炎42例临床研究.江苏中医药.2009；41(7)：28-29.
38胡建华,钱英,姚乃礼,等. “截断逆挽法”治疗慢性乙型重型肝炎临床疗效观察.中西医结合肝病杂志.2010；20(4)：200-203.
39贡桂英,刘霞,马建红.中西医结合治疗慢性乙型重型肝炎43例临床观察.世界中医药.2009；4(4)：194-195.
40周滔,刘成海,顾元龙,俞宪民,周奚钟,刘宗良.开窍承气液灌肠对慢性重型乙型肝炎肝性脑病的治疗作用.中国中西医结合消化杂志.2006；14(5)：305-307.
41王桦,章文平,廖洪.肝肾清毒饮联合中药灌肠治疗慢性重型乙型肝炎临床研究.辽宁中医杂志.2010；37(11)：2198-2200.
42邱华,毛德文,胡振斌,黄彬,等.慢性重型肝炎中医综合治疗方案的多中心临床研究.中西医结合肝病杂志.2008；18(5)：260-263.
43陈斌,孙克伟,彭杰,肖德梅,等.基于阳黄-阴阳黄-阴黄辨证模式治疗慢性重型肝炎的临床观察.中国中医药科技.2012；19(1)：57-58-66.
44刘翔,胡佳,郑欢欢,欧阳钦.重肝合剂联合血浆置换术治疗慢性重型肝炎40例.江西中医药.2010；10(10)：26-27.
45阮清发,洪昱钤,郑全胜,吴丽,赵俊芳.中药联合血浆置换治疗慢性重型肝炎的临床研究.光明中医.2011；26(12)：2439-2441.
46林恢,李芹,张娟娟.中药联合血浆置换治疗慢性重型肝炎临床观察.传染病信息.2009；22(5)：305-307.
47阮清发,吴丽,赵俊芳,洪昱钤,郑全胜.茵芍桂芪汤治疗血浆置换后慢性重型肝炎临床研究.中国中医急症.2011；20(9)：1397-1398.
48赵文霞,马素平,叶放,刘江凯.益气活血颗粒联合单重血浆置换治疗慢性重型肝炎30例临床观察.河南中医.2011；31(2)：141-143.
49黄学军.茵陈术附汤加味治疗慢性重型肝炎26例.国际中医中药杂志.2008；30(5)：350-352.
50李芹,林恢,刘政芳,陈丽芳,潘晨,张娟娟.人工肝支持系统联合中药治疗慢性重型肝炎临床研究.中西医结合肝病杂志.2010；20(1)：12-14.
51张旸.谭善忠.慢性重型肝炎/肝衰竭的中医病因病机特点研究进展.中西医结合肝病杂志.2011；21(06)：380-383.
52徐翔,郦柏平,张慧芬,等.大黄的研究进展.上海中医药杂志.2003；37(4)： 55-59.
53 Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. BMJ. 2010; 340:c332.
1. Gamez-Pozo A, Ferrer N I., Ciruelos E, et al. Shotgun proteomics of archival triple-negative breast cancer samples. Proteomics Clin Appl. 2013; 3-4:283-91.
2. Barratt C L. The human sperm proteome:the potential for new biomarkers of male fertility and a transformation in our understanding of the spermatozoon as a machine:commentary on the article'Identification of proteomic differences in asthenozoospermic sperm samples'by Martinez etal. Hum Reprod.2008; 6:1240-41.
3. Petricoin E F, Zoon K C, Kohn E C, et al. Clinical proteomics: translating benchside promise into bedside reality. Nat Rev Drug Discov.2002; 9:683-95.
4. Kovacs A, Guttman A. Medicinal chemistry meets proteomics: fractionation of the human plasma proteome. Curr Med Chem.2013; 4: 483-90.
5. Millioni R, Tolin S, Fadini G P, et al. High confidence and sensitivity four-dimensional fractionation for human plasma proteome analysis Amino Acids.2012; 5:2199-202.
6. Kovacs A, Sperling E, Lazar J, et al. Fractionation of the human plasma proteome for monoclonal antibody proteomics-based biomarker discovery. Electrophoresis.2011; 15:1916-25.
7. Bjorhall K, Miliotis T, Davidsson P. Comparison of different depletion strategies for improved resolution in proteomic analysis of human serum samples. Proteomics.2005; 1:307-17.
8. Chen H S, Rejtar T, Andreev V, et al. High-speed, high-resolution monolithic capillary LC-MALDI MS using an off-line continuous deposition interface for proteomic analysis. Anal Chem.2005; 8: 2323-31.
9. Ross P L, Huang Y N, Marchese J N, et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics.2004; 12:1154-69.
10. Kawada N, Kristensen D B, Asahina K, et al. Characterization of a stellate cell activation-associated protein (STAP) with peroxidase activity found in rat hepatic stellate cells. J Biol Chem.2001; 27: 25318-23.
11. Kim T R, Yang J S, Shin S, et al. Statistical torsion angle potential (STAP) energy functions for protein structure modeling:A bicubic interpolation approach. Proteins.2013; Feb 14. Online. (to be published)
12. Wang H, Wu G, Park H J, et al. Protective effect of Phellinus linteus polysaccharide extracts against thioacetamide-induced liver fibrosis in rats: a proteomics analysis. Chin Med.2012; 1:23.
13. Liu E H, Chen M F, Yeh T S, et al. A useful model to audit liver resolution from cirrhosis in rats using functional proteomics. J Surg Res.2007; 2:214-23.
14. Lin D, Wu X, Ji X, et al. A novel canine model of portal vein stenosis plus thioacetamide administration-induced cirrhotie portal hypertension with hypersplenism. Cell Biochem Biophys.2012; 1: 245-55.
15. An J H, Seong J, Oh H, et al. Protein expression profiles in a rat cirrhotic model induced by thioacetamide. Korean J Hepatol.2006; 1: 93-102.
16. Poon T C, Hui A Y, Chan H L, et al. Prediction of liver fibrosis and cirrhosis in chronic hepatitis B infection by serum proteomic fingerprinting:a pilot study. Clin Chem.2005; 2:328-35.
17. Xu X Q, Leow C K, Lu X, et al. Molecular classification of liver cirrhosis in a rat model by proteomics and bioinformatics. Proteomics. 2004; 10:3235-45.
18. Nault J C, Zucman R J. Molecular classification of hepatocellular adenomas. Int J Hepatol.2013; 2013:1-7.
19. Thompson S M, Callstrom M R, Knudsen B E, et al. Molecular Bioluminescence Imaging as a Noninvasive Tool for Monitoring Tumor Growth and Therapeutic Response to MRI-Guided Laser Ablation in a Rat Model of Hepatocellular Carcinoma. Invest Radiol.2012; 6:413-21.
20. Yokoyama Y, Kuramitsu Y, Takashima M, et al. Proteomic profiling of proteins decreased in hepatocellular carcinoma from patients infected with hepatitis C virus. Proteomics.2004; 7:2111-16.
21. Kimura A, Sogawa K, Satoh M, et al. The application of a three-step serum proteome analysis for the discovery and identification of novel biomarkers of hepatocellular carcinoma. Int J Proteomics.2012; 2012:623190 (1-12).
22. Kanamori H, Kawakami T, Effendi K, et al. Identification by differential tissue proteome analysis of talin-1 as a novel molecular marker of progression of hepatocellular carcinoma. Oncology.2011; 5-6:406-15.
23. Zeindl-Eberhart E, Klugbauer S, Dimitrijevic N, et al. Proteome analysis of rat hepatomas:carcinogen-dependent tumor-associated protein variants. Electrophoresis.2001; 14:3009-18.
24. Megger D A, Bracht T, Kohl M, et al. Proteomic differences between hepatocellular carcinoma and non-tumorous liver tissue investigated by a combined 2D-DIGE and label-free quantitative proteomics study. Mol Cell Proteomics.2013 Mar 5. [Epub ahead of print]
25. Suo A, Zhang M, Yao Y, et al. Proteome analysis of the effects of sorafenib on human hepatocellular carcinoma cell line HepG2. Med Oncol.2012; 3:1827-36.
26. Ding S J, Li Y, Tan Y X, et al. From proteomic analysis to clinical significance:overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis. Mol Cell Proteomics.2004; 1: 73-81.
27.申定珠,陶庆,都金星,等.基于差异蛋白质组学解析一贯煎对大鼠肝硬化形成的影响.中西医结合学报.2010；2：158-67.
28.李骢,姜妙娜,等.中药肝复康干预肝星状细胞及肝组织的蛋白质组学分析.现代生物医学进展.2009；16：3020-25.
1. 肝衰竭诊疗指南.中华肝脏病杂志.2006；9：643-46.
2. 柳芳芳,苏海滨,王慧芬,等.HBV相关慢加急性肝衰竭发病诱因分析.传染病信息.2010；3：161-64.
3. Zoulim F, Locarnini S. Optimal management of chronic hepatitis B patients with treatment failure and antiviral drug resistance. Liver Int.2013; 33 Suppll:116-24.
4. 刘晓燕,胡锦华.1977例急性、 亚急性、 慢加急性肝衰竭患者的病因与转归分析.中华肝脏病杂志.2008；10：772-75.
5. 孙庆丰,吕勇,徐道振,等.乙型肝炎病毒e抗原及DNA载量对慢性乙型重型肝炎预后的影响.中华肝脏病杂志.2006；6：146-49.
6. 韩乾国,王文雅,杨尧.病毒复制水平对慢性重型乙型肝炎病情及预后影响的初步评价.华西医学.2006；1：115-18.
7. Yu JW,Sun LJ,Zhao YH,et al. Prediction value of model for end-stage liver disease scoring system on prognosis in patientswith acute-on-chronic hepatitis B liver failure after plasma ex-change and lamivudine treatment. J Gastroenterol Hepatol.2008; 8 Pt 1:1242-49.
8. 罗育春,陈大兰.肝硬化患者血清谷丙转氨酶、谷草转氨酶和总胆红素与肝纤维化标志物的相关性研究.实用预防医学.2011；8：711-14.
9. 张钟儒.天门冬氨酸转氨酶和丙氨酸转氨酶的稳定性.临床生物化学与检验学分册.2010；3：41-43.
10.张耿林,高志良.乙型肝炎相关慢加急性肝衰竭的免疫学特征及治疗策略.中国病毒病杂志.2011；1：5-8.
11. Huang K, Hu J H, Wang H F, et al. Survival and prognostic factors in hepatitis B virus-related acute-on-chronic liver failure. World J Gastroenterol.2011; 29:3448-52.
12.谢仕斌,吴元凯,朱建芸,等.慢加急性肝衰竭预后评分系统的建立与评估.中山大学学报(医学科学版).2011；6：834-40.
1 Sarin SK, Kumar A, Almeida JA, et al.. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int.2009; 1:269-82.
2 Olson JC, Kamath PS. Acute-on-chronic liver failure:concept, natural history, and prognosis. Curr Opin Crit Care.2011; 2:165-9.
3 Ling Q, Xu X, Wei Q, et al.. Downgrading MELD improves the outcomes after liver transplantation in patients with acute-on-chronic hepatitis B liver failure. PLoS One.2012; 1:e30322.
4 Bernardi M, Gitto S, Biselli M. The MELD score in patients awaiting liver transplant:strengths and weaknesses. J Hepatol.2011; 6:1297-306.
5 Mao W, Ye B, Lin S, Fu Y, Chen Y, Chen Y. Prediction value of model for end-stage liver disease scoring system on prognosis in the acute on chronic liver failure patients with plasma exchange treatment. Asaio J. 2010; 5:475-78.
6 Sun QF, Ding JG, Xu DZ, et al.. Prediction of the prognosis of patients with acute-on-chronic hepatitis B liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model.J Viral Hepat.2009; 7:464-70.
7 Liu H, Han T, Tian J, et al.. Monitoring oxidative stress in acute-on-chronic liver failure by advanced oxidation protein products. Hepatol Res.2012; 2:171-80.
8 Ren F, Chen Y, Wang Y, et al.. Comparative serum proteomic analysis of.patients with acute-on-chronic liver failure:alpha-1-acid glycoprotein maybe a candidate marker for prognosis of hepatitis B virus infection. J Viral Hepat.2010; 11:816-24.
9 Tasaka S, Koh H, Yamada W, et al.. Attenuation of endotoxin-induced acute lung injury by the Rho-associated kinase inhibitor, Y-27632. Am J Respir Cell Mol Biol.2005; 6:504-10.
10 Zhou H, Andonegui G, Wong CH, Kubes P. Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. J Immunol.2009; 8:5244-50.
11 Twu YC, Gold MR, Teh HS. TNFR1 delivers pro-survival signals that are required for limiting TNFR2-dependent activation-induced cell death (AICD) in CD8+ T cells. Eur J Immunel.2011; 2:335-44.
12 Baumann S, Dostert A, Novae N, et al.. Glucocorticoids inhibit activation-induced cell death (ATCD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimer. Blood.2005; 2:617-25.
13 Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology.2000; 4:864-71.
14 Chen TM, Lin CC, Huang PT, Wen CF. Neutrophil-to-lymphocyte ratio associated with mortality in early hepatocellular carcinoma patients after radiofrequency ablation. J Gastroenterol Hepatol.2012; 3:553-61.
15 Hung HY, Chen JS, Yeh CY, et al.. Effect of preoperative neutrophil-lymphocyte ratio on the surgical outcomes of stage Ⅱ colon cancer patients who do not receive adjuvant chemotherapy. Int JColorectal Dis.2011; 8:1059-65.
16 Imtiaz F, Shafique K, Mirza SS, Ayoob Z, Vart P, Rao S. Neutrophil lymphocyte ratio as a measure of systemic inflammation in prevalent chronic diseases in Asian population. Int Arch Med.2012; 1:2.
17 Zahorec R. Ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy.2001; 1:5-14.
18 Azab B, Jaglall N, At all ah JP, et al. Neutrophil-lymphocyte ratio as a predictor of adverse outcomes of acute pancreatitis. Pancreatology. 2011; 4:445-52.
19 Muhmmed SM, Bahnacy JA, Ali AA, Pathare AV, Alkindi SS, Uwe WF. Predictive value of neutrophil to lymphocyte ratio in outcomes of patients with acute coronary syndrome. Arch Med Res.2010; 8:618-22.
20 Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol.2009; 3:162-74.
21 Pillay J, Kamp VM, van Hoffen E, et al.. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1.J Clin Invest.2012; 1:327-36.
22 Brandau S, Trellakis S, Bruderek K, et al.. Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. J Leukoc Biol. 2011; 2:311-7.
23 Mao WL, Chen Y, Chen YM, Li LJ. Changes of serum cytokine levels in patients with acute on chronic liver failure treated by plasma exchange. J Clin Gastroenterol.2011; 6:551-5. 24 Hu X, Ma S, Huang X, et al.. Interleukin-21 is upregulated in hepatitis B-related acute-on-chronic liver failure and associated with severity of liver disease. J Viral Hepat.2011; 7:458-67.
25 Wu Z, Han M, Chen T, Yan W, Ning Q. Acute liver failure:mechanisms of immune-mediated liver injury. Liver Int.2010; 6:782-94.
26 Liu Q. Role of cytokines in the pathophysiology of acute-on-chronic liver failure. Blood Purif.2009; 4:331-41.
27 Di Campli C, Zocco MA, Gaspari R, et al.. The decrease in cytokine concentration during albumin dialysis correlates with the prognosis of patients with acute on chronic liver failure. Transplant Proc.2005; 6: 2551-3.
28 Marques PE, Amaral SS, Pires DA, et al.. Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. Hepatology.2012.5:1971-82.
29 Bhatia V, Bhardwaj P, Elikkottil J, Batra J, Saraya A. A 7-day profile of oxidative stress and antioxidant status in patients with acute liver failure. Hepatol Int.2008; 4:465-70.
30 Gregory B, Larson AM, Reisch J, Lee WM. Acetaminophen dose does not predict outcome in acetaminophen-induced acute liver failure.J Investig Med 2010; 5:707-10.
31 Mao WL, Lou YF, Ye B, Lin S, Chen YM, Chen Y. Changes in peripheral CD4 CD25(high) regulatory T cells in the acute-on-chronic liver failure patients with plasma exchange treatment. Inflammation.2012; 2:436-44.
32 Zhang JY, Zhang Z, Lin F, et al. Interleukin-17-producing CD4 (+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology.2010; 1:81-91.
33 Wasmuth HE, Kunz D, Yagmur E, et al.. Patients with acute on chronic liver failure display "sepsis-like" immune paralysis. J Hepatol.2005; 2:195-201.
34 Lou YF, Dong W, Ye B, Lin S, Mao WL. Changes in peripheral T-lymphocytc subsets in acute-on-chronic liver failure patients with artificial liver support system. Hepatogastrocnterology.2012; 115:814-7.
35 Zou Z, Li B, Xu D, et al. Imbalanced intrahepatic cytokine expression of interferon-gamma, tumor necrosis factor-alpha, and interleukin-10 in patients with acute-on-chronic liver failure associated with hepatitis B virus infection.J Clin Gastroenterol.2009; 2:182-90.
1. 王宪波,李斌,刘慧敏.解毒凉血、健脾化湿法治疗乙型肝炎慢加急性肝功能衰竭体会.中医杂志.20：1772-76.
2. 刘慧敏,王宪波,王融冰.基于解毒凉血法的中西医结合方案治疗乙型肝炎慢加急性肝衰竭疗效分析.中西医结合肝病杂志.2011；4：197-200.
3. Murphy J F. Consort 2010 statement on randomised controlled trials. Ir Med J.2010; 5:132.
4.王家良.临床流行病学.上海科学技术出版社.2006：61-64.
5. 李兰娟.肝衰竭诊疗指南.中华内科杂志.2006；12：1053-56.
6. 中华医学会感染病学分会肝衰竭与人工肝学组,中华医学会肝病学分会重型肝病与人工肝学组,《肝衰竭诊治指南》.中华临床感染病杂志.2012；5：321-27.
7. 郑筱萸.《中药新药临床研究指导原则》.中国中医药出版社.2002：185-212.
8. Lee Y M, Fernandes M, Da C M, et al. The MELD score may help to determine optimum time for liver transplantation. Transplant Proc.2004; 10:3057-59.
9. 吴云忠,王宪波,叶航,等.基于MELD评价解毒凉血法治疗慢性乙型重型肝炎的疗效.临床肝胆病杂志.2011；5：1220-23.
10.魏思思,赵艳玲,江凤娟,等.重用赤芍治疗ANIT诱导大鼠急性淤胆型肝炎的研究.中国实验方剂学杂志.2012：12：336-39.
11.邓欣,杨大国,吴其恺,等.赤芍承气汤治疗慢性重型肝炎近期疗效观察.中西医结合肝病杂志.2004；2：310-13.
12.李凌,杨大国,吴其恺,等.赤芍承气汤对重型肝炎内毒素血症的影响.浙江中西医结合杂志.2002；9：290-92.
13.梁旭竞,唐永煌,何玮,等.丹参酮对过氧化氢致慢性乙型肝炎患者外周血淋巴细胞DNA损伤的影响.中西医结合肝病杂志.2005；2：119-22.
14.夏振信,陈金和,杨自成,等.丹参口服液治疗慢性乙型肝炎的实验研究及临床观察.湖北医学院学报.2011；4：350-53.
15.寇义华,卢军利.茵陈对黄疸型肝炎的疗效观察. 中国医药导刊.2011；5：101-04.
16.孙建光.加味茵陈蒿汤保留灌肠对慢性重症肝炎患者内毒素和血氨的影响.四川中医.2013；1：75-77.
17.李秀惠.钱英教授“截断逆挽法”治疗慢性重型肝炎的思路与方法.上海中医药杂志.2007；1：1-4.
18.覃雪英,陆启峰,覃后继,等.血浆置换联合大黄灌肠治疗重型肝炎合并肝 肾综合征疗效观察. 中国医药导报.2011；28：98-101.
1. Ross P L, Huang Y N, Marchese J N, et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics.2004:12:1154-69.
2.肝衰竭诊疗指南.中华肝脏病杂志.2006；9：643-46.
3.刘晓燕,王慧芬.肝衰竭病因研究进展.军医进修学院学报.2011；1：15-17.
4. Wlodzimirow K A, Eslami S, Abu-Hanna A, et al. A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality. Liver Int.2013; 1:40-52.
5. He W P, Hu J H, Zhao J, et al. Comparison of four prognostic models and a new Logistic regression model to predict short-term prognosis of acute-on-chronic hepatitis B liver failure. Chin Med J (Engl).2012; 13: 2272-78.
6. Dou J, Xu W, Ye B, et al. Serum vitamin B12 levels as indicators of disease severity and mortality of patients with acutc-on-chronic liver failure. Clin Chim Acta.2012; 23-24:1809-12.
7. Jalan R, Gines P, Olson J C,-et al. Acute-on chronic 1 iver failure. J Ilepatol. 2012; 6:1336-48.
8. Qi Z X, Wang L Y, Fan Y C, et al. Increased peripheral RORalpha and RORgammat mRNA expression is associated with acute-on-chronic hepatitis B liver failure. J Viral Hepat.2012; 11:811-22.
9. Zou S S, Yang W, Yan H X, et al. Role of beta-Catenin in regulating the balance between TNF-alpha-and Fas-induced acute liver injury. Cancer Lett.2013 Feb 11. [Epub ahead of print]
10. Yu D S, An F M, Gong B D, et al. The regulatory role of microRNA-1187 in TNF-alpha-mediated hepatocyte apoptosis in acute liver failure. Int J Mol Med.2012; 4:663-68.
11. Lu Y, Wang X, Yan W, et al. Liver TCRgammadelta(+) CD3(+) CD4(-) CD8(-) T cells contribute to murine hepatit is virus strain 3-induced hepatic injury through a TNF-alpha-dependent pathway. Mol Immunol.2012; 3-4:229-36.
12.叶一农,高志良. 乙型肝炎肝衰竭发生机制中的三重打击.传染病信息.2009;5：276-79.
13. Kim Y E, Yi S Y, Lee C S, et al. Gold patterned biochips for on-chip immuno-MALDI-TOF MS:SPR imaging coupled multi-protein MS analysis. Analyst. 2012; 2:386-92.
14. Wigenius J A, Fransson S, von Post F, et al. Protein biochips patterned by microcontact printing or by adsorption-soft lithography in two modes. Biointerphases.2008; 3:75-82.
15. Lueking A, Cahill D J, Mullner S. Protein biochips:A new and versatile platform technology for molecular medicine. Drug Discov Today.2005;11: 789-94.
16.赵健,黄维华,王远东,等.应用SELDI-TOF-MS技术筛选肺腺癌患者血清诊断标志物.肿瘤基础与临床.2008；1：7-9.
17. Alves R M, Vitorino R, Padrao A I, et al. iTRAQ-based quantitative proteomic analysis of submandibular glands from rats with STZ-induced hyperglycemia. J Biochem.2013; 2:209-20.
18. Nicholson J, Neelagandan K, Huart A S, et al. An iTRAQ proteomics screen reveals the effects of the MDM2 binding ligand Nutlin-3 on cellular proteostasis. J Proteome Res.2012; 11:5464-78.
19. Kaur P, Rizk N M, Ibrahim S, et al. iTRAQ-based quantitative protein expression profiling and MRM verification of markers in type 2 diabetes. J roteome Res.2012; 11:5527-39.
20. Lee J T, Lee J W, Kim J M, et al. Prognosis of hepatocellular carcinoma expressing cytokeratin 19:comparison with other liver cancers. World J Gastroenterol.2012; 34:4751-57.
21. Attallah A M, El-Far M, Abdel M C, et al. Evaluation of cytokeratin-1 in the diagnosis of hepatocellular carcinoma. Clin Chim Acta.2011; 23-24: 2310-15.
22. Xiang Z L, Zeng Z C, Tang Z Y, et al. Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma. Mol Biol Re.2011; 5:3531-39.
23. Fanni D, Nemolato S, Ganga R, et al. Cytokeratin 20-positive hepatocellular carcinoma. Eur J Hislochem.2009; 4:e32.
24. Su Q, Fu Y, Liu Y F, et al. Laminin induces the expression of cytokeratin 19 in hepatocellular carcinoma cells growing in culture. World J Gastroenterol.2003; 5:921-29.
25. Bechmann L P, Jochum C, Kocabayoglu P, et al. Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J Hepalol.2010; 4:639-47.
26.赵四海,楚雍烈,刘恩岐.角蛋白8在四氯化碳诱导的小鼠肝损伤中的表达.浙江大学学报(医学版).2010；5：335-38.
27. Ku N O, Liao J, Omary M B. Apoptosis generates stable fragments of human type Ⅰ keratins. J Biol Chem.1997; 52:33197-203.
28. Leers M P, Bjorklund V, Bjorklund B, et al. An immunohistochemical study of the clearance of apoptotic cellular fragments. Cell Mol Life Sci.2002; 8:1358-65.
29. Moshage H. Cytokines and the hepatic acute phase response. J Pathol.1997; 3:257-66.
30. Kang X, Sun L, Guo K, et al. Serum protein biomarkers screening in HCC patients with liver cirrhosis by ICAT-LC-MS/MS. J Cancer Res Clin Oncol. 2010; 8:1151-59.
31. Bachtiar I, Kheng V, Wibowo G A, et al. Alpha-1-acid glycoprotein as potential biomarker for alpha-fetoprotein-low hepatocellular carcinoma. BMC Res Notes.2010; 3:319.
32. Song E Y, Kim K A, Kim Y D, et al. Elevation of serum asialo-alpha(1) acid glycoprotein concentration in patients with hepatic cirrhosis and hepatocellular carcinoma as measured by antibody-lectin sandwich assay. Hepatol Res.2003; 4:311-7.
33. Wigmore S J, Fearon K C, Maingay J P, et al. Interleukin-8 can mediate acute-phase protein production by isolated human hepatocytes. Am J Physiol. 1997; 4 Pt 1:E720-26.
34. Alam T, Papaconstantinou J. Interaction of acute-phase-inducible and liver-enriched nuclear factors with the promoter region of the mouse alpha 1-acid glycoprotein gene-1. Biochemistry.1992; 7:1928-36.
35. Olofsson S O, Wiklund O, Boren J. Apolipoproteins A-I and B:biosynthesis, role in the development of atherosclerosis and targets for intervention against cardiovascular disease. Vasc Health Risk Manag.2007; 4:491-02.
36.成兰芝.病毒性肝炎患者血清载脂蛋C II C III变化与血脂关系.菏泽医专学报.1997：2：73-74.
37.梁丽,李斓,黄国美.肝硬化患者血清脂类及载脂蛋白的变化及意义.贵州医药.2007：8：741-42.
38. Olofsson S O, Wiklund O, Boren J. Apolipoproteins A-I and B:biosynthesis, role in the development of atherosclerosis and targets for intervention against cardiovascular disease. Vasc Health Risk Manag.2007; 4:491-502.
39. Zhang W, Cox A G, Taylor E W. Hepatitis C virus encodes a selenium-dependent glutathione peroxidase gene. Implications for oxidative stress as a risk factor in progression to hepatocellular carcinoma. MedKlin (Munich).1999; 94 Suppl 3:2-6.
40. Burk R F, Early D S, Hill K E, et al. Plasma selenium in patients with cirrhosis. Hepatology.1998; 3:794-98.
41. Hsu Y W, Tsai C F, Chen W K, et al. Protective effects of seabuckthorn (Hippophae rhamnoides L.) seed oil against carbon tetrachloride-induced hepatotoxicity in mice. Food Chem Toxicol.2009; 9:2281-88.
42. He S X, Wu B, Chang X M, et al. Effects of selenium on peripheral blood mononuclear cell membrane fluidity, interleukin-2 production and interleukin-2 receptor expression in patients with chronic hepatitis. World J Gastroenterol.2004; 23:3531-33.
43. Todorov P T, Mcdevitt T M, Meyer D J, et al. Purification and characterization of a tumor lipid-mobilizing factor. Cancer Res.1998; 11: 2353-58.
44. Stewart A J, Blindauer C A, Sadler P J. Plasma fatty acid levels may regulate the Zn (2+)-dependent activities of histidine-rich glycoprotein. Biochimie. 2009; 11-12:1518-22.
45. Saito R, Shimosawa T, Ogihara T, et al. Function of adrenomedullin in inflammatory response of liver against LPS-induced endotoxemia. APMIS.2012; 9:706-11.
46. Cederbaum A I, Yang L, Wang X, et al. CYP2E1 Sensitizes the Liver to LPS-and TNF alpha-Induced Toxicity via Elevated Oxidative and Nitrosative Stress and Activation of ASK-1 and JNK Mitogen-Activated Kinases. Int J Hepatol.2012; 2012:582790.
47. Li G, Chen W, Man C, et al. Cytosolic phospholipase A(2)alpha protects against Fas-but not LPS-induced liver injury. J Hepatol.2011; 6:1281-90.
48. Bettuzzi S, Davalli P, Astancolle S, et al. Tumor progression is accompanied by significant changes in the levels of expression of polyamine metabolism regulatory genes and clusterin (sulfated glycoprotein 2) in human prostate cancer specimens. Cancer Res.2000; 1:28-34.
49. Hurwitz A, Ruutiainen-Altman K, Marzella L, et al. Follicular atresia as an apoptotic process:atresia-associated increase in the ovarian expression of the putative apoptotic marker sulfated glycoprotein-2. J Soc Gynccol Investig.1996; 4:199-208.
50. Park J H, Park J S, Ju S K, et al. Clusterin mRNA expression in apoptotic and activated rat thymocytes. Cell Res.2003; 1:49-58.
51. Karimi S, Hemmateenejad B. Identification of discriminatory variables in proteomics data analysis by clustering of variables. Anal Chim Acta.2013; 767:35-43.
52. Sintich S M, Steinberg J, Kozlowski J M, et al. Cytotoxic sensitivity to tumor necrosis factor-alpha in PC3 and LNCaP prostatic cancer cells is regulated by extracellular levels of SGP-2 (clusterin). Prostate.1999; 2: 87-93.
53. Bailey R W, Aronow B, Harmony J A, et al. Heat shock-initiated apoptosis is accelerated and removal of damaged cells is delayed in the testis of clusterin/ApoJ knock-out mice. Biol Reprod.2002; 4:1042-53.
54. Bilezikci B, Demirhan B, Ozdemir N, et al. Expression of hepatocyte growth factor in chronic hepatitis:effect of hemodialysis. Ren Fail.2006; 7: 557-60.
55. Cheng J H, She H, Han Y P, et al. Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2008; 1:G39-49.
56. Langlois M R, Delanghe J R. Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chew.1996; 10:1589-600.
57. Luo R, Akpan I O, Hayashi R, et al. GTP-binding protein-like domain of AGAP1 is protein binding site that allosterically regulates ArfGAP protein catalytic activity. J Biol Chem.2012; 21:17176-85.
58. Staresincic L, Walker J, Dirac-Svejstrup A B, et al. GTP-dependent binding and nuclear transport of RNA polymerase Ⅱ by Npa3 protein. J Biol Chem. 2011; 41:35553-61.
59. Balasubramanian S, Messmer-Blust A F, Jeyaratnam J A, et al. Role of GTP Binding, Isoprenylation, and the C-Terminal alpha-Helices in the Inhibition of Cell Spreading by the Interferon-Induced GTPase, Mouse Guanylate-Binding Protein-2. J Interferon Cytokine Res.2010.
60. Hommers L G, Klenk C, Dees C, et al. G proteins in reverse mode: receptor-mediated GTP release inhibits G protein and effector function. J Biol Chem.2010; 11:8227-33.
61. Li L, Rezvan A, Salerno J C, et al. GTP cyelohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endothelial tetrahydrobiopterin and nitric oxide. Circ Res.2010; 2:328-36.
62. Tendler Y, Pokroy R, Panshin A, et al. p53 protein subcellular localization and apoptosis in rodent corneal epithelium cell culture following ultraviolet irradiation. Int J Mol Med. 2013; 3:540-46.
63. Yang J, Maity B, Huang J, et al. G protein inactivator RGS6 mediates myocardial cell apoptosis and cardiomyopathy caused by doxorubicin. Cancer Res.2013.
64. Pang J, Xu X, Wang X, et al. G-Protein-Coupled Receptor Kinase Interacting Protein-1 Mediates Intima Formation by Regulating Vascular Smooth Muscle Proliferation, Apoptosis, and Migration. Arterioscler Thromb Vasc Biol. 2013.
65. Nassir F, Blanchard R K, Mazur A, et al. Apol ipoprotein B mRNA editing is preserved in the intestine and liver of zinc-deficient rats. J Nutr.1996; 4:860-64.
66. Qin X, Swertfeger D K, Zheng S, et al. Apolipoprotein AIV:a potent .endogenous inhibitor of lipid oxidation. Aw J Physiol,1998; 5 Pt 2: 111836-40.
67. Fujita T,.Hemmi S, Kajiwara M, et al. Complement-mediated chronic inflammation is associated with diabetic microvascular complication. Diabetes Metab Res Rev..2012.
68. Toivola D M, Ku N O, Resurreccion E Z, et al. Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease. Hepatology.2004; 2:459-66.
69.李娟, 石英, 武聚山, 等.角蛋白K18及其33、52位丝氨酸磷酸化在HBV感染肝脏疾病中的表达及意义.临床肝胆病杂志.2008；4：243-45.
70. Inada H, Izawa I, Nishizawa M, et al. Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. J Cell Biol. 2001; 3:415-26.
71. Caul in C, Ware C F, Magin T M, et al. Keratin-dependent, epithelial resistance to tumor necrosis factor-induced apoptosis. J Cell Biol.2000; 1:17-22.
72. Gilbert S, Loranger A, Daigle N, et al. Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation. J Cell Biol.2001; 4:763-73.
73. Gilbert S, Loranger A, Marceau N. Keratins modulate c-Flip/extracellular signal-regulated kinase 1 and 2 antiapoptotic signaling in simple epithelial cells. Mol Cell Biol.2004; 16:7072-81.
74. Gilbert S, Ruel A, Loranger A, et al. Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss. Apoptosis. 2008; 12:1479-93.
75. Hattori M, Kusakabe S, Ohgusu H, et al. Structure of the rat alpha 2-macroglobulin-coding gene. Gene.1989; 2:333-40.
76. Gliemann J, Davidsen O. Characterization of receptors for alpha 2-macroglobulin-trypsin complex in rat hepatocytes. Biochim Biophys Acta. 1986; 1:49-57.
77. Zimmermann A. Liver regeneration:the emergence of new pathways. Med Sci Monit.2002; 3:A53-63.
78. Philip A, Bostedt L, Stigbrand T, et al. Binding of transforming growth factor-beta (TGF-beta) to pregnancy zone protein (PZP). Comparison to the TGF-beta-alpha 2-macroglobul in interaction. Eur J Biochem.1994; 2:687-93.
2 石清兰,毛德文.浅述肝衰竭的病因病机.实用中医药杂志.2009；25(11)：764-765.
3 韩德伍.肝功能衰竭的发病机制的研究———肠源性内毒素血症假说. 中华肝脏病杂志.1995；3(3)：134-136.
4 陈海龙,吴威中,关凤林,等.中医通里攻下法以多器官功能不全综合征时肠屏障功能保护作用的实验研究. 中国中西医结合杂志,2000;20(2)：120-122.
5 Higgins JPT, Green S, the Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions. Version 5.0.2. http://www. cochrane-handbook.org,2009.
6 谷灿立,付月箫,尚现伟,谢大亮,张沛.中西医结合治疗慢性重型病毒性肝炎临床研究.中医药学刊.2006；24(2)：377-378.
7 邱华,毛德文,黄彬,龙富立,陈月桥,王丽,武建华.解毒化瘀颗粒对慢性重型肝炎患者预后的影响. 中西医结合肝病杂志.2007;17(5)：259-260.
8 王建萍.内服退黄清肝汤在慢性重型肝炎治疗中应用分析.中国实用医药.2009；4(32)：111-112.
9 李筠,王立福,李丰衣,等.慢性重型肝炎中西医结合治疗方案研究.2011年第二十次全国中西医结合肝病学术会议论文汇编.
10高建蓉.中西医结合治疗慢性重型肝炎并腹膜炎26例.中西医结合肝杂志.1999；9(4)：4-5.
11李晶滢,过建春,姚鹏,田一梅,勾春燕,张佳莹,李秀惠.益气养阴方法治疗慢性乙型重型肝炎临床分析.中华中医药杂志.2011；26(6)：1300-1302.
12扈晓宇,吴疆,李运东,钟森,刘光伟.清肝解毒法对慢性重型肝炎病情及MELD预后的改善作用.中华中医药学会第十三届内科肝胆病学术会议论文汇编.2008.
13李召忠.三君退黄汤治疗慢性重型肝炎的研究.中国病原生物学杂志.2009；4(10)：779-781.
14李芹,李丹,张良宏.重肝合剂对慢性重型肝炎肝功能指标的改善作用.中医药临床杂志.2008；18(4)：387-388.
15邓欣,杨大国,吴其恺,陶艳艳,聂广.赤芍承气汤治疗慢性重型肝炎近期疗效观察.中西医结合肝病杂志.2004；14(2)：67-69.
16朱清静,梁红梅.丹黄方与综合疗法联用治疗慢性重型乙型肝炎的临床研究.中西医结合肝病杂志.2009；19(5)：263-265.
17安铁军.芍丹承气汤治疗慢性重症肝炎合并肠源性内毒素血症疗效观察.延边大学医学学报.2005；28(2)：129-130.
18黄加权,黄铁军,张建军,等.抗肝衰复方联合西药治疗重型肝炎临床疗效观察.中西医结合肝病杂志.2006；16(6)：331-333.
19马瑞红.中医辨证配合新鲜血浆治疗慢性重型肝炎20例疗效观察.中医临床研究.2010；2(2)：49-51.
20宋爱军,于培龙. 中西医结合治疗慢性重型肝炎疗效观察. 中华中医药学刊.2010;28(12)：2608-2610.
21傅海龙,裴蕾,魏品康. 中西医结合治疗慢性重型肝炎恢复期的临床观察.现代中西医结合杂.2004；13(5)：567.
22罗欣拉. 中西医结合治疗慢性重型肝炎湿热内蕴型35例. 中西医结合肝病杂志.2001；11(3)：178-179.
23李芳,尹盛强,邓文钦.中药治疗慢性重型肝炎疗效观察.辽宁中医杂志.2006；33(7)：845-846.
24曾德欣,张小玲.生大黄联合凯时注射液治疗早期慢性重型肝炎32例疗效观察.湖南中医药导报.2004；10(10)：11-12.
25张薇薇,秦明华.岩黄连联合灯盏花素注射液治疗慢性重型肝炎43例.新中医.2006；27(1)：21-23.
26孙克伟,陈斌,黄裕红,等.凉血解毒、清热化湿和凉血解毒、健脾温阳法治疗慢性重型肝炎的临床观察.中国中西医结合杂志.2006； 26(11)：981-983.
27许勤英,张世彬.中药保留灌肠用于慢性重型肝炎的临床观察.中国当代医药.2011；18(7)：105-106.
28那健松.中药保留灌肠治疗慢性重型肝炎疗效观察.辽宁中医杂志.2006；33(10)：1284-1286.
29过建春,施军平,陈群伟,等.中药结肠透析治疗慢性重型肝炎的临床研究.中医药学刊.2006;24(7)：1254-1255.
30李文勇,钱宜丹,邱绍勤,王淑平,彭秋萍,张振纲,田德英.结肠灌洗后中药保留灌肠治疗慢性重型肝炎内毒素血症的临床评价.实用肝脏病杂志.2009;12(2)：133-134.
31石伟珍,王宇芳,过建春,等.结肠灌洗联合中药结肠透析治疗慢性重型肝炎对患者血清内毒素与肿瘤坏死因子α等的影响.医药导报.2008,27(8)：935-937.
32吴其恺,徐晓婧,郑燕群,王平,刘晓晖.结肠透析联合中药灌肠治疗慢性重型乙型肝炎的临床观察.中西医结合肝病杂志.2009；19(5)：269-271.
33积明,王邦茂.序贯结肠透析联合人工肝治疗慢性重型肝炎25例.世界华人消化杂志,2009,17(35)：3657-3660.
34王利东.大黄水煎液灌肠治疗慢性重型肝炎65例临床观察.中国中医药信息杂志,2000,7(10)：46-47.
35肠透析配合中药灌肠治疗慢性重型肝炎疗效观察.现代中西医结合杂志.2011,20(34)：4333-4334.
36张囡囡,汪静,刘鹏,张志霞. 中医药多途径联合治疗慢性乙型重型肝炎的临床研究.辽宁中医药杂志.2009；36(7)：1137-1138.
37刘鹏,张囡囡,杨华秀,魏嵋.中药凉血解毒化瘀多渠道给药治疗慢性重型 肝炎42例临床研究.江苏中医药.2009；41(7)：28-29.
38胡建华,钱英,姚乃礼,等. “截断逆挽法”治疗慢性乙型重型肝炎临床疗效观察.中西医结合肝病杂志.2010；20(4)：200-203.
39贡桂英,刘霞,马建红.中西医结合治疗慢性乙型重型肝炎43例临床观察.世界中医药.2009；4(4)：194-195.
40周滔,刘成海,顾元龙,俞宪民,周奚钟,刘宗良.开窍承气液灌肠对慢性重型乙型肝炎肝性脑病的治疗作用.中国中西医结合消化杂志.2006；14(5)：305-307.
41王桦,章文平,廖洪.肝肾清毒饮联合中药灌肠治疗慢性重型乙型肝炎临床研究.辽宁中医杂志.2010；37(11)：2198-2200.
42邱华,毛德文,胡振斌,黄彬,等.慢性重型肝炎中医综合治疗方案的多中心临床研究.中西医结合肝病杂志.2008；18(5)：260-263.
43陈斌,孙克伟,彭杰,肖德梅,等.基于阳黄-阴阳黄-阴黄辨证模式治疗慢性重型肝炎的临床观察.中国中医药科技.2012；19(1)：57-58-66.
44刘翔,胡佳,郑欢欢,欧阳钦.重肝合剂联合血浆置换术治疗慢性重型肝炎40例.江西中医药.2010；10(10)：26-27.
45阮清发,洪昱钤,郑全胜,吴丽,赵俊芳.中药联合血浆置换治疗慢性重型肝炎的临床研究.光明中医.2011；26(12)：2439-2441.
46林恢,李芹,张娟娟.中药联合血浆置换治疗慢性重型肝炎临床观察.传染病信息.2009；22(5)：305-307.
47阮清发,吴丽,赵俊芳,洪昱钤,郑全胜.茵芍桂芪汤治疗血浆置换后慢性重型肝炎临床研究.中国中医急症.2011；20(9)：1397-1398.
48赵文霞,马素平,叶放,刘江凯.益气活血颗粒联合单重血浆置换治疗慢性重型肝炎30例临床观察.河南中医.2011；31(2)：141-143.
49黄学军.茵陈术附汤加味治疗慢性重型肝炎26例.国际中医中药杂志.2008；30(5)：350-352.
50李芹,林恢,刘政芳,陈丽芳,潘晨,张娟娟.人工肝支持系统联合中药治疗慢性重型肝炎临床研究.中西医结合肝病杂志.2010；20(1)：12-14.
51张旸.谭善忠.慢性重型肝炎/肝衰竭的中医病因病机特点研究进展.中西医结合肝病杂志.2011；21(06)：380-383.
52徐翔,郦柏平,张慧芬,等.大黄的研究进展.上海中医药杂志.2003；37(4)： 55-59.
53 Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. BMJ. 2010; 340:c332.
1. Gamez-Pozo A, Ferrer N I., Ciruelos E, et al. Shotgun proteomics of archival triple-negative breast cancer samples. Proteomics Clin Appl. 2013; 3-4:283-91.
2. Barratt C L. The human sperm proteome:the potential for new biomarkers of male fertility and a transformation in our understanding of the spermatozoon as a machine:commentary on the article'Identification of proteomic differences in asthenozoospermic sperm samples'by Martinez etal. Hum Reprod.2008; 6:1240-41.
3. Petricoin E F, Zoon K C, Kohn E C, et al. Clinical proteomics: translating benchside promise into bedside reality. Nat Rev Drug Discov.2002; 9:683-95.
4. Kovacs A, Guttman A. Medicinal chemistry meets proteomics: fractionation of the human plasma proteome. Curr Med Chem.2013; 4: 483-90.
5. Millioni R, Tolin S, Fadini G P, et al. High confidence and sensitivity four-dimensional fractionation for human plasma proteome analysis Amino Acids.2012; 5:2199-202.
6. Kovacs A, Sperling E, Lazar J, et al. Fractionation of the human plasma proteome for monoclonal antibody proteomics-based biomarker discovery. Electrophoresis.2011; 15:1916-25.
7. Bjorhall K, Miliotis T, Davidsson P. Comparison of different depletion strategies for improved resolution in proteomic analysis of human serum samples. Proteomics.2005; 1:307-17.
8. Chen H S, Rejtar T, Andreev V, et al. High-speed, high-resolution monolithic capillary LC-MALDI MS using an off-line continuous deposition interface for proteomic analysis. Anal Chem.2005; 8: 2323-31.
9. Ross P L, Huang Y N, Marchese J N, et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics.2004; 12:1154-69.
10. Kawada N, Kristensen D B, Asahina K, et al. Characterization of a stellate cell activation-associated protein (STAP) with peroxidase activity found in rat hepatic stellate cells. J Biol Chem.2001; 27: 25318-23.
11. Kim T R, Yang J S, Shin S, et al. Statistical torsion angle potential (STAP) energy functions for protein structure modeling:A bicubic interpolation approach. Proteins.2013; Feb 14. Online. (to be published)
12. Wang H, Wu G, Park H J, et al. Protective effect of Phellinus linteus polysaccharide extracts against thioacetamide-induced liver fibrosis in rats: a proteomics analysis. Chin Med.2012; 1:23.
13. Liu E H, Chen M F, Yeh T S, et al. A useful model to audit liver resolution from cirrhosis in rats using functional proteomics. J Surg Res.2007; 2:214-23.
14. Lin D, Wu X, Ji X, et al. A novel canine model of portal vein stenosis plus thioacetamide administration-induced cirrhotie portal hypertension with hypersplenism. Cell Biochem Biophys.2012; 1: 245-55.
15. An J H, Seong J, Oh H, et al. Protein expression profiles in a rat cirrhotic model induced by thioacetamide. Korean J Hepatol.2006; 1: 93-102.
16. Poon T C, Hui A Y, Chan H L, et al. Prediction of liver fibrosis and cirrhosis in chronic hepatitis B infection by serum proteomic fingerprinting:a pilot study. Clin Chem.2005; 2:328-35.
17. Xu X Q, Leow C K, Lu X, et al. Molecular classification of liver cirrhosis in a rat model by proteomics and bioinformatics. Proteomics. 2004; 10:3235-45.
18. Nault J C, Zucman R J. Molecular classification of hepatocellular adenomas. Int J Hepatol.2013; 2013:1-7.
19. Thompson S M, Callstrom M R, Knudsen B E, et al. Molecular Bioluminescence Imaging as a Noninvasive Tool for Monitoring Tumor Growth and Therapeutic Response to MRI-Guided Laser Ablation in a Rat Model of Hepatocellular Carcinoma. Invest Radiol.2012; 6:413-21.
20. Yokoyama Y, Kuramitsu Y, Takashima M, et al. Proteomic profiling of proteins decreased in hepatocellular carcinoma from patients infected with hepatitis C virus. Proteomics.2004; 7:2111-16.
21. Kimura A, Sogawa K, Satoh M, et al. The application of a three-step serum proteome analysis for the discovery and identification of novel biomarkers of hepatocellular carcinoma. Int J Proteomics.2012; 2012:623190 (1-12).
22. Kanamori H, Kawakami T, Effendi K, et al. Identification by differential tissue proteome analysis of talin-1 as a novel molecular marker of progression of hepatocellular carcinoma. Oncology.2011; 5-6:406-15.
23. Zeindl-Eberhart E, Klugbauer S, Dimitrijevic N, et al. Proteome analysis of rat hepatomas:carcinogen-dependent tumor-associated protein variants. Electrophoresis.2001; 14:3009-18.
24. Megger D A, Bracht T, Kohl M, et al. Proteomic differences between hepatocellular carcinoma and non-tumorous liver tissue investigated by a combined 2D-DIGE and label-free quantitative proteomics study. Mol Cell Proteomics.2013 Mar 5. [Epub ahead of print]
25. Suo A, Zhang M, Yao Y, et al. Proteome analysis of the effects of sorafenib on human hepatocellular carcinoma cell line HepG2. Med Oncol.2012; 3:1827-36.
26. Ding S J, Li Y, Tan Y X, et al. From proteomic analysis to clinical significance:overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis. Mol Cell Proteomics.2004; 1: 73-81.
27.申定珠,陶庆,都金星,等.基于差异蛋白质组学解析一贯煎对大鼠肝硬化形成的影响.中西医结合学报.2010；2：158-67.
28.李骢,姜妙娜,等.中药肝复康干预肝星状细胞及肝组织的蛋白质组学分析.现代生物医学进展.2009；16：3020-25.
1. 肝衰竭诊疗指南.中华肝脏病杂志.2006；9：643-46.
2. 柳芳芳,苏海滨,王慧芬,等.HBV相关慢加急性肝衰竭发病诱因分析.传染病信息.2010；3：161-64.
3. Zoulim F, Locarnini S. Optimal management of chronic hepatitis B patients with treatment failure and antiviral drug resistance. Liver Int.2013; 33 Suppll:116-24.
4. 刘晓燕,胡锦华.1977例急性、 亚急性、 慢加急性肝衰竭患者的病因与转归分析.中华肝脏病杂志.2008；10：772-75.
5. 孙庆丰,吕勇,徐道振,等.乙型肝炎病毒e抗原及DNA载量对慢性乙型重型肝炎预后的影响.中华肝脏病杂志.2006；6：146-49.
6. 韩乾国,王文雅,杨尧.病毒复制水平对慢性重型乙型肝炎病情及预后影响的初步评价.华西医学.2006；1：115-18.
7. Yu JW,Sun LJ,Zhao YH,et al. Prediction value of model for end-stage liver disease scoring system on prognosis in patientswith acute-on-chronic hepatitis B liver failure after plasma ex-change and lamivudine treatment. J Gastroenterol Hepatol.2008; 8 Pt 1:1242-49.
8. 罗育春,陈大兰.肝硬化患者血清谷丙转氨酶、谷草转氨酶和总胆红素与肝纤维化标志物的相关性研究.实用预防医学.2011；8：711-14.
9. 张钟儒.天门冬氨酸转氨酶和丙氨酸转氨酶的稳定性.临床生物化学与检验学分册.2010；3：41-43.
10.张耿林,高志良.乙型肝炎相关慢加急性肝衰竭的免疫学特征及治疗策略.中国病毒病杂志.2011；1：5-8.
11. Huang K, Hu J H, Wang H F, et al. Survival and prognostic factors in hepatitis B virus-related acute-on-chronic liver failure. World J Gastroenterol.2011; 29:3448-52.
12.谢仕斌,吴元凯,朱建芸,等.慢加急性肝衰竭预后评分系统的建立与评估.中山大学学报(医学科学版).2011；6：834-40.
1 Sarin SK, Kumar A, Almeida JA, et al.. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int.2009; 1:269-82.
2 Olson JC, Kamath PS. Acute-on-chronic liver failure:concept, natural history, and prognosis. Curr Opin Crit Care.2011; 2:165-9.
3 Ling Q, Xu X, Wei Q, et al.. Downgrading MELD improves the outcomes after liver transplantation in patients with acute-on-chronic hepatitis B liver failure. PLoS One.2012; 1:e30322.
4 Bernardi M, Gitto S, Biselli M. The MELD score in patients awaiting liver transplant:strengths and weaknesses. J Hepatol.2011; 6:1297-306.
5 Mao W, Ye B, Lin S, Fu Y, Chen Y, Chen Y. Prediction value of model for end-stage liver disease scoring system on prognosis in the acute on chronic liver failure patients with plasma exchange treatment. Asaio J. 2010; 5:475-78.
6 Sun QF, Ding JG, Xu DZ, et al.. Prediction of the prognosis of patients with acute-on-chronic hepatitis B liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model.J Viral Hepat.2009; 7:464-70.
7 Liu H, Han T, Tian J, et al.. Monitoring oxidative stress in acute-on-chronic liver failure by advanced oxidation protein products. Hepatol Res.2012; 2:171-80.
8 Ren F, Chen Y, Wang Y, et al.. Comparative serum proteomic analysis of.patients with acute-on-chronic liver failure:alpha-1-acid glycoprotein maybe a candidate marker for prognosis of hepatitis B virus infection. J Viral Hepat.2010; 11:816-24.
9 Tasaka S, Koh H, Yamada W, et al.. Attenuation of endotoxin-induced acute lung injury by the Rho-associated kinase inhibitor, Y-27632. Am J Respir Cell Mol Biol.2005; 6:504-10.
10 Zhou H, Andonegui G, Wong CH, Kubes P. Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. J Immunol.2009; 8:5244-50.
11 Twu YC, Gold MR, Teh HS. TNFR1 delivers pro-survival signals that are required for limiting TNFR2-dependent activation-induced cell death (AICD) in CD8+ T cells. Eur J Immunel.2011; 2:335-44.
12 Baumann S, Dostert A, Novae N, et al.. Glucocorticoids inhibit activation-induced cell death (ATCD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimer. Blood.2005; 2:617-25.
13 Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology.2000; 4:864-71.
14 Chen TM, Lin CC, Huang PT, Wen CF. Neutrophil-to-lymphocyte ratio associated with mortality in early hepatocellular carcinoma patients after radiofrequency ablation. J Gastroenterol Hepatol.2012; 3:553-61.
15 Hung HY, Chen JS, Yeh CY, et al.. Effect of preoperative neutrophil-lymphocyte ratio on the surgical outcomes of stage Ⅱ colon cancer patients who do not receive adjuvant chemotherapy. Int JColorectal Dis.2011; 8:1059-65.
16 Imtiaz F, Shafique K, Mirza SS, Ayoob Z, Vart P, Rao S. Neutrophil lymphocyte ratio as a measure of systemic inflammation in prevalent chronic diseases in Asian population. Int Arch Med.2012; 1:2.
17 Zahorec R. Ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy.2001; 1:5-14.
18 Azab B, Jaglall N, At all ah JP, et al. Neutrophil-lymphocyte ratio as a predictor of adverse outcomes of acute pancreatitis. Pancreatology. 2011; 4:445-52.
19 Muhmmed SM, Bahnacy JA, Ali AA, Pathare AV, Alkindi SS, Uwe WF. Predictive value of neutrophil to lymphocyte ratio in outcomes of patients with acute coronary syndrome. Arch Med Res.2010; 8:618-22.
20 Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol.2009; 3:162-74.
21 Pillay J, Kamp VM, van Hoffen E, et al.. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1.J Clin Invest.2012; 1:327-36.
22 Brandau S, Trellakis S, Bruderek K, et al.. Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. J Leukoc Biol. 2011; 2:311-7.
23 Mao WL, Chen Y, Chen YM, Li LJ. Changes of serum cytokine levels in patients with acute on chronic liver failure treated by plasma exchange. J Clin Gastroenterol.2011; 6:551-5. 24 Hu X, Ma S, Huang X, et al.. Interleukin-21 is upregulated in hepatitis B-related acute-on-chronic liver failure and associated with severity of liver disease. J Viral Hepat.2011; 7:458-67.
25 Wu Z, Han M, Chen T, Yan W, Ning Q. Acute liver failure:mechanisms of immune-mediated liver injury. Liver Int.2010; 6:782-94.
26 Liu Q. Role of cytokines in the pathophysiology of acute-on-chronic liver failure. Blood Purif.2009; 4:331-41.
27 Di Campli C, Zocco MA, Gaspari R, et al.. The decrease in cytokine concentration during albumin dialysis correlates with the prognosis of patients with acute on chronic liver failure. Transplant Proc.2005; 6: 2551-3.
28 Marques PE, Amaral SS, Pires DA, et al.. Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. Hepatology.2012.5:1971-82.
29 Bhatia V, Bhardwaj P, Elikkottil J, Batra J, Saraya A. A 7-day profile of oxidative stress and antioxidant status in patients with acute liver failure. Hepatol Int.2008; 4:465-70.
30 Gregory B, Larson AM, Reisch J, Lee WM. Acetaminophen dose does not predict outcome in acetaminophen-induced acute liver failure.J Investig Med 2010; 5:707-10.
31 Mao WL, Lou YF, Ye B, Lin S, Chen YM, Chen Y. Changes in peripheral CD4 CD25(high) regulatory T cells in the acute-on-chronic liver failure patients with plasma exchange treatment. Inflammation.2012; 2:436-44.
32 Zhang JY, Zhang Z, Lin F, et al. Interleukin-17-producing CD4 (+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology.2010; 1:81-91.
33 Wasmuth HE, Kunz D, Yagmur E, et al.. Patients with acute on chronic liver failure display "sepsis-like" immune paralysis. J Hepatol.2005; 2:195-201.
34 Lou YF, Dong W, Ye B, Lin S, Mao WL. Changes in peripheral T-lymphocytc subsets in acute-on-chronic liver failure patients with artificial liver support system. Hepatogastrocnterology.2012; 115:814-7.
35 Zou Z, Li B, Xu D, et al. Imbalanced intrahepatic cytokine expression of interferon-gamma, tumor necrosis factor-alpha, and interleukin-10 in patients with acute-on-chronic liver failure associated with hepatitis B virus infection.J Clin Gastroenterol.2009; 2:182-90.
1. 王宪波,李斌,刘慧敏.解毒凉血、健脾化湿法治疗乙型肝炎慢加急性肝功能衰竭体会.中医杂志.20：1772-76.
2. 刘慧敏,王宪波,王融冰.基于解毒凉血法的中西医结合方案治疗乙型肝炎慢加急性肝衰竭疗效分析.中西医结合肝病杂志.2011；4：197-200.
3. Murphy J F. Consort 2010 statement on randomised controlled trials. Ir Med J.2010; 5:132.
4.王家良.临床流行病学.上海科学技术出版社.2006：61-64.
5. 李兰娟.肝衰竭诊疗指南.中华内科杂志.2006；12：1053-56.
6. 中华医学会感染病学分会肝衰竭与人工肝学组,中华医学会肝病学分会重型肝病与人工肝学组,《肝衰竭诊治指南》.中华临床感染病杂志.2012；5：321-27.
7. 郑筱萸.《中药新药临床研究指导原则》.中国中医药出版社.2002：185-212.
8. Lee Y M, Fernandes M, Da C M, et al. The MELD score may help to determine optimum time for liver transplantation. Transplant Proc.2004; 10:3057-59.
9. 吴云忠,王宪波,叶航,等.基于MELD评价解毒凉血法治疗慢性乙型重型肝炎的疗效.临床肝胆病杂志.2011；5：1220-23.
10.魏思思,赵艳玲,江凤娟,等.重用赤芍治疗ANIT诱导大鼠急性淤胆型肝炎的研究.中国实验方剂学杂志.2012：12：336-39.
11.邓欣,杨大国,吴其恺,等.赤芍承气汤治疗慢性重型肝炎近期疗效观察.中西医结合肝病杂志.2004；2：310-13.
12.李凌,杨大国,吴其恺,等.赤芍承气汤对重型肝炎内毒素血症的影响.浙江中西医结合杂志.2002；9：290-92.
13.梁旭竞,唐永煌,何玮,等.丹参酮对过氧化氢致慢性乙型肝炎患者外周血淋巴细胞DNA损伤的影响.中西医结合肝病杂志.2005；2：119-22.
14.夏振信,陈金和,杨自成,等.丹参口服液治疗慢性乙型肝炎的实验研究及临床观察.湖北医学院学报.2011；4：350-53.
15.寇义华,卢军利.茵陈对黄疸型肝炎的疗效观察. 中国医药导刊.2011；5：101-04.
16.孙建光.加味茵陈蒿汤保留灌肠对慢性重症肝炎患者内毒素和血氨的影响.四川中医.2013；1：75-77.
17.李秀惠.钱英教授“截断逆挽法”治疗慢性重型肝炎的思路与方法.上海中医药杂志.2007；1：1-4.
18.覃雪英,陆启峰,覃后继,等.血浆置换联合大黄灌肠治疗重型肝炎合并肝 肾综合征疗效观察. 中国医药导报.2011；28：98-101.
1. Ross P L, Huang Y N, Marchese J N, et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics.2004:12:1154-69.
2.肝衰竭诊疗指南.中华肝脏病杂志.2006；9：643-46.
3.刘晓燕,王慧芬.肝衰竭病因研究进展.军医进修学院学报.2011；1：15-17.
4. Wlodzimirow K A, Eslami S, Abu-Hanna A, et al. A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality. Liver Int.2013; 1:40-52.
5. He W P, Hu J H, Zhao J, et al. Comparison of four prognostic models and a new Logistic regression model to predict short-term prognosis of acute-on-chronic hepatitis B liver failure. Chin Med J (Engl).2012; 13: 2272-78.
6. Dou J, Xu W, Ye B, et al. Serum vitamin B12 levels as indicators of disease severity and mortality of patients with acutc-on-chronic liver failure. Clin Chim Acta.2012; 23-24:1809-12.
7. Jalan R, Gines P, Olson J C,-et al. Acute-on chronic 1 iver failure. J Ilepatol. 2012; 6:1336-48.
8. Qi Z X, Wang L Y, Fan Y C, et al. Increased peripheral RORalpha and RORgammat mRNA expression is associated with acute-on-chronic hepatitis B liver failure. J Viral Hepat.2012; 11:811-22.
9. Zou S S, Yang W, Yan H X, et al. Role of beta-Catenin in regulating the balance between TNF-alpha-and Fas-induced acute liver injury. Cancer Lett.2013 Feb 11. [Epub ahead of print]
10. Yu D S, An F M, Gong B D, et al. The regulatory role of microRNA-1187 in TNF-alpha-mediated hepatocyte apoptosis in acute liver failure. Int J Mol Med.2012; 4:663-68.
11. Lu Y, Wang X, Yan W, et al. Liver TCRgammadelta(+) CD3(+) CD4(-) CD8(-) T cells contribute to murine hepatit is virus strain 3-induced hepatic injury through a TNF-alpha-dependent pathway. Mol Immunol.2012; 3-4:229-36.
12.叶一农,高志良. 乙型肝炎肝衰竭发生机制中的三重打击.传染病信息.2009;5：276-79.
13. Kim Y E, Yi S Y, Lee C S, et al. Gold patterned biochips for on-chip immuno-MALDI-TOF MS:SPR imaging coupled multi-protein MS analysis. Analyst. 2012; 2:386-92.
14. Wigenius J A, Fransson S, von Post F, et al. Protein biochips patterned by microcontact printing or by adsorption-soft lithography in two modes. Biointerphases.2008; 3:75-82.
15. Lueking A, Cahill D J, Mullner S. Protein biochips:A new and versatile platform technology for molecular medicine. Drug Discov Today.2005;11: 789-94.
16.赵健,黄维华,王远东,等.应用SELDI-TOF-MS技术筛选肺腺癌患者血清诊断标志物.肿瘤基础与临床.2008；1：7-9.
17. Alves R M, Vitorino R, Padrao A I, et al. iTRAQ-based quantitative proteomic analysis of submandibular glands from rats with STZ-induced hyperglycemia. J Biochem.2013; 2:209-20.
18. Nicholson J, Neelagandan K, Huart A S, et al. An iTRAQ proteomics screen reveals the effects of the MDM2 binding ligand Nutlin-3 on cellular proteostasis. J Proteome Res.2012; 11:5464-78.
19. Kaur P, Rizk N M, Ibrahim S, et al. iTRAQ-based quantitative protein expression profiling and MRM verification of markers in type 2 diabetes. J roteome Res.2012; 11:5527-39.
20. Lee J T, Lee J W, Kim J M, et al. Prognosis of hepatocellular carcinoma expressing cytokeratin 19:comparison with other liver cancers. World J Gastroenterol.2012; 34:4751-57.
21. Attallah A M, El-Far M, Abdel M C, et al. Evaluation of cytokeratin-1 in the diagnosis of hepatocellular carcinoma. Clin Chim Acta.2011; 23-24: 2310-15.
22. Xiang Z L, Zeng Z C, Tang Z Y, et al. Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma. Mol Biol Re.2011; 5:3531-39.
23. Fanni D, Nemolato S, Ganga R, et al. Cytokeratin 20-positive hepatocellular carcinoma. Eur J Hislochem.2009; 4:e32.
24. Su Q, Fu Y, Liu Y F, et al. Laminin induces the expression of cytokeratin 19 in hepatocellular carcinoma cells growing in culture. World J Gastroenterol.2003; 5:921-29.
25. Bechmann L P, Jochum C, Kocabayoglu P, et al. Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J Hepalol.2010; 4:639-47.
26.赵四海,楚雍烈,刘恩岐.角蛋白8在四氯化碳诱导的小鼠肝损伤中的表达.浙江大学学报(医学版).2010；5：335-38.
27. Ku N O, Liao J, Omary M B. Apoptosis generates stable fragments of human type Ⅰ keratins. J Biol Chem.1997; 52:33197-203.
28. Leers M P, Bjorklund V, Bjorklund B, et al. An immunohistochemical study of the clearance of apoptotic cellular fragments. Cell Mol Life Sci.2002; 8:1358-65.
29. Moshage H. Cytokines and the hepatic acute phase response. J Pathol.1997; 3:257-66.
30. Kang X, Sun L, Guo K, et al. Serum protein biomarkers screening in HCC patients with liver cirrhosis by ICAT-LC-MS/MS. J Cancer Res Clin Oncol. 2010; 8:1151-59.
31. Bachtiar I, Kheng V, Wibowo G A, et al. Alpha-1-acid glycoprotein as potential biomarker for alpha-fetoprotein-low hepatocellular carcinoma. BMC Res Notes.2010; 3:319.
32. Song E Y, Kim K A, Kim Y D, et al. Elevation of serum asialo-alpha(1) acid glycoprotein concentration in patients with hepatic cirrhosis and hepatocellular carcinoma as measured by antibody-lectin sandwich assay. Hepatol Res.2003; 4:311-7.
33. Wigmore S J, Fearon K C, Maingay J P, et al. Interleukin-8 can mediate acute-phase protein production by isolated human hepatocytes. Am J Physiol. 1997; 4 Pt 1:E720-26.
34. Alam T, Papaconstantinou J. Interaction of acute-phase-inducible and liver-enriched nuclear factors with the promoter region of the mouse alpha 1-acid glycoprotein gene-1. Biochemistry.1992; 7:1928-36.
35. Olofsson S O, Wiklund O, Boren J. Apolipoproteins A-I and B:biosynthesis, role in the development of atherosclerosis and targets for intervention against cardiovascular disease. Vasc Health Risk Manag.2007; 4:491-02.
36.成兰芝.病毒性肝炎患者血清载脂蛋C II C III变化与血脂关系.菏泽医专学报.1997：2：73-74.
37.梁丽,李斓,黄国美.肝硬化患者血清脂类及载脂蛋白的变化及意义.贵州医药.2007：8：741-42.
38. Olofsson S O, Wiklund O, Boren J. Apolipoproteins A-I and B:biosynthesis, role in the development of atherosclerosis and targets for intervention against cardiovascular disease. Vasc Health Risk Manag.2007; 4:491-502.
39. Zhang W, Cox A G, Taylor E W. Hepatitis C virus encodes a selenium-dependent glutathione peroxidase gene. Implications for oxidative stress as a risk factor in progression to hepatocellular carcinoma. MedKlin (Munich).1999; 94 Suppl 3:2-6.
40. Burk R F, Early D S, Hill K E, et al. Plasma selenium in patients with cirrhosis. Hepatology.1998; 3:794-98.
41. Hsu Y W, Tsai C F, Chen W K, et al. Protective effects of seabuckthorn (Hippophae rhamnoides L.) seed oil against carbon tetrachloride-induced hepatotoxicity in mice. Food Chem Toxicol.2009; 9:2281-88.
42. He S X, Wu B, Chang X M, et al. Effects of selenium on peripheral blood mononuclear cell membrane fluidity, interleukin-2 production and interleukin-2 receptor expression in patients with chronic hepatitis. World J Gastroenterol.2004; 23:3531-33.
43. Todorov P T, Mcdevitt T M, Meyer D J, et al. Purification and characterization of a tumor lipid-mobilizing factor. Cancer Res.1998; 11: 2353-58.
44. Stewart A J, Blindauer C A, Sadler P J. Plasma fatty acid levels may regulate the Zn (2+)-dependent activities of histidine-rich glycoprotein. Biochimie. 2009; 11-12:1518-22.
45. Saito R, Shimosawa T, Ogihara T, et al. Function of adrenomedullin in inflammatory response of liver against LPS-induced endotoxemia. APMIS.2012; 9:706-11.
46. Cederbaum A I, Yang L, Wang X, et al. CYP2E1 Sensitizes the Liver to LPS-and TNF alpha-Induced Toxicity via Elevated Oxidative and Nitrosative Stress and Activation of ASK-1 and JNK Mitogen-Activated Kinases. Int J Hepatol.2012; 2012:582790.
47. Li G, Chen W, Man C, et al. Cytosolic phospholipase A(2)alpha protects against Fas-but not LPS-induced liver injury. J Hepatol.2011; 6:1281-90.
48. Bettuzzi S, Davalli P, Astancolle S, et al. Tumor progression is accompanied by significant changes in the levels of expression of polyamine metabolism regulatory genes and clusterin (sulfated glycoprotein 2) in human prostate cancer specimens. Cancer Res.2000; 1:28-34.
49. Hurwitz A, Ruutiainen-Altman K, Marzella L, et al. Follicular atresia as an apoptotic process:atresia-associated increase in the ovarian expression of the putative apoptotic marker sulfated glycoprotein-2. J Soc Gynccol Investig.1996; 4:199-208.
50. Park J H, Park J S, Ju S K, et al. Clusterin mRNA expression in apoptotic and activated rat thymocytes. Cell Res.2003; 1:49-58.
51. Karimi S, Hemmateenejad B. Identification of discriminatory variables in proteomics data analysis by clustering of variables. Anal Chim Acta.2013; 767:35-43.
52. Sintich S M, Steinberg J, Kozlowski J M, et al. Cytotoxic sensitivity to tumor necrosis factor-alpha in PC3 and LNCaP prostatic cancer cells is regulated by extracellular levels of SGP-2 (clusterin). Prostate.1999; 2: 87-93.
53. Bailey R W, Aronow B, Harmony J A, et al. Heat shock-initiated apoptosis is accelerated and removal of damaged cells is delayed in the testis of clusterin/ApoJ knock-out mice. Biol Reprod.2002; 4:1042-53.
54. Bilezikci B, Demirhan B, Ozdemir N, et al. Expression of hepatocyte growth factor in chronic hepatitis:effect of hemodialysis. Ren Fail.2006; 7: 557-60.
55. Cheng J H, She H, Han Y P, et al. Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2008; 1:G39-49.
56. Langlois M R, Delanghe J R. Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chew.1996; 10:1589-600.
57. Luo R, Akpan I O, Hayashi R, et al. GTP-binding protein-like domain of AGAP1 is protein binding site that allosterically regulates ArfGAP protein catalytic activity. J Biol Chem.2012; 21:17176-85.
58. Staresincic L, Walker J, Dirac-Svejstrup A B, et al. GTP-dependent binding and nuclear transport of RNA polymerase Ⅱ by Npa3 protein. J Biol Chem. 2011; 41:35553-61.
59. Balasubramanian S, Messmer-Blust A F, Jeyaratnam J A, et al. Role of GTP Binding, Isoprenylation, and the C-Terminal alpha-Helices in the Inhibition of Cell Spreading by the Interferon-Induced GTPase, Mouse Guanylate-Binding Protein-2. J Interferon Cytokine Res.2010.
60. Hommers L G, Klenk C, Dees C, et al. G proteins in reverse mode: receptor-mediated GTP release inhibits G protein and effector function. J Biol Chem.2010; 11:8227-33.
61. Li L, Rezvan A, Salerno J C, et al. GTP cyelohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endothelial tetrahydrobiopterin and nitric oxide. Circ Res.2010; 2:328-36.
62. Tendler Y, Pokroy R, Panshin A, et al. p53 protein subcellular localization and apoptosis in rodent corneal epithelium cell culture following ultraviolet irradiation. Int J Mol Med. 2013; 3:540-46.
63. Yang J, Maity B, Huang J, et al. G protein inactivator RGS6 mediates myocardial cell apoptosis and cardiomyopathy caused by doxorubicin. Cancer Res.2013.
64. Pang J, Xu X, Wang X, et al. G-Protein-Coupled Receptor Kinase Interacting Protein-1 Mediates Intima Formation by Regulating Vascular Smooth Muscle Proliferation, Apoptosis, and Migration. Arterioscler Thromb Vasc Biol. 2013.
65. Nassir F, Blanchard R K, Mazur A, et al. Apol ipoprotein B mRNA editing is preserved in the intestine and liver of zinc-deficient rats. J Nutr.1996; 4:860-64.
66. Qin X, Swertfeger D K, Zheng S, et al. Apolipoprotein AIV:a potent .endogenous inhibitor of lipid oxidation. Aw J Physiol,1998; 5 Pt 2: 111836-40.
67. Fujita T,.Hemmi S, Kajiwara M, et al. Complement-mediated chronic inflammation is associated with diabetic microvascular complication. Diabetes Metab Res Rev..2012.
68. Toivola D M, Ku N O, Resurreccion E Z, et al. Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease. Hepatology.2004; 2:459-66.
69.李娟, 石英, 武聚山, 等.角蛋白K18及其33、52位丝氨酸磷酸化在HBV感染肝脏疾病中的表达及意义.临床肝胆病杂志.2008；4：243-45.
70. Inada H, Izawa I, Nishizawa M, et al. Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. J Cell Biol. 2001; 3:415-26.
71. Caul in C, Ware C F, Magin T M, et al. Keratin-dependent, epithelial resistance to tumor necrosis factor-induced apoptosis. J Cell Biol.2000; 1:17-22.
72. Gilbert S, Loranger A, Daigle N, et al. Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation. J Cell Biol.2001; 4:763-73.
73. Gilbert S, Loranger A, Marceau N. Keratins modulate c-Flip/extracellular signal-regulated kinase 1 and 2 antiapoptotic signaling in simple epithelial cells. Mol Cell Biol.2004; 16:7072-81.
74. Gilbert S, Ruel A, Loranger A, et al. Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss. Apoptosis. 2008; 12:1479-93.
75. Hattori M, Kusakabe S, Ohgusu H, et al. Structure of the rat alpha 2-macroglobulin-coding gene. Gene.1989; 2:333-40.
76. Gliemann J, Davidsen O. Characterization of receptors for alpha 2-macroglobulin-trypsin complex in rat hepatocytes. Biochim Biophys Acta. 1986; 1:49-57.
77. Zimmermann A. Liver regeneration:the emergence of new pathways. Med Sci Monit.2002; 3:A53-63.
78. Philip A, Bostedt L, Stigbrand T, et al. Binding of transforming growth factor-beta (TGF-beta) to pregnancy zone protein (PZP). Comparison to the TGF-beta-alpha 2-macroglobul in interaction. Eur J Biochem.1994; 2:687-93.